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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 Two subjects were withdrawn due to AEs.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. Copyright 2009 the GlaxoSmithKline group of companies. All rights reserved. Unauthorized copying or use of this information is prohibited - 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 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 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:
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