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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of Xyrem with an Open- Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy

    Summary
    EudraCT number
    		 2014-001389-93
    Trial protocol
    		 FI   NL   IT   FR  
    Global end of trial date
    25 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Aug 2019
    First version publication date
    16 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13-005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02221869
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Jazz Pharmaceuticals
    Sponsor organisation address
    3170 Porter Drive, Palo Alto, United States,
    Public contact
    Grace Wang, Senior Director, Jazz Pharmaceuticals, +1 6504962687, grace.wang@jazzpharma.com
    Scientific contact
    Grace Wang, Senior Director, Jazz Pharmaceuticals, +1 6504962687, grace.wang@jazzpharma.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?
    Yes
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    10 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objectives are: 1) To evaluate the efficacy of Xyrem (sodium oxybate) oral solution in the treatment of cataplexy in pediatric subjects with narcolepsy 2) To evaluate the safety of Xyrem in the treatment of cataplexy in pediatric subjects with narcolepsy for up to one year
    Protection of trial subjects
    Safety was assessed by the incidence of TEAEs, and descriptively for vital signs, 12-lead ECG, PSG parameters, clinical laboratory results, and other assessments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2014
    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
    Netherlands: 8
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    United States: 62
    Worldwide total number of subjects
    106
    EEA total number of subjects
    44
    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)
    38
    Adolescents (12-17 years)
    68
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 106 subjects were enrolled. Xyrem-naïve subjects (n=74) entered the Dose Titration Period (3 to 10 weeks). Xyrem-naïve and on Xyrem subjects (n= 99) entered the Stable Dose Period (2 to 3 weeks). 96 subjects then entered the Double-Blind Randomized Withdrawal Period (2 weeks). 95 subjects then entered the Open-label Safety Period (38 to 47 weeks).

    Pre-assignment
    Screening details
    		 Subjects aged 7-17 who were being treated with Xyrem or Xyrem naïve were eligible for the study. 63 subjects were randomized and 33 received open-label Xyrem during the Double-blind Treatment Period. 106 and 63 subjects comprised the Enrolled population and the Efficacy population respectively.

    Period 1
    Period 1 title
    Double-blind Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Randomized to Xyrem
    Arm description
    		 Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Xyrem
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks.

    Arm title
    		 Randomized to Xyrem Placebo
    Arm description
    		 Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Xyrem Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Xyrem placebo at a volume and regimen equivalent to the stable dose of Xyrem.

    Number of subjects in period 1 [1]
    		Randomized to Xyrem Randomized to Xyrem Placebo
    Started
    31
    32
    Completed
    30
    32
    Not completed
    1
    0
         Other
    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: Subjects reported in the baseline period represent the randomized population in the Double-blind Treatment Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomized to Xyrem
    Reporting group description
    		 Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks.

    Reporting group title
    Randomized to Xyrem Placebo
    Reporting group description
    		 Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.

    Reporting group values
    		 Randomized to Xyrem Randomized to Xyrem Placebo Total
    Number of subjects
    		 31 32 63
    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)
    		 12 14 26
        Adolescents (12-17 years)
    		 19 18 37
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 13 15 28
        Male
    		 18 17 35

    End points

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    End points reporting groups
    Reporting group title
    Randomized to Xyrem
    Reporting group description
    		 Active Xyrem continued as a double-blind treatment at the stable dose taken and regimen taken in the prior 2 weeks.

    Reporting group title
    Randomized to Xyrem Placebo
    Reporting group description
    		 Xyrem placebo was initiated as a double-blind treatment at a volume and regimen equivalent to the Xyrem dose taken in the prior 2 weeks.

    Primary: Change in Weekly Number of Cataplexy Attacks

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    End point title
    		 Change in Weekly Number of Cataplexy Attacks
    End point description
    End point type
    Primary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)
    End point values
    		 Randomized to Xyrem Randomized to Xyrem Placebo
    Number of subjects analysed
    31
    32
    Units: number of attacks
        median (inter-quartile range (Q1-Q3))
    0.27 (-1.00 to 2.50)
    12.71 (3.44 to 19.77)
    Statistical analysis title
    		 Change in Weekly Number of Cataplexy Attacks
    Comparison groups
    Randomized to Xyrem Placebo v Randomized to Xyrem
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Clinical Global Impression of Change (CGIc) for Cataplexy Severity

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    End point title
    		 Clinical Global Impression of Change (CGIc) for Cataplexy Severity
    End point description
    End point type
    Secondary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)
    End point values
    		 Randomized to Xyrem Randomized to Xyrem Placebo
    Number of subjects analysed
    29
    32
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.4 ± 1.12
    -1.5 ± 1.19
    No statistical analyses for this end point

    Secondary: Change in the Epworth Sleepiness Scale (ESS) (CHAD) Score

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    End point title
    		 Change in the Epworth Sleepiness Scale (ESS) (CHAD) Score
    End point description
    End point type
    Secondary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)
    End point values
    		 Randomized to Xyrem Randomized to Xyrem Placebo
    Number of subjects analysed
    30
    31
    Units: score on a scale
        median (inter-quartile range (Q1-Q3))
    0.0 (-1.0 to 2.0)
    3.0 (1.0 to 5.0)
    No statistical analyses for this end point

    Secondary: CGIc for Narcolepsy Overall

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    End point title
    		 CGIc for Narcolepsy Overall
    End point description
    End point type
    Secondary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)
    End point values
    		 Randomized to Xyrem Randomized to Xyrem Placebo
    Number of subjects analysed
    29
    32
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.4 ± 0.95
    -1.4 ± 1.13
    No statistical analyses for this end point

    Secondary: Change in Quality of Life (QoL; SF-10 Physical and Psychosocial Summary Score) From the End of the Stable Dose Period to the End of the Double-blind Treatment Period

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    End point title
    		 Change in Quality of Life (QoL; SF-10 Physical and Psychosocial Summary Score) From the End of the Stable Dose Period to the End of the Double-blind Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double-blind Treatment Period (2 weeks)
    End point values
    		 Randomized to Xyrem Randomized to Xyrem Placebo
    Number of subjects analysed
    30
    30
    Units: score on a scale
    median (inter-quartile range (Q1-Q3))
        SF-10 Physical Summary Score
    0 (-2.73 to 2.50)
    0 (-8.42 to 2.73)
        SF-10 Psychosocial Summary Score
    0 (-6.24 to 2.68)
    -2.67 (-8.02 to 2.67)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety data are provided through the 120 day update (30 April 2018)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety Population
    Reporting group description
    		 Safety population who took study drug

    Serious adverse events
    		 Safety Population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 104 (1.92%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety Population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 104 (71.15%)
    Investigations
    Weight decreased
         subjects affected / exposed
    12 / 104 (11.54%)
         occurrences all number
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 104 (5.77%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    17 / 104 (16.35%)
         occurrences all number
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    18 / 104 (17.31%)
         occurrences all number
    20
    Vomiting
         subjects affected / exposed
    17 / 104 (16.35%)
         occurrences all number
    19
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    19 / 104 (18.27%)
         occurrences all number
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 104 (6.73%)
         occurrences all number
    9
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 104 (4.81%)
         occurrences all number
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 104 (7.69%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2014
    Modified Exclusion Criteria.
    01 Apr 2015
    Modified Inclusion Criteria and certain study procedures.
    05 Aug 2015
    Modified Inclusion and Exclusion Criteria. Modified certain study procedures.
    05 Apr 2016
    Modified Exclusion Criteria. Modified certain study procedures.

    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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