In February 2013, Glaxosmithkline (GSK) Announced a Commitment To

In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register.

The following guiding principles have been applied to the disclosure:  Information will be excluded in order to protect the privacy of patients and all named persons associated with the study  Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register.  Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered CONFIDENTIAL HM2009/00361/00HM2009/00361/00 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies NKP106254

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Study Report

Title: Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant + paroxetine combination in an enriched population of subjects with tinnitus & hearing loss.

Phase: II

Compound Number: GW597599

Effective Date: 10-DEC-2009

Description: Tinnitus associated with hearing loss is a high prevalent audiologic disorder with important unmet needs as far as therapy is concerned. The present study explored the possible beneficial effects on tinnitus loudness or annoyance of a combination drug treatment aimed to increase the local inhibitory activity of neural circuitries involved in sound perception and generation. Two 14 day treatment conditions, i.e., SSRI paroxetine (20 mg/day) plus the NK1 antagonist vestipitant (25mg /day) or vestipitant alone (25 mg /day), were compared to placebo in patients suffering from tinnitus. Effects on principal endpoints were collected within 4 hrs from last administration. Audiometry and computer-based Automated Psychoacoustics were performed as instrumental endpoints to support subjective scores.

There were no serious adverse events, deaths or pregnancies. Two subjects were withdrawn due to AEs. The study drugs were generally well tolerated. The frequency of AEs was similar across the three treatment periods, though a slightly higher frequence of adverse events was reported with the combination vestipitant+paroxetine than with either vestipitant or placebo alone.

No statistically significant treatment effect was detected for VAS Tinnitus scores (intensity, tone, distress), VAS Arousal-Anxiety, THI or Tinnitus Aggravation scores assessed on Days 1 and 14. However, a statistically significant worsening of VAS Tinnitus intensity and distress scores were observed after vestipitant vs placebo on the basis of the data collected on diary card (Days 2 to 13).

No relevant differences in Vestipitant plasma concentrations were observed between the subjects given the combination with Paroxetine and those receiving vestipitant alone.

No specific PK/PD relationships were observed between the primary PD endpoints and vestipitant plasma concentrations.

- 1 - 1 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies NKP106254

Subject: Randomised, placebo, crossover, balanced, repeated dose, vestipitant (GW597599), paroxetine, combination, Tinnitus, Hearing Loss, loudness, annoyance, distress, audiometry, psychoacoustics, sleep, depression, anxiety.

Author(s):

Indication Studied: Tinnitus associated with hearing loss

Initiation Date: 05 Dec 2006

Completion Date: 06 Aug 2009

Date of Report: 10-DEC-2009

- 2 - 2 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Synopsis

Identifier: HM2009/00361/00 Study Number: NKP106254

Investigator(s):

MD, PhD (co-ordinating PI); PhD (Investigator); (Investigator).

Study center(s):

1 centre in 1 country (UK).

Publication(s):

None at the time of this report

Study period:

Initiation Date: 05 Dec 2006

Completion Date: 06 Aug 2009

Phase of development: II

Objectives:

Primary:

• To measure the change in tinnitus loudness (intensity;VAS) after single (Day 1) and repeated (Day 14) administration of either vestipitant + paroxetine combination, or vestipitant alone vs. placebo. Secondary:

• To measure the change in tinnitus subjective features (i.e., tinnitus pitch and distress, and general alertness/anxiety levels), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level (i.e., visual scales, heart rate and blood pressure), clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep). • To evaluate safety and tolerability of vestipitant alone and the combination vestipitant + paroxetine at single dose.

- 4 - 3 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

• To evaluate the PK/PD relationships between steady state exposure of vestipitant and vestipitant + paroxetine combination with each of the various pharmacodynamic endpoints. Exploratory:

• To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant + paroxetine combination and placebo. Methodology:

This was a randomised, double-blind, placebo-controlled, cross-over study investigating the effects of single dose and repeated dosing of vestipitant + paroxetine combination and vestipitant alone vs. placebo.

Subjects suffering from tinnitus attended the research unit for a screening visit. On Day 1, following the baseline measurements, subjects were randomized to one of the six repeated dosing treatment sequences. The Treatment Phase consisted of three 14-day treatment periods separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests were performed on Day 1 and Day 14 of each treatment period. All subjects received all treatments and a follow up visit was performed 14 days after the final dose of study medication. Treatments were: placebo, vestipitant 25 mg/day and vestipititant 25 mg/day + paroxetine 20 mg/day.

Blood samples were collected for the analysis of paroxetine (BRL29060), and vestipitant (GW597599) just before dosing and 3h after dosing on Day 1 and Day 14 . All blood samples were collected into Potassium-EDTA uniquely labelled collection tubes and immediately chilled on crushed water ice. Plasma was separated by centrifugation (2000 g or approximately 3000 rpm for 15 minutes at +4°C) within 1 hour of collection. The resultant plasma was transferred to 2 uniquely labeled 3.6 mL polypropylene Nunc tubes, frozen immediately and stored at –20°C or colder until transferred on solid carbon dioxide for analysis. One of the aliquot was used to assay BRL29060 the other to assay GW597599.

Human plasma samples were analyzed for BRL29060 and GW597599 using a validated analytical method based on protein precipitation, followed by High Performance Liquid Chromatography (HPLC) coupled with tandem mass-spectrometry (MS/MS) analysis. The lower limit of quantification (LLQ) for BRL29060 and GW597599 were 0.100 ng/mL using a 50 µL aliquot of human plasma with a higher limit of quantification (HLQ) of 100 ng/mL. The computer systems that were used on this study to acquire and quantify data included Analyst Version 1.4.2 and SMS2000 version 2.1.

Quality Control samples (QC), prepared at 3 different analyte concentrations and stored with study samples, were analyzed with each batch of samples against separately prepared calibration standards. For the analysis to be acceptable, no more than one-third of the total QC results and no more than one-half of the results from each concentration level were to deviate from the nominal concentration by more than 15%. The applicable analytical runs met all predefined run acceptance criteria.

- 5 - 4 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Subjects were assigned to study treatment in accordance with the randomization schedule provided by a Statistician within DB GSK produced using validated software (Randall) prior to the start of the study.

The following six sequences were used:

A/B/C, A/C/B, B/A/C, B/C/A, C/A/B and C/BA

Where A represents placebo, B represents Vestipitant alone and C represents the combination between Vestipitant and Paroxetine

Subject Disposition and Demographics:

Number of subjects planned, N: 24 Number of subjects randomized, N: 24 Number of subjects included in All subjects (safety) population, n (%): 24 Number of subjects included in PK population, n (%): 24 Number of subjects completed as planned, n (%): 22 (92) Number of subjects withdrawn (any reason), n (%): 2 (8) Number of subjects withdrawn for SAE, n (%): 0 Number of subjects withdrawn for AE, n (%): 2 (8) Reasons for subject withdrawal, n (%) Lost to follow-up 0 Adverse events 2 (8) Protocol violation 0 Other 0 Demographics Age in Years, Mean (SD) 55.5 (5.7) Sex, n (%) Female: 6 (25) Male: 18 (75) BMI (kg/m2), Mean (SD) 27.2 (4.2) Height (cm), Mean (SD) 173.1 (7.1) Weight (kg), Mean (SD) 81.8 (15.2) Ethnicity, n (%) Hispanic or Latino: 0 Not Hispanic or Latino: 24 (100) Race, n (%) African American/African Heritage 0 American Indian or Alaskan Native 0 Asian – East Asian Heritage 0 Asian – Japanese Heritage 0 Asian – South East Asian Heritage 0 Native Hawaiian or Other Pacific Islander 0 White – Arabic/North African Heritage 0 White – White/Caucasian/European Heritage 24 (100)

- 6 - 5 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Diagnosis and main criteria for inclusion:

• Male or female subjects diagnosed with tinnitus according to a standard audiology visit and examination, including otoscopy and audiograms • Subject with aTHI severity grade of mild or greater (THI≥ 18) • Subjects must be 18-65 years of age inclusive. • Subjects with no significant underlying medical conditions (please refer to the Protocol for full details) • Subjects should not currently be on prescription, non-prescription or psychotropic drugs or antidepressants. Treatment administration:

Initial Supply (04th October 2006)

Product Bulk Batch Packed Batch Number Number

PTM, GW597599 (Vestipitant) tablet (ALN Formulation), 30 tablets / bottle

GW597599 25mg tablet (AK Formulation), 30 tablets / bottle

PTM, BRL29060 (Paroxetine) capsules (UG Formulation), 10 capsules / bottle

BRL29060 (Paroxetine) 20mg capsules (HR Formulation), 10 capsules / bottles

Re-Supply (12th September 2007)

Pack Description Input Batch Lot Number Number

30 x GW597599 (Vestipitant) 25mg tablets

10 x BRL29060 (Paroxetine) 20mg capsules

- 7 - 6 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Endpoints:

Primary

• Visual Analog Scales (VAS) to measure the change in tinnitus loudness (intensity) as perceived at the moment of the measurement at 2 hrs after dosing (or at any other time point vs. pre-dose baseline in their respective treatment session). Secondary

• Visual Analog Scales (VAS) to measure the level in tinnitus pitch and tinnitus distress as perceived at the moment of the measurement • VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) • Self-report questionnaires (integrated evaluation referring to the subject’s condition before dosing on the day of testing): Tinnitus Handicap Inventory (THI) & Quick Inventory of Depressive Symptomatology (QIDS-SR-16) • Clinician rated scales (annoyance of tinnitus and annoyance of hyperacusis questions) • Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam • PK samples Exploratory

• Diary (to be filled in the evening) • VAS for tinnitus loudness (intensity), pitch, and/or distress (integrated assessment of the whole day) • Number of hyperacusis episodes, brief description of the generator, and VAS distress rating of the overall distress Statistical methods:

Sample Size Considerations Data for Visual Analogue Scales for Loudness were obtained from the author (Baguley DM et al, Otology and Neurotology; 2005, 26:169- 176). From a re-analysis of these data on 16 subjects, a within-subject standard deviation of VAS change from pre-dose baseline of 12.88 mm was derived. In the same study an effect of about 28 mm was observed for Lidocaine. Assuming that the within subject SD in this study is the same observed in a previous study (Baguley DM et al, Otology and Neurotology; 2005, 26:169-176) and an effect of 14 mm (half of the effect seen for Lidocaine), 19 evaluable subjects would provide a 90% power. Assuming a drop-out rate not greater than 20% this lead to a sample size of 24 subjects.

- 8 - 7 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Final Analyses

• VAS tinnitus (intensity, tone, distress) and arousal/anxiety, Tinnitus Handicap Inventory (THI) total score & Tinnitus Aggravation Scores For each domain, data were summarized by treatment and time and plotted. For each domain data were analyzed using a mixed effect model including terms for:

• Fixed effects: period, treatment, time point (day 1 2h post dose, day14 pre- dose, day 14 2h post dose), time point*treatment • Random effects: subject, subject*period. Treatment means were estimated on each time point and treatment differences were reported with 95% confidence intervals.

• Annoyance of Hyperacusis, diary (Tinnitus scores and hyperacusis) Data (mean values over the treatment period for diary data) will be analyzed using a mixed effect model including terms for:

• Fixed effects: period, treatment • Random effects: subject Treatment means will be estimated and treatment differences will be reported with 95% confidence intervals.

• Changes in conduct of the study or planned analyses Some minor deviations from the procedure indicated in the RAP were applied to:

•

• Assume a 0 hyperacusis distress score when no episodes of hyperacusis was reported.

• PK/PD Descriptive statistics of Paroxetine and Vestipitant plasma concentrations were calculated. PK/PD relationships between the primary PD endpoints and Vestipitant plasma concentrations were explored by visual inspection of the individual data

- 9 - 8 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Summary Results:

Safety:

Placebo Vestipitant Vestipitant + Most Frequent Adverse Events Paroxetine N=23 N=23 N=24 n (%) n (%) n (%) Any AE 14 (61) 16 (70) 21 (88) Most Common AEs: (≥ 3 subjects in any treatment group):

Nervous System Disorders: Any Event 11 (48) 11 (48) 16 (67) Headache 10 (43) 8 (35) 12 (50) Dizziness 1 (4) 3 (13) 6 (25) Somnolence 0 1 (4) 5 (21) Balance Disorder 0 0 4 (17) Lethargy 1 (4) 0 3 (13)

Gastrointestinal Disorders: Any Event 6 (26) 6 (26) 10 (42) Nausea 3 (13) 1 (4) 6 (25)

Psychiatric Disorders: Any Event 3 (13) 5 (22) 9 (38) Depression 1 (4) 3 (13) 1 (4) Insomnia 0 2 (9) 3 (13)

Ear and Labyrinth Disorders Any Event 2 (9) 5 (22) 6 (25) Tinnitus 0 4 (17) 3 (13)

General Disorders and Adminstration Site Conditions: Any Event 2 (9) 4 (17) 9 (38) Fatigue 1 (4) 4 (17) 5 (21) Feeling Abnormal 1 (4) 0 4 (17)

Respiratory, Thoracic and Mediastinal Disorders: Any Event 0 1 (4) 6 (25) Oropharyngeal Pain 0 1 (4) 3 (13)

- 10 - 9 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Placebo Vestipitant Vestipitant + Most Frequent Adverse Events Paroxetine Related to IP N=23 N=23 N=24 n (%) n (%) n (%) Any AE related to investigational product 10 (43) 12 (52) 16 (67) Most Common AEs: (≥ 3 subjects in any treatment group0):

Nervous System Disorders: Any Event 7 (30) 8 (35) 9 (38) Headache 4 (17) 5 (22) 7 (29) Somnolence 0 1 (4) 4 (17) Dizziness 1 (4) 3 (13) 3 (13) Lethargy 1 (4) 0 3 (13)

Gastrointestinal Disorders: Any Event 5 (22) 2 (9) 8 (33) Nausea 3 (13) 1 (4) 6 (25) Diarrhoea 1 (4) 1 (4) 3 (13)

General Disorders and Adminstration Site Conditions: Any Event 1 (4) 4 (17) 6 (25) Fatigue 1 (4) 4 (17) 3 (13) Feeling Abnormal 0 0 3 (13)

Ear and Labrynth Disorders: Any Event 0 5 (22) 4 (17) Tinnitus 0 4 (17) 2 (8)

There were two withdrawals due to an adverse event.

•

- 11 - 10 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Though the frequency of adverse events was generally similar across the three treatment periods, the frequency was slightly higher for the combination of vestipitant + paroxetine (88%) than for either vestipitant (70%) or placebo (61%) alone. The most common adverse events belonged to the nervous system disorders (headache, somnolence & dizziness) and gastrointestinal system disorders (nausea & dyspepsia) groups. There were no clinically significant laboratory abnormalities or changes from baseline. There were no clinically significant ECG findings, QT changes, or clinically significant vital sign changes.

PK and PK/PD:

PK data are summarised in Table 1 and Table 2. No relevant differences in Vestipitant plasma concentrations were observed between the subjects given the combination with Paroxetine and those receiving Vestipitant alone. No specific PK/PD relationships were observed between the primary PD endpoints and Vestipitant plasma concentrations. An example of the lack of PK/PD relationship is shown in Figure 1.

Table 1 Summary of Plasma Vestipitant Pharmacokinetic Concentration- Time Data (ng/ml)

Treatment N Day Planned n No. Mean SD Median Min. Max. Relative Inputted Time Vestipitant 23 Day 1 Pre- 23 23 0.0 0.0 0 0 Dose 3 Hrs 23 0 60.6 18.4 63.2 32 112 Day 14 Pre- 21 1 11.4 7.5 9.8 0 25 Dose 3 Hrs 22 0 61.8 31.6 60.0 24 144 Vest. + 24 Day 1 Pre- 24 24 0.0 0.0 0 0 Parox Dose 3 Hrs 24 0 62.3 21.9 63.3 13 123 Day 14 Pre- 23 0 13.0 11.7 7.9 2 55 Dose 3 Hrs 23 0 57.6 23.0 51.6 24 108

Table 2 Summary of Plasma Paroxetine Pharmacokinetic Concentration- Time Data (ng/ml) Treatment N Day Planned n No. Mean SD Median Min. Max. Relative Inputted Time Vest. + 24 Day 1 Pre- 24 23 0.0 0.0 0 0 Parox Dose 3 Hrs 24 0 6.1 6.3 2.9 0 21 Day 14 Pre- 23 0 32.0 21.7 27.2 4 99 Dose 3 Hrs 23 0 41.3 27.4 33.7 12 135

- 12 - 11 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Figure 1 Delta from placebo in VAS_TINS score vs. Vestipitant concentrations

Pharmacodynamic and biomarker:

VAS Tinnitus scores (Intensity, tone, distress)

Plots showing means (± SD) by treatment and time point are presented in Figure 2, Figure 3 and Figure 4.

Figure 2 Intensity

- 13 - 12 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Figure 3 Tone

Figure 4 Distress

No statistically significant treatment effect was detected for any endpoint at any time point. Treatment differences were always negligible and very far from the level of statistical significance. A summary of the statistical analysis of the Tinnitus VAS “Intensity” scores is reported in Table 3.

- 14 - 13 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Table 3 Summary of Statistical Analysis of VAS Tinnitus scores (Intensity)

Param. Time Comparison LSmean LSmean Diff. 95% C.I. p- Test Ref. value Treat. Treat. Intensity Day 1 2H PD Vest.+Parox.-Pla 54.8 51.1 3.7 ( -4.8, 0.388 12.3) Vestipitant -Pla 54.3 51.1 3.2 ( -5.3, 0.451 11.8) Vest.+Parox.- 54.8 54.3 0.5 ( -8.1, 0.914 Vest. 9.0) Day 14 pre- Vest.+Parox.-Pla 54.2 51.4 2.7 ( -4.5, 0.451 dose 10.0) Vestipitant -Pla 53.5 51.4 2.1 ( -5.3, 0.569 9.4) Vest.+Parox.- 54.2 53.5 0.6 ( -6.7, 0.860 Vest. 8.0) Day 14 2h Vest.+Parox.-Pla 56.3 51.7 4.7 ( -3.0, 0.229 PD 12.3) Vestipitant -Pla 56.0 51.7 4.3 ( -3.4, 0.268 12.0) Vest.+Parox.- 56.3 56.0 0.4 ( -7.4, 0.927 Vest. 8.1)

Similar results were observed for the other VAS endpoints (tone and distress).

VAS Arousal-Anxiety

No statistically significant treatment effect was detected for any endpoint at any time point. The largest difference, even if not statistically significant, was about a greater level of drowsiness following the 2 active drugs vs placebo. Mean values (+-SD) are reported in Figure 5.

- 15 - 14 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Figure 5 Plot of mean values (± SD) by treatment and time point (Active- Drowsy)

A summary of the statistical analysis regarding this endpoint is reported in Table 4.

- 16 - 15 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Table 4 Summary of Statistical Analysis of VAS scores (Active-Drowsy)

Param. Time Comparison LSmean LSmean Diff. 95% C.I. p- Test Ref. value Treat. Treat. Active- Day 1 2H Vest.+Parox.- 49.6 41.8 7.7 ( -1.4, 0.095 Drowsy PD Pla 16.9) Vestipitant -Pla 49.7 41.8 7.9 ( -1.3, 0.092 17.1) Vest.+Parox.- 49.6 49.7 -0.1 ( -9.3, 0.978 Vest. 9.0) Day 14 pre- Vest.+Parox.- 42.8 39.6 3.2 ( -7.8, 0.562 dose Pla 14.2) Vestipitant -Pla 47.5 39.6 7.9 ( -3.3, 0.164 19.1) Vest.+Parox.- 42.8 47.5 -4.7 (-15.9, 0.405 Vest. 6.5) Day 14 2h Vest.+Parox.- 52.9 44.3 8.6 ( -1.0, 0.079 PD Pla 18.3) Vestipitant -Pla 46.6 44.3 2.3 ( -7.4, 0.632 12.1) Vest.+Parox.- 52.9 46.6 6.3 ( -3.4, 0.197 Vest. 16.0)

THI

No statistically significant effect was detected among the active treatments vs placebo at any time point. However at the Day 1 2H time point, the THI total score was lower for Vestipitant + Paroxetine and the difference was statistically significant vs Vestipitant alone. This effect was not confirmed at the other time points.

A summary of the results of the statistical analysis is reported in Table 5.

- 17 - 16 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Table 5 Summary of Statistical Analysis of THI total scores

Param. Time Comparison LSmean LSmean Diff. 95% C.I. p- Test Ref. value Treat. Treat. Total Day 1 2H Vest.+Parox.-Pla 26.5 29.4 -2.9 ( -6.1, 0.078 score PD 0.3) Vestipitant -Pla 30.4 29.4 1.0 ( -2.2, 0.539 4.2) Vest.+Parox.- 26.5 30.4 -3.9 ( -7.1, - 0.020 Vest. 0.6) Day 14 pre- Vest.+Parox.-Pla 31.4 31.4 0.0 ( -6.1, 0.993 dose 6.1) Vestipitant -Pla 32.7 31.4 1.3 ( -4.8, 0.669 7.5) Vest.+Parox.- 31.4 32.7 -1.3 ( -7.4, 0.675 Vest. 4.9) Day 14 2h Vest.+Parox.-Pla 27.4 28.3 -0.8 ( -6.6, 0.768 PD 4.9) Vestipitant -Pla 29.8 28.3 1.6 ( -4.2, 0.588 7.3) Vest.+Parox.- 27.4 29.8 -2.4 ( -8.1, 0.404 Vest. 3.3)

QIDS-SR

No statistically significant treatment effect was detected. Scores were relatively low (mean values around 4, while the maximum value of the scale is 27) for all the treatments.

Tinnitus Aggravation Score

No statistically significant treatment effect was detected. The largest difference was observed after 2 hours from dosing at Day 1 in the comparison Vestipitant – Placebo. The difference was close to the level of the statistical significance but it wasn’t confirmed at the other time points.

- 18 - 17 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

A summary of the results of the statistical analysis is reported in Table 6.

Table 6 Summary of Statistical Analysis of Tinnitus Aggravations scores

Param. Time Comparison LSmean LSmean Diff. 95% p- Test Ref. C.I. value Treat. Treat. Score (0- Day 1 2H Vest.+Parox.-Pla 3.5 3.7 -0.2 ( -1.0, 0.593 7) PD 0.6) Vestipitant -Pla 2.9 3.7 -0.7 ( -1.5, 0.056 0.0) Vest.+Parox.- 3.5 2.9 0.5 ( -0.2, 0.158 Vest. 1.3) Day 14 pre- Vest.+Parox.-Pla 3.2 3.2 -0.0 ( -0.8, 0.933 dose 0.7) Vestipitant -Pla 3.5 3.2 0.2 ( -0.5, 0.529 1.0) Vest.+Parox.- 3.2 3.5 -0.3 ( -1.0, 0.475 Vest. 0.5) Day 14 2h Vest.+Parox.-Pla 3.3 2.9 0.4 ( -0.3, 0.245 PD 1.1) Vestipitant -Pla 2.9 2.9 0.1 ( -0.7, 0.885 0.8) Vest.+Parox.- 3.3 2.9 0.4 ( -0.3, 0.308 Vest. 1.1)

Annoyance of Hyperacusis

No statistically significant treatment effect was detected. Scores were relatively low (mean values around 1, median values of 0) for all the treatments.

Tinnitus VAS scores (diary – mean over the treatment period)

A statistically significant worsening of intensity and distress scores were observed after Vestipitant vs placebo. A plot of intensity mean values (+- SD) is presented in Figure 6.

- 19 - 18 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

Figure 6 Plot of mean values (± SD) by treatment and time (Intensity)

Number of episodes of Hyperacusis and distress (diary – mean over the treatment period)

No statistically significant treatment effect was detected. Number of episodes and distress scores were relatively low for all the treatments.

Results Summary & Conclusion:

• No statistically significant treatment effect was detected for VAS Tinnitus scores (intensity, tone and distress) at any time point. Treatment differences were always negligible and very far from the level of statistical significance. • No statistically significant treatment effect was detected for any VAS Arousal- Anxiety endpoint . The largest difference, even if not statistically significant, was a greater level of drowsiness following the 2 active drugs cf placebo • No statistically significant effect was detected among the active treatments vs placebo at any endpoint for THI. However at the Day 1 2h time point the THI total score was lower for Vestipitant + Paroxetine and the difference was statistically significant vs Vestipitant alone. This effect was not confirmed at the other time points. • No statistically significant treatment effect was detected on Tinnitus Aggravation scores. The largest difference was observed after 2 hours from dosing at Day 1 in the comparison Vestipitant – Placebo. The difference was close to the level of the statistical significance but it wasn’t confirmed after repeated dosing.

- 20 - 19 CONFIDENTIAL HM2009/00361/00HM2009/00361/00 NKP106254

• A statistically significant worsening of VAS Tinnitus intensity and distress scores were observed after Vestipitant vs placebo on the basis of the data collected on diary card. • No further clear effect was observed on the remaining PD endpoints • There were no serious adverse events, deaths or pregnancies. Two subjects were withdrawn due to AEs. The study drugs were generally well tolerated. The frequency of AEs was similar across the three treatment periods, though a slightly higher frequence of adverse events was reported with the combination vestipitant+paroxetine than with either vestipitant or placebo alone. • No relevant differences in Vestipitant plasma concentrations were observed between the subjects given the combination with Paroxetine and those receiving Vestipitant alone. • No specific PK/PD relationships were observed between the primary PD endpoints and Vestipitant plasma concentrations. Date of Report:

Dec-2009

- 21 - 20 CONFIDENTIAL HM2009/00361/00 NKP106254

Study Population Data Source Tables

Page Table 9.1 Summary of Demographic Characteristics (All subjects Population) ...... 22 Table 9.2 Summary of Race and Racial Combination Details (All subjects Population) ...... 24 Table 9.3 Summary of Subject Disposition (All subjects Population) ...... 25

21 Protocol: NKP106254 Page 1 of 2 Population: All subjects Table 9.1 Summary of Demographic Characteristics

Total (N=24) ------Age (yrs) n 24 Mean 55.5 SD 5.68 Median 54.5 Min. 47 Max. 65

Sex n 24 Female 6 (25%)

Male 18 (75%) CONFIDENTIAL

Ethnicity n 24 Hispanic/Latino 0 22 Not Hispanic/Latino 24 (100%)

Height (cm) n 24 Mean 173.1 SD 7.13 Median 172.5 Min. 158 Max. 185

Weight (kg) n 24 Mean 81.8 SD 15.16 Median 81.7 Min. 57 HM2009/00361/00 Max. 107 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 2 Population: All subjects Table 9.1 Summary of Demographic Characteristics

Total (N=24) ------Body Mass Index (kg/m^2) n 24 Mean 27.18 SD 4.187 Median 26.72 Min. 20.8 Max. 36.1 CONFIDENTIAL 23 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: All subjects Table 9.2 Summary of Race and Racial Combination Details

Total (N=24) ------Race n 24 African American/African Heritage 0 American Indian or Alaska Native 0 Asian - Central/South Asian Heritage 0 Asian - East Asian Heritage 0 Asian - Japanese Heritage 0 Asian - South East Asian Heritage 0 Asian - Mixed Race 0 Native Hawaiian or other Pacific Islander 0

White - Arabic/North African Heritage 0 CONFIDENTIAL White - White/Caucasian/European Heritage 24 (100%) White - Mixed Race 0 Mixed Race 0 24 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: All subjects Table 9.3 Summary of Subject Disposition

Total (N=24) ------Completion Status Completed 22 (92%) Withdrawn 2 (8%)

Primary[1]/subreason[2] for withdrawal Adverse event 2 (8%) Lack of efficacy 0 Protocol deviation 0 Subject reached protocol-defined stopping 0

criteria CONFIDENTIAL Study closed/terminated 0 Lost to follow-up 0 Investigator discretion 0 25 Withdrew consent 0 Did not meet continuation criteria 0 Consent to continue not obtained 0 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

[1] Subjects may only have one primary reason for withdrawal [2] Percentages for subreasons may sum to more or less than 100%. Subjects may have more than one subreason underneath a single primary reason. Subjects are not required to indicate subreasons. CONFIDENTIAL HM2009/00361/00 NKP106254

Safety Data Source Tables

Page Table 10.1 Summary of Exposure to study drug (All subjects Population) . . . 27 Table 10.2 Summary of All Adverse Events (All subjects Population) ...... 28 Table 10.3 Summary of Drug Related Adverse Events (All subjects Population) ...... 32 Table 10.4 Summary of Haematology Laboratory Values (All subjects Population) ...... 35 Table 10.5 Summary of Chemistry Laboratory Values (All subjects Population) ...... 41 Table 10.6 Summary of Urinalysis Dipstick Results (All subjects Population) 49 Table 10.7 Summary of ECG Findings (All subjects Population) ...... 51 Table 10.8 Summary of ECG Values (All subjects Population)...... 52 Table 10.9 Summary of Vital Signs (All subjects Population) ...... 55

26 Protocol: NKP106254 Page 1 of 1 Population: All subjects Table 10.1 Summary of Exposure to study drug

Placebo Vestipitant Vest.+Parox. (N=23) (N=23) (N=24) ------Cumulative duration n 23 23 24 Mean 14.0 13.8 13.5 SD 0.00 0.83 2.65 Median 14.0 14.0 14.0 Min. 14 10 1 Max. 14 14 14

Cumulative dose Vesti. n 23 23 24 Mean 0.0 345.7 336.5

SD 0.00 20.85 66.34 CONFIDENTIAL Median 0.0 350.0 350.0 Min. 0 250 25 Max. 0 350 350 27 Cumulative dose Parox. n 23 23 24 Mean 0.0 0.0 269.2 SD 0.00 0.00 53.07 Median 0.0 0.0 280.0 Min. 0 0 20 Max. 0 0 280 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

Note: Duration is expressed in days and cumulative doses expressed in mg Protocol: NKP106254 Page 1 of 4 Population: All subjects Table 10.2 Summary of All Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------ANY EVENT 14 (61%) 16 (70%) 21 (88%) 23 (96%)

Nervous system disorders Any event 11 (48%) 11 (48%) 16 (67%) 18 (75%) Headache 10 (43%) 8 (35%) 12 (50%) 14 (58%) Dizziness 1 (4%) 3 (13%) 6 (25%) 7 (29%) Somnolence 0 1 (4%) 5 (21%) 6 (25%) Balance disorder 0 0 4 (17%) 4 (17%) Lethargy 1 (4%) 0 3 (13%) 4 (17%)

Migraine 2 (9%) 2 (9%) 1 (4%) 3 (13%) CONFIDENTIAL Poor quality sleep 1 (4%) 0 1 (4%) 2 (8%) Tremor 0 0 2 (8%) 2 (8%) Disturbance in attention 0 0 1 (4%) 1 (4%) 28 Dizziness postural 1 (4%) 0 0 1 (4%) Hypoaesthesia 0 0 1 (4%) 1 (4%) Memory impairment 1 (4%) 0 0 1 (4%) Sedation 0 0 1 (4%) 1 (4%) Tension headache 1 (4%) 0 0 1 (4%) HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 2 of 4 Population: All subjects Table 10.2 Summary of All Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------Gastrointestinal disorders Any event 6 (26%) 6 (26%) 10 (42%) 15 (63%) Nausea 3 (13%) 1 (4%) 6 (25%) 9 (38%) Dyspepsia 2 (9%) 0 2 (8%) 4 (17%) Constipation 2 (9%) 0 1 (4%) 3 (13%) Diarrhoea 1 (4%) 1 (4%) 3 (13%) 3 (13%) Toothache 1 (4%) 1 (4%) 0 2 (8%) Abdominal distension 0 1 (4%) 0 1 (4%) Abdominal pain upper 0 1 (4%) 0 1 (4%)

Anal haemorrhage 1 (4%) 0 0 1 (4%) CONFIDENTIAL Dry mouth 0 0 1 (4%) 1 (4%) Dysphagia 0 0 1 (4%) 1 (4%) Flatulence 0 1 (4%) 0 1 (4%) 29 Gastrooesophageal reflux disease 0 1 (4%) 0 1 (4%) Hyperchlorhydria 1 (4%) 0 0 1 (4%) Mouth ulceration 0 0 1 (4%) 1 (4%) Oral pain 0 0 1 (4%) 1 (4%)

Psychiatric disorders Any event 3 (13%) 5 (22%) 9 (38%) 10 (42%) Depression 1 (4%) 3 (13%) 1 (4%) 4 (17%) Insomnia 0 2 (9%) 3 (13%) 4 (17%) Anxiety 0 2 (9%) 1 (4%) 3 (13%) Depressed mood 2 (9%) 1 (4%) 1 (4%) 3 (13%) Abnormal dreams 0 0 1 (4%) 1 (4%) Agitation 0 1 (4%) 0 1 (4%) Anorgasmia 0 0 1 (4%) 1 (4%) HM2009/00361/00 Confusional state 0 0 1 (4%) 1 (4%) Hypervigilance 0 0 1 (4%) 1 (4%) Loss of libido 0 0 1 (4%) 1 (4%) NKP106254 Middle insomnia 0 0 1 (4%) 1 (4%) Restlessness 0 0 1 (4%) 1 (4%)

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 3 of 4 Population: All subjects Table 10.2 Summary of All Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------Ear and labyrinth disorders Any event 2 (9%) 5 (22%) 6 (25%) 10 (42%) Tinnitus 0 4 (17%) 3 (13%) 7 (29%) Ear pain 1 (4%) 2 (9%) 0 2 (8%) Vertigo positional 1 (4%) 0 1 (4%) 2 (8%) Autophony 1 (4%) 0 1 (4%) 1 (4%) Deafness 0 0 1 (4%) 1 (4%) Ear discomfort 0 0 1 (4%) 1 (4%) Vertigo 0 0 1 (4%) 1 (4%) CONFIDENTIAL General disorders and administration site conditions Any event 2 (9%) 4 (17%) 9 (38%) 11 (46%) 30 Fatigue 1 (4%) 4 (17%) 5 (21%) 8 (33%) Feeling abnormal 1 (4%) 0 4 (17%) 4 (17%) Irritability 1 (4%) 0 0 1 (4%) Malaise 0 1 (4%) 0 1 (4%)

Musculoskeletal and connective tissue disorders Any event 3 (13%) 4 (17%) 3 (13%) 7 (29%) Back pain 1 (4%) 1 (4%) 1 (4%) 3 (13%) Arthralgia 1 (4%) 1 (4%) 1 (4%) 2 (8%) Groin pain 0 1 (4%) 0 1 (4%) Muscle spasms 1 (4%) 1 (4%) 0 1 (4%) Muscle twitching 0 0 1 (4%) 1 (4%) Myalgia 1 (4%) 0 0 1 (4%) HM2009/00361/00 Neck pain 1 (4%) 0 0 1 (4%) Pain in extremity 1 (4%) 0 0 1 (4%) NKP106254 NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 4 of 4 Population: All subjects Table 10.2 Summary of All Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------Respiratory, thoracic and mediastinal disorders Any event 0 1 (4%) 6 (25%) 6 (25%) Oropharyngeal pain 0 1 (4%) 3 (13%) 3 (13%) Cough 0 0 2 (8%) 2 (8%) Dysphonia 0 0 1 (4%) 1 (4%) Tachypnoea 0 0 1 (4%) 1 (4%) Throat tightness 0 0 1 (4%) 1 (4%) Yawning 0 0 1 (4%) 1 (4%) CONFIDENTIAL Infections and infestations Any event 1 (4%) 1 (4%) 1 (4%) 3 (13%) Nasopharyngitis 1 (4%) 1 (4%) 1 (4%) 3 (13%) 31 Injury, poisoning and procedural complications Any event 0 1 (4%) 0 1 (4%) Joint sprain 0 1 (4%) 0 1 (4%)

Metabolism and nutrition disorders Any event 0 0 1 (4%) 1 (4%) Decreased appetite 0 0 1 (4%) 1 (4%)

Renal and urinary disorders Any event 0 0 1 (4%) 1 (4%) Pollakiuria 0 0 1 (4%) 1 (4%) HM2009/00361/00 HM2009/00361/00 Skin and subcutaneous tissue disorders Any event 0 0 1 (4%) 1 (4%) Hyperhidrosis 0 0 1 (4%) 1 (4%) NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 1 of 3 Population: All subjects Table 10.3 Summary of Drug Related Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------ANY EVENT 10 (43%) 12 (52%) 16 (67%) 18 (75%)

Nervous system disorders Any event 7 (30%) 8 (35%) 9 (38%) 13 (54%) Headache 4 (17%) 5 (22%) 7 (29%) 9 (38%) Somnolence 0 1 (4%) 4 (17%) 5 (21%) Dizziness 1 (4%) 3 (13%) 3 (13%) 4 (17%) Lethargy 1 (4%) 0 3 (13%) 4 (17%) Balance disorder 0 0 2 (8%) 2 (8%)

Disturbance in attention 0 0 1 (4%) 1 (4%) CONFIDENTIAL Dizziness postural 1 (4%) 0 0 1 (4%) Hypoaesthesia 0 0 1 (4%) 1 (4%) Poor quality sleep 1 (4%) 0 0 1 (4%) 32 Sedation 0 0 1 (4%) 1 (4%) Tremor 0 0 1 (4%) 1 (4%)

Gastrointestinal disorders Any event 5 (22%) 2 (9%) 8 (33%) 13 (54%) Nausea 3 (13%) 1 (4%) 6 (25%) 9 (38%) Constipation 2 (9%) 0 1 (4%) 3 (13%) Diarrhoea 1 (4%) 1 (4%) 3 (13%) 3 (13%) Dyspepsia 2 (9%) 0 0 2 (8%) Dry mouth 0 0 1 (4%) 1 (4%) Dysphagia 0 0 1 (4%) 1 (4%) Gastrooesophageal reflux disease 0 1 (4%) 0 1 (4%) HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 2 of 3 Population: All subjects Table 10.3 Summary of Drug Related Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------Psychiatric disorders Any event 2 (9%) 5 (22%) 6 (25%) 8 (33%) Depression 1 (4%) 2 (9%) 1 (4%) 3 (13%) Insomnia 0 2 (9%) 2 (8%) 3 (13%) Anxiety 0 2 (9%) 0 2 (8%) Depressed mood 1 (4%) 1 (4%) 0 2 (8%) Agitation 0 1 (4%) 0 1 (4%) Anorgasmia 0 0 1 (4%) 1 (4%) Confusional state 0 0 1 (4%) 1 (4%)

Hypervigilance 0 0 1 (4%) 1 (4%) CONFIDENTIAL Loss of libido 0 0 1 (4%) 1 (4%) Middle insomnia 0 0 1 (4%) 1 (4%)

33 General disorders and administration site conditions Any event 1 (4%) 4 (17%) 6 (25%) 8 (33%) Fatigue 1 (4%) 4 (17%) 3 (13%) 6 (25%) Feeling abnormal 0 0 3 (13%) 3 (13%) Malaise 0 1 (4%) 0 1 (4%)

Ear and labyrinth disorders Any event 0 5 (22%) 4 (17%) 8 (33%) Tinnitus 0 4 (17%) 2 (8%) 6 (25%) Ear discomfort 0 0 1 (4%) 1 (4%) Ear pain 0 1 (4%) 0 1 (4%) Vertigo 0 0 1 (4%) 1 (4%) HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 3 of 3 Population: All subjects Table 10.3 Summary of Drug Related Adverse Events

System Organ Class Placebo Vestipitant Vest.+Parox. Total Preferred Term (N=23) (N=23) (N=24) (N=24) ------Respiratory, thoracic and mediastinal disorders Any event 0 0 2 (8%) 2 (8%) Oropharyngeal pain 0 0 1 (4%) 1 (4%) Throat tightness 0 0 1 (4%) 1 (4%) Yawning 0 0 1 (4%) 1 (4%)

Musculoskeletal and connective tissue disorders

Any event 1 (4%) 1 (4%) 1 (4%) 2 (8%) CONFIDENTIAL Muscle spasms 1 (4%) 1 (4%) 0 1 (4%) Muscle twitching 0 0 1 (4%) 1 (4%)

34 Renal and urinary disorders Any event 0 0 1 (4%) 1 (4%) Pollakiuria 0 0 1 (4%) 1 (4%) HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

Note: Total is total number of subjects experiencing the event not total number of events. Protocol: NKP106254 Page 1 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Basophils (GI/L) Placebo 23 Day 1 PRE-DOSE 23 0.01 0.029 0.00 0.0 0.1 Day 14 PRE-DOSE 23 0.00 0.021 0.00 0.0 0.1

Vestipitant 23 Day 1 PRE-DOSE 23 0.00 0.021 0.00 0.0 0.1 Day 14 PRE-DOSE 23 0.01 0.029 0.00 0.0 0.1

Vest.+Parox. 24 Day 1 PRE-DOSE 24 0.00 0.020 0.00 0.0 0.1 Day 14 PRE-DOSE 22 0.00 0.000 0.00 0.0 0.0 CONFIDENTIAL

Eosinophils (GI/L) Placebo 23 Day 1 PRE-DOSE 23 0.14 0.099 0.10 0.0 0.4 Day 14 PRE-DOSE 23 0.15 0.095 0.10 0.0 0.4 35 Vestipitant 23 Day 1 PRE-DOSE 23 0.13 0.093 0.10 0.0 0.3 Day 14 PRE-DOSE 23 0.14 0.094 0.10 0.0 0.3

Vest.+Parox. 24 Day 1 PRE-DOSE 24 0.15 0.114 0.15 0.0 0.4 Day 14 PRE-DOSE 22 0.10 0.076 0.10 0.0 0.3

Hemoglobin (G/L) Placebo 23 Day 1 PRE-DOSE 23 141.9 11.39 143.0 122 159 Day 14 PRE-DOSE 23 141.7 11.35 143.0 119 157

Vestipitant 23 Day 1 PRE-DOSE 23 140.7 11.19 141.0 121 160 Day 14 PRE-DOSE 23 141.3 10.00 143.0 121 158 HM2009/00361/00 HM2009/00361/00 Vest.+Parox. 24 Day 1 PRE-DOSE 24 141.6 11.37 142.5 117 159 Day 14 PRE-DOSE 22 140.3 11.09 142.5 115 160 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Hematocrit (1) Placebo 23 Day 1 PRE-DOSE 23 0.4159 0.03328 0.4160 0.360 0.480 Day 14 PRE-DOSE 23 0.4141 0.03263 0.4160 0.349 0.463

Vestipitant 23 Day 1 PRE-DOSE 23 0.4115 0.03176 0.4100 0.357 0.469 Day 14 PRE-DOSE 23 0.4165 0.03003 0.4220 0.350 0.468

Vest.+Parox. 24 Day 1 PRE-DOSE 24 0.4130 0.03496 0.4100 0.337 0.472 Day 14 PRE-DOSE 22 0.4104 0.03047 0.4165 0.339 0.475 CONFIDENTIAL

Lymphocytes (GI/L) Placebo 23 Day 1 PRE-DOSE 23 1.55 0.385 1.50 0.9 2.3 Day 14 PRE-DOSE 23 1.62 0.427 1.60 0.9 2.8 36 Vestipitant 23 Day 1 PRE-DOSE 23 1.53 0.439 1.50 0.9 2.6 Day 14 PRE-DOSE 23 1.53 0.453 1.50 0.8 2.6

Vest.+Parox. 24 Day 1 PRE-DOSE 24 1.51 0.371 1.50 0.9 2.4 Day 14 PRE-DOSE 22 1.46 0.396 1.40 0.9 2.2

Mean Corpuscle Placebo 23 Day 1 PRE-DOSE 23 341.0 6.67 342.0 326 353 Hemoglobin concentration (G/L) Day 14 PRE-DOSE 23 342.3 6.02 341.0 334 358 HM2009/00361/00 HM2009/00361/00 Vestipitant 23 Day 1 PRE-DOSE 23 342.0 7.36 344.0 325 354 Day 14 PRE-DOSE 23 339.5 6.95 339.0 324 356 NKP106254 NKP106254 Vest.+Parox. 24 Day 1 PRE-DOSE 24 343.1 5.44 343.0 332 353 Day 14 PRE-DOSE 22 342.0 6.45 341.0 331 356 Protocol: NKP106254 Page 3 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Mean Corpuscle Placebo 23 Day 1 PRE-DOSE 23 31.07 1.274 31.10 28.0 33.1 Hemoglobin (PG) Day 14 PRE-DOSE 23 31.11 1.213 31.10 28.1 32.9

Vestipitant 23 Day 1 PRE-DOSE 23 31.02 1.080 31.10 28.5 32.8 Day 14 PRE-DOSE 23 30.90 1.243 31.00 28.2 33.0

Vest.+Parox. 24 Day 1 PRE-DOSE 24 31.20 1.337 31.25 27.8 33.9

Day 14 PRE-DOSE 22 31.19 1.226 31.20 28.0 32.9 CONFIDENTIAL

Mean Corpuscle Placebo 23 Day 1 PRE-DOSE 23 91.10 3.758 90.90 84.1 101.5 37 Volume (FL) Day 14 PRE-DOSE 23 90.90 3.184 90.80 83.7 96.1

Vestipitant 23 Day 1 PRE-DOSE 23 90.72 3.548 90.10 81.8 96.6 Day 14 PRE-DOSE 23 91.03 3.664 90.60 82.2 98.6

Vest.+Parox. 24 Day 1 PRE-DOSE 24 90.93 3.491 90.85 81.7 97.9 Day 14 PRE-DOSE 22 91.21 3.939 91.25 82.6 98.4

Monocytes (GI/L) Placebo 23 Day 1 PRE-DOSE 23 0.44 0.170 0.40 0.1 0.8 Day 14 PRE-DOSE 23 0.45 0.188 0.40 0.1 1.1

Vestipitant 23 Day 1 PRE-DOSE 23 0.46 0.159 0.40 0.2 0.8 HM2009/00361/00 Day 14 PRE-DOSE 23 0.41 0.136 0.40 0.2 0.7

Vest.+Parox. 24 Day 1 PRE-DOSE 24 0.43 0.149 0.40 0.1 0.7 NKP106254 Day 14 PRE-DOSE 22 0.40 0.115 0.40 0.2 0.6 Protocol: NKP106254 Page 4 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Mean Platelet Placebo 23 Day 1 PRE-DOSE 23 9.49 1.709 8.90 7.3 13.9 Volume (FL) Day 14 PRE-DOSE 23 9.38 1.655 8.70 7.9 13.5

Vestipitant 23 Day 1 PRE-DOSE 23 9.45 1.581 9.00 7.2 13.5 Day 14 PRE-DOSE 23 9.32 1.352 9.00 7.5 12.7

Vest.+Parox. 24 Day 1 PRE-DOSE 24 9.42 1.635 8.90 6.9 13.1

Day 14 PRE-DOSE 22 9.46 1.649 9.00 7.4 13.1 CONFIDENTIAL

Total Neutrophils Placebo 23 Day 1 PRE-DOSE 23 3.67 1.125 3.40 2.1 6.1 38 (ANC - Absolute Neutrophil Count) (GI/L) Day 14 PRE-DOSE 23 3.56 1.009 3.50 1.9 6.1

Vestipitant 23 Day 1 PRE-DOSE 23 3.52 1.109 3.30 1.6 6.5 Day 14 PRE-DOSE 23 3.66 1.017 3.50 2.1 5.8

Vest.+Parox. 24 Day 1 PRE-DOSE 24 3.56 1.079 3.35 1.6 5.7 Day 14 PRE-DOSE 22 3.82 1.259 3.65 2.1 7.1 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 5 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Platelet count Placebo 23 Day 1 PRE-DOSE 22 210.9 67.49 202.5 90 398 (GI/L) Day 14 PRE-DOSE 23 213.4 60.92 211.0 91 357

Vestipitant 23 Day 1 PRE-DOSE 23 212.4 58.66 223.0 91 376 Day 14 PRE-DOSE 23 209.2 60.08 215.0 105 389

Vest.+Parox. 24 Day 1 PRE-DOSE 24 209.5 60.58 204.0 91 387

Day 14 PRE-DOSE 22 211.8 66.62 207.5 86 381 CONFIDENTIAL

Red Blood Cell Placebo 23 Day 1 PRE-DOSE 23 4.573 0.4081 4.580 3.83 5.67 39 count (TI/L) Day 14 PRE-DOSE 23 4.561 0.4043 4.580 3.96 5.51

Vestipitant 23 Day 1 PRE-DOSE 23 4.540 0.3829 4.560 3.89 5.41 Day 14 PRE-DOSE 23 4.580 0.3592 4.590 4.02 5.54

Vest.+Parox. 24 Day 1 PRE-DOSE 24 4.545 0.3974 4.485 3.84 5.39 Day 14 PRE-DOSE 22 4.506 0.3853 4.430 3.81 5.65

RDW - Red Cell Placebo 23 Day 1 PRE-DOSE 23 13.61 0.814 13.50 12.5 15.5 Distribution Width (%) Day 14 PRE-DOSE 23 13.56 0.764 13.40 12.0 14.9 HM2009/00361/00

Vestipitant 23 Day 1 PRE-DOSE 23 13.60 0.796 13.60 11.8 15.9 Day 14 PRE-DOSE 23 13.67 0.628 13.70 12.4 14.9 NKP106254

Vest.+Parox. 24 Day 1 PRE-DOSE 24 13.57 0.725 13.45 12.2 14.7 Day 14 PRE-DOSE 22 13.52 0.603 13.50 12.5 15.2 Protocol: NKP106254 Page 6 of 6 Population: All subjects Table 10.4 Summary of Haematology Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------White Blood Cell Placebo 23 Day 1 PRE-DOSE 23 5.85 1.435 5.50 3.4 8.8 count (GI/L) Day 14 PRE-DOSE 23 5.79 1.315 5.50 3.8 8.4

Vestipitant 23 Day 1 PRE-DOSE 23 5.68 1.306 5.60 3.5 9.0 Day 14 PRE-DOSE 23 5.77 1.279 5.60 3.7 8.2

Vest.+Parox. 24 Day 1 PRE-DOSE 24 5.68 1.299 5.40 3.1 7.8

Day 14 PRE-DOSE 22 5.80 1.434 5.65 3.6 9.6 CONFIDENTIAL 40 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Albumin/Globulin Placebo 23 Day 1 PRE-DOSE 23 1.83 0.292 1.80 1.4 2.4 ratio Day 14 PRE-DOSE 23 1.81 0.257 1.80 1.4 2.4

Vestipitant 23 Day 1 PRE-DOSE 23 1.78 0.259 1.70 1.4 2.3 Day 14 PRE-DOSE 23 1.80 0.275 1.70 1.5 2.4

Vest.+Parox. 24 Day 1 PRE-DOSE 24 1.86 0.308 1.80 1.4 2.6

Day 14 PRE-DOSE 22 1.82 0.310 1.80 1.4 2.4 CONFIDENTIAL

Albumin (G/L) Placebo 23 Day 1 PRE-DOSE 23 43.7 2.12 44.0 40 47 41 Day 14 PRE-DOSE 23 43.1 2.02 43.0 40 48

Vestipitant 23 Day 1 PRE-DOSE 23 43.0 2.01 43.0 40 46 Day 14 PRE-DOSE 23 43.3 2.07 44.0 39 46

Vest.+Parox. 24 Day 1 PRE-DOSE 24 43.2 2.18 43.5 39 47 Day 14 PRE-DOSE 22 43.4 1.59 43.0 40 46

Alkaline Placebo 23 Day 1 PRE-DOSE 23 64.4 15.67 62.0 41 105 Phosphatase (IU/L) Day 14 PRE-DOSE 23 63.3 14.72 59.0 44 95

Vestipitant 23 Day 1 PRE-DOSE 23 63.9 16.29 61.0 39 110 HM2009/00361/00 Day 14 PRE-DOSE 23 65.4 15.88 65.0 41 107

Vest.+Parox. 24 Day 1 PRE-DOSE 24 62.8 14.44 61.0 40 100 NKP106254 Day 14 PRE-DOSE 22 63.1 14.89 60.0 41 96 Protocol: NKP106254 Page 2 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Alanine Amino Placebo 23 Day 1 PRE-DOSE 23 24.8 10.72 23.0 10 53 Transferase (IU/L) Day 14 PRE-DOSE 23 23.1 9.01 25.0 10 42

Vestipitant 23 Day 1 PRE-DOSE 23 21.7 8.27 21.0 11 41 Day 14 PRE-DOSE 23 20.8 7.79 23.0 11 44

Vest.+Parox. 24 Day 1 PRE-DOSE 24 23.9 13.98 20.5 11 77

Day 14 PRE-DOSE 22 18.8 7.26 18.0 8 37 CONFIDENTIAL

Aspartate Amino Placebo 23 Day 1 PRE-DOSE 23 23.1 6.68 21.0 13 35 42 Transferase (IU/L) Day 14 PRE-DOSE 23 21.6 5.53 21.0 13 34

Vestipitant 23 Day 1 PRE-DOSE 23 22.2 6.63 22.0 12 37 Day 14 PRE-DOSE 23 20.1 5.13 20.0 14 36

Vest.+Parox. 24 Day 1 PRE-DOSE 24 22.0 6.12 21.5 11 37 Day 14 PRE-DOSE 22 20.0 5.23 19.0 13 36

Total Bilirubin Placebo 23 Day 1 PRE-DOSE 23 11.0 5.14 9.0 5 27 (UMOL/L) Day 14 PRE-DOSE 23 11.1 4.61 10.0 6 25 HM2009/00361/00 HM2009/00361/00 Vestipitant 23 Day 1 PRE-DOSE 23 12.4 9.44 9.0 6 52 Day 14 PRE-DOSE 23 10.0 6.34 8.0 4 35 NKP106254 NKP106254 Vest.+Parox. 24 Day 1 PRE-DOSE 24 10.7 4.95 9.5 5 28 Day 14 PRE-DOSE 22 10.8 6.01 9.0 5 32 Protocol: NKP106254 Page 3 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Calcium (MMOL/L) Placebo 23 Day 1 PRE-DOSE 23 2.345 0.0712 2.330 2.25 2.51 Day 14 PRE-DOSE 23 2.330 0.0672 2.330 2.23 2.49

Vestipitant 23 Day 1 PRE-DOSE 23 2.321 0.0686 2.320 2.22 2.43 Day 14 PRE-DOSE 23 2.312 0.0700 2.320 2.16 2.43

Vest.+Parox. 24 Day 1 PRE-DOSE 24 2.313 0.0793 2.310 2.16 2.47 Day 14 PRE-DOSE 22 2.316 0.0593 2.315 2.21 2.42 CONFIDENTIAL

Cholesterol Placebo 23 Day 1 PRE-DOSE 23 4.915 0.9117 4.790 3.49 7.34 (MMOL/L) 43 Day 14 PRE-DOSE 23 4.974 0.8924 4.880 3.46 6.86

Vestipitant 23 Day 1 PRE-DOSE 23 4.939 0.9029 4.720 3.18 6.55 Day 14 PRE-DOSE 23 4.936 1.0230 4.830 2.97 6.86

Vest.+Parox. 24 Day 1 PRE-DOSE 24 4.927 0.9529 4.885 3.28 6.53 Day 14 PRE-DOSE 22 4.928 0.9440 4.880 3.10 6.61

Creatine Kinase Placebo 23 Day 1 PRE-DOSE 23 134.1 105.89 86.0 53 394 (IU/L) Day 14 PRE-DOSE 23 123.0 94.32 81.0 45 401

Vestipitant 23 Day 1 PRE-DOSE 23 153.6 151.29 80.0 55 575 HM2009/00361/00 Day 14 PRE-DOSE 23 117.2 88.02 73.0 46 305

Vest.+Parox. 24 Day 1 PRE-DOSE 24 130.0 94.89 91.0 49 378 NKP106254 Day 14 PRE-DOSE 22 111.7 76.02 81.0 50 339 Protocol: NKP106254 Page 4 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Creatinine Placebo 23 Day 1 PRE-DOSE 23 84.0 15.23 87.0 60 110 (UMOL/L) Day 14 PRE-DOSE 23 86.0 17.57 90.0 60 118

Vestipitant 23 Day 1 PRE-DOSE 23 84.8 14.65 86.0 63 109 Day 14 PRE-DOSE 23 86.0 14.48 89.0 57 105

Vest.+Parox. 24 Day 1 PRE-DOSE 24 87.5 14.43 89.5 64 109

Day 14 PRE-DOSE 22 86.1 15.85 84.0 64 116 CONFIDENTIAL

Gamma Glutamyl Placebo 23 Day 1 PRE-DOSE 23 35.1 27.67 28.0 12 127 44 Transferase (IU/L) Day 14 PRE-DOSE 23 34.9 29.14 26.0 11 141

Vestipitant 23 Day 1 PRE-DOSE 23 33.4 32.50 23.0 11 164 Day 14 PRE-DOSE 23 35.7 41.18 22.0 12 211

Vest.+Parox. 24 Day 1 PRE-DOSE 24 33.9 26.60 23.0 10 125 Day 14 PRE-DOSE 22 31.8 27.29 21.5 9 133

Globulin (G/L) Placebo 23 Day 1 PRE-DOSE 23 24.4 3.63 24.0 19 31 Day 14 PRE-DOSE 23 24.5 3.41 25.0 18 30

Vestipitant 23 Day 1 PRE-DOSE 23 24.7 3.26 25.0 19 30 HM2009/00361/00 Day 14 PRE-DOSE 23 24.3 3.13 25.0 18 30

Vest.+Parox. 24 Day 1 PRE-DOSE 24 23.8 3.66 24.5 17 30 NKP106254 Day 14 PRE-DOSE 22 24.3 3.56 25.0 18 30 Protocol: NKP106254 Page 5 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Glucose (MMOL/L) Placebo 23 Day 1 PRE-DOSE 23 5.97 2.145 5.50 4.0 13.5 Day 14 PRE-DOSE 23 5.91 1.767 5.50 4.1 13.3

Vestipitant 23 Day 1 PRE-DOSE 23 6.08 2.033 5.60 4.6 13.3 Day 14 PRE-DOSE 23 5.94 2.042 5.50 3.4 13.6

Vest.+Parox. 24 Day 1 PRE-DOSE 24 6.08 2.024 5.55 3.0 14.2 Day 14 PRE-DOSE 22 5.45 0.880 5.55 3.9 7.2 CONFIDENTIAL

Potassium (MMOL/L) Placebo 23 Day 1 PRE-DOSE 23 4.08 0.187 4.00 3.8 4.5 Day 14 PRE-DOSE 23 4.07 0.226 4.10 3.7 4.6 45 Vestipitant 23 Day 1 PRE-DOSE 23 4.09 0.264 4.00 3.8 4.6 Day 14 PRE-DOSE 23 4.04 0.248 4.00 3.5 4.6

Vest.+Parox. 24 Day 1 PRE-DOSE 24 4.09 0.319 4.05 3.7 4.8 Day 14 PRE-DOSE 22 4.06 0.234 4.05 3.8 4.7

Lactate Placebo 23 Day 1 PRE-DOSE 23 144.0 22.49 141.0 118 208 Dehydrogenase (IU/L) Day 14 PRE-DOSE 23 140.3 22.76 139.0 109 203

Vestipitant 23 Day 1 PRE-DOSE 23 138.9 24.25 130.0 106 210 HM2009/00361/00 Day 14 PRE-DOSE 23 136.9 23.30 131.0 112 199

Vest.+Parox. 24 Day 1 PRE-DOSE 24 141.4 28.83 132.0 111 223 NKP106254 Day 14 PRE-DOSE 22 137.2 27.19 129.0 101 222 Protocol: NKP106254 Page 6 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Sodium (MMOL/L) Placebo 23 Day 1 PRE-DOSE 23 140.0 1.99 140.0 137 144 Day 14 PRE-DOSE 23 139.7 1.61 140.0 134 142

Vestipitant 23 Day 1 PRE-DOSE 23 139.9 1.93 140.0 135 145 Day 14 PRE-DOSE 23 140.2 1.93 140.0 137 145

Vest.+Parox. 24 Day 1 PRE-DOSE 24 140.0 1.78 140.0 135 143 Day 14 PRE-DOSE 22 139.5 2.20 139.5 133 144 CONFIDENTIAL

Phosphorus, Placebo 23 Day 1 PRE-DOSE 23 0.981 0.1743 0.980 0.69 1.24 inorganic (MMOL/L) 46 Day 14 PRE-DOSE 23 1.038 0.1812 1.050 0.76 1.42

Vestipitant 23 Day 1 PRE-DOSE 23 0.994 0.1546 0.980 0.68 1.33 Day 14 PRE-DOSE 23 1.034 0.1799 1.010 0.74 1.37

Vest.+Parox. 24 Day 1 PRE-DOSE 24 1.027 0.1755 0.960 0.73 1.43 Day 14 PRE-DOSE 22 1.005 0.1830 1.025 0.58 1.31

Triglycerides Placebo 23 Day 1 PRE-DOSE 23 1.494 0.8422 1.200 0.59 3.70 (MMOL/L) Day 14 PRE-DOSE 23 1.430 0.6735 1.240 0.68 3.13

Vestipitant 23 Day 1 PRE-DOSE 23 1.336 0.7002 1.270 0.50 3.08 HM2009/00361/00 Day 14 PRE-DOSE 23 1.364 0.7380 1.110 0.60 4.00

Vest.+Parox. 24 Day 1 PRE-DOSE 24 1.403 0.7219 1.150 0.55 3.25 NKP106254 Day 14 PRE-DOSE 22 1.203 0.5204 1.145 0.51 2.29 Protocol: NKP106254 Page 7 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Total Protein Placebo 23 Day 1 PRE-DOSE 23 68.1 4.49 67.0 60 78 (G/L) Day 14 PRE-DOSE 23 67.6 4.22 67.0 61 77

Vestipitant 23 Day 1 PRE-DOSE 23 67.7 3.91 68.0 60 76 Day 14 PRE-DOSE 23 67.6 3.70 68.0 61 76

Vest.+Parox. 24 Day 1 PRE-DOSE 24 67.0 4.62 67.0 58 77

Day 14 PRE-DOSE 22 67.7 3.76 68.0 61 75 CONFIDENTIAL

Troponin I (UG/L) Placebo 23 Day 1 PRE-DOSE 23 0.10 0.000 0.10 0.1 0.1 47 Day 14 PRE-DOSE 23 0.10 0.000 0.10 0.1 0.1

Vestipitant 23 Day 1 PRE-DOSE 23 0.10 0.000 0.10 0.1 0.1 Day 14 PRE-DOSE 23 0.10 0.000 0.10 0.1 0.1

Vest.+Parox. 24 Day 1 PRE-DOSE 24 0.10 0.000 0.10 0.1 0.1 Day 14 PRE-DOSE 23 0.10 0.000 0.10 0.1 0.1

Urea/BUN (MMOL/L) Placebo 23 Day 1 PRE-DOSE 23 5.51 1.006 5.50 4.0 7.9 Day 14 PRE-DOSE 23 5.43 0.983 5.30 3.8 7.3

Vestipitant 23 Day 1 PRE-DOSE 23 5.73 1.475 5.40 2.8 10.0 Day 14 PRE-DOSE 23 5.84 1.049 5.70 4.5 8.3 HM2009/00361/00

Vest.+Parox. 24 Day 1 PRE-DOSE 24 5.62 1.382 5.35 3.7 9.1 Day 14 PRE-DOSE 22 5.57 1.288 5.45 3.2 8.1 NKP106254 Protocol: NKP106254 Page 8 of 8 Population: All subjects Table 10.5 Summary of Chemistry Laboratory Values

Planned Relative Lab Test Treatment N Day Time n Mean SD Median Min. Max. ------Uric acid (UMOL/L) Placebo 23 Day 1 PRE-DOSE 23 342.8 63.49 347.0 242 469 Day 14 PRE-DOSE 23 351.3 65.62 362.0 225 453

Vestipitant 23 Day 1 PRE-DOSE 23 350.4 58.15 348.0 228 443 Day 14 PRE-DOSE 23 359.4 67.20 359.0 240 504

Vest.+Parox. 24 Day 1 PRE-DOSE 24 345.5 59.96 348.0 232 494 Day 14 PRE-DOSE 22 330.5 62.86 317.0 207 470 CONFIDENTIAL 48 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 2 Population: All subjects Table 10.6 Summary of Urinalysis Dipstick Results

SCREENING FOLLOW-UP Test (N=24) (N=24) ------Urine Bilirubin (dipstick) 0.2 0 0 1+ 0 0 3+ 0 0 NEGATIVE 24 (100%) 24 (100%) TRACE 0 0

Urine Occult Blood (dipstick) 0.2 0 0 1+ 0 1 (4%) 3+ 0 0

NEGATIVE 24 (100%) 23 (96%) CONFIDENTIAL TRACE 0 0

Urine Glucose (dipstick) 0.2 0 0 49 1+ 0 0 3+ 1 (4%) 0 NEGATIVE 23 (96%) 23 (96%) TRACE 0 1 (4%)

Urine Ketones (dipstick) 0.2 0 0 1+ 0 0 3+ 0 0 NEGATIVE 24 (100%) 23 (96%) TRACE 0 1 (4%)

Urine Nitrite (dipstick) 0.2 0 0 1+ 0 0 3+ 0 0 HM2009/00361/00 NEGATIVE 24 (100%) 24 (100%) TRACE 0 0 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 2 Population: All subjects Table 10.6 Summary of Urinalysis Dipstick Results

SCREENING FOLLOW-UP Test (N=24) (N=24) ------Urine Protein (dipstick) 0.2 0 0 1+ 0 0 3+ 0 0 NEGATIVE 23 (96%) 24 (100%) TRACE 1 (4%) 0

Urine Urobilinogen (dipstick) 0.2 24 (100%) 24 (100%) 1+ 0 0 3+ 0 0

NEGATIVE 0 0 CONFIDENTIAL TRACE 0 0

Urine Leukocyte Esterase test for detecting WBC (dipstick) 0.2 0 0 50 1+ 1 (4%) 1 (4%) 3+ 0 0 NEGATIVE 22 (92%) 22 (92%) TRACE 1 (4%) 1 (4%) HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: All subjects Table 10.7 Summary of ECG Findings

Placebo Vestipitant Vest.+Parox. (N=23) (N=23) (N=24) ------Day 1 PRE-DOSE n 20 20 21 Normal 18 (90%) 19 (95%) 20 (95%) Abnormal - Not clinically significant 2 (10%) 1 (5%) 1 (5%) Abnormal - Clinically significant 0 0 0

3 HRS n 23 23 24 Normal 22 (96%) 22 (96%) 23 (96%)

Abnormal - Not clinically significant 1 (4%) 1 (4%) 1 (4%) CONFIDENTIAL Abnormal - Clinically significant 0 0 0

51 Day 14 PRE-DOSE n 20 18 20 Normal 17 (85%) 16 (89%) 18 (90%) Abnormal - Not clinically significant 3 (15%) 2 (11%) 2 (10%) Abnormal - Clinically significant 0 0 0

3 HRS n 23 22 23 Normal 21 (91%) 20 (91%) 21 (91%) Abnormal - Not clinically significant 2 (9%) 2 (9%) 2 (9%) Abnormal - Clinically significant 0 0 0 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 3 Population: All subjects Table 10.8 Summary of ECG Values

Planned Relative Treatment N Day Time n Mean SD Median Min. Max. ------Heart rate (BPM) Placebo 23 Day 1 PRE-DOSE 20 69.6 10.87 70.0 52 95 3 HRS 23 62.4 8.71 64.0 44 76 Day 14 PRE-DOSE 20 66.4 11.68 66.5 43 86 3 HRS 23 62.3 10.46 60.0 47 91

Vestipitant 23 Day 1 PRE-DOSE 20 65.4 10.15 64.5 44 84 3 HRS 23 59.7 7.08 61.0 47 76 Day 14 PRE-DOSE 18 64.3 9.27 62.0 50 84

3 HRS 22 61.7 9.35 62.5 48 81 CONFIDENTIAL

Vest.+Parox. 24 Day 1 PRE-DOSE 21 68.4 13.50 66.0 40 95 3 HRS 24 60.1 11.11 59.0 40 93 52 Day 14 PRE-DOSE 20 64.6 9.43 62.5 48 82 3 HRS 23 57.7 8.07 58.0 39 76

PR Interval (MSEC) Placebo 23 Day 1 PRE-DOSE 20 166.0 28.71 160.0 116 252 3 HRS 23 169.8 27.77 168.0 120 252 Day 14 PRE-DOSE 20 168.0 25.15 164.0 127 236 3 HRS 23 172.6 24.79 168.0 132 232

Vestipitant 23 Day 1 PRE-DOSE 20 168.0 27.41 166.0 116 248 3 HRS 23 171.1 28.26 168.0 124 244 Day 14 PRE-DOSE 18 169.6 26.22 168.0 124 236 3 HRS 22 172.8 26.47 170.0 132 240 HM2009/00361/00 HM2009/00361/00 Vest.+Parox. 24 Day 1 PRE-DOSE 21 165.8 23.30 168.0 120 225 3 HRS 24 169.0 25.36 164.0 136 244 Day 14 PRE-DOSE 20 165.2 25.68 164.0 124 244 NKP106254 3 HRS 23 172.5 28.19 164.0 128 256 Protocol: NKP106254 Page 2 of 3 Population: All subjects Table 10.8 Summary of ECG Values

Planned Relative Treatment N Day Time n Mean SD Median Min. Max. ------QRS Duration (MSEC) Placebo 23 Day 1 PRE-DOSE 20 89.3 10.90 89.0 72 118 3 HRS 23 92.1 10.45 90.0 72 120 Day 14 PRE-DOSE 20 90.4 10.81 89.0 70 108 3 HRS 23 91.5 10.84 92.0 74 118

Vestipitant 23 Day 1 PRE-DOSE 20 88.7 10.98 87.0 68 116 3 HRS 23 93.1 10.65 94.0 74 122 Day 14 PRE-DOSE 18 90.7 11.72 90.0 70 118

3 HRS 22 92.0 10.81 92.0 70 120 CONFIDENTIAL

Vest.+Parox. 24 Day 1 PRE-DOSE 21 90.9 10.05 92.0 70 110 3 HRS 24 92.9 10.38 94.0 70 118 53 Day 14 PRE-DOSE 20 90.3 11.24 88.0 72 118 3 HRS 23 91.7 10.94 92.0 72 122

QT Interval (MSEC) Placebo 23 Day 1 PRE-DOSE 20 396.0 29.71 400.0 344 452 3 HRS 23 410.1 29.86 408.0 356 468 Day 14 PRE-DOSE 20 400.6 31.05 396.0 348 484 3 HRS 23 410.7 30.16 404.0 360 468

Vestipitant 23 Day 1 PRE-DOSE 20 401.8 30.86 400.0 352 480 3 HRS 23 416.3 29.36 420.0 372 488 Day 14 PRE-DOSE 18 404.2 25.20 410.0 348 436 3 HRS 22 408.5 31.12 408.0 360 460 HM2009/00361/00 HM2009/00361/00 Vest.+Parox. 24 Day 1 PRE-DOSE 21 396.6 34.60 400.0 344 480 3 HRS 24 415.3 32.55 414.0 352 472 Day 14 PRE-DOSE 20 403.6 32.47 402.0 352 476 NKP106254 3 HRS 23 420.7 30.41 420.0 372 484 Protocol: NKP106254 Page 3 of 3 Population: All subjects Table 10.8 Summary of ECG Values

Planned Relative Treatment N Day Time n Mean SD Median Min. Max. ------QTcB (MSEC) Placebo 23 Day 1 PRE-DOSE 20 421.1 22.91 424.0 379 462 3 HRS 23 415.7 18.79 414.0 376 455 Day 14 PRE-DOSE 20 416.9 22.60 414.5 368 453 3 HRS 23 415.0 23.09 413.0 366 458

Vestipitant 23 Day 1 PRE-DOSE 20 416.3 25.55 415.5 364 477 3 HRS 23 412.8 20.45 409.0 378 451 Day 14 PRE-DOSE 18 415.7 23.02 417.5 375 463

3 HRS 22 411.1 19.45 408.5 370 450 CONFIDENTIAL

Vest.+Parox. 24 Day 1 PRE-DOSE 21 418.0 22.83 421.0 364 450 3 HRS 24 411.3 24.09 408.5 358 461 54 Day 14 PRE-DOSE 20 415.2 23.11 412.0 378 462 3 HRS 23 409.7 21.30 409.0 370 441

QTcF (MSEC) Placebo 23 Day 1 PRE-DOSE 20.0 412.23 19.241 415.82 377.9 450.4 3 HRS 23.0 413.62 18.275 416.62 374.4 452.7 Day 14 PRE-DOSE 20.0 411.03 18.667 414.66 375.8 445.9 3 HRS 23.0 413.26 19.907 417.81 369.3 443.0

Vestipitant 23 Day 1 PRE-DOSE 20.0 411.14 22.631 408.89 364.0 458.6 3 HRS 23.0 413.81 20.675 410.72 381.9 456.1 Day 14 PRE-DOSE 18.0 411.64 19.511 414.12 365.8 448.2 3 HRS 22.0 409.99 18.816 410.88 368.0 438.6 HM2009/00361/00 HM2009/00361/00 Vest.+Parox. 24 Day 1 PRE-DOSE 21.0 410.26 19.378 412.40 358.6 441.2 3 HRS 24.0 412.27 20.611 413.87 361.3 451.2 Day 14 PRE-DOSE 20.0 411.06 22.300 408.71 376.0 455.3 NKP106254 3 HRS 23.0 413.07 20.031 416.35 374.6 447.9 Protocol: NKP106254 Page 1 of 2 Population: All subjects Table 10.9 Summary of Vital Signs

Planned Relative Treatment N Day Time n Mean SD Median Min. Max. ------Systolic BP (mmHg) Placebo 23 Day 1 PRE-DOSE 23 129.1 20.07 128.0 102 165 3 HRS 23 130.2 17.97 132.0 101 162 Day 14 PRE-DOSE 23 127.8 17.05 123.0 102 164 3 HRS 23 124.7 18.19 128.0 95 164

Vestipitant 23 Day 1 PRE-DOSE 23 127.5 19.05 132.0 99 162 3 HRS 23 124.3 16.79 126.0 100 154 Day 14 PRE-DOSE 21 129.0 17.50 132.0 100 161

3 HRS 22 124.8 15.85 124.0 99 164 CONFIDENTIAL

Vest.+Parox. 24 Day 1 PRE-DOSE 24 128.8 17.76 132.5 96 162 3 HRS 24 127.1 22.87 130.5 71 169 55 Day 14 PRE-DOSE 23 130.4 18.74 134.0 95 171 3 HRS 23 126.0 19.42 128.0 90 178

Diastolic BP (mmHg) Placebo 23 Day 1 PRE-DOSE 23 76.5 10.10 79.0 58 90 3 HRS 23 77.0 11.84 81.0 54 93 Day 14 PRE-DOSE 23 76.8 9.03 77.0 58 89 3 HRS 23 74.1 9.25 77.0 56 91

Vestipitant 23 Day 1 PRE-DOSE 23 78.4 11.50 78.0 61 100 3 HRS 23 73.7 10.49 75.0 52 88 Day 14 PRE-DOSE 21 76.3 8.80 79.0 57 89 3 HRS 22 74.4 8.06 77.0 60 88 HM2009/00361/00 HM2009/00361/00 Vest.+Parox. 24 Day 1 PRE-DOSE 24 77.3 9.60 78.0 55 92 3 HRS 24 74.5 11.48 76.0 41 90 Day 14 PRE-DOSE 23 76.0 10.03 79.0 56 93 NKP106254 3 HRS 23 74.1 10.33 76.0 54 88 Protocol: NKP106254 Page 2 of 2 Population: All subjects Table 10.9 Summary of Vital Signs

Planned Relative Treatment N Day Time n Mean SD Median Min. Max. ------Heart Rate (bpm) Placebo 23 Day 1 PRE-DOSE 23 69.4 12.06 70.0 44 94 3 HRS 23 61.9 8.42 62.0 45 76 Day 14 PRE-DOSE 23 67.7 12.86 68.0 42 87 3 HRS 23 62.1 10.50 62.0 42 88

Vestipitant 23 Day 1 PRE-DOSE 23 66.9 10.55 65.0 44 88 3 HRS 23 59.4 7.95 61.0 41 74 Day 14 PRE-DOSE 21 65.6 9.53 65.0 48 80

3 HRS 22 60.7 8.79 63.0 45 80 CONFIDENTIAL

Vest.+Parox. 24 Day 1 PRE-DOSE 24 68.1 12.22 68.0 39 91 3 HRS 24 60.0 11.40 59.0 35 96 56 Day 14 PRE-DOSE 23 63.7 9.41 63.0 43 82 3 HRS 23 56.5 6.95 57.0 40 73 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 CONFIDENTIAL HM2009/00361/00 NKP106254

Pharmacokinetic Data Source Figures and Tables

Page Figure 11.1 Mean (+ SD) Plasma Vestipitant Concentration-Time Plots (Linear and Semi-log) (PK Population) ...... 58 Figure 11.2 Mean (+ SD) Plasma Paroxetine Concentration-Time Plots (Linear and Semi-log) (PK Population) ...... 59 Table 11.1 Summary of Plasma Vestipitant Pharmacokinetic Concentration-Time Data (ng/mL) (PK Population) ...... 60 Table 11.2 Summary of Plasma Paroxetine Pharmacokinetic Concentration-Time Data (ng/mL) (PK Population) ...... 61

57 CONFIDENTIAL HM2009/00361/00 NKP106254

58 CONFIDENTIAL HM2009/00361/00 NKP106254

59 Protocol: NKP106254 Page 1 of 1 Population: PK Table 11.1 Summary of Plasma Vestipitant Pharmacokinetic Concentration-Time Data (ng/mL)

Planned Relative No. Treatment N Day Time n Imputed Mean SD Median Min. Max. ------Vestipitant 23 Day 1 PRE-DOSE 23 23 0.0 0.0 0 0 3 HRS 23 0 60.6 18.39 63.2 32 112

Day 14 PRE-DOSE 21 1 11.4 7.46 9.8 0 25 3 HRS 22 0 61.8 31.62 60.0 24 144

Vest.+Parox. 24 Day 1 PRE-DOSE 24 24 0.0 0.0 0 0 3 HRS 24 0 62.3 21.92 63.3 13 123 CONFIDENTIAL Day 14 PRE-DOSE 23 0 13.0 11.69 7.9 2 55 3 HRS 23 0 57.6 23.01 51.6 24 108 60 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

SD is blank where more than 30% of the values have been imputed Note: LLQ = 0.1 ng/mL Protocol: NKP106254 Page 1 of 1 Population: PK Table 11.2 Summary of Plasma Paroxetine Pharmacokinetic Concentration-Time Data (ng/mL)

Planned Relative No. Treatment N Day Time n Imputed Mean SD Median Min. Max. ------Vest.+Parox. 24 Day 1 PRE-DOSE 24 23 0.0 0.0 0 0 3 HRS 24 0 6.1 6.32 2.9 0 21

Day 14 PRE-DOSE 23 0 32.0 21.70 27.2 4 99 3 HRS 23 0 41.3 27.42 33.7 12 135 CONFIDENTIAL 61 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

SD is blank where more than 30% of the values have been imputed Note: LLQ = 0.1 ng/mL CONFIDENTIAL HM2009/00361/00 NKP106254

Pharmacodynamic Data Source Figures and Tables

Page Figure 12.1 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Intensity (Pharmacodynamic Population) ...... 65 Figure 12.2 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Tone (Pharmacodynamic Population)...... 66 Figure 12.3 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Distress (Pharmacodynamic Population) ...... 67 Figure 12.4 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Tired vs Energetic) (Pharmacodynamic Population) ...... 68 Figure 12.5 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Active vs Drowsy) (Pharmacodynamic Population) ...... 69 Figure 12.6 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Tense vs Peaceful) (Pharmacodynamic Population) ...... 70 Figure 12.7 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Worried vs Relaxed) (Pharmacodynamic Population) ...... 71 Figure 12.8 Plot of THI Total score mean values (+-SD) by treatment and time (Pharmacodynamic Population) ...... 72 Figure 12.9 Plot of QIDS-SR Total score mean values (+-SD) by treatment and time (Pharmacodynamic Population) ...... 73 Figure 12.10 Plot of Tinnitus Aggravation mean scores (+-SD) by treatment and time (Pharmacodynamic Population) ...... 74 Figure 12.11 Plot of Annoyance of Hyperacusis mean values (+-SD) by treatment and time (Pharmacodynamic Population) ...... 75 Figure 12.12 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Intensity - Treatment period (Diary) (Pharmacodynamic Population) ...... 76 Figure 12.13 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Tone - Treatment period (Diary) (Pharmacodynamic Population) . . 77 Figure 12.14 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Distress - Treatment period (Diary) (Pharmacodynamic Population) ...... 78

62 CONFIDENTIAL HM2009/00361/00 NKP106254

Figure 12.15 Plot of number of Hyperacusis episodes mean values (+-SD) by treatment and day -Treatment period (Diary) (Pharmacodynamic Population) ...... 79 Figure 12.16 Plot of Annoyance of Hyperacusis (distress) mean values (+-SD) by treatment and day -Treatment period (Diary) (Pharmacodynamic Population) ...... 80 Table 12.1 Summary Statistics of VAS Tinnitus scores by treatment and time (Pharmacodynamic Population) ...... 81 Table 12.2 Summary of Statistical Analysis of VAS Tinnitus scores (Pharmacodynamic Population) ...... 84 Table 12.3 Summary Statistics of VAS Arousal-Anxiety scores by treatment and time (Pharmacodynamic Population) ...... 87 Table 12.4 Summary of Statistical Analysis of VAS Arousal-Anxiety scores (Pharmacodynamic Population) ...... 91 Table 12.5 Summary Statistics of THI total scores by treatment and time (Pharmacodynamic Population) ...... 95 Table 12.6 Summary of Statistical Analysis of THI Total scores (Pharmacodynamic Population) ...... 96 Table 12.7 Summary Statistics of QIDS-SR total scores by treatment and time (Pharmacodynamic Population) ...... 97 Table 12.8 Summary of Statistical Analysis of QIDS-SR total scores (Pharmacodynamic Population) ...... 98 Table 12.9 Summary Statistics of Tinnitus Aggravation Scores by treatment and time (Pharmacodynamic Population) ...... 99 Table 12.10 Summary of Statistical Analysis of Tinnitus Aggravation Scores (Pharmacodynamic Population) ...... 100 Table 12.11 Summary Statistics of Annoyance of Hyperacusis by treatment and time (Pharmacodynamic Population) ...... 101 Table 12.12 Summary of Statistical Analysis of Annoyance of Hyperacusis (Pharmacodynamic Population) ...... 102 Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY) (Pharmacodynamic Population)...... 103 Table 12.14 Summary of Statistical Analysis of VAS Tinnitus scores mean value over the treatment period (Pharmacodynamic Population) ...... 124

63 CONFIDENTIAL HM2009/00361/00 NKP106254

Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY) (Pharmacodynamic Population) . 127 Table 12.16 Summary of Statistical Analysis of number of Hyperacusis episodes and distress mean value over the treatment period (Pharmacodynamic Population) ...... 141

64 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.1 90 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Intensity

60 CONFIDENTIAL

VAS score 50 65

20 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.2 100 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Tone

70 CONFIDENTIAL

VAS score 60 66

30 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.3 70 Plot of VAS Tinnitus mean values (+-SD) by treatment and time - Distress

50 CONFIDENTIAL 40 VAS score 67

10 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.4 90 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Tired vs Energetic)

60 CONFIDENTIAL

VAS score 50 68

20 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.5 90 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Active vs Drowsy)

60 CONFIDENTIAL 50 VAS score 69 40

10 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.6 100 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Tense vs Peaceful)

80 CONFIDENTIAL 70 VAS score 70

40 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.7 100 Plot of VAS arousal-anxiety mean values (+-SD) by treatment and time (Worried vs Relaxed)

80 CONFIDENTIAL 70 VAS score 71

40 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.8 60 Plot of THI Total score mean values (+-SD) by treatment and time

40 CONFIDENTIAL 30 THI score 72

0 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.9 10 Plot of QIDS-SR Total score mean values (+-SD) by treatment and time

6 CONFIDENTIAL

73 4 QIDS-SR score

0 HM2009/00361/00 HM2009/00361/00 Day 1 Day 14 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.10 7 Plot of Tinnitus Aggravation mean scores (+-SD) by treatment and time

4 CONFIDENTIAL

3 74 Tinnitus score

0 HM2009/00361/00 HM2009/00361/00 Day 1 Pre Day 1 2H PD Day 14 Pre Day 14 2H PD Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.11 5 Plot of Annoyance of Hyperacusis mean values (+-SD) by treatment and time

2 CONFIDENTIAL

1 75 Distress score

-1

-2 HM2009/00361/00 HM2009/00361/00 Day 1 Day 14 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.12 90 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Intensity - Treatment period (Diary)

60 CONFIDENTIAL

VAS score 50 76

20 HM2009/00361/00 HM2009/00361/00 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.13 100 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Tone - Treatment period (Diary)

70 CONFIDENTIAL

VAS score 60 77

30 HM2009/00361/00 HM2009/00361/00 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.14 80 Plot of VAS Tinnitus mean values (+-SD) by treatment and day Distress - Treatment period (Diary)

50 CONFIDENTIAL 40 VAS score 78 30

0 HM2009/00361/00 HM2009/00361/00 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.15 6 Plot of number of Hyperacusis episodes mean values (+-SD) by treatment and day -Treatment period (Diary)

2 CONFIDENTIAL

1 79 No of episodes

-1

-2

-3 HM2009/00361/00 HM2009/00361/00 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Figure 12.16 4 Plot of Annoyance of Hyperacusis (distress) mean values (+-SD) by treatment and day -Treatment period (Diary)

2 CONFIDENTIAL 1 80 Distress score

-1

-2 HM2009/00361/00 HM2009/00361/00 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 Day 10 Day 11 Day 12 Day 13 Planned Relative Time Placebo Vestipitant Vestipitant+Parox. NKP106254 Protocol: NKP106254 Page 1 of 3 Population: Pharmacodynamic Table 12.1 Summary Statistics of VAS Tinnitus scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Intensity 1 PRE-DOSE n 23 23 24 Mean 52.0 55.5 55.6 SD 23.98 20.69 24.15 Median 55.0 54.0 58.5 Min. 8 13 15 Max. 97 90 95

2 HRS n 23 23 24 Mean 50.0 53.3 54.7

SD 26.88 21.03 23.10 CONFIDENTIAL Median 53.0 50.0 51.0 Min. 9 14 15 Max. 96 88 94 81 14 PRE-DOSE n 23 21 23 Mean 50.3 51.4 52.9 SD 26.14 23.38 23.40 Median 51.0 54.0 50.0 Min. 3 18 2 Max. 97 89 88

2 HRS n 23 22 23 Mean 50.6 54.0 55.0 SD 25.25 22.95 23.40 Median 51.0 52.0 58.0 Min. 4 9 6 Max. 98 90 89 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 2 of 3 Population: Pharmacodynamic Table 12.1 Summary Statistics of VAS Tinnitus scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Tone 1 PRE-DOSE n 23 23 24 Mean 64.1 65.6 66.8 SD 23.41 21.62 23.59 Median 73.0 71.0 73.0 Min. 20 22 20 Max. 97 94 96

2 HRS n 23 23 24 Mean 67.6 65.0 65.9

SD 22.82 23.11 22.81 CONFIDENTIAL Median 75.0 71.0 73.0 Min. 19 17 20 Max. 96 92 94 82 14 PRE-DOSE n 23 21 23 Mean 65.7 65.6 65.2 SD 22.37 24.19 23.20 Median 69.0 74.0 72.0 Min. 13 15 11 Max. 97 96 94

2 HRS n 23 22 23 Mean 65.7 64.8 66.5 SD 23.92 26.42 23.44 Median 73.0 73.0 74.0 Min. 17 9 7 Max. 98 95 95 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 3 of 3 Population: Pharmacodynamic Table 12.1 Summary Statistics of VAS Tinnitus scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Distress 1 PRE-DOSE n 23 23 24 Mean 39.4 41.8 37.6 SD 22.57 20.61 20.65 Median 40.0 38.0 37.5 Min. 5 6 9 Max. 84 80 88

2 HRS n 23 23 24 Mean 36.7 40.0 38.0

SD 21.90 19.44 19.14 CONFIDENTIAL Median 40.0 37.0 36.0 Min. 7 11 11 Max. 82 73 84 83 14 PRE-DOSE n 23 21 23 Mean 37.6 38.8 39.9 SD 22.73 21.82 23.39 Median 38.0 31.0 33.0 Min. 3 12 2 Max. 84 85 79

2 HRS n 23 22 23 Mean 37.3 39.3 37.7 SD 24.39 22.33 22.16 Median 30.0 38.5 35.0 Min. 3 9 6 Max. 83 80 81 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 1 of 3 Population: Pharmacodynamic Table 12.2 Summary of Statistical Analysis of VAS Tinnitus scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Intensity Day 1 2H PD Vest.+Parox.-Pla 54.8 51.1 3.7 ( -4.8, 12.3) 0.388

Vestipitant -Pla 54.3 51.1 3.2 ( -5.3, 11.8) 0.451

Vest.+Parox.-Vest. 54.8 54.3 0.5 ( -8.1, 9.0) 0.914

Day 14 pre-dose Vest.+Parox.-Pla 54.2 51.4 2.7 ( -4.5, 10.0) 0.451

Vestipitant -Pla 53.5 51.4 2.1 ( -5.3, 9.4) 0.569 CONFIDENTIAL

Vest.+Parox.-Vest. 54.2 53.5 0.6 ( -6.7, 8.0) 0.860

84 Day 14 2h PD Vest.+Parox.-Pla 56.3 51.7 4.7 ( -3.0, 12.3) 0.229

Vestipitant -Pla 56.0 51.7 4.3 ( -3.4, 12.0) 0.268

Vest.+Parox.-Vest. 56.3 56.0 0.4 ( -7.4, 8.1) 0.927 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 3 Population: Pharmacodynamic Table 12.2 Summary of Statistical Analysis of VAS Tinnitus scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Tone Day 1 2H PD Vest.+Parox.-Pla 65.6 68.9 -3.3 ( -9.6, 3.0) 0.297

Vestipitant -Pla 66.3 68.9 -2.6 ( -8.9, 3.8) 0.421

Vest.+Parox.-Vest. 65.6 66.3 -0.8 ( -7.1, 5.6) 0.811

Day 14 pre-dose Vest.+Parox.-Pla 65.9 67.0 -1.1 ( -6.4, 4.2) 0.676

Vestipitant -Pla 67.7 67.0 0.6 ( -4.7, 6.0) 0.811 CONFIDENTIAL

Vest.+Parox.-Vest. 65.9 67.7 -1.8 ( -7.1, 3.6) 0.515

85 Day 14 2h PD Vest.+Parox.-Pla 67.1 67.0 0.1 ( -5.2, 5.5) 0.966

Vestipitant -Pla 66.4 67.0 -0.6 ( -6.0, 4.8) 0.823

Vest.+Parox.-Vest. 67.1 66.4 0.7 ( -4.7, 6.1) 0.790 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 3 of 3 Population: Pharmacodynamic Table 12.2 Summary of Statistical Analysis of VAS Tinnitus scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Distress Day 1 2H PD Vest.+Parox.-Pla 38.1 36.8 1.2 ( -5.8, 8.3) 0.731

Vestipitant -Pla 40.3 36.8 3.5 ( -3.6, 10.5) 0.330

Vest.+Parox.-Vest. 38.1 40.3 -2.3 ( -9.3, 4.8) 0.524

Day 14 pre-dose Vest.+Parox.-Pla 40.3 37.7 2.5 ( -5.6, 10.7) 0.532

Vestipitant -Pla 40.7 37.7 3.0 ( -5.2, 11.2) 0.470 CONFIDENTIAL

Vest.+Parox.-Vest. 40.3 40.7 -0.4 ( -8.6, 7.8) 0.917

86 Day 14 2h PD Vest.+Parox.-Pla 38.1 37.5 0.7 ( -7.8, 9.1) 0.873

Vestipitant -Pla 40.7 37.5 3.2 ( -5.3, 11.7) 0.451

Vest.+Parox.-Vest. 38.1 40.7 -2.5 (-11.0, 5.9) 0.551 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 4 Population: Pharmacodynamic Table 12.3 Summary Statistics of VAS Arousal-Anxiety scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Worried-Relaxed 1 PRE-DOSE n 23 23 24 Mean 70.2 73.4 70.4 SD 11.85 14.74 18.46 Median 70.0 77.0 71.5 Min. 50 39 33 Max. 91 100 97

2 HRS n 23 23 24 Mean 73.3 73.1 73.6

SD 13.99 20.17 18.94 CONFIDENTIAL Median 76.0 78.0 78.0 Min. 47 10 19 Max. 94 98 99 87 14 PRE-DOSE n 23 21 23 Mean 75.1 73.7 76.3 SD 13.07 19.00 13.36 Median 78.0 74.0 78.0 Min. 50 17 37 Max. 94 95 99

2 HRS n 23 22 23 Mean 78.4 78.2 75.7 SD 12.77 12.13 20.95 Median 80.0 76.5 80.0 Min. 48 58 10 Max. 98 97 99 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 2 of 4 Population: Pharmacodynamic Table 12.3 Summary Statistics of VAS Arousal-Anxiety scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Active-Drowsy 1 PRE-DOSE n 23 23 24 Mean 33.2 41.9 29.8 SD 18.65 16.98 15.30 Median 27.0 38.0 28.0 Min. 6 13 2 Max. 78 84 59

2 HRS n 23 23 24 Mean 41.3 49.5 49.2

SD 17.52 23.70 25.06 CONFIDENTIAL Median 49.0 47.0 47.5 Min. 7 14 2 Max. 70 94 89 88 14 PRE-DOSE n 23 21 23 Mean 39.1 46.4 41.6 SD 18.65 21.12 23.69 Median 41.0 53.0 46.0 Min. 4 16 2 Max. 70 88 87

2 HRS n 23 22 23 Mean 43.8 47.4 51.5 SD 23.91 25.06 24.98 Median 46.0 49.0 56.0 Min. 4 7 2 Max. 86 94 90 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 3 of 4 Population: Pharmacodynamic Table 12.3 Summary Statistics of VAS Arousal-Anxiety scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Tired-Energetic 1 PRE-DOSE n 23 23 24 Mean 58.7 55.7 63.1 SD 20.62 15.90 20.42 Median 64.0 58.0 64.5 Min. 21 28 12 Max. 85 78 97

2 HRS n 23 23 24 Mean 54.6 48.3 51.9

SD 20.42 23.00 23.50 CONFIDENTIAL Median 53.0 50.0 50.5 Min. 23 5 9 Max. 95 83 96 89 14 PRE-DOSE n 23 21 23 Mean 57.6 51.6 57.8 SD 19.79 19.69 22.01 Median 53.0 55.0 58.0 Min. 29 18 19 Max. 93 81 97

2 HRS n 23 22 23 Mean 57.1 51.4 51.8 SD 23.79 20.86 22.65 Median 57.0 50.5 53.0 Min. 12 15 6 Max. 93 87 97 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 4 of 4 Population: Pharmacodynamic Table 12.3 Summary Statistics of VAS Arousal-Anxiety scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Tense-Peacerful 1 PRE-DOSE n 23 23 24 Mean 68.5 72.2 70.2 SD 12.46 18.42 18.29 Median 70.0 77.0 71.0 Min. 43 31 27 Max. 91 100 98

2 HRS n 23 23 24 Mean 73.3 71.0 73.8

SD 14.22 20.94 12.98 CONFIDENTIAL Median 77.0 75.0 75.0 Min. 43 8 44 Max. 94 97 98 90 14 PRE-DOSE n 23 21 23 Mean 70.0 69.6 74.4 SD 16.22 18.92 11.64 Median 73.0 71.0 72.0 Min. 28 17 54 Max. 95 95 98

2 HRS n 23 22 23 Mean 76.5 77.5 74.9 SD 12.33 12.44 18.62 Median 75.0 79.0 78.0 Min. 48 55 11 Max. 97 95 98 HM2009/00361/00 NKP106254 NKP106254

Additional time points (1h and 3h post dose) collected only in the first 3 subjects are not included Protocol: NKP106254 Page 1 of 4 Population: Pharmacodynamic Table 12.4 Summary of Statistical Analysis of VAS Arousal-Anxiety scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Worried-Relaxed Day 1 2H PD Vest.+Parox.-Pla 73.3 73.3 -0.0 ( -9.1, 9.1) 0.997

Vestipitant -Pla 73.1 73.3 -0.2 ( -9.4, 9.0) 0.959

Vest.+Parox.-Vest. 73.3 73.1 0.2 ( -8.9, 9.3) 0.962

Day 14 pre-dose Vest.+Parox.-Pla 75.5 75.2 0.3 ( -7.3, 8.0) 0.932

Vestipitant -Pla 73.7 75.2 -1.5 ( -9.3, 6.3) 0.702 CONFIDENTIAL

Vest.+Parox.-Vest. 75.5 73.7 1.8 ( -6.0, 9.7) 0.642

91 Day 14 2h PD Vest.+Parox.-Pla 74.7 78.4 -3.7 (-11.4, 4.1) 0.346

Vestipitant -Pla 78.8 78.4 0.4 ( -7.5, 8.2) 0.920

Vest.+Parox.-Vest. 74.7 78.8 -4.1 (-11.9, 3.8) 0.302 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 4 Population: Pharmacodynamic Table 12.4 Summary of Statistical Analysis of VAS Arousal-Anxiety scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Active-Drowsy Day 1 2H PD Vest.+Parox.-Pla 49.6 41.8 7.7 ( -1.4, 16.9) 0.095

Vestipitant -Pla 49.7 41.8 7.9 ( -1.3, 17.1) 0.092

Vest.+Parox.-Vest. 49.6 49.7 -0.1 ( -9.3, 9.0) 0.978

Day 14 pre-dose Vest.+Parox.-Pla 42.8 39.6 3.2 ( -7.8, 14.2) 0.562

Vestipitant -Pla 47.5 39.6 7.9 ( -3.3, 19.1) 0.164 CONFIDENTIAL

Vest.+Parox.-Vest. 42.8 47.5 -4.7 (-15.9, 6.5) 0.405

92 Day 14 2h PD Vest.+Parox.-Pla 52.9 44.3 8.6 ( -1.0, 18.3) 0.079

Vestipitant -Pla 46.6 44.3 2.3 ( -7.4, 12.1) 0.632

Vest.+Parox.-Vest. 52.9 46.6 6.3 ( -3.4, 16.0) 0.197 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 3 of 4 Population: Pharmacodynamic Table 12.4 Summary of Statistical Analysis of VAS Arousal-Anxiety scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Tired-Energetic Day 1 2H PD Vest.+Parox.-Pla 51.5 54.7 -3.2 (-12.5, 6.1) 0.490

Vestipitant -Pla 48.7 54.7 -6.0 (-15.3, 3.4) 0.207

Vest.+Parox.-Vest. 51.5 48.7 2.7 ( -6.6, 12.0) 0.557

Day 14 pre-dose Vest.+Parox.-Pla 57.1 57.7 -0.6 ( -9.4, 8.2) 0.893

Vestipitant -Pla 51.4 57.7 -6.2 (-15.2, 2.7) 0.169 CONFIDENTIAL

Vest.+Parox.-Vest. 57.1 51.4 5.6 ( -3.3, 14.6) 0.212

93 Day 14 2h PD Vest.+Parox.-Pla 51.1 57.2 -6.1 (-14.9, 2.8) 0.172

Vestipitant -Pla 52.8 57.2 -4.4 (-13.3, 4.5) 0.327

Vest.+Parox.-Vest. 51.1 52.8 -1.7 (-10.6, 7.2) 0.701 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 4 of 4 Population: Pharmacodynamic Table 12.4 Summary of Statistical Analysis of VAS Arousal-Anxiety scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Tense-Peacerful Day 1 2H PD Vest.+Parox.-Pla 73.5 73.1 0.3 ( -7.7, 8.4) 0.930

Vestipitant -Pla 71.0 73.1 -2.2 (-10.3, 5.9) 0.588

Vest.+Parox.-Vest. 73.5 71.0 2.5 ( -5.5, 10.5) 0.526

Day 14 pre-dose Vest.+Parox.-Pla 73.2 69.8 3.4 ( -4.8, 11.6) 0.409

Vestipitant -Pla 69.5 69.8 -0.3 ( -8.6, 8.1) 0.950 CONFIDENTIAL

Vest.+Parox.-Vest. 73.2 69.5 3.7 ( -4.7, 12.0) 0.382

94 Day 14 2h PD Vest.+Parox.-Pla 73.8 76.3 -2.5 ( -9.7, 4.7) 0.492

Vestipitant -Pla 77.9 76.3 1.5 ( -5.8, 8.9) 0.675

Vest.+Parox.-Vest. 73.8 77.9 -4.0 (-11.3, 3.3) 0.275 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.5 Summary Statistics of THI total scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Total score 1 PRE-DOSE n 23 23 24 Mean 32.5 33.0 31.8 SD 20.19 19.11 19.16 Median 32.0 36.0 32.0 Min. 4 6 2 Max. 90 84 82

2 HRS n 23 23 24 Mean 28.9 29.8 26.6

SD 20.51 21.27 17.93 CONFIDENTIAL Median 26.0 32.0 31.0 Min. 4 2 0 Max. 86 84 60 95 14 PRE-DOSE n 23 21 23 Mean 30.9 31.0 31.0 SD 20.03 21.03 18.17 Median 28.0 32.0 34.0 Min. 4 2 2 Max. 90 90 78

2 HRS n 23 22 23 Mean 27.7 29.0 27.0 SD 21.13 20.08 18.78 Median 24.0 29.0 28.0 Min. 0 2 2 Max. 90 86 78 HM2009/00361/00 NKP106254 NKP106254

For the first 3 subjects the post dose assessment was taken after 3 hours Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.6 Summary of Statistical Analysis of THI Total scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Total score Day 1 2H PD Vest.+Parox.-Pla 26.5 29.4 -2.9 ( -6.1, 0.3) 0.078

Vestipitant -Pla 30.4 29.4 1.0 ( -2.2, 4.2) 0.539

Vest.+Parox.-Vest. 26.5 30.4 -3.9 ( -7.1, -0.6) 0.020

Day 14 pre-dose Vest.+Parox.-Pla 31.4 31.4 0.0 ( -6.1, 6.1) 0.993

Vestipitant -Pla 32.7 31.4 1.3 ( -4.8, 7.5) 0.669 CONFIDENTIAL

Vest.+Parox.-Vest. 31.4 32.7 -1.3 ( -7.4, 4.9) 0.675

96 Day 14 2h PD Vest.+Parox.-Pla 27.4 28.3 -0.8 ( -6.6, 4.9) 0.768

Vestipitant -Pla 29.8 28.3 1.6 ( -4.2, 7.3) 0.588

Vest.+Parox.-Vest. 27.4 29.8 -2.4 ( -8.1, 3.3) 0.404 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.7 Summary Statistics of QIDS-SR total scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day (N=23) (N=23) (N=24) ------Total Score 1 n 23 23 24 Mean 4.5 4.4 3.6 SD 3.07 3.23 2.78 Median 4.0 4.0 3.0 Min. 0 1 0 Max. 11 16 12

14 n 22 21 23 Mean 4.0 4.1 4.7

SD 3.11 3.68 3.89 CONFIDENTIAL Median 3.0 3.0 4.0 Min. 0 0 0 Max. 11 14 14 97 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.8 Summary of Statistical Analysis of QIDS-SR total scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Total Score Day 14 Vest.+Parox.-Pla 4.7 4.0 0.6 ( -1.1, 2.3) 0.465

Vestipitant -Pla 4.1 4.0 0.1 ( -1.7, 1.8) 0.953

Vest.+Parox.-Vest. 4.7 4.1 0.6 ( -1.1, 2.3) 0.509 CONFIDENTIAL 98 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.9 Summary Statistics of Tinnitus Aggravation Scores by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day Pl. Time (N=23) (N=23) (N=24) ------Score (0-7) 1 PRE-DOSE n 20 20 21 Mean 3.4 3.1 3.5 SD 1.73 1.55 2.14 Median 4.0 3.0 4.0 Min. 0 0 0 Max. 6 6 6

2 HRS n 20 20 21 Mean 3.7 2.9 3.4

SD 1.66 1.68 1.94 CONFIDENTIAL Median 4.0 3.0 4.0 Min. 0 0 0 Max. 6 6 6 99 14 PRE-DOSE n 20 18 20 Mean 3.2 3.2 3.1 SD 1.67 1.66 2.04 Median 3.0 3.0 4.0 Min. 0 0 0 Max. 6 6 6

2 HRS n 20 19 19 Mean 2.9 2.9 3.1 SD 1.93 1.66 1.91 Median 3.0 3.0 3.0 Min. 0 0 0 Max. 6 6 6 HM2009/00361/00 NKP106254 NKP106254

No data available for the first 3 subjects Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.10 Summary of Statistical Analysis of Tinnitus Aggravation Scores

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Score (0-7) Day 1 2H PD Vest.+Parox.-Pla 3.5 3.7 -0.2 ( -1.0, 0.6) 0.593

Vestipitant -Pla 2.9 3.7 -0.7 ( -1.5, 0.0) 0.056

Vest.+Parox.-Vest. 3.5 2.9 0.5 ( -0.2, 1.3) 0.158

Day 14 pre-dose Vest.+Parox.-Pla 3.2 3.2 -0.0 ( -0.8, 0.7) 0.933

Vestipitant -Pla 3.5 3.2 0.2 ( -0.5, 1.0) 0.529 CONFIDENTIAL

Vest.+Parox.-Vest. 3.2 3.5 -0.3 ( -1.0, 0.5) 0.475

100 Day 14 2h PD Vest.+Parox.-Pla 3.3 2.9 0.4 ( -0.3, 1.1) 0.245

Vestipitant -Pla 2.9 2.9 0.1 ( -0.7, 0.8) 0.885

Vest.+Parox.-Vest. 3.3 2.9 0.4 ( -0.3, 1.1) 0.308 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.11 Summary Statistics of Annoyance of Hyperacusis by treatment and time

Placebo Vestipitant Vest.+Parox. Domain Day (N=23) (N=23) (N=24) ------Distress score 1 n 20 20 21 Mean 1.0 1.6 1.2 SD 2.08 2.28 1.97 Median 0.0 0.0 0.0 Min. 0 0 0 Max. 6 7 6

14 n 20 18 20 Mean 1.0 1.2 0.7

SD 1.59 1.93 1.45 CONFIDENTIAL Median 0.0 0.0 0.0 Min. 0 0 0 Max. 5 7 5 101 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

No data available for the first 3 subjects Protocol: NKP106254 Page 1 of 1 Population: Pharmacodynamic Table 12.12 Summary of Statistical Analysis of Annoyance of Hyperacusis

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Distress Score Day 14 Vest.+Parox.-Pla 0.6 1.0 -0.4 ( -1.2, 0.5) 0.406

Vestipitant -Pla 1.3 1.0 0.3 ( -0.6, 1.2) 0.526

Vest.+Parox.-Vest. 0.6 1.3 -0.6 ( -1.5, 0.2) 0.149 CONFIDENTIAL 102 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 2 n 23 23 23 Mean 48.65 59.74 53.13 SD 22.683 17.754 20.888 Median 53.00 63.00 56.00 Min. 5.0 21.0 12.0 Max. 91.0 86.0 86.0

DAY 3 n 23 23 23 Mean 52.35 58.52 50.70

SD 21.557 16.973 21.764 CONFIDENTIAL Median 53.00 64.00 46.00 Min. 6.0 22.0 10.0 Max. 94.0 80.0 89.0 103 DAY 4 n 23 23 23 Mean 53.91 61.70 52.13 SD 20.670 18.900 20.897 Median 52.00 64.00 61.00 Min. 5.0 15.0 10.0 Max. 90.0 94.0 87.0

DAY 5 n 23 23 22 Mean 53.17 61.48 56.59 SD 22.637 21.620 20.909 Median 56.00 64.00 56.50 Min. 11.0 10.0 8.0 Max. 96.0 90.0 90.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 2 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 6 n 23 23 23 Mean 53.30 61.96 56.39 SD 21.883 19.326 21.099 Median 55.00 70.00 56.00 Min. 13.0 20.0 22.0 Max. 96.0 91.0 91.0

DAY 7 n 23 23 23 Mean 52.74 60.78 47.91

SD 23.223 19.815 23.417 CONFIDENTIAL Median 58.00 60.00 48.00 Min. 5.0 20.0 10.0 Max. 94.0 90.0 93.0 104 DAY 8 n 23 23 23 Mean 53.70 59.22 54.35 SD 22.810 23.071 22.405 Median 56.00 60.00 51.00 Min. 9.0 6.0 14.0 Max. 93.0 93.0 92.0

DAY 9 n 23 23 23 Mean 51.00 58.83 56.30 SD 24.634 22.669 21.276 Median 51.00 68.00 55.00 Min. 6.0 16.0 22.0 Max. 95.0 89.0 95.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 3 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 10 n 23 23 22 Mean 48.65 59.87 52.59 SD 25.938 25.344 23.890 Median 51.00 67.00 56.00 Min. 6.0 15.0 9.0 Max. 93.0 95.0 96.0

DAY 11 n 23 23 23 Mean 51.52 59.87 58.30

SD 25.580 23.833 22.768 CONFIDENTIAL Median 51.00 67.00 62.00 Min. 9.0 7.0 9.0 Max. 97.0 92.0 94.0 105 DAY 12 n 18 19 21 Mean 55.50 59.00 54.76 SD 24.791 23.293 25.239 Median 49.50 68.00 52.00 Min. 4.0 16.0 9.0 Max. 96.0 90.0 95.0

DAY 13 n 16 16 21 Mean 52.31 59.13 55.33 SD 26.542 22.450 22.990 Median 55.50 66.00 55.00 Min. 8.0 8.0 9.0 Max. 96.0 92.0 89.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 4 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity Mean DT n 23 23 23 Mean 52.32 60.01 54.26 SD 20.983 19.587 20.730 Median 52.67 62.58 55.42 Min. 11.8 17.4 15.0 Max. 93.4 86.6 89.7

DAY 15 n 22 23 23 Mean 52.91 59.96 56.43

SD 24.642 22.854 23.277 CONFIDENTIAL Median 52.50 56.00 58.00 Min. 16.0 10.0 11.0 Max. 96.0 92.0 89.0 106 DAY 16 n 23 23 23 Mean 53.22 61.00 55.65 SD 25.459 21.671 22.958 Median 53.00 65.00 55.00 Min. 17.0 19.0 15.0 Max. 97.0 92.0 89.0

DAY 17 n 23 23 23 Mean 57.13 59.22 60.26 SD 23.594 23.433 23.048 Median 60.00 61.00 64.00 Min. 18.0 20.0 20.0 Max. 95.0 96.0 96.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 5 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 18 n 23 23 23 Mean 55.48 59.04 56.17 SD 23.710 22.055 20.904 Median 58.00 65.00 56.00 Min. 14.0 21.0 24.0 Max. 95.0 94.0 88.0

DAY 19 n 23 23 23 Mean 58.43 63.74 52.78

SD 21.734 22.093 24.770 CONFIDENTIAL Median 60.00 70.00 53.00 Min. 18.0 21.0 7.0 Max. 98.0 96.0 90.0 107 DAY 20 n 23 23 23 Mean 59.52 57.83 51.48 SD 21.559 21.167 24.812 Median 62.00 56.00 53.00 Min. 18.0 23.0 12.0 Max. 95.0 93.0 94.0

DAY 21 n 23 23 23 Mean 58.43 61.87 55.00 SD 21.989 20.455 23.407 Median 53.00 61.00 57.00 Min. 23.0 21.0 9.0 Max. 91.0 95.0 89.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 6 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 22 n 23 23 23 Mean 56.57 60.22 51.96 SD 22.195 24.174 24.315 Median 56.00 61.00 53.00 Min. 19.0 22.0 3.0 Max. 90.0 95.0 91.0

DAY 23 n 21 23 23 Mean 57.43 58.78 52.43

SD 21.683 22.091 26.536 CONFIDENTIAL Median 59.00 60.00 50.00 Min. 15.0 16.0 3.0 Max. 85.0 91.0 94.0 108 DAY 24 n 21 23 23 Mean 54.90 59.96 57.48 SD 23.816 24.550 25.933 Median 55.00 61.00 66.00 Min. 18.0 12.0 2.0 Max. 96.0 93.0 96.0

DAY 25 n 20 23 21 Mean 54.85 61.09 50.43 SD 22.763 24.698 24.020 Median 54.00 55.00 54.00 Min. 15.0 13.0 3.0 Max. 93.0 94.0 93.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 7 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Intensity DAY 26 n 20 20 20 Mean 55.25 58.90 51.85 SD 25.252 28.939 24.858 Median 54.50 58.50 55.50 Min. 20.0 13.0 7.0 Max. 96.0 98.0 84.0

DAY 27 n 2 1 Mean 52.50 94.00

SD 30.406 CONFIDENTIAL Median 52.50 94.00 Min. 31.0 94.0 Max. 74.0 94.0 109 DAY 28 n 1 Mean 39.00 SD Median 39.00 Min. 39.0 Max. 39.0

Mean PT n 23 23 23 Mean 57.29 60.06 54.60 SD 22.087 21.268 22.247 Median 54.00 58.08 56.75 Min. 20.2 21.3 11.0 Max. 93.7 92.8 88.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 8 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 2 n 23 23 23 Mean 64.83 66.78 61.96 SD 23.194 21.414 25.530 Median 72.00 71.00 71.00 Min. 15.0 12.0 9.0 Max. 94.0 91.0 92.0

DAY 3 n 23 23 23 Mean 66.74 65.83 62.30

SD 22.578 23.159 25.294 CONFIDENTIAL Median 75.00 71.00 67.00 Min. 21.0 11.0 13.0 Max. 95.0 92.0 95.0 110 DAY 4 n 23 23 23 Mean 66.87 66.52 63.70 SD 21.678 23.345 23.832 Median 74.00 72.00 72.00 Min. 27.0 10.0 8.0 Max. 93.0 92.0 93.0

DAY 5 n 23 23 22 Mean 65.30 67.26 64.36 SD 23.910 23.487 23.838 Median 74.00 74.00 72.50 Min. 23.0 9.0 6.0 Max. 96.0 91.0 93.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 9 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 6 n 23 23 23 Mean 65.30 67.39 63.35 SD 23.600 22.879 24.033 Median 73.00 73.00 69.00 Min. 18.0 12.0 11.0 Max. 96.0 92.0 93.0

DAY 7 n 23 23 23 Mean 66.30 67.87 61.65

SD 23.507 21.803 24.809 CONFIDENTIAL Median 72.00 74.00 68.00 Min. 21.0 15.0 9.0 Max. 95.0 89.0 92.0 111 DAY 8 n 23 23 23 Mean 66.26 66.74 63.43 SD 21.093 26.485 23.863 Median 71.00 74.00 68.00 Min. 25.0 4.0 18.0 Max. 93.0 94.0 93.0

DAY 9 n 23 23 23 Mean 65.87 66.39 66.52 SD 21.035 25.534 20.776 Median 73.00 74.00 72.00 Min. 21.0 6.0 21.0 Max. 95.0 91.0 93.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 10 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 10 n 23 23 22 Mean 63.57 69.39 64.41 SD 24.168 23.249 23.352 Median 74.00 75.00 71.00 Min. 15.0 18.0 17.0 Max. 94.0 95.0 94.0

DAY 11 n 23 23 23 Mean 64.04 68.17 67.17

SD 23.463 23.513 21.796 CONFIDENTIAL Median 76.00 76.00 73.00 Min. 21.0 8.0 20.0 Max. 96.0 93.0 94.0 112 DAY 12 n 18 19 21 Mean 65.06 69.53 65.00 SD 24.910 22.991 25.612 Median 71.50 76.00 76.00 Min. 18.0 10.0 9.0 Max. 97.0 93.0 94.0

DAY 13 n 16 16 21 Mean 64.69 67.31 64.76 SD 26.265 23.332 23.407 Median 73.50 75.00 74.00 Min. 21.0 8.0 10.0 Max. 97.0 90.0 93.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 11 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone Mean DT n 23 23 23 Mean 65.57 67.38 64.36 SD 21.772 22.397 23.190 Median 72.18 74.25 72.42 Min. 22.2 12.2 13.3 Max. 93.8 91.5 92.6

DAY 15 n 22 23 23 Mean 63.82 67.78 68.09

SD 22.803 25.273 23.000 CONFIDENTIAL Median 71.00 75.00 71.00 Min. 21.0 9.0 10.0 Max. 97.0 93.0 92.0 113 DAY 16 n 23 23 23 Mean 66.35 69.39 67.48 SD 22.922 22.944 21.538 Median 71.00 75.00 71.00 Min. 25.0 17.0 17.0 Max. 97.0 94.0 94.0

DAY 17 n 23 23 23 Mean 66.87 68.87 68.52 SD 22.347 23.162 21.679 Median 72.00 75.00 74.00 Min. 18.0 19.0 19.0 Max. 95.0 95.0 94.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 12 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 18 n 23 23 23 Mean 69.00 69.39 66.39 SD 23.440 22.468 21.618 Median 78.00 77.00 74.00 Min. 17.0 21.0 23.0 Max. 96.0 95.0 94.0

DAY 19 n 23 23 23 Mean 67.30 68.78 66.26

SD 23.552 24.128 25.647 CONFIDENTIAL Median 76.00 76.00 75.00 Min. 21.0 14.0 13.0 Max. 98.0 95.0 94.0 114 DAY 20 n 23 23 23 Mean 68.04 69.04 68.70 SD 21.660 22.522 21.609 Median 72.00 76.00 73.00 Min. 17.0 23.0 24.0 Max. 96.0 94.0 95.0

DAY 21 n 23 23 23 Mean 67.65 69.00 64.96 SD 22.086 21.965 24.285 Median 75.00 76.00 72.00 Min. 21.0 14.0 15.0 Max. 93.0 94.0 93.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 13 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 22 n 23 23 23 Mean 66.43 69.22 64.39 SD 22.799 23.894 25.639 Median 74.00 78.00 72.00 Min. 18.0 11.0 17.0 Max. 93.0 97.0 94.0

DAY 23 n 21 23 23 Mean 67.38 68.74 65.52

SD 22.105 24.510 24.766 CONFIDENTIAL Median 77.00 78.00 72.00 Min. 20.0 18.0 3.0 Max. 94.0 94.0 95.0 115 DAY 24 n 21 23 23 Mean 66.05 67.13 65.74 SD 22.484 25.816 25.401 Median 71.00 75.00 71.00 Min. 16.0 13.0 4.0 Max. 97.0 94.0 95.0

DAY 25 n 20 23 21 Mean 64.20 68.57 64.00 SD 25.158 23.905 26.171 Median 72.50 78.00 70.00 Min. 18.0 20.0 3.0 Max. 96.0 93.0 94.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 14 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Tone DAY 26 n 20 20 20 Mean 65.50 66.00 63.70 SD 26.621 27.730 26.142 Median 73.50 77.50 71.50 Min. 16.0 11.0 14.0 Max. 96.0 98.0 94.0

DAY 27 n 2 1 Mean 80.50 92.00

SD 13.435 CONFIDENTIAL Median 80.50 92.00 Min. 71.0 92.0 Max. 90.0 92.0 116 DAY 28 n 1 Mean 71.00 SD Median 71.00 Min. 71.0 Max. 71.0

Mean PT n 23 23 23 Mean 67.31 68.70 66.43 SD 22.329 23.351 23.231 Median 74.42 78.00 71.75 Min. 27.0 16.3 14.6 Max. 94.7 94.0 93.8 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 15 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 2 n 23 23 23 Mean 38.13 47.74 43.83 SD 21.615 16.853 20.830 Median 34.00 48.00 47.00 Min. 5.0 10.0 7.0 Max. 81.0 73.0 83.0

DAY 3 n 23 23 23 Mean 41.43 45.04 39.04

SD 20.122 15.973 18.678 CONFIDENTIAL Median 38.00 42.00 41.00 Min. 7.0 9.0 5.0 Max. 80.0 72.0 81.0 117 DAY 4 n 23 23 23 Mean 44.30 49.87 39.26 SD 19.928 20.139 18.914 Median 46.00 50.00 41.00 Min. 3.0 14.0 8.0 Max. 84.0 88.0 80.0

DAY 5 n 23 23 22 Mean 41.57 46.43 45.45 SD 21.998 20.396 18.842 Median 46.00 46.00 48.00 Min. 6.0 10.0 8.0 Max. 83.0 84.0 82.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 16 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 6 n 23 23 23 Mean 42.96 50.13 43.35 SD 21.502 20.132 19.837 Median 43.00 49.00 41.00 Min. 10.0 14.0 9.0 Max. 80.0 89.0 83.0

DAY 7 n 23 23 23 Mean 42.43 49.43 39.52

SD 20.850 20.246 20.845 CONFIDENTIAL Median 40.00 47.00 38.00 Min. 5.0 18.0 9.0 Max. 80.0 83.0 78.0 118 DAY 8 n 23 23 23 Mean 43.74 47.35 44.91 SD 20.987 22.997 20.045 Median 41.00 48.00 46.00 Min. 9.0 6.0 6.0 Max. 82.0 83.0 83.0

DAY 9 n 23 23 23 Mean 38.43 48.43 44.17 SD 22.254 22.719 19.142 Median 40.00 53.00 48.00 Min. 5.0 14.0 8.0 Max. 83.0 87.0 85.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 17 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 10 n 23 23 22 Mean 36.13 50.09 42.77 SD 22.509 24.748 23.346 Median 33.00 51.00 46.00 Min. 5.0 7.0 5.0 Max. 80.0 97.0 84.0

DAY 11 n 23 23 23 Mean 37.17 46.52 46.30

SD 21.430 24.286 23.584 CONFIDENTIAL Median 32.00 40.00 45.00 Min. 5.0 11.0 5.0 Max. 82.0 84.0 85.0 119 DAY 12 n 18 19 21 Mean 40.72 47.53 44.19 SD 20.682 24.116 24.332 Median 42.00 51.00 44.00 Min. 3.0 12.0 4.0 Max. 80.0 85.0 85.0

DAY 13 n 16 16 21 Mean 44.00 46.44 43.62 SD 23.056 21.982 22.250 Median 42.50 43.50 48.00 Min. 7.0 14.0 7.0 Max. 80.0 88.0 85.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 18 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress Mean DT n 23 23 23 Mean 41.00 47.80 43.17 SD 18.950 18.850 18.660 Median 38.33 49.73 49.00 Min. 10.5 12.5 7.8 Max. 81.0 78.8 82.6

DAY 15 n 22 23 23 Mean 43.09 49.35 41.74

SD 25.810 23.706 22.720 CONFIDENTIAL Median 39.00 47.00 43.00 Min. 5.0 11.0 4.0 Max. 89.0 87.0 85.0 120 DAY 16 n 23 23 23 Mean 43.65 48.91 41.26 SD 25.027 21.131 25.019 Median 37.00 46.00 40.00 Min. 9.0 8.0 3.0 Max. 89.0 88.0 82.0

DAY 17 n 23 23 23 Mean 46.04 47.96 50.22 SD 23.405 25.083 26.160 Median 46.00 44.00 54.00 Min. 7.0 8.0 8.0 Max. 89.0 91.0 89.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 19 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 18 n 23 23 23 Mean 43.65 47.57 44.26 SD 25.346 20.922 23.423 Median 39.00 45.00 37.00 Min. 7.0 15.0 7.0 Max. 88.0 85.0 88.0

DAY 19 n 23 23 23 Mean 48.43 50.83 40.78

SD 23.880 22.615 25.570 CONFIDENTIAL Median 47.00 55.00 39.00 Min. 7.0 9.0 4.0 Max. 88.0 86.0 84.0 121 DAY 20 n 23 23 23 Mean 48.30 45.65 42.43 SD 21.611 21.997 25.083 Median 49.00 46.00 42.00 Min. 8.0 9.0 7.0 Max. 89.0 87.0 85.0

DAY 21 n 23 23 23 Mean 48.48 50.43 43.61 SD 21.778 20.830 21.120 Median 45.00 56.00 42.00 Min. 11.0 9.0 2.0 Max. 89.0 91.0 80.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 20 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 22 n 23 23 23 Mean 45.91 49.78 41.30 SD 21.134 23.351 22.754 Median 47.00 44.00 40.00 Min. 9.0 12.0 3.0 Max. 89.0 94.0 91.0

DAY 23 n 21 23 23 Mean 48.00 47.96 41.65

SD 21.333 21.908 23.736 CONFIDENTIAL Median 51.00 47.00 37.00 Min. 8.0 11.0 1.0 Max. 79.0 88.0 89.0 122 DAY 24 n 21 23 23 Mean 45.62 47.39 46.87 SD 22.384 23.610 25.284 Median 48.00 53.00 44.00 Min. 8.0 6.0 1.0 Max. 82.0 93.0 96.0

DAY 25 n 20 23 21 Mean 42.00 48.61 39.05 SD 22.141 23.754 22.475 Median 42.50 51.00 38.00 Min. 7.0 6.0 2.0 Max. 78.0 94.0 84.0 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 21 of 21 Population: Pharmacodynamic Table 12.13 Summary Statistics of VAS Tinnitus scores by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 26 n 20 20 20 Mean 43.15 47.00 41.80 SD 23.057 27.378 22.435 Median 41.00 44.00 39.00 Min. 9.0 5.0 5.0 Max. 88.0 92.0 81.0

DAY 27 n 2 1 Mean 47.50 71.00

SD 24.749 CONFIDENTIAL Median 47.50 71.00 Min. 30.0 71.0 Max. 65.0 71.0 123 DAY 28 n 1 Mean 40.00 SD Median 40.00 Min. 40.0 Max. 40.0

Mean PT n 23 23 23 Mean 46.91 48.41 43.20 SD 21.383 20.186 20.516 Median 46.25 50.25 39.08 Min. 8.4 10.1 5.6 Max. 88.8 85.2 82.3 HM2009/00361/00 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 1 of 3 Population: Pharmacodynamic Table 12.14 Summary of Statistical Analysis of VAS Tinnitus scores mean value over the treatment period

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Intensity Treat. period Vest.+Parox.-Pla 54.4 52.2 2.2 ( -4.0, 8.3) 0.481

Vestipitant -Pla 59.9 52.2 7.7 ( 1.5, 13.8) 0.016

Vest.+Parox.-Vest. 54.4 59.9 -5.5 (-11.7, 0.6) 0.077 CONFIDENTIAL 124 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 3 Population: Pharmacodynamic Table 12.14 Summary of Statistical Analysis of VAS Tinnitus scores mean value over the treatment period

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Tone Treat. period Vest.+Parox.-Pla 63.9 65.9 -2.1 ( -6.6, 2.5) 0.363

Vestipitant -Pla 67.5 65.9 1.5 ( -3.0, 6.1) 0.502

Vest.+Parox.-Vest. 63.9 67.5 -3.6 ( -8.2, 1.0) 0.118 CONFIDENTIAL 125 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 3 of 3 Population: Pharmacodynamic Table 12.14 Summary of Statistical Analysis of VAS Tinnitus scores mean value over the treatment period

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Distress Treat. period Vest.+Parox.-Pla 43.3 40.8 2.4 ( -2.9, 7.7) 0.363

Vestipitant -Pla 47.9 40.8 7.0 ( 1.7, 12.3) 0.011

Vest.+Parox.-Vest. 43.3 47.9 -4.6 ( -9.9, 0.7) 0.087 CONFIDENTIAL 126 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 1 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 2 n 23 23 23 Mean 1.43 1.22 1.13 SD 3.314 3.643 2.897 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 12.0 17.0 10.0

DAY 3 n 23 23 23

Mean 1.09 0.87 0.43 CONFIDENTIAL SD 2.521 2.581 1.472 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 127 Max. 9.0 12.0 7.0

DAY 4 n 23 23 23 Mean 0.91 1.04 0.43 SD 2.214 2.402 1.701 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 10.0 10.0 8.0

DAY 5 n 23 23 22 Mean 0.91 0.74 0.45 SD 2.661 2.158 1.184 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 11.0 10.0 5.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 2 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 6 n 23 23 23 Mean 0.48 0.48 0.61 SD 1.675 1.377 1.500 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 8.0 6.0 7.0

DAY 7 n 23 23 23

Mean 0.39 0.83 0.43 CONFIDENTIAL SD 1.469 2.167 1.502 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 128 Max. 7.0 10.0 7.0

DAY 8 n 23 23 23 Mean 0.61 0.83 0.61 SD 1.469 2.387 1.924 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 11.0 9.0

DAY 9 n 23 23 23 Mean 0.65 0.96 0.91 SD 1.748 2.163 2.214 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 6.0 9.0 10.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 3 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 10 n 23 23 22 Mean 0.48 0.83 0.64 SD 1.442 2.367 1.733 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 11.0 8.0

DAY 11 n 23 23 23

Mean 0.70 1.09 0.96 CONFIDENTIAL SD 1.550 2.922 2.549 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 129 Max. 7.0 14.0 12.0

DAY 12 n 18 19 21 Mean 0.67 0.58 0.76 SD 1.455 2.063 2.234 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 6.0 9.0 10.0

DAY 13 n 16 16 21 Mean 0.50 1.06 0.86 SD 1.095 2.999 3.038 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 4.0 12.0 14.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 4 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes Mean DT n 23 23 23 Mean 0.76 0.85 0.68 SD 1.717 2.276 1.843 Median 0.08 0.10 0.17 Min. 0.0 0.0 0.0 Max. 7.3 10.9 8.9

DAY 15 n 22 23 22

Mean 0.41 0.91 0.55 CONFIDENTIAL SD 1.182 2.448 2.132 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 130 Max. 5.0 11.0 10.0

DAY 16 n 23 23 23 Mean 2.57 0.78 0.43 SD 10.418 2.713 1.674 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 50.0 13.0 8.0

DAY 17 n 23 23 23 Mean 0.57 0.57 0.78 SD 1.308 1.562 2.315 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 5.0 7.0 11.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 5 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 18 n 23 23 23 Mean 0.39 0.78 0.70 SD 1.196 2.763 1.917 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 13.0 9.0

DAY 19 n 23 23 23

Mean 0.52 0.70 0.70 CONFIDENTIAL SD 1.238 1.964 2.494 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 131 Max. 5.0 9.0 12.0

DAY 20 n 23 23 23 Mean 0.65 0.65 0.61 SD 1.668 2.308 1.924 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 7.0 11.0 9.0

DAY 21 n 23 23 23 Mean 0.78 0.43 1.00 SD 2.110 1.502 2.594 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 9.0 7.0 10.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 6 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 22 n 23 23 23 Mean 0.74 0.74 5.00 SD 1.789 2.340 20.815 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 8.0 11.0 100.0

DAY 23 n 21 23 23

Mean 0.90 0.83 0.48 CONFIDENTIAL SD 3.048 2.708 1.880 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 132 Max. 14.0 13.0 9.0

DAY 24 n 21 23 23 Mean 1.00 0.61 0.83 SD 3.701 2.311 1.969 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 17.0 11.0 8.0

DAY 25 n 20 23 21 Mean 0.95 0.74 0.67 SD 3.332 2.200 2.394 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 15.0 10.0 11.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 7 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------No. episodes DAY 26 n 20 20 20 Mean 1.00 0.60 0.65 SD 3.129 2.257 2.033 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 14.0 10.0 9.0

DAY 27 n 2 1

Mean 0.00 0.00 CONFIDENTIAL SD 0.000 Median 0.00 0.00 Min. 0.0 0.0 133 Max. 0.0 0.0

DAY 28 n 1 Mean 0.00 SD Median 0.00 Min. 0.0 Max. 0.0

Mean PT n 23 23 23 Mean 0.93 0.69 1.10 SD 2.246 2.181 2.922 Median 0.08 0.00 0.08 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 9.2 10.5 11.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 8 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 2 n 23 23 23 Mean 1.13 0.83 0.70 SD 1.914 1.669 1.521 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 6.0 6.0 5.0

DAY 3 n 23 23 23

Mean 0.74 0.83 0.43 CONFIDENTIAL SD 1.389 1.527 1.080 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 134 Max. 5.0 5.0 4.0

DAY 4 n 23 23 23 Mean 0.83 1.00 0.22 SD 1.614 1.834 0.850 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 6.0 7.0 4.0

DAY 5 n 23 23 22 Mean 0.48 0.57 0.55 SD 1.238 1.273 1.299 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 5.0 5.0 4.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 9 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 6 n 23 23 23 Mean 0.39 0.43 0.70 SD 0.941 1.161 1.428 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 3.0 4.0 5.0

DAY 7 n 23 23 23

Mean 0.26 0.70 0.39 CONFIDENTIAL SD 0.752 1.363 1.158 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 135 Max. 3.0 4.0 4.0

DAY 8 n 23 23 23 Mean 0.70 0.52 0.52 SD 1.579 1.163 1.238 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 6.0 4.0 4.0

DAY 9 n 23 23 23 Mean 0.43 0.74 0.83 SD 1.080 1.573 1.497 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 4.0 6.0 5.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 10 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 10 n 23 23 22 Mean 0.35 0.61 0.55 SD 0.935 1.373 1.143 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 3.0 4.0 4.0

DAY 11 n 23 23 23

Mean 0.74 0.96 0.83 CONFIDENTIAL SD 1.356 1.609 1.586 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 136 Max. 5.0 5.0 5.0

DAY 12 n 18 19 21 Mean 1.11 0.37 0.57 SD 1.779 0.955 1.399 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 3.0 5.0

DAY 13 n 16 16 21 Mean 0.69 0.63 0.48 SD 1.302 1.258 1.078 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 4.0 4.0 4.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 11 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress Mean DT n 23 23 23 Mean 0.65 0.67 0.56 SD 0.915 0.953 0.911 Median 0.09 0.10 0.25 Min. 0.0 0.0 0.0 Max. 3.0 3.3 4.1

DAY 15 n 22 23 22

Mean 0.32 0.65 0.23 CONFIDENTIAL SD 0.839 1.434 0.869 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 137 Max. 3.0 5.0 4.0

DAY 16 n 23 23 23 Mean 0.74 0.70 0.22 SD 1.573 1.579 0.850 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 6.0 4.0

DAY 17 n 23 23 23 Mean 0.52 0.78 0.87 SD 1.123 1.858 1.890 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 4.0 6.0 6.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 12 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 18 n 23 23 23 Mean 0.35 0.35 0.91 SD 0.935 1.027 1.703 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 3.0 4.0 5.0

DAY 19 n 23 23 23

Mean 0.65 0.61 0.43 CONFIDENTIAL SD 1.434 1.305 1.161 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 138 Max. 5.0 4.0 4.0

DAY 20 n 23 23 23 Mean 0.70 0.39 0.43 SD 1.259 0.941 1.161 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 4.0 3.0 4.0

DAY 21 n 23 23 23 Mean 0.91 0.22 0.70 SD 1.881 0.671 1.579 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 6.0 3.0 6.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 13 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 22 n 23 23 23 Mean 0.61 0.52 0.70 SD 1.196 1.238 1.663 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 4.0 5.0 7.0

DAY 23 n 21 23 23

Mean 0.71 0.70 0.39 CONFIDENTIAL SD 1.586 1.396 1.158 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 139 Max. 5.0 5.0 4.0

DAY 24 n 21 23 23 Mean 0.43 0.39 0.78 SD 1.121 1.158 1.757 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 4.0 4.0 6.0

DAY 25 n 20 23 21 Mean 0.55 0.74 0.38 SD 1.276 1.657 1.071 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 5.0 6.0 4.0 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 14 of 14 Population: Pharmacodynamic Table 12.15 Summary Statistics of number of Hyperacusis episodes and distress by treatment and day (DIARY)

Placebo Vestipitant Vest.+Parox. Domain Day/Period (N=23) (N=23) (N=24) ------Distress DAY 26 n 20 20 20 Mean 0.65 0.20 0.30 SD 1.309 0.696 0.801 Median 0.00 0.00 0.00 Min. 0.0 0.0 0.0 Max. 5.0 3.0 3.0

DAY 27 n 2 1

Mean 0.00 0.00 CONFIDENTIAL SD 0.000 Median 0.00 0.00 Min. 0.0 0.0 140 Max. 0.0 0.0

DAY 28 n 1 Mean 0.00 SD Median 0.00 Min. 0.0 Max. 0.0

Mean PT n 23 23 23 Mean 0.58 0.52 0.54 SD 0.908 0.795 0.847 Median 0.08 0.00 0.33 Min. 0.0 0.0 0.0 HM2009/00361/00 Max. 3.7 3.3 3.8 NKP106254 NKP106254

Note: DT = During Treatment, PT = Post Treatment Protocol: NKP106254 Page 1 of 2 Population: Pharmacodynamic Table 12.16 Summary of Statistical Analysis of number of Hyperacusis episodes and distress mean value over the treatment period

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

No. of episodes Treat. period Vest.+Parox.-Pla 0.7 0.7 -0.0 ( -0.4, 0.3) 0.854

Vestipitant -Pla 0.8 0.7 0.1 ( -0.3, 0.5) 0.551

Vest.+Parox.-Vest. 0.7 0.8 -0.1 ( -0.5, 0.2) 0.436 CONFIDENTIAL 141 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 Protocol: NKP106254 Page 2 of 2 Population: Pharmacodynamic Table 12.16 Summary of Statistical Analysis of number of Hyperacusis episodes and distress mean value over the treatment period

LSmean LSmean Param. Time Comparison Test Treat. Ref. Treat. Diff. 95% C.I. p-value ------

Distress score Treat. period Vest.+Parox.-Pla 0.6 0.6 -0.1 ( -0.3, 0.2) 0.604

Vestipitant -Pla 0.7 0.6 0.0 ( -0.2, 0.3) 0.740

Vest.+Parox.-Vest. 0.6 0.7 -0.1 ( -0.4, 0.2) 0.396 CONFIDENTIAL 142 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies NKP106254

Division: Worldwide Development Retention Category: GRS019 Information Type: Protocol Amendment

Compound Number: GW597599

Effective Date: 23-APR-2008

Protocol Amendment Number: 02

Description: The purpose of this amendment is to document the changes and clarifications to the endpoints, eligibility criteria and study assessments.

Author: (CPDM CSSO), (CPDM CSSO), (CPDM), (CUC), (CUC), (CUC)

1 1 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 TheThe GlaxoSmithKline GlaxoSmithKline group group of companies of companies NKP106254

Revision Chronology:

VM2005/00076/00 2006-JUL-24 Original

VM2005/00076/01 2007-JUN-03 Amendment No.01:

1. Change of Investigator 2. Addition of new site 3. Changes and clarifications of inclusion and exclusion criteria 4. Clarifications in the text of the protocol VM2005/00076/02 2008-APR-23 Amendment No.02:

1. Clarifications to the study endpoints 2. Changes and clarifications of the inclusion and exclusion criteria 3. Changes and clarifications to study assessments.

2 2 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00 NKP106254 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

SPONSOR/MEDICAL MONITOR INFORMATION PAGE

Medical Monitor and Sponsor Contact Information:

Role Name Day Time After-hours Fax Number GSK Address Phone Phone/Cell/ Number Pager Number Primary GlaxoSmithKline Medical New Frontiers Science Park Monitor Third Avenue Harlow, Essex CM19 5AW, UK Secondary GlaxoSmithKline Medical Five Moore Drive Monitor P.O. 13398 Research Triangle Park, NC 27709-3398, USA

Tertiary GlaxoSmithKline Medical Via Alessandro Fleming Monitor 2/4-37135 Verona, Italy

Sponsor Registered Address:

GlaxoSmithKline Research & Development Limited 980 Great West Road Brentford Middlesex, TW8 9GS UK

In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate company (or designee). If applicable, the details of the alternative Sponsor and contact person in the territory will be provided to the relevant regulatory authority as part of the clinical trial application.

Regulatory Agency Identifying Number(s): EudraCT No.2006-003295-36

4 4 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol, as amended by this protocol amendment.

Investigator Name:

Investigator Address:

Investigator Phone Number:

Investigator Signature Date

5 5 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00 NKP106254

TABLE OF CONTENTS

Page ABBREVIATIONS ...... 9 PROTOCOL SUMMARY ...... 11 1. INTRODUCTION ...... 19 1.1. Background ...... 19 1.2. Rationale for the use of NK1 antagonist and Selective Serotonin Uptake Inhibitors to improve tinnitus...... 21 1.2.1. Preclinical studies ...... 21 1.2.2. Single dosing ...... 22 1.2.3. Repeated dosing ...... 23 1.3. Dose Rationale...... 25 2. OBJECTIVE(S) ...... 26 2.1. Primary ...... 26 2.2. Secondary ...... 26 2.3. Exploratoy ...... 26 3. ENDPOINT(S) ...... 27 3.1. Primary ...... 27 3.2. Secondary ...... 27 3.3. Exploratory ...... 27 4. STUDY DESIGN ...... 28 5. STUDY POPULATION ...... 28 5.1. Number of Subjects ...... 28 5.2. Eligibility Criteria...... 29 5.2.1. Inclusion Criteria ...... 29 5.2.2. Exclusion Criteria ...... 30 5.2.3. Other Eligibility Criteria Considerations ...... 32 6. STUDY ASSESSMENTS AND PROCEDURES ...... 32 6.1. Screening ...... 32 6.2. Treatment ...... 33 6.2.1. Pregnancy ...... 35 6.3. Efficacy...... 36 6.3.1. Visual Analog Scales (VAS) to measure tinnitus intensity, pitch and distress ...... 36 6.3.2. Self-scored questionnaires...... 36

6 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00 NKP106254

6.3.3. Daily Diary ...... 36 6.3.4. Tinnitus Matching ...... 36 6.4. Pharmacokinetics ...... 37 6.5. Pharmacodynamics ...... 38 6.5.1. Visual Analog Scales (VAS) to measure general alertness/anxiety levels ...... 38 6.5.2. Audiometry ...... 38 6.5.3. Psychoacoustic measurements ...... 38 6.6. Pharmacogenetics ...... 38 7. LIFESTYLE AND/OR DIETARY RESTRICTIONS ...... 38 8. INVESTIGATIONAL PRODUCT(S)...... 38 8.1. Description of Investigational Product ...... 38 8.2. Dosage and Administration ...... 38 8.3. Dose Rationale...... 39 8.4. Blinding ...... 40 8.5. Treatment Assignment ...... 40 8.6. Packaging and Labeling ...... 41 8.7. Handling and Storage ...... 41 8.8. Product Accountability ...... 41 8.9. Assessment of Compliance ...... 41 8.10. Treatment of Investigational Product Overdose...... 41 8.11. Occupational Safety ...... 41 9. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ...... 42 9.1. Permitted Medications ...... 42 9.2. Prohibited Medications ...... 42 10. SUBJECT COMPLETION AND WITHDRAWAL ...... 42 10.1. Subject Completion ...... 42 10.2. Subject Withdrawal ...... 42 10.2.1. Subject Withdrawal from Study ...... 42 10.3. Screen and Baseline Failures ...... 43 11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) . . 43 11.1. Definition of an AE ...... 43 11.2. Definition of a SAE ...... 43 11.2.1. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs ...... 44

7 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00 NKP106254

11.2.2. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs ...... 44 11.3. Time Period, and Frequency of Detecting AEs and SAEs ...... 46 11.4. Prompt Reporting of SAEs to GSK ...... 46 11.4.1. Timeframes for Submitting SAE Reports to GSK ...... 46 11.5. AE and SAE Documentation and Follow-up Procedures ...... 46 12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ...... 47 12.1. Hypotheses ...... 47 12.2. Study Design Considerations...... 47 12.2.1. Sample Size Assumptions ...... 47 12.2.2. Sample Size Sensitivity ...... 47 12.2.3. Sample Size Re-estimation ...... 47 12.3. Data Analysis Considerations ...... 47 12.3.1. Analysis Populations ...... 47 12.3.2. Analysis Data Sets ...... 48 12.3.3. Treatment Comparisons...... 48 12.3.4. Interim Analysis ...... 48 12.3.5. Key Elements of Analysis Plan ...... 48 13. STUDY ADMINISTRATION...... 50 13.1. Regulatory and Ethical Considerations, Including the Informed Consent Process ...... 50 13.2. Quality Control (Study Monitoring) ...... 51 13.3. Quality Assurance ...... 51 13.4. Study and Site Closure ...... 51 13.5. Records Retention ...... 52 13.6. Provision of Study Results and Information to Investigators ...... 52 13.7. Data Management ...... 53 14. REFERENCES ...... 54 Appendices ...... 58 Appendix 1: Time and Events Table...... 58 Appendix 2: Paroxetine Global Datasheet ...... 60 Appendix 3: Pharmacogenetic Research ...... 104 Appendix 4: Inhibitors and inducers of Cytocrome P450 2D6 and 3A ...... 109 Appendix 5: Protocol Changes – Amendment 02 ...... 110 Appendix 6: Protocol changes – Amendment 01 ...... 153

8 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

ABBREVIATIONS

AE Adverse Event AUC Area Under Curve CIB Clinical Investigators Brochure CNS Central Nervous System CO2 Carbon Dioxide DCN Dorsal Coclear Nucleus ECG Electrocardiogram ENT Ear, nose, throat GABA Gamma Amino Butyric Acid GSK GlaxoSmithKline h hour HADS Hospital Anxiety and Depression Scale HDPE High Density Polyethylene HIV Human Immunodeficiency Virus 5-HT 5-Hydroxytryptamine / Serotonin IHC Inner Hair Cells i.p. intra peritoneal IUD Intra Uterine Device kg kilogram LSEQ Leeds Sleep Evaluation Questionnaire MAOI Monoamine Oxidase Inhibitor mg Milligram min minute ml millolitre MSDS Material Safety Data Sheet NK1 Neurokinin 1 Ng Nanogram OCD Obsessive Compulsive Disorder PD Pharmacodynamic PET Positron Emission Tomography PK Pharmacokinetic PSG Polysomnography qEEG Quantative Electroencephalogram QIDS Quick Inventory of Depressive Symptomatology rCBF Regional Cerebral Blood Flow RO Receptor Occupancy SAD Seasonal Affective Disorder SAE Serious Adverse Event SP Substance P SRM Study Reference Manual SSRI Selective Serotonin Re-uptake Inhibitor TCA Tricyclic Andidepressant THI Tinnitus Handicap Inventory VAS Visual Analogue Scale VNTB Ventral Nucleus of Trapezoid Body

9 9 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies None NONMEM

10 10 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL SUMMARY

Rationale

The proposed treatment in this study is a combination between paroxetine, a marketed selective serotonin reuptake inhibitor (SSRI) drug, and vestipitant (also indicated as GW597599), a novel NK1 antagonist.

Paroxetine is a phenylpiperidine compound, which acts as a potent SSRI at the synaptic cleft, increasing the levels of serotonin in the brainstem, limbic structures and cortex. Paroxetine, as other SSRIs, has been approved as treatment for Depression and several Anxiety Disorders. One recent randomized study in patients suffering from tinnitus showed modest improvements at 50 mg/day for 8 weeks [Robinson, 2005].

Vestipitant (GW597599) is a potent and selective NK1 receptor antagonist which has been extensively studied in healthy volunteers, in depressed patients and patients with SAD showing a good safety profile. NK1 antagonists were never studied in patients suffering from tinnitus.

Preclinical studies

Recent preclinical studies indicate that the combination of paroxetine and the NK1 antagonist vestipitant produced anxiolytic effects when low doses are combined. The social interaction test in the gerbil was used to assess the anxiolytic-like properties of the NK1 antagonists, and of the combination of vestipitant and paroxetine [GlaxoSmithKline Document Number VH2003/00021/00]. These effects are similar to those generated by the benzodiazepine diazepam at 0.01 and 0.1 mg/kg ip.

The supposed mechanism of action of diazepam and all benzodiazepine in generating anxiolytic effects is related to the increased efficacy of GABAergic neurotransmission in several limbic brain structures, namely the amygdala, the hippocampus, the basal ganglia, and the periacqueductal gray [Nemeroff, 2003].

In our laboratories GABAergic interneurons of the basolateral amygdala were studied using electrophysiology in vitro on preparations of rat brain slices. These interneurons express NK1 receptors. When the endogenous agonist SP was infused inhibition of the firing of the neurons was observed, a phenomenon related to the blockade of potassium current. This current was found to be generated by a Kv3 channel, in this case the Kv3.2. The Kv3 channel family (Kv3.1–Kv3.4) displays a positively shifted voltage dependence of activation and fast activation/deactivation kinetics, features that confer on Kv3 channels the ability to accelerate the repolarisation of the action potential efficiently and specifically. Thus, Kv3 channels confer the ability on neurons to fire action potentials at high frequencies, in some cases several hundred hertz, participating to the generation of EEG gamma oscillations. The application of serotonin to the basolateral amygdala preparation produced the opposite effects, increasing firing of the GABAergic interneurons and enhancing the Kv-potassium current. Preliminary experiment in vivo indicates that the co-administration of NK1 antagonists (that block the inhibiting effects of endogenous SP on GABAergic neurons) and SSRIs (that increase the firing of

11 11 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

GABAergic neurons by increasing the availability of synaptic serotonin) increases gamma oscillation. Therefore, the increase in firing of GABAergic interneurons generated by NK1 antagonist alone and by the combination between NK1 antagonist and SSRI may be one of the mechanisms involved in the anxiolytic effects observed with these compounds in vivo.

Since there is evidence that this mechanism is at work also in the auditory nuclei, we propose to use the same approach (i.e., NK1 antagonist with or without combination with SSRI) in tinnitus, where the increase in firing of local GABAergic interneurons can be beneficial. In fact, brainstem auditory nuclei are enriched with NK1 receptors [Hafidi, 2002] and Kv3 channels, the expression pattern of which is tonotopically organised in the trapezoid body nucleus (i.e., higher expression at the high frequency map [Li, 2001; Grigg, 2000]. At the cellular level, Kv3 channels and NK1 receptors are mostly expressed in those inhibitory neurons (e.g., the GABAergic stellate interneurons) involved in the modulation of acoustic transmission. Substance P is involved in the processing of high frequency auditory signals in the DCN [Guo, 1999] and able to activate the auditory nuclei of VNTB via NK1 receptors [Wang, 1998]. Serotonin could exert its action via several receptors which are co-expressed in the auditory neurons [Cransac, 1998], possibly via 5-HT2b receptors.

According to these expression patterns and functional roles, we expect synergic action of NK1 antagonists and SSRIs on the inhibitory systems of the central auditory nuclei, resulting in tinnitus improvement.

Clinical studies: Single dose

The effects of single and repeated doses of benzodiazepines are well known, showing anxiolytic and hypnotic properties. The acute administration of SSRIs, including paroxetine, is known to induce anxiety, while the chronic dosing induces anxiolytic effects. Overdosing of SSRIs are associated with report of tinnitus. Less information is available in the literature concerning the effects of single or repeated administration of NK1 antagonists, and almost nothing about the combination of SSRIs and NK1 antagonists. A brief summary of the evidence supporting the anxiolytic and hypnotic properties of the NK1 antagonist effect is presented below.

Acute administration of vestipitant was studied in healthy volunteers at 15 mg and 25 mg doses (GSK NKD10014). Both doses produced transient pharmaco-EEG changes consisting of initial increases in delta and theta waves (2 h post-dose). Sleep spectral analysis indicated increased beta and gamma band power similar to those generated by benzodiazepines (i.e., lorazepam 2 mg). Interestingly, evidence from the literature suggests that the increase of gamma oscillations and power are associated with Kv3- related activity on different neural systems, including the increased firing of GABAergic interneurons [Traub, 2003].

12 12 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

with anxiety were selected. Both alprazolam 0.75 mg and vestipitant 15 mg produced significant reductions of the scores and reduced the frequency of escape reactions (i.e., request to interrupt the procedure).

Using the same 7% CO2 challenge procedure in the same centre, a randomized, double blind, placebo controlled balanced incomplete block crossover study (GSK NKP100690) was carried out to evaluate the change in response to 7% CO2 and the pharmacokinetic profiles of acute administration of the combination of low dose vestipitant and paroxetine. A trend towards significant anxiolytic effect was observed with both treatments, i.e., vestipitant 15 mg + paroxetine 7.5 mg, or vestipitant 7.5 mg + paroxetine 5 mg, as well as with vestipitant 15 mg alone, or with alprazolam 0.75 mg alone. On the contrary, a trend towards an increase in anxiety was seen after the administration of paroxetine 7.5 mg alone. A prospectively planned PK/PD analysis was conducted to explore the correlation between different levels of exposure of vestipitant and paroxetine alone and in combination. The PK/PD analysis indicated that the anxiolytic effect is maximized in subjects with concentrations of vestipitant and paroxetine corresponding to doses 15 mg and 7.5 mg, respectively.

Clinical studies: Repeated dose

Antidepressants are often prescribed for the treatment of tinnitus, in spite of the limited evidence of their efficacy. Only 3 randomised controlled studies with antidepressant have been published [Mihail, 1988; Robinson, 2005; Simpson, 2000]. Paroxetine was used in the last one conducted in patients suffering from tinnitus without depression [Robinson, 2005]. The treatment, based on a flex dose ranging from 20 to 50 mg day, produced no differentiation from placebo in most of the scales or questionnaires used. However, significant effects were seen on the single item of the THI scale concerning the “severity” of tinnitus without affecting other parameters. The results of this study suggest that only a subgroup of patients receive benefits from full-dose paroxetine treatments.

The effects of chronic treatment with the NK1 antagonist (GR205171) and SSRI (paroxetine or citalopram) as independent treatments were also studied in a brain imaging paradigm measuring changes in brain activation following chronic treatment in subjects with Social Anxiety Disease (SAD). Activation was induced by a public speaking task, a stressful experience for subjects suffering from SAD. The test was performed while the subject was sitting in the imaging scanner before and after the pharmacologic treatment. Activation of amygdala or adjacent medio-temporal area was measured as changes of regional cerebral blood flow (rCBF) assessed with radioactive water (water*-PET). Subjective anxiety during the public speaking stressful experience was scored using the STAI-state scale. Attenuations of exaggerated activation of amygdala or adjacent medio-temporal area were observed in patients with SAD when exposed to public speaking following 6-8 week treatment with paroxetine (20 mg/day, study NKD10020) or citalopram (40 mg/day, [Furmark, 2005]. In the same paradigm 4 weeks treatment with the NK1 antagonist GR205171 produced attenuation of public speaking-induced activation in the same brain regions of SAD patients, similar to those observed with SSRI [Furmark, 2005]. All these changes were associated with significant improvements of

13 13 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254 subjective anxiety score (STAI-state). In this study the striatal NK1 receptor occupancy was measured and estimated as >85% at the steady state.

Overall, the convergent observation of reduced activation in brain areas involved in anxiety processing and the reduced subjective score of anxiety following treatment are supportive of anxiolytic properties for NK1 antagonists.

Interestingly, vestipitant alone was assessed as the treatment of Major Depressive Disorder and of SAD in 3 trials, one of them with neuroimaging (NKD20005, NKD 20006, and NKD10020). In these trials the regimen was 15 mg daily for 8 weeks. All studies failed to show separation from placebo, most likely due to the low exposure levels at steady state related to the vestipitant metabolic auto-induction, delivering an estimated receptor occupancy <70%. Consistently, no change in activation of amygdala produced by Public Speaking was observed with water*-PET (NKD10020).

More recently, a study performed with the combination vestipitant 15 mg + paroxetine 7.5 mg administered daily for 8 weeks and using the same PET paradigm showed modest but significant attenuation in the rCBF of amygdala and a reduced STAI-state score at the end of the treatment. In a larger clinical study (n=60 per arm) the same regimen showed significant differences of clinical score when the SADS scale was used for the analysis, while the LSAS scale did not reveal differentiation from placebo. The lack of effects observed at lower doses of the combination (e.g., vestipitant 5 mg and paroxetine 5 mg) suggests that clinically relevant effects can be achieved with doses of paroxetine higher than 7.5mg and of vestipitant higher than 15mg see studies (NKP103401 and NKP102280).

In conclusion, acute administration studies indicate that vestipitant alone at the dose of 15-25 mg can produce changes in the EEG, PSG sleep, and response to CO2-induced anxiety in the same direction of those produced by benzodiazepines. Data on the anxiolytic effects of the combination of vestipitant and paroxetine in human are less robust, but when associated with the preclinical evidence, they suggest that the possibility exists that they may produce improvements in the symptoms experienced by tinnitus patients.

Dose Rationale

14 14 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254 promoting effects were associated with plasma concentrations of about 20-30 ng/ml, generally reached with 15 mg or 25 mg doses, and suggesting that RO>90% in striatum is critical to achieving effects. In line with this conclusion are the results of the Phase II studies in MDD and SAD performed at the regimen of 15 mg daily, resulting in no clinical effects and a plasma concentration of approximately 10 ng/ml. It has been calculated that a daily dose of 25 mg for 12-14 days should deliver plasma levels of 38.3ng/ml (range: 16-63) when measured at 4 h after last day administration. For this reason the dose presently proposed for vestipitant is 25 mg/day, and the main endpoints of the study are collected within 4 hrs from last administration.

When administered for 12 days the 25 mg daily dose, reaches AUC value of 496ng*h/mL (range: 199.5-824.3), well within the upper exposure range of the daily dose of 15 mg (AUC: 327ng*h/mL, range: 99.5-694.7). This observation is important for assessing the safety risk associated with this range of exposures, since the majority of Phase II trials were conducted with a dose of 15 mg. Overall, hundreds of subjects were exposed to this compound, with a low occurrence of mild averse events (AEs).. Common AEs reported include somnolence, fatigue, headache, upper respiratory tract infection, diarrhoea, erectile dysfunction, and, in one study only, evidence of rash.

Paroxetine daily dosing in chronic treatment is considered among one of the most effective treatments for depression and several anxiety disorders. Paroxetine has been dosed in tens of millions of patients around the world. The daily dose ranges from 20 to 60 mg/day. Recently, a dose of 12.5 mg/d of paroxetine CR (corresponding to 10 mg of paroxetine IR, the formulation to be used in this study) has been shown to be beneficial in depression patients, although a higher dose (25 mg) exhibits a more robust therapeutic effect (Study 29060/810). In clinical practice a titration is often used, starting with initial doses of 10 or 20 mg, then increased weekly with increments of 10 mg to a maximum of up to 50 or 60 mg. Nevertheless, SSRIs have some limitations; in particular almost one third of treated patients do not respond to these compounds and their onset of action is after 3-4 weeks of therapy. Paroxetine is metabolised mainly by CYP2D6 and is a potent inhibitor of this enzyme. As a result, an accumulation of paroxetine is seen at steady state. Paroxetine did not influence the exposure of terfenadine, a CYP3A4 substrate, in humans. The administration of SSRIs is accompanied by some adverse events that reduce the patients' compliance especially during medium/long-term treatment, the most common being gastrointestinal disorders, sleep disturbances, weight gain and sexual dysfunction. The dose proposed in this study is 20 mg/day.

Drug Interaction and Toxicity studies were conducted in animals, exploring the combination of low dose vestipitant and paroxetine (see CIB). In humans, safety, tolerability and pharmacokinetic effects of the combination of vestipitant (5mg/day) and paroxetine (2.5, 5 and 10 mg/day) were investigated for 2 weeks in study 597599/001. The combination of paroxetine and vestipitant was generally safe and well tolerated in this study (see CIB). The safety and tolerability of this combination of low doses of vestipitant and paroxetine was assessed in two other trials in SAD with various exposure groups, i.e., vestipitant 5-15 mg, paroxetine 5-7.5 mg daily for 8 weeks (studies NKP103401 and NKP102280). The analysis of the results confirmed the safety and tolerability profile observed in Healthy Volunteers, indicating also no pharmacokinetic interaction of relevance. Interestingly, signals for efficacy were detectable in the range of

15 15 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

the highest exposure for both compounds, suggesting that clinically relevant effects can be achieved with doses of paroxetine > 7.5 mg and of vestipitant > 10 mg.

Objective(s)

Primary

To measure the change in tinnitus loudness (VAS) after single (Day 1) and repeated (Day 14) administration of either vestipitant + paroxetine combination, or vestipitant alone vs. placebo. Secondary

• To measure the change in tinnitus subjective features (i.e., tinnitus pitch, intensity and distress), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level, clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep). • To evaluate safety and tolerability of vestipitant alone and the combination vestipitant + paroxetine at single dose. • To evaluate the PK/PD relationships between steady state exposure of vestipitant and vestipitant + paroxetine combination with each of the various pharmacodynamic endpoints Exploratory

To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant + paroxetine combination and placebo.

Endpoint(s)

Primary

Visual Analog Scales (VAS) to measure the change in tinnitus loudness as perceived at the moment of the measurement at 2 hrs after dosing (or at any other time point vs. pre- dose baseline in their respective treatment session).

Secondary

16 16 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

4. Clinician rated scales: a. Annoyance of Tinnitus: Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005; Zenner, 2005] Annoyance of Hyperacusis: Answer to questions: (i), “Do you feel hypersensitive to noise?” (yes/no response); and (ii), if yes, a score >1 (on the 0–7 scale) for the overall impact of hyperacusis on everyday life [Dauman, 2005]. 5. Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam. 6. PK samples collected at Day 1 (2 and 5 hours post-dose) and Day 14 (pre-dose, 2, 5 hours post-dose). Exploratory

• Diary (to be filled in the evening): a. VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) b. Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress Study Design

This is a randomised, double-blind, placebo-controlled, cross-over study that investigates the effects of single dose and repeated dosing of vestipitant + paroxetine combination and vestipitant alone vs. placebo.

Subjects suffering from tinnitus will attend the research unit for a screening visit. On Day 1, following the baseline measurements subjects will be randomized to one of the six repeated dosing treatment sequences. The Treatment Phase consists of three 14-day treatment periods separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests will be performed on Day 1 and Day 14 of each treatment period within 4 hrs after dosing. All subjects will receive all treatments and a follow up visit will be performed 14 days after the final dose of study medication. Treatments are:

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

17 17 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The screening visit consists of informed consent, clinical assessments for tinnitus diagnosis, including audiogram, questionnaires, a physical examination, vital signs, ECG, laboratory test on blood and urine samples, and the review of treatment, medication and medical history.

Study Population

Number of Subjects

Twenty-four subjects suffering with continuous tinnitus for at least six months will be recruited in the study to obtain at least 19 subjects completing the study.

Study Assessments

For detailed study assessments refer to Section 6 and Appendix 1: Time and Events Table.

18 18 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

1. INTRODUCTION

1.1. Background

Tinnitus, also known as the ringing in the ears, has been defined as “the conscious expression of a sound that originates in an involuntary manner in the head of its owner”. This symptom occurs in about 10-15% of the general population, reaching disabling levels of severity in 0.5-1%. Tinnitus is a symptom with multiple aetiologies. It is commonly associated with sensorineural hearing loss, but may arise at many ignition points within the auditory pathway. Tinnitus, as internally generated experience of sound, can be characterised by its pitch, loudness (or intensity), timbre, and associated distress. About 40% of subjects with troublesome tinnitus also suffer from hyperacusis, a troublesome sensitivity and distress to everyday life sounds that would not trouble the majority of individuals [Hazell, 1992]. Overall, it is generally accepted that the main problem of tinnitus relates more to the psychological response to the chronic distressing stimulus than to the psychophysical characteristics of the sound [Mc Combe, 2001].

Present treatments utilise counselling based therapy, the efficacy of which is difficult to determine using controlled trials. Uncertainty surrounding the mechanism of tinnitus generation makes it difficult to devise an effective treatment. The most consistent but transient pharmacological effect is produced by iv infusion of lidocaine, with up to 60% of subject responding with tinnitus partial or complete inhibition [Baguley, 2005]; [Kalcioglu, 2005]. Some evidence of improvements is reported when benzodiazepines or gabaergic drugs [Gananca, 2002; Bauer, 2006], trycyclic antidepressants, or SSRIs [Mihail, 1988; Sullivan, 1993; Golden, 1994; Robinson, 2005; Zoger, 2006] were chronically administered, while nimodipine and lamotrigine did not show efficacy indicating a clear unmet need for a better pharmacologic therapy.

Initial evidence of the relevance of novel therapeutic approaches can be obtained in small trials using an enriched population of subjects and modern instrumental endpoints that may provide useful and objective surrogates of clinical endpoints. This approach is supported by Regulatory Agencies, such as the FDA or EMEA, with the aim to reduce the risk of failure at a later stage, where more subjects are exposed and the costs exponentially increase. In particular, these small trials are valued when novel molecular targets or mechanisms of actions are at stake i.e., when previous evidence of efficacy for a given mechanism is not available.

Neurobiology of tinnitus

Several hypotheses have been proposed to explain the generation of tinnitus, some of them not mutually exclusive [Baguley, 2005; Eggermont, 2005]. The most accepted model maintains that tinnitus results form inappropriate plastic re-organisation of the auditory central pathways in response to damage, e.g., acoustic traumas or age-related hearing loss. When severe acoustic traumas are produced in rats, features of enhanced activity progressively develop in the dorsal coclear nucles (DCN). This trauma generally leads to damage of the Inner Hair Cells (IHC) of Corti’s organ, resulting into a denervation-related central reorganisation of the auditory central system. Multiunit activity recorded in DCN of the damaged rats in a sound-proof environment shows

19 19 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

spontaneous generation of action potentials that resemble those produced when intact animals are exposed to tome of low-to-moderate intensity.

[Brozoski, 2002], using auditory lever-press discrimination performance in chinchilla, demonstrated that the spontaneous firing of DCN fusiform cells, whose that mediate acoustic information processing, was significantly increased following acoustic trauma. Since chinchilla were trained to discriminate between tones before trauma, the occurrence of a spontaneous responding on the 1 Hz tone-associated lever after trauma was considered indicative of spontaneous generation of acoustic signals. In this model the stellate interneuron (type II cell) of DCN acts as an inhibitor of the spontaneously firing fusiform neurons (type IV cell). Stellate interneurons send synapses to the cell body and the dendrites of fusiform neurons. Stellate interneurones receive direct input from IHC of the Corti’s organ. It has been proposed that when the inhibitory interneurons receive less afferent stimuli due to a peripheral auditory damage (e.g., hypoacusia), their activity is reduced, resulting in an increase drive of excitatory input and increase firing of the fusiform neurons. Since fusiform neurons are projecting to higher acoustic centres, a “phantom” acoustic sensation of tinnitus is generated. In support of this mechanism, inhibitory neurotransmitter GABA and glycine were identified in the stellate interneurons of DCN [Alibardi, 2003]. The presence of GABA-A receptors on the fusiform neurons indicate that their firing can be modulated by GABA released from stellate interneurons [Campos, 2001]. The relevance of this mechanism is supported by pharmacologi experiments, showing that the GABA-A agonist gabapentin reduces tinnitus in an animal model of noise-induced hear loss [Bauer, 2001]. Similar effects were replicated in rats. In a recent open label study gabapentin was chronically administered to tinnitus subjects selected for having the audiogram and a clinical history compatible with acoustic trauma, producing signals of clinical improvement [Bauer, 2006]. These data are in line with the clinical evidence that benzodiazepines have been used successfully to reduce tinnitus in subjects [Gananca, 2002]. However, the abuse liability and side effects associated to the use of benzodiazepine limits the extensive application of this therapeutic approach. Overall, the data suggest that the enhancement of GABAergic neurotransmission can be a relevant component of the mechanism of action of benzodiazepine and gabapentine as agent that ameliorate tinnitus.

Recent publications suggest that other neurotransmitter systems are implicated in the central control of the auditory nuclei. In particular, serotonin (5-HT) has been involved in the gating and modulation of the processing of acoustic information. Serotonin neurons of the raphe nuclei send projection to most of the central auditory nuclei [Thompson, 1994]. Simpson & Davies [Simpson, 2000] suggested that disruption of 5- HT neurotransmission can lead to reduction of the inhibitory auditory filtering, possibly acting by enhancing the local interneuron inhibitory effects. This proposal is supported by attenuating effects of the SSRI citalopram on the Loudness Dependence of the Auditory Evoked Potential in volunteers [Nathan, 2006] an observation compatible with the current view of the local circuits organisation in DCN and IC [Alibardi, 2003] and functional rile of serotonin in the auditory system [Cransac, 1998]. Therefore, increased extracellular serotonin availability would be beneficial. In line with this interpretation, a partial but clinical relevant effect was reported with chronic SSRI treatment in patients with tinnitus [Golden, 1994]; [Robinson, 2005]; [Zoger, 2006]. In fact, most of the improvements were recorded around the “distressing”or annoyance feature of tinnitus,

20 20 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

rather than those related to its acoustic properties (e.g., [Robinson, 2005]). This observation is consistent with the important role played by amygdala and the emotional arousal system in the pathogenesis of tinnitus [Jastreboff, 1994].

The partially satisfactory effect of SSRI treatments is suggesting that other mechanisms are at work. Recent attention has received the neurotransmitter Substance P (SP), a neurokinin (NK) family peptide binding preferentially to the NK1 receptor. SP and NK1 receptors are widely expressed throughout the fear-processing pathways of the brain. Enhanced SP neurotransmission is associated to stress, and can contribute to anxiety and fear [Rupniak, 1994; Kramer, 1998]. Substance P terminals are also enriching the auditory system, in particular on the coclear nuclei [Wynne, 1997]. Recent evidence suggests that in guinea pigs substance P is involved in the processing of high frequency auditory signals in the DCN [Guo, 1999]. When administered to the Vental Nucleus of Trapezoid Body (VNTB) substance P produced excitatory effects on auditory nuclei neurons mediated by NK1 receptor activation [Wang, 1998]. NK1antagonists show anxiolytic effects in preclinical studies [Kramer, 1998]. No information of NK1 antagonist effects on hearing or auditory functions is available in humans.

1.2. Rationale for the use of NK1 antagonist and Selective Serotonin Uptake Inhibitors to improve tinnitus.

The proposed treatment in this study is a combination between paroxetine, a marketed SSRI drug, and vestipitant (also indicated as GW597599), a novel NK1 antagonist.

Paroxetine is a phenylpiperidine compound, which acts as a potent and selective serotonin reuptake inhibitor (SSRI) at the synaptic cleft, increasing the levels of serotonin in the brainstem, limbic structures and cortex. Paroxetine, as other SSRI, has been approved as treatment for Depression and several Anxiety Disorders. One recent randomized study in patients suffering from tinnitus showed modest improvements at 50 mg/day for 8 weeks [Robinson, 2005].

1.2.1. Preclinical studies

Recent preclinical studies indicate that the combination of paroxetine and the NK1 antagonist vestipitant produced anxiolytic effect when low doses are combined. The social interaction test in the gerbil was used to assessment of the anxiolytic-like properties of the NK1 antagonists, and of the combination of vestipitant and paroxetine [GlaxoSmithKline Document Number VH2003/00021/00]. These effects are similar to those generated by the benzodiazepine diazepam at 0.01 and 0.1 mg/kg ip.

21 21 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

In our laboratories GABAergic interneurons of the basolateral amygdala were studies using electrophysiology in vitro on preparations of rat brain slices. These interneurons express NK1 receptors. When the endogenous agonist SP was infused inhibition of the firing of the neurons was observed, a phenomenon related to the blockade of a potassium current. This current was found to be generated by a Kv3 channel, in this case the Kv3.2. The Kv3 channel family (Kv3.1–Kv3.4) displays a positively shifted voltage dependence of activation and fast activation/deactivation kinetics, features that confer on Kv3 channels the ability to accelerate the repolarisation of the action potential efficiently and specifically. Thus, Kv3 channels confer the ability on neurons to fire action potentials at high frequencies, in some cases several hundred hertz participating to the generation of EEG gamma oscillations. The application of serotonin to the basolateral amygdala preparation produced the opposite effects, increasing firing of the GABAergic interneurons and enhancing the Kv-potassium current. Preliminary experiment in vivo indicates that the co-administration of NK1 antagonists (that block the inhibiting effects of endogenous SP on GABAergic neurons) and SSRIs (that increase the firing of GABAergic neurons by increasing the availability of synaptic serotonin) increases gamma oscillation. Therefore, the increase firing of GABAergic interneurons generated by NK1 antagonist alone and by the combination between NK1 antagonist and SSRI may be one of the mechanisms involved in the anxiolytic effects observed with these compounds in vivo.

Since there is evidence that this mechanism is at work also in the auditory nuclei, we propose to use the same approach (i.e., NK1 antagonist with or without combination with SSRI) in tinnitus, where the increase firing of local GABAergic interneurons can be beneficial. In fact, brainstem auditory nuclei are enriched on NK1 receptors [Hafidi, 2002] and on Kv3 channels, the expression pattern of which is tonotopically organised in the trapezoid body neuclus (i.e., higher expression at the high frequency map, [Li, 2001; Grigg, 2000]. At the cellular levels, Kv3 channels and NK1 receptors are mostly expressed in those inhibitory neurons (e.g., the GABAergic stellate interneurons) involved in the modulation of acoustic transmission. Substance P is involved in the processing of high frequency auditory signals in the DCN [Guo, 1999] and able to activate the auditory nuclei of VNTB via NK1 receptors [Wang, 1998]. Serotonin could exert it action via several receptors which are co-expressed in the auditory neurons [Cransac, 1998] possibly via 5-HT2b receptors.

According to this expression patterns and functional role, there is expectation of synergic action of NK1 antagonist and SSRI on the inhibitory systems of the central auditory nuclei, resulting in tinnitus improvement.

1.2.2. Single dosing

The effects of single and repeated doses of benzodiazepines are well known, showing anxiolytic and hypnotic properties. On the contrary, the acute administration of SSRI, including paroxetine, is known to induce anxiety, while the chronic dosing induces anxiolytic effects. Overdosing of SSRI are associated with report of tinnitus. Less information is available on the literature concerning the effects of single or repeated administration of NK1 antagonist, and almost nothing about the combination of SSRI and

22 22 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

NK1 antagonists. A brief summary of the evidence supporting the anxiolytic and hypnotic properties of the NK1 antagonist effect is presented below.

Acute administration of vestipitant was studied in healthy volunteer at 15 mg and 25 mg doses (GSK NKD10014). Both doses produced transient pharmaco-EEG changes consisting of initial increases in delta and theta waves (2 h post-dose). Sleep spectral analysis indicated increased beta and gamma band power similar to those generated by benzodiazepines (i.e., lorazepam 2 mg). Interestingly, evidence from the literature suggests that the increase of gamma oscillations and power to be associated to Kv3- related activity on different neural system, including the increased firing of GABAergic interneurons [Traub, 2003].

In another study in healthy volunteers the effects of the acute administration of vestipitant 15 mg were compared to the attenuating effects of single dose alprazolam 0.75 mg and to placebo on transient anxiety generated by 7% CO2 breathing (GSK NKG10007), [Poma, 2005].Healthy volunteers with susceptibility to respond to the 7%CO2 challenge with anxiety were selected. Both alprazolam 0.75 and vestipitant 15 mg produced significant reductions of the scores and reduced the frequency of escape reactions (i.e., request to interrupt the procedure).

Using the same 7% CO2 challenge procedure in the same centre, a randomized, double blind, placebo controlled balanced incomplete block crossover study (GSK NKP100690) was carried out to evaluate the change in response to 7% CO2 and the pharmacokinetic profiles of acute administration of the combination of low dose vestipitant and paroxetine. A trend towards significant anxiolytic effect was observed with both treatment, i.e., vestipitant 15 mg + paroxetine 7.5 mg, or vestipitant 7.5 mg + paroxetine 5mg, as well as with vestipitant 15 mg alone, or with alprazolam 0.75 mg alone. On the contrary, a trend towards an increase in anxiety was seen after the administration of paroxetine 7.5 mg alone. A prospectively planned PK/PD analysis was conducted to explore the correlation between different level of exposure of vestipitant and proxetine alone and in combination. The PK/PD analysis indicated that the anxiolytic effect is maximized in subjects with concentrations of vestipitant and paroxetine corresponding to doses 15 mg and 7.5 mg, respectively.

1.2.3. Repeated dosing

Antidepressants are often prescribed for the treatment of tinnitus, in spite of the limited evidence of their efficacy. Only 3 randomised controlled studies with antidepressant have been published [Mihail, 1988; Sullivan, 1993; Robinson, 2005]. Paroxetine was used in the last one conducted in patients suffering from tinnitus without depression [Robinson, 2005]. The treatment, based on a flex dose ranging from 20 to 50 mg day, produced no differentiation from placebo in most of the scales or questionnaires used. However, significant effects were seen on the single item of the THI scale concerning the “severity” of tinnitus without affecting other parameters. The results of this study suggest that only a subgroup of patients receive benefits from full-dose paroxetine treatments.

The effects of chronic treatment with NK1 antagonist (GR205171) and SSRI (paroxetine or citalopram) as independent treatments were also studied in a brain imaging paradigm

23 23 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

measuring changes in brain activation following chronic treatment in subjects with Social Anxiety Disease (SAD). Activation was induced by a public speaking task, a stressful experience for subjects suffering from SAD. The test was performed while the subject was sitting into the imaging scanner before and after the pharmacologic treatment. Activation of amygdala or adjacent medio-temporal area was measured as changes of regional cerebral blood flow (rCBF) assessed with radioactive water (water*-PET). Subjective anxiety during the public speaking stressful experience was scored using the STAI-state scale. Attenuations of exaggerated activation of amygdala or adjacent medio-temporal area were observed in patients with SAD when exposed to public speaking following 6-8 week treatment with paroxetine (20 mg/day, study NKD10020) or citalopram (40 mg/day, [Furmark, 2005]). In the same paradigm 4 week treatment with the NK1 antagonist GR205171 produced attenuation of public speaking-induced activation in the same brain regions of SAD patients, similar to those observed with SSRI [Furmark, 2005]. All these changes were associated to significant improvements of subjective axienty score (STAI-state). In this study the striatal NK1 receptor occupancy was measured and estimated >85% at the steady state.

Interestingly, vestipitant alone was assessed as the treatment of Major Depressive Disorder and of SAD in 3 trials, one of them of neuroimaging (NKD20005, NKD 20006, and NKD10020). In these trials the regimen was 15 mg daily for 8 weeks. All studies failed to show separation from placebo, most likely due to the low exposure levels at the steady state related to the vestipitant metabolic auto-induction, delivering an estimated receptor occupancy <70%. Consistently, no change in activation of amygdala produced by Public Speaking was observed with water*-PET.

More recently, a study performed with the combination vestipitant 15 mg + paroxetine 7.5 mg administered daily for 8 weeks and using the same PET paradigm showed modest but significant attenuation in the rCBF of amygdala and a reduced STAI-state score at the end of the treatment. In a larger clinical study (n=60 per arm) the same regimen showed significant differences of clinical score when the SADS scale was used for the analysis, while the LSAS scale did not revealed differentiation to placebo. The lack of effects observed at lower doses of the combination (e.g., vestipitant 5 mg and paroxetine 5 mg) suggests that clinically relevant effects can be achieved with doses of paroxetine higher than 7.5mg and of vestipitant higher than 15mg (see studies NKP103401 and NKP102280).

In conclusion, acute administration studies indicate that vestipitant alone at the dose of 15-25 mg can produce changes in the EEG, PSG sleep, and response to CO2-induced anxiety in the same direction of those produced by benzodiazepine. Data on the anxiolytic effects of the combination of vestipitant ad paroxetine in human are less robust, but when associated to the preclinical evidence, they suggest the possibility to produce changes of the symptoms of the tinnitus patients.

24 24 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

1.3. Dose Rationale

Vestipitant is characterised by a potential for drug interactions, food effects, affinity for P-glycoprotein, autoinduction (0.75 at 15 mg, 0.50 at 25 mg), and hepatic enzyme elevation at high doses. Vestipitant is mainly metabolised by CYP3A4 and has been shown to be a moderate inhibitor of this enzyme in healthy volunteers administered a dose of 15 mg/day for 10 consecutive days (2 to 3 fold increases in midazolam exposures). Vestipitant did not influence the exposures of debrisoquine, a substrate of CYP2D6. Single dose pharmacodynamic studies showed that anxiolyic and sleep- promoting effects were associated with plasma concentrations of about 20-30 ng/ml, generally reached with 15 mg or 25 mg doses, and suggesting that RO>90% in striatum is critical to achieving effects. In line with this conclusion are the results of the Phase II studies in MDD and SAD performed at the regimen of 15 mg daily, resulting in no clinical effects and plasma concentration of approximately 10 ng/ml. It has been calculated that a daily dose of 25 mg for 12-14 days should deliver plasma levels of 38.3ng/ml (range: 16-63) when measured at 4 hrs after last day administration. For this reason the dose presently proposed for vestipitant is 25 mg/day, and the main endpoints of the study are collected within 4 hrs from last administration.

When administered for 12 days the 25 mg daily dose, reaches AUC value of 496ng*h/mL (range: 199.5-824.3), almost overlapping the upper exposure range of the daily dose of 15 mg (AUC: 327ng*h/mL, range: 99.5-694.7). This observation is important for assessing the safety risk associated with these range of exposures, since the majority of Phase II trials were conducted with a dose of 15 mg. Overall, hundreds of subjects were exposed to this compound, with a low occurrence of mild averse events (AEs). Common AEs reported include somnolence, fatigue, headache, upper respiratory tract infection, diarrhea, erectile dysfunction, and, in one study only, evidence of rash.

Paroxetine daily dosing in chronic treatment is considered among the most effective treatments for depression and several anxiety disorders. Paroxetine has been dosed in tens of millions of patients around the world. The daily dose ranges from 20 to 60 mg/day. Recently, a dose of 12.5 mg/d of paroxetine CR (corresponding to 10 mg of paroxetine IR, the formulation to be used in this study) has been shown to be beneficial in depression patients, although a higher dose (25 mg) exhibits a more robust therapeutic effect (Study 29060/810). In clinical practice a titration is often use, starting with initial doses of 10 or 20 mg, then increased weekly with increments of 10 mg to a maximum of up to 50 or 60 mg. Nevertheless, SSRIs have some limitations; in particular almost one third of treated patients do not respond to these compounds and their onset of action is after 3-4 weeks of therapy. Paroxetine is metabolised mainly by CYP2D6 and is a potent inhibitor of this enzyme. As a result an accumulation of paroxetine is seen at steady state. Paroxetine did not influence the exposure of terfenadine, a CYP3A4 substrate, in humans. The administration of SSRIs is accompanied by some adverse events that reduce

25 25 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

the patients' compliance especially during medium/long-term treatment, the most common being gastrointestinal disorders, sleep disturbances, weight gain and sexual dysfunction. The dose proposed in this study is 20 mg/day.

2. OBJECTIVE(S)

2.1. Primary

To measure the change in tinnitus loudness (VAS) after single (Day 1) and repeated (Day 14) administration of either vestipitant + paroxetine combination, or vestipitant alone vs. placebo.

2.2. Secondary

• To measure the change in tinnitus subjective features (i.e., tinnitus pitch, intensity and distress, and general alertness/anxiety levels), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level (i.e., visual scales, heart rate and blood pressure), clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep). • To evaluate safety and tolerability of vestipitant alone and the combination vestipitant + paroxetine at single dose. • To evaluate the PK/PD relationships between steady state exposure of vestipitant and vestipitant + paroxetine combination with each of the various pharmacodynamic endpoints. 2.3. Exploratoy

To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant + paroxetine combination and placebo.

26 26 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

3. ENDPOINT(S)

3.1. Primary

3.2. Secondary

1. Visual Analog Scales (VAS) to measure the level in tinnitus pitch, intensity and tinnitus distress as perceived at the moment of the measurement 2. VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) 3. Self-report questionnaires (integrated evaluation referring to the subject’s condition before dosing on the day of testing): a. Tinnitus Handicap Inventory (THI) b. Quick Inventory of Depressive Symptomatology (QIDS-SR 16) 4. Clinician rated scales: a. Annoyance of Tinnitus: Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005; Zenner, 2005] b. Annoyance of Hyperacusis: Answer to questions: (i), “Do you feel hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–7 scale) for the overall impact of hyperacusis on everyday life [Dauman, 2005]. 5. Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam. PK samples collected at Day 1 (2 and 5 hours post-dose) and Day 14 (pre-dose, 2, 5 hours post-dose). 3.3. Exploratory

27 27 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

4. STUDY DESIGN

Subjects suffering from tinnitus will attend the research unit for a screening visit. On Day 1, following the baseline measurements, subjects will be randomized to one of the six repeated dosing treatment sequences. The Treatment Phase consists of three 14-day treatment periods separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests will be performed on Day 1 and Day 14 of each treatment period within 4 hrs after dosing. All subjects will receive all treatments and a follow up visit will be performed 14 days after the final dose of study medication. Treatments are:

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

The screening visit consists of informed consent, clinical assessment for tinnitus diagnosis, including audiogram, questionnaires, a physical examination, vital signs, ECG, laboratory test on blood and urine samples, and the review of treatment, medication and medical history.

5. STUDY POPULATION

5.1. Number of Subjects

Twenty-four subjects suffering with continuous tinnitus for at least six months will be recruited in the study to obtain at least 19 evaluable subjects completing the study.

28 28 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

5.2. Eligibility Criteria

5.2.1. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female subjects diagnosed with tinnitus according to a standard audiology visit and examination, including otoscopy and audiograms. 2. Subject with aTHI severity grade of mild or greater (THI≥ 18, [Newman, 1998]). 3. Subjects must be 18-65 years of age inclusive. 4. The subject must have the ability to comprehend the key components of the consent form and must have given written informed consent to participate in the study prior to commencing any study specific procedures. 5. Women of childbearing potential, who have a negative pregnancy test result at screening and pre-dose on Day 1 for all the 3 treatment sessions, must be able to commit to either of the following: • Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug, OR • Agrees to consistent and correct use of an acceptable method of birth control; GSK acceptable Contraceptive Methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows: a. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or b. Oral contraceptives (either combined or progestogen only); Double-barrier method of contraception consisting of condom and an occlusive cap (diaphragm or cervical/ vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository);

IUD with a documented failure rate of less than 1% per year;

If subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active.

6. Women of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses).

29 29 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

5.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Subject with a THI grade of “No handicap” [Newman, 1998] i.e. THI score of less than 18. 2. Subjects with one of the following medical conditions: a. Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant or paroxetine b. Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug c. Subjects with known Meniere Disease or Otosclerosis d. Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows: • QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period e. Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designee considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5- fold higher than the upper limit of normal at screening. f. Subjects positive for hepatitis C antibody or hepatitis B surface antigen. g. Subjects who are not euthyroid based on clinical examination and laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. h. Subjects with current or past history of clinically significant hepatic (subjects with hepatic impairment [ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening] or a history of liver dysfunction), cardiac, renal (serum creatinine higher than 124umol/l), neurologic, cerebrovascular, metabolic, pulmonary disease or gastrointestinal bleeding. i. Subjects with a current condition of, or history of psychosis. j. Subjects who have had a myocardial infarction within 1 year prior to screening visit. k. Subjects with current or past history of seizure disorders (except for febrile seizures in childhood). l. Subjects with known current or past history of cancer

30 30 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

m. Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject's participation in the study. 3. Current or history of (within 6 months of the study) regular alcohol consumption defined as: • For males: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units. • For females: an average weekly intake of greater than 14 units or an average daily intake of greater than 2 units. • One unit is equivalent to a half-pint (220 mL) of beer or 1 (125 mL) measure of spirits or 1 glass (125 mL) of wine. 4. Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. 5. Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:- • MAOIs or Fluoxetine –4 weeks prior to Screening (Visit 1) • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening (Visit 1) • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening (Visit 1). Subjects prescribed Beta- adrenergic blockers may also be excluded due to potential drug-drug interactions. • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1 • Any herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening (Visit 1) 6. The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. 7. The subject had a medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Day 1 of all the 3 Treatment Sessions which is known to interfere with CYP2D6 or CYP3A isozymes (see CIB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.).

31 31 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

8. The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to the Screening, Visit 1, e.g., sumatriptan, naritriptan, ergotamine, alosetron. 9. The subject took thioridazine within 14 days prior to the Screening, Visit 1. 10. Subjects who have used an investigational drug or have participated in a clinical trial with an investigational medicinal product within 6 months of Screening, Visit 1. 11. Subjects who have exhibited intolerance to NK1 antagonists or SSRIs. 12. Women who have a positive HCG pregnancy test at screen visit or a positive urine or blood HCG pregnancy test performed by the investigator at the baseline visits (i.e., at Day 1 of each Treatment Session) or who are breastfeeding. 13. Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration. 14. Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study). 15. Subjects, who have donated a unit of blood (500ml) or more within the previous month or who intend to donate blood within one month of completing the study. 5.2.3. Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: vestipitant Clinical Investigator’s Brochure [Clinical Investigator's Brochure: GW597599, Version 6] and prescribing information for paroxetine: [Appendix 2, Global Data Sheet for Paroxetine].

6. STUDY ASSESSMENTS AND PROCEDURES

6.1. Screening

After providing full informed consent, subjects will undergo a medical screen to determine their eligibility for participation based on the criteria outlined in this protocol. Subjects will be screened within 28 days prior to administration of study medication on Day 1. Written informed consent must be obtained prior to any protocol-specific procedures.

Visit 1: Screening

The following assessments will be completed during screening to determine the subject’s eligibility for enrolment. If a subject has had the audiological procedures performed prior to study start (up to 3 months ago), these results may be accepted for this study.

The screening visit consists of the clinical assessment for tinnitus diagnosis, and also includes:

32 32 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Demography • Medical and Medication history • Physical examination • 12-lead ECG • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position • Clinical laboratory assessments: haematology, biochemistry, urinalysis, screens for hepatitis B and C, and urine screen for drugs of abuse, alcohol breath test. • Pregnancy test (urine or serum HCG) • Evaluation of Eligibility Criteria • Otological screen • Audiometry (Tonal Audiogram & Tinnitus Matching) • Self-scored HADS • Tinnitus Handicap Inventory (THI) • Agreement to participate in the study • Question: “How aggravated are you by tinnitus?” (8-point scale) • Annoyance of Hyperacusis. • Self-scored 16-item Quick Inventory of Depressive Symptoms(QIDS-SR 16) • VAS anxiety/arousal scores (tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed). • Diary for home scoring (training and request to try at home) 6.2. Treatment

Visit: 2, 4, and 6: Day 1 of each Treatment Period

The visit starts with a brief interview about general conditions and Vital Signs. Blood samples will be collected for safety laboratory, PGx research and for PK analyses.

Subjects will be asked to complete questionnaires at various timpoints these will includes VAS scales for tinnitus and arousal/anxiety, THI and QIDS. Subjects will be asked to report the occurrence of any AEs. For detailed timing of assessments refer to Appendix 1. Time and Events Table.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is discharged from the research unit, following vital signs and ECG measurements.

Clinic Staff to remind subjects to call the unit, if they feel unwell, experience any adverse events or if there are any changes to their mood during the washout periods between treatments.

33 33 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Visits 3, 5 and 7: Day (12-14) of each Treatment Period

Subjects maybe asked to come in between days 12-14, which is typically referred to as day 14. The visit starts with a brief interview about general conditions and vital signs will be measured. Blood samples will be collected for safety laboratory analysis and for the pre-dose PK measurements.

The Diary for home scoring is obtained, and the remaining tablets are requested for compliance checking.

For details of all assessments and timings refer to Appendix 1. Time and Events Table.

A Diary for home scoring (inter-treatment score) will be given to be returned at the next visit.

A light snack is served. Then the subject is free to go home, following an abbreviated physical exam for safety, including ECG and vital signs.

Clinic Staff to remind subjects to call the unit, if they feel unwell, experience any adverse events or if there are any changes to their mood during the washout periods between treatments.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

Information about general condition, occurrence of AEs, or any other potential issue will be obtained between 6-8 days from the beginning of the treatment. In case of detection of any SAE or AEs of clinical relevance the subject will be asked to come immediately to the Unit for a thorough medical assessment, and an attempt will be made to obtain a PK sample.

Visit 8, Follow Up (12 to 14 days after last study drug administration)

• Adverse Events and Concomitant Medication recording • Physical examination • 12-lead ECG • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position; • Clinical safety laboratory tests (haematology, clinical chemistry and urinalysis) • Pregnancy test (urine or serum HCG) • VAS scales for tinnitus and arousal/anxiety

34 34 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Any clinically significant abnormal results from the follow-up visit will be re-assessed until either stabilised or resolved.

6.2.1. Pregnancy

Pregnancy testing (urine or serum HCG) will be performed at screening, Day 1 and Follow up visits.

6.2.1.1. Time period for collecting pregnancy information

Subjects who become pregnant during the study should discontinue the study immediately. Subjects should be instructed to notify the investigator that they become pregnant either during the treatment phase of the study or within 7 days of last dose of study medication.

6.2.1.2. Action to be taken if pregnancy occurs

The investigator will collect pregnancy information on any female subject, who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of a subject's pregnancy. The subject will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE (see AE/SAE section of the protocol and the SRM for definitions and a description of follow-up).

A spontaneous abortion is always considered to be an SAE and will be reported as such. Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered reasonably related to the investigational product by the investigator, will be reported to GSK as described in section entitled, "Post-study AEs and SAEs" of the SRM. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

6.2.1.3. Action to be taken if pregnancy occurs in a female partner of a male study subject

The investigator will attempt to collect pregnancy information on any female partner of a male study subject who becomes pregnant while participating in this study. The investigator will record pregnancy information on the appropriate form and submit it to GSK within 2 weeks of learning of the partner’s pregnancy. The partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any premature termination of the pregnancy will be reported.

35 35 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

6.3. Efficacy

6.3.1. Visual Analog Scales (VAS) to measure tinnitus intensity, pitch and distress

VAS for tinnitus (intensity, pitch and distress) consists of 3 lines 100 mm-long with a 0 on the left end and a 10 on the right traced aside to the word “tinnitus intensity”, “tinnitus tone” and “tinnitus distress”. The same scales were used in Baguley et al. [Baguley, 2005] and Zenner [Zenner, 2005].

6.3.2. Self-scored questionnaires

The answer to the questionnaires referring to the Tinnitus Handicap Inventory (THI), as described in Kuk et al. [Kuk, 1990] but referring only to the current day of dosing, to be filled out up just before leaving the clinic.

The answer to the following questionnaires, referred as an integrated response concerning the subject’s conditions before dosing on the test day:

1. Tinnitus Handicap Inventory (THI), standard questionnaire as described in McCombe [Mc Combe, 2001] and Kuk [Kuk, 1990] 2. Leed Sleep Evaluation Questionnaire, as described in Hindmarch [Hindmarch, 2005] 3. Quick Inventory of Depressive Symptoms QIDS as described in Rush et al. [Rush, 2006]. 6.3.3. Daily Diary

The diary should be filled out every evening, considering the events of the day. The tinnitus VAS should be a sort of integrated assessment of how it has been during the day.

1. VAS for tinnitus loudness (i.e. intensity), pitch, and/or distress, scored as integrated assessment of the whole day. 2. Number of doses of benzodiazepines, hypnotic or herbal remedies consumed during the day 3. Number of hyperacusis episodes, brief description of the generator, VAS distress rating of the overall distress produced by hyperacusis event, and the number of site/situation that had been avoided in anticipation of hyperacusis occurrence. Study Assessments Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005]

Annoyance of Hyperacusis: Answer to questions: (i), “Do you felt hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–7scale) for the overall impact of hyperacusis on everyday life [Dauman, 2005].

6.3.4. Tinnitus Matching

Tinnitus Matching is defined as the audiometric process of determining the intensity and spectral nature that best matches subjective tinnitus.

36 36 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Pitch Match (PMF= Pitch Match Frequency)

Before beginning testing, ask the patient to describe what the tinnitus sounds like.

Use the adaptive (bracketing) method to find the pitch match frequency.

The aim of the test is to find the frequency of pure -tone which comes closest to the pitch of the most troublesome tinnitus sounds.

Explain to the patient - in terms suited to his/her understanding, and with examples from the audiometer- what you mean by pitch. He/she will her several tones presented one at a time through the left earphone. Instruct him to indicate whether each sound is “higher” or “lower” or “the same” in pitch than his/her tinnitus.

A not-masked pure-tone audiogram should be available prior to tinnitus testing and the level of the tone presented for the pitch matching of tinnitus should be between 10 - 20 dB SL at a comfortable level.

Start at the highest frequency available (8kHz) and present the tone for about 2 seconds. Repeat until the patient responds, leaving him/her time between each tone to listen to his/her tinnitus.

The next presentation (if the tinnitus is lower than 8kHz) will be the lowest frequency available. Using a bracketing technique successively eliminate the extremes of the frequency range, and gradually ‘home in’ on the tinnitus pitch match frequency (PMF). Stop when the tinnitus has been localised to the nearest octave: if possible, persuade the patient to choose one frequency. If the pitch of the innitus is below the lowest test frequency or above the hisghes, record as such. If the paient finds it impossible to make a meaningful pitch record, record as such.

Intensity Matching

Increase from threshold (t) at PMF in 1 dB steps using continous presentation (press interrupt)

Continue increasing the dB as described until matched loudness level is reached (i) Record the sensation level which is (i) - (t) = S

Perform the test in both ears starting with the most troublesome first.

6.4. Pharmacokinetics

Blood samples (approximately 7 mL each) for vestipitant and paroxetine pharmacokinetic assessment will be taken pre-dose and at scheduled timepoints (i.e., a total of 6 samples, see below) from an in-dwelling cannula.

All blood samples will be collected into Potassium-EDTA uniquely labelled collection tubes and immediately chilled on crushed water ice. Plasma will be separated by centrifugation (2000 g or approximately 3000 rpm for 15 minutes at +4°C) within 1 hour of collection. The resultant plasma will be transferred to 2uniquely labeled 3.6 mL

37 37 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

polypropylene Nunc tubes (approximately 1.7 mL of plasma in each tube), frozen immediately and stored at –20°C or colder until transferred on solid carbon dioxide for analysis. One of the aliquot will be used to assay paroxetine, the other to assay vestipitant.

The sample and storage tubes will be labeled with study number, subject number, nominal time of sample collection and analyte to be assayed.

PK samples are collected at the 1st day and 14th day of each treatment period (i.e., at pre- dose and 2-3 hrs after dosing (i.e., 2 samples).

6.5. Pharmacodynamics

6.5.1. Visual Analog Scales (VAS) to measure general alertness/anxiety levels

VAS for arousal/anxiety consists of 4 scales (100 mm long each) anchored to the following opposite words: a) tired-energetic b) active-drowsy c) tense-peaceful d) worried-relaxed. The same scales were used in Posserud et al. [Posserud, 2004].

6.5.2. Audiometry

Tonal audiometry test will be performed according to the standard diagnostic procedure.

6.5.3. Psychoacoustic measurements

Psychoacoustic assessment of tinnitus pitch, timbre, loudness and intensity will be performed according to procedure validated [Henry, 2004].

6.6. Pharmacogenetics

Information regarding pharmacogenetic research is included in Appendix 3.

7. LIFESTYLE AND/OR DIETARY RESTRICTIONS

No particular restriction applies, with exception from grapefruit whose consumption should be restricted for the duration of all the study.

8. INVESTIGATIONAL PRODUCT(S)

8.1. Description of Investigational Product

Vestipitant 25 mg and matching placebo will be supplied as white to off-white film coated round tablets in HDPE bottle

Paroxetine 20 mg and matching placebo will be supplied as capsules in HDPE bottle

8.2. Dosage and Administration

Each subject will be randomly assigned to receive, one of the following treatments:

38 38 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Cross-over administration (once daily) of:

1. vestipitant 25 mg + dummy capsule placebo, 2. vestipitant 25 mg + paroxetine 20 mg, 3. placebo dummy tablet + placebo dummy capsule Each treatment period will consist of a 14 daily dosing regimen. Treatment will be orally administered (1 tablet or dummy tablet and 1 capsule or dummy capsule a day).

Treatment periods will be separated by a washout period of at least 14 days.

8.3. Dose Rationale

The rationale for a monotherapy with vestipitant is based on its pharmacokinetic and receptor occupancy (RO) assumptions that have been proposed to explain these mixed clinical results obtained with Merk’s aprepitant (MK869) and vestipitant (GW597599). Vestipitant is characterised by a potential for drug interactions, food effects, affinity for P-glycoprotein, autoinduction (0.75 at 15 mg, 0.50 at 25 mg), and hepatic enzyme elevation at high doses. Vestipitant is mainly metabolised by CYP3A4 and has been shown to be a moderate inhibitor of this enzyme in healthy volunteers administered a dose of 15 mg/day for 10 consecutive days (2 to 3 fold increases in midazolam exposures). Vestipitant did not influence the exposures of debrisoquine, a substrate of CYP2D6. Pharmacodynamic anxiolyic effects, when observed, were associated with higher exposure (about 30 ng/ml), suggesting that RO>90% in striatum is critical to achieving efficacy. Vestipitant was safely administered in humans at doses up to 25 mg in single and repeated doses, up to 28 days. Several hundred subjects were exposed to this compound, with no relevant averse events. For example, in study NKD20005 the most common emergent adverse event possibly associated with vestipitant (defined as >5% and at least 2X that of placebo) was fatigue. However, in that study (and in the NKD100020 and NKD20006) the average exposure was 10.9 ng/ml, well below the levels of 30 ng/ml associated to > 9O% RO receptors in the striatum. It has been calculated that a daily dose of 25 mg for 14 days should deliver a RO > 9O% at steady state. The dose presently proposed for vestipitant is 25 mg/day.

Paroxetine daily dosing in chronic treatment is considered among the most effective treatments for depression and several anxiety disorders. Paroxetine has been dosed in tens of millions of patients around the world. The daily dose ranges from 20 to 60 mg/day. Recently, a dose of 12.5 mg/d of paroxetine CR (corresponding to 10 mg of paroxetine IR, the formulation to be used in this study) has been shown to be beneficial in some depression patients, although a higher dose (25 mg/d) exhibits a more robust therapeutic effect (Study 29060/810). In clinical practice a titration is often use, starting with initial doses of 10 or 20 mg, then increased weekly with increments of 10 mg to a maximum of up to 50 or 60 mg. Nevertheless, SSRIs have some limitations; in particular almost one third of treated patients do not respond to these compounds and their onset of action is after 3-4 weeks of therapy. Paroxetine is metabolised mainly by CYP2D6 and is a potent inhibitor of this enzyme. As a result an accumulation of Paroxetine is seen at steady state. Paroxetine did not influence the exposure of terfenadine, a CYP3A4 substrate, in humans. The administration of SSRIs is accompanied by some adverse events that reduce

39 39 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Drug Interaction and Toxicity studies were conducted in animals, exploring the combination of low dose vestipitant and paroxetine (see Investigator Brochure).

In humans, safety, tolerability, and pharmacokinetic effects of 14-day co-administration of vestipitant (5mg/day) and paroxetine (2.5, 5 and 10 mg/day) were investigated in study 597599/001. The combination of paroxetine and vestipitant was generally safe and well tolerated in this study (see CIB). The safety and tolerability of this combination of low doses of vestipitant and paroxetine was assessed in two other trials in SAD with various exposure groups (i.e., vestipitant 5-15 mg, paroxetine 5-7.5 mg daily for 8 weeks, studies NKP103401 and NKP102280). The analysis of the results confirmed the safety and tolerability profile observed in Healthy Volunteers, indicating also no pharmacokinetic interaction. Interestingly, signals for efficacy were detectable in the range of the highest exposure for both compounds, suggesting that clinically relevant effects can be achieved with doses of paroxetine > 7.5 mg and of vestipitant > 10 mg.

For this reason the dose indicated for this study will be 20 mg for paroxetine and 25 mg for vestipitant.

8.4. Blinding

Only in the case of an emergency, when knowledge of the investigational product is essential for the clinical management or welfare of the subject, the investigator may unblind a subject’s treatment assignment. The investigator will, whenever possible, discuss options with the Medical Monitor, on-call physician, or appropriate GSK study personnel before unblinding. If the blind is broken for any reason and the investigator is unable to contact GSK prior to unblinding, the investigator must notify GSK as soon as possible following the unblinding incident without revealing the subject’s study treatment assignment, unless the information is important to the safety of subjects remaining in the study. In addition, the investigator will record the date and reason for revealing the blinded treatment assignment for that subject in the appropriate data collection tool (as defined in Section 13.7).

If a serious adverse event (SAE; as defined in Section 11.2, "Definition of an SAE") is reported to GSK, Global Clinical Safety and Pharmacovigilance (GCSP) staff may unblind the treatment assignment for the individual subject. If an expedited regulatory report to one or more regulatory agencies is required, the report will identify the subject’s treatment assignment. When applicable, a copy of the regulatory report may be sent to investigators in accordance with relevant regulations, GSK policy, or both.

8.5. Treatment Assignment

Subjects will be assigned to study treatment in accordance with the randomization schedule provided by GSK CPSP.

The following six sequences will be used:

40 40 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

A/B/C, A/C/B, B/A/C, B/C/A, C/A/B and C/BA

Where A, represents placebo, B represents Vestipitant alone and C represents the combination between Vestipitant and Paroxetine

8.6. Packaging and Labeling

The contents of the label will be in accordance with all applicable regulatory requirements.

8.7. Handling and Storage

Investigational product must be dispensed or administered according to procedures described herein. Only subjects enrolled in the study may receive investigational product, in accordance with all applicable regulatory requirements. Only authorized site staff may supply or administer investigational product. All investigational products must be stored in a secure area with access limited to the investigator and authorized site staff and under physical conditions that are consistent with investigational product-specific requirements.

8.8. Product Accountability

The investigator, institution, or the head of the medical institution (where applicable) is responsible for investigational product accountability, reconciliation, and record maintenance. In accordance with all applicable regulatory requirements, the investigator or the head of the medical institution (where applicable), or designated site staff (e.g., storage manager, where applicable) must maintain investigational product accountability records throughout the course of the study. The responsible person(s) will document the amount of investigational product received from and returned to GSK (when applicable), the amount supplied and/or administered to and returned by subjects, if applicable.

8.9. Assessment of Compliance

Subjects will be required to record on a diary card the date and time when taking the dose at home.

8.10. Treatment of Investigational Product Overdose

No specific antidote exists for vestipitant or for paroxetine. Any overdosage of study medication will require general supportive therapies.

8.11. Occupational Safety

Investigational product is not expected to pose significant occupational safety risk to site staff under normal conditions of use and administration. A Material Safety Data Sheet (MSDS)/equivalent document describing occupational hazards and recommended handling precautions either will be provided to the investigator, where this is required by local laws, or is available upon request from GSK.

41 41 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

However, precautions are to be taken to avoid direct skin contact, eye contact, and generating aerosols or mists. In the case of unintentional occupational exposure notify the monitor.

Precaution will be taken to avoid direct contact with the investigational product. A Material Safety Data Sheet (MSDS) describing occupational hazards and recommended handling precautions will be provided to the investigator.

9. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES

9.1. Permitted Medications

All concomitant medications taken during the study will be recorded in the CRF. The minimum requirement is that drug name and the dates of administration are to be recorded.

9.2. Prohibited Medications

For prohibited medications refer to Appendix 4 (Inhibitors and inducers of Cytocrome P450 2D6 and 3A.) and to prescribing information for paroxetine (Appendix 3: Global Data Sheet for Paroxetine).

10. SUBJECT COMPLETION AND WITHDRAWAL

10.1. Subject Completion

Subjects who complete all study sessions (screening, the 3 treatment periods and post study follow up) will be considered as having completed the study.

10.2. Subject Withdrawal

10.2.1. Subject Withdrawal from Study

For individual subjects, the criteria for withdrawal from the study are:

• Mental status changes (such as agitation, confusion and anxiety) and/or motor abnormalities (such as hyperreflexia evolving into myoclonus within 6 hours, myoclonus, increased muscle tone, tremor, shivering and muscle rigidity), as assessed by the study physician. • Poor tolerability. • Liver chemistry abnormalities: see Section 11.2.2.1. • If an elevation of CK is ≥5X ULRR and symptoms suggestive of skeletal muscle effects are reported by any subject (e.g. soreness, cramping and/or pain), that subject must be withdrawn from the trial and followed up. • If an elevation of CK is ≥ 8X ULRR in any subject, that subject must be withdrawn from the trial and followed up.

42 42 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• If any post-screening elevation of troponin I is > 1X ULRR or > 2X screening value in any subject, that subject must be withdrawn from the trial and followed up. If similar SAEs occur in more than one subject, no further subject will be dosed until a full safety review of the data has taken place. Relevant reporting and discussion with the GSK medical monitor, relevant GSK personnel and with the Research Ethics Committee will then take place prior to any resumption of dosing.

If AEs which are of moderate or severe intensity and are consistent across subjects, reasonably attributable in the opinion of the investigator to dosing with the investigational product, are observed in more than 50% of the subjects, no further subject will be dosed until a full safety review of the data has taken place. Relevant reporting and discussion with the GSK medical monitor, relevant GSK personnel and with the Research Ethics Committee will then take place prior to any resumption of dosing.

10.3. Screen and Baseline Failures

Failures at the screening visit are those subjects who are not eligible to start the study following a screening assessment.

A log of all subjects screened for the study but not entered in the trial will be maintained. The reason(s) for excluding subjects will be recorded

11. ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE)

The investigator is responsible for the detection and documentation of events meeting the criteria and definition of an AE or SAE, as provided in this protocol. During the study when there is a safety evaluation, the investigator or site staff will be responsible for detecting, documenting and reporting AEs and SAEs, as detailed in both this section of the protocol and in the AE/SAE section of the SRM.

11.1. Definition of an AE

Any untoward medical occurrence in a subject or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product.

Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse or misuse.

11.2. Definition of a SAE

A serious adverse event is any untoward medical occurrence that, at any dose:

a. Results in death Is life-threatening

43 43 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which the subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe. Requires hospitalization or prolongation of existing hospitalization NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have been appropriate in the physician’s office or out-subject setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. Results in disability/incapacity, or NOTE: The term disability means a substantial disruption of a person’s ability to conduct normal life functions. This definition is not intended to include experiences of relatively minor medical significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or prevent everyday life functions but do not constitute a substantial disruption. Is a congenital anomaly/birth defect Medical or scientific judgement should be exercised in deciding whether reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. These should also be considered serious. Examples of such events are invasive or malignant cancers, intensive treatment in an emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or development of drug dependency or drug abuse. 11.2.1. Disease-Related Events and/or Disease-Related Outcomes Not Qualifying as SAEs

N/A

11.2.2. Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs

Abnormal laboratory findings (e.g., clinical chemistry, hematology, urinalysis) or other abnormal assessments that are judged by the investigator as clinically significant will be recorded as AEs or SAEs if they meet the definition of an AE or SAE. Clinically significant abnormal laboratory findings or other abnormal assessments that are detected during the study or are present at baseline and significantly worsen following the start of the study will be reported as AEs or SAEs. However, clinically significant abnormal laboratory findings or other abnormal assessments that are associated with the disease being studied, unless judged by the investigator as more severe than expected for the

44 44 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254 subject’s condition, or that are present or detected at the start of the study and do not worsen, will not be reported as AEs or SAEs.

The investigator will exercise his or her medical and scientific judgment in deciding whether an abnormal laboratory finding or other abnormal assessment is clinically significant.

11.2.2.1. Liver Chemistry Stopping Criteria

Stop study drug, repeat liver chemistries, and closely follow if:

• ALT ≥ 3xULN and bilirubin ≥ 1.5xULN (>35% direct) requires rapid evaluation, specialist consultation, where possible, and prompt GSK notification) • ALT ≥ 3xULN Subjects meeting the above liver chemistry stopping criteria should not be retreated (or rechallenged) with study drug, as more severe injury (including fatality) may occur with rechallenge, if drug-induced liver injury. Subjects meeting these liver chemistry stopping criteria should complete the procedures required in the protocol for the last study treatment visit, while continuing safety followup as outlined below.

If a subject exhibits ALT ≥ 3x ULN and bilirubin ≥ 1.5x ULN (>35% direct):

• Study drug should be immediately discontinued and the subject followed closely • Consultation with a specialist is recommended (e.g. hepatologist), where possible, to include close followup of liver chemistries, prothrombin time (as the short-lived coagulation proteins sensitively reflect liver synthetic function), clinical and mental status (i.e. to detect encephalopathy), assessment of appearance or worsening of fatigue, nausea, vomiting, abdominal pain, jaundice, fever, or rash • GSK personnel should be notified of this event within 24 hours • Follow up liver chemistries (ALT, AST, alkaline phosphatase, and bilirubin) should be obtained twice weekly until values are clearly falling and resolution to normal or screening values should be documented • Measure autoimmune markers: antinuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney microsomal antibodies (if available) • Perform liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate liver disease For subjects exhibiting either ALT ≥ 3x ULN and bilirubin ≥ 1.5x ULN (>35% direct bilirubin) or ALT ≥ 3xULN:

• Study drug should be immediately discontinued and the subject followed • Obtain CPK, LDH, and viral hepatitis serology: Hepatitis A IgM antibody, Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM), Hepatitis C RNA; CMV testing: IgM antibody or CMV PCR; EBV testing: heterophile antibody, monospot testing, or EBV PCR; Hepatitis E IgM antibody

45 45 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Follow up liver chemistries (ALT, AST, alkaline phosphatase, and bilirubin) should be monitored until values normalize, substantively improve, or stabilize • Include on adverse event pages any clinical symptoms of hepatitis: fatigue, nausea, vomiting, abdominal pain, jaundice, fever, or rash • Include on concomitant medication pages any use of acetaminophen, herbal remedies, other over the counter medications, putative hepatotoxins, or alcohol • A blood sample should be collected as soon as possible (preferably within 12 hours of the last dose) for pharmacokinetic analysis. The time of the last dose of study drug, and the actual time and date of the blood sample should be recorded in the case report form. Blood samples may be collected for DNA analysis (whole blood in EDTA tube) *, transcriptomics (Paxgene 5 ml tube)*, metabolomics, or other laboratory evaluations (e.g. paraoxonase 1, HDL-cholesterol, etc.).

11.3. Time Period, and Frequency of Detecting AEs and SAEs

From the time a subject consents to participate in the study until he or she has completed the study (including any follow-up period), all SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing therapy) or related to a GSK concomitant medication, will be reported promptly to GSK.

11.4. Prompt Reporting of SAEs to GSK

SAEs will be reported promptly to GSK as described in the following table once the investigator determines that the event meets the protocol definition of an SAE.

11.4.1. Timeframes for Submitting SAE Reports to GSK

Initial SAE Reports Follow-up Information on a Previously Reported SAE Type of SAE Time Frame Documents Time Frame Documents All SAEs 24 hrs "SAE" data 24 hrs Updated "SAE" collection tool data collection tool

11.5. AE and SAE Documentation and Follow-up Procedures

The investigator will review and adhere to the following procedures, which are outlined in detail in the AE/SAE section of the SRM:

• Method of Detecting AEs and SAEs • Recording of AEs and SAEs • Evaluating of AEs and SAEs • Completion and Transmission of SAE Reports to GSK

46 46 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Follow-up of AEs and SAEs • Post-study AEs and SAEs • Regulatory Reporting Requirements for SAEs 12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS

12.1. Hypotheses

The null hypothesis (H0) is that the difference Vestipitant + Paroxetine Combination vs placebo = 0, while the alternative hypothesis (H1) assumes a difference between the two treatments.

12.2. Study Design Considerations

The crossover study design has been selected to maximise the precision of estimation treatment comparisons.

12.2.1. Sample Size Assumptions

Data for Visual Analogue Scales for Loudness were obtained from the author of Baguley [Baguley, 2005]. From a re-analysis of these data on 16 subjects, a within-subject standard deviation of VAS change from pre-dose baseline of 12.88 mm was derived. In the same study an effect of about 28 mm was observed for Lidocaine. Assuming that the within subject SD in this study will be the same observed in Baguley [Baguley, 2005] and an effect of 14 mm (half of the effect seen for Lidocaine) 19 evaluable subjects would provide a 90% power. Assuming a drop-out rate not greater than 20% this leads to a sample size of 24 subjects

12.2.2. Sample Size Sensitivity

If the within subjects variability is increased up to 14 mm, 23 evaluable subjects are needed to provide a 90% power while 19 evaluable subjects would provide a power of about 85%.

12.2.3. Sample Size Re-estimation

None planned.

12.3. Data Analysis Considerations

12.3.1. Analysis Populations

Safety population: all subjects who receive at least one dose of a study drug.

Pharmacodynamic population: all subjects in safety population who provide data for at least 1 post-dose pharmacodynamic assessment.

Pharmacokinetic Concentration population: all subjects for whom a pharmacokinetic sample is obtained and analysed

47 47 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Pharmacokinetic Parameter population: all subjects providing pharmacokinetic parameters for at least one treatment

12.3.2. Analysis Data Sets

Observed case data will be used for all reporting. i.e. no missing data will be imputed.

12.3.3. Treatment Comparisons

12.3.3.1. Primary Comparisons of Interest

Primary comparisons of interest are:

• Vestipitant + Paroxetine Combination vs placebo at 2h post dosing day 1 and day 14 • Vestipitant vs placebo at 2h post dosing day 1 and day 14 12.3.3.2. Other Comparisons of Interest

Other comparisons of interest are:

• Vestipitant + Paroxetine Combination vs Vestipitant at 2h post dosing at day 1 and day 14 • Comparisons at the other time points 12.3.4. Interim Analysis

None planned

12.3.5. Key Elements of Analysis Plan

12.3.5.1. Efficacy Analyses

Not applicable

12.3.5.2. Safety Analyses

No formal statistical analysis is planned on safety data. All safety parameters will be reported according to the specific treatment the subject received

Extent of Exposure

A listing by subject including treatment administered in each period will be generated with dates and times of the treatment administered. The number of subjects exposed to study drug will be tabulated for each treatment group.

Adverse Events

Adverse events will be coded and classified by organ class and preferred (coded) term using MedDRA. All adverse events will be listed.

48 48 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

A summary of the number and percent of subjects reporting each AE at least once will be produced by treatment for all AEs and also for drug-related AEs and for serious AEs.

A listing showing the relationship of AE verbatim text to group terms and body systems will also be produced.

A listing of withdrawals due to AEs during the study will be provided.

Clinical Laboratory Evaluations

Haematology and clinical chemistry data will be listed by regimen and subject. The listings for each subject will be flagged high and low relative to the normal range, where applicable. Clinically significant laboratory results will additionally be listed and summarised.

Urinalysis data will be listed. Values of clinical concern will be listed and summarised.

Vital Signs

Vital signs data (systolic blood pressure, diastolic blood pressure, heart rate) data will be listed by regimen and subject. The listings for each subject will be flagged high and low relative to the normal range, where applicable. Clinically significant vital signs will additionally be listed and summarised.

Summary statistics for vital signs data (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on Day 1 of each Treatment Session.

ECG

ECG data will be listed by regimen and subject. The listings for each subject will be flagged high and low relative to the normal range, where applicable. Clinically significant vital signs will additionally be listed and summarised.

Summary statistics for ECG (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on Day 1 of each Treatment Session.

12.3.5.3. Health Outcomes Analyses

Not applicable

12.3.5.4. Pharmacokinetic Analyses

A population PK analysis will be conducted on the pooled data from Day 1 and Day 14 using the model previously derived from the study 597599/001 using NONMEM software. The following parameters will be estimated AUC(0-24), Cmax, tmax, Cavg, and CL/F on Day 14.

49 49 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Summary statistics will be derived for all the estimated PK parameters for VESTIPITANT and paroxetine.

12.3.5.5. Pharmacodynamics Analyses

The data for change from baseline (i.e., pre-dose on day 1 of each treatment) in VAS scales (loudness, pitch, intensity) or other endpoints will be analysed using a repeated measures mixed model analysis of variance, including terms for

• fixed effects: sequence, period, treatment, time point, time point*treatment • covariates: baseline, baseline*timepoint • random effects: subject, subject*period. Treatment means will be estimated on each time point and. treatment comparisons will be estimated with 95% confidence intervals.

12.3.5.6. Pharmacokinetics/Pharmacodynamics Analyses

The PK/PD relationship between vestipitant and paroxetine PK and the various pharmacodynamic endpoints of interest will be explored using plasma concentration and or average exposure. The appropriate modelling techniques including continuous and categorical methods will be investigated. This analysis will be conducted by a qualified person within CPK, GSK Verona.

12.3.5.7. Biomarker(s) Analyses

None.

13. STUDY ADMINISTRATION

13.1. Regulatory and Ethical Considerations, Including the Informed Consent Process

GSK will obtain favorable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country.

The study will be conducted in accordance with all applicable regulatory requirements.

The study will also be conducted in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following:

• IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents • Subject informed consent • Investigator reporting requirements

50 50 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

GSK will provide full details of the above either verbally, in writing or both.

Written informed consent will be obtained for each subject before he or she can participate in the study.

13.2. Quality Control (Study Monitoring)

In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the PIMS record will serve as the source document.

GSK will monitor the study consistent with the demands of the study and site activity to verify that the:

• Data are authentic, accurate, and complete. • Safety and rights of subjects are being protected. • Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements. The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

13.3. Quality Assurance

To ensure compliance with GCP and all applicable regulatory requirements, GSK may conduct a quality assurance audit. Regulatory agencies may also conduct a regulatory inspection of this study. Such audits/inspections can occur at any time during or after completion of the study. If an audit or inspection occurs, the investigator and institution agree to allow the auditor/inspector direct access to all relevant documents and to allocate his/her time and the time of his/her staff to the auditor/inspector to discuss findings and any relevant issues.

13.4. Study and Site Closure

Upon completion or premature discontinuation of the study, the monitor will conduct site closure activities with the investigator or site staff, as appropriate, in accordance with applicable regulations, GCP, and GSK procedures.

In addition, GSK reserves the right to temporarily suspend or prematurely discontinue this study at any time for reasons including, but not limited to, safety or ethical issues or severe non-compliance. For multicenter studies, this can occur at one or more or at all sites. If GSK determines such action is needed, GSK will discuss this with the investigator or the head of the medical institution (where applicable), including the reasons for taking such action, at that time. When feasible, GSK will provide advance

51 51 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

notification to the investigator or the head of the medical institution, where applicable, of the impending action prior to it taking effect.

GSK will promptly inform all other investigators or the head of the medical institution (where applicable), and/or institutions conducting the study if the study is suspended or terminated for safety reasons. GSK will also promptly inform the regulatory authorities of the suspension or termination of the study and the reason(s) for the action. If required by applicable regulations, the investigator or the head of the medical institution (where applicable) must inform the IEC/IRB promptly and provide the reason for the suspension or termination.

13.5. Records Retention

Following closure of the study, the investigator or the head of the medical institution (where applicable) must maintain all site study records, except for those required by local regulations to be maintained by someone else, in a safe and secure location. The records must be maintained to allow easy and timely retrieval, when needed (e.g., audit or inspection), and, whenever feasible, to allow any subsequent review of data in conjunction with assessment of the facility, supporting systems, and staff. Where permitted by local laws/regulations or institutional policy, some or all of these records can be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); however, caution needs to be exercised before such action is taken. The investigator must assure that all reproductions are legible and are a true and accurate copy of the original, and meet accessibility and retrieval standards, including re-generating a hard copy, if required. Furthermore, the investigator must ensure there is an acceptable back-up of these reproductions and that an acceptable quality control process exists for making these reproductions.

GSK will inform the investigator of the time period for retaining these records to comply with all applicable regulatory requirements. The minimum retention time will meet the strictest standard applicable to that site for the study, as dictated by any institutional requirements or local laws or regulations, or GSK standards/procedures; otherwise, the retention period will default to 15 years.

The investigator must notify GSK of any changes in the archival arrangements, including, but not limited to, the following: archival at an off-site facility, transfer of ownership of the records in the event the investigator leaves the site.

13.6. Provision of Study Results and Information to Investigators

When required by applicable regulations, the investigator signatory for the clinical study report will be determined at the time the report is written. When the clinical study report is completed, GSK will provide the investigator with a full summary of the study results. The investigator is encouraged to share the summary results with the subjects, as appropriate. In addition, the investigator will be given reasonable access to review the relevant statistical tables, figures, and reports and will be able to review the results for the entire study at a GSK site or other mutually agreeable location.

52 52 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

GSK will provide the investigator with the randomization codes for their site after the statistical analysis for the entire study has been completed.

13.7. Data Management

The data collection tool for this study will beGSK-defined case report forms (CRFs). In all cases, subject initials will not be collected nor transmitted to GSK. Subject data necessary for analysis and reporting will be entered/transmitted into a validated database or data system. Clinical data management will be performed in accordance with applicable GSK standards and data cleaning procedures. Original CRFs will be retained by GSK, while the investigator will retain a copy.

53 53 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

14. REFERENCES

Alibardi L. Ultrastructural distribution of glycinergic and GABAergic neurons and axon terminals in the rat dorsal cochlear nucleus, with emphasis on granule cell areas. J. Anatomy. 2003;203:31-56.

Baguley DM, Wilkins I, Axon PR, Moffat DA. The inhibitory effect of intravenous lidocaine infusion on tinnitus after translabyrinthine removal of vestibular schwannoma: a double blind, placebo-controlled, crossover study. Otology & Neurotology. 2005;26:169-176.

Bauer CA, Brozoski TJ. Assessing tinnitus and propective tinnitus therapeutics using a psychophysical animal model. Jaro. 2001;2:54-64.

Bauer CA, Brozoski TJ. Effect of gabapentin on the sensation and impact of tinnitus. Laryngoscope. 2006;116:675-681.

Brozoski TJ, Bauer CA, Caspary DM. Elevated fusiform cell activity in the dorsal cochlear nucleus of chinchillas and psychophysical evidence of tinnitus. J. Neurosci. 2002;22:2383-2390.

Campos ML, de Cabo C, Wisden W, Juiz JM, Merlo D. Expression of GABA(A) receptor subunits in rat brainstem pathways: cochlear nuclei, superior olivary complex and nucleus of the lateral lemniscus. Neurosci. 2001;102:625-638.

Cransac H, Cottet-Emard JM, Hellstrom S, Peyrin L. Specific sound-induced noradrenergic and serotonergic activation in central auditory structures. Hearing Res. 1998;118:151-156.

Dauman R, Bouscau-Faure F. Assessment and amelioration of hyperacusis in tinnitus patients. Acta Oto-Laryngologica. 2005;125:503-509.

Eggermont JJ. Tinnitus: neurobiological substrates. Drug Discovery Today. 2005;10:1283-1290.

Furmark T, L. Appel Wahlstedt F, Zancan S, Jacobsson E, Flycht K, Bergstrom M, Merlo-Pich E, Nilsson L, Bani M, Langstrom B, Fedrikson M. Attenuated regional cerebral blood flow in patients wih socu=ial phobia after treatment with the neuruokinin- 1 antagonist GR205171 or citalopram. Biologic. Psychiatry. 2005;58:132-142.

Gananca MM, Caovilla HH, Gananca FF, Gananca CF, Munhoz MS, da Silva ML, Serafini F. Clonazepam in the pharmacological treatment of vertigo and tinnitus. Int. Tinnitus J. 2002;8:50-53.

GlaxoSmithKline Document Number VH2003/00021/00.Assessment of the pharmacological activity of paroxetine, GW597599 and their combination in gerbil Social Interaction test.

Golden RN, Evans DL. Antidepressants and tinnitus. Arch. Int. Med. 1994;154:1411.

54 54 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Grigg JJ, Brew HM, Tempel BL. Differential expression of voltage-gated potassium channel genes in auditory nuclei of the mouse brainstem. Hearing Res. 2000;140:77-90.

Guo M, Wang J. The effects of substance P antibody on tuning curve of auditory evoked potential of cochlear nucleus and inferior colliculus in guinea-pigs. Chinese J. Otorhinolaryngology. 1999;34:70-73`.

Hafidi A, Beurg M, Bouleau Y, Dulon D. Comparative distibution of NK1, NK2 and NK3 receptors in the rat brainstem auditory nuclei. Brain Res. 2002;947:299-306.

Hazell JWP, Sheldrake JB. Tinnitus 91: Proceedings of the 4th Int. Tinnitus Seminar. . ed. Amsterdam:Kugler; 1992.

Henry JA, Rheinsburg B, Ellingson RM. Computer-automated tinnitus assessment using patient control of stimulus parameters. J. Rehabiitation Res. & Development. 2004;41:871-888.

Hindmarch I, Dawson J, Stanley N. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep. 2005;28:187-193.

Jastreboff P, Hazell JW, Graham RL. neurophysiological model of tinnitus dependence of the minimal masking level on treatment outcome. Hearing Res. 1994;80:216-232.

Kalcioglu MT, Bayindir T, Erdem T, Ozturan O. Objective evaluation of the effects of intravenous lidocaine on tinnitus. Hearing Res. 2005;199:81-88.

Kramer MS, Cutler N, Feighner J et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science. 1998;281:1640-1645.

Kuk FK, Tyler RS, Russel D, Jordan H. The psychometric properties of a tinnitus handicap questionnaire. Ear Hear. 1990;11:434-435.

Li W, Kaczmarek LK, Perney TM. Localisation of two high threshold potassium channel subunits in the rat central auditory system. J. Comp. Neurol. 2001;437:196-218.

Marrosu F, Santoni F, Puligheddu M, Barberini L, Maleci A, Ennas F, Mascia M Zanetti G, Tuveri A, Biggio G. Increase in 20 - 50 Hz (gamma frequencies) power spectrum and synchronization after chronic vagal nerve stimulation. Clin. Neurophysiology. 2005;116:2026-2036.

Mc Combe A, Baguley D, Coles R, Mc Kenna L, Mc Kinney C, Windle-Taylor P. Guideline for the grading of tinnitus severity. Clin. Otolaryngol. 2001;26:399.

Mihail RC, Crowley JM, Walden BE, Fishburn JL et al.,. The tricyclic imipramine in the treatment of tinnitus. Ann. Otol. Rhinol. Laryngol. 1988;97:120-123.

Nathan PJ, Segrave R, Phan KL, O'Neill B, Croft RJ. Direct evidence that acutely enhancing serotonin with the selective serotonin reuptake inhibitor citalopram modulates

55 55 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

the loudness dependence of the auditory evoked potential (LDAEP) marker of central serotonin function. Human Psychopharmacol. 2006;21:47-52.

Nemeroff CB. The role of GABA in the pathaphysiology and treatment of anxiety disorders. Psychopharmacol. Bull. 2003;37:133-146.

Newman CW, Sandridge SA. Jacobson GP. Psychometric adequacy of the Tinnitus Handicap Inventory (THI) for evaluating treatment outcome. [Journal Article]. Journal of the American Academy of Audiology. 1998;9 (2):153-60.

Poma SZ, Milleri S, Squasante L, Nucci G, Perini GI< Merlo-Pich E. Characterisation of a 7% carbon dioxide (CO2) inhalation paradigm to evoke anxiety symptoms in healthy subjects. J. Psychopharmacol. 2005;19:494-503.

Posserud I. Agerforz P. Ekman R. Bjornsson ES. Abrahamsson H. Simren M. Altered visceral perceptual and neuroendocrine response in patients with irritable bowel syndrome during mental stress. [Journal Article. Research Support, Non-U.S. Gov't] Gut. 53(8):1102-8, 2004 Aug.

Robinson SK, Viirre ES, Bailey KA, Gerke MA, Harris J eta l. Randomised placebo- controlled trial of a selective serotonin reuptake inhibitor in the treatment of non depressed tinnitus subjects. Psychosomatic Med. 2005;67:981-988.

Rupniak NMJ, Williams AR. Differential inhibition of foot tapping and chromodacryorrhoea in gerbil by CNS penetrant and non-penetrant tachykinin NK1 receptor antagonists. Eur. J. Pharmacol. 1994;265:179-183.

Rush AJ, Bernstein IH, Trivedi MH, Carmody TJ et al. An evaluation of the quick inventory of depressive symptomatology and the hamilton rating scale for depression: a sequenced treatment alternatives to relieve depression trial report. Biol. Psychiatry. 2006;59:493-501.

Simpson JJ, Davies WE. A review of evidence in support of a role for 5-HT in the perception of tinnitus. Hearing Res. 2000;145:1-7.

Sullivan J, Kanton W, Russo L, Dobie R, Sakai C. A randomised trial of nortripyline for severe chronic tinnitus: effects on depression, disability and tinnitus symptoms. Arch. In. Med. 1993;153:2251-2259.

Thompson GC, Thompson AM, Garrett KM, Britton BH. Serotonin receptors in the cental auditory system. Otolaryngology-Head and Neck Surgery. 1994;110:93-102.

Traub RD, Cunningham MO, Gloveli T, Le Beau FE, Bibbig A, Buhl EH, Whittington MA. GABA-enhanced collective behaviour in neuronal axons underlies persistent gamma frequency oscillations. Proc. Nat. Acad. Sci. 2003;100:11047-11052.

Wang X, Robertson D. Substance P-induced inward current in identified auditory efferent neurones in rat brainstem slices. J. Neurophysiology. 1998;80:218-229.

56 56 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Wynne B, Robertson D. Somatastatin and substance P-like immunoreactivity in the auditory brainstem of the adult rat. J. Chem. Neuroanatomy. 1997;12:259-266.

Zenner HP, De Maddalena H. Validity and reliability study of three tinnitus self- assessment scales: loudness, annoyance and change. Acta Oto-Laryngologica. 2005;125:1184-1188.

Zoger S, Svedlund J, Holgers KM. The effects of sertraline on severe tinnitus suffering - a randomised, double-blind, placebo-controlled study. J. Clin. Psychopharmacol. 2006;26:32-39.

57 57 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Appendices

Appendix 1: Time and Events Table

Procedures Screening Treatment Treatment Treatment Follow- Period 1 Period 2 Period 3 Up Visit 1 2 3 4 5 6 7 8

Day1 -28 1 14 1 14 1 14 12-14 days post final dose Medication, Medical history and 9 9 9 9 9 9 9 Demography2 Physical examination 9 9 9 9 9 12-lead ECG 9 9 9 9 9 9 9 9 Vital signs 9 9 9 9 9 9 9 9 Clinical Safety laboratory tests 9 9 9 9 9 9 9 9 Pregnancy test (urine or serum) 9 9 9 9 9

Eligibility Criteria Evaluation 9 1 1 ENT screening 9 Audiometry (Tonal audiogram & 9 Tinnitus Matching) Self-scored HADS 9 Self-scored THI for the day 9 9 9 9 9 9 9 Agreement to participate in the 9 study Washout up to 14 days up to 14 Washout days up to 14 Washout Training for Diary for home scoring 9 Question” How aggravated you 9 9 9 9 9 9 9 are?” Self-scored QIDS-16 9 9 9 9 9 9 9 Tinnitus VAS / Arousal VAS 9 9 9 9 9 9 9 9 Reported AEs 9 9 9 9 9 9 9 Diary for home scoring: blank 9 9 9 9 9 9 9 form3 Diary for home scoring: filled form3 9 9 9 9 9 9 9 Annoyance of Hyperacusis score 9 9 9 9 9 9 (0-7) for the day Dosing4 9 9 9 9 9 9 Blood samples for PK 9 9 9 9 9 9 measurements

Phone call for assessment5 9 9 9 9 9 9

Pharmacogenetic sampling6 9 1. Flexibility surrounding treatment days ±2 2. Only Medical History and Medication will be updated during the study 3. Subjects will be given a training diary at screening, during each visit a blank diary will be given to the subjects and subjects will be asked to return the completed/ filled diary at the next visit. 4. Dosing will be performed daily for each 14-day treatment period. 5. Phone calls to subjects at mid-time during treatment phases (at one week from the start of dosing in each treatment period. 6. Pharmacogenetic sample will be obtained predose on Day 1 of Treatment Period 1.

58 58 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Treatment Periods: 1, 2 & 3: Days: 1 and 14

Procedure Pre- 10 min 0 50 min 1h 2h 3h 4h dose Pre- dose Medical History & Concomitant 9 Medication Update Physical examination1 9 12 lead ECG 9 9 Vital Signs 9 9 Clinical Safety laboratory lests 9 Pregnancy test (urine or serum)7 9 Self-scored THI 9 9 Quiet Room 9 9 Question “How aggravated you are?” 9 94 94 Self-scored QIDS3 9 VAS Arousal & anxiety3 9 9 VAS Tinnitus3 9 9 Reported AEs5 9 Diary for home scoring: blank -dispensed 9 to subject Diary for home scoring: filled -returned 9 Annoyance of Hyperacusis score (0-7) 9 Dosing 9 Blood samples for PK measurements 9 9 Pharmacogenetic Sampling2 9 Light snack6 9 1. Physical Examination will be performed on Day 14 ONLY of each treatment period 2. Pharmacogenetic sample will be taken on Day 1 treatment period 1 ONLY 3. Assessments completed in the Quiet Room 4. Assessments completed between 2 -3 h post dose 5. Any occurrence of AEs will be recorded 6. Light snack will be given after study procedures have been completed, may be earlier than 4h post dose. 7. Pregrancy will be performed on Day 1 ONLY of each treatment period.

59 59 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Appendix 2: Paroxetine Global Datasheet

GLOBAL PRESCRIBER INFORMATION

TITLE

Paroxetine hydrochloride.

SCOPE

Trade Name(s)

AROPAX™, DEROXAT™, SEROXAT™, PAXIL™, PAXIL CR™, AROPAX CR™ , SEROXAT CR™

Formulation, Strength and Device* (*if appropriate)

Immediate release tablets:

Paroxetine hydrochloride 10mg tablet 20mg tablet 30mg tablet 40mg tablet

Equivalent to paroxetine 10mg 20mg 30mg 40mg

(as the hydrochloride) (11.38mg) (22.8mg) (34.2mg) (45.6mg)

Controlled release tablets:

Paroxetine hydrochloride 12.5mg CR tablet 25mg CR tablet 37.5mg CR tablet

Equivalent to paroxetine 12.5mg 25mg 37.5mg

(as the hydrochloride) (14.25mg) (28.51mg) (42.76mg)

Oral suspension:

Paroxetine hydrochloride:

Equivalent to paroxetine 2mg/ml

(as the hydrochloride) (2.29mg/ml)

INN/BAN/USAN name: Paroxetine

Film coated tablets for oral administration.

Suspension for oral administration.

60 60 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Excipients

Immediate release tablets:

Dibasic calcium phosphate (dihydrate) USP/Ph. Eur.

Sodium Starch Glycollate BP

Magnesium Stearate NF

Hypromellose* USP/Ph. Eur.

Titanium Dioxide (EEC No. 171)* BP/Ph. Eur.

Macrogolum 400* Ph. Eur.

Polysorbate 80* Ph. Eur.

Indigo Carmine (EEC No. 132) aluminium lake**

* present in the film coat only

** present in the film coat of the 30 mg tablet only.

Controlled release tablets:

Hydroxypropyl methylcellulose USP/Ph. Eur.

Polyvinylpyrrolidone

Lactose Monohydrate

Magnesium Stearate Ph. Eur

Colloidal silicon dioxide

Glyceryl behenate

Methacrylic acid copolymer type C

Talc

Triethyl citrate

One or more of the following colourants:

Yellow ferric oxide

Red ferric oxide

61 61 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

D&C Red No. 30

D&C Yellow No. 6

D&C Yellow No. 10

FD&C Blue No. 2

Oral suspension:

Polacrilin potassium NF

Microcrystalline Cellulose* Ph. Eur.

Propylene Glycol Ph. Eur.

Glycerol (Glycerin) Ph. Eur.

Sorbitol (70% Solution crystallising) Ph. Eur.

Methyl parahydroxybenzoate Ph. Eur. (statement needed)

Propyl parahydroxybenzoate Ph. Eur. (statement needed)

Sodium Citrate Dihydrate Ph. Eur.

Citric Acid Anhydrate Ph. Eur.

Sodium Saccharin Ph. Eur.

Natural Orange 74388-74

Natural Lemon 74940-74

FD&C Yellow No. 6 (E.E.C. No. 110)

Silicone antifoam

Purified water Ph. Eur.

* Microcrystalline cellulose containing 15% w/w carboxmethyl cellulose sodium

62 62 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

CLINICAL INFORMATION

Indications

IMMEDIATE RELEASE TABLETS/ORAL SUSPENSION:

• Adults DEPRESSION

Depression of all types, including reactive and severe depression and depression accompanied by anxiety [1].

In the treatment of depressive disorders, paroxetine exhibits comparable efficacy to standard antidepressants [2 to 19].

There is also some evidence that paroxetine may be of therapeutic value in patients who have failed to respond to standard therapy. In general, improvement in patients starts after one week but does not become superior to placebo until the second week of therapy [1, 20, 21].

Morning dosing with paroxetine does not have any detrimental effect on either the quality or duration of sleep. Moreover, patients are likely to experience improved sleep as they respond to paroxetine therapy [22].

Where it is clinical practice to co-prescribe short-acting hypnotics with antidepressants, no additional adverse events have been recorded [1].

Paroxetine is effective in improving depression and suicidal ideation concurrently during the first few weeks of therapy [23].

Results of studies in which patients received paroxetine treatment for up to one year indicate that paroxetine is effective in preventing the relapse and also recurrence of depressive symptoms [24 to 27].

OBSESSIVE COMPULSIVE DISORDER

Paroxetine has been shown to be effective in the treatment of Obsessive Compulsive Disorder (OCD) [159 to 161].

In a placebo-controlled trial, the efficacy of paroxetine in the treatment of OCD has been maintained for at least 1 year. Paroxetine was also effective in preventing the relapse of OCD [162].

PANIC DISORDER

Paroxetine has been shown to be effective in the treatment of Panic Disorder with and without agoraphobia [166 to 169].

63 63 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The combination of paroxetine and cognitive-behavioural therapy has been shown to be significantly more effective than cognitive-behavioural therapy alone in the treatment of Panic Disorder.

In a placebo-controlled trial, the efficacy of paroxetine in the treatment of Panic Disorder has been maintained for up to 1 year [170].

Paroxetine has also been shown to be effective in the prevention of relapse of Panic Disorder.

SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA

Paroxetine has been shown to be effective in the treatment of Social Anxiety Disorder/Social Phobia. The maintained efficacy of paroxetine in the long term treatment of Social Anxiety Disorder/Social Phobia has been demonstrated in a Relapse Prevention Study [187 to 190].

GENERALISED ANXIETY DISORDER

Paroxetine has been shown to be effective in the treatment of Generalised Anxiety Disorder. The maintained efficacy of paroxetine in the long term treatment of Generalised Anxiety Disorder has been demonstrated in a Relapse Prevention Study.

POST-TRAUMATIC STRESS DISORDER

Paroxetine has been shown to be effective in the treatment of Post-traumatic Stress Disorder.

ALL INDICATIONS

• Children and adolescents (<18 years) Paroxetine is not indicated for use in children or adolescents aged <18 years (see Warnings and Precautions).

Controlled clinical studies in children and adolescents with major depressive disorder failed to demonstrate efficacy, and do not support the use of paroxetine in the treatment of depression in this population (see Warnings and Precautions). [198]

The safety and efficacy of paroxetine in children aged <7 years has not been studied.

CONTROLLED RELEASE TABLETS:

• Adults MAJOR DEPRESSIVE DISORDER

Paroxetine CR tablets are indicated for the treatment of major depressive disorder [194].

64 64 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PREMENSTRUAL DYSPHORIC DISORDER

Paroxetine CR tablets are indicated for the treatment of premenstrual dysphoric disorder (PMDD) [194].

PANIC DISORDER

Paroxetine CR tablets have been shown to be effective in the treatment of Panic Disorder with or without agoraphobia [194].

SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA

Paroxetine CR Tablets have been shown to be effective in the treatment of Social Anxiety Disorder/Social Phobia.

The effectiveness of paroxetine CR tablets in the long-term treatment of Social Anxiety Disorder/Social Phobia has not been evaluated. Therefore, if paroxetine CR tablets are to be administered for extended periods in the treatment of Social Anxiety Disorder/Social Phobia, the physician should periodically re-evaluate the long-term usefulness of paroxetine CR for the individual patient.

ALL INDICATIONS

• Children and adolescents (<18 years) Paroxetine is not indicated for use in children or adolescents aged <18 years (see Warnings and Precautions).

The efficacy of paroxetine CR tablets has not been studied in children or adolescents aged <18 years; however, controlled clinical studies with paroxetine IR tablets in children and adolescents with major depressive disorder failed to demonstrate efficacy, and do not support the use of paroxetine in the treatment of depression in this population (see Warnings and Precautions). [198]

The safety and efficacy of paroxetine in children aged <7 years has not been studied.

Dosage and Administration

IMMEDIATE RELEASE FORMULATIONS:

• Adults It is recommended that paroxetine is administered once daily in the morning with food. The tablet should be swallowed rather than chewed [22, 30].

DEPRESSION

The recommended dose is 20 mg daily. Some patients not responding to a 20 mg dose may benefit from dose increases in 10 mg/day increments, up to a maximum of 50 mg/day according to the patient's response [1, 28].

65 65 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within 2 to 3 weeks of initiation of therapy and thereafter as judged clinically appropriate.

Patients with depression should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months.

OBSESSIVE COMPULSIVE DISORDER

The recommended dose is 40 mg daily. Patients should start on 20 mg and the dose can be increased weekly in 10 mg increments. Some patients will benefit from having their dose increased up to a maximum of 60 mg/day [163].

Patients with OCD should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

PANIC DISORDER

The recommended dose is 40mg daily. Patients should be started on 10mg/day and the dose increased weekly in 10mg increments according to patient's response. Some patients may benefit from having their dose increased up to a maximum of 60mg/day [166 to 169].

A low initial starting dose is recommended to minimise the potential worsening of panic symptomatology which is generally recognised to occur early in the treatment of this disorder [174 to 176].

Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA

The recommended dose is 20mg daily. Some patients not responding to a 20mg dose may benefit from having dose increases in 10mg increments as required, up to a maximum of 50mg/day according to the patient's response.

GENERALISED ANXIETY DISORDER

POST-TRAUMATIC STRESS DISORDER

66 66 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

CONTROLLED RELEASE TABLETS:

• Adults Paroxetine CR tablets should be administered as a single daily dose, usually in the morning, with or without food. Patients should be informed that paroxetine CR tablets should not be chewed or crushed, and should be swallowed whole.

MAJOR DEPRESSIVE DISORDER

The recommended initial dose is 25 mg/day. Some patients not responding to a 25 mg dose may benefit from dose increases in 12.5 mg/day increments, up to a maximum of 62.5 mg/day according to patient response. Dose changes should occur at intervals of at least one week.

As with all antidepressant drugs, dosage should be reviewed and adjusted if necessary within 2 to 3 weeks of initiation of therapy and thereafter as judged clinically appropriate.

Patients with depression should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months.

PANIC DISORDER

Patients should begin treatment on 12.5 mg/day and the dose increased weekly in 12.5 mg/day increments according to patient response. Some patients may benefit from having their dose increased up to a maximum of 75 mg/day.

A low initial starting dose is recommended to minimise the potential worsening of panic symptomatology which is generally recognised to occur early in the treatment of this disorder.

Patients with panic disorder should be treated for a sufficient period to ensure that they are free from symptoms. This period may be several months or even longer.

PREMENSTRUAL DYSPHORIC DISORDER

The recommended initial dose is 12.5 mg/day. Some patients not responding to a 12.5 mg dose may benefit from having their dose increased to 25 mg/day. Dose changes should occur at intervals of at least one week.

Paroxetine CR may be administered daily throughout the menstrual cycle or limited to intermittent dosing in the luteal phase of the menstrual cycle, depending on physician assessment.

Patients with PMDD should be periodically assessed to determine the need for continual treatment.

67 67 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

SOCIAL ANXIETY DISORDER/SOCIAL PHOBIA

The recommended initial dose is 12.5mg daily. Some patients not responding to a 12.5mg dose may benefit from having dose increases in 12.5mg/day increments as required, up to a maximum of 37.5mg/day according to the patient's response. Dose changes should occur at intervals of at least one week.

General Information

DISCONTINUATION OF PAROXETINE

As with other psychoactive medications, abrupt discontinuation should generally be avoided (see sections Warnings and Precautions & Adverse Reactions). The taper phase regimen used in recent clinical trials involved a decrease in the daily dose by 10 mg/day at weekly intervals. When a daily dose of 20 mg/day (equivalent to 25 mg/day controlled release tablets) was reached, patients were continued on this dose for one week before treatment was stopped. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose, but at a more gradual rate [197, 198].

Populations

• Elderly Increased plasma concentrations of paroxetine occur in elderly subjects, but the range of concentrations overlaps with that observed in younger subjects [31].

Immediate Release formulations:

Dosing should commence at the adult starting dose and may be increased up to 40 mg daily.

Controlled Release formulations:

Dosing should commence at 12.5 mg/day and may be increased up to 50 mg daily.

• Children and adolescents (<18 years) Paroxetine is not indicated for use in children or adolescents aged <18 years (see Indications and Warnings and Precautions).

• Renal/hepatic impairment Increased plasma concentrations of paroxetine occur in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or in those with hepatic impairment. Therefore, dosage should be restricted to the lower end of the dosage range [32 to 34].

68 68 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Contraindications

Known hypersensitivity to paroxetine and excipients.

Paroxetine should not be used in combination with monoamine oxidase (MAO) inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) or within 2 weeks of terminating treatment with MAO inhibitors. Likewise, MAO inhibitors should not be introduced within 2 weeks of cessation of therapy with paroxetine (see Interactions). [215]

Paroxetine should not be used in combination with thioridazine, because, as with other drugs which inhibit the hepatic enzyme CYP450 2D6, paroxetine can elevate plasma levels of thioridazine (see Interactions). Administration of thioridazine alone can lead to QTc interval prolongation with associated serious ventricular arrhythmia such as torsades de pointes, and sudden death.

Paroxetine should not be used in combination with pimozide (see Interactions). [204]

Warnings and Precautions

Children and Adolescents (<18 years)

Treatment with antidepressants is associated with an increased risk of suicidal thinking and behaviour in children and adolescents with Major Depressive Disorder (MDD) and other psychiatric disorders. In clinical trials of paroxetine in children and adolescents, adverse events related to suicidality (suicide attempts and suicidal thoughts) and hostility (predominantly aggression, oppositional behaviour and anger) were more frequently observed in patients treated with paroxetine compared to those treated with placebo (see Adverse Reactions). Long-term safety data in children and adolescents concerning growth, maturation and cognitive and behavioural development are lacking [198, 200].

Clinical worsening and suicide risk in adults

Young adults, especially those with MDD, may be at increased risk for suicidal behaviour during treatment with paroxetine. An analysis of placebo controlled trials of adults with psychiatric disorders showed a higher frequency of suicidal behaviour in young adults (prospectively defined as aged 18-24 years) treated with paroxetine compared with placebo (17/776 [2.19%] versus 5/542 [0.92%]), although this difference was not statistically significant. In the older age groups (aged 25-64 years and ≥65 years), no such increase was observed. In adults with MDD (all ages), there was a statistically significant increase in the frequency of suicidal behaviour in patients treated with paroxetine compared with placebo (11/3455 [0.32%] versus 1/1978 [0.05%]; all of the events were suicide attempts). However, the majority of these attempts for paroxetine (8 of 11) were in younger adults aged 18-30 years. These MDD data suggest that the higher frequency observed in the younger adult population across psychiatric disorders may extend beyond the age of 24. [211]

69 69 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Patients with depression may experience worsening of their depressive symptoms and/or the emergence of suicidal ideation and behaviours (suicidality) whether or not they are taking antidepressant medications. This risk persists until significant remission occurs. It is general clinical experience with all antidepressant therapies that the risk of suicide may increase in the early stages of recovery. Other psychiatric conditions for which paroxetine is prescribed can be associated with an increased risk of suicidal behaviour, and these conditions may also be co-morbid with MDD. Additionally, patients with a history of suicidal behaviour or thoughts, young adults, and those patients exhibiting a significant degree of suicidal ideation prior to commencement of treatment, are at a greater risk of suicidal thoughts or suicide attempts. All patients should be monitored for clinical worsening (including development of new symptoms) and suicidality throughout treatment, and especially at the beginning of a course of treatment, or at the time of dose changes, either increases or decreases. [201, 211]

Patients, (and caregivers of patients) should be alerted about the need to monitor for any worsening of their condition (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour or thoughts of harming themselves and to seek medical advice immediately if these symptoms present. It should be recognised that the onset of some symptoms, such as agitation, akathisia or mania, could be related either to the underlying disease state or the drug therapy (see Akathisia and Mania and Bipolar Disorder below; Adverse Reactions). [201]

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who experience clinical worsening (including development of new symptoms) and/or the emergence of suicidal ideation/behaviour, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. [201]

Akathisia

Rarely, the use of paroxetine or other SSRIs has been associated with the development of akathisia, which is characterised by an inner sense of restlessness and psychomotor agitation such as an inability to sit or stand still usually associated with subjective distress. This is most likely to occur within the first few weeks of treatment.

Serotonin Syndrome/Neuroleptic Malignant Syndrome

On rare occasions development of a serotonin syndrome or neuroleptic malignant syndrome-like events may occur in association with treatment of paroxetine, particularly when given in combination with other serotonergic and/or neuroleptic drugs. As these syndromes may result in potentially life-threatening conditions, treatment with paroxetine should be discontinued if such events (characterised by clusters of symptoms such as hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, mental status changes including confusion, irritability, extreme agitation progressing to delirium and coma) occur and supportive symptomatic treatment should be initiated. Paroxetine should not be used in combination with serotonin-precursors (such as L-tryptophan, oxitriptan) due to the risk of serotonergic syndrome (see Contraindications and Interactions).

70 70 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Mania and Bipolar disorder

A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone can increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Prior to initiating treatment with an antidepressant, patients should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that paroxetine is not approved for use in treating bipolar depression. As with all antidepressants, paroxetine should be used with caution in patients with a history of mania.

Monoamine Oxidase Inhibitors

Treatment with paroxetine should be initiated cautiously at least 2 weeks after terminating treatment with MAO inhibitors and dosage of paroxetine should be increased gradually until optimal response is reached (see Contraindications and Interactions).

i. Renal/hepatic impairment Caution is recommended in patients with severe renal impairment or in those with hepatic impairment. (See Dosage and Administration).

Epilepsy

As with other antidepressants, paroxetine should be used with caution in patients with epilepsy [1].

Seizures

Overall the incidence of seizures is less than 0.1% in patients treated with paroxetine [1]. The drug should be discontinued in any patient who develops seizures.

ECT

There is little clinical experience of the concurrent administration of paroxetine with ECT.

Glaucoma

As with other SSRIs, paroxetine can cause mydriasis and should be used with caution in patients with narrow angle glaucoma [218].

Hyponatraemia

Hyponatraemia has been reported rarely, predominantly in the elderly. The hyponatraemia generally reverses on discontinuation of paroxetine.

71 71 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Haemorrhage

Skin and mucous membrane bleedings (including gastrointestinal bleeding) have been reported following treatment with paroxetine. Paroxetine should therefore be used with caution in patients concomitantly treated with drugs that give an increased risk for bleeding, and in patients with a known tendency for bleeding or those with predisposing conditions.

Cardiac Conditions

The usual precautions should be observed in patients with cardiac conditions [1].

Symptoms seen on discontinuation of paroxetine treatment in adults:

In clinicals trials in adults, adverse events seen on treatment discontinuation occurred in 30% of patients treated with paroxetine compared to 20% of patients treated with placebo. The occurrence of discontinuation symptoms is not the same as the drug being addictive or dependence producing as with a substance of abuse.

Dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, tremor, confusion, sweating, headache, diarrhoea have been reported. Generally these symptoms are mild to moderate, however, in some patients they may be severe in intensity. They usually occur within the first few days of discontinuing treatment, but there have been very rare reports of such symptoms in patients who have inadvertently missed a dose. Generally these symptoms are self-limiting and usually resolve within 2 weeks, though in some individuals they may be prolonged (2-3 months or more). It is therefore advised that paroxetine should be gradually tapered when discontinuing treatment over a period of several weeks or months, according to the patient's needs (see "Discontinuation of Paroxetine", Dosage and Administration). [206]

Symptoms seen on discontinuation of paroxetine treatment in children and adolescents:

In clinical trials in children and adolescents, adverse events seen on treatment discontinuation occurred in 32% of patients treated with paroxetine compared to 24% of patients treated with placebo. Events reported upon discontinuation of paroxetine at a frequency of at least 2% of patients and which occured at a rate at least twice that of placebo were: emotional lability (including suicidal ideation, suicide attempt, mood changes and tearfulness), nervousness, dizziness, nausea and abdominal pain (see Adverse Reactions).

Paroxetine Oral Suspension

Paroxetine oral suspension contains methyl and propyl hydroxybenzoate (parabens), which are known to cause urticaria, delayed type reactions such as contact dermatitis and rarely, immediate hypersensitivity reactions with bronchospasm.

72 72 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

In patients receiving oral suspension, the paroxetine plasma concentration may be influenced by gastric pH. In vitro data have shown that an acidic environment is required for release of the active drug from the suspension, hence absorption may be reduced in patients with a high gastric pH. Caution is therefore required because in certain situations the plasma paroxetine concentration may increase (e.g. following discontinuation of a proton pump inhibitor or a histamine H2-receptor antagonist) or the plasma paroxetine concentration may decrease (e.g. in patients with a high gastric pH changing therapy from tablet to oral suspension). [207]

Interactions [45 to 66, 186]

Serotonergic drugs [67 to 69] As with other SSRIs, co-administration with serotonergic drugs may lead to an incidence of 5-HT associated effects (serotonin syndrome: see Warnings and Precautions). Caution should be advised and a closer clinical monitoring is required when serotonergic drugs (such as L-tryptophan, triptans, tramadol, SSRIs, lithium and St. John's Wort – Hypericum perforatum – preparations) are combined with paroxetine. Concomitant use of paroxetine and MAO inhibitors (including linezolid, an antibiotic which is a reversible non-selective MAO inhibitor) is contraindicated (see Contraindications). [215]

Pimozide Increased pimozide levels have been demonstrated in a study of a single low dose pimozide (2 mg) when co-administered with paroxetine. This is explained by the known CYP2D6 inhibitory properties of paroxetine. Due to the narrow therapeutic index of pimozide and its known ability to prolong QT interval, concomitant use of pimozide and paroxetine is contraindicated (see Contraindications). [204, 216]

Drug metabolising enzymes [53 to 57, 62, 208] The metabolism and pharmacokinetics of paroxetine may be affected by the induction or inhibition of drug metabolising enzymes.

When paroxetine is to be co-administered with a known drug metabolising enzyme inhibitor, consideration should be given to using doses at the lower end of the range. No initial dosage adjustment is considered necessary when the drug is to be co- administered with known drug metabolising enzyme inducers (e.g. carbamazepine, rifampicin, phenobarbital, phenytoin). Any subsequent dosage adjustment should be guided by clinical effect (tolerability and efficacy).

Fosamprenavir/ritonavir: Co-administration of fosamprenavir/ritonavir with paroxetine significantly decreased plasma levels of paroxetine. Any dose adjustment should be guided by clinical effect (tolerability and efficacy).

Procyclidine: Daily administration of paroxetine increases significantly the plasma levels of procyclidine. If anti-cholinergic effects are seen, the dose of procyclidine should be reduced [70].

73 73 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Anticonvulsants: carbamazepine, phenytoin, sodium valproate. Concomitant administration does not seem to show any effect on pharmacokinetic/dynamic profile in epileptic patients [53, 54, 62].

CYP2D6 inhibitory potency of paroxetine: As with other antidepressants, including other SSRIs, paroxetine inhibits the hepatic cytochrome P450 enzyme CYP2D6. Inhibition of CYP2D6 may lead to increased plasma concentrations of co-administered drugs metabolised by this enzyme. These include certain tricyclic antidepressants (e.g. amitriptyline, nortriptyline, imipramine and desipramine), phenothiazine neuroleptics (e.g. perphenazine and thioridazine, see Contraindications), risperidone, atomoxetine, certain Type 1c antiarrhythmics (e.g. propafenone and flecainide) and metoprolol [37 to 44, 177 to 180, 202].

Tamoxifen is a pro-drug requiring metabolic activation by CYP2D6. Inhibition of CYP2D6 by paroxetine may lead to reduced plasma concentrations of an active metabolite and hence reduced efficacy of tamoxifen. [220]

CYP3A4

An in vivo interaction study involving the co-administration under steady state conditions of paroxetine and terfenadine, a substrate for cytochrome CYP3A4, revealed no effect of paroxetine on terfenadine pharmacokinetics. A similar in vivo interaction study revealed no effect of paroxetine on alprazolam pharmacokinetics and vice-versa. Concurrent administration of paroxetine with terfenadine, alprazolam and other drugs that are CYP3A4 substrates would not be expected to cause a hazard [191 to 193].

Drugs affecting gastric pH

In vitro data have shown that dissociation of paroxetine from the oral suspension is pH-dependant. Therefore, drugs that alter gastric pH (such as proton pump inhibitors or histamine H2-receptor antagonists) may affect plasma paroxetine concentrations in patients taking the oral suspension (see Warnings and Precautions). [207]

Clinical studies have shown the absorption and pharmacokinetics of paroxetine to be unaffected or only marginally affected (i.e. at a level which warrants no change in dosing regimen) by:

• food [29, 30]

• antacids [35, 36]

• digoxin [47 to 49]

• propranolol [46]

• alcohol: paroxetine does not increase the impairment of mental and motor skills caused by alcohol, however, the concomitant use of paroxetine and alcohol is not advised. [63 to 66]

74 74 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Pregnancy and Lactation

Fertility

No Text.

Pregnancy

Animal studies have not shown any teratogenic or selective embryotoxic effects. [71, 72] Recent epidemiological studies of pregnancy outcomes following maternal exposure to antidepressants in the first trimester have reported an increase in the risk of congenital malformations, particularly cardiovascular (e.g. ventricular and atrial septal defects), associated with the use of paroxetine. The data suggest that the risk of having an infant with a cardiovascular defect following maternal paroxetine exposure is approximately 1/50, compared with an expected rate for such defects of approximately 1/100 infants in the general population. [205, 210]

The prescribing physician will need to weigh the option of alternative treatments in women who are pregnant or are planning to become pregnant, and should only prescribe paroxetine if the potential benefit outweighs the potential risk. If a decision is taken to discontinue paroxetine treatment in a pregnant woman, the prescriber should consult Dosage and Administration - Discontinuation of Paroxetine and Warnings and Precautions – Symptoms seen on discontinuation of paroxetine treatment in adults.

There have been reports of premature birth in pregnant women exposed to paroxetine or others SSRIs, although a causal relationship with drug therapy has not been established [199].

Neonates should be observed if maternal use of paroxetine continues into the later stages of pregnancy, because there have been reports of complications in neonates exposed to paroxetine or other SSRIs late in the third trimester of pregnancy. However, a causal association with drug therapy has not been confirmed. Reported clinical findings have included: respiratory distress, cyanosis, apnoea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypertonia, hypotonia, hyperreflexia, tremor, jitteriness, irritability, lethargy, constant crying and somnolence. In some instances the reported symptoms were described as neonatal withdrawal symptoms. In a majority of instances the complications were reported to have arisen either immediately or soon (<24 hours) after delivery.

In one epidemiological study, the use of SSRIs (including paroxetine) after the first 20 weeks of pregnancy, was associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN). The absolute risk among those who used SSRIs late in pregnancy was reported to be about 6 to 12 per 1000 women, compared to 1 to 2 per 1000 women in the general population. [212]

Lactation

Small amounts of paroxetine are excreted into breast milk. In published studies, serum concentrations in breast-fed infants were undetectable (<2 ng/ml) or very low (<4 ng/ml).

75 75 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

No signs of drug effects were observed in these infants. Nevertheless, paroxetine should not be used during lactation unless the expected benefits to the mother justify the potential risks for the infant.

Ability to perform tasks that require judgement, motor or cognitive skills

Clinical experience has shown that therapy with paroxetine is not associated with impairment of cognitive or psychomotor function. However, as with all psychoactive drugs, patients should be cautioned about their ability to drive a car and operate machinery [63 to 66].

Although paroxetine does not increase the mental and motor skill impairments caused by alcohol, the concomitant use of paroxetine and alcohol is not advised [63 to 66].

Adverse Reactions [1, 158, 163, 171, 196 to 197, 203, 206, 209, 213, 214, 217, 218, 219]

Some of the adverse experiences listed below may decrease in intensity and frequency with continued treatment and do not generally lead to cessation of therapy. Adverse drug reactions are listed below by system organ class and frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100, <1/10), uncommon (≥ 1/1,000, <1/100), rare (≥ 1/10,000, <1/1,000), very rare (<1/10,000), including isolated reports. The frequencies of common and uncommon events were generally determined from pooled safety data from a clinical trial population of >8000 paroxetine-treated patients and are quoted as excess incidence over placebo. Rare and very rare events were generally determined from post-marketing data and refer to reporting rate rather than true frequency.

Blood & lymphatic system disorders

Uncommon: abnormal bleeding, predominantly of the skin and mucous membranes (mostly ecchymosis). Very rare: thrombocytopenia.

Immune system disorders

Very rare: allergic reactions (including urticaria and angioedema).

Endocrine disorders

Very rare: syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

Metabolism & nutrition disorders

Common: increases in cholesterol levels, decreased appetite. Rare: hyponatraemia.

76 76 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Hyponatraemia has been reported predominantly in elderly patients and is sometimes due to syndrome of inappropriate anti-diuretic hormone secretion (SIADH).

Psychiatric disorders

Common: somnolence, insomnia, agitation. Uncommon: confusion, hallucinations. Rare: manic reactions.

These symptoms may be due to the underlying disease.

Nervous system disorders

Common: dizziness, tremor, headache. Uncommon: extrapyramidal disorders. Rare: convulsions, akathisia. Very rare: serotonin syndrome (symptoms may include agitation, confusion, diaphoresis, hallucinations, hyperreflexia, myoclonus, shivering tachycardia and tremor).

Reports of extrapyramidal disorders including oro-facial dystonia have been received in patients sometimes with underlying movement disorders or who were using neuroleptic medication.

Eye disorders

Common: blurred vision. Uncommon: mydriasis (see Warnings and Precautions). Very rare: acute glaucoma.

Cardiac disorders

Uncommon: sinus tachycardia

Vascular disorders

Uncommon: postural hypotension.

Respiratory, thoracic and mediastinal disorders

Common: yawning.

Gastrointestinal disorders

Very common: nausea. Common: constipation, diarrhoea, dry mouth. Very rare: gastrointestinal bleeding.

77 77 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Hepato-biliary disorders

Rare: elevation of hepatic enzymes. Very rare: hepatic events (such as hepatitis, sometimes associated with jaundice and/or liver failure).

Elevation of hepatic enzymes has been reported. Post-marketing reports of hepatic events (such as hepatitis, sometimes associated with jaundice, and/or liver failure) have also been received very rarely. Discontinuation of paroxetine should be considered if there is prolonged elevation of liver function test results.

Skin & subcutaneous tissue disorders

Common: sweating. Uncommon: skin rashes. Very rare: photosensitivity reactions.

Renal & urinary disorders

Uncommon: urinary retention, urinary incontinence.

Reproductive system & breast disorders

Very common: sexual dysfunction. Rare: hyperprolactinaemia / galactorrhoea.

General disorders & administration site conditions

Common: asthenia, body weight gain. Very rare: peripheral oedema.

Symptoms seen on discontinuation of paroxetine treatment:

Common: Dizziness, sensory disturbances, sleep disturbances, anxiety, headache. Uncommon: Agitation, nausea, tremor, confusion, sweating, diarrhoea.

As with many psychoactive medicines, discontinuation of paroxetine (particularly when abrupt) may lead to symptoms such as dizziness, sensory disturbances (including paraesthesia, electric shock sensations and tinnitus), sleep disturbances (including intense dreams), agitation or anxiety, nausea, headache, tremor, confusion, diarrhoea and sweating. In the majority of patients, these events are mild to moderate and are self- limiting. No particular patient group appears to be at higher risk of these symptoms; it is therefore advised that when paroxetine treatment is no longer required, gradual discontinuation by dose tapering be carried out (see Dosage and Administration & Warnings and Precautions).

Adverse Events from Paediatric Clinical Trials

In paediatric clinical trials the following adverse events, were reported at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo: emotional

78 78 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

lability (including self-harm, suicidal thoughts, attempted suicide crying and mood fluctuations), hostility, decreased appetite, tremor, sweating, hyperkinesia and agitation. Suicidal thoughts and suicide attempts were mainly observed in clinical trials of adolescents with Major Depressive Disorder. Hostility occurred particularly in children with obsessive compulsive disorder, and especially in younger children less than 12 years of age) [198].

In studies that used a tapering regimen (daily dose decreased by 10 mg/day at weekly intervals to a dose of 10 mg/day for one week), symptoms reported during the taper phase or upon discontinuation of paroxetine at a frequency of at least 2% of patients and occurred at a rate at least twice that of placebo were: emotional lability, nervousness, dizziness, nausea and abdominal pain (see Warnings and Precautions) [198].

Overdosage

Symptoms and Signs

A wide margin of safety is evident from available overdose information on paroxetine.

Experience of paroxetine in overdose has indicated that, in addition to those symptoms mentioned under 'Adverse Reactions', vomiting, fever, blood pressure changes, involuntary muscle contractions, anxiety and tachycardia have been reported. [217, 218]

Patients have generally recovered without serious sequelae even when doses of up to 2000 mg have been taken alone. Events such as coma or ECG changes have occasionally been reported and, very rarely a fatal outcome, but generally when paroxetine was taken in conjunction with other psychotropic drugs, with or without alcohol.

Treatment

No specific antidote is known.

The treatment should consist of those general measures employed in the management of overdose with any antidepressant. Where appropriate, the stomach should be emptied by lavage. Following evacuation, 20 to 30 g of activated charcoal may be administered every 4 to 6 h during the first 24 h after ingestion. Supportive care with frequent monitoring of vital signs and careful observation is indicated.

Clinical Pharmacology

Pharmacodynamics

ATC Code

No Text.

Mechanism of Action

Paroxetine is a potent and selective inhibitor of 5-hydroxytryptamine (5-HT, serotonin) uptake and its antidepressant action and effectiveness in the treatment of OCD and Panic

79 79 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Disorder is thought to be related to its specific inhibition of 5-HT uptake in brain neurones [73 to 85, 164, 165, 172, 173].

Paroxetine is chemically unrelated to the tricyclic, tetracyclic and other available antidepressants.

Paroxetine has low affinity for muscarinic cholinergic receptors and animal studies have indicated only weak anticholinergic properties [75, 81, 90 to 95].

In accordance with this selective action, in vitro studies have indicated that, in contrast to tricyclic antidepressants, paroxetine has little affinity for alpha1, alpha2 and beta- adrenoceptors, dopamine (D2), 5-HT1 like, 5-HT2 and histamine (H1) receptors. This lack of interaction with post-synaptic receptors in vitro is substantiated by in vivo studies which demonstrate lack of CNS depressant and hypotensive properties [75, 81, 96 to 100].

Pharmacodynamic Effects

Paroxetine does not impair psychomotor function and does not potentiate the depressant effects of ethanol [63 to 66, 83, 101 to 111].

As with other selective 5-HT uptake inhibitors, paroxetine causes symptoms of excessive 5-HT receptor stimulation when administered to animals previously given monoamine oxidase (MAO) inhibitors or tryptophan [67, 68].

Behavioural and EEG studies indicate that paroxetine is weakly activating at doses generally above those required to inhibit 5-HT uptake. The activating properties are not "amphetamine-like" in nature [96 to 99, 101 to 108, 112 to 113].

Animal studies indicate that paroxetine is well tolerated by the cardiovascular system [68, 100, 114 to 121].

Paroxetine produces no clinically significant changes in blood pressure, heart rate and ECG after administration to healthy subjects [111].

Studies indicate that, in contrast to antidepressants which inhibit the uptake of noradrenaline, paroxetine has a much reduced propensity to inhibit the antihypertensive effects of guanethidine [122].

Pharmacokinetics

Absorption

Paroxetine is well absorbed after oral dosing and undergoes first-pass metabolism. Paroxetine CR tablets control the dissolution rate of paroxetine over a period of 4 to 5 h. In addition to controlling the rate of drug release in vivo, an enteric coat delays the start of drug release until paroxetine CR tablets have left the stomach. Compared to immediate release formulations of paroxetine, controlled release tablets have a reduced absorption rate [123, 124].

80 80 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Due to first-pass metabolism, the amount of paroxetine available to the systemic circulation is less than that absorbed from the gastrointestinal tract. Partial saturation of the first-pass effect and reduced plasma clearance occur as the body burden increases with higher single doses or on multiple dosing. This results in disproportionate increases in plasma concentrations of paroxetine and hence pharmacokinetic parameters are not constant, resulting in non-linear kinetics. However, the non-linearity is generally small and is confined to those subjects who achieve low plasma levels at low doses [128].

Steady state systemic levels are attained by 7 to 14 days after starting treatment with immediate or controlled release formulations and pharmacokinetics do not appear to change during long-term therapy [125 to 128].

Distribution

Paroxetine is extensively distributed into tissues and pharmacokinetic calculations indicate that only 1% of the paroxetine in the body resides in the plasma [130].

Approximately 95% of the paroxetine present in the plasma is protein bound at therapeutic concentrations [131].

No correlation has been found between paroxetine plasma concentrations and clinical effect (adverse experiences and efficacy) [129].

Transfer to human breast milk, and to the foetuses of laboratory animals, occurs in small amounts [132 to 137].

Metabolism

The principal metabolites of paroxetine are polar and conjugated products of oxidation and methylation which are readily cleared. In view of their relative lack of pharmacological activity, it is most unlikely that they contribute to paroxetine's therapeutic effects [86, 87].

Metabolism does not compromise paroxetine's selective action on neuronal 5-HT uptake [87 to 89].

Elimination

Urinary excretion of unchanged paroxetine is generally less than 2% of dose whilst that of metabolites is about 64% of dose. About 36% of the dose is excreted in faeces, probably via the bile, of which unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism [123, 124].

NOTE: The alternative wording given below may be used to replace the above statement:

About 64% of the dose is excreted in the urine; urinary excretion of unchanged paroxetine is generally less than 2% of the dose. About 36% of the dose is excreted in the faeces, probably via the bile; faecal excretion of unchanged paroxetine represents less than 1% of the dose. Thus paroxetine is eliminated almost entirely by metabolism.

81 81 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Metabolite excretion is biphasic, being initially a result of first-pass metabolism and subsequently controlled by systemic elimination of paroxetine [124].

The elimination half-life is variable but is generally about 1 day.

Special Patient Populations

• Elderly and Renal/Hepatic Impairment

Increased plasma concentrations of paroxetine occur in elderly subjects, in subjects with severe renal and in those with hepatic impairment, but the range of plasma concentrations overlaps that of healthy adult subjects [31 to 34].

Clinical Studies

No Text.

NON-CLINICAL INFORMATION

Toxicology studies have been conducted in rhesus monkeys and albino rats; in both, the metabolic pathway is similar to that described for humans. As expected with lipophilic amines, including tricyclic antidepressants, phospholipidosis was detected in rats. Phospholipidosis was not observed in primate studies of up to one year duration at doses that were 6 times higher than the recommended range of clinical doses [87, 138 to 147].

Carcinogenesis: In two year studies conducted in mice and rats, paroxetine had no tumorigenic effect [148 to 149].

Genotoxicity: Genotoxicity was not observed in a battery of in vitro and in vivo tests [150 to 157].

PHARMACEUTICAL INFORMATION

Chemical Structure

No Text.

Shelf-Life

Immediate release tablets:

2 years.

Controlled release tablets:

2 years.

Oral suspension:

2 years.

82 82 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Storage

Immediate release tablets:

Store in a dry place at a temperature not exceeding 30oC.

Controlled release tablets:

Store in a dry place at a temperature not exceeding 25oC.

Oral suspension:

Store at a temperature not exceeding 25oC.

Nature and Contents of Container

As registered locally.

Incompatibilities

There are no known incompatibilities with paroxetine immediate or controlled release tablets or suspension. The tablet should be swallowed whole, not chewed.

Use and Handling

No special instructions.

83 83 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

REFERENCES

[1] Summary of clinical documentation; Paroxetine marketing authorisation application, December 1989. Note: Pivotal efficacy studies are defined in Annex 2.

[2] PAR 03-001. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. April 1989.

[3] PAR 03-002. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. April 1989.

[4] PAR 03-003. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. May 1989.

[5] PAR 03-004. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. June 1989.

[6] PAR 03-005. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. May 1989.

[7] PAR 03-006. A double blind, imipramine and placebo controlled study of paroxetine in depressed outpatients. March 1989.

[8] MDUK/29060/III/83/12. A study to assess the effectiveness and tolerance of paroxetine by double blind comparison with placebo and mianserin. September 1989.

[9] MDB/PAR/1/B/C/D/EM. Investigation of the efficacy and safety of paroxetine in patients with depression: A controlled study. September 1989.

[10] MDF/29060/III/84/1/2/3/4/5/6M. A study to assess the efficacy and tolerance of paroxetine in patients with depression by double-blind comparison with clomipramine. October 1989.

[11] MDD/29060/III/84/01-04. A multi-centre study to assess the effectiveness and tolerance of paroxetine by comparison with amytriptyline. October 1989.

[12] DFG/29060/III/85/119/DUAG. A double-blind comparative study of paroxetine and clomipramine to assess

84 84 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

efficacy and to evaluate the correlation between plasma concentration and effect. November 1989.

[13] MDUK/PAR/013. A trial to assess the effectiveness and tolerance of paroxetine by double-blind comparison with amitriptyline in the treatment of depressed patients in general practice. October 1989.

[14] MDUK/032. A double-blind study to compare the efficacy and tolerability of paroxetine and amitriptyline in a multi-centre general practice study in depressed patients. October 1989.

[15] MDSA/29060/III/86/03 . Assessment of the efficacy and tolerability of paroxetine by double-blind comparison with amitriptyline in depressed patients. October 1989.

[16] MDUK/29060/III/83/022. A study to assess the efficacy and tolerance of paroxetine in patients with depression by double-blind comparison with mianserin. September 1989.

[17] USA PAR 06 and 11. A multi-centre, doxepin controlled, double-blind study of paroxetine in geriatric out-patients with major depressive disorders. October 1989.

[18] MDF/29060/1727M. A prospective randomised, double-blind, multicentre study of the efficacy and tolerance of paroxetine versus clomipramine in the treatment of endogenous depression in the elderly. October 1989.

[19] MDED/29060/III/87/1728M. A multi-centre, double-blind study to investigate the safety and efficacy of paroxetine in comparison with clomipramine in the treatment of reactive depression in elderly patients. October 1989.

85 85 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[20] MDUK/PAR 014. A trial to assess the effectiveness and tolerance of paroxetine by double-blind comparison with placebo using a novel "shifted crossover" design. October 1989.

[21] MDSA/29060/III/86/1182A. A study to assess the tolerance of paroxetine in short and long term therapy and to assess the efficacy and tolerance in a subset of patients in whom previous antidepressant therapy had failed. An open study. October 1989.

[22] MDUK/PAR/85/041. A study to assess the efficacy and tolerability of paroxetine by double-blind comparison of morning and evening dosing. October 1986.

[23] Meta analysis performed with sub-sets of the paroxetine database. Paroxetine Marketing Authorisation Application.

[24] PAR 083. A double-blind comparative, multi-centre study of paroxetine and placebo in preventing depressive episodes in recurrent major depressive disorders. January 1992.

[25] PAR 04. A double-blind extension of protocol PAR 03. October 1989.

[26] MDUK/29060/III/82/013 (pilot) MDUK/29060/III/82/013. A long term continuation of study MDUK/13/ to compare the tolerance and maintained efficacy of paroxetine and amitriptyline. November 1989.

[27] DFG.119. A double-blind continuation of study DFG.119 DUAG to compare the tolerance and maintained efficacy of paroxetine and clomipramine. November 1989.

[28] PAR 078. A multi-centre, double-blind randomised study comparing a 20mg to 30mg dose of paroxetine and amitriptyline 75mg to 150mg in major depression in patients aged 18-65 years old. August 1991 (interim report).

[29] HP/85/3. Two-part sequential study comparing absorption of 30mg tablets of paroxetine in fasting and non-fasting volunteers. April 1986.

[30] HPG 50/82/A. A double-blind, placebo controlled two-part crossover study to investigate the bioavailability of BRL-29060 (paroxetine) in healthy male volunteers after a single oral dose of 60mg BRL-29060 in the fasting and non-fasting states. September 1983.

86 86 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[31] MDA/29060/III/187/2/3/4. An open pharmacokinetic and pharmacodynamic study of paroxetine (20-50mg daily) in the treatment of major depressive disorder. October 1989.

[32] DOYLE, G.D., LAHER, M., KELLY, J.G., BYRNE, M.M., CLARKSON, A. & ZUSSMAN, B.D. The pharmacokinetics of paroxetine in renal impairment. Acta Psych. Scand., 1989; 80 (Suppl. 350): 89-90.

[33] HP/85/70. A study to determine absorption and elimination kinetics of paroxetine in subjects with impaired renal function. January 1988.

[34] DFG-310. Pharmacokinetics of paroxetine in patients with hepatic dysfunction. April 1990.

[35] HPG 25/83. An open two-part crossover study in healthy male volunteers to examine the effects of co-administration of Aludrox on the pharmacokinetics of BRL-29060 (paroxetine) after a single dose of 30mg BRL-29060.

[36] GREB, W.H., BRETT, M.A., BUSCHER, G., DIERDORF, H.D., VON SCHRADER, H.W., WOLF, D., MELLOWS, G. & ZUSSMAN, B.D. Absorption of paroxetine under various dietary conditions and following antacid intake. Acta Psych. Scand., 1989; 80 (Suppl. 350): 99-101.

[37] BROSEN, K. Recent developments in hepatic drug oxidation. Implications for clinical pharmacokinetics. Clin. Pharmacokinetics, 1990; 18 (3): 220-239.

[38] (interim report). A comparative study of the effects of paroxetine and other drugs on cytochrome P450IID6 activity in human liver microsomes. 1991.

87 87 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[39] 29060/105/MA/001. Paroxetine. An open study to investigate the effects of paroxetine (30mg o.d. for 14 days) on sparteine oxidase polymorphism in healthy volunteer subjects. August 1991.

[40] CAVANAGH, S.V. Drug-drug interaction of fluoxetine with tricyclics. Psychosomatics, 1990; 31 (3): 338-392.

[41] WESTERMEYER, J. Fluoxetine-induced tricyclic toxicity; extent and duration. J. Clin. Pharmacol, 1991; 31: 338-392.

[42] NELSON, J.C., MAZURE, C.M., BOWERS, M.B. & JATLOW, P.I. A preliminary, open study of the combination of fluoxetine and desipramine for rapid treatment of major depression. Gen. Psychiatry, 1991; 48: 303.

[43] BROSEN, K. & GRAM, L.F. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur. J. Clin. Pharmacol, 1989; 36: 537-547.

[44] Gram, L.F. & Brosen, K. Conditions under which genetic polymorphisms are clinically relevant. Proceedings of the European Consensus Conference on Pharmacogenetics, Besançon, France, 24/25 October 1989.

[45] HPG 30/84. A single-blind study to determine pharmacokinetics and tolerance of paroxetine and methyldopa and any interactions between them under steady state conditions of both compounds. April 1986.

[46] HPG 19/84. A single-blind study to examine the pharmacokinetics of paroxetine and propranolol and any interaction between them under steady state conditions. March 1986.

[47] HPG1-04/85/A. An open two-part study to investigate the effects of paroxetine (BRL-29060) on the pharmacokinetics of digoxin and cardiovascular tolerance. May 1986.

[48] MDUK/022/29060/I/1987/048. A study to assess the interaction of paroxetine with digoxin in normal human volunteers. February 1989.

[49] PAR 15-01. A multiple-dose, steady state design, pharmacokinetic evaluation of the intereaction between paroxetine and digoxin. September 1989.

88 88 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[50] PAR 14-01. A multiple-dose steady-state design pharmacokinetic evaluation of the interaction between paroxetine and warfarin. September 1989.

[51] HP/84/57/A. A comparative study of the pharmacokinetics of paroxetine in females who are and are not taking oral contraceptives. January 1987.

[52] HP/82/59A. Pharmacokinetic profile of antipyrine before and after administration of paroxetine. June 1983.

[53] DFG-311. Study to elucidate any interaction between four anticonvulsants and paroxetine. August 1989.

[54] HP/86/63. A study to assess the effect of repeat dosing with paroxetine 30 mg o.d. on the pharmacokinetics of phenytoin in healthy male volunteers. December 1987.

[55] HPG 26/84. An open study for the pharmacokinetics of orally administered paroxetine before and after the oral administration of cimetidine to healthy male volunteers. February 1986.

[56] PAR 13-01. A multiple-dose, steady state design, pharmacokinetic evaluation of the interaction between paroxetine and cimetidine. September 1989.

[57] HPG 34/84. Pharmacokinetics of paroxetine before and after an eventual liver enzyme induction caused by multiple oral dosing of phenobarbitone to healthy male volunteers. April 1986.

[58] PAR 10-01. A multiple-dose, steady-state design, pharmacokinetic evaluation of the interaction between paroxetine and diazepam. September 1989.

[59] HP/84/54/A. A study to assess the CNS effects of oxazepam alone and in combination with paroxetine. March 1986.

[60] HP/84/74/A. A study to assess the CNS effects of paroxetine and any interaction with the sedative effects of amylobarbitone. February 1986.

[61] HP/84/12/A. A study to assess the CNS effects of paroxetine and haloperidol and any interaction of paroxetine with the sedative effects of haloperidol. May 1986.

89 89 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[62] HPG 37/84. Pharmacokinetics of paroxetine before and after multiple oral dosing of phenytoin to healthy male volunteers. May 1986.

[63] HINDMARSH, I. & HARRISON, C. The effects of paroxetine and other antidepressants in combination with alcohol in psychomotor activity related to car driving. Human Psychopharmacology, 1988; 3: 13-20.

[64] MCCLELLAND, G.R. & RAPTOPULOUS, P. Psychomotor effects of paroxetine and amitriptyline alone and in combination with ethanol. Br. J. Clin. Pharmacol., 1985; 19: 578P.

[65] COOPER, S.M., JACKSON, D., LOUDON, J.M., MCCLELLAND, G.R. & RAPTOPOULOS, P. The psychomotor effects of paroxetine alone and in combination with haloperidol., amylobarbitone, oxazepam or alcohol. Acta Psych. Scand, 1989; 80 (Suppl. 350): 53-55.

[66] MDUK/022/29060/1/83/053. A double-blind placebo controlled comparative investigation of the effects of psychomotor performance of paroxetine and amitriptyline with or without alcohol in adult subjects. June 1992.

[67] RAD/Paroxetine/P/91. Effect of the combination of paroxetine and monoamine oxidase inhibitors on the CNS in the rat. March 1987.

[68] HAMILTON, T.C., Norton, J., Poyser, R.H. & Thormahlen,D. Comparison of some effects of paroxetine with amitriptyline on the cardiovascular system in animals. Arzneim-Forsch/Drug Res, 1986; 36: 460-463.

[69] 29060/62. An interaction study of paroxetine on lithium plasma levels in depressed patients stabilised on lithium therapy. May 1991.

[70] HPG1-01/85/A. A single blind, two-part placebo controlled study to investigate the pharmacokinetics and effects of paroxetine (BRL 29060) and procyclidine and any interaction between them in healthy male volunteers. June 1986.

[71] Reprotox Order No. 296/A. Paroxetine. Teratology study in the rat. April 1981.

[72] Reprotox Order No. 297/A. Paroxetine. Teratology study in the New Zealand white rabbit. April 1981.

90 90 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[73] RAD/Paroxetine/P/12. Inhibition of serotonin uptake by rat fore-brain synaptosomes. 7th June 1977.

[74] RAD/Paroxetine/P/17. Inhibition of noradrenaline uptake by synaptosomes prepared from several regions of rat brain. 7th June 1977.

[75] RAD/Paroxetine/P/84. Biochemical effects of the antidepressant paroxetine, a specific 5- hydroxytryptamine uptake inhibitor. April 1987.

[76] MAGNUSSEN, I. Tonder, K. & Engbaek, F. Paroxetine, a potent selective long-acting inhibitor of synaptosomal 5-HT uptake in mice. J. Neural Transmission, 1982; 55: 217-226.

[77] HYTTEL, J. Citalopram - Pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity. Prog. Neuro-Psychopharmacology & Biol. Psychiat, 1982; 6: 277-295.

[78] TANIGAKI, N., Manno, K., Sugihara, K., Miki, N., Ichida, S. & Yoshida, H. Specific inhibitory action of the novel antidepressant paroxetine on uptake of serotonin (5-HT). Folia Pharmacology Jpn, 1987; 89: 175-180.

[79] MELLERUP, E.T., Plenge, P. & Engelstoft, M. RAD/Paroxetine/P/86 High affinity binding of [3H] paroxetine and [3H] imipramine to human platelet membranes. Eur. J. Pharmacology, 1983; 96: 303-309.

[80] HABERT, E., Graham, D., Tahraoui, L., Claustre, Y. & Langer, S.Z. RAD/Paroxetine/P/85 Characterisation of [3H] paroxetine binding to rat cortical membranes. Eur. J. Pharmacology, 1985; 118: 107-114.

[81] JOHNSON, A.M. An overview of the animal pharmacology of paroxetine. Acta. Psych. Scand., 1989; 80, (Suppl. 350): 14-20.

[82] MARSDEN, C.A., TYRER, P., CASEY, P. & SEIVEWRIGHT, N. Changes in human whole blood 5-hydroxytryptamine (5-HT) and platelet 5-HT uptake during treatment with paroxetine, a selective 5-HT uptake inhibitor. Journal of Psychopharmacology, 1987; 1 (4): 24.

[83] MD/PAR/001 and 001 C/R A comparison of the effects of single doses of paroxetine, amitriptyline and placebo on the tyramine pressor response, salivary volume and sedation; and repeat doses of paroxetine and placebo on the tyramine pressor response and

91 91 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

salivary volume. Related Publication: Hasan, S.M., Wainscott, G. & Turner, P. A comparison of the effect of paroxetine and amitriptyline on the tyramine pressor response test. Br. J. Clin. Pharmacology, 1985; 19: 705-706.

[84] HP/82/22/A/1. Double-blind tolerance study of 40 mg of paroxetine. July 1983.

[85] LUND, J., LOMHOLT, B., FABRICIUS, J., CHRISTENSEN, J.A. & BECHGAARD, E. Paroxetine: Pharmacokinetics, tolerance and depletion of blood 5-HT in man. Acta Pharmacol. Toxicol., 1979; 44: 289-295.

[86] HP/83/88. Metabolism studies in healthy male subjects following a single oral dose of 14C- BRL 29060A equivalent to 30 mg pfb. March 1986.

[87] HADDOCK, R.E., JOHNSON, A.M., LANGLEY, P.F., NELSON, D.R., POPE, J.A., THOMAS, D.R. & WOODS, F.R. Metabolic pathway of paroxetine in animals and man and the comparative pharmacological properties of its metabolites. Acta Psych. Scand, 1989; 80 (Suppl.350): 24-26.

[88] RAD/Paroxetine/P/51A. The effect of the unconjugated forms of the metabolites of paroxetine on 5- hydroxytryptamine (5-HT) and noradrenaline (NA) uptake into rat hypothalamic synaptosomes in vitro. October 1986.

[89] RAD/Paroxetine/P/92. The effects of metabolites of paroxetine on 5-hydroxytryptamine (5-HT) and noradrenaline (NA) uptake into rat hypothalamic synaptosomes in vitro and following intravenous administration ex vivo. June 1987.

[90] RAD/Paroxetine/P/19. Affinity of 5HT-update inhibitors for muscarinic receptors in rat brain. 11th August 1977.

[91] RAD/Paroxetine/P/52/A. Effect of paroxetine and unconjugated forms of its metabolites on the in vitro binding of the muscarinic cholinergic receptor ligand, [3H]-QNB, and on oxotremorine induced symptoms in mice. 23rd August 1984.

[92] RAD/Paroxetine/P/35/A. Peripheral in vitro inhibition of acetylcholine, serotonin and histamine. 7th June 1977.

[93] RAD/Paroxetine/P/38. Effect of imipramine, amitriptyline and paroxetine on pilocarpine induced salivation in the mouse. January 1981.

92 92 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[94] RAD/Paroxetine/P/39. Effect of paroxetine and imipramine on pupil diameter in the mouse. January 1981.

[95] THOMAS, D.R., NELSON, D.R. & JOHNSON, A.M. Biochemical effects of the antidepressant paroxetine, a specific 5- hydroxytryptamine uptake inhibitor. Psychopharmacology, 1987; 93: 193-200.

[96] RAD/Paroxetine/P/49. Effect of paroxetine on the quantitative EEG of the conscious rat. 15th June 1984.

[97] KLEINLOGEL, H. & BURKI, H.R. Effects of the selective 5-hydroxytryptamine uptake inhibitors paroxetine and zimelidine on EEG sleep and waking stages in the rat. Neuropsychobiology, 1987; 17: 206-212.

[98] ED. A. BÉS ET AL. 1986. The EEG profile of paroxetine in the rat. Senile dementias; early detection, Borjeix, M.G., Berbey, B. and Cahn, J. p. 424-429. John Libbey Eurotext.

[99] WATANABE, S., Ohta, H., Ohno, M., Tani, Y., Furuya, Y., Ueki, S., Man'no, K. & Sugihara, K. Electroencephalographic effects of the new antidepressant paroxetine in the rabbit. Arzneim, Forsch/Drug Res, 1988; 38: 322-340.

[100] CAIN, C.R., HAMILTON, T.C., NORTON, J., PETERSEN, E.N. POYSER, R.H. & THORMÄHLEN, D. Relative lack of cardiotoxicity of paroxetine in animal models. Acta Psych. Scand., 1989; 80 (Suppl. 350): 27-30.

[101] RAD/Paroxetine/P/37. Effect of paroxetine and imipramine on the general behaviour and response of mice (observation test). January 1981.

[102] RAD/Paroxetine/P/108/A. Effect of BRL 29060A on motor co-ordination in mice-inclined plane. September 1986.

[103] RAD/Paroxetine/P/109. Evaluation of oral BRL 29060A for potential effects on motor co-ordination (grasping test in mice). November 1986.

[104] RAD/Paroxetine/P/110. Effects of BRL 29060A on motor co-ordination in rats rotarod. September 1986.

93 93 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[105] RAD/Paroxetine/P/21/A. The effect of paroxetine, amphetamine, scopolamine and imipramine on the motility of rats. 11th August 1977.

[106] RAD/Paroxetine/P/107. Effects of BRL 29060A on spontaneous motor activity in mice. August 1986.

[107] RAD/Paroxetine/P/103. Effect of paroxetine and d-amphetamine on spontaneous locomotor activity in the mouse. June 1987.

[108] RAD/Paroxetine/P/45. The induction of stereotyped behaviour by nomifensine and paroxetine in the rat. June 1981.

[109] RAD/Paroxetine/P/62. The effect of paroxetine on ethanol-induced loss of righting reflex in mice. 21 September 1983.

[110] MDUK/022/29060/I/82/015. A comparison of the effect of paroxetine and amitriptyline in single doses of psychomotor performance. October 1987.

[111] MDUK/022/29060/I/84/015B. To assess the effect of repeated dosing with paroxetine, amitriptyline and placebo on psychomotor skills and cardiac function in volunteers. June 1988. Related publication: WARRINGTON, S.J., DANA-HAERI, J. & SINCLAIR, A. J. Cardiovascular and psychomotor effects of repeated doses of paroxetine: a comparison with amitriptyline and placebo in healthy men. Acta. Psychiatr. Scand., 1989; 80 (Suppl. 350): 42-44.

[112] GOUDIE, A.J., DUBICKI, W. & LEATHLEY, M. Paroxetine, a selective 5-hydroxytryptamine uptake inhibitor with antidepressant properties, lacks amphetamine-like stimulus properties in an operant drug discrimination bioassay in rodents. J. Pharm. Pharmacology, 1988; 40: 192-196.

[113] RAD/Paroxetine/P111. Assessment of stimulus properties of paroxetine in animals trained to discriminate d-amphetamine. 27th October 1986.

[114] RAD/Paroxetine/P/23/A. Effect of infusion of paroxetine, amitriptyline and imipramine on the cardiovascular system of the anaesthetised dog. 3rd August 1977.

[115] YOKOTA, S., ISHIKURA, Y. & ONO, H. Cardiovascular effects of paroxetine, a newly developed antidepressant, in anaesthetised dogs in comparison with those of imipramine, amitriptyline and

94 94 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

clomipramine. Japan. J. Pharmacol., 1987; 45: 335-342.

[116] RAD/Paroxetine/P/76. Evidence for the 5HT-mediated cardiovascular effects of paroxetine in the anaesthetised cat. November 1984.

[117] LANGE, S.C., JULIEN, R.M. & FOWLER, G.W. Biphasic effects of imipramine in experimental models of epilepsy. Epilepsia, 1976; 17: 183-195.

[118] RAD/Paroxetine/P/101. A comparison of the effects of paroxetine and amitriptyline on fast action potentials in guinea-pig ventricular muscle. 13th November 1984.

[119] RAD/Paroxetine/P/30/A. Changes in contractility and refractory period by FG 7051, FG 4963, amitriptyline and imipramine in guinea-pig isolated papillary muscle. 3rd June 1977.

[120] RAD/Paroxetine/P/24/A. The effect of thymoleptic drugs on the response to selective electrical stimulation of the sympathetic nerves to the heart or to the blood vessels in the pithed rat. 7th June 1977.

[121] RAD/Paroxetine/P/25. Potentiation of the heart rate increasing effect of noradrenaline. 7th June 1981.

[122] PETERSEN, E.N. The interaction of desipramine and the 5-HT uptake inhibitors femoxetine and paroxetine with the acute hypotensive effect of guanethidine in conscious spontaneously hypertensive rats. J. Pharm. Pharmacology, 1979; 31: 638-640.

[123] HP/83/88. Metabolism studies in healthy male subjects following a single oral dose of 14C- BRL 29060 equivalent to 30 mg pfb. March 1986.

[124] KAYE, C.M., HADDOCK, R.E., LANGLEY, P.F., MELLOWS, G., TASKER, T.C.G., ZUSSMAN, B.D. & GREB, W.H. A review of the metabolism and pharmacokinetics of paroxetine in man. Acta Psych. Scand., 1989; 80 (Suppl. 350): 60-75.

[125] HP/86/78. A study to assess the pharmacokinetics and tolerance of single oral doses and repeat oral doses of paroxetine in healthy elderly subjects and a control population. July 1989.

[126] HP/87/88. A study to assess the pharmacokinetics and tolerance of single and repeat oral

95 95 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

doses of paroxetine in healthy elderly subjects and a young adult control group. September 1989.

[127] HP/85/33/A. A comparison of the pharmacokinetics of paroxetine after a single oral dose before and after thirty days of once daily oral administration. March 1986.

[128] D89970/29060/107. Global assessment of the pharmacokinetic profile of paroxetine in man. July 1989.

[129] TASKER, T.C.G., KAYE, C.M., ZUSSMAN, B.D. & LINK, C.G.G. Paroxetine plasma levels: lack of correlation with efficacy or adverse events. Acta Psych. Scand., 1989; 80 (Suppl. 350): 152-155.

[130] HP/83/76. A study of the tolerance, pharmacokinetics and bioavailability of paroxetine. February 1987.

[131] D87046/29060/100. The in vitro protein binding of paroxetine in man. August 1989.

[132] RAD/Paroxetine/M/18. Paroxetine in milk from lactating mice, rats and humans. 28th May 1986.

[133] RAD/Paroxetine/M/26. Determination of paroxetine in human milk and in rat's milk. 8th September 1980.

[134] RAD/Paroxetine/M/16/A. Distribution of paroxetine (FG 7051) in mice. 18th July 1978.

[135] HRC/BRL 1084/84875. Concentrations of radioactivity in maternal blood and foetal tissue of rats following a single oral dose of 14C-BRL-29060A at 15 mg pfb/kg. 24th October 1984.

[136] RAD/Paroxetine/M/24. Plasma concentrations of FG 7051 after daily administration of FG 7051 hydrochloride (1-6 mg/kg) for 12 days during a rabbit teratology study. 18th June 1980.

[137] HRC/BRL 1085/84874. Concentrations of radioactivity in maternal blood and foetal tissue of rabbits following a single oral dose of 14C-BRL-29060A at 6 mg pfb/kg. 7th March 1985.

[138] T80074/29060A/M/PO/A/2. BRL-29060A. An acute toxicity study in the mouse by the oral route. April 1981.

96 96 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[139] T80071/29060A/R/PO/A/2. BRL-29060A. An acute toxicity study in the rat by the oral route. April 1981.

[140] KELVIN, A.S., DE G. MITCHELL, I. & WHITE, D.J. General and genetic toxicity of paroxetine. Acta Psych. Scand., 1989; 80 (Suppl. 350): 34-36.

[141] D83623/29060A/55. Comparison of radiometabolite patterns following a single oral dose of 14C-BRL 29060A to rat and man. 10th September 1986.

[142] D84601/29060A/59. Comparison of radiometabolite patterns following a single oral dose of 14C-BRL 29060A to rhesus monkey and man. 10th September 1986.

[143] BRL 899-G/8219/1. BRL 29060A. Toxicity to rats when administered in the diet for 26 weeks followed by a 6 week withdrawal period. 7th September 1983.

[144] P/NT:DW/82/46/djw. BRL: 29060A. 6 month oral toxicity study in rats at Huntington Research Centre (Project BRL 899). Results of electron microscopic examination of liver, mesenteric lymph node and retina. July 1982.

[145] BRL 918-G/821002. BRL 29060A. Potential toxicity to rats when administered in the diet for 52 weeks followed by an 8 week withdrawal period. 8th November 1984.

[146] P/NT/83/28/af. BRL 29060A. T82904/29060A/R/PO/RDS. A 52 week oral toxicity study in rats at Huntingdon Research Centre (Project BRL 918). Results of electron microscopic examination of liver, mesenteric lymph node and retina. 5th September 1983.

[147] LULLMAN, H., LULLMANN-RAUCH, R. & WASSERMANN, O. Lipidosis induced by amphiphilic cationic drugs. Biochem. Pharmacol., 1978; 27: 1103-1108.

[148] BRL 1029/85333. BRL 29060A. Assessment of the potential tumorigenic effects in prolonged dietary administration to mice. 15th August 1985.

[149] BRL 912-G/831026. BRL 29060A. Potential tumorgenicity to rats during long term dietary administration. 2nd April 1985.

[150] T82/784/29060A/A. BRL 29060A. Report of microbial DNA repair tests with E. coli WP2 and CM871 in liquid culture. 26th May 1982.

97 97 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[151] T86/758/29060. BRL 29060A. Report of unscheduled DNA synthesis (DNA Repair) in Hela cell cultures. December 1986.

[152] Litton Bionetics Inc. Project No. 20998. Mutagenicity evaluation of paroxetine hydrochloride in the Ames' Salmonella/microsome plate test. September 1979.

[153] BASF Report VP/FBA 8022. Studies on a possible induction of point mutations by paroxetine hydrochloride in the Ames' Salmonella/microsome test. 5th March 1980.

[154] 84/BRL033/409. BRL 29060A. Investigation of mutagenic activity in the TK ± mouse lymphoma cell mutation system. July 1984.

[155] T83/702/29060A/A. BRL 29060A. Report of in vitro metaphase analysis with human lymphocytes in culture. 12th October 1983.

[156] T83/700/29060A. BRL 29060A. Report of a micronucleus test in the mouse. 20th October 1983.

[157] T84/724/29060A. BRL 29060A. Report of a dominant lethal assay in the rat. July 1985.

[158] Safety Update, Volume 1. Paroxetine Hydrochloride Tablets. February 1992.

[159] MY-1022/BRL-029060/1/CPMS-116. Paroxetine versus placebo in the treatment of Obsessive Compulsive Disorder. August 1994.

[160] MY-1037/BRL-029060/1/CPMS-136. A double-blind study to assess the short term efficacy and tolerance of a flexible dose of paroxetine compared with a flexible dose of clomipramine and placebo in the treatment of Obsessive Compulsive Disorder. August 1994.

[161] MY-1028/BRL-029060/1/CPMS-118. Paroxetine versus clomipramine and placebo in the treatment of Obsessive Compulsive Disorder. September 1994.

[162] MY-1046/BRL-029060/1/CPMS-126. Long term treatment with paroxetine of outpatients with Obsessive Compulsive Disorder. An extension of the fixed dose study. October 1994.

[163] Summary of clinical documentation: Marketing Authorisation Application for paroxetine in the treatment of Obsessive Compulsive Disorder. November 1994.

98 98 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[164] KENNET, G.A., LIGHTOWLER, S., DE BIASI, V., STEVENS, N.C. & BLACKBURN, T.P. Chronic treatment with paroxetine and fluoxetine, but not desipramine, desensitises 5-HT2c receptor function. Br. J. Pharmcol., 1994; 112: 643P.

[165] KENNET, G.A., LIGHTOWLER, S., DE BIASI, V., STEVENS, N.C. & BLACKBURN, T. P. m-CPP-induced mouth movements, a model of OCD? Neuropsychopharmacol., 1994; 10: 174-178.

[166] MY-1002/BRL-029060/1/CPMS-108. A double-blind randomised, multi-centre, placebo controlled study of paroxetine in combination with psychotherapy in the treatment of panic disorder. January 1995.

[167] MY-1047/BRL-029060/1/CPMS-120. Fixed dose study of paroxetine 10, 20, and 40 mg and placebo in the treatment of panic disorder. February 1995.

[168] MY-1036/BRL-029060/1/CPMS-187. A double-blind placebo-controlled comparative study of paroxetine and clomipramine in the treatment of panic disorder. December 1994.

[169] MY-1048/BRL-029060/1/CPMS-223. A double-blind multi-centred, fixed-dose study of paroxetine, alprazolam and placebo in the treatment of panic disorder. January 1995.

[170] MY-1051/BRL-29060/1/CPMS-228. A long-term extension of a double-blind, placebo-controlled comparative study of paroxetine and clomipramine in the treatment of panic disorder. February 1995.

[171] Summary of clinical documentation: Marketing Authorisation Application for paroxetine in the treatment of Panic Disorder. March 1995.

[172] LIGHTOWLER, S., KENNET, G.A., WILLIAMSON, I.J.R., BLACKBURN, T.P. & TULLOCH, I.F. Anxiolytic -like effects of paroxetine in a rat social interaction test. Pharmacol. Biochem. Behav., 1994; 49: 281-285.

[173] CADOGAN, A.K., WRIGHT, I.K., COOMBS, I., MARSDEN, C.A., KENDALL, D.A., & TULLOCH, I. Repeated paroxetine administration in the rat produces a decreased [3H]- ketanserin binding and an anxiolytic profile in the x-maze. Br. J. Pharmacol., 1992; 107: 108P.

[174] GORMAN J.M., LIEBOWIT M.R., FRYER A.J., GOETZ D., CAMPEAS R.B., FYER M.R., DAVIES S.O. & KLEIN D. F.

99 99 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

An open trial of fluoxetine in the treatment of panic attacks. J. Clin. Psychopharmacol., 1987; 7: 329 - 332.

[175] DEN BOER J. A., WESTENBERG H. G., KAMERBEEK, W. D., VERHOEVEN W. M. & KAHN R S. Effect of serotonic uptake inhibition in anxiety disorders: a double-blind comparison of clomipramine and fluvoxamine. Int. Clin. Psychopharmacol., 1987; 2: 21 - 32.

[176] ZITRIN C.N., KLEIN D.F., WOERNER M. G. & ROSS D.C. Treatment of phobias. 1. Comparison of imipramine hydrochloride and placebo. Arch. Gen. Psychiatry, 1983; 40: 125 - 138.

[177] CREW H.K., LENNARD, M.S., TUCKER G.T., WOOD F.R. & HADDOCK R.S. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br. J. Clin. Pharmacol, 1992; 34: 262 - 265.

[178] DEVANE, C.L., NEMEROFF, C.B. & MONTANO, C.B. Pharmacogenetics and drug metabolism of newer antidepressant agents. J. Clin. Psychiatry, 1994; 55 (12) suppl.: 38 - 45.

[179] LEINONEN, E., KOPONEN, H.J. & LEPOLA, U. Paroxetine increases serum trimipramine concentration. A report of two cases. Hum. Psychopharmacol., 1995; 10 (4): 345 - 347.

[180] BROSEN, K., HANSEN, H.G., NIELSEN, K.K., SINDRUP, S.H. & GRAM, L.F. Inhibition by paroxetine of desipramine metabolism in extensive but not in poor metabolizers of sparteine. Eur. J. Clin. Pharmacol., 1993; 44: 349 - 355.

[181] UENO, S., OTANI, K., KANEKO, S., Koshiro, K., Kondoh, K., Kotani,Y. & Sano,A. Cytochrome P-450 2D6 gene polymorphism is not associated with neuroleptic malignant syndrome. Biological Psychiatry, 1996; 40: 72 - 74.

[182] TEUTH, M.J. Am J Emerg Med, 1994; 12 (2): 212 - 216.

[183] MARTINDALE. 1996. The Extra Pharmacopoeia (31st edition). 691. The Pharmaceutical Press.

[184] SIMPSON, B.M., PI, E.H. & SRAMEK, j.j. 1996. Meylers Side Effects of Drugs. 117 - 135. Amsterdam: Elsevier.

[185] DSM IV Source Book (1994), 1st edition. DSMIV Task Force, American Psychiatric Association. 533 - 543

100 100 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

[186] ARMSTRONG, C.A. & SCHWEITZER, SM. Delirium associated with paroxetine and benztropine combination. Am J Psychiatry, 1997; 154 (4): 581 - 582.

[187] BRL-029060/RSD-1008X7/2. A Randomized, Double-Blind Comparison of Paroxetine and Placebo in the Treatment of Generalized Social Phobia, Study 382. March 1998.

[188] BRL-029060/RSD-100J8X/1. A Randomised, Double-Blind Study of Paroxetine and Placebo in the Treatment of Social Phobia, Study 502. February, 1998.

[189] BRL-029060/RSD-100JSK/2. A Randomized, Double-Blind, Fixed-Dose Comparison of 20, 40, 60 mg Daily Paroxetine and Placebo in the Treatment of Generalized Social Phobia, Study 454. March 1998.

[190] BRL-029060/RSD-100KCS/3. An Extension Trial Comparing Paroxetine and Placebo in the Long Term Treatment of Generalized Social Phobia, Study 470. March 1998.

[191] BRL-029060/RSD-100-4T0/1. An in vitro investigation into the inhibition of the metabolism of CYP3A substrates by paroxetine and ketoconazole. April 1996.

[192] BRL-29060/486. The effect of paroxetine on the PD and PK of terfenadine in healthy adult males. April 1996.

[193] BRL-29060/665. A Phase I Pharmacokinetic and Pharmacodynamic Study on the Potential Drug- Drug Interactions between Paroxetine and Alprazolam.

[194] IRF to support submission of paroxetine CR tablets for the treatment of MDD, panic disorder and PMDD in International Markets.

[195] Regulatory Supporting Document: Paroxetine – Disease related suicidality.

[196] Regulatory Supporting Document: Paroxetine – Formatting of adverse events in a body system and frequency classification.

[197] Regulatory Supporting Document: Paroxetine – Discontinuation Symptoms.

[198] Common Technical Document to Support the Use of Paroxetine in Children with Obsessive Compulsive Disorder and Social Anxiety Disorder.

[199] Regulatory Supporting Document: Paroxetine – Premature Births.

101 101 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[200] Regulatory Supporting Document: Paroxetine – Suicidal thinking and behaviour in paediatric patients. HM2005/00093/00, 2005.

[201] Regulatory Supporting Document: Paroxetine – Clinical worsening associated with psychiatric disorders. HM2005/00092/00, 2005.

[202] Regulatory Supporting Document: Paroxetine – Interaction with atomoxetine. HM2004/00502/02, 2005.

[203] Regulatory Supporting Document: Paroxetine – Agitation. HM2004/00452/02, 2005.

[204] Regulatory Supporting Document: Paroxetine – Interaction with pimozide. HM2005/00269/00, 2005.

[205] Regulatory Supporting Document: Paroxetine – Congenital malformations. HM2005/00439/01, 2005.

[206] Regulatory Supporting Document: Paroxetine – Reports of tinnitus. HM2005/00373/00, 2005.

[207] Regulatory Supporting Document: Paroxetine Suspension – Use by achlorhydric patients. HM2005/00476/00, 2005.

[208] Regulatory Supporting Document: Paroxetine – Interaction between paroxetine and fosamprenavir/ritonavir. HM2005/00160/03, 2005.

[209] Regulatory Supporting Document: Paroxetine – Urinary incontinence. HM2005/00339/00, 2005.

[210] Regulatory Supporting Document: Paroxetine and risk of congenital malformations following maternal exposure during pregnancy. HM2005/00597/00, 2005.

[211] Regulatory Supporting Document: Paroxetine – Clinical worsening and suicide risk in adults. D2006-1856, 2006.

[212] Regulatory Supporting Document: Paroxetine – reports of persistent pulmonary hypertension in newborn infants exposed in utero. HM2006/00323/00, 2006.

[213] Regulatory Supporting Document: Paroxetine and increases in cholesterol levels. HM2006/00134/00, 2006.

102 102 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

[214] Regulatory Supporting Document: Paroxetine and weight changes. HM2006/00137/00, 2006.

[215] Regulatory Supporting Document: Interaction with linezolid. HM2007/00084/01, 2007.

[216] Regulatory Supporting Document: Interaction with pimozide update. HM2007/00149/01, 2007.

[217] Regulatory Supporting Document: Paroxetine and headache. HM2007/00043/00, 2007.

[218] Regulatory Supporting Document: Paroxetine and mydriasis. HM2007/00238/00, 2007.

[219] Regulatory Supporting Document: Postural hypotension and other blood pressure changes. HM2007/00130/01, 2007.

[220] Regulatory Supporting Document: Paroxetine – Pharmacological interaction with tamoxifen. HM2008/00086/00, 2008.

AROPAX, DEROXAT, SEROXAT, PAXIL, PAXIL CR, AROPAX CR and SEROXAT CR are trademarks of the GlaxoSmithKline group of companies.

103 103 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Appendix 3: Pharmacogenetic Research

Pharmacogenetics – Background

Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of PGx analysis include:

Drug Disease Gene Outcome Abacavir HIV HLA (human Caucasian males with HLA B57 variant were [Hetherington, 2002; leukocyte at increased risk for experiencing Mallal, 2002] antigen) hypersensitivity to abacavir Tranilast Restenosis UGT1A1 Drug induced hyperbilirubinemia explained by prevention following high proportion of affected subjects having 7/7 coronary bypass TA repeat genotype, consistent with clinically [Roses, 2002] benign Gilbert’s Syndrome ABT-761 Asthma ALOX5 ALOX5 Sp1 promoter genotype (x,x) [Drazen, 1999] associated with reduced response to 5- lipoxygenase inhibitor ABT-761

A key component to successful PGx research is the collection of samples during the conduct of clinical studies.

Pharmacogenetic Research Objectives

If at any time it appears there is potential variability in response in this clinical study or in a series of clinical studies with vestipitant and paroxetine that may be attributable to genetic variations of subjects, the following objectives may be investigated:

• Relationship between genetic variants and the pharmacokinetics of investigational product; • Relationship between genetic variants and safety and/or tolerability of investigational product • Relationship between genetic variants and efficacy of investigational product Study Population

Any subject who has given informed consent to participate in the clinical study, has met all the entry criteria for the clinical study, and receives investigational product may take part in the PGx research. Any subject who has received an allogeneic bone marrow transplant must be excluded from the PGx research.

104 104 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Subject participation in the PGx research is voluntary and refusal to participate will not indicate withdrawal from the clinical study. Refusal to participate will involve no penalty or loss of benefits to which the subject would otherwise be entitled.

Study Assessments and Procedures

In addition to any blood samples take for the clinical study, a whole blood sample (~10ml) will be collected for the PGx research using a tube containing EDTA. The PGx sample is labeled (or “coded”) with a study specific number that can be traced or linked back to the subject by the investigator or site staff. Coded samples do not carry personal identifiers (such as name or social security number). The blood sample will be taken on a single occasion unless a duplicate sample is required due to inability to utilize the original sample. It is recommended that the blood sample be taken at the first opportunity after a subject has been randomized and provided informed consent for PGx research, but may be taken at any time while the subject is participating in the clinical study.

If deoxyribonucleic acid (DNA) is extracted from the blood sample, the DNA may be subjected to sample quality control analysis. This analysis will involve the genotyping of several genetic markers to confirm the integrity of individual samples. If inconsistencies are noted in the analysis, then those samples may be destroyed.

Subject Withdrawal from Study

If a subject who has consented to participate in PGx research withdraws from the clinical study for any reason other than lost to follow-up, the subject will be given the following options concerning the PGx sample, if already collected:

• PGx research continues per the subject’s consent; or, • Any remaining sample is destroyed If a subject withdraws consent from the PGx research or requests sample destruction, the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records. In either case, GSK will only keep study information collected/generated up to that point.

Screen and Baseline Failures

If a blood sample for PGx research has been collected and it is determined that the subject does not meet the entry criteria for participation in the clinical study, then the investigator must complete the appropriate documentation to request sample destruction within the timeframe specified by GSK and maintain the documentation in the site study records.

Pharmacogenetics Analyses

The need to conduct PGx analysis may be identified after a study (or set of studies) of vestipitand and paroxetine has been completed and the study data reviewed. For this reason, samples may be kept for up to 15 years after the last subject completes the study

105 105 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

or GSK may destroy the samples sooner. In special cases, the samples may not be studied. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond vestipitand and paroxetine .Generally GSK will utilize two approaches to explore genetic variation in drug response.

1. Specific sections of DNA may be selected from areas of the genome (e.g., candidate genes) known to encode the drug target, drug metabolizing enzymes, areas associated with mechanisms underlying adverse events, and those linked to study disease and, thus, linked to drug response. 2. The candidate genes that may be investigated in this study are the receptors, transporters, second messenger mediators and enzymes involved in the pathways of the neurotransmitters directly modified by the two compounds, i.e., substance P and serotonin. In addition, continuing research may identify other enzymes, transporters, proteins, or receptors that may be involved in response to vestipitant and paroxetinet. The genes that may code for these proteins may also be studied.

• By evaluating large numbers of polymorphic markers (e.g., single nucleotide polymorphisms or SNPs) throughout the genome, sets of markers may be identified that correspond to differential drug response. Hardy-Weinberg Equilibrium Testing

The genotypic frequencies of each polymorphism will be evaluated for conformity to those expected under normal conditions by employing Hardy-Weinberg Equilibrium testing.

Comparison of Demographic and Baseline Characteristics by Genotype

Differences in baseline clinical characteristics and potential contributing covariates may be summarized and compared among genotype (or haplotype) subgroups.

Evaluation of Genotypic Effects

Analyses may be carried out to evaluate the degree of association between subject genotype (or haplotype) and selected parameters (e.g., pharmacokinetics, efficacy and safety). Where such genotypic tests are inappropriate (for example, where the number of marker genotypes is too large and/or the frequency of individual genotypes too small), allelic tests may be conducted. Allelic tests evaluate whether the frequency of each marker allele is the same in responders and non-responders.

Evaluation of Treatment by Genotype and Gene-Gene Interaction

In addition to evaluating the main effects of the genotypes (haplotypes or alleles) on the selected parameters, the possibility of a treatment group by genotype (haplotype or allele) interaction will also be explored. If appropriate, the joint effects of multiple markers (gene-gene interactions) may also be evaluated.

106 106 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Linkage Disequilibrium

For pairs of polymorphisms, the degree to which alleles from the two sites are correlated (linkage disequilibrium) may also be evaluated. If the genotypes at two polymorphic sites within a gene are shown to be statistically associated with a response to investigational product, the degree of linkage disequilibrium will aid interpretation in that it will indicate the extent to which the two sites are exerting independent effects.

Multiple Comparisons and Multiplicity

To the extent that multiple markers are evaluated (especially in the case of a genome scan for association), an adjustment to observed p-values may be made to limit erroneous conclusions due to multiple tests.

Power and Sample Size Considerations

The ability to detect differential drug response among genotypes at a polymorphic site depends on the total number of subjects genotyped and the frequency distribution of the different genotypes. Consequently, genotyping analyses are plausible for those polymorphic sites where the number of subjects comprising the genotypic groups is sufficiently large; however, these frequencies will not be known until sufficient samples have been collected and genotyping is complete.

Estimates of sample sizes required to demonstrate genotype effects vary considerably, depending on the assumptions made about allele frequency, genetic effect size, and mechanism of inheritance [Davies, 2000; Cardon, 2000]. In the work by Palmer and Cookson [Palmer, 2001], which assumed a genotype relative risk of 1.5, it was estimated that more than 300 cases and 600 controls would be needed to conduct a genetic association analysis. In contrast, McCarthy and Hilfiker [McCarthy, 2000] showed that with a genotype relative risk of 2.16 and a relatively commonly occurring genotype, only 30 cases and 30 controls would be needed to demonstrate an association.

Published PGx examples include abacavir hypersensitivity reaction [Hetherington, 2002; Mallal, 2002] and tranilast induced hyperbilirubinemia [Roses, 2002] where genetic markers have been found to significantly associate with hypersensitivity reaction (abacavir) and hyperbilirubinemia (tranilast). These examples show that small sample sizes typically encountered in Phase I and Phase II studies may be sufficient to identify clinically relevant genetic associations.

Informed Consent

Subjects who do not wish to participate in the PGx research may still participate in the clinical study. PGx informed consent must be obtained prior to any blood being taken for PGx research.

107 107 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

References

Cardon LR, Idury RM, Harris TJR, Witte JS, Elston RC. Testing drug response in the presence of genetic information: sampling issues for clinical trials. Pharmacogenetics. 2000; 10:503-10.

Davies WE. El Rafaie A. Epidemiology of tinnitus. In:Tylers RS, eds. Tinnitus Handbook. Singular, San Diego, CA, 2000, pg.1-23.

Drazen JM, Yandava CN, Dube L, Szcerback N, Hippensteel R, Pillari A, Israel E, Schork N, Silverman ES, Katz DA, Drajesk J. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nature Genet. 1999; 22:168-70.

Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet. 2002; 359:1121-2.

Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002; 359:727-32.

McCarthy JJ, Hilfiker R. The use of single-nucleotide polymorphism maps in pharmacogenomics. Nat Biotechnol. 2000; 18:505-8.

Palmer LJ, Cookson WO. Using single nucleotide polymorphisms as a means to understanding the pathophysiology of asthma. Respir Res. 2001; 2:102-12.

Roses AD. Genome-based pharmacogenetics and the pharmaceutical industry. Nat Rev Drug Discov. 2002; 1:541-9.

108 108 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Appendix 4: Inhibitors and inducers of Cytocrome P450 2D6 and 3A

CYP Inhibitors inducers 2D6 amiodarone levomepromazine dexamethasone buproprion metoclopramide rifampin celecoxib methadone chlorpromazine mibefradil chlorpheniramine moclobemide cimetidine paroxetine clomipramine quinidine cocaine ranitidine doxorubicin ritonavir fluoxetine sertraline halofantrine terbinafine red-haloperidol 3A HIV Antivirals: erythromycin HIV Antivirals: delaviridine fluconazole efavirenz indinavir fluvoxamine nevirapine nelfinavir gestodene barbiturates ritonavir grapefruit juice carbamazepine saquinavir itraconazole glucocorticoids amiodarone ketoconazole modafinil NOT azithromycin mifepristone phenobarbital cimetidine nefazodone phenytoin ciprofloxacin norfloxacin rifampin clarithromycin norfluoxetine St. John's wort diethyl- dithiocarbamate mibefradil troglitazone diltiazem verapamil pioglitazone rifabutin

109 109 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Appendix 5: Protocol Changes – Amendment 02

Summary of Amendment Changes with Rationale

Procedure changes are detailed in the revised Time and Events table: Change 34.

Removed Study Procedures

Originally the protocol was designed to specifically enrich the study population, based on patient eligibility responding to the lidocaine test and HADS score. Due to lack of recruitment experienced to date, this protocol amendment removes the lidocaine test (with associated study procedures on second screening visit) and HADS eligibility criteria. The study population will continue to be enriched based on the original criteria of ‘subjects suffering with continuous tinnitus for at least six months’.

The above changes are detailed below as Changes 6, 7, 8, 16, 17, 19 and 21.

Modification of Study Procedures/Criteria

Some exisiting protocol procedures have been modified to allow conduct, facilitation and interpretation of study.

• The subject diary of tinnitus and hyperacusis during the treatment period has been changed from a secondary objective/endpoint to exploratory tertiary objective/endpoint. Changes 2, 3, 4 and 5.

• Decisions regarding subject withdrawal from the study due to adverse event reporting has been expanded to detail decision making steps. Change 32.

• To allow flexibility of assessment, the pregnancy test at screening may be performed as urine or serum samples, rather than restricting to a urine sample. Changes 24 and 25.

• Originally the washout periods between treatments was fixed. In order to facilitate patient availability and recruitment, the amendment includes a flexible washout period of upto 14 days. Change 34.

• Clarification of alcohol intake requirements, and female contraception guidance in the eligibility criteria based on GSKs current standards. Changes 18 and 19.

• Subjects prescribed Beta-adrenergic blockers may also be excluded due to potential drug-drug interactions. Change 19. Synopsis Changes

The original protocol synopsis contained detailed procedural information, and therefore this amendment has streamlined the synopsis to provide an overview of the design. The study details remain in the main text and Time & Events tables. Changes 8, 9, 10, 11, 12, 13, 14, 15 and 16.

110 110 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Clarification. Consolidation and Consistency Changes

This protocol amendment also takes the opportunity to clarify, consolidate (referencing to Time & Events Table), correct typographical/grammar errors (which may not be specifically detailed below) and consistency in terminology to facilitate protocol readability.

• References to an updated Investigator Brochure and updated Paroextine Global Prescriber information have also been corrected. Changes 20 and 35. • Clarification regarding the original protocol test of Tinnituts Matching has been added. Change 28. The changes not denoted above are captured as Change 1, 4, 17 (text has been included into the lists of eligibility criteria), 19, 21, 22, 23, 26, 27, 29, 30, 31, 33. As a result of some sections or a study visit being removed, section numbering/visit numbers may have changed; these changes have not been detailed below to facilitate reading the protocol amendment.

List of Specific Changes

1. Section: Throughout document

Throughout document text originally stating ‘vestipitant – paroxetine’ was changed to to vestipitant + paroxetine’ for clarification.

2. Section: Protocol Summary, Objectives, Secondary and Section 2.2 Secondary Objectives

PREVIOUS TEXT

To measure the change in tinnitus subjective features (i.e., tinnitus pitch and distress, and general alertness/anxiety levels), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level (i.e., visual scales, heart rate and blood pressure), clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep).

To evaluate safety and tolerability of vestipitant alone and the combination paroxetine- vestipitant at single dose.

To evaluate the PK/PD relationships between steady state exposure of vestipitant and paroxetine-vestipitant combination with each of the various pharmacodynamic endpoints

To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant-paroxetine combination and placebo.

111 111 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

REVISED TEXT

• To measure the change in tinnitus subjective features (i.e., tinnitus pitch, intensity and distress, and general alertness/anxiety levels), audiometry, psychoacoustic assessment of tinnitus pitch, timbre, loudness using an automated system, emotional/alertness level (i.e., visual scales, heart rate and blood pressure), clinical scores (i.e., Tinnitus Handicap Inventory and Annoyance of Hyperacusis; Diary for tinnitus, hyperacusis, and sleep). • To evaluate safety and tolerability of vestipitant alone and the combination paroxetine-vestipitant vestipitant + paroxetine at single dose. • To evaluate the PK/PD relationships between steady state exposure of vestipitant and paroxetine-vestipitant vestipitant + paroxetine combination with each of the various pharmacodynamic endpoints. • To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant-paroxetine combination and placebo. 3. New Section: Protocol Summary, Objectives, Exploratory and Section 2.3 Exploratory

NEW TEXT

To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant + paroxetine combination and placebo

4. Section: Protocol Summary Endpoints, Secondary and Section 3.2. Secondary Endpoints

PREVIOUS TEXT

1. Visual Analog Scales (VAS) to measure the level in tinnitus pitch and tinnitus distress as perceived at the moment of the measurement 2. VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) 3. Pure Tone Audiometry (Audiogram) 4. Psychoacoustic assessment (automated if possible) of tinnitus pitch, timbre, intensity 5. Self-report questionnaires (integrated evaluation referring only to the day of testing after dosing): Tinnitus Handicap Inventory (THI) 6. Self-report questionnaires (integrated evaluation referring to the past week, up to the moment of measurement): a. Tinnitus Handicap Inventory (THI) b. Quick Inventory of Depressive Symptomatology (QIDS-SR 16). c. Leeds Sleep Evaluation Questionnaire (LSEQ) 7. Diary (to be filled in the evening):

112 112 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

a. Number of benzodiazepines, analgesic or any other calming infuses consumed during days b. VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) c. Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress REVISED TEXT

1. Visual Analog Scales (VAS) to measure the level in tinnitus pitch, intensity and tinnitus distress as perceived at the moment of the measurement 2. VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) 3. Pure Tone Audiometry (Audiogram) 4. Psychoacoustic assessment (automated if possible) of tinnitus pitch, timbre, intensity 7. 5. 3. Self-report questionnaires (integrated evaluation referring only to the subject’s condition before dosing on the day of testing after dosing): a. Tinnitus Handicap Inventory (THI) b. Quick Inventory of Depressive Symptomatology (QIDS-SR 16) 8. 6. Self-report questionnaires (integrated evaluation referring to the past week, up to the moment of measurement): a. Tinnitus Handicap Inventory (THI) b. Quick Inventory of Depressive Symptomatology (QIDS-RS 16). c. Leeds Sleep Evaluation Questionnaire (LSEQ) 9. 7. Diary (to be filled in the evening): a. Number of benzodiazepines, analgesic or any other calming infuses consumed during days b. VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) c. Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress 5. New Section: Protocol Summary, Exploratory Endpoints and New Section 3.3. Exploratory Endpoints

NEW TEXT

• Diary (to be filled in the evening): a. VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day).

113 113 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

b. Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress. 6. Section: Protocol Summary, Study Design and Section 4 Study Design

PREVIOUS TEXT

This is a randomised, double-blind, placebo-controlled, cross-over study that investigates the effects of single dose and repeated dosing of vestipitant-paroxetine combination and vestipitant alone vs. placebo in an enriched population of tinnitus patients.

Subjects suffering from tinnitus will be attending the clinics for 2 screening visits, then randomized to one of the six repeated dosing treatment sequences. Treatment phase consists in 3 treatment periods of 14-day separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests will be performed at the Day 1 and on the 14th Day of each treatment period within 4 hrs after dosing. All subjects will receive all treatments and a follow up visit will be performed 14 days after last drug dosing. Treatments are:

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

14 days 14 days 2nd period 3rd period (eg. Screening st 1 period (eg. vestipitant + vestipitant) (eg.placebo) paroxetine) ll 14 days 14 Days 14 days

Follow up Testing Sessions

The main enrichment criteria of the population included is based on the presence of a mild-to-moderate auditory impairment that could be related to acoustic trauma (i.e., either as historical record, self-report, or tonal audiogram profile) and a positive response to the lidocaine test.

The first screening visit consists in the clinical assessment for tinnitus diagnosis, including audiogram, questionnaires and medical visit, ECG, laboratory test on blood and urine, current treatment, and their agreement to participate in the study.

114 114 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

and distress of tinnitus, and the presence of hyperacusis, will be collected at 5 minutes pre-infusion time and immediately at the end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. Subject will be included only in case of:

a. there is consistency between the placebo and the lidocaine pre-infusion VAS values for loudness (i.e. intensity); the consistency is defined as: a difference in VAS loudness of less than, or equal to 30% between the highest and the lowest pre- infusion values AND b. the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is 10mm or more than the reduction observed following placebo iv infusion. REVISED TEXT

This is a randomised, double-blind, placebo-controlled, cross-over study that investigates the effects of single dose and repeated dosing of vestipitant-paroxetine vestipitant + paroxetine combination and vestipitant alone vs. placebo. in an enriched population of tinnitus patients.

Subjects suffering from tinnitus will be attending the research unit clinics for 2 a screening visits. On Day 1, following the baseline measurements, subjects then will be randomized to one of the six repeated dosing treatment sequences. The Treatment pPhase consists in of 3 three 14-day treatment periods of 14-day separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests will be performed at the on Day 1 and on the 14th Day 14 of each treatment period within 4 hrs after dosing. All subjects will receive all treatments and a follow up visit will be performed 14 days after the final dose of study medication after last drug dosing. Treatments are:

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

115 115 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The first screening visit consists in the of informed consent, clinical assessments for tinnitus diagnosis, including audiogram, questionnaires, and a physical examination, vital signs, and medical visit, ECG, laboratory test on blood and urine samples, and the review of current treatment, medication and medical history., and their agreement to participate in the study.

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit. In the second visit the subject will be taken to a quiet room for testing lidocaine response. Subjects will be administered first an intravenous (iv) infusion of placebo (normal saline), and second an iv infusion of lidocaine (1.5 mg/kg body weight) for 5 min in a single blind manner. VAS for pitch, loudness (i.e. intensity), and distress of tinnitus, and the presence of hyperacusis, will be collected at 5 minutes pre-infusion time and immediately at the end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. Subject will be included only in case of:

b. the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is 10mm or more than the reduction observed following placebo iv infusion. 7. Section: Protocol Summary, Study Population, Number of Subjects and Section 5.1 Number of Subjects

PREVIOUS TEXT

Twenty-four subjects will be recruited in the study to obtain at least 19 subjects completing the study.

REVISED TEXT

Twenty-four subjects suffering with continuous tinnitus for at least six months will be recruited in the study to obtain at least 19 subjects completing the study.

116 116 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

8. Section: Protocol Summary, Eligibilty Criteria

PREVIOUS TEXT

Eligibility Criteria

Eligible subjects will be male or female subjects, aged between 18 and 65 years, with a confirmed diagnosis of tinnitus, based on standardized ONH visit and examination, including otoscopy and audiograms. Subject with completely normal audiogram or those with severe hearing loss will be excluded. In case of identified disorder associated to tinnitus, e.g., Meniere Disease or Otosclerosis, subjects will be also excluded.

Patients should have been suffering with tinnitus for at least six months, and should not be reported as intermittent. Subjects with severe anxiety and depression scores will be excluded as identified by a HADS score >=11. Beck Inventory for Depression, version 2, will be used to qualify the residual level of depressive symptoms in those subjects that will be included in the study.

Enrichment criteria will be based on the documented presence of auditory impairment and the capacity to detect transient changes in tinnitus loudness (i.e. intensity) to lidocaine infusion (see Section 4; reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is 10mm or more than the reduction observed following placebo iv infusion). This criterion is arbitrary but related to previous experience [Baguley, 2005].

REVISED TEXT

Text has been removed.

9. Section: Protocol Summary, Inclusion Criteria

PREVIOUS TEXT

Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

117 117 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• The subject must have the ability to comprehend the key components of the consent form and must have given written informed consent to participate in the study prior to commencing any study specific procedures. • Women of childbearing potential, who have a negative urine pregnancy test result at screening and pre-dose on Day 1 for all the 3 treatment sessions, must be able to commit to either of the following: Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug, OR Agrees to consistent and correct use of an acceptable method of birth control; GSK acceptable Contraceptive Methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows: a. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or b. Oral contraceptives (either combined or progestogen only); Double-barrier method of contraception consisting of spermicide with either condom or diaphragm; IUD with a documented failure rate of less than 1% per year; If subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active. • Women of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses). REVISED TEXT

The above eligibility criteria have been removed.

10. Section: Protocol Summary, Exclusion Criteria

PREVIOUS TEXT

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

118 118 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Subject with no audiogram deficit and with normal hearing • Subjects that do not respond to the lidocaine infusion test (i.e., the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is not 10mm or more than the reduction observed following placebo iv infusion) or showing a large variability in pre-infusion values (i.e., the difference between the placebo and the lidocaine pre-infusion VAS for loudness (ie intensity) is more than 30%) • Subjects with one of the following medical conditions: • Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant, Paroxetine or lidocaine • Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug • Subject with pathologic level of anxiety or depression or obsessive compulsive disorder (OCD), as assessed by a score of 11 or more with The Hospital Anxiety and Depression Scale (HADS≥11) • Subjects with hepatic impairment (ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening) or a history of liver dysfunction. • Subjects with renal impairment (serum creatinine higher than 124umol/l). • Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows: • QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period • QTc >= 480 msec for patients with Bundle Branch Block • Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designee considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5- fold higher than the upper limit of normal at screening. • Subjects positive for HIV 1 or II, hepatitis C antibody or hepatitis B surface antigen • Subjects who are not euthyroid based on laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. • Subjects with current or past history of clinically significant hepatic, cardiac, renal, neurologic, cerebrovascular, metabolic or pulmonary disease.

119 119 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Subjects who have had a myocardial infarction within 1 year prior to screening visit. • Subjects with current or past history of seizure disorders (except for febrile seizures in childhood). • Subjects with known current or past history of cancer • Subjects with known porphyria, or allergy to amide local anaesthetics • Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject’s participation in the study. • Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. • Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:- • Depot neuroleptics – 12 weeks prior to Screening Visit 1 • MAOIs or Fluoxetine –4 weeks prior to Screening Visit 1 • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening Visit 1 • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening Visit 1 • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1 • Any CNS-active herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening Visit 1 • The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. • The subject had a medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Day 1 of all the 3 Treatment Sessions which is known to interfere with CYP2D6 or CYP3A isozymes (see IB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.).

120 120 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to the Screening, Visit 1, e.g., sumatriptan, naritriptan, ergotamine, alosetron. • The subject took thioridazine within 14 days prior to the Screening, Visit 1. • Subjects who have used an investigational drug or have participated in an investigational trial within 6 months of the Screening, Visit 1. • Subjects who have exhibited intolerance to NK1 antagonists or SSRIs • Women who have a positive urine HCG pregnancy test at screen visit or a positive urine dipstick HCG pregnancy test performed by the investigator at the baseline visits (i.e., at Day 1 of each Treatment Session) or who are lactating • Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration in the study. • Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study). • Subjects, who have donated a unit of blood (500ml) or more within the previous month or who intend to donate blood within one month of completing the study REVISED TEXT

The above text has been removed.

11. Section: Protocol Summary, Other Eligibility Criteria Considerations

PREVIOUS TEXT

Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: vestipitant Clinical Investigator’s Brochure [Clinical Investigator's Brochure: GW597599, Edition 1] and prescribing information for paroxetine: [Appendix 2, Global Data Sheet for Paroxetine].

REVISED TEXT

The above text has been removed.

121 121 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

12. Section: Protocol Summary, Study Assessments, Screening

PREVIOUS TEXT

Screening

There will be 2 screening visits:

Visit 1 (Screening 1st part)

The following assessments will be completed at screening to determine the subject’s eligibility for enrolment no more than 28 days prior to Day 1 visit. However, should the subject have had the audiological procedures performed prior to study start (up to 3 months ago), these results may be accepted.

The first screening visit consists of the clinical assessment for tinnitus diagnosis, including:

• Demography • Medical and Medication history. • Physical examination, • 12-lead ECG. • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position • Clinical laboratory assessments: haematology, biochemistry, urinalysis, screens for hepatitis B and C, human immunodeficiency virus (HIV) and urine screen for drugs of abuse, alcohol breath test. • Pregnancy test (Urine HCG) • Evaluation of Eligibility Criteria • Otological screen • Otoacoustic emissions (OAE) • Tonal Audiogram, • Speech Audiogram • self-scored HADS • Tinnitus Handicap Inventory (THI) • Agreeement to participate on in the study • Diary for home scoring (training and request to try at home) • Question: « How aggravated are you by tinnitus?” (8-point scale) • Annoyance of Hyperacusis. • Self-scored 16-item Quick Inventory of Depressive Symptoms(QIDS-SR 16)

122 122 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• VAS anxiety/arousal scores (tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed). Visit 2: Screening (2nd part)

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit.

The following assessments will be completed no more than 14 days prior to Day 1 visit:

• Assessment about the proper filling of the Diary for home scoring • Testing of lidocaine response : • Under continuous cardiac monitoring, subjects will be administered first an intravenous (iv) infusion of placebo (normal saline), and second an iv infusion of lidocaine (1.5 mg/kg body weight), for 5 min, in a single blind manner. VAS for pitch, loudness (i.e. intensity), and distress of tinnitus, and the presence of hyperacusis, will be collected at 5 minutes pre-infusion time and immediately at the end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. • The patient will not be discharged from the unit until at least 45 min after the completion of the second infusion. An acceptable lidocaine response (see criteria above and Sections 4 and Section 5.1.3.) will be required for progression to the main part of the study.

In case the subject is included, pregnancy testing (Urine HCG) for woman and blood sample collection for pharmacogenetic (PGx) assessments (if consent obtained, for all) will be performed. The latter sample (i.e., PGx) can be collected any time during the study.

REVISED TEXT

For detailed study assessments refer to Section 6 and Appendix 1: Time and Events Table.

13. Section: Protocol Summary, Treatment: Visit 3, 5, and 7: Day 1

PREVIOUS TEXT

The visit starts with a brief interview about general conditions, Vital Signs, and Medical Examination. Blood is collected for safety laboratory parameters and for PK assessment.

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005), the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events, and occurrence of AEs will be asked, all referring to the last 2 weeks, separated in two scores, i.e., the 1st week and the 2nd week.

The subject will be taken to a quiet room and after about 10 min pre-dose VAS scales for tinnitus (i.e., scales for intensity, pitch and distress) and VAS for arousal/anxiety (i.e.,

123 123 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

scales anchored to tired-energetic, active-drowsy, tense-peaceful, worried-relaxed) are self-scored.

While in the quiet room the subject is asked to fill the pre-dose self-scored THI, LSEQ and QIDS-16 focusing on events regarding the last 2 weeks.

The dose (i.e., two tablets) is administered.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is discharged from the research unit, following a medical examination for safety, including vital signs, ECG and Romberg.

REVISED TEXT

The above text has been removed.

14. Section: Protocol Summary, Study Assessments, Visits 4, 6 and 8: Day (12-14)

PREVIOUS TEXT

Visits 4, 6 and 8: Day (12-14)

Subjects maybe asked to come in between days 12-14, which is typically referred to as day 14. The visit starts with a brief interview about general conditions, Vital Signs, and Medical Examination. Blood is collected for safety laboratory testing and for the pre-dose PK measurements.

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005] the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week of treatment and the 2nd week of treatment. Spontaneous reports of occurrence of AEs during the 2 previous week is collected

124 124 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The Diary for home scoring is obtained, and the remaining tablets are requested for compliance checking.

The subject is then taken to a quiet room and then, after about 10 min, pre-dose VAS scales (VAS tinnitus and arousal/anxiety) are self-scored.

The dose (i.e., two tablets) is administered.

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured for last time.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (inter-treatment score) will be given, to be returned at the next visit.

A Diary/symptom card for home scoring (after last dose) will be given, to be returned at follow up visit.

A light snack is served. Then the subject is free to go home, following a medical exam for safety, including ECG, vital signs and Romberg.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

REVISED TEXT

Above text has been removed.

125 125 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

15. Section: Protocol Summary, Study Assessments, Visit 9, Follow Up (12 to 14 days after last study drug administration)

PREVIOUS TEXT

Visit 9, Follow Up (12 to 14 days after last study drug administration)

• Adverse Events and Concomitant Medication recording • Physical examination • 12-lead ECG • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position; • Clinical safety laboratory tests (haematology, clinical chemistry and urinalysis) • Pregnancy test (Urine HCG) Any clinically significant abnormal results from the follow-up visit will be re-assessed until either stabilised or resolved.

REVISED TEXT

The above text has been removed.

16. Section 1.1 Background, Rationale for enrichment in the selection of the study population

PREVIOUS TEXT

Rationale for the enrichment in the selection of the study population

Population enrichment is a commonly used procedure to reduce the biological variance within a group of subjects with the same diagnosis for a given disease. Given the recognised heterogeneity of the possible mechanisms involved in tinnitus, a restriction of the inclusion criteria for the study population is necessary. The clinical requirements are the presence of:

1. Mild or greater severity of tinnitus (i.e., THI entry score > = 18), stable (i.e., occurring as symptom for more than 6 month,), non-pulsatile, preferably lateralised, not related to otosclerosis, acoustic neuroma, or Meniere Disease, or complicated by self-arming behaviour (e.g., failed surgery) or litigations for insurance compensation related to tinnitus [Mc Combe, 2001; Newman, 1998]. 2. Mild-to-moderate acquired sensorineural hearing loss such as acoustic trauma, a condition associated with reorganisation of auditory system maps [Eggermont, 2005]. This criterion is in line with the reduced tinnitus loudness and distress scores obtained following a treatment with gabapentin in a population enriched for evidence of acoustic trauma [Bauer, 2006]. 3. Non-pathologic level of anxiety or depression, as assessed with The Hospital Anxiety and Depression Scale (HADS) and the Beck Inventory (II). The exclusion of

126 126 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

co-morbid Psychiatric Disorders is proposed to minimize the possible confounding effects of direct antidepressant or anxiolytic properties of the treatment on specific tinnitus characteristics; 4. Pharmacologic requirement that the subjects recognise a transient detectable reduction or improvement of the characteristic of tinnitus in response to lidocaine iv infusion. The endpoints to assess the lidocaine infusion will be based on the same VAS for tinnitus pitch (tone), loudness (intensity) and distress (annoyance) previously used in similar studies [Baguley, 2005]. The capacity to respond to lidocaine is considered as an inclusion criterion since: It gives an example to the subject about his/her possibility of detecting a clinically relevant effect of a pharmacologic treatment; It offers the possibility for the subject to identify a possible “anchoring” condition of changes in some audiologic characteristics of tinnitus rather than psychologic ones (e.g., distress, anxiety), as delivered by benzodiazepines; It increases the probability to obtain a more precise description of possible clinical effects to another effective therapy, in particular for the measurement at the single dose treatment. Expectations about treatment outcome must be properly managed by informing the subjects that the novel treatment may deliver different effects in intensity and quality, and that the lidocaine test is a simple assessment of their capacity to respond to it.

In case the subjects will be under chronic pharmacologic treatment at the moment of the enrolment, they will be asked to stop this treatment before being enrolled in the trial. The same measurements that are performed at baseline should be taken at about one week from the cessation of the previous treatment. Attention will be given to the application of a proper down-titration procedure to avoid withdrawal syndrome. Occasional use of benzodiazepines or hypnotic is allowed, but dosing should be reported in the diary.

REVISED TEXT

The above text has been removed.

17. Section 5.2 Eligibility Criteria

PREVIOUS TEXT

5.1.1. Eligibility Criteria

127 127 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

will be used to qualify the residual level of depressive symptoms in those subjects that will be included in the study.

REVISED TEXT

Text has been removed.

18. Section 5.2.1 Inclusion Criteria

PREVIOUS TEXT

5.1.2. Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

• Male or female subjects with a diagnosed tinnitus according to standardized ONH visit and examination, including otoscopy and audiograms • Subject with THI severity grade of mild or greater (THI >= 18, [Newman, 1998]). • Subjects must be 18-65 years of age inclusive. • Subjects willing to restrict alcohol intake to 1-2 unit or less per day. A unit is equivalent to 220 ml of beer or one measure of spirits (25ml) or one-two glass of wine (125 ml). • The subject must have the ability to comprehend the key components of the consent form and must have given written informed consent to participate in the study prior to commencing any study specific procedures. • Women of childbearing potential, who have a negative urine pregnancy test result at screening and pre-dose on Day 1 for all the 3 treatment sessions, must be able to commit to either of the following: Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug, OR Agrees to consistent and correct use of an acceptable method of birth control; GSK acceptable Contraceptive Methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows: a. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or

128 128 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

b. Oral contraceptives (either combined or progestogen only); Double-barrier method of contraception consisting of spermicide with either condom or diaphragm; IUD with a documented failure rate of less than 1% per year; If subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active. • Women of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses). REVISED TEXT

5.1.2 5.2.1 Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. Male or female subjects with a diagnosed with tinnitus according to a standardized audiology ONH visit and examination, including otoscopy and audiograms. 2. Subject with a THI severity grade of mild or greater (THI ≥>= 18, [Newman, 1998]). 3. Subjects must be 18-65 years of age inclusive. 4. Subjects willing to restrict alcohol intake to 1-2 unit or less per day. A unit is equivalent to 220 ml of beer or one measure of spirits (25ml) or one-two glass of wine (125 ml). 10. 5. 4. The subject must have the ability to comprehend the key components of the consent form and must have given written informed consent to participate in the study prior to commencing any study specific procedures. 11. 6. 5. Women of childbearing potential, who have a negative urine pregnancy test result at screening and pre-dose on Day 1 for all the 3 treatment sessions, must be able to commit to either of the following: • Complete abstinence from intercourse for two weeks before exposure to the study drug, throughout the clinical trial, and for a period after the trial to account for elimination of the drug, OR • Agrees to consistent and correct use of an acceptable method of birth control; GSK acceptable Contraceptive Methods, when used consistently and in accordance with both the product label and the instructions of a physician, are as follows: a. Male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject, or b. Oral contraceptives (either combined or progestogen only);

129 129 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Double-barrier method of contraception consisting of spermicide with either condom and or an occlusive cap (diaphragm or cervical/ vault caps) with a vaginal spermicidal agent (foam/gel/film/cream/suppository); IUD with a documented failure rate of less than 1% per year; If subjects indicate they will remain abstinent during the period described above, they must agree to follow GSK guidelines for the consistent and correct use of an acceptable method of birth control should they become sexually active. 12. 5. 6. Women of non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal. For purposes of this study, postmenopausal is defined as one year without menses). 19. Section 5.2.2 Exclusion Criteria

PREVIOUS TEXT

5.1.3. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

130 130 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Subjects with hepatic impairment (ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening) or a history of liver dysfunction. • Subjects with renal impairment (serum creatinine higher than 124umol/l). • Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows: • QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period • QTc >= 480 msec for patients with Bundle Branch Block • Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designee considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5- fold higher than the upper limit of normal at screening. • Subjects positive for HIV 1 or II, hepatitis C antibody or hepatitis B surface antigen • Subjects who are not euthyroid based on laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. • Subjects with current or past history of clinically significant hepatic, cardiac, renal, neurologic, cerebrovascular, metabolic or pulmonary disease. • Subjects who have had a myocardial infarction within 1 year prior to screening visit. • Subjects with current or past history of seizure disorders (except for febrile seizures in childhood). • Subjects with known current or past history of cancer • Subjects with known porphyria, or allergy to amide local anaesthetics • Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject's participation in the study. • Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. • Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:-

131 131 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Depot neuroleptics – 12 weeks prior to Screening Visit 1 • MAOIs or Fluoxetine –4 weeks prior to Screening Visit 1 • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening Visit 1 • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening Visit 1 • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1 • Any CNS-active herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening Visit 1 • The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. • The subject had a medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Day 1 of all the 3 Treatment Sessions which is known to interfere with CYP2D6 or CYP3A isozymes (see IB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.). • The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to the Screening, Visit 1, e.g., sumatriptan, naritriptan, ergotamine, alosetron. • The subject took thioridazine within 14 days prior to the Screening, Visit 1. • Subjects who have used an investigational drug or have participated in an investigational trial within 6 months of the Screening, Visit 1. • Subjects who have exhibited intolerance to NK1 antagonists or SSRIs • Women who have a positive urine HCG pregnancy test at screen visit or a positive urine dipstick HCG pregnancy test performed by the investigator at the baseline visits (i.e., at Day 1 of each Treatment Session) or who are lactating • Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration in the study. • Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study). • Subjects, who have donated a unit of blood (500ml) or more within the previous month or who intend to donate blood within one month of completing the study

132 132 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

REVISED TEXT

5.1.3 5.2.2. Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. Subject with a THI of grade of “No handicap” [Newman, 1998] i.e. THI score of less than 18. 13. 2. Subject with pathologic level of anxiety or depression as assessed be the Hospital Anxiety and Depression Scale (HADS≥11) 14. 3. Subject with no audiogram deficit and with normal hearing 15. 4. Subjects that do not respond to the lidocaine infusion test (i.e., the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is not 10mm or more than the reduction observed following placebo iv infusion) or showing a large variability in pre-infusion values (i.e., the difference between the placebo and the lidocaine pre-infusion VAS for loudness (ie intensity) is more than 30%) 16. 5. 2. Subjects with one of the following medical conditions: a. Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant or Pparoxetine or lidocaine b. Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug c. Subjects with known Meniere Disease or Otosclerosis. d. Subject with pathologic level of anxiety or depression or obsessive compulsive disorder (OCD), as assessed by a score of 11 or more with The Hospital Anxiety and Depression Scale (HADS≥11) e. Subjects with hepatic impairment (ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening) or a history of liver dysfunction. f. Subjects with renal impairment (serum creatinine higher than 124umol/l). d. Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows: • QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period. • QTc >= 480 msec for patients with Bundle Branch Block

133 133 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

e. Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designee considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5-fold higher than the upper limit of normal at screening. f. Subjects positive for HIV 1 or II, hepatitis C antibody or hepatitis B surface antigen g. Subjects who are not euthyroid based on clinical examination and laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. h. Subjects with current or past history of clinically significant hepatic (subjects with hepatic impairment [ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening] or a history of liver dysfunction), cardiac, renal (serum creatinine higher than 124umol/l), neurologic, cerebrovascular, metabolic, or pulmonary disease or gastrointestinal bleeding. i. Subjects with a current condition of, or history of psychosis. j. Subjects who have had a myocardial infarction within 1 year prior to screening visit. k. Subjects with current or past history of seizure disorders (except for febrile seizures in childhood). l. Subjects with known current or past history of cancer m. Subjects with known porphyria, or allergy to amide local anaesthetics m. Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject’s participation in the study. 3. Current or history of (within 6 months of the study) regular alcohol consumption defined as: • For males: an average weekly intake of greater than 21 units or an average daily intake of greater than 3 units. • For females: an average weekly intake of greater than 14 units or an average dailiy intake of greater than 2 units. • One unit is equivalent to a half-pint (220 mL) of beer or 1 (125 mL) measure of spirits or 1 glass (125 mL) of wine. 4. Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. 5. Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:- • Depot neuroleptics – 12 weeks prior to Screening Visit 1

134 134 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• MAOIs or Fluoxetine –4 weeks prior to Screening (Visit 1) • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening (Visit 1) • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening (Visit 1). Subjects prescribed Beta- adrenergic blockers may also be excluded due to potential drug-drug interactions. • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1 • Any CNS-active herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening Visit 1 6. The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. 7. The subject had a medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Day 1 of all the 3 Treatment Sessions which is known to interfere with CYP2D6 or CYP3A isozymes (see CIB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.). 8. The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to the Screening, Visit 1, e.g., sumatriptan, naritriptan, ergotamine, alosetron. 9. The subject took thioridazine within 14 days prior to the Screening, Visit 1. 10. Subjects who have used an investigational drug or have participated in an clinical trial with an investigational medicinal product trial within 6 months of the Screening, Visit 1. 11. Subjects who have exhibited intolerance to NK1 antagonists or SSRIs. 12. Women who have a positive urine HCG pregnancy test at screen visit or a positive urine or blood dipstick HCG pregnancy test performed by the investigator at the baseline visits (i.e., at Day 1 of each Treatment Session) or who are lactating breastfeeding. 13. Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration. in the study. 14. Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study).

135 135 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

15. Subjects, who have donated a unit of blood (500ml) or more within the previous month or who intend to donate blood within one month of completing the study. 20. Section 5.2.3 Other Eligibility Criteria Considerations

PREVIOUS TEXT

5.1.4 Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: vestipitant Clinical Investigator’s Brochure [Clinical Investigator's Brochure: GW597599, Edition 1] and prescribing information for paroxetine: [Appendix 2, Global Data Sheet for Paroxetine].

REVISED TEXT

5.1.4 5.2.3. Other Eligibility Criteria Considerations

To assess any potential impact on subject eligibility with regard to safety, the investigator must refer to the following document(s) for detailed information regarding warnings, precautions, contraindications, adverse events, and other significant data pertaining to the investigational product(s) being used in this study: vestipitant Clinical Investigator’s Brochure [Clinical Investigator's Brochure: GW597599, Edition 1 Version 6] and prescribing information for paroxetine: [Appendix 2, Global Data Sheet for Paroxetine].

21. Section 6.1 Screening

PREVIOUS TEXT

After providing full informed consent, subjects will undergo a medical screen to determine their eligibility for participation based on the criteria outlined in this protocol. Subjects will be screened within 28 days prior to administration of study medication. The study investigator or a sub-investigator will discuss with each subject the nature of the study, its requirements, and its restrictions. Written informed consent must be obtained prior to any protocol-specific procedures.

There will be 2 screening visits:

Visit 1 (Screening 1st part)

The first screening visit consists in the clinical assessment for tinnitus diagnosis, including:

136 136 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Demography • Medical and Medication history. • Physical examination, • 12-lead ECG. • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position • Clinical laboratory assessments: haematology, biochemistry, urinalysis, screens for hepatitis B and C, human immunodeficiency virus (HIV) and urine screen for drugs of abuse, alcohol breath test. • Pregnancy test (Urine HCG) • Evaluation of Eligibility Criteria • Otological screen • Otoacoustic emissions (OAE) • Tonal Audiogram, • Speech Audiogram • self-scored HADS • Tinnitus Handicap Inventory (THI) • Agreement to participate in the study • Question: « How aggravated are you by tinnitus?” (8-point scale) • Annoyance of Hyperacusis. • Self-scored 16-item Quick Inventory of Depressive Symptoms(QIDS-SR 16) • VAS anxiety/arousal scores (tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed). • Diary for home scoring (training and request to try at home) Visit 2: Screening (2nd part)

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit.

The following assessments will be completed no more than 14 days prior to Day 1 visit:

137 137 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. • The patient will not be discharged from the unit until at least 45 min after the completion of the second infusion. An acceptable lidocaine response (see criteria above and Section 4 and Section 5.1.3.) will be required for progression to the main part of the study.

REVISED TEXT

After providing full informed consent, subjects will undergo a medical screen to determine their eligibility for participation based on the criteria outlined in this protocol. Subjects will be screened within 28 days prior to administration of study medication on Day 1. The study investigator or a sub-investigator will discuss with each subject the nature of the study, its requirements, and its restrictions. Written informed consent must be obtained prior to any protocol-specific procedures.

There will be 2 screening visits:

Visit 1: (Screening 1st part)

The following assessments will be completed during at screening to determine the subject’s eligibility for enrolment. no more than 28 days prior to Day 1 visit. If a subject has had the audiological procedures performed prior to study start (up to 3 months ago), these results may be accepted for this study. However, should the subject have had the audiological procedures performed prior to study start (up to 3 months ago), these results may be accepted.

The first screening visit consists in of the clinical assessment for tinnitus diagnosis and also includes including:

138 138 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Evaluation of Eligibility Criteria • Otological screen • Otoacoustic emissions (OAE) • Audiometry (Tonal Audiogram & Tinnitus Matching) • Speech Audiogram • sSelf-scored HADS • Tinnitus Handicap Inventory (THI) • Agreement to participate in the study • Question: «“How aggravated are you by tinnitus?” (8-point scale) • Annoyance of Hyperacusis. • Self-scored 16-item Quick Inventory of Depressive Symptoms(QIDS-SR 16) • VAS anxiety/arousal scores (tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed). • Diary for home scoring (training and request to try at home) Visit 2: Screening (2nd part)

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit.

The following assessments will be completed no more than 14 days prior to Day 1 visit:

Assessment about the proper filling of the Diary for home scoring • Testing of lidocaine response : • Under continuous cardiac monitoring, subjects will be administered first an intravenous (iv) infusion of placebo (normal saline), and second an iv infusion of lidocaine (1.5 mg/kg body weight), for 5 min, in a single blind manner. VAS for pitch, loudness (i.e. intensity), and distress of tinnitus, and the presence of hyperacusis, will be collected at 5 minutes pre-infusion time and immediately at the end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. • The patient will not be discharged from the unit until at least 45 min after the completion of the second infusion. An acceptable lidocaine response (see criteria above and Section 4 and Section 5.1.3.) will be required for progression to the main part of the study.

If the subject is eligible for the study In case the subject is included, pregnancy testing (Urine HCG) for woman and blood sample collection will be collected for pharmacogenetic (PGx) assessments (if consent has been obtained, for all). will be performed. The latter sample (i.e., PGx) can be collected any time during the study.

139 139 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

22. Section 6.2 Treatment, Visits 2, 4, and 6: Day 1

PREVIOUS TEXT

Visits 3, 5, and 7: Day 1

The visit starts with a brief interview about general conditions, Vital Signs, and Medical Examination. Blood is collected for safety laboratory parameters and for PK assessment.

The subject will be taken to a quiet room and after about 10 min pre-dose VAS scales for tinnitus (i.e., scales for intensity, pitch and distress) and VAS for arousal/anxiety (i.e., scales anchored to tired-energetic, active-drowsy, tense-peaceful, worried-relaxed) are self-scored.

While in the quiet room the subject is asked to fill the pre-dose self-scored THI, LSEQ and QIDS-16 focusing on events regarding the last 2 weeks.

The dose (i.e., two tablets) is administered.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is discharged from the research unit , following a medical examination for safety, including vital signs, ECG and Romberg.

REVISED TEXT

Visits: 2, 4, and 6 3, 5, and 7: Day 1 of each Treatment Period

The visit starts with a brief interview about general conditions and Vvital Ssigns. and Medical Examination. Blood samples will be is collected for safety laboratory, PGx research and for PK analyses parameters and for PK assessment.

140 140 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Subjects will be asked to complete questionnaires at various timepoints these include VAS scales for tinnitus and arousal/ anxiety, THI and QIDS. Subjects will be asked to report the occurrence of any AEs. For detailed timing of assessments refer to Appendix 1. Time and Events Table. Questions about: «How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005), the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events, and occurrence of AEs will be asked, all referring to last 2 weeks, separated in two scores, i.e., the 1st week and the 2nd week.

While in the quiet room the subject is asked to fill the pre-dose self-scored THI, LSEQ and QIDS-16 focusing on events regarding the last 2 weeks.

The dose (i.e., two tablets) is administered.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is discharged from the research unit, following a medical examination for safety, including vital signs, and ECG measurements and Romberg. Clinic Staff to remind subjects to call the unit, if they feel unwell, experience any adverse events or if there are any changes to their mood during the washout periods between treatments.

23. Section 6.2 Treatment Visits 3, 5 and 7: Day 12 - 14

PREVIOUS TEXT

Visits 4, 6 and 8: Day (12-14)

Subjects maybe asked to come in between days 12-14, which is typically referred to as day 14. The visit starts with a brief interview about general conditions, Vital Signs, and

141 141 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Medical Examinations. Blood is collected for safety laboratory testing and for the pre- dose PK measurements.

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005] , the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week of treatment and the 2nd week of treatment. Spontaneous reports of occurrence of AEs during the 2 previous week is collected

The Diary for home scoring is obtained, and the remaining tablets are requested for compliance checking.

The subject is then taken to a quiet room and then, after about 10 min, pre-dose VAS scales (VAS tinnitus and arousal/anxiety) are self-scored.

The dose (i.e., two tablets) is administered.

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured for last time.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (inter-treatment score) will be given to be returned at the next visit.

A Diary/symptom card for home scoring (after last dose) will be given, to be returned at follow up visit.

A light snack is served. Then the subject is free to go home, following a medical exam for safety, including ECG, vital signs and Romberg.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

Information about general condition, occurrence of AEs, or any other potential issue will be obtained between 6-8 days from the beginning of the treatment. In case of detection of

142 142 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

any SAE or AEs of clinical relevance the subject will be asked to come immediately to the Unit for a thorough medical assessment, and an attempt will be made to obtain PK sample.

REVISED

Visits: 3, 5 and 7: Day 12 -14 of each Treatment Period Visits 4, 6 and 8: Day (12-14)

Subjects maybe asked to come in between days 12-14, which is typically referred to as day 14. The visit starts with a brief interview about general conditions,and Vvital Ssigns will be measured..and abbreviated Medical Examination. Blood samples will be is collected for safety laboratory analysis testing and for the pre-dose PK measurements.

During the visit, subjects will be asked to complete questionnaires and VAS scales at various timepoints. Blood samples will be collected for PK analysis, study medication will be administered. Questions about: «“How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, [Robinson, 2005] , the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week of treatment and the 2nd week of treatment. Spontaneous reports of occurrence of AEs during the period between visits and during the visit will be recorded. 2 previous week is collected.

The Diary for home scoring is obtained, and the remaining tablets are requested for compliance checking.

For details of all assessments and timings refer to Appendix 1. Time and Events Table.

The subject is then taken to a quiet room and then, after about 10 min, pre-dose VAS scales (VAS tinnitus and arousal/anxiety) are self-scored.

The dose (i.e., two tablets) is administered.

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured for last time.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

143 143 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

A Diary for home scoring (inter-treatment score) will be given to be returned at the next visit.

A Diary/symptom card for home scoring (after last dose) will be given, to be returned at follow up visit.

A light snack is served. Then the subject is free to go home, following an abbreviated medical physical examination for safety, including ECG, and vital signs. and Romberg.

Clinic Staff to remind subjects to call the unit, if they feel unwell, experience any adverse events or if there are any changes to their mood during the washout periods between treatments.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

24. Section 6.2 Treatment, Visit 9, Follow Up, Bullet

PREVIOUS TEXT

Visit 9, Follow Up (12 to 14 days after last study drug administration)

• Pregnancy test (Urine HCG) REVISED TEXT

Visit 98, Follow Up (12 to 14 days after last study drug administration)

• Pregnancy test (Uurine or serum HCG) • VAS scales for tinnitus and arousal/anxiety.

25. Section 6.2.1 Pregnancy

PREVIOUS TEXT

Pregnancy testing (Urine HCG) will be performed at screening, Day 1 and Follow up visits.

REVISED TEXT

Pregnancy testing (Uurine or serum HCG) will be performed at screening, Day 1 and Follow up visits.

144 144 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

26. Section 6.3.2 Self-scored questionnaires, paragraphs 1 and 2

PREVIOUS TEXT

The answer to the following questionnaires, referred as integrated response concerning the subject’ conditions during the 2 week immediately before the test day:

REVISED TEXT

The answer to the following questionnaires, referred as an integrated response concerning the subject’s conditions before dosing on the test day: during the 2 week immediately before the test day:

27. Section 6.3.3. Daily Diary, last paragragh

PREVIOUS TEXT

Annoyance of Hyperacusis: Answer to questions: (i), “Do you felt hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–10scale) for the overall impact of hyperacusis on everyday life [Dauman, 2005].

REVISED TEXT

Annoyance of Hyperacusis: Answer to questions: (i), “Do you felt hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–710scale) for the overall impact of hyperacusis on everyday life [Dauman, 2005].

28. New Section 6.3.4 Tinnitus Matching

NEW TEXT

Tinnitus Matching is defined as the audiometric process of determining the intensity and spectral nature that best matches subjective tinnitus.

Pitch Match (PMF= Pitch Match Frequency)

Before beginning testing, ask the patient to describe what the tinnitus sounds like.

145 145 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Use the adaptive (bracketing) method to find the pitch match frequency.

The aim of the test is to find the frequency of pure -tone which comes closest to the pitch of the most troublesome tinnitus sounds.

Start at the highest frequency available (8kHz) and present the tone for about 2 seconds. Repeat until the patient responds, leaving him/her time between each tone to listen to his/her tinnitus.

Intensity Matching

Increase from threshold (t) at PMF in 1 dB steps using continous presentation (press interrupt)

Continue increasing the dB as described until matched loudness level is reached (i) Record the sensation level which is (i)- (t) = S

Perform the test in both ears starting with the most troublesome first.

29. Section 6.5.3. Psychoacoustic measurements

PREVIOUS TEXT

Automated psychoacoustic assessment of tinnitus pitch, timbre, loudness will be performed according to procedure recently validated [Henry, 2004].

REVISED TEXT

Automated pPsychoacoustic assessment of tinnitus pitch, timbre, loudness and intensity will be performed according to procedure recently validated [Henry, 2004].

146 146 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

30. Section 8.2. Dosage and Administration

PREVIOUS TEXT

Each subject will be randomly assigned to receive for each period, one of the treatment:

Cross-over administration (once daily) of:

1. vestipitant 25 mg + dummy capsule placebo, 2. vestipitant 25 mg + paroxetine 20 mg, 3. placebo dummy tablet + placebo dummy capsule Each treatment period will consist of 14 daily dosing regimen, orally administer (1 tablet or dummy tablet and 1 capsule or dummy capsule a day).

Treatment periods will be separated by a period of 14 days of wash-out.

REVISED TEXT

Each subject will be randomly assigned to receive for each period, one of the following treatments:

Cross-over administration (once daily) of:

Treatment periods will be separated by a washout period of at least 14 days. of wash-out.

31. Section 8.3 Dose Rationale, paragraph 4, sentence 4.

PREVIOUS TEXT

The analysis of the preliminary results confirmed the safety and tolerability profile observed in HV, indicating also no pharmacokinetic interaction.

REVISED TEXT

The analysis of the preliminary results confirmed the safety and tolerability profile observed in Healthy Volunteers, indicating also no pharmacokinetic interaction.

147 147 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

32. Section 10.2.1. Subject Withdrawal from Study, bullet points: 1, 4, 5, 6 and last paragraph

PREVIOUS TEXT

• Mental status changes (such as agitation, confusion and anxiety) and/or motor abnormalities (such as hyperreflexia evolving into myoclonus within 6 hours, myoclonus, increased muscle tone, tremor, shivering and muscle rigidity), as assessed by the study neurologist. • If an elevation of CK is ≥5X ULRR and symptoms suggestive of skeletal muscle effects are reported by any subject (e.g. soreness, cramping and/or pain), that subject must be withdrawn from the trial and followed. • If an elevation of CK is ≥ 8X ULRR in any subject, that subject must be withdrawn from the trial and followed. • If any post-screening elevation of troponin I is > 1X ULRR or > 2X screening value in any subject, that subject must be withdrawn from the trial and followed If 50% or more subjects are withdrawn due to an AE, the study will be stopped

REVISED TEXT

• Mental status changes (such as agitation, confusion and anxiety) and/or motor abnormalities (such as hyperreflexia evolving into myoclonus within 6 hours, myoclonus, increased muscle tone, tremor, shivering and muscle rigidity), as assessed by the study physician. • If an elevation of CK is ≥5X ULRR and symptoms suggestive of skeletal muscle effects are reported by any subject (e.g. soreness, cramping and/or pain), that subject must be withdrawn from the trial and followed up. • If an elevation of CK is ≥ 8X ULRR in any subject, that subject must be withdrawn from the trial and followed up. • If any post-screening elevation of troponin I is > 1X ULRR or > 2X screening value in any subject, that subject must be withdrawn from the trial and followed up. If 50% or more subjects are withdrawn due to an AE, the study will be stopped

If similar SAEs occur in more than one subject, no further subject will be dosed until a full safety review of the data has taken place. Relevant reporting and discussion with the GSK medical monitor, relevant GSK personnel and with the Research Ethics Committee will then take place prior to any resumption of dosing.

148 148 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

33. Section 10.3. Screen and Baseline Failures, paragraph 1

PREVIOUS TEXT

Failures at either of the screening visits (pre-study) are those subjects who have not been eligible to start the study following a screening assessment.

REVISED TEXT

Failures at either of the screening visits (pre-study) are those subjects who are have not been eligible to start the study following a screening assessment.

34. Section: Appendix 1: Time and Events Table

PREVIOUS TEXT

Screening Treatment Follow- Visit 1 Visit 2 Visit 3,5,7 Visit 4,6,8 up washout Day -28 -14 0, 28, 12-14, (12- 12-14 56 40-42, 14)- to days 68-70 28, (40- after 42) to last 56 dose Medical history and Demography 9 Physical examination 9 9 9 9 12-lead ECG 9 9 9 9 Vital signs 9 9 9 9 Clinical Safety laboratory tests 9 9 9 9 Pregnancy test (Urine) 9 9 Eligibility Criteria Evaluation 9 ENT screening 9 Otoacustic emission (OAE) 9 Audiometry (Tonal audiogram) 9 9 9 Speech audiogram 9 Self-scored HADS 9 Self-scored THI and LSEQ 9 9 9 Agreement to participate in the study 9 Training for Diary for home scoring 9 Question” How aggravated you are?” 9 9 9 Self-scored QUID-16 9 9 9 Lidocaine test 9 Tinnitus VAS / Arousal VAS 9 9 9 Reported AEs 9 9 9 Diary for home scoring: blank form 9 Diary for home scoring: filled form 9 9 Annoyance of Hyperacusis score (0-10) 9 9 9 Blood samples for PK measurements 9 9 Automated Psychoacoustic assessment of 9 9 tinnitus pitch, timbre, intensity THI and Hyperacusis for the day 9 9 Phone call for assessment 9 9 Pharmacogenetic sampling 9

149 149 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

REVISED TEXT Procedures Screening Treatment Treatment Treatment Follow- Period 1 Period 2 Period 3 Up Visit 1 2 2 3 4 5 6 7 8 Day1 -28 -14 1 14 1 14 1 14 12-14 days post final dose Medication, Medical history and 9 9 9 9 9 9 9 Demography2 Physical examination 9 9 9 9 9 12-lead ECG 9 9 9 9 9 9 9 9 Vital signs 9 9 9 9 9 9 9 9 Clinical Safety laboratory tests 9 9 9 9 9 9 9 9 Pregnancy test (urine or serum) 9 9 9 9 9 Eligibility Criteria Evaluation 9 ENT screening 9 Otoacustic emission (OAE) 9

1 1 Audiometry (Tonal audiogram) 9 9 9 9 9 9 9 Audiometry(Tonal audiogram & 9 Tinnitus Matching) Speech audiogram 9 Self-scored HADS 9

Self-scored THI for the day and 9 9 9 days up to 14 Washout 9 9 days up to 14 Washout 9 9 LSEQ Agreement to participate in the 9 study Training for Diary for home scoring 9 Question” How aggravated you 9 9 9 9 9 9 9 are?” Self-scored QUIDS-16 9 9 9 9 9 9 9 Lidocaine test 9 Tinnitus VAS / Arousal VAS 9 9 9 9 9 9 9 9 Reported AEs 9 9 9 9 9 9 9 Diary for home scoring: blank 9 9 9 9 9 9 9 form3 Diary for home scoring: filled form3 9 9 9 9 9 9 9 Annoyance of Hyperacusis score 9 9 9 9 9 9 (0-107) for the day Dosing4 9 9 9 9 9 9 Continued

150 150 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Procedures Screening Treatment Treatment Treatment Follow- Period 1 Period 2 Period 3 Up Visit 1 2 2 3 4 5 6 7 8 Day1 -28 -14 1 14 1 14 1 14 12-14 days post Washout up to 14 Washout up to 14 Washout final dose Blood samples for PK 9 9 9 9 9 9 measurements Automated Psychoacoustic 9 9 9 9 9 9 assessment of tinnitus pitch, timbre, intensity

THI and Hyperacusis for the day 9 9 9 9 9 9

Phone call for assessment5 9 9 9 9 9 9

Pharmacogenetic sampling6 9 9 1. Flexibility surrounding treatment days ±2 2. Only Medical History and Medication will be updated during the study 3. Subjects will be given a training diary at screening, during each visit a blank diary will be given to the subjects and subjects will be asked to return the completed/ filled diary at the next visit. 4. Dosing will be performed daily for each 14-day treatment period. 5. Phone calls to subjects at mid-time during treatment phases (at one week from the start of dosing in each treatment period. 6. Pharmacogenetic sample will be obtained predose on Day 1 of Treatment Period 1.

151 151 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Treatment Periods: 1, 2 & 3: Days: 1 and 14

Procedure Pre- 10 min 0 50 min 1h 2h 3h 4h dose Pre- dose Medical History & Concomitant 9 Medication Update Physical examination1 9 12 lead ECG 9 9 Vital Signs 9 9 Clinical Safety laboratory lests 9 Pregnancy test (urine or blood)7 9 Self-scored THI 9 9 Quiet Room 9 9 Question “How aggravated you are?” 9 94 94 Self-scored QIDS3 9 VAS Arousal & anxiety3 9 9 VAS Tinnitus3 9 9 Reported AEs5 9 Diary for home scoring: blank - 9 dispensed to subject Diary for home scoring: filled -returned 9 Annoyance of Hyperacusis score (0-7) 9 Dosing 9 Blood samples for PK measurements 9 9 Pharmacogenetic Sampling2 9 Light snack6 9 1. Physical Examination will be performed on Day 14 ONLY of each treatment period 2. Pharmacogenetic sample will be taken on Day 1 treatment period 1 ONLY 3. Assessments completed in the Quiet Room 4. Assessments completed between 2 -3 h post dose 5. Any occurrence of AEs will be recorded 6. Light snack will be given after study procedures have been completed, may be earlier than 4h post dose. 7. Pregnancy will be performed on Day 1 ONLY of each treatment period.

35. Section: Appendix 2

Paroxetine Global Prescriber Information

Version Number: 23

Version date: 29 April 2004

REVISED

Version Number: 33

Version date: January 31, 2008.

152 152 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

Appendix 6: Protocol changes – Amendment 01

PROTOCOL CHANGE 1

Location in Protocol:

Sponsor signatory page

Change from:

Sponsor Signatory:

Dr Date VP, Clinical Molecular Imaging Translational Medicine and Genetics Acting Head, Psychiatry Clinical Pharmacology and Discovery Medicine GlaxoSmithKline

Professor of Psychiatry Imperial College, London Adjunct Professor of Psychiatry and Radiology Columbia University, New York

Change to:

Sponsor Signatory:

M.D. Date Vice President, Psychiatry Clinical Pharmacology and Discovery Medicine

PROTOCOL CHANGE 2

Location in Protocol:

Investigator Protocol Agreement page

153 153 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254NKP106254

Change from:

Investigator Name:

Investigator Signature Date

Investigator Name: Dr

Investigator Signature Date

Change to:

Investigator Name:

Investigator Signature Date

PROTOCOL CHANGE 3

Location in Protocol :

Abbreviations

154 154 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change from:

5-HT 5-Hydroxytryptamine / Serotonin AE Adverse Event AUC Area Under Curve CIB Clinical Investigators Brochure CNS Central Nervous System CO2 Carbon Dioxide DCN Dorsal Coclear Nucleus ECG Electrocardiogram GABA Gamma Amino Butyric Acid GSK GlaxoSmithKline h hour HADS Hospital Anxiety and Depression Scale HDPE High Density Polyethylene HIV Human Immunodeficiency Virus IHC Inner Hair Cells i.p. intra peritoneal IUD Intra Uterine Device kg kilogram LSEQ Leeds Sleep Evaluation Questionnaire MAOI Monoamine Oxidase Inhibitor mg Milligram min minute ml millolitre MSDS Material Safety Data Sheet NK1 Neurokinin 1 Ng Nanogram OCD Obsessive Compulsive Disorder PD Pharmacodynamic PET Positron Emission Tomography PK Pharmacokinetic PSG Polysomnography qEEG Quantative Electroencephalogram QIDS Quick Inventory of Depressive Symptomatology rCBF Regional Cerebral Blood Flow RO Receptor Occupancy SAD Seasonal Affective Disorder SAE Serious Adverse Event SP Substance P SRM Study Reference Manual SSRI Selective Serotonin Re-uptake Inhibitor TCA Tricyclic Andidepressant THI Tinnitus Handicap Inventory VAS Visual Analogue Scale VNTB Ventral Nucleus of Trapezoid Body

155 155 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change to:

5-HT 5-Hydroxytryptamine / Serotonin AE Adverse Event AUC Area Under Curve CIB Clinical Investigators Brochure CNS Central Nervous System CO2 Carbon Dioxide DCN Dorsal Coclear Nucleus ECG Electrocardiogram ENT Ear, nose, throat GABA Gamma Amino Butyric Acid GSK GlaxoSmithKline h hour HADS Hospital Anxiety and Depression Scale HDPE High Density Polyethylene HIV Human Immunodeficiency Virus IHC Inner Hair Cells i.p. intra peritoneal IUD Intra Uterine Device kg kilogram LSEQ Leeds Sleep Evaluation Questionnaire MAOI Monoamine Oxidase Inhibitor mg Milligram min minute ml millolitre MSDS Material Safety Data Sheet NK1 Neurokinin 1 Ng Nanogram OCD Obsessive Compulsive Disorder PD Pharmacodynamic PET Positron Emission Tomography PK Pharmacokinetic PSG Polysomnography qEEG Quantative Electroencephalogram QIDS Quick Inventory of Depressive Symptomatology rCBF Regional Cerebral Blood Flow RO Receptor Occupancy SAD Seasonal Affective Disorder SAE Serious Adverse Event SP Substance P SRM Study Reference Manual SSRI Selective Serotonin Re-uptake Inhibitor TCA Tricyclic Andidepressant THI Tinnitus Handicap Inventory VAS Visual Analogue Scale VNTB Ventral Nucleus of Trapezoid Body

156 156 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 4

Location in Protocol:

Protocol Summary and Section 2.2, Objectives

Deleted text

and Minimal Masking Level…

PROTOCOL CHANGE 5

Location in protocol:

Protocol summary and Section 3, Endpoints

Deleted text (Secondary Endpoint - 4.)

Minimal Masking Level

Change from:

Primary

Visual Analog Scales (VAS) to measure the change in tinnitus loudness as perceived at the moment of the measurement at 2 hrs after dosing (or at any other time point vs. pre- dose baseline).

Secondary

1. Visual Analog Scales (VAS) to measure the level in tinnitus pitch and tinnitus distress as perceived at the moment of the measurement 2. VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) 3. Pure Tone Audiometry (Audiogram) 4. Psychoacoustic assessment (automated if possible) of tinnitus pitch, timbre, intensity, Minimal Masking Level 5. Self-report questionnaires (integrated evaluation referring only to the day of testing after dosing): Tinnitus Handicap Inventory (THI) 6. Self-report questionnaires (integrated evaluation referring to the past week, up to the moment of measurement): a) Tinnitus Handicap Inventory (THI) b) Quick Inventory of Depressive Symptomatology (QIDS-SR 16). c) Leeds Sleep Evaluation Questionnaire (LSEQ) 7. Diary (to be filled in the evening):

157 157 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

c. Number of benzodiazepines, analgesic or any other calming infuses consumed during days d. VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) e. Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress 8. Clinician rated scales: d) Annoyance of Tinnitues: Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, (Robinson, 2005)(Zenner, 2005) e) Annoyance of Hyperacusis: Answer to questions: (i), “Do you felt hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–10 scale) for the overall impact of hyperacusis on everyday life (Dauman, 2005). 9. Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam. 10. PK samples collected at Day 1 (2 and 5 hours post-dose) and Day 14 (pre-dose, 2, 5 hours post-dose). Change to:

Primary

Secondary

1. Visual Analog Scales (VAS) to measure the level in tinnitus pitch and tinnitus distress as perceived at the moment of the measurement 2. VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed) 3. Pure Tone Audiometry (Audiogram) 4. Psychoacoustic assessment (automated if possible) of tinnitus pitch, timbre, intensity 5. Self-report questionnaires (integrated evaluation referring only to the day of testing after dosing): Tinnitus Handicap Inventory (THI) 6. Self-report questionnaires (integrated evaluation referring to the past week, up to the moment of measurement): f) Tinnitus Handicap Inventory (THI) g) Quick Inventory of Depressive Symptomatology (QIDS-SR 16). h) Leeds Sleep Evaluation Questionnaire (LSEQ) 7. Diary (to be filled in the evening):

158 158 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

i) Number of benzodiazepines, analgesic or any other calming infuses consumed during days j) VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) k) Number of hyperacusis, brief description of the generator, and VAS distress rating of the overall distress 8. Clinician rated scales: l) Annoyance of Tinnitus: Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005, Zenner 2005) m) Annoyance of Hyperacusis: Answer to questions: (i), “Do you feel hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0–7 scale) for the overall impact of hyperacusis on everyday life (Dauman 2005). 9. Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam. 10. PK samples collected at Day 1 (2 and 5 hours post-dose) and Day 14 (pre-dose, 2, 5 hours post-dose) PROTOCOL CHANGE 6

Location in Protocol:

Protocol Summary and Section 4, Study Design

Change from:

Subjects suffering from tinnitus will be attending the clinics for 2 screening visits, then randomized to one of the six repeated dosing treatment sequences. Treatment phase consists of 3 treatment periods of 14 days each, separated by a wash-out interval of 14 days. Assessment with self-rated scales, audiogram, and psychoacoustic tests will be performed at the Day 1 and on the 14th Day of each treatment period within 4 hrs following last dose. All subjects will receive all treatments and a follow up visit will be performed 14 days after last drug dosing. Treatments are:

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

159 159 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

14 days 14 days 2nd period 3rd period (eg. Screening st 1 period (eg. vestipitant + vestipitant) (eg.placebo) paroxetine) ll 14 days 14 Days 14 days

Follow up Testing Sessions

The first screening visit will consist of the clinical assessment for tinnitus diagnosis, including audiograms and questionnaires, and a medical screen including, ECG, laboratory tests on blood and urine, current treatment, and their agreement to participate in the study.

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit. The second visit will be conducted in a quiet room where the subject will be tested for a lidocaine response. Subjects will be infused with placebo or lidocaine (1.5 mg/kg body weight) for 5 min in a randomized, balanced order, being blind of the treatment. VAS for pitch, loudness, and distress of tinnitus, and the presence of hyperacusis, will be collected at pre-infusion time and 5 min after each infusion. The two infusions will be separated by at least 20-30 min. Subjects will only be included if: a) there is consistency between the two pre-infusion values (a difference of less than 30% between the highest and the lowest pre-infusion, baseline value) b) there is a reduction from baseline in VAS for loudness after lidocaine of at least 10mm greater than the reduction following placebo.

Change to:

160 160 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

1. placebo 2. vestipitant 25 mg/day + paroxetine 20 mg/day 3. vestipitant 25 mg/day

14 days 14 days 2nd period 3rd period (eg. Screening st 1 period (eg. vestipitant + vestipitant) (eg.placebo) paroxetine) ll 14 days 14 Days 14 days

Follow up Testing Sessions

AND b) the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is 10mm or more than the reduction observed following placebo iv infusion.

161 161 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 7

Location in Protocol:

Protocol Summary and section 5.1.1, Eligibility Criteria

Change from:

Eligibility Criteria

Eligible subjects will be male or female subjects, aged between 18 and 60 years, with a confirmed diagnosis of tinnitus, based on standardized ONH visit and examination, including otoscopy and audiograms. Subjects with completely normal audiogram or those with severe hearing loss will be excluded. In cases where a disorder is associated with tinnitus, such as Meniere’s Disease or Otosclerosis, subjects will also be excluded.

Patients should have been suffering with tinnitus for at least six months. Subjects with severe anxiety and depression scores will be excluded, based on the HADS score <11. Beck Inventory for Depression, version 2, will be used to qualify the residual level of depressive symptoms in those subjects that will be included in the study.

Enrichment criteria will be based on the documented presence of auditory impairment and the capacity to detect transient changes in tinnitus loudness to lidocaine infusion (reduction of 20% or more vs. placebo normalized to baseline). This criterion is arbitrary but related to previous experience [Baguley, 2005]. Change to:

Eligibility Criteria

162 162 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 8

Location in protocol:

Protocol Summary and section 5.1.2, Inclusion Criteria

Change from:

Inclusion Criteria

• Subject with THI severity grade of 3 or 4 (THI < 36, (Mc Combe, 2001). • Subjects must be 18-60 years of age inclusive. Change to:

• Subject with THI severity grade of mild or greater (THI >= 18, [Newman, 1998] • Subjects must be 18-65 years of age inclusive. PROTOCOL CHANGE 9

Location in Protocol:

Section 5.1.2, Inclusion Criteria

Change from:

Subjects willing to restrict alcohol intake to 1-2 unit or less per day. A unit is equivalent to 300-600 ml of beer or one measure of spirits or one-two glass of wine.

Change to:

Subjects willing to restrict alcohol intake to 1-2 unit or less per day. A unit is equivalent to 220 ml of beer or one measure of spirits (25ml) or one-two glass of wine (125 ml). PROTOCOL CHANGE 10

Location in protocol:

Protocol Summary and section 5.1.3, Exclusion Criteria

Change from:

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Subject with THI severity grade = 5 or ≤ 2 (Mc Combe, 2001) • Subject with pathologic level of anxiety or depression as assessed by the Hospital Anxiety and Depression Scale (HADS≥11)

163 163 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Subject with no audiogram deficit and with normal hearing • Subjects that do not respond to the lidocaine infusion test (i.e., tinnitus loudness score to lidocaine infusion with a reduction from baseline not greater than 10 mmof the reduction observed after placebo) or showing a large variability in pre-infusion values (a difference of at least 30% between the highest and the lowest pre-infusion value) • Subjects with one of the following medical conditions: • Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant or Paroxetine • Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug • Subject with pathologic level of anxiety or depression or OCD, as assessed with The Hospital Anxiety and Depression Scale (HADS≥11) • Subjects with hepatic impairment or a history of liver dysfunction, which, in the judgement of the investigator would preclude their inclusion in the study. • Subjects with renal impairment (serum creatinine higher than ). • Subjects positive for HIV 1 or II, hepatitis C antibody or hepatitis B surface antigen • Subjects having clinically significant abnormal laboratory, ECG or physical examination findings not resolved by the the baseline visit (Day 1, Treatment Period 1). • Subjects who are not euthyroid based on laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. • Subjects with a history of clinically significant hepatic, cardiac, renal, neurologic, cerebrovascular, metabolic or pulmonary disease. • Subjects who have had a myocardial infarction within 1 year prior to screening visit. • Subjects with a history of seizure disorders (except for febrile seizures in childhood). • Subjects with history of cancer • Subjects with a history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject 's participation in the study. • Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 24 hours prior to their Screening Visit. If a subject has a positive alcohol breath test

164 164 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

or positive urine illicit drug screen, this subject will be excluded and the test may not be repeated. • Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below prior to the Screening Visit:- • Depot neuroleptics – at least 12 weeks • MAOIs or Fluoxetine – at least 4 weeks • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics – at least 14 days • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) – at least 14 days • The subject took thioridazine within 14 days prior to Day 1 Visit. • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or at least 14 days, whichever is longer • Any CNS-active herbal/natural supplement or preparation known or thought to have any psychoactive effects – at least 14 days • The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. • The subject had medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Baseline Visit, which is known to interfere with CYP2D6 or CYP3A isozymes (see IB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.). • The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to Baseline Visit, e.g., sumatriptan, naritriptan, ergotamine, alosetron. • The subject took thioridazine within 14 days prior to Baseline Visit. • Subjects who have used an investigational drug or have participated in an investigational trial within 6 months of the screening visit • Subjects who have exhibited intolerance to NK1 antagonists or SSRIs • Women who have a positive urine HCG pregnancy test at screen visit or a positive urine dipstick HCG pregnancy test performed by the investigator at the baseline visit or who are lactating • Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration in the study.

165 165 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study). Subjects, who have donated a unit of blood (500 ml) or more within the previous 56 days or who intend to donate blood within one month of completing the study Change to:

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Subject with THI of grade “No handicap” [Newman, 1998] i.e. THI score of less than 18 • Subject with pathologic level of anxiety or depression as assessed be the Hospital Anxiety and Depression Scale (HADS≥11) • Subject with no audiogram deficit and with normal hearing • Subjects that do not respond to the lidocaine infusion test (i.e., the reduction from pre-infusion in VAS for loudness (i.e.intensity) after lidocaine iv infusion is not 10mm or more than the reduction observed following placebo iv infusion) or showing a large variability in pre-infusion values (i.e., the difference between the placebo and the lidocaine pre-infusion VAS for loudness (ie intensity) is more than 30%). • Subjects with one of the following medical conditions: • Subjects with any serious medical disorder or condition that would, in the investigator's opinion, preclude the administration of vestipitant, Paroxetine or lidocaine • Existence of any surgical or medical condition which, in the judgement of the investigator, might interfere with the absorption, distribution, metabolism or excretion of the drug • Subject with pathologic level of anxiety or depression or obsessive compulsive disorder (OCD), as assessed by a score of 11 or more with The Hospital Anxiety and Depression Scale (HADS≥11) • Subjects with hepatic impairment (ALT, AST, bilirubin, alkaline phosphatase, GGT must be below 1.5-fold higher than the upper limit of normal at screening) or a history of liver dysfunction. • Subjects with renal impairment (serum creatinine higher than 124umol/l). • Subjects with a 12-lead ECG at screening, which in the opinion of the Principal Investigator or physician designee has abnormalities that will compromise safety in this study. Specific exclusion criteria with regard to QT interval (either QTcb or QTcf, machine or manual over-read, males or females) are as follows: • QTc >=450 msec, based on single or average QTc value of triplicate ECGs obtained over a brief recording period

166 166 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• QTc >= 480 msec for patients with Bundle Branch Block • Subjects with laboratory parameters outside the reference range for this age group will only be included if the Principal Investigator or designee considers that such findings will not introduce additional risk factors. In any case, liver function tests (bilirubin, ALT, AST or alkaline phosphatase) must be below 1.5-fold higher than the upper limit of normal at screening. • Subjects positive for HIV 1 or II, hepatitis C antibody or hepatitis B surface antigen • Subjects who are not euthyroid based on laboratory results at the Screening Visit. Subjects maintained on thyroid medication must be euthyroid for a period of at least six months prior to the Screening Visit. • Subjects with current or past history of clinically significant hepatic, cardiac, renal, neurologic, cerebrovascular, metabolic or pulmonary disease. • Subjects who have had a myocardial infarction within 1 year prior to screening visit. • Subjects with current or past history of seizure disorders (except for febrile seizures in childhood). • Subjects with known current or past history of cancer • Subjects with known porphyria, or allergy to amide local anaesthetics • Subjects with current or past clinically significant history of drug or other allergy (atopy) which, in the opinion of the Investigator, contraindicates the subject 's participation in the study. • Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. • Subjects who have taken psychotropic drugs or antidepressants within the time frames specified below:- • Depot neuroleptics – 12 weeks prior to Screening Visit 1 • MAOIs or Fluoxetine –4 weeks prior to Screening Visit 1 • Antidepressants other than MAOIs or fluoxetine (e.g. TCAs, SSRIs, NSRIs), anxiolytics, lithium, other mood stabilisers (including anticonvulsants) and oral antipsychotics –14 days prior to Screening Visit 1 • Beta-adrenergic blockers if used to treat anxiety or its physical manifestations (e.g. tremor) –14 days prior to Screening Visit 1 • Opiates, hypnotics, benzodiazepines, and all other sedatives (including sedating antihistamines) – 5 half-lives or 14 days, whichever is longer prior to Screening Visit 1

167 167 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Any CNS-active herbal/natural supplement or preparation known or thought to have any psychoactive effects –14 days prior to Screening Visit 1 • The subject has been using prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication, unless in the opinion of the Investigator and sponsor the medication will not interfere with the study procedures or compromise subject safety. • The subject had a medication or food (e.g. grapefruit or grapefruit juice) within 14 days prior to Day 1 of all the 3 Treatment Sessions which is known to interfere with CYP2D6 or CYP3A isozymes (see IB, Inhibitors and inducers of Cytocrome P450 2D6 and 3A.). • The subject had a non-psychotropic medication with a serotonergic mechanism of action within 14 days prior to the Screening, Visit 1, e.g., sumatriptan, naritriptan, ergotamine, alosetron. • The subject took thioridazine within 14 days prior to the Screening, Visit 1. • Subjects who have used an investigational drug or have participated in an investigational trial within 6 months of the Screening, Visit 1. • Subjects who have exhibited intolerance to NK1 antagonists or SSRIs • Women who have a positive urine HCG pregnancy test at screen visit or a positive urine dipstick HCG pregnancy test performed by the investigator at the baseline visits (i.e., at Day 1 of each Treatment Session) or who are lactating • Female subjects who intend to get pregnant or male subjects who intend to father a child within the next 4 weeks following the last study drug administration in the study. • Subjects who, in the opinion of the investigator, would be noncompliant with the visit schedule or study procedures (e.g., illiteracy or planned vacations, planned hospitalisations during the study). • Subjects, who have donated a unit of blood (500ml) or more within the previous month or who intend to donate blood within one month of completing the study PROTOCOL CHANGE 11

Location in Protocol

Section 5.1.3, Exclusion Criteria

Deleted text

Subjects have a positive blood alcohol level of ≥ 15 mg/dL (0.015%) positive blood alcohol

168 168 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change from:

Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive blood alcohol level of ≥ 15 mg/dL (0.015%) at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 24 hours prior to their Screening Visit. If a subject has a positive blood alcohol or positive urine illicit drug screen, this subject will be excluded and the test may not be repeated.

Change to:

Subjects have a positive urine test at Screening for illicit drug use and/or a history of substance abuse or dependence (alcohol or drugs) within the past 12 months. Subjects have a positive alcohol breath test at the Screening Visit. Note subjects must be told to avoid consumption of alcoholic beverages for at least 8 hours prior to their Screening Visit. If a subject has a positive alcohol breath test or positive illicit drug results, this subject is excluded and the test may not be repeated. PROTOCOL CHANGE 12

Location in Protocol:

Protocol Summary and Section 6.1, Study Assessments

Change from:

Visit 1 (Screening 1st part)

The following assessments will be completed at screening to determine the subject’s eligibility for enrolment no more than 28 days prior to Day 1 visit:

The first screening visit consists in the clinical assessment for tinnitus diagnosis, including:

169 169 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

• Otoacoustic emissions (OAE) • Tonal Audiogram, • Speech Audiogram • self-scored HADS • Tinnitus Handicap Inventory (THI) • Agreement to participate in the study • Question: « How aggravated are you by tinnitus?” (8-point scale) • Annoyance of Hyperacusis. • Self-scored 16-item Quick Inventory of Depressive Symptoms(QIDS-SR 16) • Self-scored THI • VAS for 4 anxiety/arousal (tired-energetic, active-drowsy, tense-peaceful, and worried-relaxed): baseline and at the end study. • Diary for home scoring (training and request to try at home) Visit 2: Screening (2nd part)

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit.

The following assessments will be completed no more than 14 days prior to Day 1 visit:

• Assessment about the proper filling of the Diary for home scoring • Testing of lidocaine response : • Under continuous cardiac monitoring, subjects will undergo two infusions, one placebo and one lidocaine (1.5 mg/kg body weight), each lasting 5 min. The infusions will be administered in a single blind, randomized manner, with a balanced treatment order.The two infusions will be separated by at least 20-30 min. • VAS for pitch, intensity, and distress of tinnitus, and for presence of hyperacusis, will be collected at baseline (pre-infusion) and at 5 min after the each infusion. • The patient will not be discharged from the unit until at least 45 min after the completion of the second infusion. An acceptable lidocaine response (see criteria above) will be required for progression to the main part of the study.

170 170 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change to:

Visit 1 (Screening 1st part)

The second screening visit will be carried out only if the subject is found clinically eligible during the first visit.

171 171 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The following assessments will be completed no more than 14 days prior to Day 1 visit:

• Assessment about the proper filling of the Diary for home scoring • Testing of lidocaine response : Under continuous cardiac monitoring, subjects will be administered first an intravenous (iv) infusion of placebo (normal saline), and second an iv infusion of lidocaine (1.5 mg/kg body weight), for 5 min, in a single blind manner. VAS for pitch, loudness (i.e. intensity), and distress of tinnitus, and the presence of hyperacusis, will be collected at 5 minutes pre-infusion time and immediately at the end of the 5 min infusion. The start of the second iv infusion will be 35 minutes (window of 35 to 40 minutes) after the end of the first iv infusion. The patient will not be discharged from the unit until at least 45 min after the completion of the second infusion. An acceptable lidocaine response (see criteria above and Sections 4 and Section 5.1.3.) will be required for progression to the main part of the study.

PROTOCOL CHANGE 13

Location in Protocol:

Protocol summary and Section 6.2, Treatment

Change from:

Treatment: Visit 3, 5, and 7: Day 1

Visit 3, 5, and 7: Day 1

The visit starts with a brief interview about general conditions, Vital Sign, and Medical Examinations. Blood is collected for safety & tolerability Lab testing and for PK assessment.

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005), the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events, and occurrence of AEs will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week and the 2nd week.

The subject is then led in a quite room and then, after about 10 min, baseline VAS scales for tinnitus (i.e., scales for intensity, pitch and distress) and VAS for arousal/anxiety (i.e., scales anchored to tired-energetic, active-drowsy, tense-peaceful, worried-relaxed) are self-scored.

The dose (i.e., two tablets) is administered.

172 172 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured.

Than a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is let free to go home, following a medical exam for safety, including vital signs, ECG and Romberg. The subject will be dismissed only if eligible.

Visit 4, 6 and 8: Day 14

The visit starts with a brief interview about general conditions, Vital Sign, and Medical Examinations. Blood is collected for Lab testing and for the pre-dose PK measurements.

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005), the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week of treatment and the 2nd week of treatment. Spontaneous reports of occurrence of AEs during the 2 previous week is collected

The Diary for home scoring is obtained, and the blister of tablets is requested for compliance checking.

The subject is then led in a quite room and then, after about 10 min, baseline VAS scales (VAS tinnitus and arousal/anxiety) are self-scored.

The dose (i.e., two tablets) is administered.

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

173 173 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured for last time.

Than a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (inter-treatment score) will be given to be returned at the next visit.

A light snack is served. Then the subject is let free to go home, following a medical exam for safety, including ECG, vital signs and Romberg.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

Visit 9, Follow Up (14 days after last study drug administration)

• Adverse Events and Concomitant Medication recording • Physical examination • 12-lead ECG • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position; • Clinical safety laboratory tests (haematology, clinical chemistry and urinalysis) • Pregnancy test (Urine HCG) Any clinically significant abnormal results from the follow-up visit will be re-assessed until either stabilised or resolved.

Change to:

Treatment:Visit 3, 5, and 7: Day 1

The visit starts with a brief interview about general conditions, Vital Signs, and Medical Examination. Blood is collected for safety laboratory parameters and for PK assessment.

174 174 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

The subject will be taken to a quiet room and after about 10 min pre-dose VAS scales for tinnitus and VAS arousal/anxiety (i.e., scales for intensity, pitch and distress) and VAS for arousal/anxiety (i.e., scales anchored to tired-energetic, active-drowsy, tense- peaceful, worried-relaxed) are self-scored.

While in the quiet room the subject is asked to fill the pre-dose self-scored THI, LSEQ and QIDS-16 focusing on events regarding the last 2 weeks.

The dose (i.e., two tablets) is administered.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (treatment scores) will be given to be returned at the next visit.

A light snack is served. Then the subject is discharged from the research unit , following a medical examination for safety, including vital signs, ECG and Romberg.

Visits 4, 6 and 8: Day (12-14)

Questions about: « How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale, Robinson 2005), the Annoyance of Hyperacusis, the occurrence of any or relevant Stress Life Events will be asked, all referring the last 2 weeks, separated in two scores, i.e., the 1st week of treatment and the 2nd week of treatment. Spontaneous reports of occurrence of AEs during the 2 previous week is collected

The Diary for home scoring is obtained, and the remaining tablets are requested for compliance checking.

The subject is then taken to a quiet room and then, after about 10 min, pre-dose VAS scales (VAS tinnitus and arousal/anxiety) are self-scored.

The dose (i.e., two tablets) is administered.

175 175 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

While in the quiet room the subject is asked to fill the self-scored THI, LSEQ and QIDS- 16 focusing on events regarding the last 2 weeks.

At 1 hr and 2 hr after dosing VAS scales (VAS tinnitus and arousal/anxiety) are measured again.

Between 2 and 3 hr after dosing, Audiometry and Automated Psychoacoustic assessment of tinnitus pitch, timbre, and intensity are performed.

At the end of the psychoacoustic tests (e.g. at about 3 hr after dosing), the subject returns to the quiet room and VAS scales (VAS tinnitus and arousal/anxiety score) are measured for last time.

Then a second blood sample for PK is collected.

The subject fills the THI questionnaire applied only to the current day. Any AEs perceived by the subjects following dosing are recorded.

A Diary for home scoring (inter-treatment score) will be given to be returned at the next visit.

A Diary/symptom card for home scoring (after last dose) will be given, to be returned at follow up visit.

A light snack is served. Then the subject is free to go home, following a medical exam for safety, including ECG, vital signs and Romberg.

Phone calls at mid-time during treatment phases (at one week from dosing start in each treatment period)

Visit 9, Follow Up (12 to 14 days after last study drug administration)

• Adverse Events and Concomitant Medication recording • Physical examination • 12-lead ECG • Vital signs (pulse rate, systolic and diastolic blood pressure) in semi-supine position; • Clinical safety laboratory tests (haematology, clinical chemistry and urinalysis) • Pregnancy test (Urine HCG) Any clinically significant abnormal results from the follow-up visit will be re-assessed until either stabilised or resolved.

176 176 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 14

Location in Protocol:

Section 1.1, Introduction

Change from:

Rationale for the enrichment in the selection of the study population

1. Moderate-to-severe tinnitus (i.e., THI entry score >36), stable (i.e., occurring as symptom for more than 6 month,), non-pulsatile, preferably lateralised, not related to otosclerosis, acoustic neuroma, or Meniere Disease, or complicated by self-arming behaviour (e.g., failed surgery) or litigations for insurance compensation related to tinnitus (Mc Combe, 2001) Change to:

Rationale for the enrichment in the selection of the study population

Location in Protocol:

Section 6.3.3, Daily Diary

Change from:

The diary should be filled every evening, considering the events of the day. The tinnitus VAS should be a sort of integrated assessment of how it has been during the day.

1. VAS for tinnitus loudness, pitch, and/or distress, scored as integrated assessment of the whole day.

177 177 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change to:

The diary should be filled every evening, considering the events of the day. The tinnitus VAS should be a sort of integrated assessment of how it has been during the day.

1. VAS for tinnitus loudness (i.e. intensity), pitch, and/or distress, scored as integrated assessment of the whole day. PROTOCOL CHANGE 16

Location in Protocol:

Section, 6.5.1, Visual Analog Scales (VAS) to measure general alertness/anxiety levels.

Change from:

VAS for arousal/anxiety consists of 4 scales anchored to the following opposite words: a) tired-energetic b) active-drowsy c) tense-peaceful d) worried-relaxed.

Change to:

PROTOCOL CHANGE 17

Location in Protocol:

Section 6.5.3, Psycoacustic measurements

Deleted text

Minimal Masking Level…

PROTOCOL CHANGE 18

Location in protocol:

Section 10.3, Screen and Baseline Failures

Change from

Screening/baseline failures are those subjects who have not been eligible to start the study following a screening and/or baseline assessment.

A log of all subjects screened for the study but not entered in the trial will be maintained. The reason(s) for excluding subjects will be recorded

178 178 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change to:

Failures at either of the screening visits (pre-study) are those subjects who have not been eligible to start the study following a screening assessment.

A log of all subjects screened for the study but not entered in the trial will be maintained. The reason(s) for excluding subjects will be recorded

PROTOCOL CHANGE 19

Location in Protocol:

Section 11.2.2.1, Liver Chemistry Stopping Criteria

Change from

Follow up liver chemistries (ALT, AST, alkaline phosphatase, and bilirubin) should be obtained twice weekly until values are clearly falling and resolution to normal or baseline should be documented Change to:

Follow up liver chemistries (ALT, AST, alkaline phosphatase, and bilirubin) should be obtained twice weekly until values are clearly falling and resolution to normal or screening values should be documented PROTOCOL CHANGE 20

Location in Protocol:

Section 12.3.5.2, Clinical Laboratory Evaluations

Change from:

Clinical Laboratory Evaluations

Summary statistics for haematology and clinical chemistry data (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on day 1 of each treatment.

Urinalysis data will be listed. Values of clinical concern will be listed and summarised.

Vital Signs

Vital signs data (systolic blood pressure, diastolic blood pressure, heart rate) data will be listed by regimen and subject. The listings for each subject will be flagged high and low

179 179 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

relative to the normal range, where applicable. Clinically significant vital signs will additionally be listed and summarised.

Summary statistics for vital signs data (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on day 1 of each treatment.

ECG

Summary statistics for ECG (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on day 1 of each treatment.

Change to:

Clinical Laboratory Evaluations

Summary statistics for haematology and clinical chemistry data (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on Day 1 of each Treatment Session. Urinalysis data will be listed. Values of clinical concern will be listed and summarised.

Vital Signs

Summary statistics for vital signs data (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on Day 1 of each Treatment Session.

ECG

Summary statistics for ECG (including change from baseline) will be produced by regimen, day and time. Baseline will be pre-dose on Day 1 of each Treatment Session.

180 180 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 21

Location in Protocol:

Section, 12.3.5.6, Pharmacokinetics/Pharmacodynamics Analyses Deleted Text

Lorazepam

181 181 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

PROTOCOL CHANGE 22

Location in Protocol:

Appendix 1: Time and Events

Change from:

Screening Treatment Follow- Visit 1 Visit 2 Visit 3,5,7 Visit 4,6,8 up washout -28 -14 0, 28, 56 14, 42, 14-28, 42-- 28 Day 56 70 Medical history and Demography √ Physical examination √ √ √ 12-lead ECG √ √ √ Vital signs √ √ √ Clinical Safety laboratory tests √ √ √ Pregnancy test (Urine) √ √ √ Eligibility Criteria Evaluation √ ENT screening √ Otoacustic emission (OAE) √ Audiometry (Tonal audiogram) √ √ √ Speech audiogram √ Self-scored HADS √ Self-scored THI and LSEQ √ √ √ √ √ √ Agreement to participate in the study √ Training for Dairy for home scoring √ Question” How aggravated you are?” √ √ √ Self-scored QUID-16 √ √ √ Lidocaine test √ Tinnitus VAS / Arousal VAS √ √ √ Reported AEs √ √ √ Dairy for home scoring: blank form √ Dairy for home scoring: filled form √ Annoyance of Hyperacusis score (0- √ √ √ 10) Blood samples for PK measurements √ √ Automated Psychoacoustic √ √ assessment of tinnitus pitch, timbre, intensity THI and Hyperacusis for the day √ √ Phone call for assessment √ √ Pharmacogenetic sampling √

182 182 VM2005/00076/02 CONFIDENTIAL HM2009/00361/00VM2005/00076/02 NKP106254

Change to:

Screening Treatment Follow- Visit 1 Visit 2 Visit 3,5,7 Visit 4,6,8 up washout Day -28 -14 0, 28, 56 12-14, (12-14) 12-14 40-42, to 28, days 68-70 (40-42) after last to 56 dose Medical history and Demography 9 Physical examination 9 9 9 9 12-lead ECG 9 9 9 9 Vital signs 9 9 9 9 Clinical Safety laboratory tests 9 9 9 9 Pregnancy test (Urine) 9 9 Eligibility Criteria Evaluation 9 ENT screening 9 Otoacustic emission (OAE) 9 Audiometry (Tonal audiogram) 9 9 9 Speech audiogram 9 Self-scored HADS 9 Self-scored THI and LSEQ 9 9 9 Agreement to participate in the study 9 Training for Diary for home scoring 9 Question” How aggravated you are?” 9 9 9 Self-scored QUID-16 9 9 9 Lidocaine test 9 Tinnitus VAS / Arousal VAS 9 9 9 Reported AEs 9 9 9 Diary for home scoring: blank form 9 Diary for home scoring: filled form 9 9 Annoyance of Hyperacusis score (0- 9 9 9 10) Blood samples for PK measurements 9 9 Automated Psychoacoustic 9 9 assessment of tinnitus pitch, timbre, intensity THI and Hyperacusis for the day 9 9 Phone call for assessment 9 9 Pharmacogenetic sampling 9

183 183 CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 The GlaxoSmithKline group of companies NKP106254

Division: Worldwide Development Retention Category: GRS019 Information Type: Clinical Pharmacology Reporting and Analysis Plan

Title: Clinical Pharmacology Reporting and Analysis Plan for study NKP102654: Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss

Compound Number: GW597599+BRL-029060

Effective Date: 10-JUL-2009

Description:

The purpose of this reporting and analysis plan (RAP) is to describe the planned analyses and output to be included in the Clinical Pharmacology Study Report for Protocol NKP106254. This RAP is intended to describe the safety, pharmacokinetics and pharmacodynamics analyses required for the study. This document will be provided to the study team members to convey the content of the Statistical Analysis Complete (SAC)] deliverable.

Identifier/Version Number: [VM2008/00054/00]

Author’s Name and Functional Area:

Discovery Biometrics

Approved by:Approved by electronically.

CPSSO CPMS Discovery Medicine, Neurosciences CEDD CPSSO DB Programmer

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 The GlaxoSmithKline group of companies NKP106254

The Discovery Biometrics Director (or designee) will give final approval

Discovery Biometrics ( Statistics 02-MAR-09 Manager)

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

TABLE OF CONTENTS

PAGE

1. INTRODUCTION...... 8

2. STUDY OBJECTIVE(S) AND ENDPOINT(S) ...... 8 2.1. Study Objective(s) ...... 8 2.1.1. Primary Objective(s) ...... 8 2.1.2. Secondary Objective(s)...... 8 2.2. Study Endpoint(s) ...... 9 2.2.1. Primary Endpoint(s) ...... 9 2.2.2. Secondary Endpoints(s)...... 9 2.3. Exploratory Endpoints...... 10

3. STUDY DESIGN ...... 10

4. PLANNED ANALYSES ...... 10 4.1. Interim Analyses ...... 10 4.2. Final Analyses ...... 11 4.2.1. Decision Critical Results ...... 11

5. ANALYSIS POPULATIONS ...... 11

6. HYPOTHESES AND TREATMENT COMPARISONS ...... 11

7. TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS...... 12

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING ...... 12 8.1. Reporting Conventions ...... 12 8.2. Data Management ...... 12 8.3. Premature Withdrawal and Missing Data ...... 13 8.4. Baseline Definition...... 13 8.5. Derived and Transformed Data...... 13 8.5.1. Change from Baseline ...... 15 8.5.2. Pharmacokinetic Parameters...... 15 8.5.3. Multiple Measurements at One Timepoint...... 15 8.6. Values of Potential Clinical Importance...... 16

9. STUDY POPULATION ...... 17

10. SAFETY ANALYSES ...... 17

11. PHARMACOKINETIC ANALYSES...... 17 11.1. Drug Concentration Measures ...... 18 11.2. Deriving and Summarizing Pharmacokinetic Parameters...... 18 11.3. Statistical Analyses...... 18 11.4. Population Pharmacokinetic Analyses ...... 18

12. PHARMACODYNAMIC AND BIOMARKERS ANALYSES...... 18 12.1. Pharmacodynamic Analyses...... 18

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...... 21

14. PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES ...... 21 14.1. Pharmacogenetic Analyses ...... 21

15. EFFICACY ANALYSES...... 21

16. HEALTH OUTCOMES ANALYSES...... 21

17. REFERENCES...... 22

18. ATTACHMENTS ...... 23 18.1. Table of Contents for Data Display Specifications...... 23 18.1.1. Study Population...... 24 18.1.2. Safety Figures & Tables...... 25 18.1.3. Pharmacokinetic Figures and Tables...... 26 18.1.4. Pharmacodynamic Figures and Tables...... 27 18.1.5. ICH Listings ...... 30 18.1.6. Other Listings ...... 31 18.2. Data Display Specifications (Example Shells)...... 31

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

LIST OF ABBREVIATIONS

AE Adverse Event ALT Alanine aminotransferase (SGPT) ANOVA Analysis of Variance AST Aspartate aminotransferase (SGOT) AUC Area under concentration-time curve AUC(0-∞) Area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time %AUCex Percentage of AUC(0-∞) obtained by extrapolation AUC(0-x) Area under the concentration-time curve from zero (pre-dose) to some fixed nominal time x AUC(0-t) Area under the concentration-time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments AUC(0-τ) Area under the concentration-time curve over the dosing interval BQL Below the quantification limit BUN Blood urea nitrogen CBC Complete blood count CI Confidence Interval Cmax Maximum observed concentration Cmin Minimum observed concentration CDMP Clinical Document Management and Publishing CO2 Carbon dioxide CPDM Clinical Pharmacology and Discovery Medicine CPDS Clinical Pharmacology Data Sciences CPK Creatine phosphokinase CPSR Clinical Pharmacology Study Report CP-RAP Clinical Pharmacology Reporting and Analysis Plan CRF Case Report Form CRO Contract Research Organization CRU Clinical Research Unit CSSO Clinical Science and Study Operations CV Coefficient of variance DB Discovery Biometrics DBP Diastolic blood pressure DDS Drug Development Sciences DMPK Discovery Medicine Pharmacokinetics ECG Electrocardiogram EDC Electronic data capture GCP Good Clinical Practice GCSP Global Clinical Safety and Pharmacovigilence GGT Gamma glutamyltransferase GLS Geometric Least-Squares GSK GlaxoSmithKline h/hr Hour(s)

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

HR Heart rate IB Investigator’s Brochure ICH International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use IDMC Independent Data Monitoring Committee IDSL Integrated Data Standards Library IEC Independent Ethics Committee IND Investigational New Drug IP Investigational Product IRB Institutional Review Board IU International Unit IV Intravenous Kg Kilogram λz Terminal phase rate constant L Liter LFTs Liver function tests ln Naperian (natural) logarithm LOQ Limit of quantification LLQ Lower limit of quantification µg Microgram µL Microliter MedDRA Medical Dictionary for Regulatory Activities Mg Milligrams mL Milliliter msec Milliseconds NQ Non-quantifiable concentration measured as below LLQ PD Pharmacodynamic PGx Pharmacogenetics PK Pharmacokinetic QC Quality control QD Once daily RAP Reporting and Analysis Plan RBC Red blood cells SAE Serious adverse event(s) SAS Statistical Analysis Software SD Standard deviation SOP Standard Operating Procedure SPM Study Procedures Manual SUSAR Suspected, Unexpected, Serious Adverse drug Reaction ULN Upper limit of normal WBC White blood cells

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

Trademark Information

Trademarks of the GlaxoSmithKline Trademarks not owned by the group of companies GlaxoSmithKline group of companies None NONMEM

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

1. INTRODUCTION

The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be included in the Clinical Pharmacology Study Report for Protocol NKP106254:

Revision Chronology:

VM2005/00076/00 2006-JUL-24 Original

VM2005/00076/01 2007-JUN-03 1. Change of Investigator 2. Addition of new site 3. Changes and clarifications of inclusion and exclusion criteria 4. Clarifications in the text of the protocol

VM2005/00076/02 2008-APR-23 1. Clarifications to the study endpoints 2. Changes and clarifications of the inclusion and exclusion criteria Changes and clarifications to study assessments.

All decisions regarding final analysis, as defined in this RAP document, have been made prior to Database Freeze (unblinding) of the study data. Interim analyses are detailed within Section 4.1 where applicable.

2. STUDY OBJECTIVE(S) AND ENDPOINT(S)

2.1. Study Objective(s)

2.1.1. Primary Objective(s)

To measure the change in tinnitus loudness (VAS) after single (Day 1) and repeated (Day 14) administration of either vestipitant + paroxetine combination, or vestipitant alone vs. placebo.

2.1.2. Secondary Objective(s)

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

• To evaluate safety and tolerability of vestipitant alone and the combination vestipitant + paroxetine at single dose. • To evaluate the PK/PD relationships between steady state exposure of vestipitant and vestipitant + paroxetine combination with each of the various pharmacodynamic endpoints. Additional exploratory objective:

• To measure the change in Diary parameters of tinnitus and hyperacusis during the treatment period between the vestipitant + paroxetine combination and placebo.

2.2. Study Endpoint(s)

2.2.1. Primary Endpoint(s)

2.2.2. Secondary Endpoints(s)

• Visual Analog Scales (VAS) to measure the level in tinnitus pitch and distress as perceived at the moment of the measurement • VAS to measure arousal/anxiety (i.e., tired-energetic, active-drowsy, tense- peaceful, and worried-relaxed) • Self-report questionnaires (integrated evaluation referring to the subject’s condition before dosing on the day of testing): • Tinnitus Handicap Inventory (THI) • Quick Inventory of Depressive Symptomatology (QIDS-SR 16)

Clinician rated scales:

• Annoyance of Tinnitus: Question: “How aggravated are you by tinnitus? Please rate from 0 to 7 point of intensity” (8-point scale) • Annoyance of Hyperacusis: Answer to questions: (i), “Do you feel hypersensitive to noise? (yes/no response); and (ii), if yes, a score >1 (on the 0– 7 scale) for the overall impact of hyperacusis on everyday life. Safety and tolerability: recording of adverse events, blood pressure and heart rate at each visit, and electrocardiogram, laboratory safety assessments and physical exam. PK samples collected at Day 1 (pre-dose and 2-5 hours post-dose) and Day 14 (pre- dose and 2-5 hours post-dose).

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

2.3. Exploratory Endpoints

Diary (to be filled in the evening):

• VAS for tinnitus loudness, pitch, and/or distress (integrated assessment of the whole day) • Number of hyperacusis episodes, brief description of the generator, and VAS distress rating of the overall distress

3. STUDY DESIGN

Subjects will be assigned to study treatment in accordance with the randomization schedule provided by a Statistician within DB GSK produced using validated software (Randall) prior to the start of the study.

The following six sequences will be used:

A/B/C, A/C/B, B/A/C, B/C/A, C/A/B and C/BA

Where A, represents placebo, B represents Vestipitant alone and C represents the combination between Vestipitant and Paroxetine

4. PLANNED ANALYSES

4.1. Interim Analyses

No formal interim analyses are planned.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

4.2. Final Analyses

The final planned analyses will be performed after all subjects have completed the study and after database freeze/unblinding. See Section 9 to Section 13 for all final planned analyses for this study.

4.2.1. Decision Critical Results

Headline data focussed on main PD endpoint will be released after two weeks from DBF.

See Section 18 for more details.

5. ANALYSIS POPULATIONS

All Subjects Population

The ‘All Subjects population’ is defined as all subjects who receive at least one dose of study medication. Pharmacodynamic Population

All subjects in the previous population who provide data for at least 1 post-dose pharmacodynamic assessment.

Note that in the reporting, all efficacy and pharmacodynamic endpoints described in the study protocol will be categorized as “pharmacodynamic”

Pharmacokinetic (PK) Population The ‘PK population' is defined as subjects in the ‘All Subjects’ population for whom a pharmacokinetic sample was obtained and analysed.

6. HYPOTHESES AND TREATMENT COMPARISONS

This study is designed to test for superiority. The null hypothesis for the treatment comparison will be that there is no difference between Vestipitant + Paroxetine and placebo in the primary endpoint (change in tinnitus loudness measured by means of a VAS scale). The alternative hypothesis will be that there is a difference. Symbolically, this is expressed as follows:

H(0): µ(test) = µ(reference)

H(1) : µ(test) ≠ µ(reference)

A two-sided t-test with α=0.05 will be used to test this hypothesis.

Given the exploratory nature of this study no adjustment for multiplicity will be carried- out to handle the different tests carried-out at the 2 different days.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

7. TREATMENT AND OTHER SUB-GROUP DESCRIPTIONS FOR DATA DISPLAYS

Table 1 Treatment groups

Randomisation Final Data Display (i.e. HARP / other) Code Treatment Description Treatment Description A Placebo Placebo B Vestipitant 25 mg Vestipitant C Vestipitant 25 mg + Paroxetine 20 mg Vest.+Parox.

8. GENERAL CONSIDERATIONS FOR DATA ANALYSES AND HANDLING

8.1. Reporting Conventions

All data will be reported according to the actual treatment the subject received.

Nominal time will be utilized in the descriptive summaries in mean and median plots.

When data are summarized by time only values taken at the pre-specified planned time will be used. In case of planned duplicate/triplicate measurements, the mean value will be summarised. Unscheduled or unplanned readings will be listed.

Any deviations from the analyses in the RAP will be identified in the final clinical pharmacology study report.

All programming will be performed using SAS version 9, or later release, in a UNIX environment. Programs will be imported into HARP and the final output will be produced by running drivers in HARP.

8.2. Data Management

Data are collected using PIMS but SI data sets will be created to allow the analysis via HARP.

Table 2 Other data management activities

Data Type Source Format of Planned Date Responsibility Data of Final File

PK (1) SMS PKHARP before DBR DMPK PK (2) PKHARP 2 days after DB programmer DBF

PK (1) = Vestipitant/Paroxetine concentrations; PK(2) = File merging PK (1) with time deviations

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

8.3. Premature Withdrawal and Missing Data

All subjects who withdraw prematurely from the study/study drug will be documented and the reason for their withdrawal recorded in the final Clinical Pharmacology Study Report (CPSR). All available data from subjects who withdraw will be listed and all available planned data will be included in the summaries according to the populations defined in Section 5.

8.4. Baseline Definition

Table 3 indicates the baseline to be used in the analyses of safety data. Baseline for pharmacodynamic analyses will be discussed in Section 12.

Table 3 baseline definition

The following table indicates the baseline day to be used in the analysis:

Parameter Baseline Safety : Vital Signs and ECG Day 1 pre-dose for each session Labs data Screening

8.5. Derived and Transformed Data

THI:

THI is a self reported questionnaire with 25 items. Each item has 3 potential answers with “yes” = 4 points, “sometimes” = 2 points, “no” = 0 points.

A total score ranging from 0 (indicating no tinnitus handicap) to 100 (the worst patients’s annoyance) will be derived

Handling of missing values

Provided no more than 2 responses are missing, the total score will be calculated adjusting for the missing data as follows:

Total score = (25/number of non missing values) * observed total score

The score will be rounded to the nearest integer number.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

QIDS-SR 16

The QIDS-SR 16 is a self-report rating scale that assesses symptom severity of DSM-IV diagnostic criterion for major depressive disorder. The QIDS-SR 16 contains 16 separate items which correspond to 9 DSM-IV symptom criterion domains: [sad mood, concentration, self-criticism, suicidal ideation, interest, energy/fatigue, sleep disturbance (initial, middle, and late insomnia or hypersomnia), decrease/increase in appetite/weight, and psychomotor agitation/retardation].

Derivation

The QIDS-SR total score is calculated by summing the following items:

• The highest score obtained on any of the four sleep items (Items 1, 2, 3 and 4) • Item 5 (feeling sad) • The highest score obtained on any of the four appetite/weight items (Items 6, 7, 8 and 9) • Item 10 (concentration/decision making) • Item 11 (view of myself) • Item 12 (thoughts of death or suicide) • Item 13 (general interest) • Item 14 (energy level) • The highest score obtained on either of the two psychomotor items (Items 15 and 16)

The highest possible score is 27, which represents the most severe measure of depression; the lowest possible score is 0, which represents an absence of depression.

Due to the small number of items, missing data will not be imputed for the QIDS total score. If any of the 9 items above are missing, the total score will not be calculated at that visit. Note that in the three situations above where an item is obtained from the highest score of a number of questions, as long as one question is present, the item will be present. For example, if questions 1, 2 and 4 are missing, but question 3 is present, the first item score will be present and hence the total score can still be calculated.

THI and QIDS-SR total scores will be derived by the research coordinator and included in the data-base. Individual items results won’t be data-based and therefore STATS won’t re-calculate the total scores

LABs:

Values below the limit of quantification (i.e. expressed as < x.x) will be set up as ½ of limit of quantification for producing summary statistical displays, while they will be clearly identified as BQL in listings (i.e. labelled as ‘< x.x.’).

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

ECG

QTcF values will be derived in this way:

Firstly RR will be derived as (QT/QTcB)**2 and then QTcF will be derived as = QT/(RR)**(1/3).

RR won’t be included in any display.

Note that QTcB is the QTc value automatically provided by the machine

Diary:

The following data, recorded daily from day 2 to day 13, will be considered:

a) Tinnitus VAS scales (3 scales covering pitch, intensity and distress)

b) Number of hyperacusis episodes experienced at each day

c) Distress due to hyperacusis episodes (0-7 scale)

For each endpoint, subject and treatment period, a mean value will be derived to summarize the response over the whole treatment period. The mean value won’t be derived if data are available for less than 8 days.

8.5.1. Change from Baseline

The change from baseline will be calculated by subtracting the baseline values from the individual post-randomisation values. If either the baseline or post-randomisation value is missing, the change from baseline is set to missing as well.

8.5.2. Pharmacokinetic Parameters

Not applicable

8.5.3. Multiple Measurements at One Timepoint

Where multiple measurements are recorded for a particular time point, the mean of the measurements will be calculated and used in any derivation of summary statistics. However all available data will be listed.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

8.6. Values of Potential Clinical Importance

Table 4 Laboratory Values of Potential Clinical Importance (Healthy Volunteers)

Hematology Analyte Effect Potential Clinical Importance (PCI) Range Unit White Blood Cell Count Low < 0.67 LLN x109/ L (WBC) High > 1.82 ULN x109/ L Neutrophil Count Low < 0.83 LLN x109/ L Hemoglobin High > 1.03 ULN (male) g/L High > 1.13 ULN (female) g/L Low Change from baseline > 25 [1] g/l Hematocrit High > 1.02 ULN (male) Ratio of 1 High > 1.17 ULN (female) Ratio of 1 Low Change from baseline > 0.075 [1] Ratio of 1 Platelet Count Low < 0.67 LLN x109/ L High > 1.57 ULN x109/ L Lymphocytes Low < 0.81 LLN x109/ L

Chemistry Analyte Effect Potential Clinical Importance (PCI) Unit Range/Value Albumin Low < 0.86 LLN g/L Calcium Low < 0.91 LLN mmol/L High > 1.06 ULN mmol/L Creatinine High > 1.3x ULN mmol/L High > 44.2 Change from baseline µmol/L Glucose Low < 0.71 LLN mmol/L High > 1.41 ULN mmol/L Magnesium Low < 0.63 LLN mmol/L High > 1.03 ULN mmol/L Phosphorus Low < 0.80 LLN mmol/L High > 1.14 ULN mmol/L Potassium Low < 0.86 LLN mmol/L High > 1.10 ULN mmol/L Sodium Low < 0.96 LLN mmol/L High > 1.03 ULN mmol/L Total CO2 Low < 0.86 LLN mmol/L High > 1.14 ULN mmol/L

Liver Function Test Analyte Effect Potential Clinical Importance (PCI) Range Unit ALT/SGPT High ≥ 2x ULN U/L AST/SGOT High ≥ 2x ULN U/L AlkPhos High ≥ 2x ULN U/L T Bilirubin High ≥ 1.5Xuln µmol/L T. Bilirubin + ALT High ≥ 1.5xULN T. Bilirubin µmol/L + ≥ 2x ULN ALT U/L [1] = a reduction from baseline > of the value indicated.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

Table 5 ECG Values of Potential Clinical Importance (Healthy Volunteers)

ECG Parameter Potential Clinical Importance Range (PCI) Unit Absolute QTc interval >450 msec Increase from baseline QTc >60 msec PR interval <110 and >220 msec QRS interval <75 and >110 msec

Table 6 Vital Sign Values of Potential Clinical Importance (Healthy Volunteers)

ECG Parameter Potential Clinical Importance Range (PCI) Unit Systolic Blood Pressure < 85 and > 160 mmHg Diastolic Blood Pressure < 45 and > 100 mmHg Heart Rate < 40 and > 110 bpm

9. STUDY POPULATION

Study population data will be summarised by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of Study Population tables are shown in Section 18 of the RAP.

The tables will use the “All subjects” population unless otherwise specified.

10. SAFETY ANALYSES

Safety data will be summarised and listed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

The precise format and content of Safety figures, tables and listings are shown in Section 18 of the RAP.

The tables will use the “All subjects” population unless otherwise specified.

11. PHARMACOKINETIC ANALYSES

The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be performed by, or under the direct auspices of, Clinical Pharmacology Data Sciences (CPDS), GlaxoSmithKline.

The merge of PK concentration data, randomisation and CRF data will be performed by, or under the direct auspices of, Discovery Biometrics (Programmer), GlaxoSmithKline.

Derivation of pharmacokinetic parameters will be performed by, or under the direct auspices of, Clinical Pharmacokinetic Modelling Simulation (CPMS), GlaxoSmithKline.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

11.1. Drug Concentration Measures

Blood sampling times vestipitant and vestipitant + paroxetine will be related to the time of dosing. Actual sampling times will be used to calculate all parameters. All plasma concentration data will be listed (listings 2,3). The concentration at each time point will be summarized by treatment using descriptive statistics (arithmetic mean, SD, median, minimum, and maximum) in Table 11.1-Table 11.2. Mean values will be plotted (Figure 11.1-Figure 11.2).

11.2. Deriving and Summarizing Pharmacokinetic Parameters

Not applicable

11.3. Statistical Analyses

Not applicable

11.4. Population Pharmacokinetic Analyses

If data allow, pharmacokinetic parameters for vestipitant and vestipitant + paroxetine will be estimated using mixed effect modelling approach using NONMEM VI. All calculations will be based on actual sampling times. All the derived parameters will be listed within the CPK report. This analysis will be conducted by a qualified person within CPMS, GSK Verona.

12. PHARMACODYNAMIC AND BIOMARKERS ANALYSES

12.1. Pharmacodynamic Analyses

Statistical analyses will be the responsibility of a qualified statistician in DB at GSK.

VAS tinnitus (loudness, pitch, distress)

For each domain, data will be summarized by treatment and time (Table 12.1) and plotted (Figure 12.1-Figure 12.3).

For each domain data will be analyzed using a mixed effect model including terms for:

• fixed effects: period, treatment, time point (day 1 2h post dose, day14 pre-dose, day 14 2h post dose), time point*treatment • random effects: subject, subject*period. Treatment means will be estimated on each time point and treatment differences will be reported with 95% confidence intervals. Results will be presented in Table 12.2

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

VAS arousal/anxiety

For each domain, data will be summarized by treatment and time (Table 12.3) and plotted (Figure 12.4-Figure 12.7).

For each domain data will be analyzed using a mixed effect model including terms for:

THI

Total scores will be summarized by treatment and time (Table 12.5) and plotted (Figure 12.8).

Data will be analyzed using a mixed effect model including terms for:

QIDS-SR

Total scores will be summarized by treatment and time (Table 12.7) and plotted (Figure 12.9).

Data collected on day 14 will be analyzed using a mixed effect model including terms for:

• fixed effects: period, treatment • random effects: subject Treatment means will be estimated and treatment differences will be reported with 95% confidence intervals. Results will be presented in Table 12.8

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

Question : how aggravated are you by tinnitus?

Responses will be summarized by treatment and time (Table 12.9) and plotted (Figure 12.10).

Data will be analyzed using a mixed effect model including terms for:

• fixed effects: period, treatment, time point (day 1 2h post dose, day 1 3h post dose, day14 pre-dose, day 14 2h post dose, day 14 3h post dose), time point*treatment • random effects: subject, subject*period Treatment means will be estimated on each time point and. treatment differences will be reported with 95% confidence intervals. Results will be presented in Table 12.10

Annoyance of Hyperacusis

Responses (8-point scale) will be summarized by treatment and time (Table 12.11) and plotted (Figure 12.11).

Data collected on day 14 will be analyzed using a mixed effect model including terms for:

Diary

Tinnitus VAS scale – Number of hyperacusis episodes, distress caused by hypearacusis

For each endpoint, data will be summarized by treatment and day (Table 12.13, Table 12.15, Table 12.17) and plotted (Figure 12.12-Figure 12.16).

For each domain data, mean values over the whole period will be analyzed using a mixed effect model including terms for:

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

13. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES

The PK/PD relationship between vestipitant and vestipitant + paroxetine combination and primary pharmacodynamic endpoints of interest will be explored using plasma concentration and or average exposure. The appropriate modelling techniques including continuous and categorical methods will be investigated. This analysis will be conducted by a qualified person within CPMS, GSK Verona.

14. PHARMACOGENETIC, VIRAL GENOTYPING AND PHENOTYPING ANALYSES

14.1. Pharmacogenetic Analyses

A pharmacogenetic analysis may be carried out. Further specifications regarding the analysis, if performed, will be discussed at a later date.

15. EFFICACY ANALYSES

Not applicable

16. HEALTH OUTCOMES ANALYSES

Not applicable

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

17. REFERENCES

GlaxoSmithKline Document Number: VM2005/00076/00 Study ID NKP106254. Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss. Effective date -24-Jun-2006

GlaxoSmithKline Document Number: VM2005/00076/01 Study ID NKP106254. Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss. Effective date- 03-Jun-2007

GlaxoSmithKline Document Number: VM2005/00076/02 Study ID NKP106254. Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss. Effective date- 23-Apr-2008

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18. ATTACHMENTS

18.1. Table of Contents for Data Display Specifications

Listed below are the planned figures, tables and listings to be produced for inclusion in the CRS106139 clinical study report:

• The ‘IDSL No. / Example Shell”’ column refers to the relevant example in the Integrated Data Standards Library (IDSL) data standards database

• Unless otherwise indicated, these refer to the core IDSL data standards located under:

o ‘Data Standards’ → ‘By Component’ in the IDSL database

• ‘CP’ refers to the Clinical Pharmacology (CP) modified core IDSL standards located under:

o ‘Supporting Documentation’ →’TST Use of IDSL Core Choices’ → ‘Clin Pharm’ in the IDSL

• ‘PD’ refer to the Clinical Pharmacology data standards located under ‘Data Standards’ ‘By Therapeutic Component’ → ‘Clin Pharm’ in the IDSL.

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.1. Study Population

Table Population IDSL No. / Title Additional Programming Responsibility Deliverable No. Example Shell Notes Priority 9.1 All Subjects DM3 Summary of Demographics characteristics DB prog SAC 9.2 All Subjects DM6 Summary of Race and Racial Combination Details DB prog SAC 9.3 All Subjects CP_ES1 Summary of Subject Disposition DB prog SAC

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.2. Safety Figures & Tables

Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority 10.1 All Subjects EX1 Summary of Exposure to study drug Remove daily dose section DB (Prog) SAC 10.2 All Subjects CP_AE1X Summary of All Adverse Events DB (Prog) SAC 10.3 All Subjects CP_AE1X Summary of Drug Related Adverse Events DB (Prog) SAC 10.4 All Subjects LB1 Summary of Hematology Laboratory values DB (Prog) SAC 10.5 All Subjects LB1 Summary of Chemistry Laboratory values DB (Prog) SAC

10.6 All Subjects UR3 Summary of Urinalysis Dipstick Results DB (Prog) SAC CONFIDENTIAL 10.7 All Subjects EG1 Summary of ECG findings DB (Prog) SAC 10.8 All Subjects EG2 Summary of ECG values DB (Prog) SAC 10.9 All Subjects VS1 Summary of Vital Signs DB (Prog) SAC

HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.3. Pharmacokinetic Figures and Tables

Figures

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority PKCF4 Mean (+ SD) Plasma Vestipitant Concentration- 2 curves : 1 for 11.1 PK Time Plots (Linear and Semi-log) vestipitant alone and 1 DB (Prog.) SAC for Vestip. + Paroxetine PKCF4 Mean (+ SD) Plasma Paroxetine Concentration- DB (Prog.) 11.2 PK 1 curve : Vestip.+ Parox. SAC Time Plots (Linear and Semi-log)

Tables CONFIDENTIAL

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority PKCT1 Summary of Plasma Vestipitant Pharmacokinetic DB (Prog.) 11.1 PK By treatment group (2) SAC Concentration-Time Data (units) PKCT1 Summary of Plasma Paroxetine Pharmacokinetic DB (Prog.) 11.2 PK 1 treatment group SAC Concentration-Time Data (units)

HM2009/00361/00 NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.4. Pharmacodynamic Figures and Tables

Figures

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell - Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) 12.1 PD HEADLINE and time - loudness Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) 12.2 PD HEADLINE and time - pitch Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) 12.3 PD HEADLINE

and time - distress CONFIDENTIAL Plot of VAS arousal-anxiety mean values (+-SD) by DB (Stats) 12.4 PD SAC treatment and time - tired vs energetic Plot of VAS arousal-anxiety mean values (+-SD) by DB (Stats) 12.5 PD SAC treatment and time - alert vs drowsy Plot of VAS arousal-anxiety mean values (+-SD) by DB (Stats) 12.6 PD SAC treatment and time - tense vs peaceful Plot of VAS arousal-anxiety mean values (+-SD) by DB (Stats) 12.7 PD SAC treatment and time - worried vs relaxed Plot of THI Total score mean values (+-SD) by DB (Stats) 12.8 PD SAC treatment and time Plot of QIDS-SR Total score mean values (+-SD) by DB (Stats) 12.9 PD SAC treatment Plot of Annoyance of Tinnitus mean values (+-SD) by DB (Stats) 12.10 PD SAC treatment and time Plot of Annoyance of Hyperacusis mean values (+- DB (Stats) 12.11 PD SAC SD) by treatment HM2009/00361/00 Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) 12.12 PD SAC and day – intensity (DIARY)

Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) NKP106254 12.13 PD SAC and day - pitch (DIARY)

CONFIDENTIAL VM2008/00054/00 NKP106254

Figure Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell Plot of VAS Tinnitus mean values (+-SD) by treatment DB (Stats) 12.14 PD SAC and day - distress (DIARY) Plot of Number of Hyperacusis episodes mean values DB (Stats) 12.15 PD SAC (+-sd) by treatment and day - (DIARY) Plot of Annoyance of Hyperacusis mean values (+- DB (Stats) 12.16 PD SAC SD) by treatment and day (DIARY)

Tables

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority CONFIDENTIAL Shell EX1 Summary Statistics of VAS Tinnitus scores by DB (Stats) 12.1 PD treatment and time HEADLINE EX2 Summary of Statistical Analysis of VAS Tinnitus DB (Stats) 12.2 PD HEADLINE scores EX1 Summary Statistics of VAS arousal-anxiety scores DB (Stats) 12.3 PD SAC by treatment and time EX2 Summary of Statistical Analysis of VAS arousal- DB (Stats) 12.4 PD SAC anxiety scores EX1 Summary Statistics of THI total scores by DB (Stats) 12.5 PD SAC treatment and time EX2 Summary of Statistical Analysis of THI total DB (Stats) 12.6 PD SAC scores

EX1 Summary Statistics of QIDS-SR total scores by DB (Stats) HM2009/00361/00 12.7 PD SAC treatment EX2 Summary of Statistical Analysis of QIDS-SR total DB (Stats) 12.9 PD SAC

scores NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Priority Shell EX1 Summary Statistics of Annoyance of Tinnitus by DB (Stats) 12.9 PD SAC treatment and time EX2 Summary of Statistical Analysis of Annoyance of DB (Stats) 12.10 PD SAC Tinnutus EX1 Summary Statistics of Annoyance of Hyperacusis DB (Stats) 12.11 PD SAC by treatment EX2 Summary of Statistical Analysis of Annoyance of DB (Stats) 12.12 PD SAC Hyperacusis EX1 including a mean value DB (Stats)

Summary Statistics of VAS Tinnitus scores by CONFIDENTIAL 12.13 PD over the whole treatment SAC treatment and day (DIARY) period EX2 Summary of Statistical Analysis of VAS Tinnitus DB (Stats) 12.14 PD scores (mean value over the treatment period- SAC DIARY) EX1 including a mean value DB (Stats) Summary Statistics of number of Hyperacusis 12.15 PD over the whole treatment SAC episodes by treatment and day (DIARY) period EX2 Summary of Statistical Analysis of number of DB (Stats) 12.16 PD hyperacusis episodes (mean value over the SAC treatment period- DIARY) EX1 including a mean value DB (Stats) Summary Statistics of Annoyance of Hyperacusis 12.17 PD over the whole treatment SAC by treatment and day (DIARY) period

EX2 Summary of Statistical Analysis of Annoyance of DB (Stats) HM2009/00361/00 12.18 PD Hyperacusis (mean value over the treatment SAC period - Diary)

NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.5. ICH Listings

Table Population IDSL No. / Title Programming Notes Responsibility Deliverable No. Example Shell Priority 1 All subjects DM4 Listing of Demographic Characteristics DB (prog) SAC IE4 Listing of Subjects with Inclusion/Exclusion Criteria DB (prog.) 2 All subjects SAC Deviations 3 All subjects CP_ES10X Listing of Reason for Withdrawal DB (prog.) SAC 4 All subjects CP_CM4 Listing of Concomitant Medication By Generic Term DB (prog.) SAC 5 All subjects BL2 Listing of Subjects for whom treatment blind was broken DB (prog.) SAC 6 All subjects CP_RA1 Listing of Actual and planned treatment DB (prog.) SAC 7 All subjects EX4 Listing of Exposure data DB (prog.) SAC

AE7 Listing of Subject Numbers for Individual Adverse DB (prog.) CONFIDENTIAL 8 All subjects SAC Events 9 All subjects CP_AE9 Listing of All Adverse Events DB (prog.) SAC 10 All subjects CP_AE9a Listing of SAE DB (prog.) SAC 11 All subjects CP_AE9 Listing of AE leading to Withdrawal DB (prog.) SAC CP_LB6 Listing of Haematology Abnormalities of Potential DB (prog.) 12 All subjects SAC Clinical Importance CP_LB6 Listing of all Haematology laboratory Data for subjects DB (prog.) 13 All subjects SAC with PCI abnormalities CP_LB6 Listing of Chemistry Abnormalities of Potential Clinical DB (prog.) 14 All subjects SAC Importance CP_LB6 Listing of all Clinical Chemistry laboratory Data for DB (prog.) 15 All subjects SAC subjects with PCI abnormalities 16 All subjects CP_EG6 Listing of Abnormal ECG findings DB (prog.) SAC 17 All subjects CP_EG4 Listing of ECG values of PCI DB (prog.) SAC CP_EG4 Listing of all ECG values for subjects with any value of DB (prog.)

18 All subjects SAC HM2009/00361/00 PCI 19 All subjects CP_VS5 Listing of Vital Signs of PCI DB (prog.) SAC CP_VS5 Listing of all Vital Signs for subjects with any value of DB (prog.) 20 All subjects SAC PCI NKP106254

CONFIDENTIAL VM2008/00054/00 NKP106254

18.1.6. Other Listings

Table Populatio IDSL No. / Title Programming Notes Responsibili Deliverable No. n Example ty Priority Shell All AE2 Relationship between System Organ Class and DB (prog) 1 SAC subjects Verbatim Text PKCL1X Listing of Plasma Vestipitant Pharmacokinetic DB (prog.) 2 PK SAC Concentration-Time Data PKCL1X Listing of Plasma Paroxetine Pharmacokinetic DB (prog.) 3 PK SAC Concentration-Time Data

CONFIDENTIAL

18.2. Data Display Specifications (Example Shells)

Examples are available in the the IDSL data-base. Example of non IDSL displays are available in a separate file.

HM2009/00361/00 NKP106254

CONFIDENTIAL

LIST OF INVESTIGATORS AND IECS/IRBS FOR NKP106254

Investigator Investigator/ Site no. Hospital/ Institution and IEC/IRB Committee Chair and Name of Address Committee Dr

CONFIDENTIAL 1 HM2009/00361/00 HM2009/00361/00 NKP106254 NKP106254

1 This section contained Principal Investigator’s Curriculum Vitae and has been excluded to protect Principal Investigator privacy.

CONFIDENTIAL HM2009/00361/00 NKP106254

CONFIDENTIAL NKP106254

PARTICIPANT INFORMATION SHEET Study Identification: NKP106254

Sponsor Company Name: GlaxoSmithKline Research & Development Ltd

Subject Identification Number: ......

1. STUDY TITLE Randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss

Short Title: A study investigating potential new treatments for tinnitus patients.

2. INVITATION PARAGRAPH You have been asked to take part in a clinical research study and before you decide to take part it is important for you to know why the research is being done and what it involves. It is important that you read and understand the information given to you in this information sheet. Any questions that you may have should be addressed to the Principal Investigator or his deputy at the time of the consent talk or the subsequent pre-study medical examination. If you are satisfied with this information and wish to take part in this study, you will be asked to sign the consent form in the indicated place; the supervising doctor will also sign it.

• Section 1 tells you the purpose of this study and what will happen to you if you take part. • Section 2 gives you more detailed information about the conduct of the study.

Please take time to read the following information carefully and discuss it if you wish with friends, relatives or your personal doctor (i.e., general practitioner or primary care physician). Ask us if there is anything that is not clear or if you would like more information. Take time to decide whether or not you wish to take part.

Section 1: Purpose of the study and what will happen

3. WHAT IS THE PURPOSE OF THE STUDY? Vestipitant (the study drug) is a drug with a novel mechanism of action that is being developed for the treatment of depression and anxiety, and has been studied extensively in healthy volunteers, depressed patients and patients with anxiety disorder. To date, vestipitant has shown a good safety profile. Paroxetine is a drug marketed for the treatment of depression, panic and

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 1 of 18

1 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254 anxiety disorders and has been prescribed to millions of patients worldwide. Antidepressants are often prescribed for the treatment of tinnitus, despite limited evidence of their effectiveness in tinnitus. A recent study using full dose paroxetine (50mg) in patients suffering with tinnitus showed modest improvements in the severity of tinnitus after several weeks dosing.

4. WHY HAVE I BEEN CHOSEN? You have been selected to participate as you suffer with tinnitus and we believe that you may meet the requirements for taking part in this study. If you wish to take part and you meet all the requirements following the screening visit, you will be entered into the study. You will be one of up to 24 male or female patients who suffer with tinnitus, aged 18-65 years participating in the study.

5. DO I HAVE TO TAKE PART? It is up to you to decide if you want to take part in this study. If you decide to take part, you will be asked to sign a consent form. If you sign the consent form you are still free to withdraw from the study at any time and do not have to give a reason. Withdrawing from the study will not affect the standard of care you receive.

6. WHAT WILL HAPPEN TO ME IF I DO TAKE PART? This study is a repeat dose study, which means you will have to take medication each day for three periods, each lasting 14 days, which means a total of 42 days. There are 3 different treatments, and you will receive all three of the treatments during the study. One of the treatments will be placebo (dummy drug), one will be vestipitant alone, and the other treatment will be vestipitant and paroxetine.

A placebo is a dummy treatment, which looks like the study drug or paroxetine but contains no active ingredients.

The treatments you will receive in each period will be chosen at random (i.e. by chance, just like flipping a coin).

The treatment sequences are double-blinded, which means that neither you nor the study team will know which treatment sequence you are receiving. However, we can find out immediately in an emergency situation.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 2 of 18

2 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

You will be required to attend one screening visit (lasting approximately 3-4 hours), a baseline visit for each treatment period (day 1) lasting 4-6 hours, a final visit for each treatment period (on day 12 to day 14) also lasting 4-6 hours, and a follow up visit between 12 - 14 days after the last dose of study medication. Therefore, you will be required to visit the unit about 8 times over the course of approximately 14-16 weeks.

2nd period Screening 1st period (e.g. 3rd period (e.g. (E.g. placebo) vestipitant) vestipitant + i) 14 days 14 days 14 days

Testing Washou sessions t

Treatment Period 1 On the morning of day 1 of this period, you will need to come to the unit for a 4-6 hour stay. Once we have checked that you are still suitable for participating in the study, you will complete some baseline testing, after which you will be administered the first dose of one of the three treatments mentioned above. After you have completed some questionnaires, there will be further testing of your tinnitus and hearing. You will be given a diary to take home so that you can record your symptoms. You will then be provided with a snack, after which you will be able to go home. After 6-8 days, the study nurse will contact you by telephone to check how you are doing on the study medication. After you have been taking the medication for 12 to 14 days, you will need to return to the unit for another visit lasting about 4-6 hours. This visit is a repeat of the initial (day 1) visit.

There will be a gap for about 14 days between the end of Treatment Period 1 and the start of Treatment Period 2.

Treatment Period 2 Treatment Period 2 will be the same as Treatment Period 1, except that you will receive a different treatment. Again, the study nurse will contact you by telephone after 6-8 days to check how you are doing on the study medication.

There will be a gap for about 14 days between the end of Treatment Period 2 and the start of Treatment Period 3.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 3 of 18

3 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

Treatment Period 3 Treatment Period 3 will be the same as Treatment Periods 1 & 2, except that you will receive a different treatment. Again, the study nurse will contact you by telephone after 6-8 days to check how you are doing on the study medication.

Study schedule

Screening 1 Within 28 days of the first dose, we will ask you to come in for a thorough (approximately medical screening to see if you are suitable for the study. Before the 4-6 hours) medical, a doctor will explain to you what the study involves and answer any questions that you may have. If you still wish to participate you will need to sign a consent form saying that you are willing to participate in the study. There is no guarantee that you will be accepted onto the study if you attend and pass this screening visit.

The following procedures will be performed: A full medical history and examination, including: • Height and weight • Pulse and blood pressure check • Blood tests which include checking your blood count and your liver and kidney function • Blood tests including Hepatitis B and C testing. These tests are performed routinely for your safety. If any of these results are positive you will not be able to participate in this study. This information will be kept confidential. • Urine drug screen and alcohol breath test. If either of these tests is positive you will not be able to participate in this study. This information will be kept confidential. • A pregnancy test for women • An electrocardiogram (ECG or heart tracing)

The following tests and questionnaires will be conducted (if not already performed in the Audiology Clinic) – see Section 1.10 for more details: • Audiometry (Tonal Audiogram & Tinnitus Matching) • Otological screen • Tinnitus Handicap Inventory (THI) • Annoyance of hyperacusis questioning (increased sensitivity to noise) • 16 item Quick Inventory of Depressive Symptoms (QIDS) • 4-point VAS for anxiety/arousal • Question “How aggravated are you by tinnitus?”

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 4 of 18

4 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

• Hospital and Anxiety Depression Scale, HADS (a questionnaire on your mood and feelings)

• You will be given a diary card to take home so that practice on completion of it can be performed

Days 1 & 14 Approximately 4 weeks after the screening visit, you will need to come to the unit for the first day of Treatment Period 1, when you will start to take the Treatment study medication. Periods 1 - 3 (2 weeks each with a 2 week The following assessments will be performed prior to dosing on Day 1 and rest between) then again on day 12 to 14 (of each Treatment Period):

• vital signs (blood pressure and pulse) • blood tests to include checking your blood count, your liver and kidney function, and to measure levels of study drug in the blood • pregnancy test (women) • adverse event / stressful life event questioning • You will complete questionnaires and be asked questions about your tinnitus (same as at screening)

Once these assessments are completed, you will be given the first dose of study medication. This will consist of two tablets which you will need to take once a day every morning for 12 to 14 days at approximately the same time every day. The tablets will look identical in each of the three Treatment Periods.

Once dosed, the following assessments will be performed (also in the quiet room):

• You will need to complete the questionnaires as before a few times in the day • audiometry (2 to 3 hrs after dosing) • blood sample to measure study drug levels (3-4 hrs after dosing) • adverse event questioning • you will be given a diary card to fill in at home • snack is served • discharged home with sufficient tablets to last 14 days

Once home, you should keep diary records of your tinnitus, hyperacusis, sleep, any symptoms you have and any medication you have taken. About 6- 8 days after dosing started, the study nurse will telephone you to see how you are getting on with the medication, and will ask you about any side-effects you may have experienced.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 5 of 18

5 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

You will need to return to the unit on day 12 to 14 of dosing. The assessments on day 12 to 14 will be identical to those on day 1 (listed above).

Follow up visit 12 to 14 days after your last dose of study medication taken, you will need to (about 30 return to the unit for the following procedures: minutes) • vital signs (blood pressure and pulse) • blood tests to check your blood count, your liver and kidney function • physical examination • heart tracing (ECG) • pregnancy test (women) • you will be asked about any symptoms you may have experienced which may or may not be related to the study drug • you will be asked about any other medication you may have taken

Expenses and payments:

You will receive payment in recognition of the time and inconvenience involved in taking part in this study.

If you complete the study you will receive £750.00 If for any reason following enrolment onto the study you do not receive any of the test drug or placebo you will receive £50.00.

The payment will be given to you after the follow-up has been completed successfully. A follow up visit will be required even if you withdraw / are withdrawn at an earlier stage. GSK pays basic rate tax on the honorarium payment that you receive. It is up to you to inform the Inland Revenue about the honorarium payment as it counts as taxable earnings.

You will receive the sum in full if you have to withdraw from the study for medical or safety reasons associated with participation in it. If you withdraw from the study for reasons not associated with the study, or if we withdraw you from the study for breaching the study restrictions, you will receive payment proportional to the length of your participation. For your safety, and to ensure the validity of the study data it is important that you do not breach the study restrictions. Should you not comply with the study conditions or The Volunteer Code of Conduct (available in your information pack) a proportionate deduction may be made from your total payment.

GSK has made provisions to organise or to reimburse you for the reasonable costs of travelling to and from study visits.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 6 of 18

6 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

7. WHAT DO I HAVE TO DO? You are required to comply with the following instructions and restrictions:

Adverse Events • You should report any adverse events to the study staff. An adverse event is when you feel unwell or different in anyway. After you have left the unit, you need to tell the study staff when any ongoing adverse events from the study have finished.

Medication • You may not take any prescription medication, vitamin supplements or herbal remedies for at least 7 days prior to the first dose of study drug except with the express permission of the study physician. You may not take any over-the-counter medication within 48 hours of the baseline visit and the day 14 visit.

• You should not participate in this study if you regularly take any of the following types of medication: antidepressants, antipsychotics, opioids, antimigraine drugs, thioridazine or if you have taken part in a trial with an experimental drug within the last 6 months.

• If necessary, you may receive medications for treating adverse events.

Medical history You should not take part in this study if you suffer with any of the following:

• heart attack in the last year • history of seizures e.g. epilepsy • history of cancer

Food and Drink • Study medication should be taken first thing in the morning (approximately at the same time every day) with a glass of water, also preferably with food. Remember to record the time you took the dose on the diary card.

• You must refrain from alcohol for at least 24 hours before the screening visit, and each visit to the unit and while being on the unit. Men and women should drink no more than 1 to 2 units of alcohol a day from the start of treatment period 1. 1 unit is equivalent to a half- pint (220mL) of beer or 1 measure (25mL) of spirits or 1 glass (125mL) of wine

• You should not consume large quantities of grapefruit or grapefruit- containing products for at least 14 days prior to the first dose of study medication until collection of the final blood sample on the last study day

• You will be given standardised meals at set times during your stay in

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 7 of 18

7 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

the unit

Blood donation • You must not give blood during the study unless it is part of the study assessments

Recreational drugs • The use of recreational drugs during the study is forbidden. Random drugs of abuse tests may be done throughout the study. If a test is positive you will be excluded from the study.

Driving • You should be cautious when deciding whether to drive a car or other vehicle. You should not drive if you feel unwell. Please inform the study doctor as soon as possible if this happens.

Contraception Because the effect of the study drug on the unborn or nursing child is not fully known, you will not be accepted into the study if you intend to become pregnant, are breastfeeding, or if you plan on fathering a child during the study – from the first administration of the study drug until 3 months after administration of the last dose of the study drug.

A woman will be able to participate in the study if she :

a. Is unable to become pregnant including any woman who: • Has had a hysterectomy or both ovaries removed, or • Is post-menopausal (periods stopped totally for one year). Or b. Is able to become pregnant, and agrees to one of the following: • must not have intercourse at all in the two weeks prior to administration of the study drug and throughout the study until the first menstruation after taking the last study medication, or

• must use an effective method of contraception such as o Female sterilisation o Sterilisation of male partner (i.e. vasectomy); or, o A double-barrier method: condom and an occlusive cap (diaphragm or cervical/vault caps) in combination with a vaginal spermicidal agent (foam / gel / film / cream / suppository) o Hormonal methods (the pill or an injection) o Intrauterine device (IUD or coil) from the screening visit until the first menstruation after taking the last study medication.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 8 of 18

8 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

The effects of paroxetine on the unborn foetus or nursing baby/infant are also uncertain. Some studies have suggested an increase in the risk of birth defects, particularly heart defects, in babies whose mothers received paroxetine in the first few months of pregnancy. These studies found that about 1 in 50 babies (2%) whose mothers received paroxetine in early pregnancy had a heart defect, compared with the normal rate of 1 in 100 babies (1%) seen in the general population.

If the above is not entirely clear, please consult one of the study physicians. Even if you are using the recommended forms of contraception, there is a small risk that a pregnancy can occur. Women who do become pregnant during the study should inform us immediately and men should tell us immediately if they father a child during the course of the study. In such a case we would discuss further follow-up options.

8. WHAT IS THE DRUG THAT IS BEING TESTED? Vestipitant (the study drug) is a selective NK1 receptor blocker (a new mechanism of action) that is being developed for the treatment of depression, anxiety and chemotherapy induced nausea and vomiting, and has been studied extensively in healthy volunteers, depressed patients and patients with anxiety disorder. To date, vestipitant has shown a good safety profile. Paroxetine is a selective serotonin reuptake inhibitor (SSRI). It is marketed for the treatment of depression, panic and anxiety disorders and has been prescribed to millions of patients worldwide.

Antidepressants are often prescribed for the treatment of tinnitus, despite limited evidence of their effectiveness. A recent study using full dose paroxetine in patients suffering with tinnitus showed modest improvements in the severity of tinnitus after several weeks dosing.

There is evidence to suggest that the combination of vestipitant and paroxetine may be more effective in the treatment of tinnitus than a single drug alone. The aim of this study is to determine which treatment, either single therapy (with vestipitant) or combination therapy (vestipitant plus paroxetine), is more effective in the treatment of tinnitus. We would therefore like you to complete all 3 treatment options to help us to make a proper comparison between the single treatment and the combination treatment. We would also like to know if either is better than the placebo (dummy drug) treatment.

During the study you will receive vestipitant (the study drug) with and without paroxetine (a marketed drug for depression) and placebo treatment. A placebo is a dummy treatment, which looks like the study drug but contains no active ingredients. The highest dose of vestipitant will be 25 milligrams and the highest dose of paroxetine will be 20mg which is the approved marketed dose for the treatment of depression.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 9 of 18

9 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

9. WHAT ARE THE SIDE EFFECTS OF TAKING PART?

With vestipitant (the study drug): To date approximately 485 healthy volunteers and 1134 patients have taken the study drug. Healthy volunteers have taken doses of 25mg daily for up to 28 days. Repeat daily doses of 15mg have been taken for periods of up to 12 weeks by patients participating in trials. Common adverse events reported in healthy volunteer studies conducted to date include headache, upper respiratory tract infection, gastrointestinal events, sleepiness/drowsiness (somnolence), skin rashes and fatigue. In the eight-week study in patients suffering with major depressive disorder, common adverse events included somnolence, diarrhoea, and erectile dysfunction (such as decreased sex drive, inability to have an erection, or delayed orgasm). In a 12-week, repeat dose study in Social Anxiety Disorder, the most common adverse event was fatigue. Other adverse events reported with the study drug include: nausea, dizziness, dry mouth, constipation, inability or difficulty sleeping (insomnia), heartburn, wind/excessive gas in the stomach or bowel (flatulence), sweating, stomach pain or discomfort, irritability, muscle aches and pains. All drugs may cause side-effects in some people. Because the study drug has not been studied extensively in humans it may have adverse effects that have not yet been identified.

With paroxetine (Seroxat):

Like all medicines, paroxetine can cause side-effects, but not everybody gets them. The side effects are normally mild to moderate and often subside improve or resolve as therapy continues. The most common side effects are: feeling sick (nausea), change in sex drive or sexual function (e.g. lack of orgasm and, in men abnormal erection and ejaculation), increases in the level of cholesterol in the blood, lack of appetite, not sleeping well (insomnia) or feeling sleepy, feeling dizzy or shaky (tremors), feeling agitated, blurred vision, yawning, dry mouth, diarrhoea or constipation, weight gain, feeling weak, sweating, brief increase or decrease in blood pressure, a faster than normal heartbeat, lack of movement, stiffness, shaking or abnormal movements in the mouth and tongue, skin rashes, feeling confused, having hallucinations (strange visions or sounds) an uncontrollable, involuntary passing of urine (urinary incontinence).

Some patients who have stopped taking paroxetine suddenly have had symptoms such as: feeling dizzy, unsteady or off-balance, feelings like pins and needles, burning sensations and (less commonly) electric shock sensations, including in the head, some patients have developed buzzing, hissing, whistling ringing or other persistent noise in the ears (tinnitus), sleep disturbances (vivid dreams, nightmares, inability to sleep), feeling anxious, headaches. Please let us know if you are worried about withdrawal effects when stopping paroxetine

Please refer to the patient information leaflet enclosed for further information and detail.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 10 of 18

10 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

During the study we will be monitoring you closely and taking safety blood samples. We will stop the study or withdraw a volunteer from further participation if any clinically important changes are seen.

If any clinically important findings emerge during the course of this study that would affect your participation or safety, you will be informed of these as soon as possible.

10. WHAT ARE THE POSSIBLE DISADVANTAGES AND RISKS OF TAKING PART? If you have private medical insurance you should check with the company before agreeing to take part in the study to ensure that your participation will not affect your medical insurance.

If during the study a medical condition of which you were unaware is discovered, a full report will be sent to your GP (if you have no objections) and you will be advised of the appropriate course of action to take for treatment.

Study Procedures: General procedures: Blood sampling is a safe procedure and involves the insertion of a small plastic tube (cannula) or a needle into a vein in your arm. The total amount of blood to be taken during the study is at most 240mLs – this is about half a pint and is taken over the course of several weeks, and is about half the amount that would be donated to the Blood Transfusion Service by a donor in a single session. Apart from some discomfort at the time of insertion it is unlikely to cause any problems. Occasionally, some bruising or inflammation at the needle site may occur.

All other procedures during the study including ECG and measurements of blood pressure, heart rate, urine collection and questionnaires are safe and unlikely to cause discomfort.

Pure tone audiometry: This test is perfectly safe. During this test we will test your hearing by measuring the quietest sounds that you can hear. As soon as you hear a sound (tone), you will need to press the button (or raise your finger). You then need to keep it pressed (or raised) for as long as you hear the sound (tone), no matter which ear you hear it in. You may release the button (or lower your finger) as soon as you think you no longer hear the sound (tone). Whatever the sound and no matter how faint the sound, you have to press the button (or raise your finger) as soon as you think you hear it, and release it (or lower it) as soon as you think it stops.

Tinnitus Matching: Tinnitus Matching is an audiometric process to determine the intensity and pitch that best matches your tinnitus. o Pitch Match: You will be asked to describe what the tinnitus sounds like.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 11 of 18

11 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

We will explain to you and with examples from the audiometer- what we mean by pitch. You will be presented with several tones, one at a time through the earphone. You will need to indicate whether each sound is “higher” or “lower” or “the same” in pitch than your tinnitus. This will be repeated until you respond, but you will have time between each tone to listen to your tinnitus. o Intensity Matching: We will keep increasing the loudness of the tone, until it matches the intensity of your tinnitus. It will be performed on both ears, starting with the most troublesome first.

Otological Screen: Physical examination of the ear canal with a small torch specifically designed to look into the ear canal. There are no foreseeable problems.

Questionnaires / Scoring Systems: The following questionnaires you will need to fill in yourself: • Tinnitus Handicap Inventory (THI) • A questionnaire to check if you have any symptoms of depression (Quick Inventory of Depressive Symptomatology (QIDS-SR 16)) • Hospital and Anxiety Depression Scale, HADS (a questionnaire on your mood and feelings) • A questionnaire to measure how well you sleep (Leeds Sleep Evaluation Questionnaire (LSEQ) • Visual Analogue Scale (VAS) of anxiety/arousal – this employs a four point scale with which you rate your level of anxiety (tired-energetic, active-drowsy, tense-peaceful, worried-relaxed) • Visual Analogue Scale (VAS) of tinnitus, likewise employs a sliding scale to measure intensity, pitch and distress associated with tinnitus

The following questionnaires will be completed with study personnel: • Annoyance of Tinnitus • Annoyance of Hyperacusis (sensitivity to noise)

Screening for hepatitisand drugs: Inclusion of volunteers in a clinical study who are not completely well could increase the risk involved as the study drug could cause further damage their health. Therefore, for your own safety, your blood will be checked during the selection procedure for hepatitis B and C. If you were to take part in this study whilst infected with one of these viruses, the risks involved could be increased. During the screening visit, your urine will be tested for drugs (cocaine, morphine, amphetamines, cannabis etc.). For this purpose, you will be required to provide a sample of your urine, which has

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 12 of 18

12 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254 been produced in the study centre, prior to commencement of the donations. If this test is positive you will not be able to continue in the study. The results of the test will be discussed with you privately, and will be kept confidential.

11. WHAT ARE THE POSSIBLE BENEFITS OF TAKING PART? It is possible that you may receive some clinical improvement in your tinnitus whilst taking part during the study, but it is unlikely that any improvement would last beyond the end of the study. This is an experimental study and we do not know whether your symptoms of tinnitus will improve at all. However, the information we collect during this study could be useful in supporting the development of the study drug and other similar drugs as possible treatments for tinnitus in the future.

12. WHAT HAPPENS WHEN THE RESEARCH STUDY STOPS? Taking part in this study is entirely voluntary and you can withdraw from the study at any time without giving a reason. This will not affect your possible future participation in clinical trials. So long as you continue to take part in the study you must co-operate with the Principal Investigator and/or Co-Investigator(s) and carry out all written and other instructions given in connection with the study.

The investigator or GSK can terminate your participation in the study for any of the following reasons: • If you don't follow the investigator's instructions. • Something serious happens to you, which may require treatment. • The investigator decides it is in the best interest of your health and welfare to discontinue. • There aren't enough subjects in the study. • GSK stops the study for other reasons.

13. WHAT IF THERE IS A PROBLEM? Any complaint about the way you have been dealt with during the study or any possible harm you might suffer will be addressed. Please see Section 2.18 for further details.

14. WILL MY TAKING PART IN THE STUDY BE KEPT CONFIDENTIAL? Yes. All the information about your participation in this study will be kept confidential. The details are included in Section 2.19.

15. CONTACT DETAILS: If you have any questions about the study, you should contact Dr or any other member of the study team at the (Tel:

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 13 of 18

13 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

You will receive a yellow card recording the study reference number, treatment and emergency telephone numbers should you wish to contact a doctor outside normal working hours. You should keep this card with you for the duration of the study. The site security staff will have the telephone number of medical staff should you experience problems outside normal working hours. If you experience an adverse event which you or your family consider is serious or life threatening, dial for an ambulance and do not delay treatment by attempting to contact the Physician in charge of the study.

This completes Section 1 of the Information Sheet. If the information in Section 1 has interested you and you are considering participation, please continue to read the additional information in Section 2 before making any decision.

Section 2: General study information

16. WHAT IF RELEVANT NEW INFORMATION BECOMES AVAILABLE? Sometimes during the course of a research project, new information becomes available about the treatment/drug that is being studied. If this happens, we will tell you about it and discuss whether you want to or should continue in the study. If you decide to continue in the study you will be asked to sign an updated consent form.

17. WHAT WILL HAPPEN IF I DON’T WANT TO CARRY ON WITH THE STUDY? Taking part in this study is entirely voluntary and you can withdraw from the study at any time without giving a reason. If you withdraw from the study, we will destroy all your identifiable samples, but we will need to use the data collected up to your withdrawal.

18. WHAT IF THERE IS A PROBLEM? Complaints: If you have a concern about any aspect of this study, you should ask to speak with the researchers who will do their best to answer your questions. They may be contacted by telephoning the clinical unit on

Harm: If you are injured by medicine or clinical procedure that you would not have been given outside this study, you will be compensated. Your study doctor can give you a copy of the compensation guidelines for this kind of injury.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 14 of 18

14 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

We will provide compensation for any injury caused by taking part in this study in accordance with the Association of the British Pharmaceutical Industry (ABPI) Clinical Trials Compensation Guidelines (1991).

We will pay compensation where the injury probably resulted from: • a drug being tested or administered as part of the trial protocol • any test or procedure you received as part of the trial

Any payment would be without legal commitment.

We would not be bound by these guidelines to pay compensation where • the injury resulted from a drug or procedure outside the trial protocol • the protocol was not followed

19. WILL MY TAKING PART IN THIS STUDY BE KEPT CONFIDENTIAL? Who has access to medical and personal information collected during the study? The opinion of your general practitioner may be sought regarding your suitability, and they will be informed that you are participating in the study. You should not be taking part in other drug studies.

If you decide to participate in the study, the study doctor and staff will collect medical and personal information about you as part of doing the study. People who work for or with GSK, and others like the independent ethics committee or the institutional review board (IEC/IRB) for the study or regulatory authorities responsible for approving medicines, will have access to this information at the site in order to check that the study is done properly. GSK staff who see this information at the site will keep it confidential.

The study site will also transfer to other parts of GSK some of the information it collects, in a coded form. The information transferred will not include your name, initials, address, or other direct identifiers. It will be assigned a code number that only the site can connect back to your name. Your permission to the study doctor and staff to use this information or share it with GSK and others as described below for the study doesn’t automatically end at a particular time.

Medical information about you may be produced as part of the research or study procedures. If at the time of the study, this information is known to be relevant to your medical care it will be given to the study doctor who will be encouraged to share it with you or your doctor. While you are in the study, the study site will not share with you certain new medical information about you that is created as part of the study (such as whether or not you are getting study drug, or the results of certain tests) unless the study doctor decides it is medically important to do so. This is done to stop the study results from being distorted. Once the study is over, you will be given access to medical information about you that you are entitled to see. You will be told if any of this medical information requires confirmation using a clinical test. This is important because

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 15 of 18

15 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254 some research results are for research purposes and may have only limited relevance for clinical diagnosis or treatment. At any time, you may ask your study doctor to let you see your personal information, e.g. name and address and to correct it if necessary.

What will the other parts of GlaxoSmithKline do with the information it gets? GSK may use the information that the study doctor gives it (i.e. the coded information): • By storing and analyzing it electronically to find out what this study is telling us • By sharing it with regulatory authorities that approve new medicines, or with groups that check that research is done properly • By publishing the results of the study (this will not include any information that directly identifies you) • By sharing it as part of research with other companies or universities for the purpose of further understanding or developing this drug and with other GlaxoSmithKline offices in this country and in other countries (including those outside the European Union). If the information is sent to another country, GSK will apply the same level of protection to your information, to the extent permitted by local law • By using it to plan new studies or other types of research or other medical purposes related to the development of the drug or class of drug.

20. WHAT WILL HAPPEN TO ANY SAMPLES I GIVE? As part of the study, blood and urine samples will be collected to establish whether you are eligible for the study, to monitor your condition and to measure study drug levels.

The samples will be ‘double-coded’ which means that the samples will be labelled with a number that can be linked to your volunteer panel number. The link between the sample’s number and your volunteer number will be kept by the GSK clinical unit. Collected samples may be transferred to GSK or other researchers working with GSK. Blood and urine samples will be kept until all blood and urine markers have been looked at and the study database finalised. Thereafter, the samples will be destroyed.

21. WILL ANY GENETIC TESTS BE DONE? We would like to take blood samples for genetic research, but this will be discussed with you at a later date and will involve a separate consent form. There is no obligation for you to agree to give samples for genetic research in order to take part in this study.

22. WHAT WILL HAPPEN TO THE RESULTS OF THE RESEARCH STUDY? In the future, the results of this study will be reported in an internal study report accessed only by the sponsor and government regulatory authorities. Data may also be published in scientific journals or presented at scientific meetings. In either case you will only be identified by your subject number.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 16 of 18

16 CONFIDENTIAL HM2009/00361/00 NKP106254

GlaxoSmithKline CONFIDENTIAL NKP106254

23. WHO IS ORGANISING AND FUNDING THE RESEARCH? The study is organised and funded by GlaxoSmithKline. This study will be conducted at the

UK. Some parts of the study will be conducted at the or at (depending on the consultant who referred you to the study); and at the

The staff working at the are employees paid by GSK and GSK owns the The staff working in the are employees paid by the and in the are employees of the

24. WHO HAS REVIEWED THE STUDY? The Research Ethics Committee is an independent body, which reviews all proposed studies in healthy volunteers on a regular basis. Its objective is to safeguard the interests of the volunteers.

This study was reviewed and given a favourable ethical opinion by the

25. CONFIDENTIAL INFORMATION The information and the materials that are given to you in relation to the study are confidential information belonging to GlaxoSmithKline and should be kept private. You can discuss this information in confidence with your doctor or friends and family to decide about taking part in this study and talking about your healthcare.

NKP106254 Participant Information Sheet Version 03 25 April 2008 Page 17 of 18

17 CONFIDENTIAL HM2009/00361/00 NKP106254

18 CONFIDENTIAL HM2009/00361/00 NKP106254

19 CONFIDENTIAL HM2009/00361/00 NKP106254

20 CONFIDENTIAL HM2009/00361/00 NKP106254

21 CONFIDENTIAL HM2009/00361/00 NKP106254

22 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

Informed Consent Form and Information Sheet for Pharmacogenetic Research

GlaxoSmithKline Protocol Title:

A randomised, double-blind, placebo controlled, cross-over study comparing the effects of both single dose and repeated dosing treatment for 14 days of vestipitant or vestipitant / paroxetine combination in an enriched population of subjects with tinnitus & hearing loss

GlaxoSmithKline Protocol Number: NKP106254

Study Doctor: Dr Site Address:

Site Phone Number:

Subject Number: ______

This form is in addition to the consent form you signed for the clinical study for NKP106254.

Purpose and Description of the Research The purpose of this consent form is to explain what pharmacogenetic research is and to ask you to give a blood sample that may be used in this research. The sponsor of the research is the GlaxoSmithKline group of companies [referred to as GSK in this consent]. The study doctor and institution are paid by GSK to conduct this research. This study may include up to 24 subjects at one site.

What is pharmacogenetic research? Genes, which we inherit from our parents, may control the way we react to or handle a medicine. Pharmacogenetics is the study of differences in how our bodies respond to or handle medicines. This pharmacogenetic research is looking at genetic differences to better understand why people react differently when they get the same medicine. If it appears that there is a difference in the way people respond to or handle GW597599 (vestipitant) or BRL-029060 (paroxetine), GSK may study these differences using your genes or genetic material taken from your blood sample.

What are the benefits of participating in this research study? You may help scientists understand why people react to or handle GW597599 or BRL-029060 differently. This may help identify who is more likely to respond to GW597599 or BRL-029060 and who may experience side effects.

What exactly will participation in the research involve?

11 August 2006 Subject Initials ______PGx Information and Consent Form Version 01 Page 1 of 4

23 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

If you choose to take part in this research, a qualified medical worker will take about 10 ml (or 2 teaspoons) of your blood. In the unlikely case that there is a problem processing your sample, then we may ask you to give a second sample.

Is participation in this study voluntary? Participation in this pharmacogenetic research is voluntary. You may decline to take part now or you may decide to take part and then change your mind. GSK may store your sample for up to 15 years after the last subject completes the study or GSK may destroy your sample at an earlier time. If you decide not to participate or to withdraw your consent after starting the study, you do not have to give a reason and there will be no change to your medical treatment or to your participation in the NKP106254 study. If you withdraw from this research, your sample will be destroyed and GSK will only keep and study information collected/generated up to that point.

In special cases, your sample may not be used. This might happen if there are not enough subjects, if the study is stopped for other reasons, or if no questions are raised about how people respond to or handle GW597599 or BRL-029060.

What are the risks involved with blood sampling? The physical risks of giving a blood sample are the same as those for any blood sample taken from a vein. You may feel faint, experience mild pain, bruising, irritation or redness at the site of puncture. In rare cases an infection could develop.

What other options are there? You have the choice not to take part in this research.

How are privacy, data protection and confidentiality protected? To protect your privacy, your sample and medical information will be labeled (or “coded”) with a study subject number, not your name. Only your study doctor and his or her staff will keep the link between your subject number and your name.

Your study doctor has been told to keep your pharmacogenetic information including your consent in a separate, secure file, which is not part of your medical records. GSK will control access to its files that hold your coded information and results. Your name will not appear in any publications or reports about this research.

GSK or those working with GSK (for example, other researchers) will only work with your sample for the use stated in this consent. Samples will be stored securely. GSK will require anyone who works with your sample to agree to hold the research information and any individual results in confidence.

If your sample is studied, your individual results will only be shared with you through the study doctor if you request in writing to see the results and it is a requirement of a governmental agency or other legal authority that GSK make these results available. GSK will not release individual results to anyone else (e.g., family members, primary care physicians, insurers, or employers) under any circumstance, unless required by law. Your results are not for clinical diagnosis or treatment. The information generated is for scientific purposes.

11 August 2006 Subject Initials ______PGx Information and Consent Form Version 01 Page 2 of 4

24 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

GSK has taken appropriate measures to ensure the confidentiality of the research-related information. However, if you pass on your individual results (if obtained by you), there is a possibility that this could have an effect on your insurance or employment. This risk is similar as if you were to disclose any type of personal medical information to a third party.

Medical information, samples and research results from you and other research participants may be studied by GSK to make medicines or tests to determine the body’s response to or handling of medicine. Your information and any results will be put in a computer and stored in electronic databases. International regulations for information on computers and relevant laws on processing personal information will be strictly adhered to. Your information, sample, and results could be sent to other researchers working with GSK and to other GSK sites.

By agreeing to take part in this research, you will allow your medical information, sample, and pharmacogenetic results to be reviewed as part of collecting and analyzing study results. The people who may check this research include GSK, people working with GSK on this research, ethics committees, and regulatory authorities such as the European Medicines Agency (EMEA). These persons are required to maintain the confidentiality of the information.

Will there be compensation for participation in the research? You will not receive any payment for taking part in this pharmacogenetic research.

Commercial Issues GSK and/or others intend to claim sole ownership of any research results consistent with this consent. The results of this research may have commercial or intellectual property value. By signing this consent, you agree that GSK can apply for patents and you understand that you will not receive any financial benefit that might come from the research.

Who can you call for more information about this research study? You may contact Dr at telephone number at any time if you have questions about this study, an injury related to the blood draw for this research, or wish to withdraw from this research.

11 August 2006 Subject Initials ______PGx Information and Consent Form Version 01 Page 3 of 4

25 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

CONSENT A copy of this Consent Form (signed and dated) must be given to the subject or legal representative.

My signature below indicates that: 1. I have read this form and the research has been explained to me. 2. I have been able to discuss the research and ask questions. I am satisfied with the answers. 3. I have been given the time to consider whether or not to take part in this research. 4. I have freely decided to take part in the research study described in this form.

Subject’s Name (Please Print): ______

Subject’s Signature: ______Date: ______(Day/Month/Year)

Name and Signature of Individual Obtaining the Subject’s Consent:

Name (Please Print): ______

Signature: ______Date: ______(Day/Month/Year)

11 August 2006 Subject Initials ______PGx Information and Consent Form Version 01 Page 4 of 4

26 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

Informed Consent Form and Information Sheet for Pharmacogenetic Research

GlaxoSmithKline Protocol Title:

GlaxoSmithKline Protocol Number: NKP106254

Study Doctor: Dr Site Address:

Site Phone Number:

Subject Number: ______

This form is in addition to the consent form you signed for the clinical study for NKP106254.

What exactly will participation in the research involve?

10 July 2007 Subject Initials ______PGx Information and Consent Form Version 02 Page 1 of 4

27 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

What other options are there? You have the choice not to take part in this research.

10 July 2007 Subject Initials ______PGx Information and Consent Form Version 02 Page 2 of 4

28 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

Will there be compensation for participation in the research? You will not receive any payment for taking part in this pharmacogenetic research.

CONSENT A copy of this Consent Form (signed and dated) must be given to the subject or legal

10 July 2007 Subject Initials ______PGx Information and Consent Form Version 02 Page 3 of 4

29 CONFIDENTIAL HM2009/00361/00 NKP106254

Protocol: NKP106254

representative.

Subject’s Name (Please Print): ______

Subject’s Signature: ______Date: ______(Day/Month/Year)

Name and Signature of Individual Obtaining the Subject’s Consent:

Name (Please Print): ______

Signature: ______Date: ______(Day/Month/Year)

10 July 2007 Subject Initials ______PGx Information and Consent Form Version 02 Page 4 of 4

30 CONFIDENTIAL HM2009/00361/00 NKP106254

1 CONFIDENTIAL HM2009/00361/00 NKP106254

2 CONFIDENTIAL HM2009/00361/00 NKP106254

3 CONFIDENTIAL HM2009/00361/00 NKP106254

4 CONFIDENTIAL HM2009/00361/00 NKP106254

ICH Data Listings

Page Listing - ICH 1 Listing of Demographic Characteristics (All subjects Population) ...... 3 Listing - ICH 2 Listing of Subjects with Inclusion/Exclusion Criteria Deviations (All subjects Population) ...... 5 Listing - ICH 3 Listing of Reason for Withdrawal (All subjects Population) . . . 6 Listing - ICH 4 Listing of Concomitant Medication By Generic Term (All subjects Population) ...... 7 Listing - ICH 5 Listing of Subjects for whom Treatment Blind was Broken (All subjects Population) ...... 34 Listing - ICH 6 Listing of Actual and Planned Treatment (All subjects Population) ...... 35 Listing - ICH 7 Listing of Exposure Data (All subjects Population) ...... 38 Listing - ICH 8 Listing of Subject Numbers for Individual Adverse Events (All subjects Population) ...... 142 Listing - ICH 9 Listing of All Adverse Events (All subjects Population) ...... 153 Listing - ICH 10 Listing of Serious Adverse Events (All subjects Population) . 255 Listing - ICH 11 Listing of Adverse Events leading to Withdrawal (All subjects Population) ...... 256 Listing - ICH 12 Listing of Haematology Abnormalities of Potential Clinical Importance (All subjects Population)...... 258 Listing - ICH 13 Listing of All Haematology Laboratory Data for Subjects with PCI Abnormalities (All subjects Population) ...... 259 Listing - ICH 14 Listing of Chemistry Abnormalities of Potential Clinical Importance (All subjects Population)...... 283 Listing - ICH 15 Listing of All Clinical Chemistry Laboratory Data for Subjects with PCI Abnormalities (All subjects Population) ...... 286 Listing - ICH 16 Listing of Abnormal ECG findings (All subjects Population) . 429 Listing - ICH 17 Listing of ECG values of PCI (All subjects Population) . . . . . 433 Listing - ICH 18 Listing of all ECG values for subjects with any value of PCI (All subjects Population) ...... 444

1 CONFIDENTIAL HM2009/00361/00 NKP106254

Listing - ICH 19 Listing of Vital Signs of PCI (All subjects Population) ...... 469 Listing - ICH 20 Listing of all Vital Signs for subjects with any value of PCI (All subjects Population) ...... 474

2 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. CONFIDENTIAL HM2009/00361/00 NKP106254

Other Data Listings

Page Listing - Other 1 Relationship between System Organ Class and Verbatim Text (All subjects Population) ...... 2 Listing - Other 2 Listing of Plasma Vestipitant Pharmacokinetic Concentration-Time Data (PK Population) ...... 13 Listing - Other 3 Listing of Plasma Paroxetine Pharmacokinetic Concentration-Time Data (PK Population) ...... 37

1 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clinical Study Register. CONFIDENTIAL HM2009/00361/00 NKP106254

1 CONFIDENTIAL HM2009/00361/00 NKP106254

2 CONFIDENTIAL HM2009/00361/00 NKP106254

3 CONFIDENTIAL HM2009/00361/00 NKP106254

4 CONFIDENTIAL HM2009/00361/00 NKP106254

5 CONFIDENTIAL HM2009/00361/00 NKP106254

6 CONFIDENTIAL HM2009/00361/00 NKP106254

7 CONFIDENTIAL HM2009/00361/00 NKP106254

8 CONFIDENTIAL HM2009/00361/00 NKP106254

9 CONFIDENTIAL HM2009/00361/00 NKP106254

10 CONFIDENTIAL HM2009/00361/00 NKP106254

11 CONFIDENTIAL HM2009/00361/00 NKP106254

12 CONFIDENTIAL HM2009/00361/00 NKP106254

13 CONFIDENTIAL HM2009/00361/00 NKP106254

14 CONFIDENTIAL HM2009/00361/00 NKP106254

15 CONFIDENTIAL HM2009/00361/00 NKP106254

16 CONFIDENTIAL HM2009/00361/00 NKP106254

17 CONFIDENTIAL HM2009/00361/00 NKP106254

18 CONFIDENTIAL HM2009/00361/00 NKP106254

19 CONFIDENTIAL HM2009/00361/00 NKP106254

1 CONFIDENTIAL HM2009/00361/00 NKP106254

2 CONFIDENTIAL HM2009/00361/00 NKP106254 CONFIDENTIAL NKP106254

Supporting information for foreign clinical study, NKP106254, not conducted under an IND

1. Institutional Ethics Committee (IEC): • This study was approved by a national, regional or investigational centre ethics committee or institutional review board meeting the definition in 21 CFR 312.3(b). • The name and address of the IEC that reviewed the study are provided in modular appendices. • Approval letters from the IEC are also attached in the modular appendices for NKP106254.

2. Description of Research Facilities: • A description of the research facilities is provided in modular appendices for NKP106254.

3. Informed Consent: • Prior to the initiation of the study, investigators obtained written approval of the informed consent document from the IEC. Either the investigator or the investigator’s designee obtained the consent of the study subject. The subject was provided as much time as necessary to review the document, to inquire about details of the trial, and to decide whether or not to participate in the study. The informed consent was signed and dated by the study subject and by the person who conducted the informed consent discussion. • The sample consent form is attached in the modular appendices for NKP106254.

4. Study Conduct: • The investigator attended an initiation meeting conducted by GSK. This was face to face and also attended by the GSK medical monitor, study monitor and site staff. The aims of this meeting was to ensure compliance of the investigators and other site staff on the protocol procedures and GCP. • The investigators signed the protocol and protocol amendments, which stated their intent to comply with GCP and the protocol in the following Section entitled Study Conduct Considerations:

Regulatory and Ethical Considerations, Including the Informed Consent Process: The study will be conducted in accordance with all applicable regulatory requirements. The study will also be conducted in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the Declaration of Helsinki. This includes, but is not limited to, the following: • IRB/IEC review and favorable opinion/approval to conduct the study and of any subsequent relevant amended documents • Subject informed consent • Investigator reporting requirements GSK will provide full details of the above either verbally, in writing or both.

1 1 CONFIDENTIAL HM2009/00361/00 NKP106254 CONFIDENTIAL NKP106254

Written informed consent will be obtained for each subject before he or she can participate in the study.

• Monitoring was conducted as specified in section 5.18 of ICH E6 to ensure quality control. This is stated in the protocol (Section 13.2 - Quality Control (Study Monitoring)): In accordance with applicable regulations, GCP, and GSK procedures, GSK monitors will contact the site prior to the start of the study to review with the site staff the protocol, study requirements, and their responsibilities to satisfy regulatory, ethical, and GSK requirements. When reviewing data collection procedures, the discussion will also include identification, agreement and documentation of data items for which the CRF will serve as the source document. GSK will monitor the study consistent with the demands of the study and site activity to verify that the: Data are authentic, accurate, and complete. Safety and rights of subjects are being protected. Study is conducted in accordance with the currently approved protocol and any other study agreements, GCP, and all applicable regulatory requirements. The investigator and the head of the medical institution (where applicable) agrees to allow the monitor direct access to all relevant documents

5. Description of Drug Substance and Drug Product: • The certificate of analysis is attached in the modular appendices for NKP106254.

2 2