BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0
PASS Study Information
Title A 5-year multi-center, observational post-authorization safety study to document the utilisation of Wakix® in the treatment of narcolepsy with or without cataplexy and to collect information on its long-term safety when used in routine medical practice Protocol version identifier Version 2.0
Date of last version of protocol June 21, 2016
EU PAS register number ENCEPP/SDPP/13818 Active substance Pitolisant - ACT code: N07XX11 Medicinal product Wakix® Product reference EU/1/15/1068/001 EU/1/15/1068/002 Procedure number EMA/H/C/002616 Marketing Authorisation Holder BIOPROJET Pharma 9 rue Rameau 75002 Paris - France Ph: +33 (0)1 47 03 66 33 - Fax: +33 (0)1 47 03 66 30 Joint PASS No Research question and objectives To collect information on the long-term safety of Wakix® when used in a real-life setting; To document the drug utilisation patterns of Wakix® in routine medical practice. Country(-ies) of study France; UK; Italy; Germany Author Dr Isabelle Lecomte Bioprojet Pharma 9 rue Rameau 75002 Paris - France Tel: +33 1 47 03 66 38 - Email: [email protected]
Marketing authorisation holder(s)
Marketing Authorisation Holder BIOPROJET Pharma (sponsor) 9 rue Rameau 75002 Paris - France MAH Contact person Pascale Vernade Bioprojet Pharma 9 rue Rameau – 75002 Paris – France Tel: +33 1 47 03 66 52 Email: [email protected]
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 Signature’s Page
PROTOCOL P15-11 - ENCEPP/SDPP/13818 / WAKIX® VERSION 2.0 “PASS”
A 5-YEAR MULTI-CENTER, OBSERVATIONAL POST-AUTHORIZATION SAFETY STUDY TO DOCUMENT THE UTILIZATION OF WAKIX® IN THE TREATMENT OF NARCOLEPSY WITH AND WITHOUT CATAPLEXY AND TO COLLECT INFORMATION ON ITS LONG-TERM SAFETY WHEN USED IN ROUTINE MEDICAL PRACTICE
The study will be conducted in compliance with the following protocol and will be carried in accordance with The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Guide on Methodological Standards in Pharmacoepidemiology (Revision 4). EMA/95098/2010 and local applicable regulatory requirements in the participating countries.
I give my complete agreement on this protocol which gives all necessary information to conduct this study. I hereby accept to coordinate this study:
The Coordinator Date: ______
Medical expert Signature: ______
The Sponsor Dr Jeanne-Marie Lecomte Date: ______Bioprojet Responsible Pharmacist Signature: ______
Medical Project Manager Dr Isabelle Lecomte Date: ______Bioprojet Signature: ______
Qualified Person for Pharmacovigilance Dr Yves Joulin Date: ______Bioprojet Signature: ______
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 Signature’s Page
PROTOCOL P15-11 ENCEPP/SDPP/13818 / WAKIX®
WAKIX® POST AUTHORIZATION SAFETY STUDY (PASS)
A 5-YEAR MULTI-CENTER, OBSERVATIONAL POST-AUTHORIZATION SAFETY STUDY TO DOCUMENT THE TILISATION OF WAKIX® IN THE TREATMENT OF NARCOLEPSY WITH AND WITHOUT CATAPLEXY AND TO COLLECT INFORMATION ON ITS LONG-TERM SAFETY WHEN USED IN ROUTINE MEDICAL PRACTICE
The signature below constitutes the approval of this P15-11 PASS Protocol and the attachments, and provides the necessary assurances that this trial will be conducted according all stipulations of the protocol, including all the statements regarding confidentiality, and according to local legal and The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Guide on Methodological Standards in Pharmacoepidemiology (Revision 4). EMA/95098/2010
The site Investigator:
Name: …………………………………………………………………………
Hospital: ………………………………………………………………………
Address: ………………………………………………………………………
……………………………………………………………………..
Date: ______Signature:______
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1 TABLE OF CONTENTS
Signature’s Page ...... 3
1 TABLE OF CONTENTS ...... 4
2 LIST OF ABBREVIATIONS ...... 7
3 RESPONSIBLE PARTIES ...... 8
4 ABSTRACT - PROTOCOL P 15-11/ WAKIX® POST AUTHORIZATION SAFETY STUDY (PASS) ...... 9
5 Amendments and updates ...... 12
6 Milestones ...... 12
7 RATIONALE AND BACKGROUND ...... 13
7.1 Narcolepsy ...... 13
7.2 Pitolisant (Wakix®) ...... 14
7.3 Rational for the Post Marketing Safety Study with Pitolisant ...... 16
8 RESEARCH QUESTION AND OBJECTIVES ...... 17
9 RESEARCH METHODS...... 18
9.1 Study design ...... 18
9.1.1 General design ...... 18
9.1.2 Endpoints ...... 19
9.2 Setting ...... 21
9.2.1 Selection criteria: ...... 21
9.2.2 Study visits ...... 22
V1 – Baseline- Start of a treatment with Wakix® and inclusion of the patient in the study ...... 22
Follow-up visits: at least yearly interim visits (V2, V3, V4, V5 …) ...... 23
End of Study Visit (EOS) (V6) after 5 years or in case of Wakix® permanently stop ...... 24
9.3 Variables ...... 24
9.4 Data sources ...... 26 9.5 Study size ...... 26
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9.6 Data management ...... 28
9.6.1 Identification of any data to be recorded in the CRF and to be considered as source data .. 28
9.6.2 Data Handling and Record keeping ...... 28
9.7 Data analysis ...... 30
9.7.1 Statistical Methods ...... 30
9.7.2 Primary Endpoints ...... 31
9.7.3 Secondary endpoints ...... 31
9.7.4 Covariates ...... 32
9.7.5 External References ...... 32
9.7.6 Report ...... 33
9.8 Quality control ...... 33
QUALITY CONTROL AND AUDIT ...... 34
9.9 Limitations of the research methods ...... 34
9.10 Other aspect: Confidentiality of study source documents ...... 34
10 PROTECTION OF HUMAN SUBJECTS ...... 36
10.1 PRAC/ Ethical, Regulatory and Other Local Approval ...... 36
10.2 Emergency Actions ...... 36
10.3 Patient Informed Consent Procedure ...... 37
10.4 Data Protection ...... 37
10.5 Amending the Protocol ...... 38
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS ...... 40
11.1 DEFINITIONS ...... 40
11.2. Procedures for recording, analysing and reporting adverse events ...... 43
11.2.1 Monitoring and recording of adverse events ...... 43
11.2.2 Assessment of adverse events ...... 43
11.2.3 Reporting Serious Adverse Event or Serious Adverse Drug Reaction ...... 44
11.3. Continuous analysis and reporting ...... 45
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS ...... 47
13. REFERENCES ...... 48
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14. ANNEXES ...... 49
ANNEX I. SUMMARY OF PRODUCT CHARACTERISTICS ...... 49
Annex 2 _ ENCePP checklist for study protocol ...... 66
Annex 3 _ Consent Form ...... 67
Annex 4 – Participant Information Sheet ...... 68
Annex 5 – Case Report Form ...... 71
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2 LIST OF ABBREVIATIONS
5-HT Serotonin or 5-hydroxytryptamine AASM American Academy of Sleep Medicine ADHD Attention Deficit Hyperactivity Disorder ADR Adverse Drug Reaction AEs Adverse events BDI Beck Depression Inventory BRB Benefit-Risk Balance CCTIRS Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé CGI Clinical Global Impression CHMP Committee for Medicinal Products for Human Use CI Confidence interval CNIL Commission Nationale de l’Informatique et des Libertés CNS Central nervous system CRF Case report form CRO Contract Research Organisation CSF CerebroSpinal Fluid ECG Electrocardiogram EDS Excessive Daytime Sleepiness EMA European Medicine Agency EQ5D EuroQol 5 Dimensions questionnaire ESS Epworth Sleepiness Scale EURMP Committee for Medicinal Products for Human Use FOSQ-10 Functional Outcomes of Sleep Questionnaire GPP Guidelines for good pharmacoepidemiology practices GEP Guidelines for Good Epidemiologic Practice GVP Guideline on good pharmacovigilance Practices H3R Histamine H3 receptor ICH International conference on harmonization of technical requirements for registration of pharmaceuticals for human use ICSD International Classification of Sleep Disorders ICSR Individual Case Safety Report IEC Independent Ethics Committee IRB Institutional Review Board
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MAH Marketing Authorization Holder MedDRA Medical Dictionary for Regulatory Activity MSLT Multiple Sleep Latency Test MWT Maintenance of Wakefulness Test NSAQ Narcolepsy Symptoms Assessment Questionnaire OSA Obstructive Sleep Apnea PASS Post-Authorization Safety Study PRAC Pharmacovigilance Risk Assessment Committee RMM Repeated-Mixture-Models SADR Serious Adverse Drug Reaction SAP Statistical Analysis Plan SmPC Summary of Product Characteristics SOC System Organ Class SOREMPs Sleep-Onset Rapid Eye Movement Periods
3 RESPONSIBLE PARTIES
Protocol writer: Dr. Isabelle Lecomte (Bioprojet, Medical Director)
Other responsible parties:
Dr Catherine Scart-Gres (Head of Clinical Development)
Dr Yves Joulin (EQPPV)
Céline Baudouin (Quality Assurance Manager)
Pascale Vernade (Regulatory Affairs Manager)
Dr Stéphane Schück (Scientific Director, Kappa Santé)
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4 ABSTRACT - PROTOCOL P 15-11/ WAKIX® POST AUTHORIZATION SAFETY STUDY (PASS)
A 5-year multi-center, observational post-authorization safety study to document the drug utilisation of Wakix® in the treatment of narcolepsy with or without cataplexy and to collect Title information on its long-term safety when used in routine medical practice
Wakix® (pitolisant) is the first product of a new pharmacological class; it is the first histamine H3 receptor (H3R) antagonist/reverse agonist. Wakix® was shown effective in the treatment of patients with narcolepsy with or without cataplexy, by reducing symptoms including excessive daytime sleepiness (EDS) and cataplexy attacks. The Marketing Authorization was granted to Wakix® by the EMA/CHMP for all European countries on March 31st 2016 for the indication “treatment of narcolepsy with or without cataplexy”.
Narcolepsy is a chronic condition. To date, the clinical studies did not identify major safety Rationale and concerns with pitolisant but data on the long-term safety and efficacy of pitolisant are limited. background The CHMP requested the MAH to carry out a long-term multi-center, observational PASS to document the drug of Wakix® and to collect information on its long-term safety when used in routine medical practice.
This prospective non interventional study is being conducted pursuant to an EMA requirement in accordance with REG Art 10 and Art 10a and with DIR Art 21a and Art 22a in the framework of the application for a centralized marketing authorization for Wakix®.
Primary Objectives To collect information on the long-term safety of pitolisant Wakix® (all reported adverse events) when used in a real-life setting; To document the drug utilisation patterns of Wakix® in routine medical practice (patients’ characteristics, narcolepsy history, previous treatments, Wakix® initiation and changes, concomitant treatment).
Research Secondary objectives questions and ® objectives To assess the clinical benefit of a treatment with pitolisant (Wakix ) in a real-life setting (ESS, CGI for EDS severity, CGI for cataplexy severity, BDI) according to the physician; To assess the health care resource use (hospitalizations, emergency visits) due to narcolepsy in patients receiving pitolisant (Wakix®) throughout the course of the study; To measure the treatment compliance in patients receiving pitolisant (Wakix®) throughout the course of the study (Morisky scale); To measure quality of life (EQ5D) and disease burden (FOSQ-10) in patients receiving pitolisant (Wakix®) throughout the course of the study (work absenteeism, ability for daily
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tasks); To assess narcolepsy symptoms (by using the Narcolepsy Symptoms Assessment Questionnaire NSAQ) and satisfaction to their treatment (visual analogic scales) in patients receiving pitolisant (Wakix®) throughout the course of the study.
International, multi-center, non-interventional, prospective, open-label long-term post- authorization safety study (PASS).
The assignment of the patient to a particular therapeutic strategy will be decided within current clinical practice and the decision to prescribe pitolisant will necessarily precede and will be independent of the decision to enroll the patient into the study. The product will be prescribed and used based on the routine clinical practice as well as on the individual situation of each patient and according to the approved SmPC.
The patients will be observed during routine clinical practice. Study is planned to follow up Design patients for five years or to the end of the study. Patients will be recruited in the 4 countries where Wakix® will be first launched (i.e. France, Germany, Italy and UK), by around 8 to 10 sites in each. If the number of patients is not sufficient, back-up countries (Spain and Netherlands) may be added when Wakix® will be available on their market. Investigators will be sleep specialists mainly in charge of patients diagnosed with narcolepsy.
Primary endpoint: The proportion of patients with Adverse Event (AE) reported by the investigator during the treatment with Wakix® (defined as the period from the first dose of Wakix® to the study end visit or to the discontinuation of Wakix®).
Inclusion criteria
1. Patient being prescribed Wakix® according to the SmPC for treatment initiation; 2. Patient providing informed consent. Wakix® shall be prescribed according to the SmPC and treatment guidelines to patients diagnosed with narcolepsy with or without cataplexy. Pitolisant therapy should not be prescribed for the purpose of inclusion to this PASS, but solely for the clinical therapeutic indication. The decision to prescribe Wakix® will necessarily precede and will be independent of the decision to enroll the patient into the study. Population
Non-inclusion criteria
1- Patients with a contraindication to Wakix® as identified in the SmPC: - Hypersensitivity to the active substance or to any of the excipients, - Severe hepatic insufficiency (Child-Pugh C), - Breastfeeding.
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2- Patients already treated with pitolisant, i.e. who received pitolisant during the 12 months preceding the inclusion. Studies in animals have shown teratogenicity. In accordance with the SmPC v 31 march 2016, (annex 1), women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation. Pitolisant may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives.
No data are available in the paediatric population.
Patients demographics: age and gender Variables Medical History: narcolepsy diagnosis history, date of diagnosis, symptoms (severity and duration), previous treatments of EDS and cataplexy Comorbidities: including cardiovascular, renal and hepatic impairments Pitolisant initiation: indication for use, daily dose, titration pattern Vital signs: heart rate and blood pressure, weight and height Adverse Events (including overdosage, misuse, lack of efficacy) Epworth Sleepiness Scale (ESS)* Clinical Global Impression (CGI) for Excessive Daytime Sleepiness (EDS) severity and cataplexy severity Beck Depression Inventory 13 items (BDI)
Pitolisant administration: dose adjustment and reason for dose change
Pitolisant discontinuation and reason for discontinuation, therapeutic choice post-pitolisant Concomitant medications for narcolepsy: name, dose, date of start and discontinuation, changes in dosage, in particular antidepressant, psycho-stimulant and anti-cataplectic co-medications Number of emergency visits or hospital admissions due to narcolepsy over the last 12 months (V0) then since the last visit (Follow up visits) Patient self-assessment of the treatment compliance with 8-item Morisky scale (MMAS-8)
Patient self-assessment of the quality of life with EQ5D
Patient self-assessment of the disease burden with FOSQ10
Patient self-assessment of the narcolepsy symptoms with NSAQ
Patient self-assessment of the satisfaction with the treatment with Visual Analogic Scale Work absenteeism (presence and number of days) over the last 12 months (inclusion) and since the last visit (Follow up visits)
Data sources Data will be obtained from patients at routine patient visits to investigators. Routinely the current practice is about a minimum of 1 visit per year. Each time an investigator will see a patient for a routine visit he will record the data in the
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patient’s medical file and in a case report form (CRF) designed for the study.
Study size and Expected number of patients being prescribed Wakix® enrolled in the PASS: 300. data analysis In this long-term prospective observational study, the primary endpoint is the occurrence of all reported Adverse Events (AE). The main safety analysis will assess the rate of patients with AE (globally and per type of AE) by descriptive statistics. A descriptive analysis of AEs coded using the current MedDRA dictionary and classified by System Organ Class and Preferred Term, and assessed according the severity, relatedness, seriousness, and AEs leading to treatment discontinuation will be performed.
The drug utilisation analysis will describe the characteristic of the population (age, gender, BMI), the dosages of Wakix® (daily dose prescribed), duration of treatment, and the co- medications. Study milestones Start of data collection Q4 2016 End of data collection Q4 2022 Study progress reports Yearly Interim reports Yearly Final report of study results Q3 2023 Study duration Patients inclusion: 12 months Patients follow up: up to 60 months Study duration : 72 months
5 AMENDMENTS AND UPDATES
None
6 MILESTONES
Planned dates for the following milestones:
Start of data collection Q4 2016 End of data collection Q4 2022 Study progress reports frequency Yearly Interim reports Yearly Final report of study results Q3 2023
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7 RATIONALE AND BACKGROUND
7.1 Narcolepsy
Narcolepsy is a rare, chronic neurologic condition, known as an “orphan disease”, which affects the brains’ ability to regulate the normal sleep-wake cycle. Narcolepsy is characterized by excessive daytime sleepiness, manifested by recurrent periods of profound sleep propensity that frequently triggers inadvertent naps or lapses into sleep throughout the day, and cataplexy, sudden episodes of loss of muscle tone triggered by emotions (Scammell, 2015; Barateau, 2016). Nocturnal sleep is usually fragmented and may be associated with sleep paralysis and hypnagogic hallucinations. Other symptoms may include weight gain and obesity, impaired ability for sustained attention, deterioration in school performance and emotional lability.
Although the exact number of patients with narcolepsy is not known with certainty, the prevalence of narcolepsy in European countries varies from 0.02% to 0.05% (Longstreth, 2007; Partinen, 2014; Orphanet Report July 2015). The age of onset varies from early childhood to 50, with a bimodal distribution, including a main peak around the age of 15 and a secondary peak around 36. Even if an increase of the incidence rate of narcolepsy was reported in several countries in Europe following the 2009 H1N1 pandemic, and the vaccination campaign with Pandremix®, particularly in young <18 years old, the prevalence of the disease remains under 0.05%. The pooled incidence rate of narcolepsy for the period 2000-2010 including all periods (i.e. pre-pandemic influenza, pandemic influenza/pre-vaccination, and pandemic influenza/post-vaccination) was assessed for 6 European countries to 0.93 per 100,000 PY (95% CI: 0. 90–0.97) (Wijnans et Al. 2013).
The diagnosis criteria have been defined in the revised International Classification of Sleep Disorders (ICSD- 3, AASM 2014) and separate the narcolepsy with cataplexy (Type 1) and the narcolepsy without cataplexy (Type 2) as presented in Table 1.
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Type 1 = Narcolepsy with cataplexy Type2 =Narcolepsy without cataplexy
A. Excessive Daytime Sleepiness (EDS) occurring almost daily for at least 3 months
B. History of cataplexy, defined as sudden and transient B. Typical cataplexy is not present, although episodes of loss of muscle tone triggered by emotions, is doubtful or atypical cataplexy-like episodes may be present reported
C. 1 Diagnosis confirmed by nocturnal polysomnography followed by an MSLT Mean sleep latency on the MSLT ≤ 8 min,
And 2 or more SOREMPs (sleep-onset rapid eye movement periods) observed following sufficient nocturnal sleep (minimum 6 h) during the night prior to the test. A SOREMP (within 15 min of sleep onset) on the preceding nocturnal PSG may replace one SOREMPs on the MSLT.
C.2 Alternatively, hypocretin-1 levels in the cerebrospinal fluid (CSF) are less than or equal to 110 pg/mL, or one- third of mean normal control values.
D. Diurnal hypersomnia not better explained by another sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder
Table 1 Narcolepsy according to the International Classification of Sleep Disorders (ICSD-3) 7.2 Pitolisant (Wakix®)
Wakix® (pitolisant) is the first product of a new pharmacological class. It is the first histamine H3 receptor (H3R) antagonist/reverse agonist. By blocking H3R receptor, it enhances the histaminergic transmissions in brain and thereby exhibits strong waking effects and improves the level of attention. However no increase in dopamine release in the striatal complex including nucleus accumbens was evidenced for pitolisant. Wakix® is well and rapidly absorbed by oral route. It is extensively metabolized by the CYP450 system into numerous inactive metabolites mainly excreted in urine. Wakix® is bound to around 90% to plasmatic proteins and its apparent volume of distribution is rather large. Wakix® apparent terminal elimination half- life ranges between 10 to 12 hours and is dose independent, suggesting that single administration in the morning at adequate dosage is enough to ensure a full day coverage without high levels at night.
A diversified adult population according to gender, age groups, nature and severity of concomitant diseases was included in Wakix® clinical development program in the treatment of excessive daytime sleepiness (EDS) and cataplexy in patients suffering from narcolepsy with or without cataplexy. The Wakix® clinical program has included five main phase III studies : two pivotal placebo and modafinil controlled
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 randomized double-blind trials assessing the effect on EDS (Dauvilliers, 2013 ; EPAR, 2015); one placebo controlled randomized double-blind trial assessing the effect of Wakix® on cataplexy in narcoleptic patients with high frequency cataplexy; one open label study assessing the safety and efficacy of Wakix® on long- term; and one double-blind randomized placebo controlled study in add-on to sodium oxybate in resistant patients with residual EDS. A total of 576 narcoleptic patients were enrolled in this development program (342 were exposed to pitolisant Wakix®, 98 to modafinil, 136 to placebo). In the pivotal randomized studies, the duration of the double-blind treatment was 7 to 8 weeks while the long-term open label study provided data on a 12-month exposition to Wakix®. In this long-term pragmatic study Wakix® could be prescribed alone or in combination with current CNS psychostimulants (modafinil, methylphenidate) or anti-cataplectic drugs (Xyrem, anti-depressants).
In addition, to date the number of subjects who received pitolisant is larger because of clinical experiences in other indications than narcolepsy that evaluated mainly the effect of pitolisant on the EDS symptom associated with Parkinson disease or obstructive sleep apnea (OSA) in four 12-week phase III randomized placebo controlled studies and 9-month open label extension studies providing data with 9 months to one year of drug exposition. Indeed, some other studies tested this drug in various indications such as epilepsy or in cognition/attention improvement in patients suffering from dementia as well as in ADHD or schizophrenia. Moreover, in France more than 350 patients have received Wakix® in compassionate use program (ATU). Finally, the number of subjects who received Wakix® before its marketing authorisation allowing the assessment of its safety is close to 2000, 1200 were exposed to the drug for at least 6 months and more than 500 for at least a year.
Overall, the proportions of patients presenting at least one adverse event over Wakix® treatment was substantially comparable to those noted in control groups including placebo. This applies also for severe adverse events, serious adverse events or events inducing treatment discontinuation whatever the putative causal relationship. In the SmPC (annex 1), most frequent adverse drug reactions reported with Wakix® were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%), sleep disorders (1.1%), fall (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), fatigue (1.1%), weight increase (0.9%), abdominal pain upper (0.9%). The clinical studies did not identify major safety concerns with pitolisant. Though, limited data are available regarding long-term safety of the treatment. Remaining uncertainties have been identified and described in the Risk Management Plan of the product in particular long-term effects on depression, weight and ulcer formation, and potential of abuse/misuse and diversion
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No specific safety concern was identified in the 12-month interim analysis of the long-term study Harmony III (P09-10) neither during the long-term exposition to the drug in other tested indications such as Parkinson’s disease though that the target population is mainly elderly; thus, the impact of uncertainties regarding long-term safety profile in the overall expected benefit-risk balance of pitolisant should be further evaluated.
7.3 Rational for the Post Marketing Safety Study with Pitolisant
Narcolepsy with or without cataplexy is a chronic condition and to date, there are limited data on the long- term safety and efficacy of pitolisant through the development program of the drug in this orphan indication, even if a larger population was exposed to the drug in other indications. The clinical studies and compassionate program, including over 2000 patients in overall tested indications, did not identify major safety concerns with pitolisant but the CHMP requested the MAH to carry out a long-term, multi-centre, observational post marketing safety study (PASS) to document the drug utilisation of pitolisant in routine medical practice and to collect information on its long-term safety when used in real life setting.
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8 RESEARCH QUESTION AND OBJECTIVES
The objective of this long-term treatment study is to assess the long-term safety of Wakix® administered in real life conditions according to the SmPC in narcoleptic patients with or without cataplexy. This study is part of a European Risk Management Plan (EU RMP) agreed during the marketing authorisation application
®. for Wakix
Primary Objectives
To collect information on the long-term safety of pitolisant Wakix® (all reported adverse events) when used in a real-life setting;
To document the drug utilisation patterns of Wakix® in routine medical practice (patients’ characteristics, narcolepsy history, previous treatments, Wakix® initiation and changes, concomitant treatment).
Secondary objectives
To assess the clinical benefit of a treatment with pitolisant (Wakix®) in a real-life setting (ESS, CGI for EDS severity, CGI for cataplexy severity, BDI) according to the physician;
To assess the health care resource use (hospitalizations, emergency visits) due to narcolepsy in patients receiving pitolisant (Wakix®) throughout the course of the study;
To measure the treatment compliance in patients receiving pitolisant (Wakix®) throughout the course of the study (Morisky scale);
To measure quality of life (EQ5D) and disease burden (FOSQ-10) in patients receiving pitolisant (Wakix®) throughout the course of the study (work absenteeism, ability for daily tasks);
To assess narcolepsy symptoms by using the Narcolepsy Symptoms Assessment Questionnaire (NSAQ) and satisfaction to their treatment (visual analogic scales) in patients receiving pitolisant (Wakix®) throughout the course of the study.
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9 RESEARCH METHODS
9.1 Study design
9.1.1 General design
This will be an international, non-interventional open-label prospective multicenter long-term post- authorization safety study (PASS). Considering the real life setting and the long-term study requirements an open label study design was selected. This study is designed to be fluid and to fit with standard clinical practice.
The assignment of patients to a particular therapeutic strategy will be decided within current clinical practice and the decision to prescribe pitolisant will necessarily precede and will be independent of the decision to enrol patients into the study. The product will be prescribed and used based on the routine clinical practice as well as on the individual situation of each patient.
The patients will be observed during routine clinical practice. No additional diagnostic or therapeutic intervention outside routine clinical practice will be applied for the study (as per Article 2 (c) of 2001/20/EC). Assessments will be performed by the investigator at patients’ routine visits. As it is a non- interventional study, the frequency of visits and the actual assessments performed will be in line with the routine clinical practice and narcolepsy treatment guidelines. Each time the investigator will see the patient for a routine visit, they will complete a visit in the case report form (CRF). Visit are expected to occur at least every year. Additionally, if patients contact investigators to report a safety concern, an adverse event or pitolisant discontinuation between two visits, the investigators should make every possible attempt to collect data and report them in the CRF.
Study is planned to follow up patients for up to five years from the first prescription of Wakix® to the end of the study period or of Wakix® treatment. If a patient discontinues permanently Wakix® intake for any reason during the 5-year follow-up, the physician should complete a study end visit and patient follow-up will be stopped.
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Patients’ recruitment will be carried out in the 4 countries where Wakix® will be first launched (France; Germany; Italy; UK) over a period of 12 months. If the number of patients is not sufficient, back-up countries (Spain and Netherlands) may be added when Wakix® will be available on their market.
Investigators will be sleep specialists mainly in charge of patients with narcolepsy. Sleep specialists are expected to initiate all patients in France as stated in the French SPC) and most patients in the other countries. Main sleep specialist sites will be invited to participate to the study in each country to give the opportunity to the majority of narcoleptic patients who initiate pitolisant treatment to be enrolled in the study. To ensure the representativity of the study cohort, the investigators will be requested to consecutively recruit every patient who meets the selection criteria and who accepts to participate to the study. Eight to 10 sites per country will be involved, each of them will be center of reference for sleep disease and following a cohort of patients with narcolepsy. Patients will additionally be invited to complete self-questionnaires at baseline, three months and, then, every six months to assess their satisfaction, narcolepsy symptom perception, and quality of life and disease burden.
9.1.2 Endpoints
The study endpoints are defined as follows:
Primary endpoint
- The proportion of patients with Adverse Event (AE) reported by the investigator during the treatment course with Wakix® (defined as the period from Wakix® first dose intake to the study end visit or to the discontinuation of Wakix®).
Other safety endpoints
- The proportion of patients with Adverse Drug Reaction (ADR) reported by the investigator during the treatment course with Wakix®; - The proportion of patients with Serious Adverse Event (SAE) reported by the investigator during the treatment course with Wakix®; - The proportion of patients with Wakix® discontinuation, the reason for discontinuation (e.g. lack of efficacy, adverse event) and the time to treatment discontinuation (Kaplan Meier); - The yearly rate of patients with AE at each successive year Y1, Y2, Y3, Y4, and Y5; - The cumulative yearly rate of patients with AE at each year Y1, Y2, Y3, Y4, and Y5;
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- The distribution of AE, SAE and ADR reported by the investigator by System Organ Class and Preferred Term and the occurrence of every adverse event; - The proportion of patients with AE/SAE of special attention in the PGR and reported by the investigator (insomnia, anxiety, depression, weight changes, ulcer formation, abuse, diversion); - The mean BDI score at baseline and for each visit compared with baseline; - The incidence of patients who initiate an antidepressant co-medication for an indication of depression and not for cataplexy); - The proportion of patients with reduced kidney function (renal impairment) or with reduced liver function (hepatic impairment) being prescribed Wakix® and the pattern of use for those patients; - The proportion of patients being prescribed Wakix® with co-medication known as CYP2D6 inhibitors and the pattern of use for those patients; - The proportion of patients with a reported or an identified overdosage or misuse through the course of the study.
Secondary endpoints
- Description of Wakix® pattern of use at baseline: patients characteristic, narcolepsy history and clinical picture, comorbidities, previous treatments, Wakix® dosage at initiation, and target optimal dose after titration, co-medications at baseline; - Description of Wakix® pattern of use throughout the course of the study: Wakix® dosage changes, Wakix® interruption and reason, co-medication changes; - Mean ESS score at baseline at each follow-up visit and mean ESS changes compared with baseline, - CGI severity distribution at baseline at each follow-up visit and mean CGI changes compared with baseline (for EDS and cataplexy severity); - The yearly rate of patients with hospitalization due to narcolepsy, of patients with visits at the emergency wards due to narcolepsy at each year Y1, Y2, Y3, Y4, and Y5; - Patients self-assessment: o Rate of patients compliant with their treatment (according to the 8-item Morisky Score) at each visit o EQ5D scores at baseline and at each follow up visit o NSAQ: the Narcolepsy Symptom Assessment Questionnaire is a five-point scale ("much improved" to "much worse") that assessed changes from baseline in specific symptoms.
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Response was defined as "much improved" or "somewhat improved" overall at the follow up time measurements (Mamelak, 2015). o FOSQ-10: The Functional Outcomes of Sleep Questionnaire (FOSQ) is a disease-specific instrument designed to assess the impact of sleepiness on the ability to conduct daily activities (Waever, 1997). The FOSQ-10 is the shortened version of the FOSQ (30 items). The FOSQ-10 has been shown to perform similarly to the long version (Chasen, 2009) o Proportion of patients with work absenteeism over the previous months at baseline and at each follow up visit o Treatment satisfaction: mean VAS score at baseline and at each follow up visit
9.2 Setting
9.2.1 Selection criteria:
1. Inclusion criteria: Patient being prescribed Wakix® according to the SmPC for treatment initiation;
2. Patient providing informed consent.
Wakix® shall be prescribed according to the SmPC and treatment guidelines to patients diagnosed with narcolepsy with or without cataplexy. Pitolisant therapy should not be prescribed for the purpose of
® inclusion to this PASS, but solely for the clinical therapeutic indication. The decision to prescribe Wakix will necessarily precede and will be independent of the decision to enroll the patient into the study.
Non-inclusion criteria
1. Patients with a contraindication to Wakix® as identified in the SmPC:
- Hypersensitivity to the active substance or to any of the excipients , - Severe hepatic insufficiency (Child-Pugh C), - Breastfeeding.
2. Patients already treated with pitolisant, i.e. who received pitolisant during the 12 months preceding the inclusion visit.
Studies in animals have shown teratogenicity. In accordance with the SmPC (V. 31 March 2016 Annexe 1), women of childbearing potential have to use effective contraception during treatment and at least up to
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21 days after treatment discontinuation. Pitolisant may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives. No data are available in the paediatric population, then children should not be included.
9.2.2 Study visits
Assessments will be performed at patients’ visits. As it is a non-interventional study, the frequency of visits and the actual assessments performed will be in line with the routine clinical practice and narcolepsy treatment guidelines. No additional diagnosis or monitoring procedures will be added for the patients’ evaluation and follow up (as per Article 2 (c) of 2001/20/EC).
Physicians’ visits, diagnostic procedures, and assessments will be performed as clinically indicated in the opinion of the treating physician and according to narcolepsy treatment guidelines.
Once patients have started treatment with Wakix®, it is expected that they will be followed during 5 years. Each patient will return to see the investigator at least yearly over the course of his treatment according to standard medical practice as well as his individual situation. Study visits will be at study start (inclusion when the physician decide to prescribe Wakix®) and follow-up visits will be performed routinely on a yearly basis (or more if necessary) up to 60 months (5 years), or if Wakix® is permanently stopped until an end of study visit.
V1 – Baseline- Start of a treatment with Wakix® and inclusion of the patient in the study
For patients for whom the investigators have, independently of the study, initiated a treatment with Wakix®, the following procedures will be applied at this first visit:
- The patient will receive an information about the study and its participation: The patient will be given a written information. An informed consent will be obtained prior to entry into the study for each patient having made a positive decision to participate, either by oral agreement or by signed consent, in accordance with ICH, national and European Union requirements.
- Wakix® is prescribed by the physician to the patient according to Wakix® SPC and to usual clinical practice. The patient will buy the treatment as usually done in routine care. No treatment is provided for the study.
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- Concomitant treatments: as this is a non-interventional study assessing Wakix® treatment conditions in real life, all concomitant treatments can be prescribed. Investigators are invited to refer to the SmPC (annexe 1) to identify medications that may affect the activity of Wakix®.
- The Case Report Form (inclusion visit) is completed by the investigator based on the patient’s medical file (demographic characteristics, vital signs, high, weight, medical history, previous medications, co-medications, dosages prescribed) and interview (assessment of ESS, CGI).
- The patient is requested to complete the baseline self-assessment questionnaires (BDI, EQ5D, NSAQ, FOSQ-10 Questionnaire)
- The patient will be instructed to contact the investigator by phone in case of adverse event occurrence. In case of AE reported by the patient at any time the physician must report and document it in the CRF, whether a visit is required or not.
Follow-up visits: at least yearly interim visits (V2, V3, V4, V5 …)
The following procedures will be applied at each follow-up visit:
- The Case Report Form is completed by the investigator each time that the patient comes back for a visit based on the patient’s medical file and patient’s interview
- Wakix® dosage: the physician should record the current dosage and should tempt to identify any change of dosage since the last visit
- Wakix® safety data: adverse events (AEs) including serious adverse events (SAEs) reported spontaneously or in answer to physicians’ open questions by the patient as well as AEs detected by diagnostic procedures during routine clinical practice are documented at each visit.
- Concomitant medication are updated: any change in the dosage of the concomitant treatments should be recorded in the CRF.
- The patient is requested to complete the self-assessment questionnaires at each visit (BDI, EQ5D, NSAQ, 8_item Morisky, FOSQ-10 Questionnaire and VAS)
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- The patient should be questioned to know if any hospitalization or any unscheduled emergency visit concerning the narcolepsy disease in another wards aroused, and how many days staying away from work were due to narcolepsy since the last visit;
End of Study Visit (EOS) (V6) after 5 years or in case of Wakix® permanently stop
The final evaluation is performed either at the end of the 5-year follow up (around 60 months), at the end the study period or if the patient permanently stops Wakix® or prematurely stops his participation to the study.
The same items as for follow-up visit are completed. Additionally, the reason for Wakix® discontinuation and the therapeutic choice after Wakix®, should be documented. The visit is also completed as soon as possible for any subject who stops prematurely their treatment with Wakix® or discontinues the study for any reason. The patient observation period comprises the 1-month period following treatment discontinuation; any adverse event that occurs during this period is part of the study.
9.3 Variables
Assessments will be completed at visits undertaken by the patients. The following will be captured in the database during the study
Time of measurement
Variables Baseline End of Interim Type of variables study Treatment visits** Initiation visit***
Informed consent X
Inclusion/non-inclusion criteria X
Patients demographics (age, gender) Baseline description, X risk factors
Medical History (narcolepsy diagnosis history date of Baseline description, diagnosis, symptoms (severity and duration), risk factors, potential X previous treatments of EDS and cataplexy cofounders
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Comorbidities including cardiovascular, renal and Baseline description, X hepatic impairments risk factors, potential cofounders
Vital signs (weight and height, heart rate and blood X Outcome X X pressure)
X Epworth Sleepiness Scale (ESS)* Outcome X X
Clinical Global Impression (CGI) Outcome X X X for Excessive Daytime Sleepiness (EDS) severity Beck Depression Inventory13 items (BDI) Outcome X X X
Pitolisant initiation (indication for use, daily dose, Exposure / outcome X titration pattern)
Pitolisant administration (adjustment of dose and Exposure / outcome X reason for change of dose)
Pitolisant discontinuation and reason for Exposure / outcome X discontinuation, therapeutic choice post-pitolisant)
Concomitant medications for narcolepsy (name, Co-medications, dose, date of start and discontinuation, changes in potential cofounders X X X dosage) in particular antidepressant, psycho- stimulant and anti-cataplectic co-medications
Adverse Events (including overdosage, misuse, lack of Outcome X X efficacy)
Number of emergency visits or hospital admission Outcome due to narcolepsy over the last 12 months (V0) since X X X the last visit (Follow up)
Patient self-assessment Outcome, potential X X - of treatment compliance (Morisky scale) cofounders
- of quality of life (EQ5D)/ disease burden Outcome X X X (FOSQ-10)
- of narcolepsy symptoms (NSAQ) Outcome X X X
- of satisfaction with the treatment (VAS) Outcome X X
Work absenteeism (number of days away from work Outcome over the last 12 months (V0) since the last visit X X X (Follow up)
* In accordance with routine practice ** End Of Study visit is completed after a 60-month follow-up, at the end of the study duration, or as soon as possible for any subject who discontinues Wakix® or discontinues the study for any reason *** A visit is completed about 1visit per year in the current practice
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 9.4 Data sources
Data will be prospectively entered into the CRF by the investigator site staff based on patients’ medical file and interviews and patient questionnaires. Patients will attend the investigator site for visits during their treatment within local clinical practice. Assessments conducted during these visits are in accordance with clinical practice.
The safety data will be retrieved through physical examination including vital signs, patient’s interviews and feedbacks, assessment scales such BDI, patient’s health care resource use estimation and following the site practice or diagnosis procedures (functional tests assessing sleep including PSG, MWT, MSLT, lab tests, ECG, X-ray…) if required by the patient condition.
Patients will be provided with paper self-questionnaires during each visit for the assessment of the treatment compliance, narcolepsy symptoms, satisfaction, quality of life and disease burden.
9.5 Study size
The sample size is not based on a statistical power calculation but on the primary objective of assessing the adverse events in long-term pitolisant treatment and the feasibility of the study while narcolepsy is a rare disease. Considering that the estimated prevalence is below 5 per 10 000, a reasonable sample size for the study has been estimated at 300.
The primary endpoint is the proportion of patients with AE over the course of the study. The calculation of the sample size is based on accuracy of the estimation of confidence interval for the proportion of patients with AE at the study end visit. The number of patients required is a function of the expected percentage, the needed accuracy and the alpha risk. No data in real life settings are available to anticipate the true proportions of patients with AE after 5 years of pitolisant treatment. Under the hypothesis that proportion of patients with AE in clinical studies goes between 30 and 70% with a two-sided 95% confidence interval, a sample size of 270 patients with a complete follow-up will permit to achieve results with an accuracy of ± 5.5% to ± 6.0%. This number is increased by ~10% in order to take into account patients lost to follow-up. A total of 300 patients will be enrolled in the study within the European Union.
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Proportion ACCURACY 10 % 20 % 30 % 40 % 50 % 216 384 504 576 600 171 304 398 455 474 138 246 323 369 384 114 203 267 305 317 96 171 224 256 267 82 145 191 218 227 71 125 165 188 196 61 109 143 164 171 54 96 126 144 150 Table 2 : Required Number of Patients by Acceptable Accuracy (95% Confidence Interval) for Proportions (Normal Approximation) The study size will remain limited in terms of assessing rare adverse reactions. Such events, if associated with pitolisant use, are more likely to be detected by spontaneous reporting along with increasing post- marketing exposure. Though, the primary objective can be addressed with a satisfactory accuracy.
Based on the targeted population, recruitment will be carried out in the 4 countries where Wakix® will be commercialized in a first wave (Q2 2016-Q1 2017): France, Germany, England, and Italy. Prevalence of narcolepsy varies from 0.02% to 0.05% (Ohayon 2002, Longstreth, 2007; Partinen, 2014; Orphanet Report July 2015) and the diagnosed patients are estimated around 25% (Overseems, 2001). Out of those patients, approximately 50% (n=3000) per country are estimated being treated for narcolepsy whatever the treatment is (n=12000 for the 4 countries). Pitolisant is expected to be initiated in 10 to 15 % patients over the first year (1200-1500 patients) (forecast sales).
The study will be conducted with the 8 to 10 main sleep sites in each country. They are expected to manage 65% of the narcoleptic patients. Out of the 800 to 1000 patients the sites are expected to initiate, a recruitment of 300 patients within 12 months seems reasonable.
By way of comparison, the French Compassionate program have included 350 patients receiving pitolisant within 18 months.
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 9.6 Data management
9.6.1 Identification of any data to be recorded in the CRF and to be considered as source data
Source data consist of all information recorded in the medical file or in questionnaires that should be reported in the CRF. CRF should have the centre number and the patient number in the study. An eCRF is planned to be used for investigators visit recording; the self-questionnaire completed by patients will be in paper format.
Source data relate to but are not limited to:
Subject identification, demographic data (age, weight, height, birth date), general examination, medical history, last participation to a clinical trial if any,
Narcolepsy diagnosis history and documentation of the previously performed evaluation (tests, questionnaires…) about illness,
A complete interrogation including the patient actual symptoms of narcolepsy (severity and duration), possible complication, details of concomitant treatments including any current and previous treatments of EDS and cataplexy and any other types of treatment,
Dates and times for drug administration, concomitant medication during the study,
All data related to efficacy assessment: ESS, CGI
All data related to safety assessment: adverse events, vital signs, ECG, results of biological tolerance.
9.6.2 Data Handling and Record keeping
The Operations Manual and the Data Management Plan will detail the data entry, cleaning, clarification, and validation procedures to be followed by all relevant study staff. The collection of data for the data review will be performed under Bioprojet supervision. Visual and computer error checks will be carried out. The Investigators will be queried on errors concerning completeness and consistency.
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In order to constitute evidence with respect to product safety or regulatory or legal compliance, the Investigators, investigational sites, PRAC, data protection bodies and Ethics Committees agree to retain study-related documents in a location that is secure and to which access can be gained if required.
The following documents will be archived: the Investigator’s File containing all required study documents, the signed Informed Consent forms, when applicable, and patient-related records, the CRFs and Data Clarification Forms. The Investigator and the site should retain records for a specific time as local regulatory requirement. At the end of the regulatory delay, the investigator will inform Bioprojet of his intention to proceed to the destruction of archived data. If the records need to be retained after that duration, the investigator and the site will be notified by Bioprojet. These documents have to be available for inspection by authorized representative of Bioprojet or regulatory authorities. Bioprojet will keep in the same conditions the original CRFs and appendices (correction sheets, sheets with comments…).
A periodic reconciliation between CRF database and PV database will be done, at least every year before the database lock for interim analysis, for all ADRs and individual case safety report (ICSR).
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BIOPROJET June 21, 2016 Protocol 15-11/ PASS / Wakix® Version 2.0 9.7 Data analysis
The statistical analyses described in this section will be performed as further outlined in the Statistical Analysis Plan (SAP), which will be dated, filed and maintained by the sponsor. The final SAP will take into account any amendment to the protocol.
9.7.1 Statistical Methods
The SAS® software program (version 9.4 or higher, SAS Institute, North Carolina, USA) will be used for statistical analysis.
Quantitative variables will be described using the following descriptive statistics: sample size, number of missing values, mean, and standard deviation, median, minimum and maximum. Qualitative variables will be described using the following descriptive statistics: sample size, number of missing values, frequency and percentage of each category calculated on the responses expressed.
The bivariate statistical analyses performed will undergo statistical tests, based on the nature of the variables analyzed: For qualitative variables, the Chi2 test will be applied, apart from the theoretical sample sizes less than 5; in this case, Fisher's exact test will be used or groups of categories will be performed. For quantitative variables, when distribution is close to normal (non-significant Shapiro-Wilk test), a Student's t-test or analysis of variance will be performed. If this is not the case, non-parametric tests will be used (Wilcoxon, Kruskal-Wallis). For all statistical tests, the significance level will be 5%.
The primary population for evaluating all safety endpoints as well as patient characteristics will include all patients enrolled in this study. Missing data management will be addressed in the SAP. For the primary analysis, no imputation will be performed. Patients with missing data or incomplete followed up will be compared to patients with complete follow up to identify the differences and discuss the bias. Regression models for longitudinal data can be used to analyse repeated measures (efficacy, patients reported outcome).
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9.7.2 Primary Endpoints
Adverse event collection
Adverse events reported by the investigators will be coded using the MedDRA and assessed as described in section 11.2.2 in terms of seriousness, severity, causality and recovery. Safety results will be described in accordance with GVP Module VI.
Frequencies of patients experiencing at least one AE will be displayed globally and by System Organ Class (SOC) and preferred term (PT) according to MedDRA terminology (yearly rate and cumulative yearly rate). Summary tables will present the number of patients observed with AEs and corresponding percentages. Summaries and listings of AEs and other safety parameters (reported cases of pregnancies, lack of efficacy, overdosage and misuse) will be provided (yearly rate and cumulative yearly rate). Summary tabulations will describe the AE seriousness, intensity, causality, outcome for each specific populations.
The description will be conducted for all the reported AEs whether related to the drug or not, and then for ADR. Safety analysis will also present a specific description of SAE, and of AE related to treatment discontinuation.
Drug utilisation
The description of drug utilisation will include a: - Description of Wakix® pattern of use at baseline: patients characteristic, narcolepsy history and clinical picture, comorbidities, previous treatments, Wakix® dosage at initiation, and target optimal dose after titration, co-medications at baseline; - Description of Wakix® pattern of use throughout the course of the study: Wakix® dosage changes, Wakix® interruption and reason, co-medication changes; - Description of patients dropped out during the study period and reason(s) for early withdrawal; and description of the time to the discontinuation of the treatment (Kaplan Meier).
9.7.3 Secondary endpoints
Secondary endpoints (ESS, CGI, BDI, BMI, NSAQ, 8-item Morisky, FOSQ-10, EQ5D, hospitalization, emergency visit, work day loss) reported by investigators and patients will be described at baseline and at
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Y1, Y2, Y3, Y4 and Y5 of follow-up (+/- 3 months) for the patients still in the study at the time of the follow up. Means (with standard deviations and 95% confidence intervals) and medians at each assessment point will be calculated based on the observed values as well as changes from baseline. In addition, Mixed Models with Repeated Measured (MMRM) will be applied to measure changes from baseline.
9.7.4 Covariates
Analysis will be conducted according to:
1) The anterior treatment with 3 defined groups: o Pitolisant initiation in “De Novo patients” naïve from any psychostimulant, o “Switched” to pitolisant from previously prescribed psychostimulant and or anti- cataplectic drugs that can be stopped just before the introduction of Wakix®, o Pitolisant in “add on “to preexisting treatment for EDS (such modafinil, sodium oxybate, methylphenidate or amphetamine) or cataplexy (such as sodium oxybate, venlafaxine, serotonin recapture inhibitors, noradrenaline recapture inhibitors and clomipramine.
2) The country where the patient is enrolled
3) Age group
4) Dosage of pitolisant (at initiation, targeted dosage)
The analysis in subgroups of interest will be further described in the Statistical Analysis Plan.
9.7.5 External References
The study does not schedule to collect data for patients not treated with pitolisant (Wakix®).
Though, the characteristics of the study patients will be compared to external data sources including clinical trials with pitolisant, European available registries (Khatami, 2016) and claim databases. Additionally registries and claim databases will provide data on treatment patterns, Wakix® use, treatment duration and health care resource use. Adverse event reporting will be limited in those data sources; use of anti-depressive drugs, hospitalization and case of non-adherence can be identified.
Adverse events occurrence will be compared with those reported in clinical trials or in compassionate programs (aggregated data) with the limits of those comparisons (interventional studies for clinical trials, specific population in compassionate use).
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9.7.6 Report
The final report will be sent to the regulatory agency within the regulatory timeline. All collected adverse events should be summarized as part of the interim safety analysis and in the final study reports. Annual interim reports and the final study report will be submitted to EMA and provided to the authorities (as soon as possible within 12 months of the end of data collection). The Agency publishes the protocols and abstracts of the final study reports of PASSs in the EU post-authorization study register.
Upon the first year the safety data will be compared to the existing pitolisant safety database. Upon following years, the annual report will compare the cumulative safety data to the data reported during the period and to the safety data from the clinical program.
In the reports, based on the results the following points will be assessed and discussed: long-term safety profile, identified and potential risks identified in the RMP, identification of any new safety signals, and safety in all populations. Narratives of main cases (death, new signal) may be presented. Based on the annual review, further analysis and an amendment of the statistical analysis may be decided for the following analysis.
9.8 Quality control
Study progress conformity to the protocol will be controlled from the patients’ selection, and all along the study. Each investigator has to allow the sponsor’s mandated representative, the direct access to any control of the study progress, and to any required documents to control data reported in case report forms (hospitalization file, consultation file, results of additional exams …).
The investigator will be available to the telephone for each patient whom he has included.
The filling of the CRFs is to be legible, written with a black ball pen, without any crossing out or overload. Any crossing out, overload or modification is to be corrected by the investigator himself, dated and signed. The anonymity respect shall be applied to the filling of the case report form as to any other archived documents considered as source data (blood tests, informed consent form…).
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QUALITY CONTROL AND AUDIT
Control actions are implemented within the framework of the Quality Insurance System to check that the quality requirements of the study are respected.
The original documents generated in the course of the study will be controlled at each step of the study, both by the sponsor’s representative and the investigator, in order to guarantee the accuracy of the analyzed data.
The conduct of the study may be audited either by the Sponsor or the Competent Authorities where the study is performed. Auditors should have access to any study records (CRFs, site files, trial master files…) and sources patients’ medical documentation. Investigators accept the possibility to be audited and agree to dedicate necessary time to the proper conduct of the audit at their sites. It will enable to check that the study is being run in conformity to the protocol and to current rules and regulations.
9.9 Limitations of the research methods
This is a real life study designed to assess Wakix® use in real life conditions. It is therefore critical to the recruitment of subjects that Wakix® is first launched in the country participating in the study and then that Wakix® is prescribed by physicians. Recruitment rate of subjects and the duration of the study has been estimated based on likely prescription rates.
Owing to differing clinical practice between countries who will recruit subjects into the study the study protocol has to be flexible to allow for differing assessments conducted at each visit. It is anticipated that for some subjects there will be fewer data points than others.
9.10 Other aspect: Confidentiality of study source documents
The information included in this document, the CRF and the results of the present study are considered as confidential and should not be divulged, only in case of legal requirements. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them. The signature of the present protocol is equivalent to a confidential agreement.
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It is understood by the investigator that the information from the study will be used by the company in connection with the development of pitolisant and, therefore, may be disclosed as required to other investigators or to government agencies. In order to allow for the use of the information derived from the studies, it is understood that there is an obligation to provide the sponsor with the complete data developed during this study, under the form of a written document or computerized with the following software: Word or SAS under Windows, saved on CD-Rom.
The study drug and the information in this document and in any future information supplied may contain trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by law or regulations. All or part of the information should only be divulged, submitted for publication or claim for industrial proprietary act with the written consent of BIOPROJET.
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10 PROTECTION OF HUMAN SUBJECTS
The trial will be carried out in accordance with the guidelines on good pharmacovigilance practices Module VIII – Post-authorisation safety studies, EMA/ 330405/2012; Declaration of Helsinki (Edinburgh, 2000) completed by Notes of Clarification to articles 29 (Washington, 2002) and 30 (Tokyo, 2004) respectively, (Seoul, 2008) and revised in 2013 (Fortaleza, Brazil). The trial will also be conducted in compliance with the applicable local country laws/regulations.
10.1 PRAC/ Ethical, Regulatory and Other Local Approval
According to local country specific requirements, the protocol and associated documentation will be submitted to all relevant local approving bodies. This may include PRAC/ Ethics committees, data protection bodies, etc.
For instance in France protocol will be submitted to several committees including CNIL (Commission nationale de l'informatique et des libertés) and CCTIRS (Comité consultatif sur le traitement de l'information en matière de recherche dans le domaine de la santé).
Signed letters of positive opinion regarding the study from the relevant local approving bodies must be sent to the investigators who will provide the Sponsor/ CRO with a copy prior to the start of data collection for any subject in the EDC. Investigators or CRO/ Sponsor will submit, depending on local regulations, periodic reports to local approving bodies.
Adverse event safety reporting will be conducted in accordance with current European and local legislation.
10.2 Emergency Actions
Bioprojet accepts the right of the investigator to deviate from the protocol in an emergency when necessary to safeguard the life or the well-being of a study patient. The investigator must inform the study personnel responsible at Bioprojet of any emergency deviations and justification for the deviation as quickly as possible after the episode, in any event no later than 24 hours after the emergency. According the local regulatory requirements, the investigator or the sponsor must inform the PRAC and competent
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10.3 Patient Informed Consent Procedure
It is the responsibility of the investigator to give each patient prior to inclusion in the study, full and adequate verbal and written information about the objectives and the procedures of the study, potential risks involved, and personal and societal benefits.
The patients must be informed about their right to withdraw from the study at any time and for any reason without sanction, penalty, or loss of benefits to which they are otherwise entitled and that withdrawal from the study will not jeopardize their future medical care. Before deciding on whether or not to participate, the patient should have sufficient time to think about the study and to discuss the study with third parties. The investigators and their staff will be available to answer questions from the subject at all times. Written Patient Information (prepared in accordance with ICH, national and European Union requirements, written in non-technical language) should be given to each patient before enrolment. Furthermore, it is the responsibility of the investigator to obtain, in accordance with the pertinent local regulations, a signed Informed Consent form from each patient prior to performing any study-related procedures.
The Patient Information and Informed Consent form should be updated or amended whenever new important information becomes available that may be relevant to the patient. Modifications to these documents must be approved by Bioprojet and by the IEC before being implemented.
10.4 Data Protection
All documents that concern the studied medication and the company’s operations belonging to MAH such as patent applications, formula, manufacturing process, basic scientific data and analysis bulletins; information supplied by the company and not previously published are considered confidential and shall remain the sole property of the MAH. The investigator agrees to use this information only in accomplishing this study and he/she will not use it for other purposes without written consent from MAH
The study will be conducted in accordance with the Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data, and relevant
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The MAH will ensure that all study information will be handled and stored in such a way that it can be accurately reported, interpreted and verified, while the confidentiality of the study subjects remains protected. The analytical dataset and statistical programs used for generating the data included in the final study report will be kept in electronic format and will be available for auditing and inspection.
As per local regulations, the subject will be asked to sign and date an ICF prior to any study-specific information being collected in the eCRF. All participant-related information including case report forms, laboratory specimens, evaluation forms, reports, etc., will be kept strictly confidential. All records will be kept in a secure, locked location and only research staff will have access to the records. Participants will be identified only by means of a coded number specific to each participant. Only the investigators will keep the linking code. All computerized databases will identify participants by numeric codes only, and will be password-protected. Upon request, participant records will be made available to the MAH / CRO and applicable regulatory entities. Access to data will only be allowed to individuals necessary for quality control, audit and analysis.
The MAH is the data custodian. The pharmacovigilance data will be kept for at least ten years after the marketing authorisation has ceased to exist.
10.5 Amending the Protocol
Any change to the study must be documented in a protocol amendment. Such protocol amendments will be made jointly by Bioprojet and the investigators. Both parties will sign the protocol amendment.
In accordance with the local regulatory requirements, the sponsor or the investigators shall submit the protocol amendment for review by the Independent Ethics Committee if the change or deviation from the original protocol could increase the risks to the study patients or could adversely affect the validity of the investigation or the rights of the human subjects and shall obtain approval from the Independent Ethics Committees before such change or deviation is implemented.
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When the change or deviation to the original protocol will eliminate or reduce the risk to the study patients, the protocol amendment will be implemented before approval has been received from the Independent Ethics Committee. In such cases, the sponsor or the investigators shall notify the Independent Ethics Committees within a delay after implementation according the local regulatory requirements and shall submit the protocol amendment as soon as possible for information/favourable opinion from the Independent Ethics Committees.
If the protocol amendment is of the administrative kind, it will be sent to the Ethics Committees for information.
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11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE REACTIONS
11.1 DEFINITIONS
Period of observation
For the purpose of this study, the period of observation extends from the time the patient gives his/her informed consent until one month after the last dose taken. Any adverse event observed by the investigator or reported by the patient during the observation period must be documented in the CRF.
Adverse Event (AE)
The term Adverse Event covers any sign, symptom, syndrome, or illness which appears or worsens in a patient during the observation period in the study, and which may impair the patient’s well-being.
The term also covers laboratory findings or results of other diagnostic procedures which are considered to be clinically relevant (e.g., requiring unscheduled diagnostic procedures or treatment measures, or result in withdrawal from the study).
An adverse event may be:
- A new illness; - The worsening of a sign, or symptom of the condition under treatment, or of a concomitant illness. - An effect of the study medication; - A combination of two or more of these factors.
No causal relationship with the study medication or with the study itself is implied by the use of the term “Adverse Event.”
Adverse Drug Reaction (ADR)
An adverse reaction, in contrast to an adverse event, is characterized by the fact that a causal relationship between a medicinal product and an occurrence is suspected.
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The causal should be assessed according to the WHO-UMC system. The causality term should be:
Related / Likely Possibly related / Possible Not related / Unlikely For definition see paragraph “Assessment of Causality”
Other situations Overdose, off-label use, misuse, abuse, occupational exposure, lack of efficacy should be also reported
- Overdose refers to the administration of a quantity of a medicinal product given per administration or cumulatively, which is above the maximum recommended dose according to the authorised product information. Clinical judgement should always be applied.
- Off-label use relates to situations where the medicinal product is intentionally used for a medical purpose not in accordance with the authorised product information.
- Misuse refers to situations where the medicinal product is intentionally and inappropriately used not in accordance with the authorised product information.
- Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, which is accompanied by harmful physical or psychological effects.
- Occupational exposure refers to the exposure to a medicinal product (as defined in [DIR Art 1]), as a result of one’s professional or non-professional occupation.
- Lack of efficacy
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR)
A serious adverse event or drug reaction or any untoward medical occurrence that, at any dose, has one or more of the following attributes:
Results in death, Is life-threatening1, Requires inpatient hospitalization or prolongation of existing hospitalization, Results in persistent or significant disability/incapacity2 Is a congenital anomaly/birth defect Is medically important
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1 “Life-threatening” means that the patient was at immediate risk of death at the time of the serious adverse event; it does not refer to a serious adverse event that hypothetically might have caused death if it were more severe.
2 “Persistent or significant disability or incapacity” means that there is a substantial disruption of a person’s ability to carry out normal life functions.
3 Medical and scientific judgment should be exercised in deciding whether other adverse events may be considered serious because they jeopardize the patient, or may require intervention to prevent one of the other outcomes listed in the definition above. The List of Critical Terms (1998 adaptation of WHO Adverse Reaction Terminology Critical Terms List) should be used as guidance for adverse events that may be considered serious because they are medically important.
Cases involving cancer as an Adverse Event should be reported as “serious” using the criterion “medically important” if no other serious criterion is met.
Cases of overdose with an adverse event that meets one of the criteria given above should of course be reported as “serious”. There is no antidote; in case of overdose, the patient has to be hospitalized in order to control his/her vital functions.
Severity
The terms “severe” and “serious” are not synonymous: "severe" is used to describe the intensity (severity) of a specific event, which could be rated mild, moderate or severe. The event itself, however, may be of relatively minor medical significance (such as severe headache). “Serious” is based on patient/event outcome or action criteria usually associated with events that pose a threat to a patient’s life or functioning. “Seriousness” (not severity) serves as a guide for defining regulatory reporting obligations.
. Mild: No significant interference with the subject’s usual activities: acceptable, disappeared without residual effect
Moderate: moderate interference with study the subject’s usual activities.
Severe: major interference with study the subject’s usual activities, considered as unacceptable by the physician or required specific treatment or required discontinuation from the study.
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11.2.1 Monitoring and recording of adverse events
The occurrence of adverse events will spontaneously be reported by the nurse or the patient or discovered during investigator’s interview. The investigator or a designed member of his/her staff will probe each patient for any adverse event which may have occurred. The investigator should always ask the same question when conducting the verbal probe in order to ensure uniformity between patients. The investigator should ask: - How are you doing (feeling)? Based on the patient’s response to this question, the investigator should ask additional questions relevant to the specific compliant such as: - How severe is/was the symptom? - How often did the symptom occur? - How long did the symptom last? For each or adverse event, regardless the suspected causal relationship to study drug, the investigator have to report on the Adverse Event Report Form the relevant information of AE including the nature, the anteriority (emergent or not), the timing of event occurrence and resolution, the frequency (intermittent or continuous), the severity, the seriousness (serious/non-serious), the relationship with Wakix®, and actions taken to counteract the adverse experience. The investigator has also to pursue and obtain adequate information in order to determine the outcome of the AE and also to assess whether it meets the criteria for classification as a serious adverse event requiring immediate notification to the sponsor (see below).
Follow-up of AEs is required until the event or its after-effects will be resolved or stabilized at an acceptable level with respect to the investigator opinion, even after the date of therapy discontinuation.
11.2.2 Assessment of adverse events
AEs will be coded according to the Medical Dictionary for Regulatory Activity (MedDRA current version).
AEs will be individually listed per subject number, presenting System Organ Class (SOC), preferred term, emergence, description, date and time of onset, date and time of last study drug administration before adverse event, duration, time from onset since last study drug administration, frequency, severity and
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Assessment of Severity The severity assessment is based on the investigator’s clinical judgment by using the severity definitions. The maximum severity encountered during the evaluation period should be checked. The assessment of severity should be independent of the assessment of the seriousness of the AE.
Assessment of Causality The investigator after review of Wakix® SmPC, will make judgement considering whether or not, in his opinion, the AEs are related to Wakix® according to following definition:
Related / likely: Clearly related to the investigational agent / procedure, i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is can be confirmed by improvement on stopping and reappearance of the event after rechallenge and that could not be reasonably explained by the known characteristics of the subject’s clinical state.
Possibly related / Possible: Follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors.
Not related / Unlikely: Clearly and incontrovertibly due only to extraneous causes, and does not meet criteria listed under possible (possibly related) or likely (related).
Assessment of outcome All adverse Event outcomes should be documented at the last visit, the latest according to the following criteria: recovered, recovered with sequelae, worsened, not yet recovered, death *If an adverse event is still ongoing at the last visit the patient must be followed-up until the outcome can be documented without using the “ongoing” assessment.
11.2.3 Reporting Serious Adverse Event or Serious Adverse Drug Reaction
All AEs or ADR whatever the dose, the therapeutic or diagnostic reason, have to be recorded in the CRF and reported immediately for serious AE (within 24 hours) and within 15 days for non-serious ADR to BIOPROJET (9, rue Rameau, 75015 PARIS, France) to :
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[email protected] : +33 (0)1 47 03 66 37 +33. (0)6 27 87 57 04 : +33 (0)1 47 03 66 30
The adverse drug reactions (ADRs) will be recorded in the pharmacovigilance database according to the GVP module VI. ADR will be reported to competent authorities in accordance with the provisions of Module VI. Procedures for the collection, management (including a review by the marketing authorisation holder (MAH) if appropriate) and reporting of suspected adverse reactions/adverse events are in place and described in the Pharmacovigilance System Master File (MFL-2767).
Pharmacovigilance department should ensure that all reports of serious adverse events and suspected adverse reactions (serious and non-serious) have been received from the prescribing physician. In compliance with the good pharmacovigilance practices (Modules VI and VIII) all valid reports of adverse reactions suspected to be related to Wakix® have to be reported by the pharmacovigilance department to the regulatory authorities:
- Within 15 days from the date of initial receipt of the information for the serious suspected adverse reactions and this applies for initial and follow up information
- Within 90 days from the date of initial receipt of the information for the non-serious suspected adverse reactions.
Other adverse events will be summarized in the periodic safety updated reports and study report. The national legislation will be followed for the reporting of cases of serious and non-serious adverse reactions to the local ethics committees and investigators
11.3. Continuous analysis and reporting
Bioprojet Pharma will evaluate the data generated during the study to assess the benefit-risk balance (BRB) of Wakix®. Any new safety information that affect the BRB will be communicated in writing as and emerging safety issue to EMA by email ([email protected]).
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The Sponsor (Bioprojet) should also expedite the safety reporting (Periodic Safety Report and Annual Safety Report) to all concerned investigator/institutions and to IRBs/IECs according the local regulatory timelines.
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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS
Following the end of the study the results should be published within a year of completion of the study report (SR) if the product is already approved..
A site may publish or present the results of this protocol with a written agreement from Bioprojet. The Sponsor Bioprojet will be provided with a copy of any proposed publication or presentation at least 60 days prior to submission for review. For multi-site studies, it is mandatory that the first publication should be based on data obtained from all analysed subjects; therefore investigators participating in multi-site studies must agree not to present data gathered individually or by a subgroup of sites prior to the full, initial publication, unless this has been agreed to by all other Investigators and the Sponsor.
Publication of study results may include the presentation of such work at national and international congresses symposia, professional meetings, peer-reviewed journals, and via other appropriate channels. Named authors and contributors to such publications shall be determined by the Sponsor in accordance with both the Company Publication Policy and the criteria as outlined by standard authorship guidelines. Selected Investigators, Consultants and Scientific Advisors may be invited to be named authors on such publications by the Sponsor. If the Investigator/Consultant/Scientific Advisor agrees to participate in the publication as an author, they will be asked to participate in the creation of all versions of the document(s) in question prior to submission or public dissemination. The copyright associated with any publication will be and shall remain the sole property of the Sponsor, unless or until the copyright of the document is transferred to the scientific peer-reviewed journal prior to and as part of the publication process.
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13. REFERENCES
AASM; 2014 ICSD-3 : International Classification of Sleep Disorders, 3rd Ed. American Academy of Sleep Medicine (AASM); 2014. Barateau, 2016 Barateau L., Lopez R, Dauvilliers Y. Treatment options for narcolepsy. CNS Drugs 2016, 7 May, DOI 10.1007/s40263-016-0337-4. Beck, 1974 Beck A.T., Beamesderfer A., Assessment of depression: the Depression Inventory Psychological measurements in Psychopharmacology, Mod.Probl, Pharmacopsychiat., Vol.7,p 151-169, ed P;Pichot, Paris (Karger, Basel 1974) Busner, 2007 Busner J., Targum S.D. The Clinical Global Impression scale applying a Research Tool in Clinical Practice. Psychiatry (Edgmont). 2007 Jul; 4(7): 28–37. Chasens, 2009 Chasens ER, Ratcliffe SJ, Weaver TE. Development of the FOSQ-10: a short version of the Functional Outcomes of Sleep Questionnaire.Sleep. 2009 32(7):915-9. Dauvilliers, 2013 Dauvilliers Y, Bassetti C, Lammers GJ, Arnulf I, Mayer G, Rodenbeck A, Lehert P, Ding CL, Lecomte JM, Schwartz JC; HARMONY I study group. Pitolisant versus placebo or modafinil in patients with narcolepsy: a double-blind, randomised trial. Lancet Neurol. 2013 12(11):1068-75. EPAR, 2015 European public sessment report. EMEA. Scientifique Discussion WAKIX published 13/04/2016 available on http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Public_assessment_report/human/002616/WC500204749.pdf Guy, 1976 Guy W, editor. ECDEU Assessment Manual for Psychopharmacology. Rockville, MD: US Department of Health, Education, and Welfare Public Health Service Alcohol, Drug Abuse, and Mental Health Administration; 1976. Johns, 1991 Johns MW. A new method for measuring day time sleepiness: The Epworth Sleepiness Scale.Sleep». Sleep 1991; 14:540-5. Khatami, 2016 Khatami R and the European Narcolepsy Network. The European Narcolepsy Network (EU-NN) database. J Sleep Res. 2016 356-64. Longstreth, 2007 Longstreth et Al. The epidemiology of narcolepsy SLEEP, Vol. 30, No. 1, 2007 Mamelak, 2016 Mamelak M,Swick T, Emsellem H, Montplaisir J, Lai C, Black J. A 12-week open-label, multicentre study evaluating the safety and patient-reported efficacy of sodium oxybate in patients with narcolepsy and cataplexy Sleep Medicine 2015; 16 52–58. Morisky, 2008 Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens (Greenwich). 2008 May;10(5):348-54. Orphanet, 2015 Orphanet Report –July 2015 – Reference Number 2073 http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_alphabetic al_list.pdf Ohayon, 2002 Ohayon MM et al. Prevalence of narcolepsy symptomatology and diagnosis in the European general population; Neurology 2002, 58. 1826-183 Overeem, 2001 Overeems S, Mognot E, Van Dijk JG, Lammers GJ. Narcolepsy: Clinical features, new pathological insights and future perspectives. J. Clin Neurophysiol. 2001; 28: 78-10 Partinen, 2014 Partinen et Al. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014 Jun;13(6):600-13. Scammell, 2015 Scammell T.E. Narcolepsy. NEJM 2015; 373;27 nejm.org, 2015. Teixeira, 2004 Teixeira V.J., Faccenda J.F., Douglas NJ. Functional status in patients with narcolepsy. Sleep medicine 2004; Vol 5, 477-483. Weawer, 1997 Weaver TE, Laizner AM, Evans LK, et al. An instrument to measure functional status outcomes for disorders of excessive sleepiness. Sleep 1997;20:835-43. Wijnans, 2013 Wijnans et Al. The incidence of narcolepsy in Europe: before, during, and after the influenza A(H1N1)pdm09 pandemic and vaccination campaigns. Vaccine 2013; 31: 1246-54
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14. ANNEXES
ANNEX I. SUMMARY OF PRODUCT CHARACTERISTICS
(version 31 March 2016)
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
1. NAME OF THE MEDICINAL PRODUCT
Wakix 4.5 mg film-coated tablets Wakix 18 mg film-coated tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Wakix 4.5 mg film-coated tablet Each tablet contains 5 mg of pitolisant hydrochloride equivalent to 4.45 mg of pitolisant.
Wakix 18 mg film-coated tablet Each tablet contains 20 mg of pitolisant hydrochloride equivalent to 17.8 mg of pitolisant.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Film-coated tablet
Wakix 4.5 mg film-coated tablet White, round, biconvex film-coated tablet, 3.7 mm diameter, marked with “5” on one side.
Wakix 18 mg film-coated tablet White, round, biconvex film-coated tablet, 7.5 mm diameter marked with “20” on one side.
4. CLINICAL PARTICULARS
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4.1 Therapeutic indications
Wakix is indicated in adults for the treatment of narcolepsy with or without cataplexy (see also section 5.1).
4.2 Posology and method of administration
Treatment should be initiated by a physician experienced in the treatment of sleep disorders.
Posology
Wakix should be used at the lowest effective dose, depending on individual patient response and tolerance, according to an up-titration scheme, without exceeding the dose of 36 mg/day: - Week 1: initial dose of 9 mg (two 4.5 mg tablets) per day. - Week 2: the dose may be increased to 18 mg (one 18 mg tablet) per day or decreased to 4.5 mg (one 4.5 mg tablet) per day. - Week 3: the dose may be increased to 36 mg (two 18 mg tablets) per day.
At any time the dose can be decreased (down to 4.5 mg per day) or increased (up to 36 mg per day) according to the physician assessment and the patient’s response.
The total daily dose should be administered as a single dose in the morning during breakfast.
Maintenance of efficacy As long-term efficacy data are limited (see section 5.1), the continued efficacy of treatment should be regularly evaluated by the physician.
Special populations
Elderly Limited data are available in elderly. Therefore, dosing should be adjusted according to their renal and hepatic status.
Renal impairment In patients with renal impairment, the maximum daily dose should be 18 mg.
Hepatic impairment In patients with moderate hepatic impairment (Child-Pugh B) two weeks after initiation of treatment, the daily dose can be increased without exceeding a maximal dose of 18 mg (see section 5.2). Pitolisant is contra-indicated in patients with severe hepatic impairment (Child-Pugh C) (see section 4.3). No dosage adjustment is required in patients with mild hepatic impairment.
Paediatric population The safety and efficacy of pitolisant in children aged from 0 to 18 years old have not yet been established. No data are available.
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Method of administration
For oral use.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Severe hepatic impairment (Child-Pugh C).
Breastfeeding (see section 4.6).
4.4 Special warnings and precautions for use
Psychiatric disorders
Pitolisant should be administered with caution in patients with history of psychiatric disorders such as severe anxiety or severe depression with suicidal ideation risk.
Hepatic or renal impairment
Pitolisant should be administered with caution in patients with either renal impairment or moderate hepatic impairment (Child-Pugh B) and dosing regimen should be adapted according to section 4.2.
Gastrointestinal disorders
Gastric disorders reactions have been reported with pitolisant, therefore it should be administered with caution in patients with acid related gastric disorders (see section 4.8) or when co-administered with gastric irritants such as corticosteroids or NSAID.
Nutrition disorders
Pitolisant should be administered with caution in patients with severe obesity or severe anorexia (see section 4.8). In case of significant weight change, treatment should be re-evaluated by the physician.
Cardiac disorders
In two dedicated QT studies, supra-therapeutic doses of pitolisant (3-6-times the therapeutic dose, that is 108 mg to 216 mg) produced mild to moderate prolongation of QTc interval (10-13 ms). In clinical trials, no specific cardiac safety signal was identified at therapeutic doses of pitolisant. Nevertheless, patients with cardiac disease, co-medicated with other QT-prolonging medicinal products or known to increase the risk of repolarization disorders, or co-medicated with medicinal products that significantly increase pitolisant
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Cmax and AUC ratio (see section 4.5) or patients with severe renal or moderate hepatic impairment (see section 4.4) should be carefully monitored (see section 4.5).
Epilepsy
Convulsions were reported at high doses in animal models (see section 5.3). In clinical trials, one epilepsy aggravation was reported in one epileptic patient. Caution should be taken for patients with severe epilepsy.
Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/metabolites half-life). Pitolisant may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives (see sections 4.5 and 4.6).
Drug-drug interactions
The combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin should be avoided (see section 4.5).
Rebound effect
No rebound effect was reported during clinical trials. However, treatment discontinuation should be monitored.
4.5 Interaction with other medicinal products and other forms of interaction
Antidepressants
Tri or tetracyclic antidepressants (e.g. imipramine, clomipramine, mirtazapine) may impair the efficacy of pitolisant because they display histamine H1-receptor antagonist activity and possibly cancel the effect of endogenous histamine released in brain by the treatment.
Anti-histamines
Anti-histamines (H1-receptor antagonists) crossing the haemato-encephalic barrier (e.g. pheniramine maleate, chlorpheniramine, diphenydramine, promethazine, mepyramine) may impair the efficacy of pitolisant.
QT-prolonging substances or known to increase the risk of repolarization disorders
Combination with pitolisant should be made with a careful monitoring (see section 4.4).
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Pharmacokinetic interactions
Medicinal products affecting pitolisant metabolism
- Enzyme inducers Co-administration of pitolisant with rifampicin in multiple doses significantly decreases pitolisant mean Cmax and AUC ratio about 39% and 50%, respectively. Therefore, co-administration of pitolisant with potent CYP3A4 inducers (e.g. rifampicin, phenobarbital, carbamazepine, phenytoin) should be done with caution. With St John’s Wort (Hypericum Perforatum), due to its strong CYP3A4 inducing effect, caution should be exercised when taken concurrently with pitolisant. A clinical monitoring should be made when both active substances are combined and, eventually a dosage adjustment during the combination and one week after the inducer treatment.
- CYP2D6 inhibitors Co-administration of pitolisant with paroxetine significantly increases pitolisant mean Cmax and AUC0—72h ratio about 47% and 105%, respectively. Given the 2-fold increase of pitolisant exposure, its coadministration with CYP2D6 inhibitors (e.g. paroxetine, fluoxetine, venlafaxine, duloxetine, bupropion, quinidine, terbinafine, cinacalcet) should be done with caution. A dosage adjustment during the combination could eventually be considered.
Medicinal products that pitolisant may affect metabolism
- CYP3A4 and CYP2B6 substrates Based on in vitro data, pitolisant and its main metabolites may induce CYP3A4 and CYP2B6 at therapeutic concentrations and by extrapolation, CYP2C, UGTs and P-gp. No clinical data on the magnitude of this interaction are available. Therefore, the combination of pitolisant with substrates of CYP3A4 and having a narrow therapeutic margin (e.g. immunosuppressants, docetaxel, kinase inhibitors, cisapride, pimozide, halofantrine) should be avoided (see section 4.4). With other CYP3A4, CYP2B6 (e.g. efavirenz, bupropion), CYP2C (e.g. repaglinide, phenytoin, warfarin), P-gp (e.g. dabigatran, digoxin) and UGT (e.g. morphine, paracetamol, irinotecan) susbtrates, caution should be made with a clinical monitoring of their efficacy.
With oral contraceptives, the combination with pitolisant should be avoided and a further reliable contraceptive method used.
- Substrates of OCT1 Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 µM, the extrapolated IC50 of pitolisant is 0.795 µM.
Even if the clinical relevance of this effect is not established, caution is advised when pitolisant is administered with a substrate of OCT1 (e.g. metformin (biguanides)) (see section 5.2).
Paediatric population
Interaction studies have only been performed in adults.
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4.6 Fertility, pregnancy and lactation
Women of childbearing potential
Women of childbearing potential have to use effective contraception during treatment and at least up to 21 days after treatment discontinuation (based on pitolisant/metabolites half-life). Pitolisant/metabolites may reduce the effectiveness of hormonal contraceptives. Therefore, an alternative method of effective contraception should be used if the woman patient is using hormonal contraceptives (see section 4.5).
Pregnancy
There are no or limited amount of data from the use of pitolisant in pregnant women. Studies in animals have shown reproductive toxicity, including teratogenicity. In rats, pitolisant/metabolites were shown to cross the placenta (see section 5.3).
Pitolisant should not be used during pregnancy unless the potential benefit outweighs the potential risk for foetus.
Breast-feeding
Animal study has shown excretion of pitolisant/metabolites in milk. Therefore, breastfeeding is contraindicated during treatment with pitolisant (see section 4.3).
Fertility
Study in animals has shown effects on semen parameters, without a significant impact on reproductive performance in males and reduction on the percentage of live foetuses in treated females (see section 5.3).
4.7 Effects on ability to drive and use machines
Pitolisant has minor influence on the ability to drive and use machines.
Patients with abnormal levels of sleepiness who take pitolisant should be advised that their level of wakefulness may not return to normal. Patients with excessive daytime sleepiness, including those taking pitolisant should be frequently reassessed for their degree of sleepiness and, if appropriate, advised to avoid driving or any other potentially dangerous activity.
4.8 Undesirable effects
Summary of the safety profile
The most frequent adverse drug reactions (ADRs) reported with pitolisant were insomnia (8.4%), headache (7.7%), nausea (4.8%), anxiety (2.1%), irritability (1.8%), dizziness (1.4%), depression (1.3%), tremor (1.2%),
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sleep disorders (1.1%), fatigue (1.1%), vomiting (1.0%), vertigo (1.0%), dyspepsia (1.0%), weight increase (0.9%), abdominal pain upper (0.9%). The most serious ADRs are abnormal weight decrease (0.09%) and abortion spontaneous (0.09%).
Tabulated list of adverse reactions
The following adverse reactions have been reported with pitolisant during clinical studies enrolling more than 1094 patients in narcolepsy and other indications and are listed below as MedDRA preferred term by system organ class and frequency; frequencies are defined as: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥ 1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000); within each frequency group, adverse reactions are presented in order of decreasing seriousness:
Common Uncommon Rare Infections and infestations Sweating Metabolism and nutrition Decreased appetite Anorexia disorders Increased appetite Hyperphagia Fluid retention Appetite disorder
Psychiatric disorders Insomnia Agitation Abnormal behaviour Anxiety Hallucination Confusional state Irritability Hallucination visual, Depressed mood Depression auditory Excitability Sleep disorder Affect lability Obsessive thoughts Abnormal dreams Dysphoria Dyssomnia Hypnopompic Middle insomnia hallucination Initial insomnia Depressive symptom Terminal insomnia Hypnagogic Nervousness hallucination Tension Mental impairment Apathy Nightmare Restlessness Panic Attack Libido decreased Libido increased Nervous system disorders Headache Dyskinesia Loss of consciousness Dizziness Balance disorder Tension headache Tremor Cataplexy Memory impairment Disturbance in Poor sleep quality attention Dystonia On and off phenomenon Hypersomnia Migraine
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Psychomotor hyperactivity Restless Legs Syndrome Somnolence Epilepsy Bradykinesia Paresthesia
Eye disorders Visual acuity reduced Blepharospasm Ear and labyrinth disorders Vertigo Tinnitus Cardiac disorders Extrasystoles Bradycardia Vascular disorders Hypertension Hypotension Hot flush Respiratory, thoracic and Yawning mediastinal disorders Gastrointestinal disorders Nausea Dry mouth Abdominal distension Vomiting Abdominal pain Dysphagia Dyspepsia Diarrhoea Flatulence Abdominal discomfort Odynophagia Abdominal pain upper Enterocolitis Constipation Gastrooesophageal reflux disease Gastritis Gastrointestinal pain Hyperacidity Paraesthesia oral Stomach discomfort Skin and subcutaneous Erythema Toxic skin eruption tissue disorders Pruritus Photosensitivity Rash Hyperhidrosis Musculoskeletal and Arthralgia Neck pain connective tissue disorders Back pain Musculoskeletal chest Muscle rigidity pain Muscular weakness Musculoskeletal pain Myalgia Pain in extremity Renal and urinary disorders Pollakiuria
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Pregnancy, puerperium Abortion spontaneous and perinatal conditions Reproductive system and Metrorrhagia breast disorders General disorders and Fatigue Asthenia Pain administration site Chest Pain Night sweats conditions Feeling Abnormal Sense of oppression Malaise Oedema Peripheral oedema Investigations Weight increased Creatine Weight decreased phosphokinase Hepatic enzymes increased increased Electrocardiogram QT General physical prolonged condition abnormal Heart rate increased Electrocardiogram Gamma- repolarisation glutamyltransferase abnormality increased Electrocardiogram T wave inversion
Description of selected adverse reactions
Headache and insomnia During clinical studies, episodes of headache and insomnia have been reported (7.7 % to 8.4%). Most of these adverse reactions were mild to moderate. If symptoms persist a reduced daily dose or discontinuation should be considered.
Gastric disorders Gastric disorders caused by hyperacidity have been reported during clinical studies in 3.5% of the patients receiving pitolisant. These effects were mostly mild to moderate. If they persist a corrective treatment with proton pump inhibitor could be initiated.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
Symptoms
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Symptoms of Wakix overdose may include headache, insomnia, irritability, nausea and abdominal pain.
Management
In case of overdose, hospitalisation and monitoring of the vital functions are recommended. There is no clearly identified antidote.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other nervous system drugs, ATC code: N07XX11.
Mechanism of action
Pitolisant is a potent, orally active histamine H3-receptor antagonist/inverse agonist which, via its blockade of histamine auto-receptors enhances the activity of brain histaminergic neurons, a major arousal system with widespread projections to the whole brain. Pitolisant also modulates various neurotransmitter systems, increasing acetylcholine, noradrenaline and dopamine release in the brain. However no increase in dopamine release in the striatal complex including nucleus accumbens was evidenced for pitolisant.
Pharmacodynamic effects
In narcoleptic patients with or without cataplexy, pitolisant improves the level and duration of wakefulness and daytime alertness assessed by objective measures of ability to sustain wakefulness (e.g. Maintenance of Wakefulness Test (MWT)) and attention (e.g. Sustained Attention to Response Task (SART)).
Clinical efficacy and safety
Narcolepsy (with or without cataplexy) is a chronic condition. The effectiveness of pitolisant up to 36 mg once a day, for the treatment of narcolepsy with or without cataplexy was established in two main, 8 weeks, multicenter, randomized, double-blind, placebo-controlled, parallel group trials (Harmony I and Harmony CTP). Harmony Ibis, study with a similar design, was limited to 18 mg once a day. To date, there are limited amount of data from an open label study on long-term efficacy of Wakix in this indication.
The pivotal study (Harmony 1), double-blind, randomized, vs placebo and modafinil (400 mg/day), parallel group studies with flexible dose adaptation, included 94 patients (31 patients treated with pitolisant, 30 with placebo and 33 with modafinil). Dosage was initiated at 9 mg once a day and was increased, according to efficacy response and tolerance to 18 mg or 36 mg once a day per 1-week interval. Most patients (60%) reached the 36 mg once a day dosage. To assess the efficacy of pitolisant on Excessive Daytime Sleepiness
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(EDS), Epworth Sleepiness Scale (ESS) score was used as primary efficacy criterion. The results with pitolisant were significantly superior to those in the placebo group (mean difference: -3.33; 95%CI [-5.83 to -0.83]; p < 0.05) but did not differ significantly from the results in the modafinil group (mean difference: 0.12; 95%CI [-2.5 to 2.7]). The waking effect of the two active substances was established at similar rates (Figure 1).
FIGURE 1: CHANGES IN EPWORTH SLEEPINESS SCALE SCORE (ESS) (MEAN ± SEM) FROM BASELINE TO WEEK 8 IN HARMONY 1 STUDY
The effect on Epworth was supported in two laboratory tests of vigilance and attention (Maintenance of Wakefulness Test (MWT) (p=0.044) and Sustained Attention to Response (SART) (p=0.053, almost but not significant)).
Cataplexy attacks frequency in patients displaying this symptom was decreased significantly (p=0.034) with pitolisant (-65%) compared to placebo (-10%). The daily cataplexy rate (geometric means) was 0.52 at baseline and 0.18 at final visit for pitolisant and 0.43 at baseline and 0.39 at final visit for placebo, with a rate ration rR=0.38 [0.16 ; 0.93] (p=0.034).
The second pivotal study (Harmony Ibis) included 165 patients (67 treated with pitolisant, 33 with placebo and 65 with modafinil). The study design was similar to study Harmony I except that the maximum dose for pitolisant reached by 75% of patients was 18 mg once a day instead of 36 mg in Harmony I. As an important unbalance led to comparison of results with or without cluster grouping of sites, the most conservative approach showed non-significant ESS score decrease with pitolisant compared to placebo (pitolisant-placebo=-1.94 with p=0.065). Results from cataplexy rate at 18 mg once a day were not consistent with those of the first pivotal study (36 mg once a day).
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Improvement of the two objective tests of wakefulness and attention, MWT and SART, with pitolisant was significant versus placebo (p=0.009 and p=0.002 respectively) and non-significant versus modafinil (p=0.713 and p=0.294 respectively).
Harmony CTP, a supportive double blind, randomized, parallel group study of pitolisant versus placebo, was designed to establish pitolisant efficacy in patients with high frequency cataplexy in narcolepsy. The primary efficacy endpoint was the change in the average number of cataplexy attacks per week between the 2 weeks of baseline and the 4 weeks of stable treatment period at the end of study. 105 narcoleptic patients with high frequency weekly cataplexy rates at baseline were included (54 patients treated with pitolisant and 51 with placebo). Dosage was initiated at 4.5 mg once a day and was increased, according to efficacy response and tolerance to 9 mg, 18 mg or 36 mg once a day per 1-week interval. Most patients (65%) reached the 36 mg once a day dosage.
On the primary efficacy endpoint, Weekly Rate of Cataplexy episodes (WRC), the results with pitolisant were significantly superior to those in the placebo group (p < 0.0001), with a progressive 64% decrease from baseline to end of treatment (Figure 2). At baseline, the geometric mean of WRC was 7.31 (median=6.5 [4.5; 12]) and 9.15 (median=8.5 [5.5; 15.5]) in the placebo and pitolisant groups respectively. During the stable period (until the end of treatment), geometric mean WRC decreased to 6.79 (median=6 [3; 15]) and 3.28 (median=3 [1.3; 6]) in the placebo and pitolisant groups respectively in patients who had experienced at least one episode of cataplexy. The observed WRC in pitolisant group was about half of WRC in the placebo group: the effect size of pitolisant compared with placebo was summarized by the ratio rate rR(Pt/Pb), rR=0.512; 95%CI [0.435 to 0.603]; p < 0.0001). The effect size of pitolisant compared with placebo based on a model for WRC based on BOCF with centre as a fixed effect was 0.581, 95%CI [0.493 to 0.686]; p<0.0001.
FIGURE 2: CHANGES IN WEEKLY CATAPLEXY EPISODES (GEOMETRIC MEAN) FROM BASELINE TO WEEK 7 IN HARMONY CTP STUDY
*p<0.0001 vs placebo
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The effect of pitolisant on EDS was also assessed in this population using the ESS score. In the pitolisant group, ESS decreased significantly between baseline and the end of treatment compared to placebo with an observed mean change of -1.9 ± 4.3 and -5.4 ± 4.3 (mean ± sd) for placebo and pitolisant respectively, (p<0.0001) (Figure 3). This effect on EDS was confirmed by the results on Maintenance of Wakefulness Test (MWT). The geometric mean of the ratios (MWTFinal/MWTBaseline) was 1.8 (95%CI 1.19; 2.71, p=0.005). The MWT value in the pitolisant group was 80% higher than in the placebo group.
FIGURE 3: CHANGES IN EPWORTH SLEEPINESS SCALE SCORE (ESS) (MEAN ± SEM) FROM BASELINE TO WEEK 7 IN HARMONY CTP STUDY
Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with Wakix in one or more subsets of the paediatric population in narcolepsy with or without cataplexy (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
The exposure to pitolisant in healthy volunteers was assessed in studies involving more than 200 subjects that received doses of pitolisant in single administration up to 216 mg and for a duration up to 28 days.
Absorption
Pitolisant is well and rapidly absorbed with peak plasma concentration reached approximately three hours after administration.
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Distribution
Pitolisant exhibits high serum protein binding (>90%) and demonstrates approximately equal distribution between red blood cells and plasma.
Biotransformation
The metabolisation of pitolisant in humans is not completely characterized. The available data show that the major non-conjugated metabolites are hydroxylated derivatives in several positions. The 5- aminovaleric acid is the major phase I inactive metabolite and is found in urine and serum. It is formed under the action of CYP3A4 and CYP2D6. Several conjugated metabolites were identified, the major ones (inactive) being a glycine conjugate of the acid metabolite of O-dealkylated desaturated pitolisant and a glucuronide of a ketone metabolite of monohydroxy desaturated pitolisant.
On liver microsomes, pitolisant does not significantly inhibit the activities of the cytochromes CYP1A2, CYP2C9, CYP2C19, CYP2C8, CYP2B6, CYP2E1 or CYP3A4 and of uridine diphosphate glucuronosyl transferases isoforms UGT1A1, UGT1A4, UGT1A6, UGT1A9 and UGT2B7 up to the concentration of 13.3 µM, a level considerably higher than the levels achieved with therapeutic dose. Pitolisant is an inhibitor of CYP2D6 with moderate potency (IC50 = 2.6 µM).
Pitolisant induces CYP3A4, CYP1A2 and CYP2B6 in vitro. Clinically relevant interactions are expected with CYP3A4 and CYP2B6 substrates and by extrapolation, UGTs, CYP2C and P-gp substrates (see section 4.5).
In vitro studies indicate that pitolisant is neither a substrate nor an inhibitor of human P-glycoprotein and breast cancer resistance protein (BCRP). Pitolisant is not a substrate of OATP1B1, OATP1B3. Pitolisant is not a significant inhibitor of OAT1, OAT3, OCT2, OATP1B1, OATP1B3, MATE1, or MATE2K at the tested concentration. Pitolisant shows greater than 50% inhibition towards OCT1 (organic cation transporters 1) at 1.33 µM, the extrapolated IC50 of pitolisant is 0.795 µM (see section 4.5).
Elimination
Pitolisant has a plasma half-life of 10-12 hours. Upon repeated administrations, the steady state is achieved after 5-6 days of administration leading to an increased serum level around 100%. Inter individual variability is rather high, some volunteers showing outlier high profile (without tolerance issues).
The elimination is mainly achieved via urine (approximately 63%) through an inactive non conjugated metabolite (BP2.951) and a glycine conjugated metabolite. 25% of the dose is excreted through expired air and a small fraction (<3%) recovered in faeces where the amount of pitolisant or BP2.951 was negligible.
Linearity/non-linearity
When pitolisant dose is doubled from 27 to 54 mg, AUC0-∞ is increased by about 2.3.
Special populations
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Elderly In 68 to 80 years old patients the pharmacokinetics of pitolisant is not different compared to younger patients (18 to 45 years of age). Above 80 years old, kinetics show a slight variation without clinical relevance. Limited data are available in elderly. Therefore, dosing should be adjusted according to their renal hepatic status (see section 4.2 and 4.4).
Renal impairment In patients with impaired renal function (stages 2 to 4 according to the international classification of chronic kidney disease, i.e. creatinine clearance between 15 and 89 ml/min), Cmax and AUC tended to be increased by a factor of 2.5 without any impact on half-life (see section 4.2).
Hepatic impairment In patients with mild hepatic impairment (Child-Pugh A), there was no significant changes in pharmacokinetics compared with normal healthy volunteers. In patients with moderate hepatic impairment (Child-Pugh B), AUC increased by a factor 2.4, while half-life doubled (see section 4.2). Pitolisant pharmacokinetics after repeated administration in patients with hepatic impairment has not been evaluated yet.
Race The effect of race on metabolism of pitolisant has not been evaluated.
5.3 Preclinical safety data
After 1 month in mice, 6 months in rats and 9 months in monkeys, no adverse effect level (NOAEL) were 75, 30 and 12 mg/kg/day, p.o., respectively, providing safety margins of 9, 1 and 0.4, respectively when compared to the drug exposure at therapeutic dose in human. In rats, transient reversible convulsive episodes occurred at Tmax , that may be attributable to a metabolite abundant in this species but not in humans. In monkeys, at the highest doses, transient CNS related clinical signs including emesis, tremors and convulsions were reported. At the highest doses, no histopathological changes were recorded in monkeys and rats presented some limited histopathological changes in some organs (liver, duodenum, thymus, adrenal gland and lung).
Pitolisant was neither genotoxic nor carcinogenic.
Teratogenic effect of pitolisant was observed at maternally toxic doses (teratogenicity safety margins < 1 in rats and in rabbits). At high doses, pitolisant induced sperm morphology abnormalities and decreased motility without any significant effect on fertility indexes in male rats and it decreased the percentage of live conceptuses and increased post-implantation loss in female rats (safety margin of 1). It caused a delay in post-natal development (safety margin of 1).
Pitolisant/metabolites were shown to cross the placenta barrier in animals.
Juvenile toxicity studies in rats revealed that the administration of pitolisant at high doses induced a dose related mortality and convulsive episode that may be attributable to a metabolite abundant in rats but not in humans.
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Pitolisant blocked hERG channel with an IC50 exceeding therapeutic concentrations and induced a slight QTc prolongation in dogs.
In preclinical studies, drug dependence and drug abuse liability studies were conducted in mice, monkeys and rats. However, no definitive conclusion could be drawn on tolerance, dependence and self- administration studies.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core
Microcrystalline cellulose Crospovidone type A Talc Magnesium stearate Colloidal anhydrous silica
Coating
Polyvinyl alcohol Titanium dioxide (E171) Macrogol 3350 Talc
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Wakix 4.5 mg tablet 12 months
Wakix 18 mg tablet 30 months
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
6.5 Nature and contents of container
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High density polyethylene (HDPE) bottle with a tamper evident, child-resistant, polypropylene screw cap fitted with desiccant (silica gel).
Bottle of 30 film-coated tablets.
6.6 Special precautions for disposal
No special requirements.
7. MARKETING AUTHORISATION HOLDER
Bioprojet Pharma 9, rue Rameau 75002 Paris France Tel: +33 (0)1 47 03 66 33 Fax: +33 (0)1 47 03 66 30 e-mail: [email protected]
8. MARKETING AUTHORISATION NUMBER(S)
EU/1/15/1068/001 EU/1/15/1068/002
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 31/03/2016
10. DATE OF REVISION OF THE TEXT
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.
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Annex 2 _ ENCePP checklist for study protocol
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Annex 3 _ Consent Form
CONSENT FORM
If you agree to take part in the study, please answer the following questions (“YES” or “NO”):
1. Can you please confirm that you have read and understood the patient information sheet dated [insert date] version [insert version number] regarding the Wakix PASS study? [Please circle the answer] Yes or No
2. Can you confirm that all your questions have been answered? You understand that if you need further information later on, you are welcome to ask your doctor? [Please circle the answer] Yes or No
3. Do you understand the purpose of the study and what will be your involvement? [Please circle the answer] Yes or No
4. Do you understand that your participation is voluntary and that you are free to withdraw at any time, without giving any reason, without your medical care or legal rights being affected? [Please circle the answer] Yes or No
5. Do you understand that relevant sections of your medical notes and data collected during the study may be reviewed / examined at by authorized persons for the study purposes? [Please circle the answer] Yes or No
6. Do you agree to complete the self-assessment questionnaires during the study? [Please circle the answer] Yes or No
Patient’s name: Date: Signature:
Doctor’s name: Date: Signature:
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Annex 4 – Participant Information Sheet
PARTICIPANT INFORMATION SHEET
You are invited to take part in a study dedicated to patients presenting narcolepsy. Before you decide whether or not to participate, it is important for you to understand the objectives of the study and the consequences for you. Please take time to read the following information and feel free to ask us if anything is unclear or if you need more information.
What is the aim of this study?
Your physician has decided to prescribe you a new treatment for narcolepsy named Wakix® that was recently approved by the European Medicines Agency after having proved its efficacy and safety on excessive daytime sleepiness and cataplexy. This new compound has an original mechanism of action activating histamine neurons in the brain involved in the wakefulness maintenance and cataplexy in patients with narcolepsy. The aim of this study is to collect more information about the eventual side effects arising with this new treatment in order to assess its safety profile. The patients will be followed during five years or until the treatment interruption.
Why have I been invited? You have been invited to take part in the study as you suffer from narcolepsy and your physician, specialist in sleep disease considers that you could benefit of this new treatment. You will receive Wakix® as prescribed by your physician.
Do I have to participate? It is entirely up to you to decide whether or not you want to take part. Your decision will have no effect on your medical care.
What does the study involve? Your participation in this study does not require any additional medical examination or procedure as you will be treated according to the standard medical practice.
You will be asked to fill in questionnaires about your symptoms and your feeling, the impact of the disease on your daily life and the way you take your medication as specified below:
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• In the first year: you will be invited to complete this questionnaire three times: on the day of your enrolment in the study during the visit with your physician , 3 and 6 months later by courier if you accept • Following years: you will be asked to complete it each time you visit your physician.
In parallel, your doctor will complete a medical questionnaire about your symptoms, your treatments and the adverse events that may occur.
Will my participation in this study be kept confidential? All your details will be kept strictly confidential. Your identity will never be revealed in any publication of the study results. According to the local regulation regarding confidentiality of personal data, you are entitled to access, correct or oppose your personal data via the study doctor who knows your identity. You can also have access or via any physician to all your medical records. If you wish to exercise this right or if you have any questions, please contact your doctor specified at the end of this letter.
In case of inspection some parts of your medical records and the data collected for the study may be examined by members of regulatory authorities (e.g. Ethics Committee, National Health Agency, European Medicines Agency) to check that the study has been carried out correctly. They all have a duty of confidentiality and nothing that could reveal your identity will be disclosed outside the research site.
Who is conducting the study? The study is conducted in France, Germany, Italy and United Kingdom by a European pharmaceutical company named Bioprojet, the marketing authorization holder of Wakix®.
What are side effects of Wakix®? The most common side effects with Wakix® (which may affect less than 10% people) are insomnia (difficulty sleeping), headache, nausea (feeling sick), anxiety, irritability, dizziness, depression, tremor, sleep disorders, tiredness, vomiting, vertigo (a spinning sensation) and dyspepsia (heartburn) and they are easily managed by dose decrease. For the full list of all side effects reported with Wakix®, see the package leaflet.
What are the potential benefits of taking part in the study? Your enrollment in this study will not induce any constraint for you. You will receive standard medical care and your physician will only collect any information regarding potential side effects and your feeling regarding the treatment effect. There are no direct benefits for them to participate in the study.
What happens at the end of the study?
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Data will be analyzed along the study and at the end reports will be sent to the European Health Authorities on regular basis. The final study results will be available through the EMA website (http://www.ema.europa.eu/ema).
Action to be taken in case of problem If you have any concern during this study at any time or if you experience a side effect, please contact your doctor (contact details at the end of this sheet).
What will happen if you stop your participation to the study? You are free to interrupt your participation to the study at any time, without this affecting your care, by contacting your doctor (contact details at the end of this sheet). Information that has been already collected will be included in the analysis until you stop.
Who has approved the study? The research has been validated by the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency. Moreover like all research the project was reviewed in each country by a Research Ethics Committee to protect the interests of participants. This study has been approved by the National Research Ethics Service Committee (XXX) – Reference: xxx [To be adapted according to the country].
Contact Details: In case of adverse event or emergency or if you want to speak to your physician, you can contact Dr______at the following number: ______.
We would like to thank you for taking the time to read this information sheet. If you wish to take part in the study, please inform your doctor who will register your participation.
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Annex 5 – Case Report Form Patient
BIOPROJET - WAKIX® [Study Name] VISIT 1
Site Number: |__|__|
Protocol P15-11
A 5-year multi-center, observational post-authorization safety study to document the utilisation of Wakix® in the treatment of narcolepsy with or without cataplexy and to collect information on its long term safety when used in routine medical practice
Patient Id: |__|__|__|
Completion Date: |__|__|/|__|__|/|__|__|__|__| (DD/MM/YYYY)
Narcolepsy Symptoms Assessment – Baseline
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EQ5D
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FOSQ-10
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Beck Depression Inventory
BIOPROJET Wakix / Protocol P15-11 V___ Initials: Patient Study No.:
BDI: Beck Depression Inventory Date: / / (DD/MM/YY) Time: h min
A.
0 I do not feel sad.
1 I feel sad. I__I 2 I am sad all the time and I can't snap out of it. 3 I am so sad or unhappy that I can't stand it. B.
0 I am not particulary pessimistic or discouraged about the future
1 I feel discouraged about the future I__I 2 I feel I have nothing to look forward to 3 I feel that the future is hopeless and that things cannot improve C.
0 I do not feel like a failure
1 I feel I have failed more than the average person I__I 2 As I look back on my life, all I can see is a lot of failures 3 I feel I am a complete failure as a person (parent, husband, wife) D.
0 I am not particulary dissatisfied
1 I don’t enjoy things the way I used to I__I 2 I don’t get satisfaction out of anything anymore 3 I am dissatisfied with everything E.
0 I don’t feel particularly guilty
1 I feel bad or unworthy a good part of the time I__I 2 I feel quite guilty 3 I feel as though I am very bad or worthless
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F.
0 I don’t feel disappointed in myself
1 I am disappointed in myself I__I 2 I am disgusted with myself 3 I hate myself G.
0 I don’t have any thoughts of harming myself
1 I feel I would be better off dead I__I 2 I have definite plans about committing suicide 3 I would kill myself if I had the chance H.
0 I have not lost interest in other people
1 I am less interested in other people than I used to be I__I 2 I have lost most of my interest in other people and have little feeling for them 3 I have lost all of my interest in other people and don’t care about them at all I.
0 I make decisions about as well as ever
1 I try to put off making decisions I__I 2 I have great difficulty in making decisions 3 I can’t make any decisions at all any time J.
0 I don’t feel I look any worse than I used to 1 I am worried than I am looking old or unattractive I__I 2 I feel that there are permanent changes in my appearance and they make me look unattractive 3 I feel that I am ugly or repulsive looking K.
0 I can work about as well as before
1 It takes extra effort to get started at doing something I__I 2 I have to push myself very hard to do anything 3 I can’t do any work at all L.
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0 I don’t get any more tired than usual
1 I get tired more easily than I used to I__I 2 I get tired from doing anything 3 I get too tired to do anything M.
0 My appetite is no worse than usual
1 My appetite is not as good as it used to be I__I 2 My appetite is much worse now 3 I have no appetite at all any more
Total Score I__I__I__I
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BIOPROJET – WAKIX® [Study Name] FOLLOW-UP VISIT
Site Number: |__|__|
Protocol P15-11
A 5-year multi-center, observational post-authorization safety study to document the utilisation of Wakix® in the treatment of narcolepsy with or without cataplexy and to collect information on its long term safety when used in routine medical practice
Patient Id: |__|__|__|
Completion date: |__|__|/|__|__|/|__|__|__|__| (DD/MM/YYYY)
Narcolepsy Symptoms Assessment
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The following common narcolepsy symptoms should be rated comparing your condition prior to starting Wakix® to your condition during the past week. Check only one choice per item.
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EQ5D
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FOSQ-10
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Beck Depression Inventory
BIOPROJET Wakix / Protocol P 15-11 V___ Initials: Patient Study No.:
BDI: Beck Depression Inventory Date: / / (DD/MM/YY) Time: h min
A.
0 I do not feel sad.
1 I feel sad. I__I 2 I am sad all the time and I can't snap out of it. 3 I am so sad or unhappy that I can't stand it. B.
0 I am not particulary pessimistic or discouraged about the future
1 I feel discouraged about the future I__I 2 I feel I have nothing to look forward to 3 I feel that the future is hopeless and that things cannot improve C.
0 I do not feel like a failure
1 I feel I have failed more than the average person I__I 2 As I look back on my life, all I can see is a lot of failures 3 I feel I am a complete failure as a person (parent, husband, wife) D.
0 I am not particulary dissatisfied
1 I don’t enjoy things the way I used to I__I 2 I don’t get satisfaction out of anything anymore 3 I am dissatisfied with everything E.
0 I don’t feel particularly guilty
1 I feel bad or unworthy a good part of the time I__I 2 I feel quite guilty 3 I feel as though I am very bad or worthless F.
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0 I don’t feel disappointed in myself
1 I am disappointed in myself I__I 2 I am disgusted with myself 3 I hate myself G.
0 I don’t have any thoughts of harming myself
1 I feel I would be better off dead I__I 2 I have definite plans about committing suicide 3 I would kill myself if I had the chance H.
0 I have not lost interest in other people
1 I am less interested in other people than I used to be I__I 2 I have lost most of my interest in other people and have little feeling for them 3 I have lost all of my interest in other people and don’t care about them at all I.
0 I make decisions about as well as ever
1 I try to put off making decisions I__I 2 I have great difficulty in making decisions 3 I can’t make any decisions at all any time J.
0 I don’t feel I look any worse than I used to 1 I am worried than I am looking old or unattractive I__I 2 I feel that there are permanent changes in my appearance and they make me look unattractive 3 I feel that I am ugly or repulsive looking K.
0 I can work about as well as before
1 It takes extra effort to get started at doing something I__I 2 I have to push myself very hard to do anything 3 I can’t do any work at all L.
0 I don’t get any more tired than usual
1 I get tired more easily than I used to I__I 2 I get tired from doing anything 3 I get too tired to do anything
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M.
0 My appetite is no worse than usual
1 My appetite is not as good as it used to be I__I 2 My appetite is much worse now 3 I have no appetite at all any more
Total Score I__I__I__I
Morisky
Satisfaction regarding your treatment Wakix®
Could you rate between 0 and 10 your satisfaction regarding your treatment Wakix® using the scale below? Not satisfied at all Highly satisfied
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Annex 5 – Case Report Form Physician
BIOPROJET [Study Name] ENROLMENT VISIT
Site Number: |__|__|
Protocol P15-11
A 5-year multi-center, observational post-authorization safety study to document the utilisation of Wakix® in the treatment of narcolepsy with or without cataplexy and to collect information on its long term safety when used in routine medical practice
Patient Id: |__|__|__|
Date: |__|__|/|__|__|/|__|__|__|__| (DD/MM/YYYY)
Eligibility Criteria
Inclusion criteria Yes No
Patient being prescribed Wakix® according to the SmPC
Patient being informed and agreeing to participate
Exclusion criteria Yes No
Patient with a contraindication to Wakix® as identified in the SmPC :
Hypersensitivity to the active substance or to any of the excipients Severe hepatic insufficiency (Child6Pugh C) Breastfeeding Patient already treated with pitolisant or who received pitolisant in 12 months prior to the inclusion visit
Demographic data
Gender: Male Female
Date of birth: |__|__|/|__|__|__|__| (DD/MM/YYYY)
Height: |__|.|__|__|(Meters)
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Medical History
Narcolepsy history
Date of diagnosis: |__|__|/|__|__|/|__|__|__|__| (DD/MM/YYYY)
EDS occurring daily for at least 3 months Yes No Cataplexy Yes No PSG ( Mean sleep latency≤8mn and at least 2 Yes No SOREMP) Hypocretin level (<110 pg/l) Yes No
Diagnosis of narcolepsy Type 1 Type2
History of associated symptoms Sleep paralysis Yes No Hallucinations Yes No Automatic behaviour Yes No Dyssomnia Yes No
Comorbidities
Cardiovascular disease Yes No If yes, please specify : Coronary insufficiency Yes No Cardiac insufficiency Yes No Arrhythmia Yes No Other, specify: ………………………………………………………………… Neurological disease Yes No If yes, please specify : Depression Yes No Anxiety Yes No Other, specify: ………………………………………………………………… Renal impairment Yes No
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Hepatic impairment Yes No Cardiac insufficiency Yes No Diabetes Yes No Obesity (BMI≥ 30) Yes No Hypercholesterolemia Yes No Epilepsy Yes No Hypertension Yes No Other relevant comorbidity, specify: …………………………………………………
Prior medications for narcolepsy
Was the patient receiving treatments for narcolepsy before to be enrolled in the study?
Yes No
If yes, please specify for each treatment:
Medic Daily dose Unit Route* Start date On -going End Date ation (generic name) 1 |__|__|__|__| |__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
2 |__|__|__|__| |__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
3 |__|__|__|__| |__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
4 |__|__|__|__| |__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
5 |__|__|__|__| |__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
*: 1: oral/2: rectal/3: nasal/4: sub-cutaneous/5: intravenous/6: patch/7: other.
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Clinical signs
Vital signs
SDP: |__|__|__|mm Hg Heart rate: |__|__|__|bpm
DBP: |__|__|__|mm Hg Weight: |__|__|. |__| (Kg)
Epworth Sleepiness Scale (ESS)
Clinical Global Impression (CGI)
Considering your total clinical experience with this particular population, how ill is the patient at this time regarding his excessive daytime sleepiness?
Not assessed Normal, not at all ill
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Borderline mentally ill Mildly ill Moderately ill Markedly ill Severely ill Almost the most extremely ill patients
Medications
Wakix® initiation
Indication for use: To treat the narcolepsy
Other : specify :…………………………………………………………………………..
Daily dose: 20 mg/d
40 mg/d
Other : specify :…………………………………………………………………………..
Concomitant medications
Does your patient have a prescription for other medications?
Yes No
If yes, please specify for each treatment:
Name Daily dose Start date Ongoing End Date Primary reason for use
1 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
2 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
3 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
4 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
5 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
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Health care resources use related to narcolepsy
In the past 12 months, did the patient visit emergency medical facilities?
Yes No
If yes, specify the number of visits and the reason:_____
In the past 12 months, has the patient been admitted to the hospital?
Yes No
If yes, specify the number of time, the duration and the reason:_____
In the past 12 months, has the patient been on sick leave or out of school?
Yes No
If yes, specify the number of days/months and the reason:_____
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BIOPROJET [Study Name] FOLLOW-UP VISIT
Site Number: |__|__|
Date: |__|__|/|__|__|/|__|__|__|__| (DD/MM/YYYY)
Tableau clinique
Vital signs
SDP: |__|__|__|mm Hg Heart rate: |__|__|__|bpm
DBP: |__|__|__|mm Hg Weight: |__|__|. |__| (Kg)
Epworth Sleepiness Scale (ESS)
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Clinical Global Impression (CGIi)
Rate total improvement whether or not, in your judgment, it is due entirely to drug treatment. Compared to his condition at the enrolment visit, how has he changed?
Not assessed
Very much improved
Much improved
Minimally improved
No change
Minimally worse
Much worse
Very much worse
Medications’ follow-up
Wakix® intake follow-up
Is the patient still under Wakix®? Yes No
If yes, specify: Did the daily dose change since the last visit? Yes No If yes, specify:
Type of change: Increased Decreased
Daily dose: |__|__|__|__| mg
Reason: Tolerability
Lack of response to Wakix®
Other, specify:…………………………………………………………………..
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If no, specify: End date: |__|__|/|__|__|/|__|__|__|__|
Reason: Tolerability
Lack of response to Wakix®
Other, specify:……………………………………………………………………………..
Does the patient receive a new treatment for narcolepsy? Yes No If yes, specify: Name: Daily dose: |__|__|__|__| Start date: |__|__|/|__|__|/|__|__|__|__|
Concomitant medications
[Table with the concomitant treatments at the enrolment visit]
Is there any change in the co-medications since the last visit? Yes No If yes, please specify for each treatment the change and add new treatment, if applicable]:
Name Daily dose Start date Ongoing End Date Primary reason for use 1 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__| 2 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__| 3 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__| 4 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__| 5 |__|__|__|__| |__|__|/|__|__|/|__|__|__|__| |__|__|/|__|__|/|__|__|__|__|
Health care resources use related to narcolepsy
Since the enrolment visit, did the patient visit emergency medical facilities?
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Yes No
If yes, specify the number of time:_____
Since the enrolment visit, has the patient been admitted to the hospital?
Yes No
If yes, specify the number of time and duration:_____
In the past 12 months, has the patient been on sick leave or out of school?
Yes No
If yes, specify the number of days/months:_____
Adverse Event
Has the patient experienced any adverse events since the enrolment visit?
Yes * No
*Please complete the adverse event form. If this event is serious, please send the completed adverse event to BIOPROJET within 24 hours
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Record one AE per line
Description Intensity 1 Relationship 2 Action taken Start date Outcome Stop date Seriousness
Diagnosis if known, Possibility that AE Study Additional Other Significant select one only Is the Event an SAE? (otherwise sign / is associated with Medication treatment intervention symptom) study treatment? (select one only) given (if yes record the TT in the eCRF)
mild not applicable no no ___/___/____ death not due to __/___/__ no yes Probable/Likely unchanged yes additional (dd/mm/yyyy) AE (dd/mm/yyyy) If SAE, please complete a SAE form moderate Possible dose decreased exam death due to AE severe Unlikely Temporarily recovered Was present before stopped hospitalization without sequelae study entry: permanently (if recovered with no stopped4 hospitalization sequelae yes please complete ongoing Started before study a SAE form) unknown drug intake:
no yes Worsening after 1rst drug intake: no yes 1 Mild: No significant interference with the subject’s usual activities: acceptable, disappeared without residual effect Moderate: moderate interference with the subject’s usual activities. Severe: major interference with the subject’s usual activities, considered as unacceptable by the physician or required specific treatment or required discontinuation from the study. 2 Related / likely: Clearly related to the investigational agent / procedure, i.e. an event that follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, that is can be confirmed by improvement on stopping and reappearance of the event after rechallenge and that could not be reasonably explained by the known characteristics of the subject’s clinical state. Possibly related / Possible: Follows a reasonable temporal sequence from administration of the study intervention, follows a known or expected response pattern to the suspected intervention, but that could readily have been produced by a number of other factors. Not related / Unlikely: Clearly and incontrovertibly due only to extraneous causes, and does not meet criteria listed under possible (possibly related) or likely (related). 3 A serious adverse event or drug reaction is any untoward medical occurrence that, at any dose: Results in death / or Is life threatening (patient at risk of death at the time of the event)/ or requires inpatient hospitalization or prolongation of existing hospitalization / or results in persistence or significant disability-incapacity / or is a congenital anomaly-birth defect/or is medically important event 4if permanently stopped please withdraw the patient from the study
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