Clinical trial NCT04966741
Conditions: Bardet-Biedl Syndrome POMC Deficiency Obesity PCSK1 Deficiency Obesity LEPR Deficiency Obesity
Keywords: Bardet Biedl Syndrome POMC Deficiency PCSK1 LEPR Obesity Pediatric Obesity
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2022-03-08; Completion date: 2024-11-08
Enrollment: 12 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 3 open-label, clinical study to evaluate the efficacy, safety and tolerability of setmelanotide over 1 year of treatment, in pediatric participants aged 2 to \<6 years with obesity due to either biallelic variants of the pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) genes or Bardet-Biedl Syndrome (BBS).

Detailed description:
Pediatric participants aged 2 to \<6 years with obesity due to either biallelic variants of the POMC, PCSK1 or LEPR genes or BBS will be enrolled into this phase 3 open-label clinical trial at one of approximately 8 clinical centers in North America, Europe, or Australia. All participants will be assigned to receive setmelanotide via daily subcutaneous (SC) injection for 1 year.

Arms: arm 1: Participants with POMC)/PCSK1/LEPR biallelic mutations collectively referred to as PPL received setmelanotide at a dose of 0.5 milligrams (mg) per day (QD) via SC injection for 52 weeks. The dose was escalated by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6) to a maximum dose of 0.5 to 2.0 mg QD with the maximum dose based on body weight. Following the last dose in this study, participants who were considered likely to benefit from continued setmelanotide treatment and who had completed this trial could be eligible to enter an open-label long-term extension (LTE) trial with setmelanotide. arm 2: Participants with BBS received setmelanotide at a dose of 0.5 mg QD via SC injection for 52 weeks. The dose was escalated by increments of 0.5 mg every 2 weeks, if tolerated, at the dose escalation visits (Weeks 2, 4, and 6) to a maximum dose of 0.5 to 2.0 mg QD with the maximum dose based on body weight. Following the last dose in this study, participants who were considered likely to benefit from continued setmelanotide treatment and who had completed this trial could be eligible to enter an open-label long-term extension (LTE) trial with setmelanotide.
Interventions: intervention 1: Setmelanotide
Intervention descriptions: intervention 1: SC injection once daily.

Protocol documents:
Prot_000.pdf: 
Protocol 
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Confidential 
 
 
SETMELANOTIDE  
RM-493-033 
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 
 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
 
EudraCT Number: 2021-004167-27 
 
Trial Sponsor: 
Rhythm Pharmaceuticals, Inc. 
222 Berkeley Street  
12th Floor 
Boston, MA 02116 
 
Document Date (Version): 
22 June 2023 (V5.0) 
 
 
 
 
 
CONFIDENTIALITY NOTE 
The information contained in this document is privileged and confidential. Any distribution, copying, or disclosure 
is strictly prohibited unless such disclosure is required by federal regulations or state law. Persons to whom the 
information is disclosed must know that it is confidential and that it may not be further disclosed by them. 
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SUMMARY OF CHANGES TO THE PROTOCOL 
 
The protocol history is below: 
Version and Date of Protocol 
Comments 
Version 1.0, 01 March 2021 
Original version 
Version 1.1, 16 June 2021 
Global 
Version 1.2, 17 November 2021 
Netherlands only 
Version 2.0, 24 January 2022 
Global 
Version 3.0, 10 March 2022 
Global 
Version 4.0, 05 December 2022 
Global 
Version 5.0, 22 June 2023 
Current version 
 
Key changes in the current version (5.0) of the protocol are summarized below. 
 
Typographical, formatting, and administrative changes were also made to improve the clarity of 
the document (as applicable). 
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APPROVAL SIGNATURE PAGE 
 
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 
 
Protocol Number: 
RM-493-033  
Document Version: 
Version 5.0  
Document Date: 
22 June 2023 
 
REVIEWED/APPROVED BY: 
 
 
 
 
 
 
 
 
Rhyt
hythm
hm P
 Pha
harmaceututicals, I
, Inc
nc. 
 
Signature 
 
Date 
 
Electronically signed by:
Reason: I have reviewed and approve
Reason: I have reviewed and approve
his document.
Date: Jun 23, 2023 10:45 EDT
Date: Jun 23, 2023 10:45 EDT
23-Jun-2023
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INVESTIGATOR STATEMENT 
 
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 
 
Protocol Number: 
RM-493-033  
Document Version: 
Version 5.0  
Document Date: 
22 June 2023 
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm) 
or its designated representative(s) concerning this trial that has not been published previously 
will be kept in the strictest confidence. This documentation includes the trial protocol, 
Investigator Brochure (IB), case report forms, and other scientific data. 
This trial will not commence without the prior written approval of a properly constituted 
Institutional Review Board or Ethics Committee. No changes will be made to the trial protocol 
without the prior written approval of Rhythm and the Institutional Review Board, except where 
necessary to eliminate an immediate hazard to the patient. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
 
 
 
 
 
Investigator Name 
 
Signature of Investigator 
 
Date 
 
 
 
 
 
 
Investigational site (or name of institution) and location (printed) 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: Setmelanotide 
Title of Study: 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 center(s): Approximately 5 to 8 centers in North America, Europe and/or Asia Pacific 
Studied period (years): One year 
Estimated date first patient enrolled: February 2022  
Estimated date last patient completed: September 2023 
Phase of development: 3 
Trial Objectives: 
Primary: 
The primary objective of the trial is: 
To evaluate the effect of setmelanotide on weight-related parameters 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). 
Secondary: 
The secondary objectives of the trial are: 
To evaluate the effect of Setmelanotide on additional weight-related parameters, as well as safety and 
tolerability 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) BBS. 
Methodology: 
This is a 1-year, open-label trial. 
Screening 
The Screening Period begins with obtaining informed consent from the parent or guardian and will last 
between 1 and 8 weeks. During the Screening Period, patients will undergo all procedures as outlined in 
the Schedule of Assessments (SoA; Table 1) to determine if they meet all of the Inclusion and none of 
the Exclusion criteria of the trial. 
During the Screening Period, patients will undergo medical evaluation; and caregivers will receive 
training on injection of trial drug and other trial procedures. 
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Enrollment and trial procedures  
At the enrollment visit, patients will undergo all procedures as outlined in the SoA (Table 1) and it will 
be reconfirmed that the patient continues to meet all of the Inclusion and none of the Exclusion criteria 
of the trial. 
At the enrollment visit, the patient will have height and body weight recorded. This will be the baseline 
height and weight. To be eligible for the trial, a patient’s baseline weight must be at least 15 kg. Height 
and weight will be monitored closely during the trial.  
During the enrollment visit, the caregiver will administer the patient’s first dose of setmelanotide via 
subcutaneous (SC) injection under the supervision of the trial staff. Patients’ caregivers will be issued 
and instructed on the use of an electronic diary to capture daily compliance with injections. 
All patients will begin treatment with setmelanotide at a dose of 0.5 mg per day. Patients will then 
increase their dose by 0.5 mg increments, every 2 weeks, as described in the SoA (Table 1). The 
maximum dose level of setmelanotide used in this trial will be based on the weight bands for the 2- to 
<6-year-old patients to support an exposure similar to that observed for adults dosed at 2 to 3 mg 
set
setmelelan
anotide e once 
ce daily
ily ( (QD
QD). Th
. The m
 maximum dose level in this trial for patients who weigh <20 kg, 
 will be 0.5 mg, 1.0 mg, 1.5 mg and 2.0 mg QD, respectively.  
If a patient’s weight decreases to below 15 kg during the trial, the Investigator and Sponsor will discuss 
the patient’s status and will jointly determine if a patient should continue the current dose, decrease the 
dose or discontinue treatment with setmelanotide temporarily or permanently. A dose reduction to 
0.25 mg QD can be considered in such scenarios or in case of safety or tolerability concerns. These dose 
adjustments are considered adequate to help attain and maintain appropriate body weight in growing 
pediatric patients. 
 
At the discretion of the Investigator, the dose escalation may be paused for a patient at any step prior to 
reaching their final maintenance dose, for safety or tolerability reasons, or due to achieving adequate 
weight loss. The dose may continue to be evaluated and adjusted, at the discretion of the Investigator, as 
long as the daily dose is kept between 0.25 mg and 2.0 mg QD, according to their respective weight. 
Patients will have trial visits approximately every 4 weeks through Week 20 and then approximately 
every 8 weeks through Week 52, and assessments will be performed as per the SoA (Table 1). Due to 
the young age of the patients, it may not be possible to perform all planned assessments at each visit. 
Thus, as described in the SoA (Table 1), the Investigator may adjust the planned assessments and blood 
draws as appropriate for the optimal medical care of the patients.  
In specific, individual cases, dose escalation may be delayed compared to the originally planned 
schedule at enrollment, in order to mitigate potential tolerability issues (e.g., in case of gastrointestinal 
adverse events). If the escalation to the next dose level is delayed, the escalation period will be extended 
for that patient and the subsequent available site visits will then become “dose escalation” visits, where 
the appropriate and specific assessments related to the escalation visits will take place. 
End of Treatment 
The End of Treatment (EOT) will occur as an in-person clinic visit on Trial Week 52, which is the final 
day of treatment with setmelanotide. At the EOT, patients who are considered likely to benefit from 
continued setmelanotide treatment and who have completed this trial may be eligible to enter an open-
label long-term extension (LTE) trial with setmelanotide. Patients and or caregivers/guardians must 
meet the eligibility criteria and should discuss eligibility with the Investigator. Eligible patients may 
participate in Bridging visits (every 12 weeks) (Table 1) if the LTE is not yet active. 
All patients who discontinue treatment prematurely should attend an Early Termination of Treatment 
visit (ETT) as soon as possible after the last dose of trial treatment. Patients who discontinue treatment 
but remain enrolled in the trial should continue to complete all assessments (as Retained Dropouts). 
These patients will be required to complete the End of Study visit (EOS) as applicable following the 
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ETT (Section 5.1.5). Patients who discontinue treatment prematurely but remain enrolled and complete 
assessments through Week 52 are eligible to enroll in the optional LTE trial. 
Patients who discontinue prematurely and withdraw from the trial will not be required to complete the 
EOS following the ETT. If the ETT visit occurs 4 weeks or later following the last dose of 
Setmelanotide, then the ETT visit will replace the EOS if no AEs are being monitored. 
End of Study 
A final End of Study (EOS) visit will occur on Week 56 and may be conducted via telephone for 
patients who are not being monitored for an AE. The EOS visit is not required for patients who enroll in 
the LTE (or transition to Bridging visits prior to LTE).  
At the Investigator’s discretion and in consultation with the Sponsor, patients who have well tolerated 
setmelanotide, who are considered likely to benefit from continued treatment, and who have completed 
assessments through Week 52 may be offered continued setmelanotide treatment via: 
• 
Enrollment in a separate LTE trial. 
• 
Bridging visits until LTE availability (if the LTE trial is not active by the time of patient 
completion of this trial). See Table 1. 
• 
Commercial use of Setmelanotide QD, if applicable, according to the approved indication in 
their country, and in consultation with their prescribing physician 
Completion of trial participation for an individual patient is defined as 1 of the following: 
• 
For patients who complete trial treatment and enroll in the LTE: the in-person EOT visit at 
Week 52. 
• 
For patients who complete treatment and do not enroll in the LTE: a Week 56 visit conducted 
via telephone.  
• 
For patients who discontinue trial treatment prematurely and complete all assessments, but do 
not withdraw consent (and assent, as applicable): the latest of the Week 52 visit, the ETT visit, 
or EOS (if required). 
• 
For patients who discontinue early and withdraw consent or assent: the ETT visit. 
The end of the trial is defined as the date of the last visit of the last patient under the auspices of the 
current trial. 
Number of patients (planned): 
The trial plans to enroll approximately 10-15 pediatric patients (approximately 5 or more with biallelic 
mutations of the POMC, PCSK1, or LEPR genes and approximately 5 or more with BBS) in a pivotal 
cohort. At the discretion of the Sponsor, if additional potential patients are identified, a supplemental 
cohort may be added to gain additional experience in this pediatric patient population. 
Diagnosis and criteria for inclusion and exclusion: 
Inclusion Criteria 
1. Patients must have obesity due to either: 
a. POMC, PCSK1, or LEPR deficiency, confirmed by genetic testing demonstrating biallelic 
variants that are interpreted as pathogenic, likely pathogenic, or of undetermined 
significance (VUS) by the American College of Medical Genetics and Genomics (ACMG) 
criteria, or 
b. BBS as defined by both (1) the Beales Criteria, 1999 (Beales 1999; Appendix 1) AND 
(2) genetic confirmation of homozygous or compound heterozygous loss-of-function 
mutation in BBS genes. 
2. Age between 2 to <6 years at the time of informed consent. 


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3. Obesity, defined as body mass index (BMI) ≥97th percentile for age and gender AND body 
weight of at least 15 kg at the time of enrollment. 
4. Symptoms or behaviors of hyperphagia at any time during the patient’s life, as determined by 
the Investigator at screening. 
5. Parent or guardian of patient is able to communicate well with the Investigator, to understand 
and comply with the requirements of the trial (including once daily (QD) injection regimen and 
all other trial procedures) and is able to understand and sign the written consent. 
Exclusion Criteria: 
1. HbA1c >9.0% at screening 
2. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or 
nonalcoholic steatohepatitis (NASH). 
3. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2. 
4. History or close family history (parents or siblings) of melanoma, or patient history of 
oculocutaneous albinism. 
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive 
skin evaluation performed by the Investigator during screening. Any concerning lesions 
identified during screening will be biopsied and results known to be benign prior to enrollment. 
6. Patient is, in the opinion of the Investigator, not suitable to participate in the trial. 
7. Participation in any clinical trial with an investigational drug/device within 3 months prior to 
the first day of dosing. 
8. Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to 
setmelanotide. 
9. Significant hypersensitivity to any excipient in the trial drug. 
10. Abnormal hepatic function as evidenced by elevated Aspartate Aminotransferase (AST) and 
Alanine Aminotransferase (ALT) values >5x upper limit of normal (ULN). 
11. Any other uncontrolled endocrine, metabolic or medical condition(s) known to impact body 
weight that could potentially interfere with interpretation of trial results. 
Investigational product, dosage and mode of administration: 
Investigational product: Setmelanotide, 10 mg/mL in a sterile solution for injection 
Dosage:e: Betetween
ween 0 0.5 and 2.
nd 2.0 mg/g/da
day (
y (if a a dos
 dose of
 of 0.
 0.5 mg/day is not tolerated or if weight decreases to 
below 
 
Mode of administration: SC injection 
Duration of treatment: Total treatment with setmelanotide will be 52 weeks. Total participation in the 
trial will last up to 64 weeks, including the Screening Period and the EOS visit. 
Criteria for Evaluation: 
Primary Endpoints: 
• 
The proportion of patients demonstrating response to setmelanotide, defined as a decrease from 
baseline to 52 weeks in the patient’s body mass index (BMI) z-score of ≥0.2. 
• 
Mean percent change in BMI from baseline to Week 52. 
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Secondary Endpoints: 
• 
The following endpoints will be summarized and reported as change from baseline to 52 weeks: 
o Mean absolute change in BMI z-score per age and gender 
o Mean change in percent of the 95th percentile of BMI per age and gender 
o The mean change in vital signs and laboratory evaluations  
o The mean change in bone age  
o Mean change in Ages & Stages Questionnaires, Third Edition (ASQ®-3)  
• 
Frequency and severity of AEs will also be summarized and reported during trial conduct. 
St
Statisisticical m
l metho
hods
ds: 
Details of all statistical analyses will be described in a separate statistical analysis plan (SAP). The trial 
plans to enroll approximately 10-15 pediatric patients (approximately 5 or more patients with biallelic 
mutations of the POMC, PCSK1 or LEPR genes and approximately 5 or more patients with BBS). The 
sample size is not driven by statistical power considerations, but is primarily driven by clinical and 
practical considerations. 
The primary objective is to evaluate the effect of setmelanotide on weight-related parameters, measured 
in terms of the response rate to setmelanotide. Due to the small sample size of the trial, no statistical 
hypothesis testing is planned, and efficacy will be reported using descriptive statistics. The safety 
population, including all patients who receive at least 1 dose of setmelanotide, will be used as the 
primary analysis population for all the analyses. 
AEs will be coded by preferred term (PT) and system organ class (SOC) using the latest version of the 
Medical Dictionary for Regulatory Activities (MedDRA). All AE data will be presented in a data 
listing. Treatment-emergent AEs will be summarized by severity and relationship to trial drug. Serious 
AEs and AEs leading to early discontinuation will also be presented in data listings. 
Actual values and changes from baseline for clinical laboratory test results, vital sign measurements 
etc., will be summarized using descriptive statistics (N, mean, standard deviation, median, minimum, 
and maximum). Shift tables will be generated for clinical laboratory test results. Clinical laboratory test 
results, vital sign measurements etc., will be presented in data listings. 
The secondary objectives are to evaluate the efficacy
cacy of set
 setmelelan
anotide o
e on wei
 weight-relelatated
ed p pararameteterers,s, as 
as 
wel
well as t
 as the e safetyty a and to
 tolelerability
ility of set
 setmelelan
anotide.e. 
 
 
 No
 No st
 statatiststical
cal h hypothesi
esis was
s was mad
ade.e. T
 The co
e collect
ected
ed 
pararam
ameteterers w
s will b be su
e summararized
zed wi
 with ap
 appropriatate d
e descr
escriptive statistics. 
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Due to the small sample size, summary statistics by genotype may be provided as appropriate. 
 


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2. 
SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Enrollment Visit 
(Baseline) 
Dose Escalation 
Visits1 
Trial Visits2 
EOT  
EOS 3 
ETT  
Bridging 
Visits  
Trial Week 
-8 to -1 
 
2, 4, 6 
8, 12, 16, 20, 28, 36, 
442 
52 
56 
Q12 Weeks 
(If needed, 
In Person) 
Trial Day 
-56 to -1 
1 
15, 29, 43 
57, 85, 113, 141, 197, 
253, 309 
365 
393 
Window 
 
 
±3 
±5 
±5 
±3 
±5 
Informed Consent 
X 
 
 
 
 
 
 
 
Inclusion/ Exclusion 
X 
X 
 
 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
 
 
Physical Examination4 
X 
X* 
X 
X 
X 
 
X 
X 
Fitzpatrick classification 
scale 
 
X 
 
 
X 
 
X 
 
Comprehensive Skin 
Examination5 
X 
X 
 
X 
X 
 
X 
X 
Weight6 
X 
X 
X 
X 
X 
 
X 
X 
Height7 
X 
X 
X 
X 
X 
 
X 
X 
Vital Signs9 
X 
X 
X 
X 
X 
 
X 
X 
ECG10 
X 
X 
X 
X (W8 and 44) 
X 
 
X 
X 
Daily drug compliance11 
 
X 
X 
X 
X 
 
X 
 
Genetic Sample12, 20 
 
X 
 
 
 
 
 
 
Safety Lab Tests12 
X 
X 
X 
X 
X 
 
X 
X 
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Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Enrollment Visit 
(Baseline) 
Dose Escalation 
Visits1 
Trial Visits2 
EOT  
EOS 3 
ETT  
Bridging 
Visits  
Trial Week 
-8 to -1 
 
2, 4, 6 
8, 12, 16, 20, 28, 36, 
442 
52 
56 
Q12 Weeks 
(If needed, 
In Person) 
Trial Day 
-56 to -1 
1 
15, 29, 43 
57, 85, 113, 141, 197, 
253, 309 
365 
393 
Window 
 
 
±3 
±5 
±5 
±3 
±5 
Anti-Drug Antibodies12 
X 
 
 
X 
X 
 
X 
X 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site inspection 
 
X 
X 
X 
X 
 
X 
X 
Concomitant medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
Optional Nutritional 
Counseling17 
 
X 
X 
X 
X 
 
 
X 
Bone Age18 
 
X 
 
 
X 
 
 
 
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Table 1: 
Schedule of Assessments 
Assessment 
Screening 
Enrollment Visit 
(Baseline) 
Dose Escalation 
Visits1 
Trial Visits2 
EOT  
EOS 3 
ETT  
Bridging 
Visits  
Trial Week 
-8 to -1 
 
2, 4, 6 
8, 12, 16, 20, 28, 36, 
442 
52 
56 
Q12 Weeks 
(If needed, 
In Person) 
Trial Day 
-56 to -1 
1 
15, 29, 43 
57, 85, 113, 141, 197, 
253, 309 
365 
393 
Window 
 
 
±3 
±5 
±5 
±3 
±5 
Ages & Stages 
Questionnaires, Third 
Edition (ASQ-3)19 
 
X 
 
X 
X 
 
 
X 
Dispense Trial Drug 
 
X 
X 
X 
X** 
 
 
X 
Return Trial Drug 
 
 
X 
X 
X 
 
X 
X 
Abbreviations: ECG=electrocarardiogram
am; EO
EOS=End d of
of Study; EOT=end of treatment; ETT=Early Termination of Treatment; 
; 
LTE=Long –term extension; 
 
*Note: If there are <2 weeks between screening and enrollment, the enrollment visit physical examination may be waived. 
**Drug is dispensed at the EOT only for patients who continue to the Bridging visits. 
1 Patients should attend dose-escalation visits as appropriate per their respective escalation regimen, which is dictated by their weight, until achieving maximum 
dose level. See Section 7.3 for details. 
2 The dose may continue to be evaluated and adjusted, at the discretion of the Investigator, in 0.5 mg increments, so long as the daily dose is kept between 
0.5 mg and the weight-based maximum for the patient (see Table 3). 
3 EOS visit should occur within 4 weeks of the last dose of study drug for patients who either discontinue prematurely or for patients who are being monitored 
for an adverse event (AE) after the EOT. This visit is not required for patients who complete the Week 52 visit and either enroll in the LTE or transition to 
Bridging visits.  
4 A complete physical examination will be conducted at screening and at the EOT visit. At other timepoints, an abbreviated examination will be performed. The 
abbreviated examination should focus on heart, lungs, skin, neurologic exam, and any areas of previous abnormal findings, noting any changes from baseline. 
Tanner staging should be performed at Screening and at the EOT (Week 52) visit. It may be done at additional visits, at the discretion of the Investigator  
5 A comprehensive skin evaluation will be performed by the Investigator or qualified designee. The skin exam should include a full body skin exam (head-to-toe 
skin examination). Any concerning lesions identified during the Screening Period will be biopsied and results known to be benign prior to the first dose of 
setmelanotide. If the pre-treatment biopsy results are of concern, the patient will be excluded from the trial. Additionally, any new lesion or change in an 
existing lesion identified during the course of the trial must be evaluated by a dermatologist and biopsied, if clinically indicated in the opinion of the 
dermatologist. 
6 Weight (kg) is to be measured at the clinic using the same scale throughout the trial or at home (during virtual visits or visiting nurse visits) using the same 
scale provided to the patient as part of the clinical trial. Weight should be measured after patients have attempted to empty their bladders and after fasting for 
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at least 8 hours. Patients are to wear light clothing or underwear and no shoes, with empty pockets, and will be weighed at approximately the same time of day. 
All measurements will be recorded to the nearest tenth kg if reported with a digital scale, or half kg with a mechanical scale. 
7 Height (cm) will be measured, without shoes, socks or hats, using a wall-mounted stadiometer. The stadiometer should be calibrated by site personnel on a 
daily basis prior to height assessment. All measurements will be done in triplicate at each time point and recorded to the nearest half cm. 
8 
9 All blood pressure (BP) and heart rate (HR) measurements are to be obtained in a sitting position following at least 5 minutes of rest. All measurements will be 
taken in triplicate, approximately 2 minutes apart. When possible, BP should be taken in the non-dominant arm using the same methodology (automated or 
manual) throughout the trial. 
10 A single 12-lead ECG will be performed. If an ECG is not practical in a young patient, it may be replaced by a rhythm strip and HR and PR interval should be 
documented. 
11 A daily question querying whether the patient completed their daily injection will be asked via electronic diary. Paper versions can be used, if required. 
12 Safety laboratory tests will include CBC with platelet count and standard indices, chemistry panel (includes sodium, potassium, chloride, CO2, albumin, total 
protein, glucose, BUN, creatinine, uric acid, aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), creatine 
phosphokinase (CPK), alkaline phosphatase, total bilirubin, direct bilirubin, lactate dehydrogenase (LDH), calcium, phosphorus), thyroid- stimulating 
hormone (TSH) and urinalysis with microscopic analysis if positive findings on dipsticks warrant further examination. Due to the age of the children, it may 
not be possible to collect samples (including urine samples) for all laboratory tests at every study visit. Screening may be performed over multiple days, to 
complete the required assessments. After enr
nrolollmentnt, if all laboratory y tests are not
not possible, then the tests should be collected in the following descending order 
of priority: safety, anti-drug antibodies, 
, 
 and then n 
l. If it is not possible to collect the safety laboratory tests on two consecutive 
visits, the patient should be discussed with h the Spons
nsor. If there is a margigina
nal va
value close to the exclusion range, it is suggested to repeat the laboratory 
analyses at Investigator’s discretion. To allow for pre- and post-dose sampling, patients will attend the site visit having fasted for an 8-hour time period 
without injecting the trial product. On the day of the site visit, dosing will be conducted on site. The Investigator’s will adhere to the site-specific blood 
volume limits for safety laboratory and 
 to ensure minimal distress to the pediatric patients. If the genetic sample cannot be collected at the 
enrollment visit, it may be collected during a later trial visit. Anti-drug g antntibo
body y samplples (Section 8.5) ) are to o be
be colollected d pr
prior to dosing with setmelanotide. 
 
13
14
15
16
17
  
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18 Bone age may be read locally initially, but the Sponsor may request central reading of images. A standard bone age measurement (of the hand/wrist area) will 
be obtained at the beginning and the end of the trial to monitor for growth related safety concerns. 
19 The ASQ-3 is intended for use at six-month intervals for patients between 6 months and 3 years of age, and then at 1-year intervals through age 5. Thus, for 
patients who enter the trial at ages between 2 years and 3 years, the ASQ-3 should be administered at the Baseline visit, Week 28 visit and EOT visit. For 
patients who enter the trial between the ages of 3 and 6 years old, the ASQ-3 should only be administered at the Baseline visit and EOT visit.  
20 A blood sample will be obtained at baseline to confirm a genetic diagnosis. However, patients may be entered into the trial with documentation of previously 
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TABLE OF CONTENTS 
 
1. 
SYNOPSIS ...................................................................................................................5 
2. 
SCHEDULE OF ASSESSMENTS .............................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................20 
3. 
INTRODUCTION ......................................................................................................22 
3.1. 
Trial Rationale ............................................................................................................22 
3.2. 
Setmelanotide .............................................................................................................22 
3.3. 
Benefit/Risk Assessment ............................................................................................23 
4. 
TRIAL OBJECTIVES AND ENDPOINTS ...............................................................24 
5. 
INVESTIGATIONAL PLAN .....................................................................................25 
5.1. 
Overall Trial Design ...................................................................................................25 
5.1.1. 
Trial Population ..........................................................................................................25 
5.1.2. 
Screening Period .........................................................................................................25 
5.1.3. 
Enrollment and trial procedures ..................................................................................25 
5.1.4. 
End of Treatment ........................................................................................................26 
5.1.5. 
End of Study Visit ......................................................................................................27 
5.1.6. 
Completion of Trial Participation ...............................................................................27 
5.2. 
Site Closure and Study Termination ...........................................................................27 
5.2.1. 
Site Closure .................................................................................................................27 
5.2.2. 
Criteria for Trial Termination or Suspension .............................................................28 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................29 
6.1. 
Inclusion Criteria ........................................................................................................29 
6.2. 
Exclusion Criteria .......................................................................................................29 
6.3. 
Treatment Discontinuation and Patient Withdrawal Criteria .....................................30 
7. 
TREATMENT OF PATIENTS ..................................................................................31 
7.1. 
Description of Trial Drug ...........................................................................................31 
7.2. 
Treatment Dose Selection ...........................................................................................31 
7.2.1. 
Benzyl Alcohol Dose ..................................................................................................31 
7.2.2. 
Setmelanotide Dose ....................................................................................................31 
7.3. 
Treatment Administration ...........................................................................................39 
7.4. 
Concomitant Medications ...........................................................................................40 


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7.5. 
Treatment Compliance ................................................................................................40 
7.6. 
Randomization and Blinding ......................................................................................40 
8. 
ASSESSMENTS .........................................................................................................41 
8.1. 
General Trial Assessments .........................................................................................41 
8.1.1. 
Informed Consent/Assent ...........................................................................................41 
8.1.2. 
Demographic/Medical History ...................................................................................41 
8.1.3. 
Genetic Sample ...........................................................................................................41 
8.1.4. 
Physical Examination .................................................................................................42 
8.1.5. 
Electrocardiogram (ECG) ...........................................................................................42 
8.1.6. 
Comprehensive Skin Evaluation .................................................................................42 
8.1.7. 
Fitzpatrick Scale .........................................................................................................42 
8.2. 
Efficacy Assessments .................................................................................................42 
8.2.1. 
Weight and Height ......................................................................................................42 
8.2.2. 
 ...................................................................................................43 
8.2.3. 
Trial questionnaires ....................................................................................................43 
8.2.3.1. 
 ...........................................................43 
8.2.3.2. 
Ages & Stages Questionnaires®, Third Edition (ASQ®-3) .........................................44 
8.2.3.3. 
 ....................................44 
8.3. 
Safety Assessments .....................................................................................................44 
8.3.1. 
Vital Signs ..................................................................................................................44 
8.3.2. 
Laboratory Assessments .............................................................................................45 
8.4. 
 ....................................................................................46 
8.5. 
Anti-Drug Antibodies .................................................................................................47 
8.6. 
Adverse and Serious Adverse Events .........................................................................47 
8.6.1. 
Definition of Adverse Events .....................................................................................47 
8.6.1.1. 
Adverse Event (AE) ....................................................................................................47 
8.6.1.2. 
Serious Adverse Event (SAE) ....................................................................................48 
8.6.2. 
Relationship to Trial Drug ..........................................................................................49 
8.6.3. 
Overdose .....................................................................................................................50 
8.6.4. 
Recording Adverse Events .........................................................................................50 
8.6.5. 
Reporting Adverse Events ..........................................................................................50 
8.6.6. 
Reporting of Expedited Safety Observations by the Investigator ..............................51 
9. 
STATISTICS ..............................................................................................................52 
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9.1. 
Sample Size Determination ........................................................................................52 
9.2. 
Statistical Analyses .....................................................................................................52 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS .........................................53 
10.1. 
Trial Monitoring .........................................................................................................53 
10.1.1. 
Trial Conduct During the COVID-19 Pandemic ........................................................53 
10.2. 
Audits and Inspections ................................................................................................53 
10.3. 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) ..............54 
10.4. 
Source Documents ......................................................................................................54 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................55 
12. 
ETHICS ......................................................................................................................56 
12.1. 
Ethics Review .............................................................................................................56 
12.2. 
Ethical Conduct of the Trial .......................................................................................56 
12.3. 
Written Informed Consent ..........................................................................................56 
13. 
DATA HANDLING AND RECORDKEEPING .......................................................57 
13.1. 
Inspection of Records .................................................................................................57 
13.2. 
Retention of Records ..................................................................................................57 
13.3. 
Data Protection ...........................................................................................................57 
13.4. 
Data Quality Assurance ..............................................................................................57 
14. 
PUBLICATION POLICY ..........................................................................................59 
15. 
LIST OF REFERENCES ............................................................................................60 
APPENDICES ...............................................................................................................................61 
APPENDIX 1. BEALES CRITERIA .........................................................................................61 
APPENDIX 2. GUIDANCE ON TRIAL CONDUCT DURING THE COVID-19 
PANDEMIC ...............................................................................................................62 
APPENDIX 3. FITZPATRICK SCALE .....................................................................................63 
 


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LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................11 
Table 2: 
Trial Objectives and Endpoints ..................................................................................24 
Table 3: 
Dosing Schedule for Patients 2- to <6 Years Old .......................................................32 
 
 
 
 
 
 
 
 
 
 
Table 7: 
Safety Laboratory Tests ..............................................................................................46 
 
LIST OF FIGURES 
 
 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
ACMG 
American College of Medical Genetics and Genomics criteria 
ADA 
Anti-drug antibodies 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
ASQ-3 
Ages & Stages Questionnaires, Third Edition 
AST 
Aspartate Aminotransferase 
AUC 
Area Under Curve 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BBS 
Bardet-Biedl Syndrome 
BUN 
Blood Urea Nitrogen 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine Phosphokinase 
CRA 
Clinical Research Associate 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
EOT 
End of Treatment 
ETT 
Early Termination of Treatment visit 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
GGT 
Gamma-glutamyl transferase 
HbA1c 
Glycated hemoglobin 
HR 
Heart Rate 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LDH 
Lactate Dehydrogenase 
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Abbreviation or Specialist Term 
Explanation 
LEPR 
Leptin Receptor 
LTE 
Long-term Extension 
MC4R 
Melanocortin 4 Receptor 
mg 
Milligram 
mL 
Milliliter 
mPEG/DSPE 
N-[Carbonyl-methoxypolyethylene glycol 2000]-1,2-
distearoyl- glycero-3-phosphoethanolamine sodium salt 
NAFLD 
Non-Alcoholic Fatty Liver Disease 
NASH 
Nonalcoholic Steatohepatitis 
NOAEL 
No Observed Adverse Effect Level 
PCSK1 
Proprotein Convertase Subtilisin/kexin Type 1 
POMC 
Pro-opiomelanocortin 
 
 
PT 
Preferred Term 
QD 
Once Daily 
rIMV 
Remote Interim Monitoring Visit 
rSDM 
Remote Source Data Monitoring 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneously 
SoA 
Schedule of Assessments 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TSH 
Thyroid-Stimulating Hormone 
ULN 
Upper Limit of Normal 
VUS 
Variant of Undetermined Significance 
 
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3. 
INTRODUCTION 
3.1. 
Trial Rationale 
Human genetic trials have identified several diseases that are the result of genetic variants 
affecting the melanocortin-4 receptor (MC4R) pathway, including, but not limited to, pro-
opiomelanocortin (POMC) deficiency obesity due to mutations in the POMC gene; heterozygous 
proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency due to mutations in the PCSK1 
gene, leading to a hormone processing defect that also causes POMC deficiency obesity; and 
leptin receptor (LEPR) deficiency obesity due to mutations in the LEPR gene. These MC4R 
pathway mutations cause rare genetic diseases of obesity that start early in childhood, progress 
over time, and can become life-threatening in severity. 
Setmelanotide, an MC4R agonist, has the potential to restore reduced activity in MC4Rs in 
patients with these genetic defects in MC4R pathway. Consequently, the effect of setmelanotide 
may serve as a form of “replacement” therapy to re-establish weight and appetite control in 
patients with these disorders. 
Previous clinical trials have shown evidence that setmelanotide can help manage weight and 
reduce hunger in children with these genetic variants (Haws 2020; Clément 2020). The daily 
formulation (QD) of setmelanotide is authorized for commercial use in the United States (US) 
the European Union (EU), and Canada in adult and pediatric patients 6 years of age and older 
with obesity due to Bardet-Biedl Syndrome (BBS) (USPI 2022, EU SmPC 2022, Product 
Monograph 2023). Setmelanotide is also authorized for commercial use in the US, Great Britain 
(GB), the EU, Israel, and Canada in adult and pediatric patients 6 years of age and older with 
obesity due to pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 
(PCSK1), or leptin receptor (LEPR) deficiency (collectively PPL deficiency obesity (USPI 2022, 
EU SmPC 2022, MHRA SmPC 2022, Israel PPI 2022; Product Monograph 2023) 
In this study, the safety, tolerability, and efficacy of setmelanotide will be studied in pediatric 
patients aged 2 to <6 years with variants in POMC, PCSK1 or LEPR genes or with Bardet-Biedl 
Syndrome (BBS). 
3.2. 
Setmelanotide 
Setmelanotide is a synthetic, cyclic octapeptide (8-amino acid-containing peptide) that functions 
as a potent MC4R agonist. Setmelanotide binds with high affinity (inhibitory constant = 2.1 nM) 
to the human MC4R and is efficient in activating MC4R (50% effective concentration = 
0.27 nM). While not an analog, it retains the specificity and functionality of the naturally 
occurring POMC-derived neuropeptide, α-MSH, which is the endogenous ligand for the MC4R. 
Setmelanotide is more potent and has a much longer half-life (~10-12 hours in humans) than the 
short-lived α-MSH ligand. 
The setmelanotide peptide was initially selected for clinical development based on its acceptable 
circulating half-life as a saline formulation (2.8 - 3.5 hours in non-human primates) and the 
ability to decrease body weight gain and suppress food intake in normal rats. Pre-clinical studies 
demonstrated the efficacy of setmelanotide in suppressing food intake and body weight gain in 
diet-induced obese mice, rats, dogs, and monkeys, as well as in genetic models of obesity, 
including leptin-deficient ob/ob mice and leptin receptor deficient obese Zucker rats. Later 


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studies in obese monkeys showed that setmelanotide did not increase blood pressure (BP) or 
heart rate (HR), a potential concern observed with other MC4R agonist compounds. 
To support clinical trials, the toxicological profile of setmelanotide formulations has been 
evaluated in repeat-dose continuous SC infusion toxicity studies up to 13 weeks in duration in 
rats and monkeys. The formulation used in almost all of these studies, including the pivotal 28-
day and 13-week toxicology studies, was setmelanotide in 0.9% sodium chloride for injection 
(setmelanotide-saline formulation), tested over a range of concentrations. An International 
Council for Harmonisation (ICH)-compliant battery of in vitro and in vivo genetic toxicity 
studies that included a bacterial mutation assay, a chromosomal aberration assay in cultured 
human peripheral blood lymphocytes and a rat micronucleus study has been completed with this 
formulation. Finally, chronic, reproductive, and juvenile toxicology studies using the RM-493-
mPEG-DSPE formulation have been completed. 
Setmelanotide has been well tolerated by patients who have received it in clinical trials. 
Regardless of formulation, setmelanotide has demonstrated a mostly similar set of adverse events 
(AEs) in both short-term and long-term clinical trials. 
3.3. 
Benefit/Risk Assessment 
Current development of setmelanotide is focused on assessing the risks and benefits in several 
genetic diseases of early-onset severe obesity that result from rare genetic mutations that impair 
the hypothalamic leptin-POMC-melanocortin pathway upstream from the MC4R. Setmelanotide, 
an MC4R agonist, may restore the impaired signaling of this pathway. Data obtained to date in 
the setmelanotide clinical development program demonstrate robust reduction in weight and 
hunger in patients with rare genetic diseases of obesity. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of setmelanotide may be found in the Investigator’s Brochure (IB). 
 
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4. 
TRIAL OBJECTIVES AND ENDPOINTS 
The trial objectives and the corresponding endpoints are summarized in Table 2 below. 
Table 2: 
Trial Objectives and Endpoints 
Objective 
Endpoint 
Primary: 
To evaluate the effect of setmelanotide on weight-
related parameters 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) BBS 
• 
The proportion of patients demonstrating response 
to setmelanotide, defined as a decrease from 
baseline to 52 weeks in the patient’s body mass 
index (BMI) z-score of ≥0.2. 
• 
Mean percent change in BMI from baseline to 
Week 52. 
Secondary: 
To evaluate the effect of setmelanotide on additional 
weight-related parameters, as well as safety and 
tolerability 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) BBS 
Secondary: 
• 
The following endpoints will be summarized and 
reported as change from baseline to 52 weeks: 
− 
Mean absolute change in BMI z-score per age 
and gender 
− 
Mean change in percent of the 95th percentile 
of BMI per age and gender 
− 
The mean change in vital signs and laboratory 
evaluations  
− 
The mean change in bone age  
− 
Mean change in Ages & Stages 
Questionnaires, Third Edition (ASQ®-3)  
• 
Frequency and severity of AEs will also be 
summarized and reported during trial conduct. 
Abbreviations: AEs=adverse events; BBS=Bardet-Biedl Syndrome; BMI=body mass index; LEPR=leptin receptor; 
PC
PCSK
SK1=prop
oprototein n con
onve
vertase subtilisin/kexin type 1; POMC=pro-opiomelanocortin; 
 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Trial Design 
This is a Phase 3 multi-center, open-label trial of setmelanotide in pediatric patients aged 2 to 
<6 years with rare genetic causes of obesity. The trial is designed to evaluate safety and 
tolerability of setmelanotide as well as its efficacy on weight-related parameters in pediatric 
patients. 
5.1.1. 
Trial Population 
The trial plans to enroll pediatric patients with biallelic mutations of the POMC, PCSK1 or LEPR 
genes and pediatric patients with BBS. 
5.1.2. 
Screening Period 
The Screening Period begins with obtaining informed consent from the parent or guardian and 
will last between 1 and 8 weeks. During the Screening Period, patients will undergo all 
procedures as outlined in the Schedule of Assessments (SoA; Table 1) to determine if they meet 
all of the Inclusion (Section 6.1) and none of the Exclusion criteria (Section 6.2) for trial 
eligibility. A patient who does not meet one or more of the eligibility criteria will be considered a 
screen failure. Any patient that is rescreened is required to have a new ICF signed by the parent 
or guardian. 
During the Screening Period, patients will undergo medical evaluation; and caregivers will 
receive training on injection of trial drug and other trial procedures. 
5.1.3. 
Enrollment and trial procedures 
At the enrollment visit, patients will undergo all procedures as outlined in the SoA (Table 1) and 
it will be reconfirmed that the patient continues to meet all of the Inclusion and none of the 
Exclusion criteria of the trial. 
At the enrollment visit, the patient will have height and body weight recorded. This will be the 
baseline height and weight. To be eligible for the trial, a patient’s baseline weight must be at 
least 15 kg. Height and weight will be monitored closely during the trial. 
During the enrollment visit, the caregiver will administer the patient’s first dose of setmelanotide 
via subcutaneous (SC) injection under the supervision of the trial staff. Patients’ caregivers will 
be issued an electronic diary to capture daily compliance with injections. 
All patients will begin treatment with setmelanotide at a dose of 0.5 mg per day. Patients will 
then increase their dose by 0.5 mg increments, every 2 weeks, as described in the SoA (Table 1). 
The maximum dose level of setmelanotide used in this trial will be based on the weight bands for 
the 2- to <6-year-old patients to support an exposure similar to that observed for adults dosed at 
2 to 3 mg setmelanotide QD. The maximum dose level in this trial for patients who weigh 
ill be 0.5 mg, 1.0 mg, 1.5 mg and 2.0 mg QD, 
respectively.  
If a patient’s weight decreases to below 15 kg during the trial, the Investigator and Rhythm 
Pharmaceuticals, Inc. (henceforth Sponsor) will discuss the patient’s status and will jointly 
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determine if a patient should continue the current dose, decrease the dose or discontinue 
treatment with setmelanotide temporarily or permanently. A dose reduction to 0.25 mg QD can 
be considered in such scenarios or in case of tolerability concerns, including for example, the 
occurrence of severe renal impairment. These dose adjustments are considered adequate for the 
pediatric patients to grow in height at a normal rate and support attaining and maintaining an 
appropriate body weight.  
At the discretion of the Investigator, the dose escalation for a patient may be temporarily paused 
at any step prior to reaching their final maintenance dose, for safety or tolerability reasons, or 
due to achieving adequate weight loss. The dose may continue to be evaluated and adjusted, at 
the discretion of the Investigator, so long as the daily dose is kept between 0.25 mg and 2.0 mg 
QD, according to their respective weight.  
Patients will have trial visits approximately every 4 weeks through Week 20 and then 
approximately every 8 weeks through Week 52 and assessments will be performed as per the 
SoA (Table 1). Due to the young age of the patients, it may not be possible to perform all 
planned assessments at each visit. Thus, as described in the SoA (Table 1), the Investigator may 
adjust the planned assessments and blood draws as appropriate for the optimal medical care of 
the patients.  
In specific, individual cases, dose escalation may be delayed compared to the originally planned 
schedule at enrollment, in order to mitigate potential tolerability issues (e.g., in case of 
gastrointestinal adverse events). If the escalation to the next dose level is delayed, the escalation 
period will be extended for that patient and the subsequent available site visits will then become 
“dose escalation” visits, where the appropriate and specific assessments related to the escalation 
visits will take place. 
5.1.4. 
End of Treatment 
The End of Treatment (EOT) will occur as an in-person clinic visit on Trial Week 52, which is 
the final day of treatment with setmelanotide. At the EOT, patients who are considered likely to 
benefit from continued setmelanotide treatment and who have completed this trial may be 
eligible to enter an open-label long-term extension (LTE) trial with setmelanotide. Patients must 
meet the eligibility criteria and should discuss eligibility with the Investigator. Eligible patients 
may participate in Bridging visits (every 12 weeks) (Table 1) if the LTE is not yet active. 
All patients who discontinue treatment prematurely should attend an Early Termination of 
Treatment visit (ETT) as soon as possible after the last dose of trial treatment. Patients who 
discontinue treatment but remain enrolled in the trial should continue to complete all assessments 
(as Retained Dropouts). These patients will be required to complete the End of Study (EOS) as 
applicable following the ETT (Section 5.1.5). Patients who discontinue treatment prematurely 
but remain enrolled and complete assessments through Week 52 are eligible to enroll in the 
optional LTE trial. 
Patients who discontinue prematurely and withdraw from the trial will not be required to 
complete the EOS visit following the ETT. If the ETT visit occurs 4 weeks or later following the 
last dose of Setmelanotide, then the ETT visit will replace the EOS visit if no AEs are being 
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5.1.5. 
End of Study Visit 
A final EOS visit will occur on Week 56 and may be conducted via telephone for patients who 
are not being monitored for an AE. The EOS visit is not required for patients who enroll in the 
LTE (or transition to Bridging visits prior to enrollment in the LTE).  
At the Investigator’s discretion and in consultation with the Sponsor, patients who have well 
tolerated setmelanotide, who are considered likely to benefit from continued treatment, and who 
have completed assessments through Week 52 may be offered continued setmelanotide treatment 
via: 
• Enrollment in a separate LTE trial.  
• Bridging visits until LTE availability (if the LTE trial is not active by the time of 
patient completion of this trial). See Table 1. 
• Commercial use of setmelanotide QD, if applicable, according to the approved 
indication in their country, and in consultation with their prescribing physician. 
5.1.6. 
Completion of Trial Participation 
Completion of trial participation for an individual patient is defined as 1 of the following: 
• For patients who complete trial treatment and enroll in the LTE: the in-person EOT 
visit at Week 52. 
• For patients who complete treatment and do not enroll in the LTE: a Week 56 visit 
conducted via telephone.  
• For patients who discontinue trial treatment prematurely and complete all 
assessments, but do not withdraw consent (and assent, as applicable): the latest of the 
Week 52 visit, the ETT visit, or EOS visit (if required). 
• For patients who discontinue early and withdraw consent or assent: the ETT visit. 
The end of the trial is defined as the date of the last visit of the last patient under the auspices of 
the current trial.  
5.2. 
Site Closure and Study Termination 
5.2.1. 
Site Closure 
The Sponsor or designee reserves the right to close the trial site or terminate the trial at any time 
for any reason at the sole discretion of the Sponsor. Trial sites will be closed upon trial 
completion. A trial site is considered closed when all required documents and trial supplies have 
been collected and a trial-site closure visit has been performed. 
The Investigator may initiate trial-site closure at any time, provided there is reasonable cause and 
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Reasons for the early closure of a trial site by the Sponsor or Investigator may include but are not 
limited to: 
For trial termination: 
• Discontinuation of further trial intervention development.  
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients 
by the investigator. 
• Total number of patients enrolled earlier than expected. 
5.2.2. 
Criteria for Trial Termination or Suspension 
This trial may be prematurely terminated or suspended, if in the opinion of the Sponsor, there is 
sufficiently reasonable cause. The Sponsor will provide written notification documenting the 
reason for trial or site termination. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients. 
• Failure to enroll patients into the trial. 
• Insufficient adherence to protocol requirements. 
• Insufficient complete and/or evaluable data. 
• Plans to modify, suspend, or discontinue the development of the trial drug. 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the Independent Ethics Committees (IECs)/IRBs, the regulatory authorities, and 
any contract research organization(s) used in the trial of the reason for termination or suspension, 
as specified by the applicable regulatory requirements. The Investigator shall promptly inform 
the patients and should assure appropriate patient therapy and/or follow-up. Should the trial be 
closed prematurely, all trial materials must be returned to the Sponsor or designee. 


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6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. 
Inclusion Criteria 
1. Patients must have obesity due to either: 
a. POMC, PCSK1, or LEPR deficiency, confirmed by genetic testing demonstrating 
biallelic variants that are interpreted as pathogenic, likely pathogenic, or of 
undetermined significance (VUS) by the American College of Medical Genetics and 
Genomics criteria (ACMG), or 
b. BBS as defined by both (1) the Beales Criteria, 1999 (Beales 1999, [Appendix 1]) 
AND (2) genetic confirmation of homozygous or compound heterozygous loss-of-
function mutation in BBS genes. 
2. Age between 2 to <6 years at the time of informed consent. 
3. Obesity, defined as BMI ≥97th percentile for age and gender AND body weight of at 
least 15 kg at the time of enrollment. 
4. Symptoms or behaviors of hyperphagia at any time during the patient’s life, as 
determined by the Investigator at screening. 
5. Parent or guardian of patient is able to communicate well with the Investigator, to 
understand and comply with the requirements of the trial (including the once daily [QD] 
injection regimen and all other trial procedures) and is able to understand and sign the 
written consent. 
6.2. 
Exclusion Criteria 
1. HbA1c >9.0% at screening. 
2. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) 
or nonalcoholic steatohepatitis (NASH). 
3. Glomerular filtration rate (GFR) <60 mL/min/1.73 m2. 
4. History or close family history (parents or siblings) of melanoma, or patient history of 
oculocutaneous albinism. 
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a 
comprehensive skin evaluation performed by the Investigator during screening. Any 
concerning lesions identified during screening will be biopsied and results known to be 
benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient 
may need to be excluded from the trial. 
6. Patient is, in the opinion of the investigator, not suitable to participate in the trial. 
7. Participation in any clinical trial with an investigational drug/device within 3 months 
prior to the first day of dosing. 
8. Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to 
setmelanotide. 


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9. Significant hypersensitivity to any excipient in the trial drug. 
10. Inadequate hepatic function as evidenced by elevated aspartate aminotransferase (AST) 
and alanine aminotransferase (ALT) values >5x upper limit of normal (ULN). 
11. Any other uncontrolled endocrine, metabolic or medical condition(s) known to impact 
body weight that could potentially interfere with interpretation of trial results. 
6.3. 
Treatment Discontinuation and Patient Withdrawal Criteria 
Given this rare patient population, every effort will be made to encourage and keep patients 
enrolled in the trial until completion, regardless of premature treatment discontinuation. In the 
case of treatment discontinuation, efforts should be made to keep the patient in the trial, 
attending at a minimum the key trial visits, e.g., the EOT (and EOS as necessary) visit, for safety 
evaluations. 
The Sponsor will provide assistance for patient and caregiver travel and will provide other 
necessary logistical support to ease the burden on the patient in order to facilitate compliance. 
Patients can withdraw their consent to participate in the trial at any time. If the parent or their 
legal guardian(s) withdraw consent/assent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
If a patient and/or their legal guardian(s) withdraw from the trial, they may request destruction of 
any samples taken and not tested, and the Investigator must document this in the site trial 
records. 
Patients and their legal guardian(s) will be informed that they have the right to withdraw from 
the trial at any time for any reason, without prejudice to their medical care. The Investigator also 
has the right to withdraw patients from the trial for reasons such as: 
• AEs, which in the opinion of Investigator justifies treatment or trial withdrawal. 
• Non-adherence to trial drug regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 


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7. 
TREATMENT OF PATIENTS 
7.1. 
Description of Trial Drug 
Setmelanotide will be supplied by the Sponsor. Setmelanotide drug product (RM-493-mPEG-
DSPE formulation) is a sterile solution for injection. The product is manufactured at a 
concentration of 10.0 mg/mL. 
7.2. 
Treatment Dose Selection 
The dose of setmelanotide was chosen for this trial based on effective doses in other clinical 
trials, a review of the amount of benzyl alcohol in the formulation and the pharmacokinetic (PK) 
results in previous clinical trials. 
7.2.1. 
Benzyl Alcohol Dose 
The amount of benzyl alcohol in the formulation was compared with the amount delivered by 
Increlex (Increlex Product SmPC), an approved product containing phenol and benzyl alcohol. 
Each mL of Increlex contains 10 mg/mL mecasermin and 9 mg/mL benzyl alcohol. 
Based on Posology, the recommended starting dose of mecasermin is 0.04 mg/kg of body weight 
twice daily by an SC injection. If no significant adverse reactions occur for at least one week, the 
dose may be raised in increments of 0.04 mg/kg to the maximum dose of 0.12 mg/kg given twice 
da
daily. D
y. Dos
oses gr
 greater t than 0.12 m
 0.12 mg/g/kg 
kg BI
BID s shoul
hould not
d not be
 be e exc
xceede
ded.
 
. 
 i is w
 well withihin t
n these already a
dy appr
pprove
oved dos
d dose 
raranges g giviven to
 to s sma
mall c
ll childldreren fo
 for In
r Increrelelex. 
7.2.2. 
Setmelanotide Dose 
The dose level of setmelanotide used in this trial will be based on the weight bands for the 2- to 
<6- year-old patients (Table 3) to e
o ens
nsur
ure t the
he expo
xposurere is
 is sim
imililar to
r to ththat o
t observ
rved fo
 for a
r adults
lts d dosed 
atat 2 2 t to 3 
o 3 mg set
 setmelelan
anotide e QD
QD. 
 
 
 
 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD PPD
PPD
PPD
PPD
PPD
PPD
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Table 3: 
Dosing Schedule for Patients 2- to <6 Years Old 
Maximum Dose 
0.5 mg/day 
1.0 mg/day* 
1.5 mg/day 
2.0 mg/day 
* 
 
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Refer to the IB for additional information 
on the toxicology of setmelanotide in mPEG-DSPE. 
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7.3. 
Treatment Administration 
Setmelanotide will be administered as a SC injection. All patients will begin treatment at a dose 
of 0.5 mg of setmelanotide per day. Patients will then increase their dose by 0.5 mg increments, 
every 2 weeks, as described in the SoA (Table 1). The maximum dose level of setmelanotide 
used in this trial will be based on the weight bands for the 2- to <6-year-old patients to support 
an exposure similar to that observed for adults dosed at 2 2 to 3 
o 3 mg set
 setmelelan
anotide e QD
QD. T
. The
he 
ma
maximu
mum dose level in this trial for patients who weigh 
 
 will be 0.5 mg, 1.0 mg, 1.5 mg and 2.0 mg QD, r
, respe
pective
vely. 
y.  
If a patient’s weight decreases to below 15 kg during the trial, the Investigator and Sponsor will 
discuss the patient’s status and will jointly determine if a patient should continue the current 
dose, decrease the dose or discontinue treatment with setmelanotide temporarily or permanently. 
A dose reduction to 0.25 mg can be considered in such scenarios or in case of safety or 
tolerability concerns. These dose adjustments are considered adequate to help attain and maintain 
appropriate body weight in growing pediatric patients. 
At the discretion of the Investigator, a patient may temporarily pause the dose escalation at any 
step prior to reaching their final maintenance dose, for safety or tolerability reasons, or due to 
achieving adequate weight loss. The dose may continue to be evaluated and adjusted, at the 
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discretion of the Investigator, as 
 and 2.0 mg QD, 
according to their respective weigight.t. 
During the Dose Escalation visits (Weeks 2, 4 and 6 in SoA), the dose is to be increased as 
appropriate for the individual patient’s weight at enrollment. At each visit, the decision to 
escalate the dose is to be based on patients’ tolerability and health status. If a patient has already 
achieved their final maintenance dose prior to Week 4 or 6, the subsequent visits will not be 
considered “dose escalation” visits, but rather standard visits. 
It is recommended to maintain a 2-week interval between the dose escalations, although the dose 
may be escalated at a longer interval (i.e., within 4 weeks), depending on patient weight and 
tolerability. 
If it is not possible to achieve the final maintenance dose by Week 6 due to tolerability concerns 
(e.g., severe gastrointestinal adverse events) or due to potential effects on weight or hunger 
levels, the dose may be escalated over the next visit(s) (Week 8, etc.), with trial visits continued 
as per protocol. There is no need to perform an Unscheduled Visit 2 weeks after escalation of the 
dose unless it is required for patient safety.  
7.4. 
Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the trial must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The dose of concomitant medications used during the trial should not be changed and new 
concomitant medications should not be started during the trial, unless necessary to treat an AE. 
Patients should not make significant changes to their diet or exercise routines during the trial. 
7.5. 
Treatment Compliance 
Treatment compliance will be recorded by the pediatric patient’s caregiver. A daily question 
querying whether the patient completed their daily injection will be asked via electronic diary. 
With Sponsor approval, paper versions can be used, if required. 
7.6. 
Randomization and Blinding 
This is an open-label trial with a single treatment arm, therefore there is no randomization and 
the treatment is unblinded. 
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8. 
ASSESSMENTS 
Trial procedures and their timing are summarized in the SoA (Table 1). Adherence to the trial 
design requirements, including those specified in the SoA, is essential and required for trial 
conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable. 
When scheduled at the same time point, the order of procedures should be as follows: obtain 
vital signs, perform 12-lead ECG, and then perform blood draws (at the specified time point, if 
applicable). Adjustments may be made depending upon specific circumstances and in 
consultation with the Sponsor. 
A visiting home nurse may assist with injections at home if requested by families, provided that 
a caregiver needs or desires assistance, and this is acceptable to the investigative site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue trial treatment. 
8.1. 
General Trial Assessments 
8.1.1. 
Informed Consent/Assent 
A complete description of the trial is to be presented to the parent/legal guardian(s) of each 
potential patient and signed and dated. Informed consent/assent is to be obtained before any 
study- specific procedures are performed. In the event of an amendment to the informed consent, 
reconsent by the patient or parent/legal guardian is necessary.  
A copy of the informed consent/assent must be provided to the patient or the parent/legal 
guardian. 
8.1.2. 
Demographic/Medical History 
Medical history and demographic data including the patient’s gender, race, date of birth, and 
concomitant medication use will be obtained for all patients during the Screening Period. 
The medical history should be updated on Day 1 prior to first dose of trial drug, to assess 
continued trial eligibility and adherence to final inclusion/exclusion criteria. This medical history 
update includes a review for changes from Screening as well as a review of the patient’s recent 
medication use to assess whether any changes have occurred since the previous visit. 
Additionally, weight-related history including growth charts since birth should be obtained and 
reported. 
8.1.3. 
Genetic Sample 
A blood sample will be obtained at baseline to confirm a genetic diagnosis. However, patients 
may be entered into the trial with documentation of previously obtained genetic results. 


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8.1.4. 
Physical Examination 
A complete physical examination will be conducted at Screening and at the EOT visit. At other 
timepoints, an abbreviated examination will be performed. The abbreviated examination should 
focus on heart, lungs, skin, neurologic examination, and any areas of previous abnormal findings, 
noting any changes from baseline. Tanner staging should be performed at Screening and at the 
EOT visit (Week 52) visit. It may be done at additional visits, at the discretion of the 
Investigator. 
8.1.5. 
Electrocardiogram (ECG) 
A single 12-lead ECG will be performed at the time points designated in the SoA (Table 1). If an 
ECG is not practical in a young patient, it may be replaced by a rhythm strip and HR and pulse 
rate interval should be documented. The ECG (or HR and pulse rate) results will be interpreted 
locally by the investigator or qualified designee and documented in the patient’s medical records. 
8.1.6. 
Comprehensive Skin Evaluation 
A comprehensive skin evaluation will be performed by the Investigator or qualified designee at 
Screening. The skin exam should include a full body skin exam (head-to-toe skin examination). 
Any concerning lesions identified during the Screening Period will be biopsied and results must 
be known to be benign prior to the first dose of setmelanotide. If the pre-treatment biopsy results 
are of concern, the patient will be excluded from the trial. Additionally, any new lesion or 
change in an existing lesion identified during the trial must be evaluated by a dermatologist and 
biopsied, if clinically indicated in the opinion of the dermatologist. 
Protection from Sun 
Skin hyperpigmentation, or tanning, was observed in the cynomolgus monkey toxicology and 
human trials. These events were reversible upon cessation of trial drug. However, it is still 
uncertain if exposure to sunlight might exacerbate the tanning effects of setmelanotide. 
Therefore, patients are advised to use sunscreen and/or to wear protective clothing to avoid 
excessive exposure of their skin to sunlight and to avoid sun-tanning. 
8.1.7. 
Fitzpatrick Scale 
Each patient is to be categorized for skin type according to the Fitzpatrick scale 
(Fitzpatrick1975) at timepoints listed in the SoA. The Fitzpatrick Scale is presented Appendix 3. 
8.2. 
Efficacy Assessments 
8.2.1. 
Weight and Height 
Weight (kg) and height (cm) will be recorded at the time points designated in the SoA (Table 1). 
All measurements will be done in triplicate at each time point. 
Weight should be measured after patients have attempted to empty their bladders and after 
fasting for at least 8 hours. Patients are to wear light clothing or underwear and no shoes, with 
empty pockets, and will be weighed at approximately the same time of day. All measurements 
will be recorded to the nearest 10th of a decimal place if reported with a digital scale, or half kg 
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Whenever possible, the same scale should be used throughout the trial, including the Screening 
visit, and should be calibrated on a regular basis per manufacturer’s specifications. 
Patient’s weight will be monitored closely during the trial. If a patient’s weight decreases to 
below 15 kg, the Investigator and Sponsor will discuss the patient’s status and will jointly 
determine if that patient should continue the current dose, decrease the dose or discontinue 
treatment with setmelanotide temporarily or permanently. A dose reduction to 0.25 mg QD can 
be considered in such scenarios or in case of tolerability concerns. These dose adjustments are 
considered adequate to help attain and maintain appropriate body weight in growing pediatric 
patients 
Height (cm) will be measured without shoes, socks, or hats, using a wall-mounted stadiometer. 
The stadiometer should be calibrated by site personnel on a daily basis prior to height 
assessment. All measurements will be done in triplicate at each time point and recorded to the 
nearest half centimeter. Both weight and height measurements will be used to determine BMI 
and BMI-related assessments (i.e., Z-score and percentiles). 
8.2.3. 
Trial questionnaires 
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8.2.3.2. 
Ages & Stages Questionnaires®, Third Edition (ASQ®-3) 
The ASQ-3 is a developmental screening tool that assesses developmental progress in children 
between one month to 5 ½ years (). The ASQ-3 is intended for use at six-month intervals 
between 6 months and 3 years of age, and then at one-year intervals through age 5.  
For patients who enter the study at ages between 2 years and 3 years, the ASQ-3 will be 
administered at the Baseline visit, Week 28 visit and EOT Visit. For patients who enter the trial 
between the ages of 3 and 6 years old, the ASQ-3 will only be administered at the Baseline visit 
and EOT visit. 
Timepoints are as depicted in the SOA (Table 1). 
8.3. 
Safety Assessments 
8.3.1. 
Vital Signs 
Vital signs include systolic and diastolic blood pressure (BP), HR, respiration rate and body 
temperature (°C). Vital signs will be obtained in the sitting position following at least 5 minutes 
of rest at each time point designated in the SoA (Table 1). 
All BP and HR measurements will be taken in triplicate, approximately 2 minutes apart. When 
possible, BP should be taken in the non-dominant arm throughout the trial, using the same 
methodology (automated or manual) and ensuring that an appropriately sized cuff is used. 
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Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR. 
8.3.2. 
Laboratory Assessments 
Safety laboratory test parameters to be evaluated are listed in Table 7. 
Th
The Investigators will adhere to the site-specific blood volume limits for safety laboratory and 
 an
 analyses to ensure minimal distress to the pediatric patients. Due to the age of the children, it 
may not
y not be possible to collect all labs at every trial visit. Screening may be completed over 
multiple days, to complete the required assessments. After enrollment, if all laboratory tests are 
not possible, t the
hen t
n the
he tests s shoul
hould be
d be colollected in the following order: safety, anti-drug 
antibodies, 
. I
. If it is not possible to collect the safety laboratory 
tests on two
wo cons
onsecututive
ve vivisits, t, the
he p patient s shoul
hould be discussed with the Sponsor. To allow for 
pre- and post-dose sampling, patients will attend the site visit having fasted for an 8-hour time 
period without injecting the trial product. On the day of the site visit, dosing will be conducted 
on site. 
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Table 7: 
Safety Laboratory Tests 
Hematology 
• 
Complete Blood Count with Differential: 
− 
Hematocrit 
− 
Hemoglobin 
− 
White Blood Cells with differential 
− 
Red Blood Cells 
− 
Platelet Count 
Serum Chemistry 
• 
Sodium 
• 
Potassium 
• 
Chloride 
• 
Carbon dioxide 
• 
Creatinine 
• 
Blood urea nitrogen 
• 
Glucose 
• 
Calcium 
• 
Phosphorus 
• 
Thyroid stimulating hormone 
• 
Alkaline phosphatase 
• 
Aspartate aminotransferase 
• 
Alanine aminotransferase 
• 
Gamma glutamyl transferase 
• 
Creatine phosphokinase 
• 
Total and direct bilirubin 
• 
Lactate dehydrogenase 
• 
Albumin 
• 
Total protein 
• 
Uric acid 
Urinalysis 
• 
Color 
• 
Appearance 
• 
Specific Gravity 
• 
pH 
• 
Blood 
• 
Ketones 
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8.5. 
Anti-Drug Antibodies 
Blood samples for analysis of ADAs will be collected at the time points specified in the SoA. All 
samples should be collected before trial treatment administration on the day of collection. Any 
patient with a positive ADA will be followed every 3 months after the ADA sample analysis 
until resolution of the ADA (ie, no measurable ADA response). 
8.6. 
Adverse and Serious Adverse Events 
Adverse events (AEs) will be monitored throughout the trial. AEs will be recorded in the eCRFs 
from Screening through the EOS visit. AEs that occur after the start of trial drug administration 
will be considered treatment-emergent adverse events (TEAEs). Serious AEs (SAEs) will be 
recorded through to the EOS visit. All AEs should be monitored until they are resolved or are 
clearly determined to be due to a patient’s stable or chronic condition or intercurrent illness(es). 
All trial sites will be provided with the contact information of key trial personnel to be contacted 
in case of emergencies. 
8.6.1. 
Definition of Adverse Events 
8.6.1.1. 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence associated with the use of a drug in 
humans, whether or not it is considered drug related. Patients/caregivers will be instructed to 
contact the Investigator at any time after a patient has been enrolled, before treatment, during 
treatment, or within 30 days following the cessation of treatment, if any symptoms develop. 
A TEAE is defined as any event not present before exposure to trial drug or any event already 
present that worsens in intensity or frequency after exposure. 
A suspected adverse reaction is any AE for which there is a reasonable possibility that the trial 
drug caused the AE. For the purposes of investigational new drug safety reporting, “reasonable 
possibility” means that there is evidence to suggest a causal relationship between the trial drug 
and the AE. A suspected adverse reaction implies a lesser degree of certainty about causality 
than an adverse reaction. 
An adverse reaction is any AE caused by a trial drug. Adverse reactions belong to a subset of all 
suspected adverse reactions and indicate that there are reasons to conclude that the trial drug 
caused the event. 
An AE or suspected adverse reaction is considered “unexpected” if it is not listed in the 
Reference Safety Information section of the Investigator brochure or if it occurs with specificity 
or severity that has not been previously observed with the trial drug being tested; or, if an 
Investigator brochure is not required or available, the AE or suspected adverse reaction is not 
consistent with the risk information described in the general investigational plan or elsewhere in 
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the current application. For example, under this definition, hepatic necrosis would be unexpected 
(by virtue of greater severity) if the IB referred only to elevated hepatic enzymes or hepatitis. 
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the IB listed only cerebral vascular accidents. “Unexpected,” as used in this 
definition, also refers to AEs or suspected adverse reactions that are mentioned in the IB as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug 
but are not specifically mentioned as occurring with the particular drug under investigation. 
All AEs that occur after any patient has been enrolled, before treatment, during treatment, or 
within 30 days following the cessation of treatment, whether or not they are related to the trial, 
must be recorded on forms provided by the Sponsor. 
8.6.1.2. 
Serious Adverse Event (SAE) 
An SAE is an AE occurring during any trial phase (i.e., baseline, treatment, washout, or follow-
up), and at any dose of the investigational product, comparator or placebo, that fulfils one or 
more of the following criteria: 
• Results in death 
• It is immediately life-threatening 
• Note: “Life-threatening” refers to a situation in which the subject was at risk of death 
at the time of the event; it does not refer to an event which might have caused death if 
it were more severe. 
• It requires in-patient hospitalization or prolongation of existing hospitalization 
• Note: AEs requiring hospital admissions that are less than 24 hours in duration do not 
meet this criterion. A scheduled hospitalization for a pre-existing condition that has 
not worsened during participation in the trial does not meet this criterion. Pre-planned 
hospitalizations for an elective medical/surgical procedure or routine check-ups do 
not meet this criterion. 
• It results in a persistent or significant incapacity or substantial disruption of the ability 
to conduct normal life functions 
• It is a congenital anomaly/birth defect 
• It is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above. 
Note: Important medical events are those that may not result in death, be life 
threatening, or require hospitalization but may be considered serious when, based 
upon appropriate medical judgment, they may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or 
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All SAEs that occur after any patient has been enrolled, before treatment, during treatment, or 
within 30 days following the cessation of treatment, whether or not they are related to the trial, 
must be recorded on forms provided by the Sponsor. 
8.6.2. 
Relationship to Trial Drug 
A medically-qualified Investigator must assess the relationship of any AE (including SAEs) to 
the use of the investigational product, as related or not related, based on clinical judgment and 
using all available information, and may include consideration of the following factors: 
• Possible alternative causes of the AE, including the disease under treatment, pre-
existing conditions, concomitant use of other drugs, and presence of environmental or 
genetic factors 
• The temporal association between drug exposure and onset of the AE 
• Whether the manifestations of the AE are consistent with known actions or toxicity of 
the investigational product 
• Dechallenge: The AE resolved or improved with decreasing the dose or stopping use 
of the investigational product. Judgment should be used if multiple products are 
discontinued at the same time 
• Rechallenge: The AE recurred or worsened upon re-exposure to the investigational 
product. 
The causal relationship between the trial drug and the AE will be assessed using one of the 
following categories: 
Not Related: An AE is not associated with trial drug if: 
• Temporal relationship is lacking (e.g., the event did not occur within a reasonable 
time frame following administration of the trial drug); or 
• Other causative factors more likely explain the event (e.g., a pre-existing condition, 
other concomitant treatments); or 
• Dechallenge was either not clinically indicated or did not result in clinical 
improvement; or 
• AE did not reoccur upon rechallenge (if applicable). 
Related: An AE is attributed to the trial drug if: 
• There is a positive temporal relationship (e.g., the event occurred within a reasonable 
time frame following administration of trial drug); and 
• The AE is more likely explained by the investigational product than by another cause 
(i.e., the AE shows a pattern consistent with previous knowledge of the 
investigational product or the class of the investigational product), or the event 
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8.6.3. 
Overdose 
An overdose is a significant variation from the recommended/scheduled dosage for a product. 
For this trial, an overdose of setmelanotide is considered a dose higher than:  
• 2 mg in any patient  
• 1.5 mg in patients with body weight
• 1.0 mg in patients with body weight
• 0.5 mg in patients with body weight
8.6.4. 
Recording Adverse Events 
AEs spontaneously reported by the patient/caregiver and/or in response to an open question from 
the trial personnel or revealed by observation will be recorded during the trial at the 
investigational site. 
Clinically significant changes in laboratory values, BP, and pulse need not be reported as AEs. 
However, abnormal values that constitute an SAE or lead to discontinuation of administration of 
trial drug must be reported and recorded as an AE. 
AEs will be recorded from obtaining consent until the end of the trial. SAE information will be 
collected from obtaining consent until EOS. The AE term should be reported in standard medical 
terminology when possible. For each AE, the Investigator will evaluate and report the onset (date 
and time), resolution (date and time), intensity, causality, action taken, serious outcome (if 
applicable), and whether or not it caused the patient to discontinue the trial. 
Intensity will be assessed according to the following scale: 
• Mild (awareness of sign or symptom, but easily tolerated) 
• Moderate (discomfort sufficient to cause interference with normal activities) 
• Severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs. A severe AE may not be 
considered serious. 
8.6.5. 
Reporting Adverse Events 
All AEs reported or observed during the trial will be recorded on the AE page of the eCRF. 
Information to be collected includes drug treatment, type of event, time of onset, dosage, 
Investigator-specified assessment of severity and relationship to trial drug, time of resolution of 
the event, seriousness, any required treatment or evaluations, and outcome. Any AEs resulting 
from concurrent illnesses, reactions to concurrent illnesses, reactions to concurrent medications, 
or progression of disease states must also be reported. All AEs will be followed until they are 
resolved, stable, or judged by the Investigator to be not clinically significant. The MedDRA will 
be used to code all AEs. Any medical condition that is present at the time that the subject is 
screened but does not deteriorate should not be reported as an AE. However, if it deteriorates at 
any time during the trial, it should be recorded as an AE. 
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A referral to a mental health practitioner should be issued to the patient for any instance of 
reported AEs indicative of a change in mental health status.  
8.6.6. 
Reporting of Expedited Safety Observations by the Investigator 
Any occurrence of the following events or outcomes in a subject in the trial must be reported 
expeditiously by the Investigator or qualified designee to the Sponsor via an SAE form: 
• SAE 
• Death of a subject 
• Overdose 
• Cancer 
The Investigator is to report any of the items in the list above within24 hours of becoming aware 
of the event. Any observation reported to The Sponsor that is also an AE, is to be recorded in the 
eCRF, as well as in the subject's source documentation along with any actions taken. If not all 
information is available at the time of the initial report, follow-up SAE reports will be completed 
and submitted. The Investigator is required to follow SAEs until resolution regardless of whether 
the patients are still participating in the trial. Resolution is defined as follows: 
• Resolved with or without residual effects 
• A return to baseline for a pre-existing condition 
• The Investigator does not expect any further improvement or worsening of the event 
• Fatal outcome -If an autopsy is performed on a deceased subject, the autopsy report 
must be provided to the Sponsor as soon as it is available. 


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9. 
STATISTICS 
Details of all statistical analyses will be described in a separate Statistical Analysis Plan (SAP). 
9.1. 
Sample Size Determination 
No formal sample size determination was made based on statistical inference. The sample size is 
not driven by statistical power considerations but is primarily driven by clinical and practical 
considerations. Given the rare patient population, the trial plans to enroll approximately 10-
15 patients (approximately 5 or more pediatric patients with biallelic mutations of the POMC, 
PCSK1 or LEPR genes and approximately 5 or more pediatric patients with BBS). 
9.2. 
Statistical Analyses 
The primary objective is to evaluate the effect of setmelanotide on weight-related parameters 
measured in terms of the response rate to setmelanotide. Due to the small sample size of the trial, 
no statistical hypothesis testing is planned, and efficacy will be reported using descriptive 
statistics. The safety population, including all patients who receive at least 1 dose of 
setmelanotide, will be used as the primary analysis population for all the analyses. 
AEs will be coded by preferred term (PT) and system organ class (SOC) using the latest version 
of MedDRA and summarized. All AE data will be presented in a data listing. TEAEs will be 
summarized, including by severity and relationship to trial drug. Serious AEs and AEs leading to 
early discontinuation will also be presented in data listings. 
Actual values and changes from baseline for clinical laboratory test results, vital sign 
measurements etc. will be summarized using descriptive statistics (N, mean, standard deviation, 
median, minimum, and maximum). Shift tables will be generated for clinical laboratory test 
results. Clinical laboratory test results, vital sign measurements etc. will be presented in data 
listings. 
The secondary objectives are to evaluate the ef
e effectct o of se
 setmelelanotide e on a
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 weight
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 N
 No st
 statiststical
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 The c
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s will b be su
e summararized
zed w
 with ap
 appropriate descriptive statistics. 
Due to the small sample size, summary statistics by genotype may be provided as appropriate. 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
10.1. 
Trial Monitoring 
During the trial, a monitor from The Sponsor or designee will have regular contacts with the 
investigational site, for the following: 
• Provide information and support to the Investigator(s) and site staff 
• Confirm that facilities remain acceptable 
• Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the case report forms, and that investigational product 
accountability checks are being performed 
• Perform source data verification. This includes a comparison of the data in the case 
report forms with the patient’s medical records at the hospital or practice, and other 
records relevant to the trial. This will require direct access to all original records for 
each patient (e.g., clinic charts). 
• Record and report any protocol deviations not previously sent to The Sponsor 
• Confirm AEs and SAEs have been properly documented on eCRFs and confirm any 
SAEs have been forwarded to The Sponsor and those SAEs that met criteria for 
reporting have been forwarded to the IRB. 
The monitor will be available between monitoring visits if the Investigator(s) or other staff needs 
information or advice. 
10.1.1. 
Trial Conduct During the COVID-19 Pandemic 
The worldwide Coronavirus Disease 2019 (COVID-19) pandemic may impact the conduct of 
clinical trials due to the challenges from quarantines, site closures, travel limitations, and other 
considerations if site personnel or patients become potentially exposed to or infected with 
COVID-19. To assure the safety of patients, maintain compliance with GCP, and minimize risks 
to trial integrity, if necessary, in consultation with the Sponsor, the method of assessment may be 
changed (e.g., paper assessments replaced by electronic assessments). In addition, site visits may 
be replaced with telephone, internet-based video‑conferencing applications, or home visits by 
qualified health care professionals. Normal procedures, as detailed in this protocol, will be 
resumed as soon as possible thereafter.  
More detailed guidance on trial conduct during the COVID-19 pandemic is provided in 
Appendix 2. 
10.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, a regulatory authority, an IRB or IEC may visit the 
site to perform audits or inspections, including source data verification. The purpose of a 
Sponsor audit or inspection is to systematically and independently examine all trial-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP guidelines of the 
International Council for Harmonisation (ICH), and any applicable regulatory requirements. The 


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Investigator should contact the Sponsor immediately if contacted by a regulatory agency about 
an inspection. 
10.3. 
Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) 
The Investigator must obtain IRB/IEC approval for the investigation. Initial IRB/IEC approval, 
and all materials approved by the IRB/IEC for this trial including the written consent form and 
recruitment materials must be maintained by the Investigator and made available for inspection. 
10.4. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. Data entered in the 
eCRF that are transcribed from source documents must be consistent with the source documents 
or the discrepancies must be explained. The Investigator may need to request previous medical 
records or transfer of records, depending on the trial. Also, current medical records must be 
available. 
Any electronic trial data are to be entered into a secure, validated data processing system and a 
backup maintained. Any changes to electronic trial data will be documented. 


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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
To ensure compliance with GCP and all applicable regulatory requirements, The Sponsor may 
conduct a quality assurance audit. 


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12. 
ETHICS 
12.1. 
Ethics Review 
The final trial protocol, including the final version of the written consent, must be approved or 
given a favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must 
submit written approval to the Sponsor before he or she can enroll any patient into the trial. 
The Investigator is responsible for informing the IRB or IEC of any amendment to the protocol 
in accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit patients for the trial. The protocol must be re-approved by the IRB or IEC upon 
receipt of amendments and annually, as local regulations require. 
The Investigator is also responsible for providing the IRB or IEC with reports of any reportable 
serious adverse drug reactions from any other trial conducted with the investigational product. 
The Sponsor will provide this information to the Investigator. 
Progress reports and notifications of serious adverse drug reactions will be provided to the IRB 
or IEC according to local regulations and guidelines. 
12.2. 
Ethical Conduct of the Trial 
The trial will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/GCP, applicable regulatory requirements 
and the Sponsor’s policy on Bioethics. 
12.3. 
Written Informed Consent 
The Investigator(s) at each site will ensure that the patient and their legal guardian are given full 
and adequate oral and written information about the nature, purpose, possible risk and benefit of 
the trial. Patients and their legal guardian(s) must also be notified that they are free to 
discontinue from the trial at any time. The patients and their legal guardian(s) should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The parent/legal guardian(s) signed and dated consent must be obtained before conducting any 
trial procedures. 
The Investigator(s) must maintain the original, signed consent. A signed copy of the consent 
must be given to the parent/legal guardian(s). 


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13. 
DATA HANDLING AND RECORDKEEPING 
13.1. 
Inspection of Records 
The Sponsor will be allowed to conduct site visits to the investigate facilities for monitoring any 
aspect of the trial. The Investigator agrees to allow the monitor to inspect the drug storage area, 
trial drug stocks, drug accountability records, patient charts and trial source documents, and other 
records relative to trial conduct. 
13.2. 
Retention of Records 
The Investigator must maintain all documentation relating to the trial for a period of 2 years after 
the last marketing application approval, or if not approved 2 years following the discontinuance 
of the test article for investigation. If it becomes necessary for the Sponsor or the Regulatory 
Authority to review any documentation relating to the trial, the Investigator must permit access 
to such records. 
13.3. 
Data Protection 
Any patient records or data sets transferred to the Sponsor will contain the trial identifier only; 
patient names or any information which would make the patient identifiable will not be 
transferred. 
The patient must be informed that his/her personal trial-related data will be used by the Sponsor 
in accordance with local data protection law. The level of disclosure must also be explained to 
the patient who will be required to give consent for their data to be used as described in the 
informed consent. 
The patient must be informed that his/her medical records may be examined by Clinical Quality 
Assurance auditors or other authorized personnel appointed by the Sponsor, by appropriate IRB 
or IEC members, and by inspectors from regulatory authorities. 
13.4. 
Data Quality Assurance 
All patient data relating to the trial will be recorded on printed or eCRF unless transmitted to the 
Sponsor electronically (e.g., electronic diary). The Investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit trial-related monitoring, audits, IRB review and regulatory agency 
inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this trial including quality 
checking of the data. 


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The Sponsor assumes accountability for actions delegated to other individuals (e.g., Contract 
Research Organizations). 
Trial monitors will perform ongoing source data verification to confirm that data entered into the 
eCRF by authorized site personnel are accurate, complete, and verifiable from source documents; 
that the safety and rights of patients are being protected; and that the trial is being conducted in 
accordance with the currently approved protocol and any other trial agreements, ICH GCP, and 
all applicable regulatory requirements. 
In an exceptional case where a local restriction for the on-site Monitoring Visit at the 
investigator site is implemented (e.g., due to COVID-19), the Clinical Research Associate (CRA) 
will perform routine scheduled Remote Interim Monitoring Visits (rIMV) for active sites. The 
aim of the remote activities is to ensure adequate ongoing oversight of trial activities to identify 
and eliminate any immediate risk to the safety and integrity of the patients. Each individual 
rIMV should be approved by the Sponsor on a case-by-case basis. 
There are 5 types of rIMV that may be performed, where approved by the relevant local 
authorities, which include: 
• Remote Source Data Monitoring (rSDM) visits: The CRA will verify data remotely, 
off site if unable to be at the site. The Site coordinator will show the CRA source data 
via Zoom or alternate teleconference portal. 
• Remote Data Verification visits: The CRA will verify source data remotely, off-site if 
unable to be at the site. 
• Audio Data Verification visits: An alternative approach for remote data verification 
of critical patient data, when Monitor asks an Investigator site staff member to read 
patient source documents during a telephone call while reviewing the eCRF to verify 
patient safety is protected and the data reported by Investigator (e.g., in the eCRF) is 
accurate and complete. 
• Video Source Data Monitoring visits: Process for conducting rSDM during a video 
call/conference between the Monitor and Investigator site staff member, when the 
Investigator site staff member shares the patient source documents with the Monitor 
via camera so that the Monitor can perform Source Data Review and Source Data 
Verification as per the project-specific instructions. 
• Remote Site Monitoring Contact visits: the CRA will attend the site to review the 
investigator site file (ISF), investigative product (IP) supply, etc. 
Depending on the local regulation, some of these types of rIMV may be allowed or not. 
Records and documents, including signed informed consent forms, pertaining to the conduct of 
this trial must be retained by the Investigator for at least 2 years after the last marketing 
application approval or 2 years after formal discontinuation of the clinical development of the 
investigational product or according to applicable regulatory requirement(s). If the Investigator 
withdraws from the responsibility of keeping the trial records, custody must be transferred to a 
person willing to accept the responsibility. The Sponsor must be notified immediately by 
telephone or e-mail and the notification confirmed in writing if a custodial change occurs. 


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14. 
PUBLICATION POLICY 
All information regarding setmelanotide supplied by the Sponsor to the Investigator or generated 
as a result of any clinical trials is privileged and confidential information belonging to the 
Sponsor. The Investigator agrees to use the Sponsor confidential information solely to 
accomplish the trial and will not use such information for any other purposes without the prior 
written consent of the Sponsor. It is understood that there is an obligation to provide the Sponsor 
with complete and accurate data obtained during the trial. 
The information obtained from the clinical trial will be used towards the development of 
setmelanotide and may be disclosed by the Sponsor to regulatory authority(ies), other 
Investigators, corporate partners, or consultants as required. 
It is anticipated that the results of this trial may be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. The Sponsor generally supports 
publication of multicenter trials initially in their entirety and not as individual site data. A 
coordinating Investigator will be designated. 
Subsequently, individual Investigators may publish results from the trial in compliance with their 
agreement with the Sponsor. 
A pre-publication manuscript is to be provided to the Sponsor at least 30 days prior to the 
submission of the manuscript to a publisher. Similarly, The Sponsor will provide any company-
prepared manuscript to the Investigators for review at least 30 days prior to submission to a 
publisher. All publications and presentations must be approved in writing by the Sponsor before 
public disclosure. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 


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15. 
LIST OF REFERENCES
ASQ®-3 Questionnaire: https://agesandstages.com/products-pricing/asq3/  
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of 
Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999 Jun;36(6):437-46. 
Clément K, den Akker E, Argente J, et al. Efficacy and safety of setmelanotide, an MC4R 
agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open- 
label, multicentre, phase 3 trials. Lancet Diabetes & Endocrinology. 2020; 8(12): P960-970 
Fitzpatrick TB. Soleil et peau. J Med Esthet. 1975;2:33034. 
Haws R, Brady S, Davis E, et al. Effect of setmelanotide, a melanocortin-4 receptor agonist, on 
obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020; 22:2133–2140 
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Package Insert. U.S. Food and Drug 
Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213793s001lbl.pdf 
Accessed 20 June 2023. 
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
European Medicines Agency, 2023. 
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
Medicines and Healthcare Products Regulatory Agency.  
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide). Israel Ministry of Health. 
https://israeldrugs.health.gov.il/#!/byDrug. Accessed 20 June 2023.  
Rhythm Pharmaceuticals. IMCIVREE Product Monograph. Health Canada, 2023. 
https://pdf.hres.ca/dpd_pm/00070511.PDF. Accessed 20 June 2023. 
Increlex Product SmPC: https://www.ema.europa.eu/en/documents/product- information/
increlex-epar-product-information_en.pdf 
National Institutes of Health (NIH), National Heart Lung and Blood Institute (NHLBI). The 
Practical Guide. Identification, evaluation, and treatment of overweight and obesity in adults. 
NIH Publication No. 00-4084, October 2000. 
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APPENDICES 
APPENDIX 1. BEALES CRITERIA 
BBS clinical diagnosis as per Beales 1999 (with either 4 primary features or 3 primary and 
2 secondary features from table below): 
Bardet-Biedl Syndrome 
Primary Diagnostic Criteria 
• 
Rod cone dystrophy 
• 
Learning disabilities 
• 
Polydactyly 
• 
Hypogonadism in males 
• 
Obesity 
• 
Renal anomalies 
Secondary Diagnostic Criteria 
• 
Speech disorder/delay 
• 
Mild spasticity (especially lower limbs) 
• 
Strabismus/cataracts/astigmatism 
• 
Diabetes mellitus 
• 
Brachydactyly/syndactyly 
• 
Dental crowding/hypodontia/small 
roots/high arched palate 
• 
Developmental delay 
• 
Left ventricular hypertrophy/congenital 
heart disease 
• 
Polyuria/polydipsia (nephrogenic diabetes 
insipidus) 
• 
Hepatic fibrosis 
• 
Ataxia/poor coordination 
 


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APPENDIX 2. GUIDANCE ON TRIAL CONDUCT DURING THE 
COVID-19 PANDEMIC 
The COVID-19 pandemic could impact the conduct of this clinical trial for several reasons, 
including: self-isolation/quarantine by patients and trial-site personnel; travel restrictions/limited 
access to public places, including hospitals; and reassignment of site personnel to critical tasks. 
In accordance with recent health authority guidance, the Sponsor is providing temporary 
considerations for trial conduct in the event of disruption of the trial. This guidance does not 
supersede any local or government requirements or the clinical judgment of the Investigator. If at 
any time a patient’s safety is considered to be at risk, trial intervention will be discontinued, and 
trial follow-up will be conducted. 
If COVID-19 restrictions are imposed on or by the trial site and the site cannot fully carry out 
normal operations, the following measures are recommended on a temporary basis during the 
COVID-19 pandemic:  
• Where possible, every effort should be made to complete all protocol-required 
assessments. In place of a required site visit, a qualified healthcare provider could 
perform trial-related procedures as per the SoA (Table 1) via a home visit, including 
but not limited to collection of body weight, vital signs, physical examinations, 
ECGs, recording of AEs, collection of blood and urine samples. Most efficacy 
assessments could potentially be done off site. Investigators should use their clinical 
judgment to determine whether a patient can continue trial treatment in the absence of 
on-site clinic visits or consider alternatives such as temporary treatment interruption 
or trial discontinuation. 
• All protocol-required assessments missed due to COVID-19 restrictions should be 
documented in detail within the patients’ source documents and should be clearly 
designated as “COVID-19 RELATED”. It must be documented if a site visit is 
instead conducted remotely. Source documentation should detail how each 
assessment was collected (e.g., remote vs. on-site, central vs. local laboratory, vital 
signs taken at home by caretaker vs. delegated in-home nursing, etc.). 
• If applicable, discontinuations of trial interventions and withdrawal from the trial due 
to disruption of trial conduct by the pandemic should be documented with the prefix 
“COVID-19 RELATED” in the CRF. 
COVID-19 Infection in Trial Patients: 
There are currently no available data suggesting that patients treated with setmelanotide should 
have treatment interrupted during the COVID-19 pandemic. If a patient develops symptoms 
associated with coronavirus infection, it is recommended to confirm the diagnosis using locally 
approved laboratory kits and report it to the local health authorities, as required. Patients with 
positive test results for SARS-CoV-2 should have this recorded as an AE, and if hospitalized, 
this should be reported as a SAE. 
 
 


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APPENDIX 3. FITZPATRICK SCALE 
Skin 
Type 
Skin Color 
Characteristics 
I 
White; very fair; red or blond hair; blue eyes; freckles 
Always burns, never tans 
II 
White; fair; red or blond hair; blue, hazel, or green eyes 
Usually burns, tans with difficulty 
III 
Cream white; fair with any eye or hair color; very 
common 
Sometimes mild burn, gradually 
tans 
IV 
Brown; typical Mediterranean Caucasian skin 
Rarely burns, tans with ease 
V 
Dark Brown; mid-eastern skin types 
Very rarely burns, tans very easily 
VI 
Black 
Never burns, tans very easily 
Fitzpatrick 1975. 

SAP_001.pdf: 
  
 
 
 
 
 
                                 
Confidential 
 
  
 
Rhythm Pharmaceuticals, Inc. 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Number RM-493-033 (22 Jun 2023) 
 
 
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 
 Rhythm Pharmaceuticals, Inc.  
222 Berkeley Street  
12th Floor  
Boston, MA 02116 
 
 
Version 4.0 
 21 August 2023 
 
 
Prepared By:  
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Statistical Analysis Plan Version 4.0  
Page 2 of 33 
 
APPROVAL SIGNATURE PAGE 
Protocol 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 
Sponsor: 
Rhythm Pharmaceuticals, Inc. 
222 Berkeley Street  
12th Floor  
Boston, MA 02116 
Protocol Number: 
RM-493-033 
 
 
 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments.  All changes to the 
planned analyses will be described in the clinical study report. 
 
Sponsor Signatory: 
 
Rhythm Pharmaceuticals, Inc. 
222 Berkeley Street  
12th Floor  
Boston, MA 02116 
 
 
  
 
 
 
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Table of Contents 
1 
List of Abbreviations and Definition of Terms.................................................... 5 
2 
Introduction .......................................................................................................... 6 
3 
Study Objectives and Overall Design .................................................................. 6 
3.1 
Study Objectives .................................................................................................. 6 
3.1.1 
Primary Objective ................................................................................................ 6 
3.1.2 
Secondary Objective(s) ........................................................................................ 6 
3.1.3 
Exploratory Objective(s) ...................................................................................... 6 
3.2 
Overall Design ..................................................................................................... 6 
3.2.1 
Study Patients....................................................................................................... 7 
3.3 
Treatments and Assignment to Treatments.......................................................... 7 
3.4 
Determination of Sample Size ............................................................................. 8 
3.5 
Patient Assessments ............................................................................................. 8 
3.5.1 
Vital Signs ............................................................................................................ 8 
3.5.2 
Bone Age ............................................................................................................. 9 
3.5.3 
Physical Examination........................................................................................... 9 
3.5.4 
Comprehensive Skin Examination ....................................................................... 9 
3.5.5 
Electrocardiogram (ECG) .................................................................................... 9 
3.5.6 
Clinical Laboratory Tests ..................................................................................... 9 
3.5.7 
Inje
njectition S
on Sitite Ex
 Exami
mina
natition ................................
................................................................................. 10 
3.5.8 
............................................................................ 10 
3.5.9 
Age
Ages &
s & S
 Statage
ges Que
s Questi
stion
onna
naire
ires®, , Third E
Third Edit
dition (A
ion (ASQ
SQ®-3) ................................ 10 
3.5.10 
...................................... 12 
4 
General Analysis Conventions ........................................................................... 14 
4.1 
Study Periods ..................................................................................................... 15 
4.2 
Visit Windows ................................................................................................... 15 
4.3 
Baseline Definitions ........................................................................................... 16 
5 
Analysis Populations .......................................................................................... 16 
5.1 
Safety Population ............................................................................................... 16 
6 
Patient Disposition ............................................................................................. 17 
7 
Protocol Deviations ............................................................................................ 17 
8 
Demographic and Baseline Characteristics ....................................................... 18 
8.1 
Demographic and Baseline Characteristics ....................................................... 18 
8.2 
Medical History ................................................................................................. 18 
8.3 
Concomitant Procedures .................................................................................... 19 
8.4 
Prior and Concomitant Medications .................................................................. 19 
8.5 
Physical Examination......................................................................................... 20 
9 
Efficacy Analysis ............................................................................................... 20 
9.1 
Primary Efficacy Endpoints ............................................................................... 20 
9.1.1 
Proportion of Patients with a Decrease from Baseline to 52 Weeks in BMI Z-
score ≥ 0.2 ......................................................................................................................... 20 
9.1.2 
Mean Percent Change in BMI from Baseline to Week 52................................. 20 
9.2 
Secondary Efficacy Endpoints ........................................................................... 21 
9.2.1 
Change in BMI Percentage of the 95th Percentile .............................................. 21 
9.2.2 
Change in Weight .............................................................................................. 21 
9.2.3 
Change in BMI and BMI z-scores ..................................................................... 21 
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9.2.4 
Ages and Stages Questionnaire, Third Edition .................................................. 21 
10 
Safety Analysis .................................................................................................. 22 
10.1 
Safety Endpoints ................................................................................................ 22 
10.2 
Study Treatment ................................................................................................. 22 
10.2.1 
Study Drug Exposure ......................................................................................... 22 
10.2.2 
Treatment Administration .................................................................................. 23 
10.2.3 
Injection Site Evaluation .................................................................................... 23 
10.2.4 
Dose Level Changes .......................................................................................... 24 
10.3 
Adverse Events .................................................................................................. 24 
10.3.1 
Overview of Adverse Events ............................................................................. 24 
10.3.2 
Treatment-Emergent Adverse Events ................................................................ 24 
10.3.3 
Severity of the Adverse Event ........................................................................... 25 
10.3.4 
Relationship to Study Drug ................................................................................ 25 
10.3.5 
Death, Serious Adverse Events, Adverse Events Leading to Discontinuation .. 25 
10.4
10.4 
Clilinica
nical l Labor
borator
tory Datata................................
................................................................
....................................................
.................... 26
26 
10.5 
Vital Signs .......................................................................................................... 27 
10.6 
Electrocardiograms ............................................................................................ 27 
10.7 
Hyperpigmentation ............................................................................................ 28 
10.8 
Bone Age ........................................................................................................... 28 
10.9 
Pharmacokinetics ............................................................................................... 28 
11 
Statistical/Analytical Issues ............................................................................... 28 
11.1 
Handling of Missing Data .................................................................................. 28 
11.2 
Handling of Missing/Partial Dates ..................................................................... 28 
11.3 
Pooling of Centers in Multi-Center Studies ....................................................... 29 
11.4 
Multiple Comparisons/Multiplicity ................................................................... 29 
11.5 
Examination of Subgroups ................................................................................. 29 
12 
Interim Analysis and Data Monitoring .............................................................. 29 
13 
Quality Control .................................................................................................. 29 
14 
Tables and Listings Conventions ....................................................................... 30 
15 
References .......................................................................................................... 30 
16 
Appendices ......................................................................................................... 31 
16.1 
Schedule of Assessments ................................................................................... 31 
16.2 
Changes in Analysis Planned in the Protocol .................................................... 33 
16.3 
Change History .................................................................................................. 33 
 
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1 List of Abbreviations and Definition of Terms  
Abbreviation 
Description 
AE 
Adverse Event 
ASQ®-3 
Ages & Stages Questionnaires®, Third Edition 
ATC-3 
Anatomical Therapeutic Chemical 3rd level 
ATC-4 
Anatomical Therapeutic Chemical 4th level 
BBS 
Bardet-Biedl Syndrome 
BMI 
Body Mass Index 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
CSR 
Clinical Study Report 
CS 
Clinically Significant 
CTCAE 
Common Terminology Criteria for Adverse Events 
DAO 
Data As Observed 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
HR 
Heart Rate 
ICH 
International Conference on Harmonization 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not Clinically Significant 
PI 
Principal Investigator 
PT 
Preferred Term 
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneously 
SD 
Standard Deviation 
SoA 
Schedule of Activities 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
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2 Introduction 
This statistical analysis plan (SAP) describes the efficacy and safety summaries and 
analyses that will be performed for Study RM-493-033, 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 and is based on the study protocol Version 5.0 dated 
22 June 2023 and study Electronic Case Report Forms (eCRFs) Version 04.000 dated 21 
March 2023. 
3 Study Objectives and Overall Design 
3.1 Study Objectives 
3.1.1 
Primary Objective 
The primary objective of this study is to evaluate the effect of setmelanotide on weight-
related parameters 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).  
3.1.2 
Secondary Objective(s) 
The secondary objectives of this study are to evaluate the effect of setmelanotide on 
additional weight-related parameters, as well as safety and tolerability 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) BBS. 
3.2 Overall Design 
This is a Phase 3 multi-center, open-label study of setmelanotide in pediatric patients 
aged 2 to <6 years of age with rare genetic causes of obesity. The study is designed to 
evaluate safety and tolerability of setmelanotide as well as its efficacy on weight-related 
parameters in pediatric patients. 
The Screening Period begins with obtaining informed consent from the parent or 
guardian and will last between 1 and 8 weeks. During the Screening Period, patients will 
undergo all procedures as outlined in the Schedule of Activities (SoA; Section 16.1) to 
determine if they meet the all of the Inclusion (Section 6.1 of the protocol) and none of 
the Exclusion criteria (Section 6.2 of the protocol) for study eligibility. 
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During the Screening Period, patients will undergo medical evaluation; and caregivers 
will receive training on injection of study medication and other study procedures. 
At the enrollment visit (Day 1), the patient will have height and body weight recorded. 
This will be the baseline height and weight. To be eligible for the study, a patient’s 
baseline weight must be at least 15 kg. Height and weight will be monitored closely 
during the study. 
During the enrollment visit, the caregiver will inject the patient’s first dose of 
setmelanotide via subcutaneous (SC) injection under the supervision of the study staff. 
Patients’ caregivers will be issued an electronic diary to capture daily compliance with 
injections. 
Patients will have study visits approximately every 4 weeks through Week 20 and then 
approximately every 8 weeks through Week 52 and assessments will be performed as per 
the SoA. Due to the young age of the patients, it may not be possible to perform all 
planned assessments at each visit. Thus, as described in the SoA, the Investigator will be 
given latitude to adjust the planned assessments and blood draws as appropriate for the 
optimal medical care of their patients. 
The End of Treatment (EOT) visit will occur on Study Day 365, which is the final day of 
treatment with setmelanotide. A final End of Study (EOS) visit will occur on Study Day 
393 and will be conducted via telephone. Patients may be eligible to enroll into a long-
term extension study. 
3.2.1 
Study Patients 
The study plans to enroll approximately 10-15 pediatric patients (approximately 5 or 
more with biallelic mutations of the POMC, PCSK1 or LEPR genes and approximately 5 
or more with BBS) in a pivotal cohort. At the direction of the Sponsor, if additional 
potential patients are identified, a supplemental cohort may be added to gain additional 
experience. 
3.3 Treatments and Assignment to Treatments 
All patients will begin treatment at a dose of 0.5 mg of setmelanotide per day 
administered as a SC injection. Patients will then increase their dose by 0.5 mg 
increments, every 2 weeks, as described in the SoA (Section 16.1). The maximum dose 
level of setmelanotide used in this study will be based on the weight bands for the 2- to 
<6-year-old patients to support an exposure similar to that observed for adults dosed at 2 
to 3 mg setmelanotide QD. The maximum dose level in this study for patients who weigh 
 will be 0.5 mg, 1.0 mg, 1.5 mg and 2.0 mg 
QD, respectively.  
If a patient’s weight decreases to below 15 kg during the study, the Investigator and 
Sponsor will discuss the patient’s status and will jointly determine if a patient should 
continue the current dose, decrease the dose or discontinue treatment with setmelanotide 
temporarily or permanently.   
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A dose reduction to 0.25 mg can be considered in such scenarios or in case of safety or 
tolerability concerns, including for example, the occurrence of severe renal impairment. 
These dose adjustments are considered adequate for the pediatric patients to grow in 
height at a normal rate and support attaining and maintaining an appropriate body weight.  
At the discretion of the Investigator, a patient may temporarily pause the dose escalation 
at any step prior to reaching their final maintenance dose, for safety or tolerability 
reasons, or due to achieving adequate weight loss. The dose may continue to be evaluated 
and adjusted, at the discretion of the Investigator, so long as the daily dose is kept 
between 
 a and 2.0 mg QD, according to their respective weight. 
3.4 Determination of Sample Size  
No formal sample size determination was made based on statistical inference. The sample 
size is not driven by statistical power consideration but is primarily driven by clinical and 
practical considerations. Given the rare patient population, the study plans to enroll 
approximately 10-15 patients (approximately 5 or more pediatric patients with biallelic 
mutations of the POMC, PCSK1 or LEPR genes and approximately 5 or more pediatric 
patients with BBS).  
3.5 Patient Assessments 
3.5.1 
Vital Signs 
Vitals signs include: 
• 
Height (cm) 
• 
Weight (kg) 
• 
 
• 
Temperature (C) 
• 
Heart Rate (HR) (beats/min) 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Respiratory Rate 
Vital signs will be assessed from screening and at every post-baseline visit. Height, 
weight, HR, systolic blood pressure, and diastolic blood pressure will be measured in 
triplicates at each visit. In addition to the individual measurements the above items will 
be aggregated into a mean value per visit (i.e. mean of all height measurements). 
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3.5.2 
 Bone Age 
Bone age will be assessed at the enrollment (baseline) and EOT visits by X-ray. 
3.5.3 
Physical Examination 
A complete physical examination will be conducted at screening and at the EOT Visit. At 
other timepoints, an abbreviated examination will be performed. The abbreviated 
examination should focus on heart, lungs, skin, neurologic exam, and any areas of 
previous abnormal findings, noting any changes from baseline. Tanner staging should be 
performed at Screening and at the EOT (Week 52) visit. It may be done at additional 
visits, at the discretion of the PI. While the findings from the physical examination will 
not be captured on the eCRF, nor analyzed directly, changes from baseline in any 
physical examination findings identified by the Investigator as clinically significant (CS) 
will be recorded as an adverse event (AE).  
3.5.4 
Comprehensive Skin Examination 
Comprehensive skin examinations will also be performed per the SOA. Normal and 
abnormal findings regarding skin lesions will be assessed. At each visit skin 
hyperpigmentation, changes in skin tone, new mole development, and changes in existing 
moles will be assessed.  
3.5.5 
Electrocardiogram (ECG) 
A single 12-lead ECG recording will be performed as specified in the SOA. If an ECG is 
not practical in a young patient, it may be replaced by a rhythm strip and only HR and PR 
interval will be collected.The following items will be measured:  
 HR (beast/min) 
 PR interval (msec) 
 QRS interval (msec) 
 QT interval (msec) 
 QTcF interval (msec) 
 Overall Interpretation (Normal, Abnormal – Not Clinically Significant (NCS), 
Abnormal – CS) 
3.5.6 
Clinical Laboratory Tests 
Hematology, clinical chemistry, and urine analysis laboratory tests will be performed as 
specified in the SOA. At each applicable visit, the laboratory tests will be collected prior 
to study treatment. Due to the age of the children, it may not be possible to collect all labs 
at every study visit. Screening may be performed over multiple days, to complete the 
required assessments. After enrollment, if all lab tests are not possible, then the tests 


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should be collected in the following descending order of priority: safety, anti-drug 
antibodies, trough PK, hemoglobin A1c and then lipid panel. 
3.5.7 
Injection Site Examination 
At each visit where study treatment is administered, the injection site will be evaluated. The 
injection site evaluation will include: 
 Reaction (Erythema, Edema, Induration, Itching, Pain or Tenderness, Other) 
o Length (Erythema, Edema, Induration only) 
o Width (Erythema, Edema, Induration only) 
 Finding (None, Mild, Moderate, Severe) 
 Clinically significant (Yes, No) 
3.5.9 
Ages & Stages Questionnaires®, Third Edition (ASQ®-3) 
The ASQ®-3 is a developmental screening tool that assesses developmental progress in 
children between one month to 5 ½ years. The ASQ®-3 is intended for use at six-month 
intervals between 6 months and 3 years of age, and then at one-year intervals through age 
5. Thus, for patients who enter the study at ages between 2 years and 3 years, the ASQ-3 
will be administered at the Enrollment (Baseline) Visit, Week 28 visit and EOT Visit. For 
patients who enter the study between the ages of 3 and 6 years old, the ASQ-3 will only 
be administered at the Enrollment (Baseline) Visit and EOT Visit. 
The ASQ-3 consists of five areas: communication, gross motor, fine motor, problem 
solving, and personal-social. Each area consists of six questions that are scored Yes = 10 
points, Sometimes = 5 points, and Not yet = 0 points. The 10 free-response items will not 
be analyzed.   
The total area score is calculated by first adding up the questions within each area and 
then comparing the total area score to the respective cutoff score on the ASQ-3 scoring 
sheet to be normalized to one of three categories, which indicate whether the child’s 
development appears to be on schedule. 
• 
Below the cut-off = Further assessment with a professional may be needed. 
• 
Close to the cut-off = Providing learning activities and monitor. 
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• 
Above the cut-off = The child’s development appears to be on schedule. 
The following table presents ASQ-3 Referral cutoff scores and monitoring zone 
cutoff scores used in the analysis: 
PARCAT2 
PARAM 
Referral 
Cutoff 
Monitoring 
zone Cutoff 
30 Month Questionnaire 
Communication - 30 
33.30 
43.56 
36 Month Questionnaire 
Communication - 36 
30.99 
41.43 
42 Month Questionnaire 
Communication - 42 
27.06 
38.54 
48 Month Questionnaire 
Communication - 48 
30.72 
41.82 
54 Month Questionnaire 
Communication - 54 
31.85 
42.82 
60 Month Questionnaire 
Communication - 60 
33.19 
42.80 
30 Month Questionnaire 
Gross Motor - 30 
36.14 
44.84 
36 Month Questionnaire 
Gross Motor - 36 
36.99 
45.84 
42 Month Questionnaire 
Gross Motor - 42 
36.27 
45.15 
48 Month Questionnaire 
Gross Motor - 48 
32.78 
42.74 
54 Month Questionnaire 
Gross Motor - 54 
35.18 
44.58 
60 Month Questionnaire 
Gross Motor - 60 
31.28 
41.72 
30 Month Questionnaire 
Fine Motor - 30 
19.25 
33.02 
36 Month Questionnaire 
Fine Motor - 36 
18.07 
32.57 
42 Month Questionnaire 
Fine Motor - 42 
19.82 
33.68 
48 Month Questionnaire 
Fine Motor - 48 
15.81 
30.58 
54 Month Questionnaire 
Fine Motor - 54 
17.32 
31.72 
60 Month Questionnaire 
Fine Motor - 60 
26.54 
39.05 
30 Month Questionnaire 
Problem Solving - 30 
27.08 
38.63 
36 Month Questionnaire 
Problem Solving - 36 
30.29 
41.13 
42 Month Questionnaire 
Problem Solving - 42 
28.11 
39.82 
48 Month Questionnaire 
Problem Solving - 48 
31.3 
42.04 
54 Month Questionnaire 
Problem Solving - 54 
28.12 
39.68 
60 Month Questionnaire 
Problem Solving - 60 
29.99 
41.29 
30 Month Questionnaire 
Personal - Social - 30 
32.01 
41.94 
36 Month Questionnaire 
Personal - Social - 36 
35.33 
44.07 
42 Month Questionnaire 
Personal - Social - 42 
31.12 
41.25 
48 Month Questionnaire 
Personal - Social - 48 
26.6 
38.47 
54 Month Questionnaire 
Personal - Social - 54 
32.33 
42.55 
60 Month Questionnaire 
Personal - Social - 60 
39.07 
46.96 
 


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4 General Analysis Conventions 
. 
 
  
 
 Data for all patients in the 
clinical database will be included in the data listings.  Calculated (derived) variables will 
be listed as appropriate.  
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All efficacy, safety and baseline characteristics variables will be presented using 
descriptive statistics and figures as appropriate. Continuous variables will be summarized 
using descriptive statistics (number of observations, mean, standard deviation (SD), 
median, minimum, and maximum).  Categorical variables will be presented in frequency 
tables with number and percent of observations for each level. Missing counts for all 
variables will be presented for informational purposes only and will not be included in 
percentage calculations.  
Study days will be calculated relative to the first injection of study drug.  Day 1 will be 
the first day of study drug administration in the study. In data listings, the relative study 
day (in relation to date of first study drug administration) of all dates will be presented.  
AEs, medical history events, and concomitant treatments/procedures will be coded using 
Medical Dictionary for Regulatory Activities (MedDRA), Version 24.0 or higher. 
Prior/concomitant medications will be coded using the World Health Organization 
(WHO) Drug Dictionary Global B3, March 2021 or higher. 
Any changes from the SAP will be detailed in the Clinical Study Report (CSR). 
4.1 Study Periods 
The study has two periods: Screening and Treatment. 
• 
Screening Period – From providing informed consent to just before the 
Enrollment (Baseline) Visit (Day 1). Can range between 56 – 1 day(s) prior to the 
Enrollment (Baseline) Visit. 
• 
Treatment Period - From the Enrollment (Baseline) Visit to EOT (Day 365, or date 
of withdrawal). 
A final EOS visit will occur on Study Day 393 and will be conducted via telephone. 
Patients may be eligible to enroll into a long-term extension study. 
4.2 Visit Windows 
Study visits are expected to occur according to the protocol schedule (Section 16.1). 
Efficacy by-visit summaries and analyses will use analysis visits. Both scheduled and 
unscheduled visits (including early termination visit) will be windowed based on the 
following analysis visit windows. 
 
Analysis Visit 
Target Study Day 
Analysis Visit Window 
Baseline 
1 
≤ 1 
Week 2 
15 
2 – 22 
Week 4 
29 
23 – 36 
Week 6 
43 
37 – 50 
Week 8 
57 
51 – 71 
Week 12 
85 
72 – 99 


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Week 16 
113 
100 – 127 
Week 20 
141 
128 – 169 
Week 28 
197 
170 – 225 
Week 36 
253 
226 – 281 
Week 44 
309 
282 – 337 
Week 52 
365 
338 – 379 
Week 56 
393 
≥ 380 
If two or more assessments (include both scheduled and unscheduled assessments) are 
available for the analysis visits, then all assessments will be included in data listings and 
the following rule will be applied for determining the values to be used for the summaries 
and analyses in tables: 
 Efficacy assessments: the assessment taken closest to the target study day will be 
used for the summaries and analyses; if two visits are equally distant to the target 
study day, then the more recently occurring visit will be chosen (i.e. If the target 
study day was 01 JAN 2021 and Visit A occurred on 27 DEC 2020 and Visit B 
occurred on 06 JAN 2021 (both 5 days apart from the target study day), then Visit 
B will be chosen). 
Safety by-visit summaries and analyses will use the nominal evaluation visit, as recorded 
on the eCRF. Both scheduled and unscheduled visits (including early termination visit) 
will be windowed based on the protocol-specified windows outlined in Section 16.1. If 
two or more assessments (include both scheduled and unscheduled assessments) are 
available for the visits, then all assessments will be included in data listings and the 
following rule will be applied for determining the values to be used for the summaries 
and analyses in tables: 
 Safety assessments, including clinical laboratory tests: the scheduled visit will be 
used over any unscheduled visits conducted within window; otherwise, the latest 
assessment will be used for the summaries and analyses. 
4.3 Baseline Definitions 
For all analyses, baseline will be defined as the most recent measurement prior to the first 
administration of study drug, including assessments done at the Screening visit, 
Unscheduled visits conducted prior to study treatment, and pre-treatment assessments 
done at the Enrollment (Baseline) visit. 
In general, change from baseline ( ) will be calculated as the value at a given time point, 
X, minus the baseline value: 
 
5 Analysis Populations 
5.1 Safety Population 
The Safety Analysis Set population will include all patients who received at least 1 dose 
of study drug. 


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6 Patient Disposition 
The disposition of patients will be presented in total, including: 
• 
Number of patients screened, including screen failures 
• 
Number of patients enrolled into the study 
• 
Number of patients who completed the treatment 
• 
Number of patients who early withdrew/discontinued from the treatment 
• 
Number of patients who completed the study   
• 
Number of patients who early withdrew/discontinued from the study 
• 
Number of patients that continued onto the extension study (RM-493-022) 
• 
Number of patients in the Safety population 
Specifically, the number and percentage of patients in each of the specified categories 
above will be presented. Percentages will not be presented for the number of patients 
enrolled or screened; all other percentages will be based on the number of patients in the 
safety population. The discontinuation reason as specified on the eCRFs will also be 
summarized by number and percent under ‘Early withdrawals/discontinuations’ section. 
All patients’ disposition information (date of study completion/discontinuation, reason 
for discontinuation, date of last dose, reason for treatment discontinuation, and COVID-
19 impact) will be presented in a data listing. Inclusion/exclusion data will also be 
presented by patients in a data listing. 
7 Protocol Deviations 
A protocol deviation occurs when a patient deviates from the protocol procedures. All 
protocol deviations will be presented by patient in a data listing.  
COVID-19 Impact 
As the study started during the COVID-19 pandemic, missed/modified study visits, study 
procedures, and study dosing due to COVID-19 will be collected. A data listing will 
present any study visit, study procedure, and/or study assessment that due to COVID-19 
were: 
• 
Conducted remotely 
• 
Modified or missed 
• 
Out of window 
• 
Resulted in study discontinuation 
• 
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8 Demographic and Baseline Characteristics 
8.1 Demographic and Baseline Characteristics 
Demographic assessments for this study include: 
• 
Age (years) 
• 
Gender  
• 
Ethnicity  
• 
Race  
• 
Weight at Baseline (kg) 
• 
Height at Baseline (cm) 
• 
Body Mass Index (BMI) at Baseline (kg/
) 
• 
BMI Z-score at Baseline 
• 
Waist Circumference at Baseline (cm) 
• 
Gene Type (POMC, PCSK1, LEPR, and BBS) 
• 
Fitzpatrick Skin Type (FST) at Baseline 
Age, baseline weight, baseline height, baseline BMI, baseline BMI Z-score, and baseline 
waist circumference will be analyzed as a continuous variable. Gender, ethnicity, race, 
gene type, and baseline FST will be analyzed as categorical variables. 
Demographics characteristics will be presented by patient in a data listing. 
8.2 Medical History 
History of relevant surgical events and medical conditions will be collected. Medical 
History will be coded according to MedDRA; the version used will be noted as a footnote 
in the tables and listings.  
The number and percentage of patients reporting medical history will be summarized by 
system organ class (SOC) and preferred term (PT). SOC and PTs will be presented in 
descending frequency first and then alphabetically if there are ties. Each patient will 
contribute at most one count per summarization category.  In other words, if a patient has 
more than one medical history event with same PT, the patient will be counted only once 
for that PT. Similarly, if a patient has more than one medical history event for a SOC, the 
patient will be counted only once in that SOC.  


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Medical history information will be reported by patient in a data listing.  The listing will 
show the verbatim term (i.e., term reported by the site), the MedDRA SOC, MedDRA PT, 
event start date, and event end date (or ongoing). Medical history of weight loss 
interventions (type of intervention, start and end dates, and a summary of the outcome), 
historic height and weight (the 10 most recent height and weight measurements along 
with the date of assessment), and nutritional counseling (whether the patient completed 
nutritional counseling, and if so, the date and outcome) will be reported by patient in a 
data listing. 
8.3 Concomitant Procedures 
Concomitant procedures for this study are defined as any surgical, therapeutic, or 
diagnostic procedure that a patient has performed on or after the date of enrollment. 
Procedures will be coded using the MedDRA. The versions used for the coding will be 
noted as a footnote in the tables and listings.   
Concomitant procedures will be summarized in a table and will follow the same methods 
specified for medical history (Section 8.2). Concomitant procedure information will be 
reported by patient in a data listing.  The listing will show the verbatim term, the 
MedDRA SOC, MedDRA PT, indication, event start date, and event end date (or 
ongoing). 
8.4 Prior and Concomitant Medications  
Concomitant medications for this study are defined as any medication the patient is 
receiving at the time of enrollment, or any new medication received by the patient after 
the date of enrollment. Prior medications are medications with a stop date prior to date of 
study enrollment. Medications will be coded using the WHO Drug Dictionary. The 
versions used for the coding will be noted as a footnote in the tables and listings.   
The number and percentage of patients who receive prior and concomitant medications 
will be summarized, separately, by the WHO Drug Dictionary Anatomical Therapeutic 
Chemical 4th level (ATC-4) and the preferred name. If the 4th level term is not available, 
the next available level (e.g., ATC-3) will be used.  
ATC-4 and preferred name will be presented in descending frequency first and then 
alphabetically if there are ties. Each patient will contribute at most one count per 
summarization category.  In other words, if a patient has more than one medication with 
same preferred name, the patient will be counted only once for that preferred name. 
Similarly, if a patient has more than one medication for an ATC-4 level, the patient will 
be counted only once in that ATC-4 level and preferred name.  
Prior and concomitant medications will be presented by patient in a data listing. The 
listing will show the verbatim medication/therapy, the ATC-4 term, preferred name, 
indication, medication start date, medication end date (or ongoing), dose, dose unit, 
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8.5 Physical Examination 
Physical examination assessments will be presented by patient in data listings. The 
physical examination listing will show the date of examination, indicator examination 
was not done (if applicable), reason examination was not done, and Tanner Staging 
results (if applicable).  
9 Efficacy Analysis 
Efficacy analyses of weight, waist circumference, BMI, and BMI z-scores will be 
conducted using the data as observed (DAO) with no imputation for missing data. 
Additional analyses will be conducted using the last observation carried forward (LOCF) 
to impute any missing data. 
If needed, weight and height will first be converted into kilograms and meters, 
respectively. Given that height and body weight are collected in triplicates at each visit, 
these will first be aggregated into one averaged value per visit. Visits will then be 
compared against the analysis visit window (described in Section 4.2) to select the 
appropriate averaged values prior to calculating weight, BMI, BMI z-score, and changes. 
If height is missing for an analysis visit, then height will be imputed using LOCF.  
9.1 Primary Efficacy Endpoints 
9.1.1 
Proportion of Patients with a Decrease from Baseline to 52 Weeks in 
BMI Z-score ≥ 0.2 
A “responder” is defined as a decrease from baseline to 52 weeks in the patient’s BMI z-
score of ≥0.2. The WHO Child Growth Standards 2007 will be used for BMI z-score. At 
each visit, an indicator variable will be created to identify patients that have a decrease in 
BMI z-score from baseline of 0.2 or more, allowing for the analysis of proportion of 
patients who meet the “responder” definition. The proportion and the corresponding 2-
sided 95% CI using the Clopper-Pearson method will be reported for each visit. Sample 
SAS code to calculate the BMI z-score can be found at https://www.who.int/tools/child-
growth-standards/software.  
9.1.2 
Mean Percent Change in BMI from Baseline to Week 52 
For the analysis of Mean percent change in BMI from baseline, percent changes in BMI 
from baseline over time will be summarized using descriptive statistics. Mean percent 
change in BMI from baseline over time will also be provided graphically. A 2-sided 95% 
CI with Student’s t-distribution will be provided for Mean percent change in BMI from 
baseline. In addition, patient figures showing the percent change in BMI from baseline 
will be created. Information on the patient’s baseline BMI will be included in the figure. 


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9.2 Secondary Efficacy Endpoints 
9.2.1 
Change in BMI Percentage of the 95th Percentile 
For each patient and visit, the BMI for that patient relative to the 95th percentile for the 
corresponding age and gender will be calculated. The actual relative value, change from 
baseline in the relative value, and percent change in relative value from baseline will be 
summarized using descriptive statistics at each visit.      
9.2.2 
Change in Weight 
Weight, change in weight from baseline, and percent change in weight from baseline will 
be summarized using descriptive statistics at each visit. This information will also be 
provided graphically for change in weight from baseline and percent change in weight 
from baseline. In addition, for each patient figures showing change in weight and percent 
change in weight from baseline over time will be created. Information on the patient’s 
baseline weight, BMI, and BMI z-score will be included in the figure. 
9.2.3 
Change in BMI and BMI z-scores 
BMI, change in BMI from baseline, BMI z-score, change in BMI z-score from baseline, 
and percent change in BMI z-score from baseline will be summarized using descriptive 
statistics. This information will also be provided graphically for change in BMI from 
baseline, and change in BMI z-score from baseline. In addition, for each patient figures 
showing the change in BMI, and the change in BMI z-scores from baseline will be 
created. Information on the patient’s baseline weight, BMI, and BMI z-score will be 
included in the figure. 
9.2.4 
Ages and Stages Questionnaire, Third Edition 
The normalized categories in the five areas (see Section 3.5.9) and their shift from 
baseline will be tabulated at each visit. A listing of these data will also be provided. 
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10 Safety Analysis 
10.1 Safety Endpoints 
All safety endpoints will be based on the Safety Population. Safety endpoints include: 
• 
Safety and tolerability assessed by the frequency and severity of AEs (see Section 
10.3 for more details) 
 
• 
Safety and tolerability assessed by vital signs (see Section 10.5 for more details) 
 
• 
Safety and tolerability assessed by laboratory evaluations (see Section 10.4 for 
more details) 
 
• 
Change from baseline in metabolic parameters following treatment with 
setmelanotide, including fasting glucose, HbA1c, lipid profiles (total-, high-
density lipoprotein [HDL]-, and low-density lipoprotein [LDL]-cholesterol, 
triglycerides). 
10.2 Study Treatment  
10.2.1 
Study Drug Exposure  
Dosing of study treatment will be monitored throughout the study by having the patient 
complete a daily dosing log that records daily dosing information, including: 
• 
The time of dosing 
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• 
If the injection occurred (Yes/No) 
• 
Reason for not injecting (Forgot, Trouble with injection, Ran out/misplaced drug, 
Other) 
Study treatment duration, in weeks, will be calculated as the number of weeks patients 
were administered study drug and will be summarized using descriptive statistics. Study 
treatment duration will be calculated using the following formula: 
 
For each patient, total exposure (mg) will be summarized descriptively in a table as the 
total sum of all dose mg that a patient receives throughout the study.  
For each patient, study drug compliance will be calculated using the following formula: 
 
Patient compliance with study drug will be summarized descriptively in a table. The 
number of patients who experienced at least one dose interruption will also be presented, 
as well as the reason for the interruption. 
Study drug compliance will be presented by patient in a data listing. The listing will show 
the daily dosing study day, date of the daily dosing log, indicator if patient was injected, 
reason for not injecting, treatment duration, and compliance percentage.  
10.2.2 
Treatment Administration 
Study treatment administration will be presented by patient in a data listing. The listing 
will show the date study drug was dispensed, items dispensed, treatment administration 
date, indicator if patient was injected, reason for not injecting, dose (mg), injection 
location, and kit number. A listing containing the patient supply accountability log will 
also be created. This listing will contain the article name, item number, expiry date, lot 
ID, item type, unit, quantity dispensed, item status, date returned/reported, item 
condition, quantity returned, amount returned, and any comments.  
10.2.3 
Injection Site Evaluation 
Injection site evaluation (described in Section 3.5.6) at each visit will be summarized 
using descriptive statistics.  
Injection site evaluation will be presented by patient in a data listing. The listing will 
show the date of evaluation, indicator if patient was evaluated, reason evaluation was not 
performed, reaction, finding, indicator if CS, length (mm), and width (mm). 


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10.2.4 
Dose Level Changes 
Any dose level changes that occur throughout the study will be captured in a data listing. 
For each patient, the visit, reason for dose level change, date of new dose, new dose level 
(mg), and planned location for injection will be presented. 
10.3 Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical study patient, 
temporally associated with the use of study treatment, whether or not considered related 
to the study treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease (new or exacerbated) 
temporally associated with the use of study treatment. AEs, including Serious Adverse 
Events (SAE), will be collected from the provision of informed consent until the EOS visit. 
All AEs reported will be coded using the MedDRA version in force at the time of 
database freeze) and classified by MedDRA SOC and PT. The MedDRA version used for 
the coding will be noted as a footnote in the tables and listings. 
All AEs will be presented by patient in a data listing. The listing will show the verbatim 
term, MedDRA SOC, MedDRA PT, event start date, event end date (or ongoing), SAE 
indicator, severity, relationship to study drug, action taken with study drug, action taken, 
and outcome. 
10.3.1 
Overview of Adverse Events 
An overview summary table of AEs will be provided, including the number and 
percentage of patients reporting an AE for the following categories: 
• 
Patients with at least one treatment-emergent AE (TEAE)  
• 
Patients with at least one TEAE related to study drug  
• 
Patients with at least one TEAE leading to drug discontinuation  
• 
Patients with at least one TEAE leading to study discontinuation  
• 
Patients with at least one serious TEAE  
• 
Patients with at least one serious TEAE related to study drug 
• 
Patients with AE resulting in death on study  
10.3.2 
Treatment-Emergent Adverse Events 
A TEAE is any AE that begins or worsens in intensity on or after the date of the first 
administration of study drug. Summaries of TEAEs (including number and percentage of 
patients) will be displayed by the following: 
• 
TEAEs by MedDRA SOC and PT  
• 
TEAEs related to study drug by MedDRA SOC and PT 


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• 
TEAEs leading to drug discontinuation by MedDRA SOC and PT 
• 
TEAEs leading to study discontinuation by MedDRA SOC and PT 
• 
Serious TEAEs by MedDRA SOC and PT  
• 
Serious TEAEs related to study drug by MedDRA SOC and PT 
• 
AEs resulting in death on study by MedDRA SOC and PT 
The number and percentage of patients who experienced at least one of the events listed 
above will be summarized overall and for each SOC and each PT. SOC and PTs will be 
presented in descending frequency first and then alphabetically if there are ties. Each 
patient will contribute at most one count per summarization category.  In other words, if a 
patient has more than one TEAE with same PT, the patient will be counted only once for 
that PT. Similarly, if a patient has more than one TEAE for a SOC, the patient will be 
counted only once in that SOC and PT. 
10.3.3 
Severity of the Adverse Event 
TEAEs will also be summarized by maximum severity and will follow the same methods 
specified in Section 10.3.2. The severity of the TEAE is classified into the five Common 
Terminology Criteria for Adverse Events (CTCAE) categories of Mild, Moderate, 
Severe, Life Threatening or Disabling, and Death.  If a patient has multiple occurrences 
of the same MedDRA SOC or PT, then only the most severe event will be summarized in 
the tables for that SOC and PT.  If the severity assessment is missing, the severity of 
‘Severe’ will be assumed. 
10.3.4 
Relationship to Study Drug 
TEAEs will also be summarized by relationship to study drug and will follow the same 
methods specified in Section 10.3.2. The relationship of the TEAE is classified into two 
categories of Related and Not Related. If the relationship assessment is missing, the 
relationship will be considered related. Related TEAEs will also be summarized by 
MedDRA SOC, PT and maximum severity (defined in Section 10.3.3). If the patient 
experiences both a related and not related TEAE within a particular SOC or PT, only the 
related TEAE will be summarized in the table. 
10.3.5 
Death, Serious Adverse Events, Adverse Events Leading to 
Discontinuation 
Serious TEAEs, TEAEs leading to death, and TEAEs leading to study drug 
discontinuation will be summarized, in separate summary tables, by MedDRA SOC 
and PT, following the same methods specified in Section 10.3.2. Furthermore, serious 
TEAEs will also be summarized, separately, by MedDRA SOC, PT, maximum 
severity/relationship/ relationship and maximum severity (defined in Section 10.3.3 
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Additionally, separate patient listings also will be provided for the following: patient 
deaths, SAEs, and AEs leading to study discontinuation and drug discontinuation.   
The patient death listing will include any AEs that lead to an outcome of death, and 
will show the verbatim term, MedDRA SOC, MedDRA PT, event start date, date of 
death, severity, relationship to study drug, action taken with study drug, action taken, 
and outcome. 
The SAE listing will include any AEs that are classified as an SAE, and will show the 
verbatim term, MedDRA SOC, MedDRA PT, event start date, event end date (or 
ongoing), SAE category, severity, relationship to study drug, action taken with study 
drug, action taken, and outcome.  
The AEs leading to discontinuation listing in will include any AEs that lead to an 
outcome of discontinuation or study drug withdrawn, and will show the verbatim term, 
MedDRA SOC, MedDRA PT, event start date, event end date (or ongoing), SAE 
indicator, severity, relationship to study drug, and outcome. 
10.4 Clinical Laboratory Data 
Hematology, clinical chemistry, and urine analysis laboratory assessments, not discussed 
below in Section 10.4.1, collected at each study visit and the changes from baseline to 
any post-baseline visit will be summarized by descriptive statistics. All laboratory tests 
will be compared to their laboratory normal range. Values outside of the normal range 
will be further classified as: Low – CS, High – CS, Low – NCS, High – NCS.  
Additionally, a shift table will be created to present any change from baseline in normal 
ranges in all laboratory tests across all post-baseline visits. This table will show the 
number and percentage of patients who had values that shifted from low - CS, low-NCS, 
normal, high – NCS, or high-CS at baseline to low - CS, low-NCS, normal, high – NCS, 
or high-CS at each post-baseline visit. Percentage of patients will be calculated using the 
number of patients with a baseline value and a non-missing value at the specified post-
baseline visit as the denominator. 
All laboratory data will be presented in data listings as collected. The listings will show 
the sample date, laboratory test, indicator test was not done (if applicable), reason test 
was not done (if applicable), laboratory value, and the change from baseline. Values 
outside of the reference range will be flagged with ‘H’ for high and ‘L’ for low, 
respectively.  
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10.5 Vital Signs  
The aggregated vital signs (described in Section 3.5.1 and 3.5.2) at each study visit and 
the changes from baseline to any post-baseline visit will be summarized using descriptive 
statistics.  
Vital signs will be presented in a listing. The listing will show the assessment date, vital 
sign, indicator measurement was not done (if applicable), measurement value, and the 
change from baseline. Values will include both the triplicate measurements and their 
aggregated value, where applicable.  
10.6 Electrocardiograms 
The ECG and the changes from pre-dose baseline will be summarized descriptively at 
each visit. In addition, a shift table will be created to show any change from pre-dose 
baseline to each visit in the overall ECG interpretation.  
QTcF interval prolongation will be presented separately as well. The number and 
percentage of patients with a QTcF interval of >450 msec, >480 msec, and >500 msec 
will be summarized by visit, along with the number and percentage of patients with a 
change from pre-dose baseline in QTcF interval of 30 - < 60 msec and ≥60 msec.  
All ECG results will be presented in a data listing. The listing will show the assessment 
date, ECG measurement, indicator ECG was not done (if applicable), reason ECG was 
not done (if applicable) ECG value, the change from baseline.  
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10.7 Hyperpigmentation 
Skin examination results (described in Section 3.5.4) at each visit will be summarized by 
skin region using descriptive statistics. Results from the hyperpigmentation assessment 
will be summarized by visit descriptively, including the number of patients that 
experienced a hyperpigmentation or skin change event. The skin examination listing will 
show the date of examination, indicator examination was not done (if applicable), reason 
examination was not done, skin region, result of exam, and any noted findings. A listing 
displaying the details of skin hyperpigmentation, changes in skin tone, development of 
new moles, changes in existing moles, and AE relatedness will be created. 
10.8 Bone Age 
Bone age will be collected at the enrollment visit (baseline) and the EOT visit. Bone age 
and the change from baseline to EOT will be summarized using descriptive statistics.  
A listing of the date of x-ray, date of bone age assessment, and the result, and the change 
from baseline will be provided.  
11 Statistical/Analytical Issues 
11.1 Handling of Missing Data 
In general, the number of patients with missing values will be summarized and reported 
as appropriate in all outputs. Unless otherwise specified in the SAP, missing data will not 
be imputed. 
11.2 Handling of Missing/Partial Dates  
While every effort will be made to obtain full, complete information on all data collected 
the table below outlines the imputation rules to be followed for any missing dates. Dates 
will be presented as collected in the listings.  
Imputation Criteria for Missing/Partial Dates 
Variable 
Missing Day 
Missing Month or 
Day and Month 
Missing Year, 
Month and Year, or 
Day and Year 
Missing 
Day, Month, 
Year 
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AE/Medication 
Start Date 
Assign to the 
first of the 
month 
(i.e. UNK-JAN-
2019 becomes 
01-JAN-2019) 
Assign to the month of 
‘June’ (i.e. 01-UNK-
2019 becomes 01-JUN-
2019), provided the 
imputed date is on or 
after the patient’s 
baseline study treatment 
date; otherwise, the 
subsequent month after 
study treatment will be 
used. 
Assign to year of study 
treatment will be used 
(i.e. 01-JAN-UNK 
becomes 01-JAN-2019), 
provided the imputed 
date is on or after the 
patient’s study treatment 
date; otherwise, the 
subsequent year after 
treatment will be used. 
Assign to 
baseline study 
treatment date 
AE/Medication End 
Date 
Assign the last 
day of the 
month (i.e. 
UNK-JAN-
2019 becomes 
31-JAN-2019). 
Assign to the subsequent 
month after the start 
date. 
Assign to the year of 
baseline study 
treatment (i.e. 01-JAN-
UNK becomes 01-
JAN-2019), provided 
the imputed date is 
after the start date; 
otherwise, the 
subsequent year after 
start date will be used. 
Assumed 
medication is 
ongoing; no 
imputation 
11.3 Pooling of Centers in Multi-Center Studies 
As no site-level analyses are planned, there will be no pooling of centers.  
11.4 Multiple Comparisons/Multiplicity 
No adjustments for multiple comparisons or multiplicity will be made.  
11.5 Examination of Subgroups 
Analyses by genotype may be provided. 
12 Interim Analysis and Data Monitoring 
An interim analysis is planned for 23 August 2023, the last day study day prior to the first 
scheduled Bridging Visit (see protocol for more information). The purpose of this 
analysis is to support a regulatory submission to the European Medicines Agency (EMA). 
All efficacy analyses, demographics, medical history, concomitant procedures, prior 
medications, and concomitant medications will be created for this analysis but will only 
include patients that have completed or early discontinued from the study as of 23 August 
2023. The results of this analysis will not be considered for the purposes of modifying the 
study. 
13 Quality Control 
All data displays and analyses will adhere to the International Conference on 
Harmonization (ICH) Harmonized Tripartite Guideline: Structure and Content of 
Clinical Study Reports (ICH Topic E3). 


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All analyses will be performed using SAS® Version 9.4 (or later).
will follow its standard operating procedures in the creation and quality control of all 
tables, listings, figures, and analyses.  Sponsor or its designee will review all tables, 
listings, and figures prior to final database lock. All final SAS programs and associated 
output files will be transferred to Sponsor in agreed-upon format at project completion. 
14 Tables and Listings Conventions 
Mock-ups for statistical tables and listings will be provided.  Final formats for the 
statistical tables and listings may deviate from these mock-ups upon agreement with the 
Sponsor.  Footnotes will be used as needed to clarify the information that is presented in 
the tables and listings.  Unless otherwise requested by the Sponsor, the term ‘patient’ will 
be used in all tables and listings, in accordance with Clinical Data Interchange Standards 
Consortium (CDISC) standards. 
The table and listing mock shells, along with their programming convention, will be 
provided in a separate document.  
15 References
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16 Appendices 
16.1 Schedule of Assessments 
 
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16.2 Changes in Analysis Planned in the Protocol 
Changes in Analysis Planned in the Protocol 
CSP Section 
SAP section 
Description/Rationale of Change 
 
 
 
16.3 Change History 
The table below outlines the changes made to the SAP since the previous version.  
 
 
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