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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Randomized-Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in Subjects with Narcolepsy with Cataplexy

    Summary
    EudraCT number
    		 2016-000426-20
    Trial protocol
    		 GB   CZ   DE   ES   FR   BE   FI   HR   NL  
    Global end of trial date
    10 Jul 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2020
    First version publication date
    23 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15-006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Jazz Pharmaceuticals
    Sponsor organisation address
    3180 Porter Drive, Palo Alto, California, United States,
    Public contact
    Director, Clinical Trial Disclosure & Transparency, Jazz Pharmaceuticals, ClinicalTrialDisclosure@JazzPharma.com
    Scientific contact
    Director, Clinical Trial Disclosure & Transparency, Jazz Pharmaceuticals, ClinicalTrialDisclosure@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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jul 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of JZP-258 in the treatment of cataplexy and excessive daytime sleepiness (EDS) in subjects with narcolepsy.
    Protection of trial subjects
    Safety was assessed by the incidence of observed and reported adverse events (AEs), and changes in electrocardiograms (ECGs), clinical laboratory tests, vital signs, and the Columbia-Suicide Severity Rating Scale (C-SSRS). Safety was assessed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 79
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Spain: 36
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Czech Republic: 26
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 16
    Worldwide total number of subjects
    201
    EEA total number of subjects
    122
    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)
    195
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were evaluated for eligibility during the Screening Period (up to 30 days).

    Period 1
    Period 1 title
    Open Label Treatment and Titration
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label JZP-258
    Arm description
    		 All 201 subjects entered the Open Label Optimized Treatment and Titration Period (OL OTTP) and received at least 1 dose of study drug. During the OL OTTP (12 weeks), eligible subjects were transitioned to JZP-258 treatment based on their pre-treatment status.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JZP-258
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    During the Open-label Treatment and Titration Period (12 weeks), eligible subjects were transitioned to JZP-258 (0.5 g/mL.) treatment based on their pretreatment status (Xyrem, Xyrem and a non-Xyrem anticatapletic, non-Xyrem anticataplectic only, or no anticataplectic).

    Number of subjects in period 1
    		Open-label JZP-258
    Started
    201
    Completed
    155
    Not completed
    46
         Physician decision
    3
         Consent withdrawn by subject
    6
         Non-Compliance with Study Drug
    4
         Adverse event, non-fatal
    18
         Other
    1
         Sponsor Decision
    2
         Lost to follow-up
    3
         Lack of efficacy
    1
         Protocol deviation
    8
    Period 2
    Period 2 title
    Stable Dose
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label JZP-258
    Arm description
    		 During the Stable Dose Period, subjects received open-label JZP-258 at the same unchanged dose that they received during the last 2 weeks of the Open Label Treatment and Titration Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JZP-258
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Open-label JZP-258 (0.5 g/ mL) at the same unchanged dose as during the last 2 weeks of the Open Label Treatment and Titration Period.

    Number of subjects in period 2 [1]
    		Open-label JZP-258
    Started
    149
    Completed
    144
    Not completed
    5
         Adverse event, non-fatal
    1
         Lost to follow-up
    1
         Protocol deviation
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 201 subjects that entered the Open-label Treatment and Titration Period, 149 achieved a tolerable and efficacious dose of JZP-258 and entered the Stable Dose Period. Of those subjects, 136 were randomized.
    Period 3
    Period 3 title
    Double Blind Randomized Withdrawal
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 JZP-258
    Arm description
    		 JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JZP-258
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    JZP-258 (0.5 g/mL) at the dose taken during the last 2 weeks of the Stable Dose Period

    Arm title
    		 Placebo
    Arm description
    		 A matching oral solution to JZP-258.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    A matching oral solution to JZP-258.

    Number of subjects in period 3 [2]
    		JZP-258 Placebo
    Started
    69
    67
    Completed
    69
    59
    Not completed
    0
    8
         Randomized in error
    -
    2
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    3
         Lack of efficacy
    -
    2
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: After completing the Stable Dose Period, 136 subjects were randomized. Two subjects were randomized in error, but did not receive any dose of study drug in the DB RWP. Therefore, 134 subjects received at least 1 dose of study drug in the DB RWP.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open Label Treatment and Titration
    Reporting group description
    		 -

    Reporting group values
    		 Open Label Treatment and Titration Total
    Number of subjects
    		 201 201
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 195 195
        From 65-84 years
    		 6 6
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 122 122
        Male
    		 79 79

    End points

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    End points reporting groups
    Reporting group title
    Open-label JZP-258
    Reporting group description
    		 All 201 subjects entered the Open Label Optimized Treatment and Titration Period (OL OTTP) and received at least 1 dose of study drug. During the OL OTTP (12 weeks), eligible subjects were transitioned to JZP-258 treatment based on their pre-treatment status.
    Reporting group title
    Open-label JZP-258
    Reporting group description
    		 During the Stable Dose Period, subjects received open-label JZP-258 at the same unchanged dose that they received during the last 2 weeks of the Open Label Treatment and Titration Period.
    Reporting group title
    JZP-258
    Reporting group description
    		 JZP-258 at the dose taken during the last 2 weeks of the Stable Dose Period.

    Reporting group title
    Placebo
    Reporting group description
    		 A matching oral solution to JZP-258.

    Primary: Change in Average Weekly Number of Cataplexy Attacks

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    End point title
    		 Change in Average Weekly Number of Cataplexy Attacks
    End point description
    Subjects completed a daily Cataplexy Frequency Diary each night prior to bedtime. Subjects were to record the number of cataplexy attacks that they had each day.
    End point type
    Primary
    End point timeframe
    From the two weeks of the Stable-Dose Period to the two weeks of the Double Blind Randomized Withdrawal Period.
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    69
    65
    Units: Number
        median (inter-quartile range (Q1-Q3))
    0.00 (-0.49 to 1.75)
    2.35 (0.00 to 11.61)
    Statistical analysis title
    		 Change in Weekly Number of Cataplexy Attacks
    Comparison groups
    JZP-258 v Placebo
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Rank-based ANCOVA
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.044
         upper limit
    		 -1.5

    Secondary: Change in Epworth Sleepiness Scale (ESS) Score

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    End point title
    		 Change in Epworth Sleepiness Scale (ESS) Score
    End point description
    This is the key secondary endpoint. The Epworth Sleepiness Scale (ESS) is a self-administered questionnaire with 8 questions asking the subject how likely they would be to doze off or fall asleep in different situations.
    End point type
    Secondary
    End point timeframe
    From the end of the Stable Dose Period to the end of the Double Blind Randomized Withdrawal Period
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    69
    65
    Units: Point on Scale
        median (inter-quartile range (Q1-Q3))
    0.00 (-1.0 to 1.0)
    2.0 (0.00 to 5.0)
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIc) for Narcolepsy Overall

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    End point title
    		 Patient Global Impression of Change (PGIc) for Narcolepsy Overall
    End point description
    At the end of the Double Blind Randomized Withdrawal Period, subjects rated the change in their condition on a 7-point scale ranging from 1 = “very much improved” to 7 = “very much worse” since the last visit. This endpoint measures the percentage of subjects with worsening PGIc scores for narcolepsy overall (defined as scores of Much Worse or Very Much Worse).
    End point type
    Secondary
    End point timeframe
    At the end of the Double Blind Randomized Withdrawal Period.
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    69
    65
    Units: subjects
        number (not applicable)
    3
    29
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Change (CGIc) for Narcolepsy Overall

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    End point title
    		 Clinical Global Impression of Change (CGIc) for Narcolepsy Overall
    End point description
    At the end of the Double Blind Randomized Withdrawal Period, Investigators rated their impression of any change in the severity of the subject’s narcolepsy overall condition since the start of the Double Blind Randomized Withdrawal Period on a 7-point scale ranging from 1 = “very much improved” to 7 = “very much worse”. This endpoint measures the percentage of subjects with worsening CGIc scores for narcolepsy overall, defined as scores of Much Worse or Very Much Worse.
    End point type
    Secondary
    End point timeframe
    At the end of the Double Blind Randomized Withdrawal Period.
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    68
    65
    Units: subjects
        number (not applicable)
    4
    39
    No statistical analyses for this end point

    Secondary: Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores

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    End point title
    		 Change in 36-Item Short Form Health Survey Version 2 (SF-36v2) Scores
    End point description
    The SF-36v2 is a multi-purpose, short-form health survey with 36 questions/ items. It yields an 8-scale profile of functional health and well-being scores as well as a psychometrically-based physical and mental overall component summary measures. Two summary scores were derived using the SF-36v2. Physical Component Summary measures dimensions of functional health that are meaningful to respondents, including the impact of health and health-related changes on physical function, pain, and the ability to carry out daily roles. The Mental Component Summary component scale measures the impact of health and health-related changes on well-being, including vitality, social function, and emotional well-being.
    End point type
    Secondary
    End point timeframe
    At the end of the Double Blind Randomized Withdrawal Period.
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    67
    65
    Units: Score
    median (inter-quartile range (Q1-Q3))
        Physical Component Summary
    -0.03 (-2.07 to 2.41)
    -1.92 (-3.46 to 1.73)
        Mental Component Summary
    1.55 (-1.88 to 3.78)
    -1.92 (-6.28 to 1.34)
    No statistical analyses for this end point

    Secondary: Change in EQ-5D-5L Crosswalk Index Score and Visual Analog Scale

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    End point title
    		 Change in EQ-5D-5L Crosswalk Index Score and Visual Analog Scale
    End point description
    The EQ-5D-5L is a standardized instrument for use as a measure of health outcome that includes a descriptive system consisting of 5 dimensions (mobility, self-care, usual activities, pain/ discomfort, and anxiety/ depression). The EQ-5D-5L includes five levels of severity for each of the 5 dimensions of the descriptive system(1= no problems, 2= slight problems, 3= moderate problems, 4= severe problems, and 5= extreme problems) that reflect increasing levels of difficulty. Subjects completed the EQ-5D-5L at the end of the OL SDP and the end of the DB RWP by selecting the most appropriate level in each of the 5 dimensions.
    End point type
    Secondary
    End point timeframe
    At the end of the Double Blind Randomized Withdrawal Period.
    End point values
    		 JZP-258 Placebo
    Number of subjects analysed
    68 [1]
    65
    Units: score
    median (inter-quartile range (Q1-Q3))
        Crosswalk index
    0.00 (-0.01 to 0.03)
    0.00 (-0.05 to 0.03)
        VAS Score
    0.00 (0.00 to 5.00)
    -5.00 (-10.00 to 5.00)
    Notes
    [1] - There were 68 JZP-258 subjects included in the Crosswalk Index, and 69 in the VAS Score.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety data are summarized for all subjects who received at least 1 dose of study medication across all periods.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    JZP-258
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 JZP-258 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 201 (2.49%)
    2 / 65 (3.08%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Muscle enzyme increased
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral nerve paresis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral cardiomyopathy
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 JZP-258 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    108 / 201 (53.73%)
    12 / 65 (18.46%)
    Nervous system disorders
    Cataplexy
         subjects affected / exposed
    21 / 201 (10.45%)
    5 / 65 (7.69%)
         occurrences all number
    23
    6
    Dizziness
         subjects affected / exposed
    23 / 201 (11.44%)
    0 / 65 (0.00%)
         occurrences all number
    34
    0
    Headache
         subjects affected / exposed
    45 / 201 (22.39%)
    1 / 65 (1.54%)
         occurrences all number
    85
    1
    Somnolence
         subjects affected / exposed
    5 / 201 (2.49%)
    6 / 65 (9.23%)
         occurrences all number
    5
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    13 / 201 (6.47%)
    0 / 65 (0.00%)
         occurrences all number
    16
    0
    Nausea
         subjects affected / exposed
    27 / 201 (13.43%)
    0 / 65 (0.00%)
         occurrences all number
    32
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    17 / 201 (8.46%)
    1 / 65 (1.54%)
         occurrences all number
    21
    1
    Nasopharyngitis
         subjects affected / exposed
    19 / 201 (9.45%)
    2 / 65 (3.08%)
         occurrences all number
    21
    2
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 201 (5.47%)
    0 / 65 (0.00%)
         occurrences all number
    16
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 201 (7.46%)
    1 / 65 (1.54%)
         occurrences all number
    16
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2016
    Clinical Protocol Amendment 1.0
    07 Nov 2016
    Updates to the efficacy population and statistical methodology.
    10 Apr 2017
    Updates to the efficacy population.
    15 Dec 2017
    Addition of a 6-month OLE.
    15 May 2018
    Addition of a planned interim analysis in order to ensure the availability of study results at the earliest possible date in order to provide a low sodium treatment option alternative.

    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
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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