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    Clinical Trial Results:
    Original: An Open-Label, Long-Term Safety and Efficacy Evaluation of Diazoxide Choline Extended-Release Tablets in Participants with Prader-Willi Syndrome Amendment 3: An Open-Label, Long-Term Safety and Efficacy Evaluation of Diazoxide Choline Controlled-Release Tablet in Patients with Prader-Willi Syndrome Amendment 7: An Open-Label, Long-Term Safety and Efficacy Evaluation of Diazoxide Choline Extended-Release Tablets in Participants with Prader-Willi Syndrome with a Double-Blind, Placebo-Controlled, Randomized Withdrawal Period

    Summary
    EudraCT number
    		 2018-004216-22
    Trial protocol
    		 GB  
    Global end of trial date
    28 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Sep 2024
    First version publication date
    02 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    C602
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03714373
    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 1628876432, soleno-uk@soleno.life
    Scientific contact
    Clinical Trial Information, Soleno Therapeutics UK Limited, +44 16288756023, C602ProjectManager@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
    28 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Feb 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Open Label Extension (OLE) Period: to evaluate the long-term safety of DCCR (diazoxide choline) extended-release tablets in participants with Prader-Willi syndrome (PWS) previously enrolled in clinical study C601. Randomized Withdrawal (RW) Period: to evaluate the effects of discontinuation of treatment with DCCR (diazoxide choline) extended-release tablets and initiation of placebo compared to continued treatment with DCCR in participants with Prader-Willi syndrome (PWS) on hyperphagia as assessed by change in the hyperphagia questionnaire for clinical trials (HQ-CT) Total Score from RW Period Baseline at RW Week 16.
    Protection of trial subjects
    IDMC (Independent Data Monitoring Committee) met 3 times during the RW Period to review unblinded safety data.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 91
    Country: Number of subjects enrolled
    United Kingdom: 24
    Worldwide total number of subjects
    115
    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)
    55
    Adolescents (12-17 years)
    39
    Adults (18-64 years)
    21
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 C602 OLE (Period 1): People who completed C601 were given the option to enrol. The first subject was screened in the US on 17May18 & in the UK on 26Jun19; all sites were either hospitals or academic medical centres. C602 RW (Period 2): People who participated in C602 OLE & completed the OLE EOT Visit procedures were given the option to enrol.

    Pre-assignment
    Screening details
    		 C602 OLE (Period 1): 120 participants were eligible and 115 participants enrolled and took any amount of study drug. C602 RW (Period 2): 83 participants were eligible and 77 participants enrolled and took any amount of study drug.

    Period 1
    Period 1 title
    Open-Label Extension Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    To maintain the blinded treatment assignment in clinical study C601, dosing remained blinded during the titration period of clinical study C602.

    Arms
    Arm title
    		 DCCR (Open-Label)
    Arm description
    		 Once daily oral administration of open-label study medication.
    Arm type
    		 Open-Label

    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 were to be swallowed whole and not be broken, crushed or chewed. The target doses by weight(kg) were as follows: Subjects weighing 20 to <30 kg took 100 mg DCCR/day Subjects weighing equal to or greater than 30 to <40 kg took 150 mg DCCR/day Subjects weighing equal to or greater than 40 to <65 kg took 225 mg DCCR/day Subjects weighing equal to or greater than 65 to <100 kg took 375mg DCCR/day Subjects weighing equal to or greater than 100 to <135 kg took 450 mg DCCR/day Subjects were titrated every 2 weeks until the target dose was achieved.

    Number of subjects in period 1
    		DCCR (Open-Label)
    Started
    115
    Completed ≥13 weeks of DCCR treatment
    113
    Completed at least of DCCR treatment
    105
    Completed 2 years of DCCR treatment
    88
    Eligible to enrol in RWP as of Oct 2022
    83
    Completed
    77
    Not completed
    38
         Adverse event, not serious
    5
         Medication change
    1
         Perceived lack of effectiveness
    5
         Consent withdrawn by subject
    18
         Investigator/Caregiver decision
    2
         Non-compliance
    3
         Lost to follow-up
    4
    Period 2
    Period 2 title
    Randomised Withdrawal Period
    Is this the baseline period?
    		 No
    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 (Double-blind)
    Arm description
    		 Once daily oral administration of double-blind study medication.
    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 were to be swallowed whole and not be broken, crushed or chewed. The target doses by weight(kg) were as follows: Subjects weighing 20 to <30 kg took 100 mg DCCR/day Subjects weighing equal to or greater than 30 to <40 kg took 150 mg DCCR/day Subjects weighing equal to or greater than 40 to <65 kg took 225 mg DCCR/day Subjects weighing equal to or greater than 65 to <100 kg took 375 mg DCCR/day Subjects weighing equal to or greater than 100 to <135 kg took 450 mg DCCR/day Subjects were titrated every 2 weeks until the target dose was achieved.

    Arm title
    		 Placebo for DCCR (Double-blind)
    Arm description
    		 Once daily oral administration of double-blind study medication.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for DCCR (Double-blind)
    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 were to be swallowed whole and not be broken, crushed or chewed. The target doses by weight(kg) were as follows: Subjects weighing 20 to <30 kg took 100 mg placebo/day Subjects weighing equal to or greater than 30 to <40 kg took 150 mg placebo/day Subjects weighing equal to or greater than 40 to <65 kg took 225 mg placebo/day Subjects weighing equal to or greater than 65 to <100 kg took 375 mg placebo/day Subjects weighing equal to or greater than 100 to <135 kg took 450 mg placebo/day Subjects randomised to the placebo group were titrated on placebo, similar to the DCCR group.

    Number of subjects in period 2
    		DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Started
    38
    39
    Completed
    37
    39
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-Label Extension Period
    Reporting group description
    		 The reporting group included 115 subjects who were all being treated with DCCR.

    Reporting group values
    		 Open-Label Extension Period Total
    Number of subjects
    		 115 115
    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)
    		 55 55
        Adolescents (12-17 years)
    		 39 39
        Adults (18-64 years)
    		 21 21
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 12.9 (4 to 44) -
    Gender categorical
    Units: Subjects
        Female
    		 66 66
        Male
    		 49 49
    Subject analysis sets

    Subject analysis set title
    RW Intent-to-Treat (RWITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The RW Intent-to-Treat Population analysis set includes all participants who were randomised to DCCR or Placebo during the RW Period.

    Subject analysis set title
    RW Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The RW Safety Population consists of participants who received any amount of study drug during the RW Period.

    Subject analysis set title
    C602 Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The C602 Safety Population included all participants who received ≥1 dose of DCCR in Study C602 OLE Period.

    Subject analysis sets values
    		 RW Intent-to-Treat (RWITT) RW Safety Population C602 Safety Population
    Number of subjects
    77
    77
    115
    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)
    23
    23
    55
        Adolescents (12-17 years)
    31
    31
    39
        Adults (18-64 years)
    23
    23
    21
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    14.9 (7 to 29)
    14.9 (7 to 29)
    12.9 (4 to 44)
    Gender categorical
    Units: Subjects
        Female
    43
    43
    66
        Male
    34
    34
    49

    End points

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    End points reporting groups
    Reporting group title
    DCCR (Open-Label)
    Reporting group description
    		 Once daily oral administration of open-label study medication.
    Reporting group title
    DCCR (Double-blind)
    Reporting group description
    		 Once daily oral administration of double-blind study medication.

    Reporting group title
    Placebo for DCCR (Double-blind)
    Reporting group description
    		 Once daily oral administration of double-blind study medication.

    Subject analysis set title
    RW Intent-to-Treat (RWITT)
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The RW Intent-to-Treat Population analysis set includes all participants who were randomised to DCCR or Placebo during the RW Period.

    Subject analysis set title
    RW Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The RW Safety Population consists of participants who received any amount of study drug during the RW Period.

    Subject analysis set title
    C602 Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The C602 Safety Population included all participants who received ≥1 dose of DCCR in Study C602 OLE Period.

    Primary: Hyperphagia Questionnaire (HQ-CT) Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Hyperphagia Questionnaire (HQ-CT) Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    Hyperphagia-related behaviours were assessed by the validated hyperphagia questionnaire for clinical trials (HQ-CT), an instrument designed to measure symptoms of food related preoccupations and behaviours 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 Baseline and at Week 4, Week 8, Week 12, and Week 16. A decrease in score from baseline represented improvement.
    End point type
    Primary
    End point timeframe
    RW Period Baseline to Week 16
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    38
    39
    Units: HQ-CT Score
        least squares mean (standard error)
    2.6 ( 1.12 )
    7.6 ( 1.09 )
    Statistical analysis title
    		 Primary endpoint – Hyperphagia Questionnaire HQ-CT
    Statistical analysis description
    The primary endpoint (change from RW Baseline at Week 16 in the HQ-CT score) was analyzed using a linear mixed model for repeated measurements in the RWITT Population. Missing values were not imputed, and data collected after treatment discontinuation were included. LS mean values were based on a mixed model for repeated measures adjusting for RW Baseline HQ-CT score, treatment, visit (RW Weeks 4, 8, 12, and 16), and treatment by visit interaction, using an unstructured covariance matrix.
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0022
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.1
         upper limit
    		 -1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.57

    Secondary: Clinical Global Impression of Severity (CGI-S) Score Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Clinical Global Impression of Severity (CGI-S) Score Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    The CGI-S (1-7) was a single statement designed to assess the Investigator’s overall perception of the severity of the participant’s illness across the course of the clinical trial. The Investigator provided a response to “Considering your total clinical experience with this particular population, how ill is this patient at this time:” by rating the participant’s illness severity using a 7-point response scale: 1=“Normal, not at all ill”, 2=“Borderline ill”, 3=“Mildly ill”, 4=“Moderately ill”, 5=“Markedly ill”, 6=“Severely ill”, and 7=“Among the most extremely ill participants”.
    End point type
    Secondary
    End point timeframe
    RW Period Baseline to Week 16
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    38
    39
    Units: CGI-S Score
        least squares mean (standard error)
    0.9 ( 0.19 )
    1.4 ( 0.18 )
    Statistical analysis title
    		 Secondary endpoint - CGI-S Score
    Statistical analysis description
    The secondary endpoint (change from RW Baseline at Week 16 in CGI-S Score) was analysed using a compound symmetry matrix in the repeated measures models. LS mean values are based on a mixed model for repeated measures adjusting for RW Baseline CGI-S score as a continuous covariate, RW Baseline HQ-CT Total Score category (<13 vs. 13-36), treatment, visit (RW Week 4, 8, 12, and 16), and treatment by visit interaction, using an unstructured covariance matrix.
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0794
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.24

    Secondary: Clinical Global Impression of Improvement (CGI-I) Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Clinical Global Impression of Improvement (CGI-I) Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    The Clinical Global Impression of Improvement (CGI-I) for Improvement 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 enrollment, the subject’s condition is:” by rating the subject’s behavior using a 7-point response scale: 1=“Very much improved”, 2=“Much improved”, 3=“Minimally improved”, 4=“No change”, 5=“Minimally worse”, 6=“Much worse”, and 7=“Very much worse”. Thirty-six of 38 participants in the DCCR group and 39 of 39 in the Placebo group contributed data at Week 16.
    End point type
    Secondary
    End point timeframe
    RW Period Baseline to Week 16
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    36
    39
    Units: Participants
        Other (1-5)
    27
    21
        Much worse (6) and Very much worse (7)
    9
    18
    Statistical analysis title
    		 Secondary endpoint – CGI-I Score
    Statistical analysis description
    Reported common odds ratio (OR) is from a logistic regression proportional-odds model including fixed effects for treatment and adjusted for RW Baseline HQ-CT Total Score category (<13 vs. 13-36), with OR > 1 corresponding to values favouring DCCR. The OR (for Placebo/DCCR) is for the odds of having a higher value for the ordinal category. At Week 16, tail categories 1, 2, 3 and 4 were consolidated, as well as categories 6 and 7, to ensure ≥5 responses in each treatment group and visit/category.
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0918
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.887
         upper limit
    		 4.929

    Other pre-specified: Body Weight Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Body Weight Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    Weight (kg) was collected at RW Baseline and at RW Week 16.
    End point type
    Other pre-specified
    End point timeframe
    RW Period Baseline to Week 16.
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    38
    39
    Units: Kg
        least squares mean (standard error)
    0.8 ( 0.58 )
    2.4 ( 0.56 )
    Statistical analysis title
    		 Additional endpoint - Weight
    Statistical analysis description
    Missing values were not imputed, and data collected after treatment discontinuation are included. LS Means are based on an ANCOVA model adjusting for RW baseline weight and RW Baseline HQ-CT Total Score category (<13 versus 13-36).
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0353
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.75

    Other pre-specified: Body Mass Index (BMI) Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Body Mass Index (BMI) Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    BMI was calculated based on weight and height and was collected at RW Baseline and at RW Week 16 or EOT.
    End point type
    Other pre-specified
    End point timeframe
    RW Period Baseline to Week 16.
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    38
    39
    Units: Kg/m2
        least squares mean (standard error)
    0.2 ( 0.22 )
    0.8 ( 0.22 )
    Statistical analysis title
    		 Additional endpoint - Body Mass Index (BMI)
    Statistical analysis description
    Missing values are not imputed, and data collected after treatment discontinuation are included. LS Means are based on an ANCOVA model adjusting for RW baseline BMI and RW Baseline HQ-CT Total Score category (<13 versus 13-36).
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0336
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29

    Other pre-specified: Body Mass Index (BMI) Z-Score Change from Randomised Withdrawal (RW) Period Baseline at Week 16

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    End point title
    		 Body Mass Index (BMI) Z-Score Change from Randomised Withdrawal (RW) Period Baseline at Week 16
    End point description
    BMI Z-Scores were calculated using the Lambda, Mu, and Sigma Method (LMS) method as: Z = [((BMI / M)**L) – 1] / (S * L). LMS parameters were obtained using BMI for age charts provided by the Centers for Disease Control and Prevention (CDC). The participants age at the time of the assessment was used for calculating the Z-score. BMI Z-scores for adults was calculated using the oldest available age (20 years) from the CDC growth charts.
    End point type
    Other pre-specified
    End point timeframe
    RW Period Baseline to Week 16.
    End point values
    		 DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Number of subjects analysed
    38
    39
    Units: BMI-Z Score
        least squares mean (standard error)
    -0.02 ( 0.031 )
    0.07 ( 0.031 )
    Statistical analysis title
    		 Additional endpoint - BMI Z-score
    Statistical analysis description
    Missing values were not imputed, and data collected after treatment discontinuation are included. LS Means are based on an ANCOVA model adjusting for RW Baseline BMI Z-score and RW Baseline HQ-CT Total Score category (<13 versus 13-36).
    Comparison groups
    DCCR (Double-blind) v Placebo for DCCR (Double-blind)
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0233
    Method
    		 ANCOVA
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study medication in C602 study period through end of study period + 2 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    DCCR (Open-label)
    Reporting group description
    		 Once daily oral administration of open-label study medication.

    Reporting group title
    DCCR (Double-blind)
    Reporting group description
    		 Once daily oral administration of double-blind study medication.

    Reporting group title
    Placebo for DCCR (Double-blind)
    Reporting group description
    		 Once daily oral administration of double-blind study medication.

    Serious adverse events
    		 DCCR (Open-label) DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 115 (13.91%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body ingestion
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    2 / 115 (1.74%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dermatillomania
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 115 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 115 (0.87%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DCCR (Open-label) DCCR (Double-blind) Placebo for DCCR (Double-blind)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    114 / 115 (99.13%)
    28 / 38 (73.68%)
    29 / 39 (74.36%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    9 / 115 (7.83%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
         occurrences all number
    9
    2
    2
    Oedema peripheral
         subjects affected / exposed
    39 / 115 (33.91%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    71
    0
    0
    Pyrexia
         subjects affected / exposed
    13 / 115 (11.30%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    19
    0
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    12 / 115 (10.43%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    18
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 115 (13.91%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    17
    0
    0
    Nasal congestion
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    14
    0
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    11 / 115 (9.57%)
    5 / 38 (13.16%)
    5 / 39 (12.82%)
         occurrences all number
    12
    5
    5
    Affect lability
         subjects affected / exposed
    0 / 115 (0.00%)
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    0
    3
    1
    Aggression
         subjects affected / exposed
    9 / 115 (7.83%)
    3 / 38 (7.89%)
    5 / 39 (12.82%)
         occurrences all number
    18
    3
    7
    Anger
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    Anxiety
         subjects affected / exposed
    13 / 115 (11.30%)
    4 / 38 (10.53%)
    2 / 39 (5.13%)
         occurrences all number
    13
    4
    3
    Behaviour disorder
         subjects affected / exposed
    7 / 115 (6.09%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    8
    0
    0
    Compulsive hoarding
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    Dermatillomania
         subjects affected / exposed
    21 / 115 (18.26%)
    5 / 38 (13.16%)
    6 / 39 (15.38%)
         occurrences all number
    29
    8
    8
    Sleep disorder
         subjects affected / exposed
    0 / 115 (0.00%)
    1 / 38 (2.63%)
    3 / 39 (7.69%)
         occurrences all number
    0
    1
    4
    Suicidal ideation
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    0
    2
    1
    Investigations
    Glycosylated haemoglobin increased
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    0
    Weight increased
         subjects affected / exposed
    7 / 115 (6.09%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    9
    2
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    0
    Contusion
         subjects affected / exposed
    7 / 115 (6.09%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    0
    Ligament sprain
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    12
    0
    0
    Procedural pain
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    9
    0
    0
    Skin abrasion
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 115 (24.35%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    67
    0
    4
    Repetitive speech
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 38 (5.26%)
    2 / 39 (5.13%)
         occurrences all number
    0
    2
    2
    Somnolence
         subjects affected / exposed
    12 / 115 (10.43%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    13
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    13
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    12 / 115 (10.43%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    15
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    12
    0
    0
    Constipation
         subjects affected / exposed
    13 / 115 (11.30%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    21
    0
    0
    Diarrhoea
         subjects affected / exposed
    11 / 115 (9.57%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    14
    0
    0
    Tooth impacted
         subjects affected / exposed
    8 / 115 (6.96%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    8
    0
    0
    Vomiting
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    9
    0
    0
    Skin and subcutaneous tissue disorders
    Hirsutism
         subjects affected / exposed
    31 / 115 (26.96%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    48
    2
    1
    Hypertrichosis
         subjects affected / exposed
    72 / 115 (62.61%)
    2 / 38 (5.26%)
    5 / 39 (12.82%)
         occurrences all number
    117
    2
    5
    Pruritus
         subjects affected / exposed
    7 / 115 (6.09%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    7
    0
    2
    Rash
         subjects affected / exposed
    10 / 115 (8.70%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    11
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 115 (11.30%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    16
    0
    0
    Back pain
         subjects affected / exposed
    7 / 115 (6.09%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    9
    0
    0
    Pain in extremity
         subjects affected / exposed
    17 / 115 (14.78%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    31
    0
    4
    Infections and infestations
    COVID-19
         subjects affected / exposed
    25 / 115 (21.74%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    26
    0
    2
    Ear infection
         subjects affected / exposed
    14 / 115 (12.17%)
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    20
    2
    4
    Gastrointestinal viral infection
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    7
    0
    2
    Influenza
         subjects affected / exposed
    12 / 115 (10.43%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    12
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    18 / 115 (15.65%)
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    28
    1
    4
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 115 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    0
    2
    0
    Sinusitis
         subjects affected / exposed
    10 / 115 (8.70%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    13
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    22 / 115 (19.13%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    32
    3
    1
    Urinary tract infection
         subjects affected / exposed
    10 / 115 (8.70%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    14
    1
    2
    Viral infection
         subjects affected / exposed
    6 / 115 (5.22%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    7
    0
    0
    Metabolism and nutrition disorders
    Food craving
         subjects affected / exposed
    6 / 115 (5.22%)
    3 / 38 (7.89%)
    4 / 39 (10.26%)
         occurrences all number
    6
    4
    4
    Hyperglycaemia
         subjects affected / exposed
    27 / 115 (23.48%)
    0 / 38 (0.00%)
    0 / 39 (0.00%)
         occurrences all number
    36
    0
    0
    Hyperphagia
         subjects affected / exposed
    7 / 115 (6.09%)
    4 / 38 (10.53%)
    1 / 39 (2.56%)
         occurrences all number
    7
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 May 2019
    (Amendment 1) Extended study duration from 40 weeks to 54 weeks. Added fasting glucose measurement by glucometer on telephone call visit days and recording of levels in a paper diary. Added identification of used study medication cards as a source document since this is the first point of entry of the date and time the study medication was taken. Added Weight Band 0, for participants weighing 20 to <30 kg. Dose adjustments: 1) clarified that dose may be adjusted if the participant either loses or gains a significant amount of weight; 2) moved the option to adjust dose to Visit 6 (Week 13) and Visit 7 (Week 17).
    18 Jun 2019
    (Amendment 1a) Modified exclusion criterion 5 related to a new history in participant’s first degree relative or change in participant’s physical examination that may significantly increase the participant’s risk for thromboembolic event. Added an ECG to be performed 18‒24 hours after first dose of study medication (i.e., Visit 1) but prior to the second dose, for participants taking concomitant citalopram or escitalopram. This additional ECG is required only for participants who are currently taking citalopram or escitalopram. Removed reference to non-fasting blood tests as all blood tests will now be completed fasting. Clarified that fasting blood tests will be completed at Visit 1–6, inclusive.
    26 Sep 2019
    (Amendment 2) Added details pertaining to the C602 Extension. Updated the reason for possible study discontinuation. Clarified dose adjustment criteria for subjects participating in the C602 Extension. Updated assessments for subjects taking specific concomitant medications.
    01 Oct 2020
    (Amendment 3) Updated study duration to 5 years and changed the requirement for certain visits to be conducted via telephone versus In-Clinic. Removed the optional Home Health Nurse Visits. Revised Schedule of Events accordingly. Re-organised the Efficacy Endpoints and Exploratory Endpoints and added additional Endpoints. Clarified study early discontinuation and subject withdrawal criteria. Updated study assessments. Updated definition of baseline for the purposes of analyses.
    07 Oct 2020
    (Amendment 4) Added “Efficacy” to the title and applicable sections because the efficacy data in this study may be used to support the benefits of DCCR. Generalized description of packaging of study drug as packaging transitioned from study medication cards to bottles during this study; added details to Dose Description to support this change. Updated secondary and additional study objectives. Modified safety, efficacy, and exploratory endpoints and specified timepoints for endpoint evaluation to support changes in trial objectives. Modified requirements for subject withdrawal. Specified conditions for End of Study Visit. Updated criteria for dose adjustments and added a section on dose adjustments due to adverse events. Added section on contingency measures to the conduct of the study as a result of the COVID-19 Pandemic. Updated the statistical analysis section.
    18 May 2022
    (Amendment 5) Added randomized withdrawal period (RW Period) to obtain additional controlled data by comparing participants who are randomized to continue DCCR treatment versus those randomized to placebo. As a result, the protocol title was revised, and text was provided, or new sections were added for the following: Dose Selection Rationale, Study Duration Rationale, Population, Trial Objectives, Study Endpoints, Study Design, Randomization, Blinding, Additional Steps taken to Minimize/Avoid Bias, Packaging and Labeling, Duration of Study Participation, Discontinuation of Study, RW Period Eligibility Assessments, Participant Withdrawal, Treatments to be Administered, Dose Maintenance, Dose Adjustments, Medications, Informed Consent/Assent, Randomization into RW Period, Monitoring of Lab Results, Clinical Global Impression of Improvement (CGI-I), Hyperphagia Questionnaire for Clinical Trials (HQ-CT), PWS Profile (PWSP) Questionnaire, Individual Participant Experience Through Semi-Structured Caregiver Interviews, RW Period End of Study, and Schedule of Events. Furthermore, the Statistical Plan sections for Introduction, Sample Size Considerations, Analysis Populations, Safety Analyses, Efficacy Analyses, Subgroup Analyses, Pharmacokinetic Analysis, Termination Criteria, Interim Analyses and Handling of Missing Data were added or updated to describe aspects of the OLE Period and RW Period.
    26 Aug 2022
    (Amendment 6) Updated primary and secondary objectives, efficacy endpoints, efficacy analysis descriptions, randomisation stratification, exclusion criteria, sample size and the control of type 1 error and risk/benefit section. Clarifications were made to clearly indicate that the Sponsor is discontinuing the Open-Label Extension (OLE) Period. Updated to study assessments, visit schedule, Schedule of Events, and duration of participants in the RW Period. Added to guidance on the caregiver’s responsibilities prior to study visits. Updated the description of the Randomised Withdrawal Intent-to-Treat (RWITT) Population and subgroup analyses.
    11 Nov 2022
    (Amendment 7) Added CGI-S to the secondary objectives and 5 domain-specific CGI-S scales to the exploratory objectives. Clarified the definition of the Randomised Withdrawal Intent-to-Treat (RWITT) Population.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37919617
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