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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Study of Diazoxide Choline Controlled-Release Tablet (DCCR) in Patients with Prader-Willi Syndrome

    Summary
    EudraCT number
    		 2018-004215-50
    Trial protocol
    		 GB  
    Global end of trial date
    09 Jun 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Sep 2023
    First version publication date
    29 Mar 2023
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Minor updates and clarifications.

    Trial information

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    Trial identification
    Sponsor protocol code
    C601
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03440814
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Soleno Therapeutics UK Limited
    Sponsor organisation address
    Garden Cottage, Badgemore Park, Henley-on-Thames, United Kingdom, RG9 4NR
    Public contact
    Clinical Trial Information, Soleno Therapeutics UK Limited, 44 1491756023, soleno-uk@soleno.life
    Scientific contact
    Clinical Trial Information, Soleno Therapeutics UK Limited, 44 1491756022, C601ProjectManager@soleno.life
    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
    09 Jun 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of diazoxide choline controlled release compared to placebo on hyperphagia in PWS subjects.
    Protection of trial subjects
    IDMC (Data Safety Monitoring Board) met two times during study to review unblinded safety data.
    Background therapy
    		 Subjects were titrated to a maintenance dose over a 2-6 week period depending on subjects' weight.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 May 2018
    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
    United States: 101
    Country: Number of subjects enrolled
    United Kingdom: 25
    Worldwide total number of subjects
    126
    EEA total number of subjects
    0
    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)
    60
    Adolescents (12-17 years)
    41
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 People with PWS who met the eligibility criteria were enrolled / randomised. The first subject was screened in the US on 17May2018 and in the UK on 26Jun2019; all sites were either hospitals or academic medical centres.

    Pre-assignment
    Screening details
    		 181 subjects were screened, 158 were eligible and entered the two-week, single-blind placebo run-in period and 127 subjects were enrolled / randomised in the trial. 126 of the 127 subjects took any amount of study drug.

    Period 1
    Period 1 title
    Double blind treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Study team members were blinded to the randomised assignment. Study drug was also blinded. Placebo tablets matching the size, shape and colour of the respective DCCR tablet strengths were used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DCCR
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    DCCR
    Investigational medicinal product code
    Other name
    Diazoxide choline controlled release, Diazoxide choline extended-release
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with PWS were dosed dependent on their weight; 25mg, 75mg or 150mg DCCR tablets could be taken; DCCR was taken once daily. Tablets must be swallowed whole and should not be broken, crushed or chewed. The target dose by weight(kg) was as follows: Subjects weighing 20 to <30kg took 100mg DCCR/day Subjects weighing equal to or greater than 30 to <40kg took 150mg DCCR/day Subjects weighing equal to or greater than 40 to <65kg took 225mg DCCR/day Subjects weighing equal to or greater than 65 to <100kg took 375mg DCCR/day Subjects weighing equal to or greater than 100 to <135kg took 450mg DCCR/day Subjects randomised to the DCCR treatment group were titrated every 2 weeks until the target dose was achieved.

    Arm title
    		 Placebo for DCCR
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for DCCR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with PWS were dosed dependent on their weight; 25mg, 75mg or 150mg placebo tablets could be taken; Placebo was taken once daily. Tablets must be swallowed whole and should not be broken, crushed or chewed. The target dose by weight(kg) was as follows: Subjects weighing 20 to <30kg took 100mg placebo/day Subjects weighing equal to or greater than 30 to <40kg took 150mg placebo/day Subjects weighing equal to or greater than 40 to <65kg took 225mg placebo/day Subjects weighing equal to or greater than 65 to <100kg took 375mg placebo/day Subjects weighing equal to or greater than 100 to <135kg took 450mg placebo/day Subjects randomised to the placebo group were titrated on placebo, similar to the DCCR group.

    Number of subjects in period 1
    		DCCR Placebo for DCCR
    Started
    84
    42
    Completed
    79
    41
    Not completed
    5
    1
         Adverse event, not serious
    -
    1
         Adverse event, non-fatal
    2
    -
         Consent withdrawn by parent/legal guardian
    1
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double blind treatment period
    Reporting group description
    		 The reporting group included 126 subjects who received at least one dose of study medication.

    Reporting group values
    		 Double blind treatment period Total
    Number of subjects
    		 126 126
    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)
    		 60 60
        Adolescents (12-17 years)
    		 41 41
        Adults (18-64 years)
    		 25 25
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
        Age
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 13.4 (4 to 44) -
    Gender categorical
    Units: Subjects
        Female
    		 70 70
        Male
    		 56 56
    Subject analysis sets

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population includes all randomised subjects who had a Baseline HQ-CT value and at least one post-Baseline HQ-CT value.

    Subject analysis set title
    Intent to treat (ITT) population - Pre-COVID Analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pre-COVID analysis population consisted of all subjects who had at least one post-baseline assessment of HQ-CT prior to March 1, 2020 when a national emergency was declared in the US as a result of the COVID-19 pandemic.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomised subjects who received at least one dose of study drug.

    Subject analysis sets values
    		 Intent-to-treat (ITT) population Intent to treat (ITT) population - Pre-COVID Analysis Safety population
    Number of subjects
    124
    124
    126
    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)
    58
    58
    60
        Adolescents (12-17 years)
    41
    41
    41
        Adults (18-64 years)
    25
    25
    25
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
        Age
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    13.5 (4 to 44)
    13.5 (4 to 44)
    13.4 (4 to 44)
    Gender categorical
    Units: Subjects
        Female
    69
    69
    70
        Male
    55
    55
    56

    End points

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    End points reporting groups
    Reporting group title
    DCCR
    Reporting group description
    		 -

    Reporting group title
    Placebo for DCCR
    Reporting group description
    		 -

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population includes all randomised subjects who had a Baseline HQ-CT value and at least one post-Baseline HQ-CT value.

    Subject analysis set title
    Intent to treat (ITT) population - Pre-COVID Analysis
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pre-COVID analysis population consisted of all subjects who had at least one post-baseline assessment of HQ-CT prior to March 1, 2020 when a national emergency was declared in the US as a result of the COVID-19 pandemic.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety population includes all randomised subjects who received at least one dose of study drug.

    Primary: Hyperphagia Questionnaire (HQ-CT) Change from Baseline at Visit 7 (Week 13)

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    End point title
    		 Hyperphagia Questionnaire (HQ-CT) Change from Baseline at Visit 7 (Week 13)
    End point description
    Hyperphagia-related behaviors were assessed by the validated hyperphagia questionnaire for clinical trials (HQ-CT), an instrument designed to measure symptoms of food related preoccupations and behaviors that was completed by the caregiver. The HQ-CT consists of nine items with responses ranging from 0–4 units each (possible total score range: 0−36). The HQ-CT was assessed at Screening, Baseline (Visit 2), and approximately every 4 weeks post-dose at Week 4, Week 8, and Week 13. A decrease in score from baseline represented improvement.
    End point type
    Primary
    End point timeframe
    Baseline to Visit 7 (Week 13)
    End point values
    		 DCCR Placebo for DCCR
    Number of subjects analysed
    82
    42
    Units: HQ-CT Score
        least squares mean (standard error)
    -5.94 ± 0.879
    -4.27 ± 1.145
    Statistical analysis title
    		 Primary endpoint - HQ-CT
    Statistical analysis description
    The primary endpoint (change from Baseline at Visit 7 (Week 13) in the HQ-CT Total Score) was analysed using a linear mixed model for repeated measurements in the ITT Population. All available data from each subject was used, with no imputation of missing data.
    Comparison groups
    DCCR v Placebo for DCCR
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1983 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.24
         upper limit
    		 0.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.294
    Notes
    [1] - The primary endpoint was analysed using a linear mixed model for repeated measurements in the ITT Population. All available data from each subject was used, with no imputation of missing data.

    Secondary: Clinical Global Impression of Improvement (CGI-I) at Visit 7 (Week 13)

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    End point title
    		 Clinical Global Impression of Improvement (CGI-I) at Visit 7 (Week 13)
    End point description
    The Clinical Global Impression of Improvement (CGI-I) is a single statement designed to assess the Investigator’s overall perception of change in the subject’s condition across the course of the clinical trial.  The Investigator provided a response to “Compared to the subject’s condition at enrolment, the subject’s condition is:” by rating the subject’s behavior using a 7-point response scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, and Very much worse. The Investigator only took into account the subject’s PWS condition.
    End point type
    Secondary
    End point timeframe
    At Visit 7 (Week 13)
    End point values
    		 DCCR Placebo for DCCR
    Number of subjects analysed
    82
    42
    Units: Participants
        Very Much Improved
    0
    0
        Much Improved
    5
    0
        Minimally Improved
    25
    2
        No Change
    41
    37
        Minimally Worse
    11
    3
        Much Worse
    0
    0
        Very Much Worse
    0
    0
    Statistical analysis title
    		 CGI-I at Visit 7 (Week 13)
    Statistical analysis description
    The Clinical Global Impression of Improvement was compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) mean score test with modified ridit scores, stratified by the randomisation stratification variables.
    Comparison groups
    DCCR v Placebo for DCCR
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.0294 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [2] - Distribution difference
    [3] - The Clinical Global Impression of Improvement was compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) mean score test with modified ridit scores, stratified by the randomisation stratification variables.

    Secondary: Caregiver Global Impression of Change (GI-C) at Visit 7 (Week 13)

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    End point title
    		 Caregiver Global Impression of Change (GI-C) at Visit 7 (Week 13)
    End point description
    The Caregiver Global Impression of Change (GI-C) is a single statement designed to assess the caregiver’s overall perception of change in the subject across the course of the clinical trial.  The caregiver provided a response to “Please choose the response below that best describes the overall change in the person’s PWS since they started taking the study medication” using a 7-point graded response scale: Very much better, Moderately better, A little better, No change, A little worse, Moderately worse, and Very much worse.
    End point type
    Secondary
    End point timeframe
    At Visit 7 (Week 13)
    End point values
    		 DCCR Placebo for DCCR
    Number of subjects analysed
    82
    42
    Units: Participants
        Very Much Improved
    4
    1
        Much Improved
    6
    3
        Minimally Improved
    22
    8
        No Change
    39
    20
        Minimally Worse
    6
    5
        Much Worse
    4
    3
        Very Much Worse
    1
    2
    Statistical analysis title
    		 Caregiver GI-C at Visit 7 (Week 13)
    Statistical analysis description
    Caregiver Global Impression of Change was compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) mean score test with modified ridit scores, stratified by the randomisation stratification variables.
    Comparison groups
    DCCR v Placebo for DCCR
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4089 [4]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [4] - Caregiver Global Impression of Change was compared between treatment groups using the Cochran-Mantel-Haenszel (CMH) mean score test with modified ridit scores, stratified by the randomisation stratification variables.

    Secondary: Change in Fat Mass (kg) from Baseline at Visit 7 (Week 13)

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    End point title
    		 Change in Fat Mass (kg) from Baseline at Visit 7 (Week 13)
    End point description
    Whole body scans were performed. Reports included a breakdown of the following regions: left arm, right arm, trunk, left leg, right leg, and head. Each region was evaluated for body fat mass (g).
    End point type
    Secondary
    End point timeframe
    Baseline to Visit 7 (Week 13)
    End point values
    		 DCCR Placebo for DCCR
    Number of subjects analysed
    82
    42
    Units: Body Fat Mass (kg)
        least squares mean (standard error)
    -0.80 ± 0.356
    0.25 ± 0.444
    Statistical analysis title
    		 Change in Fat Mass (kg)
    Statistical analysis description
    LSMeans are from an analysis of covariance (ANCOVA) model with the change from Baseline at Visit 7 (Week 13) as the response, Baseline value as covariate, and randomisation stratification variables (as randomised) as factors.
    Comparison groups
    DCCR v Placebo for DCCR
    Number of subjects included in analysis
    124
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0225 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.95
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.458
    Notes
    [5] - LSMeans are from an analysis of covariance (ANCOVA) model with the change from Baseline at Visit 7 (Week 13) as the response, Baseline value as covariate, and randomisation stratification variables (as randomised) as factors.

    Post-hoc: Hyperphagia Questionnaire (HQ-CT) Change from Baseline at Visit 7 (Week 13) – Pre-COVID Analysis

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    End point title
    		 Hyperphagia Questionnaire (HQ-CT) Change from Baseline at Visit 7 (Week 13) – Pre-COVID Analysis
    End point description
    Hyperphagia-related behaviors were assessed by the validated hyperphagia questionnaire for clinical trials (HQ-CT), an instrument designed to measure symptoms of food related preoccupations and behaviors that was completed by the caregiver. The HQ-CT consists of nine items with responses ranging from 0–4 units each (possible total score range: 0−36). The HQ-CT was assessed at Screening, Baseline (Visit 2), and approximately every 4 weeks post-dose at Week 4, Week 8, and Week 13. A decrease in score from baseline represented improvement. ITT Population - pre-COVID analysis - 01Mar2020 Cutoff.
    End point type
    Post-hoc
    End point timeframe
    Baseline to Visit 7 (Week 13)
    End point values
    		 DCCR Placebo for DCCR
    Number of subjects analysed
    82
    42
    Units: HQ-CT Score
        least squares mean (standard error)
    -6.64 ± 1.001
    -3.51 ± 1.278
    Statistical analysis title
    		 Primary endpoint HQ-CT - Pre-COVID analysis
    Statistical analysis description
    Pre-COVID Analysis population consisted of all subjects who had at least one post-baseline assessment of HQ-CT prior to March 1, 2020, when a national emergency was declared in the US as a result of the COVID-19 pandemic.   The primary endpoint (change in HQ-CT score from Baseline at Visit 7 (Week 13)) was analysed using a linear mixed model for repeated measurements in the Pre-COVID Analysis. All available data collected before the March 1, 2020 cutoff from each subject were included.
    Comparison groups
    DCCR v Placebo for DCCR
    Number of subjects included in analysis
    124
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0369 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.06
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.481
    Notes
    [6] - The primary endpoint was analysed using a mixed model for repeated measurements (MMRM) in Pre-COVID Analysis.  All available data collected before the March 1, 2020 cutoff were used, with no imputation of missing data.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to Visit 7 (Week 13)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    DCCR
    Reporting group description
    		 Participants with PWS were dosed dependent on their weight; 25mg, 75mg or 150mg DCCR tablets could be taken; DCCR was taken daily. Tablets must be swallowed whole and should not be broken, crushed or chewed. The target dose by weight (kg) was as follows: Subjects weighing 20 to < 30 kg took 100mg DCCR/day Subjects weighing ≥ 30 to < 40 took 150mg DCCR/day Subjects weighing ≥ 40 to < 65 took 225mg DCCR/day Subjects weighing ≥ 65 to < 100 took 375mg DCCR/day Subjects weighing ≥ 100 to < 135 took 450mg DCCR/day Subjects randomised to the DCCR treatment group were titrated every 2 weeks until the target dose was achieved

    Reporting group title
    Placebo for DCCR
    Reporting group description
    		 Participants with PWS were dosed dependent on their weight; 25mg, 75mg or 150mg placebo for DCCR tablets could be taken; Placebo was taken daily. Tablets must be swallowed whole and should not be broken, crushed or chewed. The target dose by weight (kg) was as follows: Subjects weighing 20 to < 30 kg took 100mg placebo for DCCR/day Subjects weighing ≥ 30 to < 40 took 150mg placebo for DCCR/day Subjects weighing ≥ 40 to < 65 took 225mg placebo for DCCR/day Subjects weighing ≥ 65 to < 100 took 375mg placebo for DCCR/day Subjects weighing ≥ 100 to < 135 took 450mg placebo for DCCR/day Subjects randomised to the Placebo group were titrated on placebo, similar to the DCCR group

    Serious adverse events
    		 DCCR Placebo for DCCR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 84 (7.14%)
    0 / 42 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary oedema
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 42 (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
    		 DCCR Placebo for DCCR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    69 / 84 (82.14%)
    31 / 42 (73.81%)
    Investigations
    Blood glucose increased
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 42 (4.76%)
         occurrences all number
    5
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 84 (5.95%)
    6 / 42 (14.29%)
         occurrences all number
    5
    14
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    16 / 84 (19.05%)
    4 / 42 (9.52%)
         occurrences all number
    28
    4
    Pyrexia
         subjects affected / exposed
    5 / 84 (5.95%)
    0 / 42 (0.00%)
         occurrences all number
    6
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 42 (9.52%)
         occurrences all number
    1
    4
    Abdominal pain
         subjects affected / exposed
    1 / 84 (1.19%)
    3 / 42 (7.14%)
         occurrences all number
    1
    5
    Skin and subcutaneous tissue disorders
    Hypertrichosis
         subjects affected / exposed
    30 / 84 (35.71%)
    6 / 42 (14.29%)
         occurrences all number
    32
    6
    Hirsutism
         subjects affected / exposed
    6 / 84 (7.14%)
    3 / 42 (7.14%)
         occurrences all number
    8
    6
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 84 (10.71%)
    5 / 42 (11.90%)
         occurrences all number
    9
    7
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    10 / 84 (11.90%)
    0 / 42 (0.00%)
         occurrences all number
    10
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2018
    This study was initiated globally as Protocol Amendment 1
    19 Jul 2018
    Revised/updated study objectives/endpoints and randomisation exclusion criteria. Added all PWS Profile Questionnaire domains and updated response scales, C-SSRS and DBC-2P. Modified inclusion criteria to include participants who are 4 years and older. Discontinuation id the study section was updated to include the timing of the DSMB's review of the unblinded safety data ad to define stopping criteria for the study. Modified exclusion criterion to exclude participants with signs suggestive of a thromboembolic event. HbA1c cutoff for entry moved from a screening entry criterion to an randomisation entry criterion. Removed requirement for blood pressure at Visit 2 since they would have to meet screening entry criterion prior to this visit. Safety parameters (laboratory and physical exam) updated for clarity and completeness.
    12 Nov 2018
    Revised/updated study objectives/endpoints. Added option to expand study to include clinical sites in Europe. Revised inclusion/exclusion to clarify acceptable genetic testing methods to confirm PWS diagnosis; required caregivers to be able to communicate with investigator (not required to be in English); exclude participants from entering data on non-interventional databases. Updated visit windows. Allowed for designation of a caregiver for completion of caregiver-completed questionnaires. Updated DNA sample collection to include blood sample in the event the saliva sample was insufficient to be analysed. DXA clarified to identify body regions to be included in body composition analysis. During run-in period, allowed weight band I participants to take only 1x75mg placebo tablet and did not require them to take 1x150mg placebo tablet. Clarified dosing instructions to ensure that study medication should be taken with a beverage that is not metabolised by CYP450 1A2 or 3A4. Added section on Home Health Nurse Visit.
    26 Apr 2019
    Revised/updated study inclusion/exclusion criteria. Added weight band 0 to allow enrolment of participants weighting 20 to <30kg; changes made throughout the protocol to incorporate this change. Medications known to prolong the QTc interval (Refer to QTDrugs List on htps://crediblemeds.org/heathcare-providers/), except citalopram and synthetic steroids (i.e. oral, IM or IV) for > 7 days.
    11 Jun 2019
    Added additional ECG approximately 18-24 hours after first dose of DCCR or placebo if participant was taking citalopram or escitalopram.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Mar 2020
    While much of the study was conducted and completed prior to the onset of the COVID-19 pandemic and all subjects were enrolled and had baseline visits prior to the pandemic, a subset of subjects needed to complete some of their visits after the onset of the pandemic. The conduct of the study changed during the pandemic, with a number of study visits transitioning to telemedicine and/or home health nurse visits and in some cases, some procedures at some in-clinic visits could not be completed (for example DXA). In addition, the COVID-19 pandemic forced numerous restrictions on normal activities and often involved significant disruptions, changes in routine and schedules. Generally, this had a negative impact on both the subject, the caregiver, and the family, but in some cases, people with PWS responded positively to these changes. The pandemic therefore had a substantially adverse but inconsistent effect on the study conduct and results, particularly for subjective endpoints that relied on caregiver completed questionnaires (https://pubmed.ncbi.nlm.nih.gov/32515992/). Pandemic related effects on the subject or caregiver did not tend to impact objective endpoints, but these endpoints were impacted by the ability to obtain the data for analysis due to the shift to telemedicine or home health visits or due to limitations during an in-clinic visit. For this reason, the ITT population - Pre-COVID Analysis includes all data through March 1, 2020.
    09 Jun 2021

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    All subjects were enrolled and had baseline visits prior to the COVID-19 pandemic. Additional information is provided in the section on Interruptions.
    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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