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    Summary
    EudraCT Number:2013-001506-29
    Sponsor's Protocol Code Number:P11-06/BF2.649
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-09-05
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2013-001506-29
    A.3Full title of the trial
    DOUBLE BLIND, MULTICENTRE, RANDOMIZED, PLACEBO-CONTROLLED TRIAL TO EVALUATE SAFETY AND EFFICACY OF PITOLISANT IN CHILDREN FROM 6 TO LESS THAN 18 YEARS WITH NARCOLEPSY WITH/WITHOUT CATAPLEXY, FOLLOWED BY A PROLONGED OPEN-LABEL PERIOD
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the efficacy in reducing residual Excessive Daytime Sleepiness (EDS) and the number of cataplectic episodes (for patients with cataplexy) of BF2.649 (pitolisant) in narcoleptic children from 6 to less than 18 years.
    A.4.1Sponsor's protocol code numberP11-06/BF2.649
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/200/2013
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBioprojet
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBioprojet
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioprojet
    B.5.2Functional name of contact pointBioprojet clinical department
    B.5.3 Address:
    B.5.3.1Street Address9 rue Rameau
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75002
    B.5.3.4CountryFrance
    B.5.4Telephone number+3301 47 03 66 33
    B.5.5Fax number+3301 47 03 66 30
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name pitolisant
    D.2.1.1.2Name of the Marketing Authorisation holderBioprojet Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/459
    D.3 Description of the IMP
    D.3.1Product namePitolisant
    D.3.2Product code BF2.649
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPitolisant
    D.3.9.1CAS number 903576-44-3
    D.3.9.2Current sponsor codeBF2.649
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name wakix
    D.2.1.1.2Name of the Marketing Authorisation holderBioprojet Pharma
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/07/459
    D.3 Description of the IMP
    D.3.1Product namePitolisant
    D.3.2Product code BF2.649
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPitolisant
    D.3.9.1CAS number 903576-44-3
    D.3.9.2Current sponsor codeBF2.649
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    D.8 Placebo: 2
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Narcolepsy
    E.1.1.1Medical condition in easily understood language
    Narcolepsy
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10007737
    E.1.2Term Cataplexy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10028713
    E.1.2Term Narcolepsy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 22.1
    E.1.2Level LLT
    E.1.2Classification code 10048322
    E.1.2Term Narcolepsy aggravated
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level LLT
    E.1.2Classification code 10048323
    E.1.2Term Cataplexy aggravated
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10028715
    E.1.2Term Narcolepsy with cataplexy
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of pitolisant in reducing residual Excessive Daytime Sleepiness (EDS) and the number of cataplectic episodes (for patients with cataplexy).
    To determine safety in children and adolescents.
    E.2.2Secondary objectives of the trial
    To assess the long-term safety of BF2.649 in the treatment of EDS in narcoleptic patients with or without cataplexy.
    To assess the drug-drug interactions with possible concomitant therapies.
    To assess the efficacy of long-term therapy with BF2.649 on EDS after a prolonged treatment period.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Male and female children from 6 to less than 18 years of age (until V8) suffering from narcolepsy with or without cataplexy - meeting the International Classification of Sleep Disorders (ICSD-3) criteria (narcolepsy type 1 and 2). Diagnosis confirmed with polysomnography (to be performed if this examination was not performed within the last 12 months) and Multiple Sleep Latency Test for patients without cataplexy.
    2) PDSS score ≥ 15 during baseline period (V1+V2) / 2.
    3) Patients should be free of non-authorized medication, in particular psychostimulant treatments as from the screening visit (V0) onwards.
    4) Parents – and patients old enough to understand who have expressed a willingness to participate in the study, who have signed and dated the informed consent form prior to beginning protocol required procedures.
    5) In the opinion of the investigator, the patient must have adequate support to comply with the entire study requirements as described in the protocol (e.g., transportation to and from trial site, self rating scales and diaries completion, drug compliance, scheduled visits, tests).
    6) Female pubescent patients shall use a birth control method, judged efficient by the investigator, throughout the study and during the month following treatment discontinuation.
    7) Patients should benefit from appropriate healthy insurance system (only applicable where mandatory e.g. in France).
    E.4Principal exclusion criteria
    1) Any other conditions that can be considered the primary causes of EDS: such as sleep related breathing disorders as defined by a sleep Apnea Index ≥ 5 per hour or/and an Apnea/Hypopnea Index ≥ 10 per hour, chronic sleep deprivation, circadian sleep wake rhythm disorder or any other medical or neurological causes that could account for narcolepsy symptoms associated with EDS.
    2) Cataplectic patients treated by anticataplectics (SNRI, SSRI, sodium oxybate) which are not under a stable treatment since at least 4 weeks at the time of inclusion (V2).
    3) Patients treated for cataplexy or any other pathology, by tricyclic antidepressants (clomipramine, imipramine, mirtazapine, desmethylimipramine and protriptyline) are not authorized because they display histamine H1 receptor antagonist activity.
    4) The use of pitolisant within a 30-day period prior to initial screening visit (V0) for this trial.
    5) Current or recent (within one year) history of a substance abuse or dependence disorder including alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
    6) Any significant abnormality of the electrocardiogram and particularly Fridericia’s QTc interval (QTcF = QT/3 60/HR) higher than 450ms.
    7) Patients with severe depression (CDI ≥ 16)
    8) Patient with suicidal risk (C-SSRS)
    9) Positive urinary drug testing (test applicable to patients from 12 years)
    10) Pregnancy (defined as positive β-HCG blood test), breast-feeding, or patients and unable to use an efficient method of birth control shall not be included in the study (for pubescent female only).
    11) Patients with severe hepatic Impairment (Child Pugh C) or with any other significant abnormality in the physical examination or clinical laboratory results.
    12) Psychiatric and neurological disorders, such as moderate or severe psychosis or dementia, depression, history of seizure disorder or other problem that, in the investigator’s opinion, would preclude the patient’s participation and completion of this trial or comprise reliable representation of subjective symptoms.
    13) Active clinically significant illness, including unstable cardiovascular, endocrine, neoplastic, gastrointestinal, haematological, hepatic, immunologic, metabolic, neurological (other than narcolepsy/cataplexy), pulmonary, and/or renal disease which could interfere with the study conduct or counter-indicate the study treatments or place the patient at risk during the trial or compromise the study objectives.
    14) Prior severe adverse reactions to CNS stimulants.
    15) Known hypersensitivity to the tested treatment including active substance and excipients.
    16) The inability to continue daily activities safely, without the use of treatment against EDS.
    17) Any patient presenting congenital galactosemia, glucose-galactose malabsorption or lactase deficiency due to the presence of lactose in investigational treatments.
    18) Patients participating in another study or being in a follow–up period for another study.
    19) Cannot be contacted in case of emergency.
    E.5 End points
    E.5.1Primary end point(s)
    Change in the intensity and frequency of symptoms of narcolepsy (EDS and cataplexy) as measured by the Ullanlinna Narcolepsy Scale (UNS). We will compare the results between pitolisant and placebo groups.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary end point will be evaluated between baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of treatment: [V6 score (D49) + V7 score (D56)]/2.
    E.5.2Secondary end point(s)
    - Changes in EDS as measured by the maintenance of wakefulness test (MWT) between baseline and V7, in pitolisant and placebo groups.
    - Change in EDS measured by the Paediatric Daytime Sleepiness Scale (PDSS) between baseline: [V1 score (D-14) + V2 score (D0)]/2 and the end of treatment: [V6 score (D49) + V7 score (D56)]/2. We will compare the results between pitolisant and placebo groups.
    - Changes in EDS as measured by the Child and Adolescent Sleepiness Scale (CASS) between baseline and the end of treatment, in pitolisant and placebo groups.
    - Changes in the average number of cataplexy episodes per weeks (recorded in sleep diary by patient and/or parent/teacher) between the 2 weeks of baseline and the 2 weeks of end study treatment period (V6, V7), in pitolisant and placebo groups.
    - Differences in weekly frequency of cataplexy episodes (recorded in sleep diary by patient and/or parent/teacher) between baseline and the 4 weeks of stable treatment period (V4 to V7), in pitolisant and placebo groups.
    - Severity of EDS measured by the Clinical Global Impression of severity and change. Changes between baseline and V6, V7, in pitolisant and placebo groups.
    - Severity of cataplexy measured by the Clinical Global Impression of severity and change. Changes between baseline and V6, V7, in pitolisant and placebo groups.
    - Changes between baseline and V6, V7 will be compared for the Ullanlina narcolepsy test, in pitolisant and placebo groups.
    - Changes between baseline and V6 will be compared for the TEA-Ch test, in pitolisant and placebo groups.
    - Comparison between placebo and pitolisant groups on:
    - Withdrawal symptoms questionnaire (DSM IV)
    - Patients’ Global Opinion on treatment effect at the end of treatment.
    - Parents’ and/or Teachers’ Global Opinion on treatment effect at the end of treatment.
    - Changes between baseline and at each visit of the open-label period in EDS.
    - Safety assessment will be done on monitoring of adverse events, physical examination, vital signs, ECG and Blood Laboratory tests modifications and the mood appraisal throughout the study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Followed by 1 week of placebo single blind. Then followed by a prolonged open-label period
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Russian Federation
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The last visit of the last subject.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 108
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 54
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 54
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Patient under age incapable of giving consent personally.
    Informed Consent form will be signed by each patient (if old enough to understand) and both parents (or their legal representative) before the enrolment in the study.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 108
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The double blind phase will be followed by an open label period if patients wish to participate to have treatment access.
    Neither specific treatment or care after the patient participation in the trial are anticipated. It is assumed that the subject will be treated according to the usual physician clinical practice.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-09-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-07
    P. End of Trial
    P.End of Trial StatusCompleted
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