Clinical Trial Results:
Title: Setmelanotide (RM-493) phase 2 treatment trial in patients with rare genetic disorders of obesity. Trial design: This was a Phase 2, open-label, uncontrolled, non-randomised, proof-of-concept study over 20 weeks post-screening, with the possibility of enrolment in a separate extension study at Week 16 (study RM-493-022). It was planned to enrol approximately 235 obese patients with rare genetic diseases of obesity (RGDO) caused by genetic mutations that impact the leptin-melanocortin hypothalamic pathway (the MC4R pathway), including one of the following 10 cohorts, which shared the phenotype of early onset obesity and hyperphagia: chromosomal rearrangement of the 16p11.2 locus, Alström Syndrome (AS), Bardet Biedl Syndrome (BBS), MC4R deficiency, PPL (collective name for POMC, PCSK1, and LEPR deficiency) heterozygous, PPL composite heterozygous, PPL compound heterozygous, SH2B1 deficiency, Smith-Magenis Syndrome (SMS), and SRC1 deficiency. The protocol was amended so that patients 6 years and older with RGDO were eligible for participation. The study consisted of a 2-8 week screening period and a 16-week treatment period. After enrolment, patients entered a screening period when they completed a daily hunger questionnaire. During the treatment period, all patients initiated treatment with setmelanotide and dose escalated to the final dose of 3.0 mg once daily (QD). Patients continued dosing at 3.0 mg QD and returned to the clinic every 4 weeks (at Visits 3-5) to complete all study assessments. After 16 weeks, at Visit 6, the patient received the last setmelanotide injection and participation in the study concluded in one of the following 2 ways: • Completed Visit 6 and enrolled in a separate extension study, Rhythm Study RM-493-022. • Decided not to participate in the extension study and proceeded to the final study visit (Visit 7) at Week 20. The median duration of treatment was 17 weeks (range: 1 to 96 weeks).

Trial information Top of page
Trial identification
Sponsor protocol code	RM-493-014
Additional study identifiers
ISRCTN number	-
US NCT number	NCT03013543
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	Rhythm Clinical Trials, Rhythm Pharmaceuticals, Inc, +1 8572644280, clinicaltrials@rhythmtx.com
Scientific contact	Rhythm Clinical Trials, Rhythm Pharmaceuticals, Inc, +1 8572644280, 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	02 Jun 2023
Is this the analysis of the primary completion data?	Yes
Primary completion date	01 Mar 2022
Global end of trial reached?	Yes
Global end of trial date	01 Mar 2022
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	The primary objective was to explore the impact of setmelanotide on obesity in patients with various specific RGDO.
Protection of trial subjects	The Institutional Review Board (IRB)/Independent Ethics Committee (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). Data Safety Monitoring (DSM) was the responsibility of the Investigator, on an ongoing basis, rather than an internal safety monitoring committee. The study was also monitored by a DSM Board with outside advisors who met periodically.
Background therapy	Medications approved to treat obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion) were not allowed within 3 months of randomisation 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 randomisation, (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 enrolment, (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	Not applicable.
Actual start date of recruitment	10 Feb 2017
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	Yes
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	United States: 119
Country: Number of subjects enrolled	Canada: 3
Country: Number of subjects enrolled	Israel: 4
Country: Number of subjects enrolled	Netherlands: 13
Country: Number of subjects enrolled	Spain: 13
Country: Number of subjects enrolled	United Kingdom: 27
Country: Number of subjects enrolled	France: 6
Country: Number of subjects enrolled	Germany: 23
Country: Number of subjects enrolled	Greece: 5
Worldwide total number of subjects	213
EEA total number of subjects	60
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)	27
Adolescents (12-17 years)	63
Adults (18-64 years)	118
From 65 to 84 years	5
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	This study recruited 213 patients with RGDO in 57 centres in Europe, Israel, Canada, and the United States with the first patient enrolled on 10 Feb 2017 and the last patient visit on 01 Mar 2022. Patients were included if they had RDGO for which evidence supported a role of the leptin-melanocortin hypothalamic pathway (i.e., the MC4R pathway).
Pre-assignment
Screening details	Screening assessments included medical history, physical exam, comprehensive skin examination, laboratory tests, blood pressure, hunger scale, body composition, Columbia-Suicide Severity Rating Scale (C-SSRS) form, and energy expenditure evaluation.
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	This was an open-label, proof-of-concept study.
Arms
Are arms mutually exclusive	No
Arm title	16.p11.2
Arm description	Patients with RGDO caused by deletions in the p11.2 region of chromosome 16 encompassing the SH2B1 gene.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	AS - Alstrom Syndrome
Arm description	Patients with RGDO caused by Alström Syndrome (AS). AS is a ciliopathy characterised by a syndromic phenotype that includes progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, congestive heart failure, and marked childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	BBS - Bardet‐Biedl syndrome
Arm description	Patients with RGDO caused by BBS. BBS is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	MC4R
Arm description	Patients with RGDO with heterozygous loss-of-function MC4R variants. MC4R variants were categorized into subgroups based upon whether setmelanotide could elicit MC4R receptor activation. Activation was measured based on relative cAMP signaling between setmelanotide and alpha-MSH.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	PPL Heterozygous
Arm description	Patients with RGDO carrying heterozygous loss of function variants in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	PPL Composite Heterozygous
Arm description	Patients with RGDO carrying 2 or more heterozygous loss of function mutations in 2 or more of POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	PPL Compound Heterozygous
Arm description	Patients with RGDO carrying 2 different heterozygous loss of function mutations in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	SH2B1
Arm description	Patients with RGDO caused by SRC homology 2 B adapter protein 1 (SH2B1) loss-of-function mutations.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	SMS - Smith-Magenis Syndrome
Arm description	Patients with RGDO caused by SMS, a complex genetic disorder characterised by sleep disturbance, multiple developmental anomalies, psychiatric behaviour, and obesity. It is caused by a heterozygous 17p11.2 microdeletion containing the retinoic acid-induced 1 (RAI1) gene or mutation within RAI1. RAI1 haplo-insufficiency is thought to contribute to obesity through downregulation of brain-derived neurotrophic factor (BDNF) and POMC.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	SRC1
Arm description	Patients with RGDO caused by Steroid Receptor Coactivator-1 Deficiency (SRC1) gene deficiency.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Arm title	Overall
Arm description	The overall total of patients with RGDO from each arm.
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	Setmelanotide was administered once daily (QD) via SC injection. The therapeutic dose was 3.0 mg QD, which was achieved after dose titration. No dose >3.0 mg QD was to be administered. However, doses <3.0 mg QD could be administered, after consultation with the Sponsor, if necessary due to an AE or other safety or tolerability concern. After protocol amendment 9, the standard dose escalation was: Patients <16 years of age: 1.0 mg in Weeks 1-2, 2.0 mg in Weeks 3-4, and 3.0 mg in Weeks 5-16. Patients >=16 years of age: 2.0 mg in Weeks 1-2, and 3.0 mg between Weeks 3-16. Before amendment 9, dose titration was in 0.5 mg increments at 1-2 week intervals starting with 1.0 mg QD until a therapeutic dose was achieved or until the patient reached a maximum dose of 2.5 mg QD (prior to Amendment 6) or 3.0 mg QD (from Amendment 6). In the UK, the maximum doses were 2.0 mg and 2.5 mg, respectively, in adolescents and children.
Number of subjects in period 1 16.p11.2 AS - Alstrom Syndrome BBS - Bardet‐Biedl syndrome MC4R PPL Heterozygous PPL Composite Heterozygous PPL Compound Heterozygous SH2B1 SMS - Smith-Magenis Syndrome SRC1 Overall Started 19 4 10 49 33 5 27 22 12 32 213 Completed 19 2 7 37 22 2 20 13 9 22 153 Not completed 0 2 3 12 11 3 7 9 3 10 60      Adverse event, serious fatal - - - 1 - - - - - - 1      Consent withdrawn by subject - 2 - 5 6 2 3 1 - 4 23      Physician decision - - - - 1 - - - - - 1      Adverse event, non-fatal - - - 3 2 1 3 8 - 2 19      Other - - 2 - 2 - - - 1 - 5      Withdrawal by Parent/Guardian - - 1 1 - - - - 1 1 4      Non-compliance with study drug - - - - - - - - 1 - 1      Lost to follow-up - - - 1 - - 1 - - 2 4      Lack of efficacy - - - 1 - - - - - - 1      Protocol deviation - - - - - - - - - 1 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	16.p11.2
Reporting group description	Patients with RGDO caused by deletions in the p11.2 region of chromosome 16 encompassing the SH2B1 gene.
Reporting group title	AS - Alstrom Syndrome
Reporting group description	Patients with RGDO caused by Alström Syndrome (AS). AS is a ciliopathy characterised by a syndromic phenotype that includes progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, congestive heart failure, and marked childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus.
Reporting group title	BBS - Bardet‐Biedl syndrome
Reporting group description	Patients with RGDO caused by BBS. BBS is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction.
Reporting group title	MC4R
Reporting group description	Patients with RGDO with heterozygous loss-of-function MC4R variants. MC4R variants were categorized into subgroups based upon whether setmelanotide could elicit MC4R receptor activation. Activation was measured based on relative cAMP signaling between setmelanotide and alpha-MSH.
Reporting group title	PPL Heterozygous
Reporting group description	Patients with RGDO carrying heterozygous loss of function variants in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	PPL Composite Heterozygous
Reporting group description	Patients with RGDO carrying 2 or more heterozygous loss of function mutations in 2 or more of POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	PPL Compound Heterozygous
Reporting group description	Patients with RGDO carrying 2 different heterozygous loss of function mutations in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	SH2B1
Reporting group description	Patients with RGDO caused by SRC homology 2 B adapter protein 1 (SH2B1) loss-of-function mutations.
Reporting group title	SMS - Smith-Magenis Syndrome
Reporting group description	Patients with RGDO caused by SMS, a complex genetic disorder characterised by sleep disturbance, multiple developmental anomalies, psychiatric behaviour, and obesity. It is caused by a heterozygous 17p11.2 microdeletion containing the retinoic acid-induced 1 (RAI1) gene or mutation within RAI1. RAI1 haplo-insufficiency is thought to contribute to obesity through downregulation of brain-derived neurotrophic factor (BDNF) and POMC.
Reporting group title	SRC1
Reporting group description	Patients with RGDO caused by Steroid Receptor Coactivator-1 Deficiency (SRC1) gene deficiency.
Reporting group title	Overall
Reporting group description	The overall total of patients with RGDO from each arm.
Reporting group values 16.p11.2 AS - Alstrom Syndrome BBS - Bardet‐Biedl syndrome MC4R PPL Heterozygous PPL Composite Heterozygous PPL Compound Heterozygous SH2B1 SMS - Smith-Magenis Syndrome SRC1 Overall Total Number of subjects 19 4 10 49 33 5 27 22 12 32 213 Age categorical Units: Subjects Age continuous Units: years     arithmetic mean (standard deviation) 21.4 ± 14.58 16.0 ± 3.74 22.5 ± 14.71 22.4 ± 15.28 36.1 ± 17.23 40.4 ± 19.62 30.7 ± 20.16 33.6 ± 17.88 19.4 ± 8.10 31.3 ± 17.13 28.1 ± 17.30 - Gender categorical Units: Subjects     Female 13 3 6 27 22 4 18 15 10 25 143 143     Male 6 1 4 22 11 1 9 7 2 7 70 70 Weight at baseline Patient weight at baseline. Units: kilogram(s)     arithmetic mean (standard deviation) 113.62 ± 38.489 87.28 ± 16.360 128.04 ± 28.631 117.87 ± 32.339 143.04 ± 30.492 139.05 ± 30.957 122.08 ± 43.315 129.06 ± 39.480 92.48 ± 24.556 124.07 ± 33.717 122.98 ± 36.142 - Waist Circumference at Baseline Patient waist circumference at baseline. Units: centimetre     arithmetic mean (standard deviation) 116.84 ± 22.179 109.75 ± 14.523 126.20 ± 19.344 122.52 ± 19.697 137.95 ± 18.529 134.00 ± 19.038 128.52 ± 28.772 130.28 ± 23.029 110.14 ± 11.807 123.10 ± 21.101 125.63 ± 22.162 - BMI at Baseline Patient BMI at baseline. Body Mass Index: calculated as weight (kg) / height (m2). Units: kilogram(s)/square metre     arithmetic mean (standard deviation) 41.68 ± 10.697 35.62 ± 8.445 44.83 ± 4.068 42.49 ± 8.346 50.78 ± 11.301 50.89 ± 5.674 46.06 ± 13.255 48.18 ± 13.487 38.85 ± 8.656 45.79 ± 11.097 45.21 ± 11.048 -

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	16.p11.2
Reporting group description	Patients with RGDO caused by deletions in the p11.2 region of chromosome 16 encompassing the SH2B1 gene.
Reporting group title	AS - Alstrom Syndrome
Reporting group description	Patients with RGDO caused by Alström Syndrome (AS). AS is a ciliopathy characterised by a syndromic phenotype that includes progressive cone-rod dystrophy leading to blindness, sensorineural hearing loss, congestive heart failure, and marked childhood obesity associated with hyperinsulinemia and type 2 diabetes mellitus.
Reporting group title	BBS - Bardet‐Biedl syndrome
Reporting group description	Patients with RGDO caused by BBS. BBS is a genetically heterogeneous human obesity syndrome associated with ciliary dysfunction.
Reporting group title	MC4R
Reporting group description	Patients with RGDO with heterozygous loss-of-function MC4R variants. MC4R variants were categorized into subgroups based upon whether setmelanotide could elicit MC4R receptor activation. Activation was measured based on relative cAMP signaling between setmelanotide and alpha-MSH.
Reporting group title	PPL Heterozygous
Reporting group description	Patients with RGDO carrying heterozygous loss of function variants in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	PPL Composite Heterozygous
Reporting group description	Patients with RGDO carrying 2 or more heterozygous loss of function mutations in 2 or more of POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	PPL Compound Heterozygous
Reporting group description	Patients with RGDO carrying 2 different heterozygous loss of function mutations in POMC, PCSK1, or LEPR, causing early onset hyperphagia and obesity.
Reporting group title	SH2B1
Reporting group description	Patients with RGDO caused by SRC homology 2 B adapter protein 1 (SH2B1) loss-of-function mutations.
Reporting group title	SMS - Smith-Magenis Syndrome
Reporting group description	Patients with RGDO caused by SMS, a complex genetic disorder characterised by sleep disturbance, multiple developmental anomalies, psychiatric behaviour, and obesity. It is caused by a heterozygous 17p11.2 microdeletion containing the retinoic acid-induced 1 (RAI1) gene or mutation within RAI1. RAI1 haplo-insufficiency is thought to contribute to obesity through downregulation of brain-derived neurotrophic factor (BDNF) and POMC.
Reporting group title	SRC1
Reporting group description	Patients with RGDO caused by Steroid Receptor Coactivator-1 Deficiency (SRC1) gene deficiency.
Reporting group title	Overall
Reporting group description	The overall total of patients with RGDO from each arm.

End points Top of page

Primary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline Top of page
End point title	Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline [1] [2]
End point description	The proportion of patients in each subgroup of RGDO who achieve at least 5% reduction from baseline in body weight (i.e., are ‘responders’) after ~3 months of treatment with setmelanotide. The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Primary
End point timeframe	From baseline to after 3 months of 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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 1 to 34 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only. [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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 213 Units: percent     number (confidence interval 90%) 30.5 (25.3 to 36.1)
No statistical analyses for this end point

Primary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline Top of page

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - <12 years Top of page
End point title	Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - <12 years [3]
End point description	The proportion of patients in each subgroup of RGDO who achieve at least 5% reduction from baseline in body weight (i.e., are ‘responders’) after ~3 months of treatment with setmelanotide by age categories (<12 years). The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to 3 months
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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 27 Units: percent number (confidence interval 90%)     <12 years old 11.1 (3.1 to 26.3)
No statistical analyses for this end point

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - <12 years Top of page

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=12 and <18 years Top of page
End point title	Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=12 and <18 years [4]
End point description	The proportion of patients in each subgroup of RGDO who achieve at least 5% reduction from baseline in body weight (i.e., are ‘responders’) after ~3 months of treatment with setmelanotide by age categories (>=12 and <18 years). The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to 3 months
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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 63 Units: percent number (confidence interval 90%)     >=12 and <18 years 31.7 (22.1 to 42.7)
No statistical analyses for this end point

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=12 and <18 years Top of page

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=18 years Top of page
End point title	Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=18 years [5]
End point description	The proportion of patients in each subgroup of RGDO who achieve at least 5% reduction from baseline in body weight (i.e., are ‘responders’) after ~3 months of treatment with setmelanotide by age categories (>=18 years). The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to 3 months
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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 123 Units: percent number (confidence interval 90%)     >=18 years 34.1 (27.1 to 41.8)
No statistical analyses for this end point

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >=18 years Top of page

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >= 12 Years Top of page
End point title	Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >= 12 Years [6]
End point description	The proportion of patients in each subgroup of RGDO who achieve at least 5% reduction from baseline in body weight (i.e., are ‘responders’) after ~3 months of treatment with setmelanotide by age categories (>= 12 Years). The summary of the primary endpoint and the associated 2-sided 90% Clopper-Pearson confidence interval is provided.
End point type	Secondary
End point timeframe	From baseline to 3 months
Notes [6] - 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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 186 Units: percent number (confidence interval 90%)     >= 12 Years 33.3 (27.6 to 39.5)
No statistical analyses for this end point

Secondary: Percentage of Patients who achieved ≥5% Reduction in Body Weight from Baseline - >= 12 Years Top of page

Secondary: Percentage Body Weight change from Baseline to 3 months Top of page
End point title	Percentage Body Weight change from Baseline to 3 months [7]
End point description
End point type	Secondary
End point timeframe	From baseline to 3 months
Notes [7] - 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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 213 Units: percent     arithmetic mean (standard deviation) -2.74 ± 4.746
No statistical analyses for this end point

Secondary: Percentage Body Weight change from Baseline to 3 months Top of page

Secondary: Percentage change in Weekly Average of Daily Most Hunger Score from Baseline to 3 months Top of page
End point title	Percentage change in Weekly Average of Daily Most Hunger Score from Baseline to 3 months [8]
End point description
End point type	Secondary
End point timeframe	From baseline to 3 months
Notes [8] - 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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 114 Units: percent     arithmetic mean (standard deviation) -37.70 ± 36.762
No statistical analyses for this end point

Secondary: Percentage change in Weekly Average of Daily Most Hunger Score from Baseline to 3 months Top of page

Secondary: Percentage change in Waist Circumference from Baseline to 3 months Top of page
End point title	Percentage change in Waist Circumference from Baseline to 3 months [9]
End point description
End point type	Secondary
End point timeframe	From baseline to 3 months
Notes [9] - 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: All patients were treated with the same setmelanotide dose regimen. There was no comparators group. The numbers of patients ranged from 4 to 49 by RGDO mutation, with an overall total of 213 patients. Data were summarised using descriptive statistics only.
End point values Overall Number of subjects analysed 132 Units: percent     arithmetic mean (standard deviation) -2.35 ± 8.420
No statistical analyses for this end point

Secondary: Percentage change in Waist Circumference from Baseline to 3 months Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	From baseline to 3 months.
Assessment type	Systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	23.0
Reporting groups
Reporting group title	Overall
Reporting group description	All patients treated with setmelanotide during the study.
Serious adverse events Overall Total subjects affected by serious adverse events      subjects affected / exposed 7 / 213 (3.29%)      number of deaths (all causes) 1      number of deaths resulting from adverse events 1 Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Cardiac disorders Acute myocardial infarction      subjects affected / exposed 2 / 213 (0.94%)      occurrences causally related to treatment / all 0 / 2      deaths causally related to treatment / all 0 / 1 Nervous system disorders Typical aura without headache      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Immune system disorders Hypersensitivity      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 1 / 1      deaths causally related to treatment / all 0 / 0 Gastrointestinal disorders Gastrointestinal haemorrhage      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Infections and infestations Diverticulitis      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0 Rotavirus infection      subjects affected / exposed 1 / 213 (0.47%)      occurrences causally related to treatment / all 0 / 1      deaths causally related to treatment / all 0 / 0
Frequency threshold for reporting non-serious adverse events: 5%
Non-serious adverse events Overall Total subjects affected by non serious adverse events      subjects affected / exposed 208 / 213 (97.65%) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus      subjects affected / exposed 50 / 213 (23.47%)      occurrences all number 61 Nervous system disorders Headache      subjects affected / exposed 60 / 213 (28.17%)      occurrences all number 90 Dizziness      subjects affected / exposed 15 / 213 (7.04%)      occurrences all number 16 General disorders and administration site conditions Injection site pruritus      subjects affected / exposed 35 / 213 (16.43%)      occurrences all number 45 Injection site erythema      subjects affected / exposed 29 / 213 (13.62%)      occurrences all number 39 Fatigue      subjects affected / exposed 34 / 213 (15.96%)      occurrences all number 38 Injection site induration      subjects affected / exposed 14 / 213 (6.57%)      occurrences all number 18 Injection site pain      subjects affected / exposed 13 / 213 (6.10%)      occurrences all number 16 Injection site oedema      subjects affected / exposed 11 / 213 (5.16%)      occurrences all number 14 Blood and lymphatic system disorders Eosinophilia      subjects affected / exposed 12 / 213 (5.63%)      occurrences all number 14 Gastrointestinal disorders Nausea      subjects affected / exposed 82 / 213 (38.50%)      occurrences all number 110 Vomiting      subjects affected / exposed 32 / 213 (15.02%)      occurrences all number 41 Diarrhoea      subjects affected / exposed 23 / 213 (10.80%)      occurrences all number 23 Abdominal pain upper      subjects affected / exposed 16 / 213 (7.51%)      occurrences all number 18 Abdominal pain      subjects affected / exposed 12 / 213 (5.63%)      occurrences all number 12 Reproductive system and breast disorders Erection increased      subjects affected / exposed 20 / 213 (9.39%)      occurrences all number 23 Respiratory, thoracic and mediastinal disorders Cough      subjects affected / exposed 11 / 213 (5.16%)      occurrences all number 12 Skin and subcutaneous tissue disorders Skin hyperpigmentation      subjects affected / exposed 160 / 213 (75.12%)      occurrences all number 351 Macule      subjects affected / exposed 12 / 213 (5.63%)      occurrences all number 67 Psychiatric disorders Insomnia      subjects affected / exposed 13 / 213 (6.10%)      occurrences all number 13 Infections and infestations Nasopharyngitis      subjects affected / exposed 18 / 213 (8.45%)      occurrences all number 19 Metabolism and nutrition disorders Decreased appetite      subjects affected / exposed 11 / 213 (5.16%)      occurrences all number 11

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
14 Feb 2017	Amendment 1.0 • 2 Global Hunger Questions were added to the study to help assess hunger. • Coagulation assessments (coagulation profile (prothrombin time [PT] or international normalised ratio [INR], and partial thromboplastin time [PTT], also referred to as activated partial thromboplastin time [aPTT])) were added to safety laboratories. • For patient safety, it was clarified that the oral glucose tolerance test would not be done on patients with a diagnosis of Type 1 or Type 2 diabetes. • The list of specific hormonal, neuroendocrine, metabolic, and anti-inflammatory analytes and biomarkers to be analysed was removed from the exploratory objective.
21 Mar 2018	Amendment 6.0 • The dose titration schedule was clarified to allow for a possible second dose titration during the dose titration phase or the 10-week open label phase, if deemed necessary by the Investigator after consultation with the Sponsor. • The dose titration table was updated to clarify the maximum dose for adults and adolescents and the maximum dose for both in all countries. • Clarified that the definition of non-child bearing potential was the start of menarche and is not a criterion for Tanner Staging • The possibility of conducting certain visits at a patient’s local physician’s office was removed due to administrative and regulatory constraints. Home nursing visits arranged by Sponsor will still be possible for these visits. • Females who were breastfeeding or nursing were excluded globally • Added a statement regarding contraception required by UK regulatory authorities for females who reached Tanner Stage 5 or achieved menarche during the study and added a statement required by UK regulatory authorities regarding true abstinence.
28 Jun 2018	Amendment 7.0 • Allowed the inclusion of patients with Smith-Magenis Syndrome, SH2B1 haploinsufficiency Carboxypeptidase E Deficiency and Leptin Deficiency Obesity. • Removed the option to use placebo to practice the injection technique during screening. • Removed the option for clinic visits to be performed by a home health care professional at the patient’s home for Visits 4, 11 and 13. • Remove the optional sub-study of serial photography. • Added a screening assessment to review the specific genetic mutation for the patient to ensure eligibility. • Added guidance that blood draws could be prioritised if venous access was compromised due to the extreme obesity seen in these patients. • Added exposure and safety data for patients treated at the 3.0 mg dose. • Clarified the collection schedule for anti-RM-493 antibodies.
31 May 2019	Amendment 9.0 • Protocol Amendment 9 was completely reformatted and reorganised, using an electronic StartingPoint Submission Authoring Template. • Study Objectives o Decreased number of specific objectives. o Rearranged objectives into primary, secondary, and exploratory only; none are designated tertiary. o Eliminated secondary objectives for patients who continue into the long-term extension – extension was changed to be a separate protocol. o Deleted secondary objectives related to diabetes, and all glucose parameters except HbA1c. o Added EuroQoL-Five Dimension assessments, SF-10 and SF-12 Surveys, and Patient-Reported Behavioral Disturbance Questionnaire. o Removed PedsQL and SF-36. • Study Endpoints o Changed primary endpoint from “The primary endpoint is the mean percent change from baseline in body weight at the end of ~3 months of treatment” to “The proportion of patients in each subgroup of RGDO who achieve at least 5% body weight reduction from baseline, at ~3 months treatment with setmelanotide.”
31 May 2019	Amendment 9.0 Continued (1) • Study Design o Revised the “dose titration” phase of the study to “dose escalation to a predetermined maximum.” New study design has only 1 escalation step (from 2.0 mg/day to 3.0 mg/day for patients ≥16 years of age) and 2 escalation steps (from 1.0 mg/day to 2.0 mg/day to 3.0 mg/day for patients 12 up to 15 years of age). Both age groups undergo a total of 16 weeks of treatment. Visit times were updated accordingly. o Changed length of treatment (10 weeks to 16 weeks) and number/frequency of visits, compared to Amendment 7. o Revised the end-of-study options for patients. In Amendment 7, some patients were eligible for 1-year extension, and others were withdrawn from study. In Amendment 9, patient can choose to either exit the current study or participate in a separate Extension Study Protocol. (If that study is not yet open at the site, patient can choose to continue treatment via Bridging Visits, and then enter the new extension study when it is available.) o Added directions for patients already enrolled in the study to transition to from dose titration to dose escalation o Reduced the number of available substudies to 1 o Modified process of Data Safety Monitoring (DSM). DSM was made the responsibility of the Investigator, on an ongoing basis, rather than an internal safety monitoring committee. Study was also monitored by a DSMB with outside advisers who met periodically.
31 May 2019	Amendment 9.0 Continued (2) • Study Population o Increased number of patients planned from “up to 80” to “approximately 150” patients o Modified Inclusion and Exclusion Criteria (removed BBS/AS patients and added 16P11.2 patients; also see Summary of Changes Amendment 7 to Amendment 9 in Appendix 16.1.1 for any additional changes) o Updated Withdrawal of Patients to reflect the new statement of the primary endpoint. • Study Treatments o Added updated description of study drug dosing and dosing schedule for 2 different age groups; the maximum dose for both age groups was 3.0 mg o Added more specifics concerning Treatment Compliance. o Removed discussion of permitted medications and information regarding procedures, and updated prohibited medications section.
31 May 2019	Amendment 9.0 Continued (3) • Schedule of Assessments / Patient Assessments and Requirements o Rearranged Schedule of Assessments (Table 3) to reflect the amended study design, and updated footnotes accordingly. o Rearranged descriptions of all assessments into one section rather than into groups by Efficacy vs. Clinical Procedures and Safety, and modified assessment descriptions to reflect changes in study design. o Pulled fasting lipids and HbA1C measurements out of Safety Labs group to be listed separately in the schedule of assessments. o Updated Safety Labs (called Clinical Labs in Amendment 7) to be performed in a central laboratory, rather than in local laboratories. o Added list of laboratory test priorities to be followed if the number of blood draws was too small to perform all laboratory tests. o Added EQ-5D assessments. o Added Patient-Reported Behavioral Disturbance Questionnaire. o Removed PedsQL and SF-36, and added SF-10 and SF-12. o Removed OGTT. o Grouped hs-CRP as part of hormonal activity group, removing it from the schedule of assessments. o Deleted optional substudies ABPM, quantitative skin colour assessment, and Energy Expenditure. (“Quantitative skin colour assessment” was part of the Comprehensive Skin Exam by dermatologist, and part of Fitzpatrick scale.) o Expanded description of ECG procedures. o Added section on Hepatic Fibrosis.
31 May 2019	Amendment 9.0 Continued (4) • Adverse Events o Revised AE reporting process: AEs were reported to Advanced Clinical and the email address was provided. o Added sections to describe Assessment of Severity and relationship to study drug, and expanded the information in the AE section overall. Also added the statement, “Any elevation in PHQ-9 or C-SSRS score should be evaluated to determine whether it meets the criteria for reporting as an AE.” • Data Analysis/Statistical Procedures o Updated statements of primary objective and primary endpoint. o Stated that no formal hypothesis would be tested. • Administrative Requirements o Removed discussion of Long-Term Extensions and Pooling of Patients with the same rare genetic obesity population from other studies. o Deleted “Publication is likely to be coordinated with the investigators of RM-493-011, a sister protocol to this study ongoing in Germany with similar design and patient populations.” • Appendices o Appendix C: Added last sentence “Menarche history will be obtained for females.” o Removed “Evaluation of Abnormal Liver Function Tests (LFTs)” and all dose titration guidelines. o Removed the reproduction of “World Medical Association Declaration of Helsinki.”
20 Feb 2020	Amendment 10.0 • Added that study centres from the Middle East would be included in the study • Modified the exploratory objective and endpoints to remove hormonal assays • Lowered the age of inclusion from 12 to 6 years old • Removed bone density from the exploratory endpoints • Added that enrolment could be temporarily held • Added that the study number (014) would be the first 3 digits of the patient identification number • Changed screening window from 6 to 8 weeks • Section on hunger assessments was rearranged to more clearly describe the various hunger questionnaires used in the study • For Quality of Life / Mental Health Assessments, a clarifying statement was added to specify that if a patient’s age changed while enrolled into the clinical study, he/she should continue to complete the same version of the instrument that they had been using previously. • For the EuroQoL-Five Dimension assessment, a statement was added to specify that patients between the ages of 6 and 8 years old would not take the assessment. • The following were specified as the biomarkers to be assayed: thyroid stimulating hormone (TSH), free thyroxine (T4), leptin, insulin, and high-sensitivity C-reactive protein (hs-CRP)
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

More information Top of page