Clinical Trial Results:
Title: A Phase 3 Multi-Center, One-Year, Open-Label study of Setmelanotide in Pediatric Patients Aged 2 to <6 years of age with Rare Genetic Causes of Obesity. Trial design: This was an open-label study to evaluate the efficacy, safety, and tolerability of setmelanotide in paediatric patients with rare genetic causes of obesity (biallelic mutations of the POMC, PCSK1, or LEPR [PPL] genes or with Bardet-Biedl syndrome [BBS]). Eligible patients began treatment with setmelanotide at a dose of 0.5 mg/day. The dose was increased by increments of 0.5 mg every 2 weeks, if tolerated, at dose escalation visits (Weeks 2, 4, and 6). The maximum dose level for patients who weighed <20 kg, 20 to <30 kg, 30 to <40 kg, and >=40 kg was 0.5, 1.0, 1.5, and 2.0 mg once daily (QD), respectively. In total, 12 patients, aged 2 to <6 years were enrolled in the study. Screening assessments included medical history, abbreviated physical exam, comprehensive skin examination, laboratory tests, blood pressure. If a patient’s weight decreased to less than 15 kg during the study, the Investigator and sponsor jointly determined whether a patient's dose should change or be discontinued temporarily or permanently. A dose reduction to a minimum of 0.25 mg QD was allowed in such cases, or in case of tolerability concerns. Study assessments were performed at study visits approximately every 4 weeks through Week 20 and then approximately every 8 weeks through Week 52. The primary objective was to evaluate the effect of setmelanotide on weight-related parameters in paediatric patients aged 2 to <6 years with obesity due to either (1) biallelic variants of the PPL genes or (2) BBS. Overall, the median duration of treatment was 52.2 weeks (range: 7.1 to 54.9 weeks) and was similar in both groups of patients.

Trial information Top of page
Trial identification
Sponsor protocol code	RM-493-033
Additional study identifiers
ISRCTN number	-
US NCT number	-
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Rhythm Pharmaceuticals, Inc
Sponsor organisation address	222 Berkeley Street, 12th Floor, Boston, United States, MA 02116
Public contact	Clinical Trial Associate, Rhythm Pharmaceuticals, Inc., 01 857-264-4280, clinicaltrials@rhythmtx.com
Scientific contact	Clinical Trial Associate, Rhythm Pharmaceuticals, Inc., 01 857-264-4280, clinicaltrials@rhythmtx.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	Yes
EMA paediatric investigation plan number(s)	EMEA-002209-PIP01-17
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	04 Mar 2024
Is this the analysis of the primary completion data?	Yes
Primary completion date	04 Mar 2024
Global end of trial reached?	Yes
Global end of trial date	08 Nov 2024
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the effect of setmelanotide on weight in pediatric patients aged 2 to <6 years with obesity due to either (1) biallelic variants of the POMC, PCSK1 or LEPR genes or (2) Bardet-Biedl Syndrome (BBS) by determining if they meet a “responder” definition for change in body weight.
Protection of trial subjects	An Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved the final study protocol, including the final version of the informed consent and any changes to the informed consent. IRB or IEC approval was submitted to the Sponsor before any patient was enrolled in the study. Any amendments to the protocol were also approved by the IRB or IEC upon receipt of amendments and annually, as local regulations required in accordance with local requirements. In addition, the IRB or IEC approved all advertising used to recruit patients for the study. The study was performed in accordance with ethical principles that have their origin in the Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), and applicable regulatory requirements. The Investigator(s) at each site ensured that the patient and their legal guardian were given full and adequate oral and written information about the nature, purpose, possible risk, and benefit of the study and adequate opportunity to ask questions. The parent/legal guardian(s) signed and dated consent and assent were obtained before any study procedures were conducted. Patients and their legal guardian(s) were informed that they were free to discontinue from the study at any time.
Background therapy	All medication or vaccines (including over-the-counter or prescription medicines, vitamins, and/or herbal supplements) in use at the time of enrolment or used during the study were recorded as prior or concomitant medications, as appropriate, along with: • Reason for use • Dates of administration including start and end dates • Dosage information including dose and frequency The dose of concomitant medications used during the study was not to be changed and new concomitant medications were not to be started during the study, unless necessary to treat an AE.
Evidence for comparator	-
Actual start date of recruitment	08 Mar 2022
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Australia: 2
Country: Number of subjects enrolled	Spain: 2
Country: Number of subjects enrolled	United Kingdom: 1
Country: Number of subjects enrolled	United States: 7
Worldwide total number of subjects	12
EEA total number of subjects	2
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)	12
Adolescents (12-17 years)	0
Adults (18-64 years)	0
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	This study recruited 7 paediatric patients with biallelic mutations of the POMC, PCSK1, or LEPR genes (collectively referred to as PPL) and 5 paediatric patients with Bardet Biedl Syndrome (BBS) in Australia, Spain, United Kingdom, and the United States from 02 Mar 2022. The last patient last visit was 18 Sep 2023.
Pre-assignment
Screening details	Screening assessments included medical history, abbreviated physical exam, comprehensive skin examination, laboratory tests, and blood pressure.
Period 1
Period 1 title	Baseline (overall period)
Is this the baseline period?	Yes
Allocation method	Not applicable
Blinding used	Not blinded
Blinding implementation details	Not applicable.
Arms
Are arms mutually exclusive	Yes
Arm title	Paediatric patients with PPL
Arm description	Paediatric patients with biallelic mutations of the POMC, PCSK1, or LEPR genes.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	All eligible patients began treatment with setmelanotide at a dose of 0.5 mg per day. The setmelanotide dose was increased by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6). At each visit, the decision to escalate the dose was based on tolerability and health status. The maximum dose level in this study for patients who weigh <20 kg, 20 to <30 kg, 30 to <40 kg, and ≥40 kg was 0.5, 1.0, 1.5, and 2.0 mg QD, respectively. Height and weight were monitored closely during the study. If a patient’s weight decreased to below 15 kg during the study, a discussion regarding possible dose reduction occurred. A dose reduction to a minimum of 0.25 mg QD was allowed in such cases, or in case of tolerability concerns. The dose continued to be evaluated and adjusted, at the discretion of the investigator, as long as the daily dose was kept between 0.25 and 2.0 mg QD and did not exceed the maximum dose for the patient's weight.
Arm title	Paediatric patients with BBS
Arm description	Paediatric patients with Bardet Biedl Syndrome.
Arm type	Experimental
Investigational medicinal product name	Setmelanotide
Investigational medicinal product code
Other name
Pharmaceutical forms	Solution for injection
Routes of administration	Subcutaneous use
Dosage and administration details	All eligible patients began treatment with setmelanotide at a dose of 0.5 mg per day. The setmelanotide dose was increased by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6). At each visit, the decision to escalate the dose was based on tolerability and health status. The maximum dose level in this study for patients who weigh <20 kg, 20 to <30 kg, 30 to <40 kg, and ≥40 kg was 0.5, 1.0, 1.5, and 2.0 mg QD, respectively. Height and weight were monitored closely during the study. If a patient’s weight decreased to below 15 kg during the study, a discussion regarding possible dose reduction occurred. A dose reduction to a minimum of 0.25 mg QD was allowed in such cases, or in case of tolerability concerns. The dose continued to be evaluated and adjusted, at the discretion of the investigator, as long as the daily dose was kept between 0.25 and 2.0 mg QD and did not exceed the maximum dose for the patient's weight.
Number of subjects in period 1 Paediatric patients with PPL Paediatric patients with BBS Started 7 5 Completed 6 5 Not completed 1 0      Lost to follow-up 1 -

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	Paediatric patients with PPL
Reporting group description	Paediatric patients with biallelic mutations of the POMC, PCSK1, or LEPR genes.
Reporting group title	Paediatric patients with BBS
Reporting group description	Paediatric patients with Bardet Biedl Syndrome.
Reporting group values Paediatric patients with PPL Paediatric patients with BBS Total Number of subjects 7 5 12 Age categorical Units: Subjects     Infants and toddlers (28 days-23 months) 0 0 0     Children (2-11 years) 7 5 12     Adolescents (12-17 years) 0 0 0 Age continuous Units: years     arithmetic mean (standard deviation) 3.4 ( 0.53 ) 3.8 ( 1.30 ) - Gender categorical Units: Subjects     Female 2 3 5     Male 5 2 7 Gene Type The efficacy, safety, and tolerability of setmelanotide is being studied in paediatric patients 2 to <6 years of age with variants in POMC, PCSK1, or LEPR (PPL) genes or with BBS. This characteristic shows which rare genetic cause of obesity each group had. Units: Subjects     POMC 3 0 3     PCSK1 0 0 0     LEPR 4 0 4     BBS 0 5 5 Weight at baseline The most recent weight measurement prior to the first administration of study drug. Units: kilogram(s)     arithmetic mean (standard deviation) 44.933 ( 12.0142 ) 28.300 ( 13.0434 ) - Height at baseline The most recent height measurement prior to the first administration of study drug. Units: centimetre     arithmetic mean (standard deviation) 114.210 ( 9.3718 ) 106.740 ( 17.1072 ) - BMI at baseline The most recent body mass index (BMI) measurement prior to the first administration of study drug. Units: kg/m2     arithmetic mean (standard deviation) 34.347 ( 7.0673 ) 23.716 ( 3.5184 ) - Waist circumference at baseline The most recent waist circumference measurement prior to the first administration of study drug. Units: centimetre     arithmetic mean (standard deviation) 89.014 ( 14.3713 ) 66.213 ( 13.2926 ) - BMI Z-score at baseline BMI Z-score is a measure of how many standard deviations a child or young person's BMI is above or below the average BMI for their age and gender. Units: Z-score     arithmetic mean (standard deviation) 10.749 ( 3.8400 ) 4.233 ( 1.0742 ) -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	Paediatric patients with PPL
Reporting group description	Paediatric patients with biallelic mutations of the POMC, PCSK1, or LEPR genes.
Reporting group title	Paediatric patients with BBS
Reporting group description	Paediatric patients with Bardet Biedl Syndrome.

End points Top of page

Primary: Proportion of Patients who Achieve a Decrease in BMI Z-Score ≥0.2 from Baseline to Week 52 Top of page
End point title	Proportion of Patients who Achieve a Decrease in BMI Z-Score ≥0.2 from Baseline to Week 52 [1]
End point description	The proportion of patients who met a “responder” definition, defined as a decrease from baseline to 52 weeks in the patient’s BMI Z-score of ≥0.2. Baseline was defined as the most recent measurement prior to the first administration of study drug. Heights and weights were collected in triplicate at each visit. These were aggregated into one averaged value per visit prior to calculating the patient’s BMI and BMI Z-score. BMI Z-scores are based on the World Health Organization’s Child Growth Standards 2007. Two-sided 95% CI was calculated using the Clopper-Pearson Method.
End point type	Primary
End point timeframe	From baseline to Week 52
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: This was not a comparator study. For the primary endpoint BMI Z-score, the Z-score represents how many SDs the individual’s BMI is from the median BMI of the reference population. A “responder” was defined as a decrease from baseline to 52 weeks in the patient’s BMI Z-score of ≥0.2. The proportion of responders and the corresponding 2-sided 95% CI using the Clopper-Pearson method were reported.
End point values Paediatric patients with PPL Paediatric patients with BBS Number of subjects analysed 7 5 Units: percent     number (confidence interval 95%) 85.7 (54.1 to 100) 80.0 (28.4 to 99.5)
No statistical analyses for this end point

Primary: Proportion of Patients who Achieve a Decrease in BMI Z-Score ≥0.2 from Baseline to Week 52 Top of page

Primary: Mean Percent Change in BMI From Baseline to Week 52 Top of page
End point title	Mean Percent Change in BMI From Baseline to Week 52 [2]
End point description	The mean percent change in BMI from baseline to Week 52. Baseline was defined as the most recent measurement prior to the first administration of study drug. Heights and weights were collected in triplicates at each visit. These were aggregated into one averaged value per visit prior to calculating the patient’s BMI. Two-sided 95% CI is calculated with Student’s t-distribution.
End point type	Primary
End point timeframe	From baseline to Week 52.
Notes [2] - 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: This was not a comparator study. For the analysis of mean percent change in BMI from baseline, percent changes in BMI from baseline over time were summarized using descriptive statistics.
End point values Paediatric patients with PPL Paediatric patients with BBS Number of subjects analysed 6 5 Units: percent     arithmetic mean (confidence interval 95%) -25.597 (-37.66 to -13.54) -9.719 (-20.69 to 1.26)
No statistical analyses for this end point

Primary: Mean Percent Change in BMI From Baseline to Week 52 Top of page

Secondary: Mean Absolute Change in BMI Z-score from Baseline to Week 52 Top of page
End point title	Mean Absolute Change in BMI Z-score from Baseline to Week 52
End point description	The mean change from baseline to Week 52 in BMI Z-score. Baseline is defined as the most recent measurement prior to the first administration of study drug. Heights and weights were collected in triplicates at each visit. These were aggregated into one averaged value per visit prior to calculating the patient’s BMI and BMI Z-score. BMI Z-scores are based on the World Health Organization’s Child Growth Standards 2007.
End point type	Secondary
End point timeframe	From baseline to Week 52.
End point values Paediatric patients with PPL Paediatric patients with BBS Number of subjects analysed 6 5 Units: Z-score     arithmetic mean (standard deviation) -5.185 ( 1.8585 ) -1.331 ( 1.2295 )
No statistical analyses for this end point

Secondary: Mean Absolute Change in BMI Z-score from Baseline to Week 52 Top of page

Secondary: Mean Change in Percent of the BMI 95th Percentile from Baseline to Week 52 Top of page
End point title	Mean Change in Percent of the BMI 95th Percentile from Baseline to Week 52
End point description	The mean change from baseline to Week 52 in the percent of the BMI 95th percentile. Baseline was defined as the most recent measurement prior to the first administration of study drug. Weights were collected in triplicates at each visit. These were aggregated into one averaged value per visit.
End point type	Secondary
End point timeframe	From baseline to Week 52.
End point values Paediatric patients with PPL Paediatric patients with BBS Number of subjects analysed 6 5 Units: percent     arithmetic mean (standard deviation) -47.595 ( 17.3280 ) -14.462 ( 13.8571 )
No statistical analyses for this end point

Secondary: Mean Change in Percent of the BMI 95th Percentile from Baseline to Week 52 Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to Week 52
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	26.1
Reporting groups
Reporting group title	Overall Patients
Reporting group description	All patients from the PPL and BBS group.
Serious adverse events Overall Patients Total subjects affected by serious adverse events      subjects affected / exposed 0 / 12 (0.00%)      number of deaths (all causes) 0      number of deaths resulting from adverse events 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Overall Patients Total subjects affected by non serious adverse events      subjects affected / exposed 12 / 12 (100.00%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 25 General disorders and administration site conditions Pyrexia      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 7 Injection site bruising      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 5 Injection site pruritus      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 4 Injection site discolouration      subjects affected / exposed 3 / 12 (25.00%)      occurrences all number 3 Injection site erythema      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 3 Fatigue      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Chest discomfort      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Chills      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gait disturbance      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Impaired healing      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Induration      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Injection site induration      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Injection site oedema      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Injection site pain      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Injection site urticaria      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Thirst      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Immune system disorders Allergy to arthropod bite      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Food allergy      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Reproductive system and breast disorders Spontaneous penile erection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Genital erythema      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 3 / 12 (25.00%)      occurrences all number 4 Rhinorrhoea      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Dyspnoea      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Increased upper airway secretion      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Nasal congestion      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Oropharyngeal pain      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Psychiatric disorders Depressed mood      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Investigations Alanine aminotransferase increased      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Aspartate aminotransferase increased      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gamma-glutamyltransferase increased      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Serum ferritin decreased      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Injury, poisoning and procedural complications Fall      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 4 Skin abrasion      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Sports injury      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Arthropod bite      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Contusion      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Eye contusion      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Head injury      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Humerus fracture      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Immunisation reaction      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Radius fracture      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Skin laceration      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Tooth avulsion      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Upper limb fracture      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Nervous system disorders Headache      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Change in seizure presentation      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Dizziness      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Blood and lymphatic system disorders Iron deficiency anaemia      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Lymphadenopathy      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Ear and labyrinth disorders Ear pain      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Eye disorders Eye ulcer      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Ocular discomfort      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gastrointestinal disorders Vomiting      subjects affected / exposed 7 / 12 (58.33%)      occurrences all number 14 Diarrhoea      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 4 Abdominal pain      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Nausea      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Anal erythema      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Breath odour      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Frequent bowel movements      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gastrooesophageal reflux disease      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gingival hyperpigmentation      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Odynophagia      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Pigmentation lip      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Skin and subcutaneous tissue disorders Skin hyperpigmentation      subjects affected / exposed 9 / 12 (75.00%)      occurrences all number 47 Dermatitis      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 4 Pityriasis rosea      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 4 Skin discolouration      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Drug eruption      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Dry skin      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Eczema      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Ephelides      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Erythema      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Hand dermatitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Hyperhidrosis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Nail pigmentation      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Onychoclasis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Pruritus      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Rash pruritic      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Seborrhoeic dermatitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Skin hypopigmentation      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Musculoskeletal and connective tissue disorders Arthralgia      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Limb discomfort      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Infections and infestations Nasopharyngitis      subjects affected / exposed 5 / 12 (41.67%)      occurrences all number 12 Upper respiratory tract infection      subjects affected / exposed 4 / 12 (33.33%)      occurrences all number 7 Ear infection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 4 Otitis media      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 3 Pharyngitis streptococcal      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 3 COVID-19      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Influenza      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Pharyngotonsillitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Skin candida      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Viral upper respiratory tract infection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 2 Acarodermatitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Conjunctivitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gastroenteritis viral      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Gastrointestinal viral infection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Respiratory tract infection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Sinusitis      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Vulvovaginal mycotic infection      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1 Metabolism and nutrition disorders Appetite disorder      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Polydipsia      subjects affected / exposed 2 / 12 (16.67%)      occurrences all number 2 Decreased appetite      subjects affected / exposed 1 / 12 (8.33%)      occurrences all number 1

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
16 Jun 2021	Version 1.1: • Body weight categories were established to determine the maximum daily dose based on the patient’s body weight. • The exclusion criterion pertaining to inadequate hepatic function was added. • The statistical considerations were changed to align with the changes to the study objectives and endpoints . • Additional pharmacokinetic timepoints were added. • Text was updated to reflect the revised PK modeling. • For pediatric patients, the modified Schwartz equation will be used to calculate renal function (mL/min/1.73m2).
24 Jan 2022	Version 2.0: • Wording of the study objectives was edited to improve clarity and consistency between primary and secondary objectives and endpoints • The possibility to reduce the dose down to 0.25 mg was introduced in order to mitigate the risk of drug discontinuation, in case of tolerability/safety concerns. • The possibility for the Investigator to pause dose-escalation was further elaborated, to allow for dose adjustment which may enhance patient adherence to treatment and reaching of final maintenance dose level. • Sample size was expanded to allow enrollment of up to 15 patients to increase the chances to include patients with each of the genetic conditions. • The following inclusion criterion was added: − Symptoms or behaviors of hyperphagia at any time during the patient’s life, as determined by the Investigator at screening. • The following exclusion criterion was added − Any other uncontrolled endocrine, metabolic or medical condition(s) known to impact body weight that could potentially interfere with interpretation of study results. • Wording of the study endpoints was edited to improve clarity and better reflect the descriptive nature of the endpoints, given the small sample size. • Benefit-risk text was edited to better reflect the importance of early treatment. • The approval status of setmelanotide was updated. • The following text pertaining to the Screening period was added: - A patient who did not meet one or more of the eligibility criteria was considered a screen failure. Any patient that was rescreened was required to have a new ICF signed by the parent or guardian. • Additional text was added for clarity in case of treatment discontinuation to highlight the importance of retaining patients in the study regardless of whether they discontinued study drug prematurely.
24 Jan 2022	Version 2.0 continued: • Allowed a home nurse to assist with injections if requested. • Weight-related history including growth charts since birth would be obtained and reported. • Protection from sun was advised. • Weight was to be measured at approximately the same time of day throughout the study. • Specified that the stadiometer was to be calibrated by site personnel on a daily basis prior to height assessment. • Specified that waist circumference was to be measured at approximately the same time of day throughout the study and according to the NHLBI criteria. • Text regarding the participation in the parent exit interview was added. • Text was added regarding blood sampling during site visits. • Weight-based maximal dose values were added in the overdose section. • Given the young age of the patient population, a provision was added that if PK profile could not be obtained for a given visit due to logistical challenges, the Investigator should at least obtain sample for trough PK (pre-dose). • Text added on conducting a clinical study during the global pandemic.
10 Mar 2022	• The required baseline body weight for inclusion in the study was decreased. • Clarified criteria to permit certain telephone visits. • The text concerning dose selection was modified to reflect the changes made to the study entry weight criterion.
05 Dec 2022	Version 4.0: • Provided dose escalation instructions in the event of a tolerability concern. • Included criteria for LTE eligibility and bridging visits to the LTE, if applicable; refined definition of study completion to account for patients who transition to the LTE or terminate early or withdraw. • Added a co-primary endpoint of percent change in BMI; removed revised co-primary endpoint from secondary endpoints. • Provided instructions to delineate the conditions that would necessitate patient referral to a mental health professional. • Specified that if there were logistical challenges collecting the 10- to 12-hour post-dose PK sample, the sample could have been collected at 8 hours post-dose. • Revised the language on approved indications in global regions. • Revised the Benefit/Risk section to reflect the totality of the setmelanotide program. • Added sections to describe the following assessments: Fitzpatrick scale and ADA sample collection.
22 Jun 2023	Version 5.0: • Removed dosing diary requirements during Bridging Visits • Removed optional caregiver exit interviews • Corrected the intention to collect PK trough instead of PK profile at the ETT Visit
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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