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    Clinical Trial Results:
    A randomized, double blind study comparing BF2.649 (Pitolisant) to placebo in two parallel groups on the weekly frequency of cataplexy attacks and Excessive Daytime Sleepiness in narcoleptic patients with cataplexy

    Summary
    EudraCT number
    		 2012-003076-39
    Trial protocol
    		 HU   BG   CZ  
    Global end of trial date
    28 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Nov 2024
    First version publication date
    28 Nov 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P11-05
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 abbreviated name: HARMONY CTP
    Sponsors
    Sponsor organisation name
    Bioprojet
    Sponsor organisation address
    9 Rue Rameau, Paris, France, 75002
    Public contact
    Clinical Development Director, Bioprojet Pharma, (33) 147 03 66 33, contact@bioprojet.com
    Scientific contact
    Clinical Development Director, Bioprojet Pharma, (33) 147 03 66 33, contact@bioprojet.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to confirm the efficacy of pitolisant (BF2.649) compared to placebo to decrease the frequency of cataplexy attacks and to reduce EDS (Excessive Daytime Sleepiness) in patients suffering from narcolepsy with cataplexy.
    Protection of trial subjects
    An independent Safety Data Monitoring Committee (SDMC) was implemented and served to monitor the study progress and safety data. The SDMC reviewed blinded study information during the conduct of the study and provided the sponsor with recommendations regarding study modification, continuation or termination. Monitoring visits to the study centers were conducted periodically during the study, in order to ensure that the clinical investigators continued to meet their contractual, clinical and regulatory obligations with regard to protocol compliance, adherence to regulatory and ethical requirements and the protection of the patients’ rights and safety.
    Background therapy
    		 Several anticataplectic treatments (e.g. sodium oxybate, fluoxetine, venlafaxine) were authorized on the condition that treatment at stable doses had been taken for at least 1 month prior to the trial and the dose was not changed throughout the trial.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Apr 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 1
    Country: Number of subjects enrolled
    Serbia: 16
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Russian Federation: 40
    Country: Number of subjects enrolled
    Ukraine: 8
    Worldwide total number of subjects
    106
    EEA total number of subjects
    32
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    105
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Date of first patient enrolled: April 19th 2013, recruitment ended mid November 2014

    Pre-assignment
    Screening details
    		 During the screening visit, the investigator checked the inclusion and exclusion criteria and performed all required screening assessments. For patients treated with prohibited treatments, a 1 week wash-out period was conducted. 117 patients were screened for inclusion. Of those, 106 patients were eligible for entry into the study.

    Pre-assignment period milestones
    Number of subjects started
    		 106
    Number of subjects completed
    		 105

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Period 1
    Period 1 title
    Double-Blind (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    BF2.649 and placebo at different doses were provided in capsules. The capsules were identical in appearance to ensure that neither the patient nor the investigator or members of the clinical staff knew the identity of the study medication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BF2.649 Treatment arm (Double-blind)
    Arm description
    		 Participants who qualified for treatment were administered a Pitolisant (BF2.649) capsule by escalating doses (5-, 10-, 20-, or 40 mg/d) orally daily (OD), before breakfast with a glass of water.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pitolisant
    Investigational medicinal product code
    BF2.649
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients started with BF2.649 at 5 mg OD during first week and then took BF2.649 at 10 mg OD during second week. For the third week, the dose could be increased up to 20 mg OD or remained at medium dose (10 mg OD) or even decreased at low dose (5 mg OD), on the basis of individual efficacy and tolerance results. At D21, an individual dose adjustment could be performed again: the investigator determined the optimum dose of study treatment (i.e 5, 10, 20 mg or 40 mg OD) based on efficacy and tolerability, and assigned the patient to receive this optimum dose for the following 4 weeks.

    Arm title
    		 Placebo arm (Double-blind)
    Arm description
    		 Participants who qualified for treatment were administered a placebo capsule orally daily before breakfast with a glass of water
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Same dosage regimen than BF2.649 Treatment arm, but with placebo capsules.

    Number of subjects in period 1 [1]
    		BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind)
    Started
    54
    51
    Completed
    50
    48
    Not completed
    4
    3
         Consent withdrawn by subject
    2
    1
         Patient’s decision/lack of efficacy/adverse event
    1
    -
         Patient’s decision and lack of efficacy
    1
    1
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One included patient was prematurely withdrawn.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BF2.649 Treatment arm (Double-blind)
    Reporting group description
    		 Participants who qualified for treatment were administered a Pitolisant (BF2.649) capsule by escalating doses (5-, 10-, 20-, or 40 mg/d) orally daily (OD), before breakfast with a glass of water.

    Reporting group title
    Placebo arm (Double-blind)
    Reporting group description
    		 Participants who qualified for treatment were administered a placebo capsule orally daily before breakfast with a glass of water

    Reporting group values
    		 BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind) Total
    Number of subjects
    		 54 51 105
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 54 50 104
        From 65-84 years
    		 0 1 1
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 34 (18 to 64) 39 (18 to 66) -
    Gender categorical
    Units: Subjects
        Female
    		 28 24 52
        Male
    		 26 27 53

    End points

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    End points reporting groups
    Reporting group title
    BF2.649 Treatment arm (Double-blind)
    Reporting group description
    		 Participants who qualified for treatment were administered a Pitolisant (BF2.649) capsule by escalating doses (5-, 10-, 20-, or 40 mg/d) orally daily (OD), before breakfast with a glass of water.

    Reporting group title
    Placebo arm (Double-blind)
    Reporting group description
    		 Participants who qualified for treatment were administered a placebo capsule orally daily before breakfast with a glass of water

    Primary: Change in the Weekly Rate of Cataplexy (WRC)

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    End point title
    		 Change in the Weekly Rate of Cataplexy (WRC)
    End point description
    The measure of anticataplectic efficacy was assessed by the change in the average number of cataplexy attacks per week between the 2 weeks of baseline (Day-14 to Day 0) and the 4 weeks of stable treatment period.
    End point type
    Primary
    End point timeframe
    Between the 2 weeks of baseline (Day-14 to Day 0) and the 4 weeks of stable treatment period (Double-Bind).
    End point values
    		 BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind)
    Number of subjects analysed
    54
    51
    Units: number of cataplexy attacks per week
    geometric mean (confidence interval 95%)
        Baseline rate of WRC
    9.15 (7.60 to 11.01)
    7.31 (6.02 to 8.87)
        Stable treatment period rate of WRC
    2.27 (1.51 to 3.41)
    4.51 (2.90 to 7.02)
    Statistical analysis title
    		 Reduction of cataplexy attacks
    Statistical analysis description
    The reduction of cataplexy by 75% (WCRs/b=0.25) in the pitolisantgroup, higher than with placebo (38%; WCRs/b=0.62), was shown highly significant (Poisson regression adjusted for baseline, rate Ratio rR=0.51, 95%CI 0.43 to 0.60; p<0.0001;
    Comparison groups
    BF2.649 Treatment arm (Double-blind) v Placebo arm (Double-blind)
    Number of subjects included in analysis
    105
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Poisson regression adjusted for baseline
    Parameter type
    		 Rate Ratio
    Point estimate
    0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.43
         upper limit
    		 0.6

    Secondary: Number of cataplexy attacks per week (as recorded in CRF): change during the 2 weeks of end of treatment period

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    End point title
    		 Number of cataplexy attacks per week (as recorded in CRF): change during the 2 weeks of end of treatment period
    End point description
    Change in the average number of cataplexy attacks per week (as recorded in CRF) between the 2 weeks of baseline [(V1+V2) / 2], and the 2 weeks of end treatment period [(V5+V6) / 2];
    End point type
    Secondary
    End point timeframe
    Change in the average number of cataplexy attacks per week (as recorded in CRF) between the 2 weeks of baseline [(V1+V2) / 2], and the 2 weeks of end treatment period [(V5+V6) / 2];
    End point values
    		 BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind)
    Number of subjects analysed
    54
    51
    Units: Number of cataplexy attacks per week
    geometric mean (confidence interval 95%)
        Baseline (BL) - (Wk1+Wk2)/2
    9.15 (7.60 to 11.01)
    7.31 (6.02 to 8.87)
        Final (F) - (Wk8+Wk9)/2
    1.99 (1.29 to 3.05)
    4.26 (2.72 to 6.66)
        F/BL
    0.22 (0.15 to 0.32)
    0.58 (0.40 to 0.85)
    No statistical analyses for this end point

    Secondary: Proportion of patients with high frequency cataplexy episodes

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    End point title
    		 Proportion of patients with high frequency cataplexy episodes
    End point description
    Proportion of patients with high frequency cataplexy episodes
    End point type
    Secondary
    End point timeframe
    During whole double blind treatment duration
    End point values
    		 BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind)
    Number of subjects analysed
    54
    51
    Units: Patients with high frequency of cataplex
        High frequency at baseline > 15
    15
    9
        High frequency at stable dose > 15
    4
    12
    No statistical analyses for this end point

    Secondary: Epworth Sleepiness Scale (ESS) score

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    End point title
    		 Epworth Sleepiness Scale (ESS) score
    End point description
    ESS score: difference between the mean value during baseline [(V1+V2) / 2] and the mean value during end treatment period [(V5+V6) / 2]
    End point type
    Secondary
    End point timeframe
    During study double blind treatment
    End point values
    		 BF2.649 Treatment arm (Double-blind) Placebo arm (Double-blind)
    Number of subjects analysed
    54
    51
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (BL)
    17.4 ( 3.3 )
    17.3 ( 3.3 )
        Final (F)
    12.0 ( 5.4 )
    15.4 ( 5 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events AEs were reported during the study course and up to one month after the last study visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Pitolisant (BF2.649)
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Pitolisant (BF2.649) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 51 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1.9%
    Non-serious adverse events
    		 Pitolisant (BF2.649) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 54 (35.19%)
    17 / 51 (33.33%)
    Cardiac disorders
    Heart rate increased
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Bundle branch block right
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 54 (9.26%)
    5 / 51 (9.80%)
         occurrences all number
    5
    6
    Dizziness
         subjects affected / exposed
    0 / 54 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    Migraine
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Blood cholesterol increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood triglycerides increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Immune system disorders
    Monocyte count increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Neutrophil count increased
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    White blood cell analysis abnormal
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 54 (3.70%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Wound
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Somnolence
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Anxiety
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Apathy
         subjects affected / exposed
    1 / 54 (1.85%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    Dyssomnia
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Fatigue
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Depressed mood
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Hypersomnia
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2012
    Addition of the pitolisant 40 mg once daily dose in the treatment scheme

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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