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    Clinical Trial Results:
    A Phase 3 Trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alstrom Syndrome (AS) Patients with Moderate to Severe Obesity

    Summary
    EudraCT number
    		 2018-004058-11
    Trial protocol
    		 FR   ES   GB  
    Global end of trial date
    08 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Mar 2022
    First version publication date
    08 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RM-493-023
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03746522
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rhythm Pharmaceuticals, Inc.
    Sponsor organisation address
    222 Berkeley Street, Boston, United States, MA 02116
    Public contact
    Chief Medical Officer, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, EU_medinfo@rhythmtx.com
    Scientific contact
    Chief Medical Officer, Rhythm Pharmaceuticals, Inc., +1 857-264-4280, EU_medinfo@rhythmtx.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 May 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a trial with 2 parts: a randomised, double-blind, placebo-controlled, 14-week, double-blind treatment period followed by a 52-week open-label treatment period (total treatment period up to 66 weeks). The main objective was to assess the effect of setmelanotide on the proportion of patients (>=12 years of age at baseline) treated with setmelanotide for approximately (~) 52 weeks who achieve a clinically meaningful reduction from baseline (ie, >=10%) in body weight.
    Protection of trial subjects
    The IRB/IEC reviewed all appropriate study documentation in order to safeguard the rights, safety, and well-being of the patients. The study was only conducted at sites where IRB/IEC approval had been obtained. This study was conducted in accordance with: • Consensus ethics principles derived from international ethics guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines • The International Council for Harmonisation (ICH) Good Clinical Practices (GCP) Guideline [E6] • Applicable laws and regulatory requirements. After the study had been fully explained, written informed consent was obtained from either the patient or his/her guardian or legal representative prior to study participation. The method of obtaining and documenting the informed consent and the contents of the consent complied with ICH-GCP and all applicable regulatory requirement(s).
    Background therapy
    		 Medications approved to treat obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion) were not allowed within 3 months of randomization and were prohibited during the study. Glucagon-like peptide-1 (GLP-1) receptor agonists were permitted up to the dose approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) it was not prescribed for the treatment of obesity, (2) the dose had been stable for at least 3 months prior to randomization, (3) the patient had not experienced weight loss during the previous 3 months, and (4) the patient intended to keep the dose stable throughout the course of the study. Other medications that could theoretically cause weight loss (e.g., stimulants) were allowed so long as the patient (1) had used them at a stable dose for at least 3 months prior to randomization, (2) had not lost weight during the previous 3 months, and (3) intended to keep the dose stable through the course of the study. All concomitant medications were to be kept at a stable dose throughout the course of the study, unless a dose change was necessary to treat an adverse event (AE).
    Evidence for comparator
    		 This was a placebo controlled trial for the first 14 weeks only. Therafter, subjects were treated open-label with setmelanotide only, with no comparator group.
    Actual start date of recruitment
    23 Nov 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Scientific research
    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
    Canada: 7
    Country: Number of subjects enrolled
    United States: 33
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 5
    Worldwide total number of subjects
    52
    EEA total number of subjects
    10
    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)
    11
    Adolescents (12-17 years)
    16
    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
    		 The recruitment period started on 23 November 2018. The last patient last visit was on 08 March 2021. Patients were recruited in the United States, Canada, France, Spain, and the United Kingdom.

    Pre-assignment
    Screening details
    		 After obtaining informed consent, potential patients were screened to determine study eligibility. The screening period lasted up to 3 weeks prior to randomisation.

    Period 1
    Period 1 title
    Baseline (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
    Eligible patients were randomised via an interactive website response system. Patients were randomised patients in a 1:1 ratio, stratified by age group (≥12 years or <12 years) and disease (BBS or AS), to receive setmelanotide or placebo for the first 14 weeks of the study. For the double-blind period, placebo and setmelanotide were identical in appearance and were supplied in identical packaging. Thereafter, all patients were treated with open-label setmelanotide.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 All treated patients
    Arm description
    		 All patients were treated with setmelanotide in this study. The first 14 weeks of the study was a double-blind treatment period with patients randomised to setmelanotide or placebo. Thereafter, setmelanotide was administered open-label in all patients. Patients randomised to setmelanotide were treated for up to 66 weeks with setmelanotide (14 weeks double-blind, followed by 52 weeks open-label). Patients randomised to placebo were treated with placebo (matching setmelanotide) for 14 weeks followed by open-label setmelanotide for up to 52 weeks. Dose escalations at the start of the double-blind and open-label treatment periods are described below. A total of 38 patients (32 BBS patients and 6 AS patients) comprised the pivotal cohort.
    Arm type
    		 All treated patients

    Investigational medicinal product name
    Setmelanotide (with or without placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage by age group was as follows, including a dose escalation planned for the start of double-blind treatment (Weeks 1 and 2) and again at the start of open-label treatment to maintain the blind (Weeks 15 and 16). Setmelanotide Patients aged >=16 years: Week 1, 2.0mg setmelanotide; Week 2, 2.0mg setmelanotide; Weeks 3-14, 3.0 mg setmelanotide Week 15, 2.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Patients aged <16 years: Week 1, 1.0mg setmelanotide; Week 2, 2.0mg setmelanotide; Weeks 3-14, 3.0 mg setmelanotide Week 15, 1.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Placebo All patients randomised to placebo (regardless of age group) were treated with placebo for Weeks 1-14. Thereafter, setmelanotide dosing was open-label, as detailed above by age group, for Weeks 15 to 66.

    Arm title
    		 Setmelanotide; double-blind period
    Arm description
    		 All patients in the first 14 weeks of the study (ie, the randomised double-blind treatment period) who were treated with setmelanotide.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Setmelanotide (with or without placebo)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage by age group was as follows, including a dose escalation planned for the start of double-blind treatment (Weeks 1 and 2) and again at the start of open-label treatment to maintain the blind (Weeks 15 and 16). Setmelanotide Patients aged >=16 years: Week 1, 2.0mg setmelanotide; Week 2, 2.0mg setmelanotide; Weeks 3-14, 3.0 mg setmelanotide Week 15, 2.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Patients aged <16 years: Week 1, 1.0mg setmelanotide; Week 2, 2.0mg setmelanotide; Weeks 3-14, 3.0 mg setmelanotide Week 15, 1.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Placebo All patients randomised to placebo (regardless of age group) were treated with placebo for Weeks 1-14. Thereafter, setmelanotide dosing was open-label, as detailed above by age group, for Weeks 15 to 66.

    Arm title
    		 Placebo; double-blind period
    Arm description
    		 All patients in the first 14 weeks of the study (ie, the randomised double-blind treatment period) who were treated with placebo. At the end of the double-blind period these patients continued treatment with setmelanotide. Patients aged >=16 years: Week 1-14, placebo Week 15, 2.0 mg setmelanotide; Week 16 2.0 mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Patients aged <16 years: Week 1-14, placebo Week 15, 1.0 mg setmelanotide; Week 16, 2.0 mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients randomised to placebo received placebo under double-blind conditions for 14 weeks followed by active treatment with setmelanotide (open-label) until the end of the study. Dose escalation occurred over the first 2 weeks of the double-blind period and again at the start of the open-label period to maintain the blind. Patients aged >=16 years: Week 1-14, placebo Week 15, 2.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Patients aged <16 years: Week 1-14, placebo Week 15, 1.0mg setmelanotide; Week 16 2.0mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide

    Number of subjects in period 1
    		All treated patients Setmelanotide; double-blind period Placebo; double-blind period
    Started
    52
    27
    25
    Completed
    39
    22
    17
    Not completed
    13
    5
    8
         Transfer to extension study
    2
    -
    -
         Consent withdrawn by subject
    3
    3
    2
         Adverse event, non-fatal
    6
    2
    3
         Lost to follow-up
    2
    -
    1
         Discontinued during double-blind period
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 All treated patients, including patients treated with placebo during the double-blind placebo-controlled period (first 14 weeks of study).

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 52 52
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 11 11
        Adolescents (12-17 years)
    		 16 16
        Adults (18-64 years)
    		 25 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 19.5 ± 10.96 -
    Gender categorical
    Units: Subjects
        Female
    		 31 31
        Male
    		 21 21
    Underlying condition
    Patients with Bardet-Biedl Syndrome (BBS) or Alström Syndrome (AS) condition were eligible to participate.
    Units: Subjects
        BBS
    		 44 44
        AS
    		 8 8
    Body Mass Index (kg/m2)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 41.78 ± 11.116 -
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 107.78 ± 34.582 -

    End points

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    End points reporting groups
    Reporting group title
    All treated patients
    Reporting group description
    		 All patients were treated with setmelanotide in this study. The first 14 weeks of the study was a double-blind treatment period with patients randomised to setmelanotide or placebo. Thereafter, setmelanotide was administered open-label in all patients. Patients randomised to setmelanotide were treated for up to 66 weeks with setmelanotide (14 weeks double-blind, followed by 52 weeks open-label). Patients randomised to placebo were treated with placebo (matching setmelanotide) for 14 weeks followed by open-label setmelanotide for up to 52 weeks. Dose escalations at the start of the double-blind and open-label treatment periods are described below. A total of 38 patients (32 BBS patients and 6 AS patients) comprised the pivotal cohort.

    Reporting group title
    Setmelanotide; double-blind period
    Reporting group description
    		 All patients in the first 14 weeks of the study (ie, the randomised double-blind treatment period) who were treated with setmelanotide.

    Reporting group title
    Placebo; double-blind period
    Reporting group description
    		 All patients in the first 14 weeks of the study (ie, the randomised double-blind treatment period) who were treated with placebo. At the end of the double-blind period these patients continued treatment with setmelanotide. Patients aged >=16 years: Week 1-14, placebo Week 15, 2.0 mg setmelanotide; Week 16 2.0 mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide Patients aged <16 years: Week 1-14, placebo Week 15, 1.0 mg setmelanotide; Week 16, 2.0 mg setmelanotide; Weeks 17-66, 3.0 mg setmelanotide

    Primary: Body weight change

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    End point title
    		 Body weight change [1] [2]
    End point description
    The primary endpoint was the proportion of pivotal patients ≥12 years old who met the ≥10% weight loss threshold from baseline (i.e., responders) after approximately 1 year of treatment with setmelanotide. This analysis was performed on the FAS population, with patients who received any study drug and at least one baseline assessment. Weight was measured in triplicate at each visit and mean values analysed. The estimated proportion of pivotal patients ≥12 years of age who achieved a ≥10% reduction in body weight was compared to a historical control rate of 10%. This was not a comparative analysis. Binomial proportions for 100 imputed datasets and outcomes were combined using Rubin’s Rule to provide an overall estimate. A 1-sided 0.025 significance level was used based on the small sample size (due to rarity of the disease). Results of statistical analysis: point estimate: 32.3% (95% CI 16.7, 51.4), p=0.0006, indicating primary efficacy endpoint was met.
    End point type
    Primary
    End point timeframe
    Baseline to 1 year on active treatment
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The statistical analysis of the primary endpoint was based upon comparison with historical data at the end of the open-label treatment period. Details of the statistical analysis are included with the endpoint description.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No comparisons of efficacy for the setmelanotide and placebo groups at the end of the double-blind treatment period were planned or performed.
    End point values
    		 All treated patients
    Number of subjects analysed
    31
    Units: Subjects
    10
    No statistical analyses for this end point

    Secondary: Percentage change in body weight

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    End point title
    		 Percentage change in body weight [3]
    End point description
    Mean percentage of body weight change (kg) from baseline in pivotal patients ≥12 years old after 1 year of treatment with setmelanotide within a single group of patients based on the FAS. Analyses were based on a one-sample t-test for each of the 100 imputed datasets and assuming a mean percent change from baseline in body weight of zero. The outcomes from the 100 imputed datasets were combined using Rubin’s Rule to provide a p-value and corresponding CIs. This was evaluated at a 1-sided, 0.025 significance level. Results of statistical analysis: mean change after 52 weeks of treatment: -5.21% (95% CI -9.17, -3.77), p=0.0005, indicating this key secondary efficacy endpoint was met.
    End point type
    Secondary
    End point timeframe
    Change from baseline to Week 52
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis of this secondary endpoint was based upon data at the end of the open-label treatment period. No comparisons of the setmelanotide and placebo groups at the end of the double-blind treatment period were planned or performed.
    End point values
    		 All treated patients
    Number of subjects analysed
    31
    Units: percent
        arithmetic mean (standard deviation)
    -5.21 ± 7.895
    No statistical analyses for this end point

    Secondary: Change in hunger score

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    End point title
    		 Change in hunger score [4]
    End point description
    Evaluation of the mean percent change in hunger scores (weekly average hunger score of the daily most/worst hunger score over 24 hours) in pivotal patients ≥12 years of age at the end of approximately 1 year of treatment within a single group of patients. Analyses were based on a one-sample t-test for each of the 100 imputed datasets with an assumed mean percent change from baseline in weekly average of daily hunger scores of zero. The outcomes from the 100 imputed datasets were combined using Rubin’s Rule to provide a p-value and corresponding CIs. This was evaluated at a 1-sided, 0.025 significance level. Results of statistical analysis: mean change after 52 weeks: -30.91% (95% CI -44.09, -17.73), p<0.0001, indicating this key secondary efficacy endpoint was met.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis of this secondary endpoint was based upon data at the end of the open-label treatment period. No comparisons of the setmelanotide and placebo groups at the end of the double-blind treatment period were planned or performed.
    End point values
    		 All treated patients
    Number of subjects analysed
    16
    Units: percent
        arithmetic mean (standard deviation)
    -30.91 ± 24.733
    No statistical analyses for this end point

    Secondary: Improvement in daily hunger score

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    End point title
    		 Improvement in daily hunger score [5]
    End point description
    The proportion of pivotal patients ≥12 years of age in the FAS population who achieve a ≥25% improvement from baseline in the weekly average of the daily hunger score after ~52 weeks of treatment was analyzed similarly to the primary efficacy endpoint (described above). Prior to analysis, daily hunger scores for each of the 3 hunger assessments (worst/most) were averaged separately by week. Results of statistical analysis: point estimate: 62.5% (95% CI 35.4, 84.8); p<0.0001.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 52.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The statistical analysis of this secondary endpoint was based upon data at the end of the open-label treatment period. No comparisons of the setmelanotide and placebo groups at the end of the double-blind treatment period were planned or performed.
    End point values
    		 All treated patients
    Number of subjects analysed
    16
    Units: Subjects
    10
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events after the start of study drug administration were treatment-emergent (TEAEs). Total duration of treatment (randomised to setmelanotide/placebo): 66 weeks setmelanotide /14 weeks placebo plus 52 weeks setmelanotide.
    Adverse event reporting additional description
    TEAEs are presented for all patients who received at least 1 study drug dose. Note, 25 of the 52 treated patients were treated with placebo in the 14-week double-blind period before starting setmelanotide. NOTE: TEAEs in the 14-week double-blind period include ONLY those TEAEs with an onset during that 14-week period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    All treated patients to end of follow-up
    Reporting group description
    		 All patients treated with study drug. Total duration of treatment (randomised to setmelanotide/placebo): up to 66 weeks setmelanotide /14 weeks placebo plus up to 52 weeks setmelanotide.

    Reporting group title
    Setmelanotide during 14-week double-blind period only
    Reporting group description
    		 Patients randomised to setmelanotide for the 14-week double-blind period.

    Reporting group title
    Placebo during 14-week double-blind period only
    Reporting group description
    		 Patients randomised to placebo for the 14-week double-blind period.

    Serious adverse events
    		 All treated patients to end of follow-up Setmelanotide during 14-week double-blind period only Placebo during 14-week double-blind period only
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 27 (0.00%)
    0 / 25 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All treated patients to end of follow-up Setmelanotide during 14-week double-blind period only Placebo during 14-week double-blind period only
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 52 (100.00%)
    26 / 27 (96.30%)
    24 / 25 (96.00%)
    Investigations
    High density lipoprotein decreased
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 27 (14.81%)
    0 / 25 (0.00%)
         occurrences all number
    4
    4
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    6 / 52 (11.54%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    7
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 52 (23.08%)
    1 / 27 (3.70%)
    6 / 25 (24.00%)
         occurrences all number
    51
    20
    7
    Dizziness
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         occurrences all number
    4
    1
    2
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    26 / 52 (50.00%)
    12 / 27 (44.44%)
    11 / 25 (44.00%)
         occurrences all number
    35
    17
    12
    Injection site pruritus
         subjects affected / exposed
    20 / 52 (38.46%)
    8 / 27 (29.63%)
    9 / 25 (36.00%)
         occurrences all number
    26
    11
    9
    Injection site pain
         subjects affected / exposed
    14 / 52 (26.92%)
    3 / 27 (11.11%)
    8 / 25 (32.00%)
         occurrences all number
    19
    4
    10
    Injection site bruising
         subjects affected / exposed
    18 / 52 (34.62%)
    6 / 27 (22.22%)
    9 / 25 (36.00%)
         occurrences all number
    18
    6
    9
    Injection site induration
         subjects affected / exposed
    14 / 52 (26.92%)
    6 / 27 (22.22%)
    4 / 25 (16.00%)
         occurrences all number
    17
    6
    4
    Fatigue
         subjects affected / exposed
    6 / 52 (11.54%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         occurrences all number
    6
    1
    2
    Injection site haemorrhage
         subjects affected / exposed
    6 / 52 (11.54%)
    3 / 27 (11.11%)
    2 / 25 (8.00%)
         occurrences all number
    6
    3
    2
    Injection site oedema
         subjects affected / exposed
    6 / 52 (11.54%)
    2 / 27 (7.41%)
    1 / 25 (4.00%)
         occurrences all number
    6
    2
    1
    Injection site reaction
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    2 / 25 (8.00%)
         occurrences all number
    4
    2
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    19 / 52 (36.54%)
    7 / 27 (25.93%)
    6 / 25 (24.00%)
         occurrences all number
    25
    7
    7
    Vomiting
         subjects affected / exposed
    14 / 52 (26.92%)
    7 / 27 (25.93%)
    0 / 25 (0.00%)
         occurrences all number
    18
    9
    0
    Diarrhoea
         subjects affected / exposed
    10 / 52 (19.23%)
    2 / 27 (7.41%)
    1 / 25 (4.00%)
         occurrences all number
    12
    3
    1
    Abdominal pain upper
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    6
    0
    1
    Abdominal pain
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    4
    0
    1
    Reproductive system and breast disorders
    Spontaneous penile erection
         subjects affected / exposed
    5 / 52 (9.62%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    5
    1
    0
    Menorrhagia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    5
    0
    2
    Nasal congestion
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 27 (11.11%)
    0 / 25 (0.00%)
         occurrences all number
    3
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    0
    2
    Skin and subcutaneous tissue disorders
    Skin hyperpigmentation
         subjects affected / exposed
    33 / 52 (63.46%)
    17 / 27 (62.96%)
    0 / 25 (0.00%)
         occurrences all number
    53
    24
    0
    Acne
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    1
    Dermatitis atopic
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 27 (7.41%)
    0 / 25 (0.00%)
         occurrences all number
    3
    2
    0
    Dry skin
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    0
    2
    Skin striae
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    3
    1
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    3
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    5
    0
    1
    Arthralgia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    0 / 25 (0.00%)
         occurrences all number
    3
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 27 (7.41%)
    1 / 25 (4.00%)
         occurrences all number
    4
    2
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    4
    1
    0
    Urinary tract infection
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 27 (3.70%)
    1 / 25 (4.00%)
         occurrences all number
    4
    1
    1
    Ear infection
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    1 / 25 (4.00%)
         occurrences all number
    3
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    0
    2
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 27 (3.70%)
    0 / 25 (0.00%)
         occurrences all number
    3
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 27 (0.00%)
    2 / 25 (8.00%)
         occurrences all number
    3
    0
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Oct 2018
    The following substantive changes were introduced: • Updated the packaging description. • Optional sleep study timepoint was added to V6. • Removed the requirement for electronic storage of ECGs, recording of ECGs in triplicate, and for use of equipment capable of transmitting to a central reader. • Clarified that the optional sleep study would be performed as a standard overnight sleep study.
    04 Feb 2019
    •Synopsis updated to clarify ages of enrolment •Inclusion #2 updated to clarify the ages of enrolment •Clarification of Exclusion #2 allowable medications and timeframe •Exclusion #4 re-written to remove only DSM-V disorders •Exclusion # 7 added to exclude patients with HbA1c >9.0 at screening •Added glomerular filtration rate •Exclusion #14 added to exclude patients previously treated with setmelanotide •Exclusion #17 added to exclude patients with first degree relatives enrolled within the past 4 months •Clarification that the Investigator had direct access to the system to unblind the treatment in case of emergency •The prohibited medication section was revised •The Screening Period updated to a minimum of 1 week with at least 4 days completed in the electronic hunger diary •Schedule of Assessments updated to add the HbA1c testing noted above •The list of biomarkers to be tested for was revised (some were removed) •Extended the screening period •Table 2 footnote 8 updated to describe a minimum of 1 week of screening and to require hunger diary completion on 4 out of 7 days prior to randomization •Text removed to clarify genetic testing samples would not be used for any other purpose •Clarified that Global Hunger to be completed during visits and the Daily Hunger to be completed electronically each day •Text added to state the PWS-SEQ was to be used in place of the Global Hunger questions in patients with impaired cognitive function •Text added to state the neurocognition tests WAIS-IV or WISC-V could be waived after discussion with the sponsor •Clarified the collection of samples for ACTH and 24-hour urine •Added that archive samples would be discarded at the end of the study •Text added to further define unlikely AE relationship •Text added to describe analysis options of incomplete data •Cockcroft Gault Equation changed to the Modification of Diet in Renal Disease Study equation for patients ≥18 or the Bedside Schwartz for patients <18
    16 Aug 2020
    The following changes were introduced: • Key secondary objectives updated to reflect a mean percent change from baseline in the weekly average of the daily hunger score. Key Secondary Objectives #1 and #4 were moved to Exploratory. Key Secondary Objective #2 was re-written to specify baseline body weight. Other Secondary Objective #2 was moved to Exploratory. • Key Secondary Endpoints # 1 and #3 were removed (moved to Exploratory). Added Exploratory Endpoint describing the proportion of patients who achieve an improvement in daily hunger score. • Updated to clarify the number of patients enrolled in the Pivotal and Supplemental cohorts. • Updated Inclusion Criteria #2 to specify age at time of first dose. • The Statistical Considerations section of the Synopsis and Section 8, Data Analysis/Statistical Procedures were revised. • The Clinical Overview section was updated with current exposure numbers and entire Clinical Safety section replaced providing updated TEAEs and SAE incidence to align with the annual Investigator Brochure update. • Text was added to allow Supplemental patients to roll into the extension study starting at Visit 8 or later. • Flexibility added to visit schedule windows upon sponsor approval to accommodate difficulty in scheduling due to COVID-19, holidays, and other logistical issue. • Schedule of Assessments was updated to make WISC-V/WAIS-IV optional based on investigator discretion. • Schedule of Assessments – removed Nutritional counselling and monitoring from V 2, 4, 6, 8, 10, and 12. • Schedule of Assessments bullet 11 was removed and 6.5.8 Measures of Insulin Sensitivity/Resistance OGTT was removed. • Updated PK profile blood draw time point preferences to pre-dose 4, 6, and 8 hours. Tubes provided in lab kits collect ~6 mL alloallowing for 2 aliquots. • Clarified that study medication should be taken after obtaining vital signs.
    09 Sep 2020
    The following changes were introduced: • Change and percent change in OGTT was removed from the Exploratory Endpoints (Already done for Ver 2.1 Marshfield Clinic only). • Additional clarity was added regarding the timing of dose escalation, the associated visit or phone call, and the visit windows for these days.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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