Clinical trial NCT04963231
Conditions: Genetic Obesity
Keywords: Melanocortin-4 Receptor Genetic Obesity Leptin
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2021-11-30; Completion date: 2024-09-30
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the safety and efficacy of once daily subcutaneous (SC) administration of setmelanotide in participants with obesity and specific gene variants in the MC4R pathway.

Detailed description:

Arms: arm 1: Participants received once daily SC injection of setmelanotide from Day 1 to Week 16 in an open-label treatment stage (Stage 1). Participants ≥12 years of age started on setmelanotide 2.0 milligrams (mg) once daily for approximately 2 weeks, then increased to 3.0 mg once daily. Participants \<12 years of age started on setmelanotide 1.0 mg once daily for approximately 1 week, then increased to 2.0 mg once daily for approximately 1 week, then increased to 3.0 mg once daily. arm 2: Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of setmelanotide 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2). arm 3: Participants from Stage 1 who were eligible for Stage 2 received once daily SC injection of matching placebo 3.0 mg from Week 16 to Week 40 in a double-blind treatment Stage (Stage 2).
Interventions: intervention 1: Setmelanotide intervention 2: Placebo
Intervention descriptions: intervention 1: SC injection intervention 2: SC injection

Protocol documents:
Prot_000.pdf: 


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APPROVAL SIGNATURE PAGE 
 
Protocol Title: 
A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-
Controlled Stage), Phase 2 Trial of Setmelanotide in Patients with Specific 
Gene Variants in the Melanocortin-4 Receptor Pathway 
Protocol Number: 
RM-493-034 
Document Version: Version 2.0 (Global) 
Document Date: 
27 July 2022 
 
REVIEWED/APPROVED BY: 
 
 
 
 
  
 
 
Signature 
 
Date 
 
 
28-Jul-2022


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INVESTIGATOR STATEMENT 
 
Protocol Title: 
A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-
Controlled Stage), Placebo-Controlled, Phase 2 Trial of Setmelanotide in 
Patients with Specific Gene Variants in the Melanocortin-4 Receptor 
Pathway 
Protocol Number: 
RM-493-034 
Document Version: Version 2.0 (Global) 
Document Date: 
27 July 2022 
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm, 
the Sponsor) 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’s 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 (IRB)/Independent Ethics Committee (IEC). No changes will be 
made to the trial protocol without the prior written approval of Rhythm and the IRB/IEC, 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 Trial:  
A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled Stage), Phase 2 
Trial of Setmelanotide in Patients with Specific Gene Variants in the Melanocortin-4 Receptor 
Pathway 
Trial center(s): Approximately 80 centers in North America, Europe and the Middle East 
Studied period (years):  
Estimated date first patient enrolled: 4th Quarter (Q4) 2021 
Estimated date last patient completed: Q4 2024 
Phase of development: 2 
Objectives:  
Primary: 
• To evaluate the proportion of patients with obesity with genetic variants in a specific gene in the 
melanocortin-4 receptor (MC4R) pathway who achieve a clinically meaningful reduction in body 
weight in response to setmelanotide at the end of open-label treatment 
Secondary: 
• To evaluate change in weight parameters and hunger in response to setmelanotide in patients with 
genetic variants in a specific gene in the MC4R pathway at the end of open-label treatment  
 
 
 
 
 
  
 
 
 
 
 
 
Safety: 
• To evaluate the safety and tolerability of setmelanotide in patients with genetic variants in the 
MC4R pathway 
Methodology:  
This is a 2-stage (open-label stage followed by a randomized double-blind, placebo-controlled stage) 
Phase 2 trial of setmelanotide in patients with obesity with specific gene variants in the MC4R 
pathway. 


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Screening 
The Screening Period begins with signing the informed consent/assent form and will last between 
2 and 8 weeks. During the Screening Period, patients will undergo all procedures as outlined in the 
Schedule of Assessments (SoA) Stage 1 (Table 1) to determine if they meet the Inclusion and 
Exclusion criteria.  
During the Screening Period, patients will undergo medical evaluation and they or their caregivers 
will receive training on injection of trial medication and other trial procedures. Patients (or their 
caregivers) will be issued an electronic diary to capture daily compliance with injections (post 
enrollment) and hunger score assessments (starting during Screening). 
Stage 1 (Open-Label) 
Stage 1 of the trial begins with the enrollment visit (Study Day 1).  
During the enrollment visit, patients will undergo all procedures as outlined in the SoA Stage 1 
(Table 1), and it will be reconfirmed that the patient continues to meet all Inclusion and no Exclusion 
criteria.  
At the enrollment visit, the trial center must confirm that the patient completed the electronic diary at 
least 4 of 7 days prior to the enrollment visit. If the diary was not completed, the patient may not enter 
the trial. The enrollment visit may be re-scheduled if the remaining visit window allows. 
During the enrollment visit, the patient will have their body weight recorded. This will be the 
patient’s “Baseline Weight.” 
During the enrollment visit, the patient (or caregiver) will receive training on injections of trial 
medication and inject the first dose of setmelanotide under the supervision of the trial staff. In clinic 
doses of trial medication, including the first dose, will be administered following blood sampling for 
pharmacokinetic (PK) analysis. 
During Stage 1, the patient (or caregiver) will administer setmelanotide on a daily basis for 16 weeks. 
During this period, the patient will have in-person as well as virtual visits with the trial center using a 
validated Telehealth platform. During the virtual visits, the patient (or caregiver) will record a body 
weight measurement and be assessed for compliance with trial procedures and adverse events (AEs). 
Any visit that is planned as a virtual visit may be converted to an in-person visit at the discretion of 
the Investigator. If more than 2 virtual visits are to be converted into in-person visits, Sponsor 
approval is required. 
To be eligible to enter Stage 2 of the trial, a patient: 
• 
≥18 years old must have achieved a body mass index (BMI) at least 3% less than the Baseline 
BMI at the end of Stage 1 
• 
<18 years old must have achieved a BMI at least 3% less than the Baseline BMI or a decrease 
in BMI Z-score of at least 0.05 at the end of Stage 1 
If the patient completed the full 16 weeks of Stage 1 and at the Day 112 visit (Week 16) the patient 
has not achieved the required change from baseline in BMI or BMI Z-score (for patients <18 years), 
instead of the Stage 2 Entry Visit, the site will perform the End-of-Treatment (EOT) Visit for this 
patient. These patients will end treatment with setmelanotide and continue to be monitored for 
resolution of any ongoing serious adverse events (SAEs) with virtual visits once every 4 weeks until 
all SAEs have resolved. 
Stage 2 (Randomized Double-Blind, Placebo-Controlled Stage) 
Patients who enter Stage 2 will continue in the trial for an additional 24 weeks. Stage 2 of the trial 
will begin with the Stage 2 Entry Visit. During the Stage 2 Entry Visit, the patient will complete all 
assessments as per the SoA Stage 2 (Table 2). The patient will have a body weight recorded. This 


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measurement will be their Stage 2 Entry Weight Measurement. In clinic doses of trial medication will 
be administered following blood sampling for PK analysis. 
At the Stage 2 Entry Visit, all eligible patients will be randomized 2:1 to either continue daily 
setmelanotide or receive matching placebo. Stratification by gene will be implemented for specific 
genes that are enrolled into this trial as determined by the Sponsor. 
Patients will continue to have virtual visits and in-person clinic visits as per the SoA for Stage 2 
(Table 2).  
At the Investigator’s discretion, either (1) additional virtual or in-person visits may be scheduled or 
(2) planned virtual visits may be converted to in-person visits. If more than 2 virtual visits are to be 
converted into in-person visits, Sponsor approval is required. 
End of Treatment/End of Trial 
The EOT Visit will occur as an in-person clinic visit on Study Day 112 for patients who complete 
only Stage 1 or on Study Day 280, which is the final day of treatment with setmelanotide or placebo 
for patients who complete Stage 2. A final End of Study (EOS) Visit will occur 4 weeks after the 
EOT visit. The EOS Visit will be conducted via telephone. At the end of Stage 2, patients may be 
offered the option of enrolling into a long-term extension (LTE) trial. If required by local regulation 
or if deemed necessary to assess patient safety by physical examination or after a longer follow-up 
period, the EOS Visit may be converted to an in-person visit, and/or can occur up to Week 48. 
Switch to Treatment with Setmelanotide 
During Stage 2 of the trial, patient weight will be monitored as per the SoA Stage 2 (Table 2). 
Additional virtual visits may be scheduled at the discretion of the Investigator. 
Regardless of treatment assignment, patients will be offered to start open-label treatment with 
setmelanotide if, during a visit, a patient’s BMI has increased by at least 5% from the Stage 2 Entry 
Weight. Open-label treatment will be offered via enrollment in a separate LTE trial or, if the LTE trial 
is not available, via bridging visits until the LTE trial is available. 
To be eligible, a patient must be scheduled for an in-person visit at the clinic. At the visit, the 
patient’s body weight will be recorded. If the visit occurs within 2 weeks of an expected trial visit as 
per the SoA Stage 2 (Table 2), then the visit may replace that expected trial visit. All procedures as 
outlined in the SoA Stage 2 for the expected trial visit should occur. At this visit, the patient will 
return their double-blind trial medication supply. The patient may then be enrolled into the LTE trial 
or will be issued open-label setmelanotide and will continue in the trial via bridging visits until the 
LTE trial is available. The patient’s initial assignment to either trial medication or placebo will 
continue to be blinded to all parties. 
Ensuring Diversity of Genes 
A patient must have a pre-identified genetic variant in an established MC4R pathway gene that 
contributes to obesity to enroll in this trial. A list of genes that have variants that are eligible for 
enrollment into the trial is provided in Appendix 1. Gene variant enrollment by gene is at the 
discretion of the Sponsor. 
The trial aims to enroll up to 10 patients with each gene into the trial. Enrollment will be monitored 
by the Sponsor and further enrollment of patients with a genotype may be paused once approximately 
10 patients with that particular gene have been enrolled.  
Patient response to setmelanotide by gene will be monitored by the Sponsor during the open-label 
portion of the trial in 2 ways: the rate of patients qualifying for Stage 2 of the trial and the magnitude 
of response to setmelanotide. The Sponsor may increase or decrease the target number of patients 


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enrolled with a particular gene or may close any individual gene cohort after assessment of lack 
efficacy on 3 or more patients. The total sample size of the trial will not be increased. 
Number of patients (planned):  
Approximately 100 to 200 patients will be enrolled into this trial.  
Diagnosis and main criteria for inclusion: 
Inclusion Criteria: 
1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that 
contributes to obesity. 
Note: Genetic testing requirements and a list of genes which have variants that are eligible for 
enrollment into the trial are provided in Appendix 1.  
2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or 
Assent.  
3. Patients with obesity, defined as BMI ≥40 kg/m2 for patients ≥18 years of age or BMI ≥97th 
percentile for age and gender for patients 6 to <18 years of age based on the United States (US) 
Centers for Disease Control and Prevention criteria. 
4. Patient and/or parent or guardian 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 informed 
consent/assent. Patients who are unable to comply with all trial procedures due to cognitive 
limitations or any other reason should not be enrolled. 
5. Patient must meet one of the following requirements: 
Female participants of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy), must be confirmed non-pregnant and agree to use a highly effective form 
of contraception throughout the trial and for 90 days following the trial.  
Highly effective forms of contraception are detailed below and in Section 8.9.7:  
• 
Combined (estrogen and progestin) hormonal contraception associated with inhibition of 
ovulation (i.e., oral, intravaginal, or transdermal) 
• 
Progestin-only hormonal contraception associated with inhibition of ovulation (oral, 
implantable, or injectable) 
• 
Intrauterine device (IUD) 
• 
Intrauterine hormone-releasing system 
• 
Bilateral tubal occlusion 
• 
Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the female participant, and the vasectomized partner has received medical 
assessment of surgical success) 
• 
Sexual abstinence, only if it is the preferred and usual lifestyle of the patient 
Female participants of non-childbearing potential, defined as: permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at least 
12 months (and confirmed with a screening follicle-stimulating hormone level in the post-
menopausal lab range) and do not require contraception during the trial. 
Younger female patients who have not achieved sexual maturity at trial entry will be assessed for 
Tanner staging and required to comply with contraception requirements at first menarche. 


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Male participants with female partners of childbearing potential must agree to use a highly 
effective method contraception if they become sexually active during the trial or within 90 days 
following their participation in the trial. Male patients must also not donate sperm during and for 
90 days following their participation in the trial. 
6. Symptoms or behaviors of hyperphagia persistent during the patient’s life, including 
manifestations in childhood, as determined by the Investigator at screening. 
Exclusion Criteria: 
1. Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic 
Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants 
in MC4R, pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1), 
leptin receptor (LEPR), nuclear receptor coactivator 1 (NCOA1; steroid receptor coactivator-1 
[SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as well as 16p11.2 
chromosomal deletions that include the SH2B1 gene. 
2. Weight loss >2% in the previous 3 months.  
Patients will not be excluded for using regimens for weight maintenance or to prevent weight 
gain, such as dietary and/or exercise regimens, or medications, supplements or herbal treatments 
(e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide-1 
[GLP-1] receptor agonists, etc.), provided: 
• 
the regimen and/or dose has been stable for at least 3 months prior to randomization 
• 
the patient has not experienced weight loss >2% during the previous 3 months, AND 
• 
the patient intends to keep the regimen and/or dose stable throughout the course of the trial. 
3. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric balloon, 
intestinal barrier, etc.) within the last 6 months. All patients with a history of bariatric surgery or 
procedures must be discussed with, and receive approval from, the Sponsor prior to enrollment. 
4. Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major depressive 
disorder, bipolar disorder, schizophrenia, etc.) or documented worsening psychiatric condition 
that required changes in treatment regimen within the previous 2 years, or other psychiatric 
related risks that the Investigator believes may interfere with trial compliance or patient safety.  
5. Clinically significant depression or suicidality, as defined by: any suicidal ideation of type 4 or 5 
on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt 
during the patient’s lifetime, any suicidal behavior in the last month, or a Patient Health 
Questionnaire-9 (PHQ-9) score of ≥15 during Screening process. 
Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant 
neurocognitive impairment may be enrolled in the trial provided that there are no clinical signs or 
symptoms of significant depression or suicidal behavior in the opinion of the Investigator. 
6. Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic 
disease considered severe enough to interfere with the trial and/or confound the results. Any 
patient with a potentially clinically significant disease should be reviewed with the Sponsor to 
determine eligibility. 
7. Significant features of, or meeting the diagnostic criteria for, a genetic syndrome that is 
associated with obesity. 
Note: Although some of the genetic variants that are eligible to be enrolled into this trial are 
associated with specific syndromes, the intent of this trial is not to enroll children with significant 
cognitive impairment or other significant co-morbidities. Patients with eligible genetic variants, 
but who otherwise do not exhibit the syndrome, are eligible for enrollment. 
8. Glycated hemoglobin (HbA1C) >10.0% at Screening. 


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9. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or 
nonalcoholic steatohepatitis (NASH). Patients with NAFLD or NASH will not be excluded based 
on this criterion 
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at Screening. In patients 
≥18 years of age the Modification of Diet in Renal Disease (MDRD) Equation should be used to 
calculate eGFR. In patients <18 years of age, the Bedside Schwartz Equation should be used for 
calculation of GFR. 
11. History or close family history (parents or siblings) of melanoma, or patient history of 
oculocutaneous albinism. 
Note: If the type of skin cancer in patient’s or close family history is not known, then the patient 
should not be enrolled into the trial. 
12. 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. If any concerning lesions are 
identified during Screening, the patient should be referred to a dermatologist. 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. 
13. Patient is, in the opinion of the Investigator, not suitable to participate in the trial. 
14. Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-
lives, whichever is longer, prior to the first day of dosing. 
15. Patients previously enrolled in a clinical trial involving setmelanotide or any previous exposure to 
setmelanotide. 
16. Hypersensitivity to the active substance or to any of the excipients of the investigational 
medicinal products (active and placebo). 
17. Females who are pregnant or breastfeeding, or planning or desiring to become pregnant during 
the duration of the trial. 
18. Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article of 
the Public Health code in France). 
19. For France only: patient is <18 years of age. 
Investigational product, dosage and mode of administration: 
Investigational product: Setmelanotide, 10 mg/mL in a sterile solution for injection.  
Dosage:  
Patients 12 years of age and older: Setmelanotide 2 mg QD for approximately 2 weeks, then increased 
to setmelanotide 3 mg QD for the remainder of the trial. Note: if the starting dose of setmelanotide is 
not tolerated reduce to 1 mg QD; the lowest target dose in patients ≥12 years of age is 1.0 mg QD; 
however, in consultation with the Medical Monitor, the dose may be lowered to 0.5 mg QD if not 
tolerated. 
Patients 6 to <12 years of age: Setmelanotide 1 mg QD for approximately 1 week, then increased to 
setmelanotide 2 mg QD for approximately 1 week, then increased to setmelanotide 3 mg QD for the 
remainder of the trial. Note: if the starting dose of setmelanotide is not tolerated reduce to 0.5 mg QD; 
the lowest target dose in patients 6 to <12 years of age is 0.5 mg QD. 
Mode of administration: Subcutaneous (SC) injection 


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Duration of treatment:  
Total treatment with trial medication will be up to 40 weeks. Total participation in the trial will last 
up to 52 weeks, including the Screening Period and the EOS Visit. 
Reference therapy, dosage, and mode of administration:  
Reference product: Placebo (vehicle) in a sterile solution for injection.  
Dosage: Placebo QD (titrated in the same manner as active treatment) 
Mode of administration: SC injection 
Criteria for evaluation: 
Primary Endpoint: 
• 
The proportion of patients by genotype who demonstrate a significant clinically meaningful 
response (defined below) to setmelanotide at the end of Stage 1: 
− 
For all patients: achieving a ≥5% reduction in BMI from Baseline 
Secondary Endpoints:  
• 
Mean change and percent change in BMI from Baseline to end of Stage 1 in all patients and 
patients ≥18 years old, per gene 
• 
Mean change and percent change in body weight from Baseline to end of Stage 1 in patients 
≥18 years old, per gene 
• 
Mean change in BMI Z-score from Baseline to end of Stage 1 in patients <18 years old, per gene 
• 
Mean percent change in the weekly average of the daily maximal hunger score from Baseline to 
end of Stage 1 in patients ≥12 years old, per gene 
• 
The proportion of patients ≥12 years old, per gene, who achieve a ≥2-point reduction 
(improvement) from Baseline to end of Stage 1 in the weekly average of the daily maximal 
hunger score. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


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Statistical methods:  
The primary efficacy endpoint is the proportion of patients by genotype who demonstrate a significant 
clinically meaningful response (defined below) to setmelanotide at the end of Stage 1:  
• 
For all patients: ≥5% reduction in BMI from Baseline 
The trial is a 2-stage design: Stage 1 is open-label treatment, and Stage 2 is randomized, double-blind, 
placebo-controlled.  
The 95% exact confidence interval will be provided for the primary efficacy endpoint. The analyses 
of the efficacy endpoints in Stage 1 will be performed based on the safety analysis set, and the 
analyses of the efficacy endpoints in Stage 2 will be performed based on the full analysis set (FAS).  
AEs/SAEs will be summarized with frequencies and percentages. A by-patient AE data listing 
including onset and resolution dates, verbatim term, preferred term, treatment, severity, relationship 
to treatment, action taken, and outcome will be provided.  
Safety data including laboratory evaluations and vital signs assessments will be summarized by time 
of collection. In addition, change from baseline to any post-dose values will be summarized for vital 
signs and clinical laboratory results. Frequency of patients with abnormal safety laboratory results 
will be tabulated. 
All safety analyses and summary tables will be based on the safety analysis set. 
 
 


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2. 
SCHEDULE OF ASSESSMENTS 
Table 1: 
Schedule of Assessments – Stage 1 
Assessment 
Screening  
(In-Person) 
Enrollment 
Visit (IP) 
Phone 
Call† 
Virtual Trial Visits 
In-Person  
Trial Visits 
Early Termination 
Visit (In-Person) 
Visit Number 
 
V1 
V1c 
V2, V3, V4, V6 
V5, V7 
 
Study Week 
 
 
1 
2, 4, 6, 12,  
8, 16 
 
Study Day 
-56 to -14 
1 
7 
14*, 28, 42, 84 
56, 112 
 
Window 
 
 
+/-2 
+/-3 
+/-5 
+/-5 
Informed Consent/Assent (1) 
X 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
 
 
 
 
Genetic Sample (2) 
X 
X 
 
 
 
 
Optional WES (3) 
X 
X 
 
 
 
 
Medical History 
X 
X 
 
 
 
 
Nutrition and physical activity 
counseling and follow-up 
 
X 
X 
X 
X 
 
Physical Exam (4) 
X 
X 
 
 
X 
X 
Fitzpatrick Classification Scale 
X 
 
 
 
 
 
Comprehensive Skin Exam (5) 
X 
 
 
 
X 
X 
Weight (6) 
X 
X 
 
X 
X 
X 
Height (7) 
X 
X 
 
 
X 
X 
Vital Signs (9) 
X 
X 
 
X 
X 
X 
ECG (10) 
X 
 
 
 
X 
X 
Pregnancy (11) 
X 
X 
 
X 
X 
X 
Hunger Questions (12) 
X 
X 
 
X 
X 
X 


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Table 1: 
Schedule of Assessments – Stage 1 
Assessment 
Screening  
(In-Person) 
Enrollment 
Visit (IP) 
Phone 
Call† 
Virtual Trial Visits 
In-Person  
Trial Visits 
Early Termination 
Visit (In-Person) 
Visit Number 
 
V1 
V1c 
V2, V3, V4, V6 
V5, V7 
 
Study Week 
 
 
1 
2, 4, 6, 12,  
8, 16 
 
Study Day 
-56 to -14 
1 
7 
14*, 28, 42, 84 
56, 112 
 
Window 
 
 
+/-2 
+/-3 
+/-5 
+/-5 
Global Hunger Questions (15) 
 
X 
 
X (14) 
X 
X 
C-SSRS (16) 
X 
X 
 
X 
X 
X 
PHQ-9 (23) 
X 
X 
 
X 
X 
X 
CDI-2 (24) 
X 
X 
 
X 
X 
X 
Adverse Events 
X 
X 
X 
X 
X 
X 
Injection Site Inspection 
 
X 
 
X 
X 
X 
Concomitant Medication Review
X 
X 
X 
X 
X 
X 
Safety Laboratory Tests (17) 
X 
 
 
 
X 
X 
Trough PK (18) 
 
X 
 
 
X 
X 
Anti-Drug Antibodies (19) 
X 
 
 
 
X 
X 
Biomarkers (20) 
 
X 
 
 
X 
X 
Daily Drug Compliance (21) 
 
X 
 
X 
X 
 


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Table 1: 
Schedule of Assessments – Stage 1 
Assessment 
Screening  
(In-Person) 
Enrollment 
Visit (IP) 
Phone 
Call† 
Virtual Trial Visits 
In-Person  
Trial Visits 
Early Termination 
Visit (In-Person) 
Visit Number 
 
V1 
V1c 
V2, V3, V4, V6 
V5, V7 
 
Study Week 
 
 
1 
2, 4, 6, 12,  
8, 16 
 
Study Day 
-56 to -14 
1 
7 
14*, 28, 42, 84 
56, 112 
 
Window 
 
 
+/-2 
+/-3 
+/-5 
+/-5 
Dispense/Return Trial 
medication (22) 
 
X 
 
X 
X 
X 
Abbreviations: ADA = anti-drug antibodies; CDI-2 = Children’s Depression Inventory -2; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; 
 IP = In Person; 
 
; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetic; QoL = quality of life; WES = Whole Exome Sequencing. 
† A phone visit should occur on Day 7 (±2 days) for all patients <12 years of age; at this visit dose escalation should occur from 1 to 2 mg once daily (QD). 
* Dose escalation (from 2 mg QD to 3 mg QD) should occur at the trial visit planned for Day 14 (±3 days) and should occur on the day of that visit. 
NOTE: Additional assessments may be performed at the Investigator’s discretion as needed to ensure patient safety. 
1 
Although the trial procedures and assessments required per protocol are classified as “No or Minimal Risk” according to the 2008 Guidance Document 
“Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Pediatric Population,” considerations for reducing pain and distress in 
patients younger than 18 years of age are included in Appendix 2. 
2 
Patients will have a sample collected for confirmatory genetic testing either during Screening or at the Enrollment visit; this only needs to be completed 
1 time. The Sponsor may waive this requirement for individual patients who have a genetic sample analysis from certain testing laboratories.  
3 
All patients will be offered the opportunity to opt-in to having WES performed; a separate blood sample is not required (testing to be completed from 
confirmatory genetic sample collected either during Screening or at the Enrollment visit).  
4 
A complete physical examination will be conducted at Screening and at Visit 7 or the early termination (ET) visit and include review of peripheral lymph 
nodes, head, eyes (including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, lungs, abdomen, musculoskeletal including back, extremities and 
neurologic. At other time points, 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. In addition, Tanner Staging for assessment of pubertal 
development will be conducted for those patients who have yet to reach Tanner Stage V. Whenever possible, the same trained health care professional will 
conduct the examination and Tanner Staging.  
5 
A comprehensive skin evaluation will be performed by the Investigator or designee. The skin examination should include a full body skin examination (head-
to-toe skin examination). If any concerning lesions are identified during Screening, the patient should be referred to a dermatologist. Any concerning lesions 
identified during the Screening Period will be biopsied and results known to be benign prior to first dose of setmelanotide. If the pre-treatment biopsy results 
are of concern, the patient may be excluded from the trial. Additionally, any lesion or significant change in an existing lesion 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) 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 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 


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measurements will be recorded to the nearest 10th of a Kg if reported with a digital scale, or half Kg with a mechanical scale. Whenever possible, the scale 
should be calibrated on a regular basis per manufacturer’s specifications.  
7 
For patients ≥21 years of age, height is to be measured at Screening only. For patients aged <21 years, height is to be measured at the time points listed in the 
SoA. 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.  
 
 
 
 
9 
All vital signs measurements are to be obtained in the sitting position following at least 5 minutes of rest. All measurements will be taken in triplicate, 
approximately 2 minutes apart. When possible, blood pressure (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. For virtual visits, patients will be instructed on the proper use of 
and will be provided with WiFi/Bluetooth connected devices for measuring and transmitting data on blood pressure, and temperature during virtual trial 
visits. The data are stored and automatically transferred when connected to WiFi. 
10 A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest. 
11 A urine pregnancy test may be performed to expedite availability of results prior to dosing on Day 1. Except for virtual visits, all other pregnancy tests will be 
serum tests; dosing may continue with results pending. At sites where pregnancy tests are required for virtual visits, at Visit 1 women of child-bearing 
potential will be given urine pregnancy kits for use at each of the virtual visits. 
 
 
 
 
 
 
  
 
 
14 Assessments will only be performed at Study Weeks 4, 8, and 12. 
 
 
 
 
16 The Baseline/Screening version of the scale is the initial form of the instrument to assess suicidality in a patient’s lifetime and is administered at Screening. In 
order to be eligible for the trial, a patient at Screening cannot have a suicidal ideation of type 4 or 5, a suicide attempt during the patient’s lifetime, or any 
suicidal behavior in the last month, as per the C-SSRS. After Screening, the ‘Since Last Visit’ version of the scale will be used to assess suicidality since the 
patient’s last visit. If at any time during the trial a patient has a suicidal ideation of type 4 or 5, or any suicidal behavior, the patient should be referred to a 
mental health professional (MHP).  
17 Safety laboratory tests will include: Complete blood count (CBC) with platelet count and standard indices, chemistry panel (includes sodium, potassium, 
chloride, CO2, albumin, total protein, glucose, blood urea nitrogen [BUN], creatinine (including eGFR), 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), and urinalysis with microscopic analysis if positive findings on dipsticks warrant further examination. Safety 


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laboratories will also include a coagulation profile (prothrombin time [PT] or international normalized ratio [INR], and partial thromboplastin time [PTT] also 
referred to as activated PTT [aPTT]). 
18 A blood sample for PK will be drawn at the time points indicated before dosing, with dosing performed at the clinic. PK samples will be drawn with 
patients/caregivers being reminded there should be NO trial medication administration at home on the day of clinic visits; the drug will be administered in the 
clinic by the patient AFTER the PK sample is obtained. For the PK sample, the actual collection (clock) time will be recorded. 
19 Any patient with a positive ADA will be followed every 3 months after the ADA sample analysis until resolution of the ADA. 
20 A biomarker blood sample will be collected for metabolic, inflammation, metabolomic and/or proteomic biomarker analysis. This sample may not be 
analyzed. All samples are sent to a central laboratory. Additional details are described in the laboratory manual.  
21 A daily question querying whether the patient completed their daily injection will be asked via electronic diary. Paper versions can be used, if needed. 
22 Dispensing will be made by site staff, using the dispensation function in the Interactive Response Technology (IRT) system, as outlined in the SoA. 
Dispensing may also be made directly to the patient if required and allowed by local regulations. At the Early Termination visit, only drug return will apply. 
23 If at any time during the trial an individual patient’s PHQ9 score is ≥10, the patient should be referred to a Mental Health Professional.  
24 The CDI-2 will be administered to patients <12 years of age (self-report short form) and to caregivers of patients <12 years of age (parent version). 
 


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Table 2: 
Schedule of Assessments – Stage 2 
Assessment 
Stage 2 
Entry Visit† 
(In-Person) 
Virtual Trial 
Visits 
In-Person 
Clinic Visits 
End of 
Treatment Visit 
(In-Person) 
End-of-Study 
Visit 
(Telephone) 22 
Early 
Termination 
Visit (In-Person) 
Bridging Visits  
(if needed) 
(In-Person) 
Visit Number 
V7 
V8, V9, V11, 
V13 
V10, V12 
V14 
V15 
 
 
Study Week 
16 
18, 20, 28, 36 
24, 32 
40 
44 
 
Q12 weeks 
Study Day 
112 
126, 140, 
196, 252 
168, 224 
280 
 
 
 
Window (1) 
 
+/-3  
+/- 5 
+/- 5 
+/-3 
 
+/- 5 
Nutrition and physical activity 
counseling and follow-up 
X 
X 
X 
X 
 
 
X 
Physical Exam (2) 
X 
 
 
X 
X 
X 
X 
Comprehensive Skin Exam (3) 
X 
 
 
X 
X 
X 
X 
Vital Signs (7) 
X 
X 
X 
X 
 
X 
X 
ECG (8) 
X 
 
 
X 
 
X 
X 
Pregnancy (9) 
X 
X 
X 
X 
 
X 
X 
C-SSRS (14) 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 (21) 
X 
X 
X 
X 
X 
X 
X 
CDI-2 (23) 
X 
X 
X 
X 
X 
X 
X 


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Table 2: 
Schedule of Assessments – Stage 2 
Assessment 
Stage 2 
Entry Visit† 
(In-Person) 
Virtual Trial 
Visits 
In-Person 
Clinic Visits 
End of 
Treatment Visit 
(In-Person) 
End-of-Study 
Visit 
(Telephone) 22 
Early 
Termination 
Visit (In-Person) 
Bridging Visits  
(if needed) 
(In-Person) 
Visit Number 
V7 
V8, V9, V11, 
V13 
V10, V12 
V14 
V15 
 
 
Study Week 
16 
18, 20, 28, 36 
24, 32 
40 
44 
 
Q12 weeks 
Study Day 
112 
126, 140, 
196, 252 
168, 224 
280 
 
 
 
Window (1) 
 
+/-3  
+/- 5 
+/- 5 
+/-3 
 
+/- 5 
Randomization 
X 
 
 
 
 
 
 
 
 
Adverse events 
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 
Safety Laboratory Tests (15) 
X 
 
X 
X 
 
X 
X 
Trough PK (16) 
X 
 
X 
X 
 
X 
X 
Anti-Drug Antibodies (17) 
X 
 
 
X 
 
X 
X 
Biomarkers (18) 
X 
 
 
X 
 
X 
X 
Daily drug compliance (19) 
X 
X 
X 
X 
 
 
X 
Dispense/Return Trial 
medication (20) 
X 
 
X 
X 
 
X 
X 


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Abbreviations: ADA = anti-drug antibodies; CDI-2 = Children’s Depression Inventory -2; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; EOS = end of study; EOT = end of treatment; 
; 
; 
PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetic; Q = every. 
† The Stage 2 Entry visit is the same visit as the final visit from Stage 1. 
NOTE: Additional assessments may be performed at the Investigator’s discretion as needed to ensure patient safety. 
1 
For patients who qualify for Stage 2 at the Week 16 visit in Stage 1, the Stage 2 Baseline Visit (B1) is the same as Week 16 in Stage 1.  
2 
A complete physical examination will be conducted at the Stage 2 entry visit and at the End-of-Treatment Visit. At other time points, 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. In addition, Tanner Staging for assessment of pubertal development will be conducted for those patients who 
have yet to reach Tanner Stage V. Whenever possible, the same trained health care professional will conduct the examination and Tanner Staging. 
Assessment to be performed at Visit 15 only if that is an in-person visit. 
3 
A comprehensive skin evaluation will be performed by the Investigator or designee. The skin examination should include a full body skin examination (head-
to-toe skin examination). Any lesion or significant change in an existing lesion during the course of the trial must be evaluated by a dermatologist and 
biopsied, if clinically indicated in the opinion of the dermatologist. Assessment to be performed at Visit 15 only if that is an in-person visit. 
 
 
 
 
 
  
 
  
 
 
 
 
7 
All vital signs measurements are to be obtained in the sitting position following at least 5 minutes of rest. All measurements will be taken in triplicate, 
approximately 2 minutes apart. When possible, blood pressure (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. For virtual visits, patients will be instructed on the proper use of 
and will be provided with WiFi/Bluetooth connected devices for measuring and transmitting data on blood pressure, and temperature during virtual trial 
visits. The data are stored and automatically transferred when connected to WiFi. 
8 
A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest. 
9 
Except for virtual visits, all other pregnancy tests will be serum tests; dosing may continue with results pending. At sites where pregnancy tests are required 
for virtual visits, at Visit 7 women of child-bearing potential will be given urine pregnancy kits for use at each of the virtual visits. 
 
 
 
 
 
 


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12 Assessments will only be performed at Study Weeks 20, 28, and 36. 
 
 
 
14 The ‘Since Last Visit’ version of the scale will be used to assess suicidality since the last time the C-SSRS was administered. If at any time during the trial a 
patient has a suicidal ideation of type 4 or 5, or any suicidal behavior, the patient should be referred to a mental health professional (MHP).  
15 Safety laboratory tests will include: Complete blood count (CBC) with platelet count and standard indices, chemistry panel (includes sodium, potassium, 
chloride, CO2, albumin, total protein, glucose, blood urea nitrogen [BUN], creatinine (including eGFR), 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), and urinalysis with microscopic analysis if positive findings on dipsticks warrant further examination. Safety 
laboratories will also include a coagulation profile (prothrombin time [PT] or international normalized ratio [INR], and partial thromboplastin time [PTT] also 
referred to as activated PTT [aPTT]). 
16 A blood sample for PK will be drawn at the time points indicated before dosing, with dosing performed at the clinic. PK samples will be drawn with 
patients/caregivers being reminded there should be NO trial medication administration at home on the day of clinic visits; the drug will be administered in the 
clinic by the patient AFTER the PK sample is obtained. For the PK sample, the actual collection (clock) time will be recorded. 
17 Any patient with a positive ADA will be followed every 3 months after the ADA sample analysis until resolution of the ADA. 
18 A biomarker blood sample will be collected for metabolic, inflammation, metabolomic and/or proteomic biomarker analysis. This sample may not be 
analyzed. All samples are sent to a central laboratory. Additional details are described in the laboratory manual.  
19 A daily question querying whether the patient completed their daily injection will be asked via electronic diary. Paper versions can be used, if needed. 
20 Dispensing will be made by site staff, using the dispensation function in the Interactive Response Technology (IRT) system, as outlined in the SoA. 
Dispensing may also be made directly to the patient if required and allowed by local regulations. At the Early Termination visit, only drug return will apply. 
21 If at any time during the trial an individual patient’s PHQ9 score is ≥10, the patient should be referred to a Mental Health Professional.  
22 If required by local regulation or if deemed necessary to assess patient safety by physical examination or after a longer follow-up period, the visit may be 
converted to an in-person visit and/or can occur up to Day 336 (Week 48). If the EOS visit is converted to an in-person visit, a physical examination and a 
comprehensive skin examination should be completed at that in-person visit. Patients who enroll in the long-term extension trial will have the EOS visit at the 
same time as the EOT visit. 
23 The CDI-2 will be administered to patients <12 years of age (self-report short form) and to caregivers of patients <12 years of age (parent version).  


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TABLE OF CONTENTS 
 ......................................................................2 
APPROVAL SIGNATURE PAGE .................................................................................................5 
INVESTIGATOR STATEMENT ...................................................................................................6 
1. 
SYNOPSIS ...................................................................................................................7 
2. 
SCHEDULE OF ASSESSMENTS.............................................................................15 
TABLE OF CONTENTS ...............................................................................................................24 
LIST OF TABLES .........................................................................................................................27 
LIST OF FIGURES .......................................................................................................................27 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................28 
3. 
INTRODUCTION ......................................................................................................32 
3.1. 
Setmelanotide .............................................................................................................32 
3.2. 
Benefit/Risk Assessment ............................................................................................33 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................35 
5. 
INVESTIGATIONAL PLAN .....................................................................................37 
5.1. 
Overall Trial Design ...................................................................................................37 
5.1.1. 
Screening Period .........................................................................................................37 
5.1.2. 
Stage 1 (Open-Label) ..................................................................................................38 
5.1.3. 
Stage 2 (Randomized, Double-Blind, Placebo-Controlled Stage) ..............................38 
5.1.3.1. 
End of Treatment and End of Study ...........................................................................39 
5.1.3.2. 
Switch to Treatment with Setmelanotide ....................................................................39 
5.1.3.3. 
Trial, Site, or Cohort Suspension or Termination.......................................................39 
5.1.4. 
Genetic Diversity ........................................................................................................40 
5.1.5. 
Trial Conduct During the COVID-19 (Coronavirus) Pandemic.................................40 
5.2. 
Patient and Trial Completion ......................................................................................42 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................42 
6.1. 
Patient Inclusion Criteria ............................................................................................42 
6.2. 
Patient Exclusion Criteria ...........................................................................................43 
6.3. 
Treatment Discontinuation and Withdrawal from the Trial .......................................45 
6.4. 
Lost to Follow-up .......................................................................................................46 
6.5. 
Lifestyle Counseling ...................................................................................................46 
6.5.1. 
Physical Activity .........................................................................................................46 


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6.5.2. 
Nutrition ......................................................................................................................47 
6.5.3. 
Skin Protection ............................................................................................................47 
7. 
TREATMENT OF PATIENTS ..................................................................................47 
7.1. 
Description of Trial Medication .................................................................................47 
7.2. 
Randomization, Blinding, and Unblinding .................................................................48 
7.2.1. 
Stage 1 ........................................................................................................................48 
7.2.2. 
Stage 2 ........................................................................................................................48 
7.2.3. 
Blinding and Unblinding ............................................................................................48 
7.3. 
Administration ............................................................................................................49 
7.4. 
Drug Interruption and Stopping Rules ........................................................................49 
7.5. 
Treatment Compliance ................................................................................................50 
7.6. 
Preparation/Handling/Storage/Accountability ............................................................50 
7.7. 
Concomitant Medications ...........................................................................................50 
8. 
ASSESSMENTS.........................................................................................................51 
8.1. 
Informed Consent / Assent .........................................................................................51 
8.2. 
Inclusion/Exclusion Review .......................................................................................52 
8.3. 
Demographics, Concomitant Medications and Medical History ................................52 
8.4. 
Height .........................................................................................................................52 
8.5. 
Fitzpatrick Scale .........................................................................................................52 
8.6. 
Pharmacokinetic Assessments ....................................................................................52 
8.7. 
Efficacy Assessments .................................................................................................53 
8.7.1. 
Weight .........................................................................................................................53 
. 
.................................................................................................53 
 
 ............................................................................................53 
. 
.......................................................................................................53 
 
..........................................................................................54 
 
................................................................54 
 
..........................................................55 
 
 .................................................................................................56 
8.7.6. 
Biomarkers ..................................................................................................................56 
8.8. 
Nutrition and Physical Activity Counseling and Follow-Up ......................................56 
8.9. 
Safety Assessments .....................................................................................................56 
8.9.1. 
Vital Signs ..................................................................................................................56 


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8.9.2. 
Physical Examination .................................................................................................57 
8.9.3. 
Comprehensive Skin Examination .............................................................................57 
8.9.4. 
Electrocardiogram .......................................................................................................57 
8.9.5. 
Laboratory Assessments .............................................................................................57 
8.9.6. 
Anti-Drug Antibodies (ADA) .....................................................................................58 
8.9.7. 
Pregnancy and Contraception .....................................................................................58 
8.9.8. 
Injection Site Examination .........................................................................................59 
8.9.9. 
Suicidal Ideation and Depression Monitoring ............................................................60 
8.9.9.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................60 
8.9.9.2. 
Patient Health Questionnaire -9 (PHQ-9) ...................................................................61 
8.9.9.3. 
Children’s Depression Inventory-2 .............................................................................61 
8.9.10. 
Overdose .....................................................................................................................61 
8.9.11. 
Adverse and Serious Adverse Events .........................................................................62 
8.9.11.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................62 
8.9.11.2. 
Method of Detecting AEs and SAEs ..........................................................................62 
8.9.11.3. 
Follow-up of AEs and SAEs .......................................................................................62 
8.9.11.4. 
Regulatory Reporting Requirements for SAEs ...........................................................63 
9. 
SAFETY DATA MONITORING ..............................................................................63 
10. 
STATISTICS ..............................................................................................................63 
10.1. 
Sample Size Determination ........................................................................................64 
10.2. 
Populations for Analyses ............................................................................................64 
10.3. 
Statistical Analyses .....................................................................................................64 
10.3.1. 
Interim Analyses .........................................................................................................64 
11. 
LIST OF REFERENCES ............................................................................................65 
12. 
APPENDICES ............................................................................................................66 
APPENDIX 1. LIST OF GENES ELIGIBLE FOR ENROLLMENT AND GENETIC 
TESTING REQUIREMENTS ....................................................................................67 
APPENDIX 2. CONSIDERATIONS FOR REDUCING PAIN AND DISTRESS IN 
THE PEDIATRIC POPULATION .............................................................................69 
APPENDIX 3. FITZPATRICK SCALE.....................................................................................70 
APPENDIX 4. INJECTION SITE EVALUATIONS .................................................................71 
APPENDIX 5. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................72 


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APPENDIX 6. GUIDANCE ON TRIAL CONDUCT DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC ...............................................................................77 
APPENDIX 7. TRIAL GOVERNANCE CONSIDERATIONS ................................................79 
APPENDIX 8. DEVICES USED FOR VIRTUAL VISITS .......................................................84 
 
LIST OF TABLES 
Table 1: 
Schedule of Assessments – Stage 1 ............................................................................15 
Table 2: 
Schedule of Assessments – Stage 2 ............................................................................20 
Table 3: 
Objectives and Endpoints ...........................................................................................35 
 
LIST OF FIGURES 
Figure 1: 
Trial Design ................................................................................................................41 
 
  


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
α-MSH 
alpha-melanocyte-stimulating hormone 
ACC 
American College of Cardiology 
ACMG 
American College of Medical Genetics 
ADA 
Anti-drug antibodies 
ADV 
Audio data verification 
AE 
Adverse event 
AHA 
American Heart Association 
ALMS1 
Alström syndrome 1 
ALT 
Alanine aminotransferase 
aPTT 
Activated partial thromboplastin time 
AS 
Alström Syndrome 
AST 
Aspartate aminotransferase 
BBS 
Bardet-Biedl Syndrome 
BMI 
Body mass index 
BP 
Blood pressure 
Bpm 
Beats per minute 
BUN 
Blood urea nitrogen 
CAP 
College of American Pathologists 
CBC 
Complete blood count 
CDI-2 
Children’s Depression Inventory-2 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
COVID-19 
Coronavirus Disease 2019 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CRA 
Clinical research associate 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
% CV 
Percent coefficient of variation 


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Abbreviation or Specialist Term 
Explanation 
DCF 
Data clarification form 
DIO 
Diet-induced obesity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOS 
End of Study 
EOT 
End of Treatment 
 
 
 
 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
GB 
Great Britain 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
GFR 
Glomerular filtration rate 
GLP-1 
Glucagon-like peptide-1 
HbA1C 
Glycated hemoglobin 
HDL 
High-density lipoprotein 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IP 
In-person 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
 
Kcal 
Kilocalories 


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Abbreviation or Specialist Term 
Explanation 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
LEPR 
Leptin receptor 
LTE 
Long-term extension 
Max 
Maximum 
MC4R 
Melanocortin-4 receptor 
MDRD 
Modification of Diet in Renal Disease 
MHP 
Mental health professional 
Min 
Minimum 
mPEG/DSPE 
N-[carbonyl-methoxypolyethylene glycol 2000]-1,2-distearoyl-
glycero-3-phosphoethanolamine sodium salt 
NAFLD 
Non-alcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NCOA1 
Nuclear receptor coactivator 1 
NHLBI 
National Heart, Lung, and Blood Institute 
PCSK1 
Proprotein convertase subtilisin/kexin type 1 
PG 
PreventionGenetics 
PGIC 
Patient Global Impression of Change 
PGIS 
Patient Global Impression of Severity 
PHQ-9 
Patient Health Questionnaire-9 
PK 
Pharmacokinetic 
POMC 
Pro-opiomelanocortin 
PP 
Per-Protocol 
PPL 
POMC, PCKS1, LEPR 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
Q4 
4th quarter 
QD 
Once daily 
q.s. 
Quantity sufficient 
QW 
Once weekly 
rDV 
Remote data verification 
RGDO 
Rare genetic diseases of obesity 
Rhythm 
Rhythm Pharmaceuticals, Inc., the Sponsor 


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Abbreviation or Specialist Term 
Explanation 
rIMV 
Remote Interim Monitoring Visit 
RR 
Respiratory rate 
rSDM 
Remote source data monitoring 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDM 
Source data monitoring 
SH2B1 
SRC homology 2 B adapter protein 1 
SMC 
Site monitoring contact 
SoA 
Schedule of Assessments 
SRC1 
Steroid receptor coactivator-1 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
TOS 
The Obesity Society (2013 Guideline) 
URO 
Uncovering Rare Obesity 
US 
United States 
UV 
Ultraviolet 
VIS 
Variant Interpretation Service 
VUS 
Variant of Uncertain Significance 
WES 
Whole Exome Sequencing 
 


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3. 
INTRODUCTION 
The purpose of this Phase 2 trial is to evaluate the safety and efficacy of once daily (QD) 
subcutaneous (SC) administration of setmelanotide, a synthetic, cyclic octapeptide (8-amino 
acid-containing peptide) melanocortin-4 receptor (MC4R) agonist, in patients with obesity and 
specific gene variants in the MC4R pathway. 
The MC4R pathway is the principal regulator of mammalian energy balance and body weight. 
Originating in the hypothalamus, it concertedly modulates appetite (feelings of hunger and 
satiety and the drive to eat), energy intake (as caloric consumption), and energy expenditure 
(basal metabolism, thermogenesis, and physical activity) to define long term body weight. In 
humans and animal models, genetic variants or acquired disruptions in this pathway result in 
insufficient activation of MC4Rs leading to overconsumption of food (hyperphagia) and a 
reduction in energy utilization (Farooqi 2008).  
Setmelanotide is authorized for marketing in the United States (US), Great Britain (GB), and the 
European Union (EU) 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 (USPI 2022, EU SmPC 2021, MHRA SmPC 2021). Setmelanotide is 
also authorized for marketing in the US in adult and pediatric patients 6 years of age and older 
with obesity due to Bardet-Biedl Syndrome (BBS) (USPI 2022). 
Setmelanotide is under continued clinical investigation globally for the treatment of various rare 
genetic diseases of obesity (RGDO) as well as acquired diseases resulting in obesity (e.g., 
hypothalamic obesity) arising from variants demonstrated or hypothesized to impact signaling in 
the hypothalamic MC4R pathway. Based on accruing genetic and clinical insights, other genetic 
or acquired forms of early-onset, severe obesity and hyperphagia may also be evaluated in 
setmelanotide clinical studies. It is expected that setmelanotide would be indicated to treat the 
obesity and hyperphagia in these patient populations. 
3.1. 
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, alpha-melanocyte-stimulating hormone (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 administered as a continuous SC infusion (2.8 to 
3.5 hours in non-human primates) and the ability to decrease body weight gain and suppress food 
intake in normal rats. Additional studies demonstrated the efficacy of setmelanotide in 
suppressing food intake and body weight gain in diet-induced obese (DIO) 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 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. 


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To support clinical studies, 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. 
 
 
 
 
 
 
 
 
 
 
In addition, safety data from more than 700 clinical trial participants through a cutoff date of 
10 November 2021 demonstrate an acceptable safety profile across the populations studied, 
which include otherwise healthy subjects with obesity, patients with RGDO, and patients with 
acquired diseases resulting in obesity (e.g., hypothalamic obesity) arising from variants 
demonstrated or hypothesized to impact the hypothalamic MC4R signaling pathway. In these 
clinical studies, setmelanotide was administered QD at doses ranging from 0.5 to 5 mg and once 
weekly (QW) at doses ranging from 2.5 to 30 mg. Across the studies, the most common types of 
treatment-emergent adverse events (TEAEs) reported among setmelanotide-treated participants 
by Preferred Term included skin hyperpigmentation, nausea, and headache. Also common were 
TEAEs related to the injection site including injection site erythema, injection site pruritus, 
injection site induration, and injection site pain, each occurring in >10% of participants.  
Data obtained to date in the setmelanotide clinical program demonstrate robust weight reduction 
and hunger suppression in patients with RGDO in which the leptin-melanocortin pathway 
upstream from MC4R is involved. In Phase 3 clinical studies of patients with POMC/PCSK1 and 
LEPR (PPL) deficiency obesity, setmelanotide demonstrated clinically meaningful and 
statistically significant body weight loss and hunger score reductions and was well tolerated. 
Similarly, in a Phase 3 trial of patients with BBS and Alström syndrome (AS), setmelanotide 
significantly reduced body weight and hunger and was well tolerated, with a predictable and 
therefore manageable safety profile. 
In summary, setmelanotide’s unique mechanism of action as a MC4R agonist enables a safe and 
highly targeted approach to treat patients with severe obesity due to genetic or acquired variants 
in the MC4R signaling pathway. By restoring impaired signaling in this pathway, setmelanotide 
can serve as an indirect form of replacement therapy, with the potential for significant 
improvements in hyperphagia and body weight and related measures.  
3.2. 
Benefit/Risk Assessment 
In patients with rare genetic forms of obesity, setmelanotide has been associated with clinically 
meaningful reductions in weight and improvement in hunger. In particular, in patients with 
POMC or LEPR deficiency obesity or BBS, who are characterized by early onset obesity, severe 
hunger and progressive weight gain, setmelanotide has demonstrated clinically meaningful and 
statistically significant weight reduction. In addition to weight loss, setmelanotide has 


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demonstrated clinically meaningful and statistically significant decreases in hunger. Both the 
decreased hunger and the weight loss are maintained with continued setmelanotide treatment. 
Furthermore, following the significant weight loss with setmelanotide treatment, there were 
improvements in glycated hemoglobin (HbA1C), glucose and lipids, as well as body composition 
with decreased fat mass and decreased waist circumference. These weight loss changes were 
accompanied by improvements in quality of life. 
Setmelanotide is well tolerated. Side effects of setmelanotide are predictable, well understood 
and do not present significant safety concerns. Collectively, safety data obtained to date show 
that adverse events (AEs) commonly associated with setmelanotide include injection site 
reactions and skin hyperpigmentation. Less commonly, nausea and vomiting were reported and 
rarely, sexual events have been observed. Potential mechanistic-based events such as 
hypertension have been assessed throughout the setmelanotide clinical development program and 
have not been observed. Events associated with severe obesity such as depression and suicidal 
ideation occurred infrequently and were assessed as not related to setmelanotide. 
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. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints are described in Table 3. 
Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the proportion of 
patients with obesity with genetic 
variants in a specific gene in the 
MC4R pathway who achieve a 
clinically meaningful reduction in 
body weight in response to 
setmelanotide at the end of open-
label treatment 
• 
The proportion of patients by genotype who 
demonstrate a significant clinically meaningful 
response (defined below) to setmelanotide at the end of 
Stage 1: 
− 
For all patients: achieving a ≥5% reduction in BMI 
from Baseline 
Secondary 
• 
To evaluate change in weight 
parameters and hunger in response to 
setmelanotide in patients with 
genetic variants in a specific gene in 
the MC4R pathway at the end of 
open-label treatment 
• 
Mean change and percent change in BMI from 
Baseline to end of Stage 1 in all patients and patients 
≥18 years old, per gene  
• 
Mean change and percent change in body weight from 
Baseline to end of Stage 1 in patients ≥18 years old, per 
gene 
• 
Mean change in BMI Z-score from Baseline to end of 
Stage 1 in patients <18 years old, per gene  
• 
Mean percent change in the weekly average of the 
daily maximal hunger score from Baseline to end of 
Stage 1 in patients ≥12 years old, per gene 
• 
The proportion of patients ≥12 years old, per gene, who 
achieve a ≥2-point reduction (improvement) from 
Baseline to end of Stage 1 in the weekly average of the 
daily maximal hunger score  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 


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Table 3: 
Objectives and Endpoints 
Objectives 
Endpoints 
 
 
 
 
 
  
 
 
 
 
 
Safety 
• 
To evaluate the safety and 
tolerability of setmelanotide in 
patients with genetic variants in the 
MC4R pathway 
• 
Safety and tolerability assessed by the frequency and 
severity of AEs, changes in vital signs, and changes in 
laboratory evaluations at the end of Stage 1 and Stage 2 
AE = adverse event; BMI = body mass index; ECG = electrocardiogram; 
 
; MC4R = 
melanocortin 4 receptor. 
5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Trial Design 
This is a 2-stage (open-label stage followed by a randomized, double-blind, placebo-controlled 
stage) Phase 2 trial of setmelanotide in patients with obesity with specific gene variants in the 
MC4R pathway. Approximately 100 patients between the ages of 6 and 65 years, inclusive, are 
planned to be enrolled in Stage 2 of the trial with up to 200 patients enrolled in Stage 1 (open-
label). The trial design is depicted in Figure 1. 
5.1.1. 
Screening Period 
Upon providing informed consent/assent, patients will enter the Screening Period, during which 
they will be assessed for eligibility and complete all screening procedures as described in the 
Schedule of Assessments (SoA) Stage 1 (Table 1). During the Screening Period, patients will 
undergo medical evaluation and they or their caregivers will receive training on injection of trial 
medication and other trial procedures. Patients (or their caregivers) will be issued an electronic 
diary to capture daily compliance with injections (post enrollment) and hunger score assessments 
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5.1.2. 
Stage 1 (Open-Label) 
Stage 1 of the trial begins with the Enrollment Visit (Study Day 1). During the Enrollment Visit, 
patients will undergo all procedures as outlined in the SoA Stage 1 (Table 1) and it will be 
reconfirmed that the patient continues to meet the Inclusion and Exclusion criteria. At the 
Enrollment Visit, the trial center must confirm that the patient completed the electronic diary at 
least 4 of 7 days prior to the Enrollment Visit. If the diary was not appropriately completed, the 
patient may not enter the trial. The Enrollment Visit may be re-scheduled if the remaining visit 
window allows. 
During the Enrollment Visit, the patient will have their body weight recorded. This will be the 
patient’s “Baseline Weight.” During the Enrollment Visit, the patient (or caregiver) will receive 
training on injections of trial medication and will administer the first dose of setmelanotide under 
the supervision of the trial staff. In-clinic doses of trial medication, including the first dose, will 
be administered following blood sampling for pharmacokinetic (PK) analysis. 
During Stage 1, the patient (or caregiver) will administer setmelanotide on a daily basis for 
16 weeks. During this period, the patient will have in-person as well as virtual visits using a 
validated Telehealth platform with the trial center. During the virtual visits, the patient (or 
caregiver) will record a body weight measurement and be assessed for compliance with trial 
procedures and AEs. Any visit that is planned as a virtual visit may be converted to an in-person 
visit at the discretion of the Investigator. If more than 2 virtual visits are to be converted into in-
person visits, Sponsor approval is required. 
To be eligible to enter Stage 2 of the trial, a patient  
• ≥18 years old must have achieved a body mass index (BMI) at least 3% less than the 
Baseline BMI at the end of Stage 1 
• <18 years old must have achieved a BMI at least 3% less than the Baseline BMI or a 
decrease in BMI Z-score of at least 0.05 at the end of Stage 1 
If the patient completed the full 16 weeks of Stage 1 and at the Day 112 visit (Week 16) the 
patient has not achieved the required change in BMI or BMI Z-score (for patients <18 years) 
since the Baseline Visit, instead of the Stage 2 Entry Visit, the site will perform the End-of-
Treatment (EOT) Visit for this patient. These patients will end treatment with setmelanotide and 
continue to be monitored for resolution of any ongoing serious adverse events (SAEs) with 
virtual visits once every 4 weeks until all SAEs have resolved. 
5.1.3. 
Stage 2 (Randomized, Double-Blind, Placebo-Controlled Stage) 
Eligible patients who enter Stage 2 (see Section 5.1.2) will continue in the trial for an additional 
24 weeks. Stage 2 of the trial will begin with the Stage 2 Entry Visit. During the Stage 2 Entry 
Visit, the patient will complete all assessments as per the SoA Stage 2 (Table 2). The patient will 
have a body weight recorded. This measurement will be their Stage 2 Entry Weight 
Measurement. In clinic doses of trial medication will be administered following blood sampling 
for pharmacokinetic (PK) analysis. 
At the Stage 2 Entry Visit, all eligible patients will be randomized 2:1 to either continue daily 
setmelanotide or receive matching placebo. Stratification by gene will occur for specific genes 
being enrolled into this trial as determined by the Sponsor. Details of which genes will be 


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stratified will be provided in a separate document. Patients will have either virtual or in-person 
visits as indicated in the SoA for Stage 2 (Table 2) and depicted in Figure 1. At the Investigator’s 
discretion, either (1) additional virtual or in-person visits may be scheduled or (2) planned virtual 
visits may be converted to in-person visits. If more than 2 virtual visits are to be converted into 
in-person visits, Sponsor approval is required. 
5.1.3.1. 
End of Treatment and End of Study 
The End of Treatment Visit will occur as an in-person clinic visit on Study Day 112 for patients 
who complete only Stage 1 or on Study Day 280, which is the final day of treatment with 
setmelanotide or placebo for patients who complete Stage 2. A final End of Study (EOS) Visit 
will occur 4 weeks after the EOT visit. The EOS Visit will be conducted via telephone. At the 
end of Stage 2, patients may be offered the option of enrolling into a long-term extension (LTE) 
trial. If required by local regulation or if deemed necessary to assess patient safety by physical 
examination or after a longer follow-up period, the EOS Visit may be converted to an in-person 
visit, and/or can occur up to Week 48. 
5.1.3.2. 
Switch to Treatment with Setmelanotide 
During Stage 2 of the trial, patient weight will be monitored as per the SoA Stage 2 (Table 2). 
Additional virtual visits may be scheduled at the discretion of the Investigator. 
Regardless of treatment assignment, patients will be offered to start open-label treatment with 
setmelanotide if, during a visit, a patient’s BMI has increased by at least 5% from the Stage 2 
entry weight measurement. Open-label treatment will be offered via enrollment in a separate 
LTE trial or, if the LTE trial is not available, via bridging visits until the LTE trial is available. 
To be eligible, the patient must be scheduled for an in-person visit at the clinic. At the visit, the 
patient’s body weight will be recorded. If the visit occurs within 2 weeks of an expected trial 
visit as per the SoA Stage 2 (Table 2), then the visit may replace that expected trial visit. All 
procedures as outlined in the SoA Stage 2 for the expected trial visit should occur. At this visit, 
the patient will return their double-blind trial medication supply. The patient may then be 
enrolled into the LTE trial or will be issued open-label setmelanotide and will continue in the 
trial via bridging visits until the LTE trial is available. The patient’s initial assignment to either 
trial medication or placebo will continue to be blinded to all parties. 
5.1.3.3. 
Trial, Site, or Cohort Suspension or Termination 
This trial, any site, or any cohort of patients (for a gene, gene variants, or subset of variants) may 
be suspended or terminated, if in the opinion of the Sponsor, there is sufficiently reasonable 
cause. The Sponsor may also prioritize cohorts for enrollment at its discretion. The Sponsor will 
provide written notification documenting the reason for cohort/site/trial termination to the 
Investigator.  
Circumstances that may warrant suspension or termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enroll patients at an acceptable rate 
• Insufficient adherence to protocol requirements 


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• Insufficiently complete and/or evaluable data 
• Plans to modify, suspend or discontinue the cohort or the development of the trial 
medication 
Should the trial be closed prematurely, all trial materials must be returned to the Sponsor or 
designee. 
5.1.4. 
Genetic Diversity 
To enroll in this trial, a patient must have a pre-identified genetic variant in an established MC4R 
pathway gene that contributes to obesity. A list of genes that have variants that are eligible for 
enrollment into the trial is provided in Appendix 1. Gene variant enrollment by gene is at the 
discretion of the Sponsor. 
This trial aims to enroll up to 10 patients with each gene into the trial. Enrollment will be 
monitored by the Sponsor and further enrollment of patients with a genotype may be paused 
once 10 patients with that particular gene have been enrolled into the trial. 
Patient response to setmelanotide by gene will be monitored by the Sponsor during the open-
label portion of the trial in 2 ways: the rate of patients qualifying for Stage 2 of the trial and the 
magnitude of response to setmelanotide. The Sponsor may increase or decrease the target 
number of patients enrolled with a particular gene or may close any individual gene cohort after 
assessment of lack of efficacy on 3 or more patients. The total sample size of the trial will not be 
increased. 
It is possible that a patient may enter the trial with more than 1 eligible gene. In this situation, all 
eligible genes will be captured in the database. For analysis purposes, a single gene will be 
considered the “primary gene” for that patient, and the patient will be analyzed within that gene 
cohort. The primary gene will be defined as the eligible gene with the most significant American 
College of Medical Genetics (ACMG) categorization (e.g., Pathogenic>Likely 
Pathogenic>Variant of Uncertain Significance [VUS]). If 2 or more eligible genes share the same 
most significant ACMG categorization, then the “primary gene” will be defined as the least 
prevalent gene and the patient will be analyzed within that gene cohort. Additional sensitivity 
analyses may be conducted. The expected prevalence of the genes being enrolled into this trial 
will be provided in a separate document. 
5.1.5. 
Trial Conduct During the COVID-19 (Coronavirus) Pandemic 
The worldwide Coronavirus Disease 2019 (COVID-19) pandemic may impact the conduct of 
clinical studies due to the challenges from quarantines, site closures, travel limitations, and other 
considerations if site personnel or trial participants become potentially exposed to or infected 
with COVID-19. To assure the safety of trial participants, maintain compliance with Good 
Clinical Practice (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 6. 


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Figure 1: 
Trial Design 
 
Note: if required by local regulation or if deemed necessary to assess patient safety by physical examination or after a longer follow-up period, the EOS visit may 
be converted to an in-person visit, and/or can occur up to Week 48. 


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5.2. 
Patient and Trial Completion 
A patient is considered to have completed the trial if he/she has received the last planned dose of 
trial medication on Study Day 280 and completed the EOS telephone visit on Day 308. 
Patients who discontinue before completing the Study Day 280 EOT visit are to attend an Early 
Termination visit within 14 days (±7 days) after the last dose of trial medication for final trial 
assessments. 
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. 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective approval of protocol deviations to recruitment and enrollment criteria (i.e., protocol 
waivers or exemptions) is not permitted. 
6.1. 
Patient Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for trial participation: 
1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that 
contributes to obesity 
Note: Genetic testing requirements and a list of genes which have variants that are eligible 
for enrollment into the trial are provided in Appendix 1.  
2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or 
Assent.  
3. Patients with obesity, defined as BMI ≥40 kg/m2 for patients ≥18 years of age or BMI ≥97th 
percentile for age and gender for patients 6 to <18 years of age based on the US Centers for 
Disease Control and Prevention criteria. 
4. Patient and/or parent or guardian is able to communicate well with the Investigator, to 
understand and comply with the requirements of the trial (including the QD injection 
regimen and all other trial procedures) and is able to understand and sign the written 
informed consent/assent. Patients who are unable to comply with all trial procedures due to 
cognitive limitations or any other reason should not be enrolled. 
5. Patient must meet one of the following requirements: 
Female participants of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), must be confirmed non-pregnant and agree to use 
a highly effective form of contraception throughout the trial and for 90 days following the 
trial.  


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Highly effective forms of contraception are detailed below and in Section 8.9.7:  
• Combined (estrogen and progestin) hormonal contraception associated with inhibition 
of ovulation (i.e., oral, intravaginal, or transdermal) 
• Progestin-only hormonal contraception associated with inhibition of ovulation (oral, 
implantable, or injectable) 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole 
sexual partner of the female participant, and the vasectomized partner has received 
medical assessment of surgical success) 
• Sexual abstinence, only if it is the preferred and usual lifestyle of the patient 
Female participants of non-childbearing potential, defined as: permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at 
least 12 months (and confirmed with a screening follicle-stimulating hormone level in the 
post-menopausal lab range) and do not require contraception during the trial. 
Younger female patients who have not achieved sexual maturity at trial entry will be assessed 
for Tanner staging and required to comply with contraception requirements at first menarche. 
Male participants with female partners of childbearing potential must agree to use a highly 
effective method contraception if they become sexually active during the trial or within 
90 days following their participation in the trial. Male patients must also not donate sperm 
during and for 90 days following their participation in the trial. 
6. Symptoms or behaviors of hyperphagia persistent during the patient’s life, including 
manifestations in childhood, as determined by the Investigator at screening. 
6.2. 
Patient Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for trial participation: 
1. Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic 
Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous 
variants in MC4R, POMC, PCSK1, LEPR, nuclear receptor coactivator 1 (NCOA1; steroid 
receptor coactivator-1 [SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as 
well as 16p11.2 chromosomal deletions that include the SH2B1 gene. 
2. Weight loss >2% in the previous 3 months.  
Patients will not be excluded for using regimens for weight maintenance or to prevent weight 
gain, such as dietary and/or exercise regimens, or medications, supplements or herbal 
treatments (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, 
glucagon-like peptide-1 [GLP-1] receptor agonists, etc.), provided: 
• the regimen and/or dose has been stable for at least 3 months prior to randomization 


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• the patient has not experienced weight loss >2% during the previous 3 months, AND 
• the patient intends to keep the regimen and/or dose stable throughout the course of the 
trial. 
3. Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric 
balloon, intestinal barrier, etc.) within the last 6 months. All patients with a history of 
bariatric surgery or procedures must be discussed with, and receive approval from, the 
Sponsor prior to enrollment. 
4. Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major 
depressive disorder, bipolar disorder, schizophrenia, etc.) or documented worsening 
psychiatric condition that required changes in treatment regimen within the previous 2 years, 
or other psychiatric related risks that the Investigator believes may interfere with trial 
compliance or patient safety.  
5. Clinically significant depression or suicidality, as defined by: any suicidal ideation of type 4 
or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide 
attempt during the patient’s lifetime, any suicidal behavior in the last month, or a Patient 
Health Questionnaire-9 (PHQ-9) score of ≥15 during Screening process. 
Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant 
neurocognitive impairment may be enrolled in the trial provided that there are no clinical 
signs or symptoms of significant depression or suicidal behavior in the opinion of the 
Investigator. 
6. Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic 
disease considered severe enough to interfere with the trial and/or confound the results. Any 
patient with a potentially clinically significant disease should be reviewed with the Sponsor 
to determine eligibility. 
7. Significant features of, or meeting the diagnostic criteria for, a genetic syndrome that is 
associated with obesity. 
Note: Although some of the genetic variants that are eligible to be enrolled into this trial are 
associated with specific syndromes, the intent of this trial is not to enroll children with 
significant cognitive impairment or other significant co-morbidities. Patients with eligible 
genetic variants, but who otherwise do not exhibit the syndrome, are eligible for enrollment. 
8. HbA1C >10.0% at Screening. 
9.  History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or 
nonalcoholic steatohepatitis (NASH). Patients with NAFLD or NASH will not be excluded 
based on this criterion 
10. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at Screening. In patients 
>18 years of age the Modification of Diet in Renal Disease (MDRD) Equation should be 
used to calculate eGFR. In patients <18 years of age, the Bedside Schwartz Equation should 
be used for calculation of GFR. 
11. History or close family history (parents or siblings) of melanoma, or patient history of 
oculocutaneous albinism. 


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Note: If the type of skin cancer in patient’s or close family history is not known, then the 
patient should not be enrolled into the trial. 
12. 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. If any 
concerning lesions are identified during Screening, the patient should be referred to a 
dermatologist. 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. 
13. Patient is, in the opinion of the Investigator, not suitable to participate in the trial. 
14. Participation in any clinical trial with an investigational drug/device within 3 months or 
5 half-lives, whichever is longer, prior to the first day of dosing. 
15. Patients previously enrolled in a clinical trial involving setmelanotide or any previous 
exposure to setmelanotide. 
16. Hypersensitivity to the active substance or to any of the excipients of the investigational 
medicinal products (active and placebo). 
17. Females who are pregnant or breastfeeding, or planning or desiring to become pregnant 
during the duration of the trial. 
18. Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article 
of the Public Health code in France). 
19. For France only: patient is <18 years of age. 
6.3. 
Treatment Discontinuation and Withdrawal from the Trial 
Given this rare patient population, every effort should be made to encourage and keep patients 
enrolled in the trial until completion, unless there are any safety concerns necessitating 
withdrawal of the patient. 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 and completion of trial participation. 
Discontinuation of trial treatment or skipped visits/injections may be allowed without withdrawal 
from the trial. 
Some patients’ reason for discontinuation may be related to injection site reactions and 
burdensome laboratory/visits. Patients can be offered the option to discontinue trial medication 
but remain in the trial. These patients who stop therapy will be counted as a non-responder, 
irrespective of treatment assignment. However, they will be followed and have weight 
assessments at each visit, particularly at the final visit to determine weight trajectory for all 
patients. Patients who withdraw before completing Visit 14 are to attend an Early Termination 
visit within 14 days (±7 days) after the last dose of trial medication for final trial assessments. If 
possible, patients will be asked to determine weight assessment at the expected time of their EOT 
visit. 
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 


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If a patient withdraws from the trial, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site trial records. 
Patients 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 opinion of Investigator justifies treatment or trial withdrawal. For specific 
predefined events, additional monitoring and guidance for the Investigator is provided in 
Appendix 5. 
• Non-adherence to trial medication regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 
• Note: The Sponsor may choose to discontinue investigation of a particular genetic 
cohort/variant at any time; therefore, continued participation of patients for that genetic 
cohort/variant will be addressed at that time 
All patients withdrawn prior to completing the treatment period should be strongly encouraged to 
complete the Early Termination visit as outlined in the SoA (Table 1 and Table 2), even if they 
are no longer receiving trial medication. 
6.4. 
Lost to Follow-up 
Patients are considered as being lost to follow-up if they fail to return for scheduled evaluations 
and cannot be contacted by the site. The following actions must be taken if the patient fails to 
return to the clinic for a required trial evaluation:  
• The trial site must attempt to contact the patient and reschedule the missed evaluation 
as soon as possible and counsel the patient on the importance of maintaining the 
assigned evaluation schedule.  
• Before a patient is deemed lost to follow-up, the Investigator or designee must make 
every effort to regain contact with them or next of kin by, for example, repeat 
telephone calls, certified letter to the patient’s last known mailing address, or local 
equivalent methods. At least 3 unique documented contact attempts to follow-up over 
a period of weeks to months should be made, including at least 1 in relation to the 
final visit on Day 308. The patient should only be permanently recorded as lost to 
follow-up if they did not respond to any contact attempts by Day 308. These contact 
attempts should be documented in the patient’s medical records. 
6.5. 
Lifestyle Counseling 
6.5.1. 
Physical Activity 
During the trial, patients will receive physical activity counseling by qualified site personnel and 
will be encouraged to perform aerobic physical activity for a duration of at least 150 minutes per 
week, maintaining an average target HR of 70% of their maximum HR. Aerobic physical activity 
includes repetitive motions of large muscle groups, such as brisk walking, swimming, mowing 


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the lawn, running, dancing, etc. Maximum HR is calculated as 220 beats per minute (bpm) minus 
patient’s age in years.  
Example: if a patient is 50 years old, the maximal HR is calculated as 220 bpm –50 years of 
age = 170 bpm. For this patient, 70% of the maximal HR (0.70 × 170 bpm) is 119 bpm. 
Therefore, this patient will be encouraged to perform 150 min of aerobic physical activity per 
week targeting an average HR of 119 bpm.  
Each patient will be provided with an electronic tracker to monitor HR and physical activity to 
inform whether the target level of physical activity was fulfilled. At every virtual and in-person 
visit, each patient will be asked if they performed the target level of activity.  
6.5.2. 
Nutrition 
During the trial, patients will receive dietary counseling by qualified site personnel and will be 
encouraged to follow a diet with a reduction of 500-750 kilocalories (Kcal) per day as advised by 
the American College of Cardiology (ACC), American Heart Association (AHA), The Obesity 
Society (TOS) 2013 guidelines (Jensen 2014). At each visit (virtual and in-person) patients will 
be counselled on nutrition and compliance will be assessed by on-site personnel. 
6.5.3. 
Skin Protection 
Skin hyperpigmentation, or tanning, was observed in the cynomolgus monkey toxicology studies 
and the human studies. These events were reversible upon cessation of trial medication. 
However, it is still uncertain if exposure to sunlight might exacerbate the tanning effects of 
setmelanotide. Therefore, patients will be advised to use sunscreen and/or to wear protective 
clothing to avoid excessive exposure of their skin to sunlight and to avoid sun-tanning. 
It is also important that patients do not participate in any activities that will intentionally cause 
their skin to tan (e.g., visit ultraviolet [UV] tanning salons, use spray tanners, self-tanning 
lotions, etc.). 
7. 
TREATMENT OF PATIENTS 
7.1. 
Description of Trial Medication 
All trial medication is for investigational use only and is to be used only within the context of 
this protocol. All investigational trial medication (setmelanotide and placebo) will be supplied by 
the Sponsor. 
 
 
 
 
The reference therapy for the double-blind period of this trial is a placebo vehicle. 
 
 
 


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Setmelanotide and placebo are clear, colorless to slightly opalescent solutions essentially free of 
visible particulates and are suitable for a double-blind trial.  
7.2. 
Randomization, Blinding, and Unblinding 
7.2.1. 
Stage 1 
Stage 1 of the trial is open-label, and all patients will receive setmelanotide. 
7.2.2. 
Stage 2 
Patients who are eligible to enter Stage 2 of the trial will be randomized in a blinded manner on 
Day 112 (Stage 2 Entry Visit) in a 2:1 ratio to receive either setmelanotide (2) or placebo (1). 
The randomization schedule will be generated by the Sponsor or its designee, and trial personnel 
will use a web-based interactive response technology (IRT) system to obtain the randomization 
number for each eligible patient. 
Stage 2 of this trial is double-blinded. The patient, Investigator, and Sponsor will be blinded to 
trial treatment.  
7.2.3. 
Blinding and Unblinding 
Full details for the blinding and unblinding are provided in the separate Blinding and Unblinding 
Plan. 
Blinded randomization will occur via an IRT. 
Emergency unblinding for AEs may be performed through an IRT. The IRT will be programmed 
with blind-breaking instructions. In case of an emergency, the Investigator has the sole 
responsibility for determining if unblinding of a patient’s treatment assignment is warranted. 
Patient safety must always be the first consideration in making such a determination. If the 
Investigator decides that unblinding is warranted, the Investigator should make every effort to 
contact the Sponsor before unblinding a patient’s treatment assignment unless this could delay 
emergency treatment for the patient. The date and reason for the unblinding by the Investigator 
must be recorded. If a patient’s treatment assignment is unblinded, the Sponsor must be notified 
by the Investigator within 24 hours that an unblinding occurred. The Investigator should not 
reveal to the Sponsor the patient’s treatment allocation unless the Sponsor requests this 
information for safety purposes. 
For any unexpected SAE that is treatment-related (e.g., possible or probable), the blind will be 
lifted by the Sponsor only for that specific patient. The blind will be maintained for persons 
responsible for the ongoing conduct of the trial (such as the monitors, Investigators, etc.) and 
those responsible for data analysis and interpretation of results at the conclusion of the trial (such 
as biometrics personnel). Unblinded information will only be accessible to those who need to be 
involved in the safety reporting to Health Authorities, Independent Ethics Committees (IECs), 
and/or Institutional Review Boards (IRBs). Investigators will receive only blinded information 
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7.3. 
Administration 
Trial medication will be administered as a SC injection QD.  
Patients 12 years of age and older: trial medication (setmelanotide or matching placebo) 2 mg 
QD for approximately 2 weeks, then increased to 3 mg QD. Dose escalation should occur at the 
trial visit planned for Day 14 (±3 days) and should occur on the day of that visit.  
Note: if the starting dose of trial medication is not tolerated reduce to 1 mg QD; the lowest target 
dose in patients ≥12 years of age is 1.0 mg QD; however, in consultation with the medical 
monitor, the dose may be lowered to 0.5 mg QD if not tolerated. 
Patients 6 to <12 years of age: trial medication 1 mg QD for approximately 1 week, then 
increased to 2 mg QD for approximately 1 week, then increased to 3 mg QD. Dose escalation 
should occur during the phone call planned for Day 7 (±2 days) and at the trial visit planned for 
Day 14 (±3 days) and should occur on the day of that visit.  
Note: if the starting dose of trial medication is not tolerated reduce to 0.5 mg QD; the lowest 
target dose in patients 6 to <12 years of age is 0.5 mg QD. 
Note that the above dosing and titration scheme is based on the same dosing and titration scheme 
employed in the completed RM-493-023 Phase 3 trial in patients with BBS and AS, which 
included patients as young as 6 years of age. Review of the AEs in the overall trial population or 
the pediatric population within Trial RM-493-023 did not show an increase in the frequency or 
severity of AEs such as nausea during the titration period, despite the shorter titration period of 
setmelanotide compared to previous studies. Based on these data, the dosing and titration scheme 
above, including duration, is expected to be safe and well tolerated, and it allows patients to 
reach a targeted therapeutic and efficacious dose of setmelanotide in a more timely manner. 
Investigators may increase or decrease the dose, if necessary, to treat an AE, although a 
setmelanotide dose greater than 3 mg QD should not be used in this trial. If an Investigator feels 
that a dose adjustment is required for a reason other than an AE (e.g., exaggerated weight loss), 
the decision should be discussed with the Sponsor prior to changing the dose. 
All changes in dose other than the per-protocol dose titration should be captured as a protocol 
violation, regardless of the rationale for the dose adjustment. 
There will be extensive training of patients and caregivers (as applicable) in drug administration 
including educational materials. Trial-specific training materials will be provided to both the 
investigative staff and trial participants and caregivers.  
Patients will be reminded to bring their trial medication to in person visits and that there should 
be no trial medication administration at home on the day of clinic visits. Blood sampling for PK 
analysis will be performed prior to administration of trial medication on the day of in clinic 
visits.  
7.4. 
Drug Interruption and Stopping Rules 
Safety parameters will be monitored during the trial. Trial drug administration will be interrupted 
if certain safety parameter criteria are met, and additional assessments may be implemented. The 
Medical Monitoring plan provides for detailed instructions.  


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7.5. 
Treatment Compliance 
Accountability for the trial medication at the trial site is the responsibility of the Investigator. 
The Investigator will ensure that the trial medication is used only in accordance with this 
protocol. Where allowed, the Investigator may choose to assign drug accountability 
responsibilities to a pharmacist or other appropriate individual. Drug accountability records 
indicating the delivery date to the site, inventory at the site, use by each patient, return of all 
used/unused trial medication to the trial center, and return to the Sponsor or Sponsor’s designee 
(or disposal of the drug, if approved by the Sponsor) will be maintained by the clinical site. 
Reasons for departure from the expected dispensing regimen must also be recorded. The Sponsor 
or its designee will review drug accountability at the site during monitoring visits. 
Compliance with dosing will be monitored throughout the trial by having the patient/caregiver 
complete a daily dosing log, and by accounting for trial medication dispensed and returned (used 
and partially used). 
7.6. 
Preparation/Handling/Storage/Accountability 
Only patients enrolled in the trial may receive trial medication and only authorized site staff may 
supply or administer trial medication. All trial medication must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. The 
Investigator is responsible for trial medication accountability, reconciliation, and record 
maintenance (ie. receipt, reconciliation, and final disposition records). 
All unopened trial medication must be kept at a temperature between 2°C to 8°C. Setmelanotide 
is stable at room temperature for a short time period that will allow patients to transport trial 
medication home; ice packs and cooler bags will be provided for patients and caregivers who 
will travel long distances from the clinic. Once at home, the unopened trial medication must be 
stored in the patient’s refrigerator. Opened trial medication may be stored at room temperature 
for up to 30 days. 
For accountability, patients/caregivers will return all used trial medication kits to the clinic when 
they visit. The trial staff will record the number returned, and both clinic administered trial 
medication, as well as outpatient trial medication administration will be recorded in a trial diary. 
7.7. 
Concomitant Medications 
Medication that is considered necessary for the patient’s safety and wellbeing may be given 
during the trial at the discretion of the treating physician after discussion with the Medical 
Monitor.  
All concomitant medications should be kept at a stable dose throughout the course of the trial 
unless a dose change is necessary due to an AE.  


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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 
GLP-1 receptor agonists and anti-obesity medications may be used as long as: 
• the regimen and/or dose has been stable for at least 3 months prior to randomization 
• the patient has not experienced weight loss ≥2% during the previous 3 months, AND 
• the patient intends to keep the regimen and/or dose stable throughout the course of the 
trial. 
The Sponsor should be contacted if there are any questions regarding concomitant or prior 
therapy. 
8. 
ASSESSMENTS 
Trial procedures and their timing are summarized in the SoA (Table 1 and Table 2). 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 electrocardiogram (ECG), and perform blood draws (at the specified 
time point, if applicable). In-clinic dosing should follow PK draws. Adjustments may be made 
depending upon specific circumstances and in consultation with the Sponsor. 
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. 
Note that additional assessments may be performed at the Investigator’s discretion as needed to 
ensure patient safety. 
8.1. 
Informed Consent / Assent 
A complete description of the trial is to be presented to each potential patient and parent or legal 
guardian/representative and signed and dated informed consent and/or assent is to be obtained 
before any trial-specific procedures are performed. Patients must be informed of and provide 
consent/assent to the most current version of the informed consent form(s) (ICFs) during their 
participation in the trial, and a copy of the ICF(s) must be provided to the patient or their legally 
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Procedures conducted as part of the patient’s routine clinical management (e.g., blood count) and 
obtained before signing of the ICF may be utilized for Screening or Baseline purposes provided 
the procedures met the protocol-specified criteria and were performed within the time frame 
defined in the SoA. 
8.2. 
Inclusion/Exclusion Review 
Inclusion and exclusion criteria are to be reviewed per the SoA (Table 1) to ensure the patient is 
eligible for the trial. 
8.3. 
Demographics, Concomitant Medications and 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 
(Table 1). Additionally, the patient’s history of childhood obesity and previous weight loss 
efforts will be collected. 
The medical history should be updated on Day 1 prior to first dose of trial medication, 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. 
8.4. 
Height 
For patients ≥21 years of age, height is to be measured at Screening only. For patients aged 
<21 years, height is to be measured at the time points listed in the SoA (Table 1 and Table 2).  
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.  
8.5. 
Fitzpatrick Scale 
Each patient is to be categorized for skin type according to the Fitzpatrick scale. The Fitzpatrick 
scale is presented in Appendix 3. 
8.6. 
Pharmacokinetic Assessments 
Blood samples for determination of setmelanotide levels in plasma will be collected as indicated 
in the SoA in Table 1 and Table 2. For all blood samples for PK analysis, the actual (clock) time 
each PK blood sample is collected will be recorded in the source documents and electronic case 
report form (eCRF). Plasma will be harvested from each blood sample collected for PK analysis 
and the plasma will be frozen, shipped to a bioanalytical laboratory designated by the Sponsor, 
and analyzed for setmelanotide concentrations. 
Setmelanotide plasma PK will be assessed in all patients by trough (pre-dose) concentrations 
measured prior to dose administration in the clinic as per the SoA.  


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The trough concentration values will be reported descriptively as mean, standard deviation (SD), 
maximum (Max), minimum (Min), median, and percent coefficient of variation (% CV) based on 
dose and visit. 
8.7. 
Efficacy Assessments 
8.7.1. 
Weight 
Weight (kg) will be recorded at the time points designated in the SoA (Table 1 and Table 2). 
Whenever possible, the same scale at the site should be used throughout the trial, including the 
Screening Visit, and should be calibrated on a regular basis per the manufacturer’s instructions. 
Patients will be provided a trial-specific scale to be used at home for all virtual visits under direct 
visual observation by site personnel.  
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 kg if reported with a digital scale, or half kg with a 
mechanical scale.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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8.7.6. 
Biomarkers 
A blood sample will be collected for metabolic, inflammation, metabolomic and/or proteomic 
biomarker analysis at the time points specified in the SoA (Table 1 and Table 2). This sample 
may or may not be analyzed. All samples are sent to a central laboratory and may be sent to other 
laboratories for further analyses. Additional details are described in the laboratory manual. 
8.8. 
Nutrition and Physical Activity Counseling and Follow-Up 
Patients will be asked at every visit per the SoA (Table 1 and Table 2) if they are achieving 
nutrition and physical activity counseling target recommendations. 
8.9. 
Safety Assessments 
Safety will be assessed as described in the sections below.  
8.9.1. 
Vital Signs 
Vital signs include systolic and diastolic BP, HR, respiration rate (RR), 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 and Table 2). 
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. 
Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR. 
Participants will be instructed on the proper use of and will be provided with WiFi/Bluetooth 
connected devices for measuring and transmitting data on blood pressure and temperature during 
virtual trial visits. The data are stored and automatically transferred when connected to WiFi. 
Refer to Appendix 8 for additional details.  


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8.9.2. 
Physical Examination  
A complete physical examination will be conducted at Screening and at the EOT visit. At other 
time points, as designated in the SoA (Table 1 and Table 2), an abbreviated examination will be 
performed. 
• A complete physical examination will include review of peripheral lymph nodes, 
head, eyes (including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, 
lungs, abdomen, musculoskeletal including back, extremities, and a neurologic 
examination. 
• 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 for assessment of pubertal development will be conducted for those 
patients who have yet to reach Tanner Stage V. 
Whenever possible, the same trained health care professional will conduct the physical 
examinations and Tanner Staging. 
All physical examinations are to be conducted in adequate light. 
Changes from baseline in any physical examination findings identified by the Investigator as 
clinically significant must be recorded as an AE on the appropriate eCRF. 
8.9.3. 
Comprehensive Skin Examination 
A comprehensive skin examination will be performed by the Investigator at the time points 
designated in the SoA (Table 1 and Table 2). 
The skin examination should include a full body (head-to-toe skin examination). If any 
concerning lesions are identified during Screening, the patient should be referred to a 
dermatologist. Any concerning lesions will be biopsied by the dermatologist and results must be 
benign prior to the first dose of setmelanotide. If the pre-treatment biopsy results are of concern, 
the patient may be excluded from the trial. Additionally, any concerning lesion or change in an 
existing lesion during the course of the trial must be evaluated by the dermatologist and biopsied, 
if clinically indicated in the opinion of the dermatologist. 
8.9.4. 
Electrocardiogram 
A single 12-lead ECG will be performed at the time points designated in the SoA (Table 1 and 
Table 2). ECGs are to be performed with the patient in the supine position following a period of 
at least 10 minutes of rest.  
8.9.5. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory tests are to be collected at the time points 
designated in the SoA (Table 1 and Table 2). Clinical safety laboratory tests are to be performed 
after patients have been fasting for 8 hours. Samples are to be collected prior to setmelanotide 
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All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated according to the judgment of the Investigator. 
Clinical laboratory parameters to be evaluated, including hematology, clinical chemistry, 
coagulation studies, 
 as well as urine analysis, are identified in the SoA 
(Table 1 and Table 2). 
GFR will be calculated in patients ≥18 years of age using the MDRD Equation: glomerular 
filtration rate (GFR) = 175 × (creatinine in mg/dL)-1.154 × (age in years)-0.203 × (0.742 if 
female) × (1.210 if African American). GFR will be calculated in patients <18 years of age using 
the Bedside Schwartz Equation: GFR (mL/min/1.73 m²) = (0.41 × height in 
centimeters)/creatinine in mg/dL). 
8.9.6. 
Anti-Drug Antibodies (ADA) 
Blood samples for analysis of anti-drug antibodies (ADA) will be collected at the time points 
specified in the SoA (Table 1 and Table 2). If a patient has a positive ADA titer, they will be 
followed every 3 months after the ADA sample analysis until resolution of the ADA titer. 
8.9.7. 
Pregnancy and Contraception 
In animal reproduction studies, setmelanotide was not teratogenic at doses >10 times the 
maximum recommended human dose of 3 mg QD. No evidence of embryo-fetal toxicity was 
observed. Pre-and postnatal development studies in rats showed no adverse setmelanotide-related 
effects. Please refer to the IB for additional information. 
It is imperative all trial patients adhere to the contraception and pregnancy testing requirements 
as outlined below. 
Females of childbearing potential, defined as fertile, following menarche and until becoming 
post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral 
oophorectomy) must not be pregnant and must have a negative serum pregnancy test result at the 
Screening Visit. A urine pregnancy test may be performed to expedite availability of results prior 
to dosing on Day 1. Serum pregnancy testing will also be performed during the trial at the time 
points specified in the SoA (Table 1 and Table 2); however, setmelanotide dosing may continue 
with results pending. At Visit 1 and Visit 7, for sites where pregnancy tests are required for 
virtual visits, females of childbearing potential will be given urine pregnancy test kits for use at 
each of the virtual visits in Stage 1 and Stage 2, respectively. 
For females of childbearing potential, a highly effective form of contraception (as defined in the 
Inclusion Criteria, Section 6.1) must be used/practiced throughout the trial and for 90 days 
following the trial. 
Highly effective forms of contraception include: 
• Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal) 
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable) 
• Intrauterine device 


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• Intrauterine hormone-releasing system 
• Bilateral tubal occlusion 
• Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole 
sexual partner of the female participant, and the vasectomized partner has received 
medical assessment of surgical success) 
• Sexual abstinence, only if it is the preferred and usual lifestyle of the patient. 
Females of non-childbearing potential, defined as permanently sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral salpingectomy) or post-menopausal for at least 12 months 
(and confirmed with a screening follicle stimulating hormone level in the post-menopausal 
range) do not require contraception during the trial. 
Younger female patients who have not reached sexual maturity at trial entry will be assessed for 
Tanner Staging, and upon reaching Tanner Stage V or menarche, will be counseled on pregnancy 
and required to comply with contraception requirements, and pregnancy tests at all visits for the 
remainder of the trial. 
It is not known whether this treatment will affect spermatogenesis. Therefore, males with female 
partners of childbearing potential must agree to use contraception (e.g., if they have not had a 
vasectomy with medical assessment of surgical success then should either [a] abstain from 
reproductive sexual intercourse or [b] use a double barrier method [i.e., condom and diaphragm 
with spermicide] during intercourse) if they become sexually active during the trial and for 
90 days following the trial. Sexual abstinence is acceptable only if it is the preferred and usual 
lifestyle of the patient. Male patients must not donate sperm for 90 days following their 
participation in the trial. 
In the event of pregnancy during setmelanotide treatment, setmelanotide is to be permanently 
discontinued. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy by completing the Pregnancy Reporting Form and following the 
Sponsor reporting procedures outlined in Appendix 5. 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of trial treatment through 30 days after the last dose of setmelanotide in 
the trial. 
Note that pregnancy itself is not considered a SAE. However, abnormal pregnancy outcomes 
(e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs. 
8.9.8. 
Injection Site Examination 
Injection sites will be carefully inspected, evaluated, and scored at the time points outlined in the 
SoA (Table 1 and Table 2) during the trial period. The injection site evaluation will include 
identification and measurement of areas of erythema, edema, and induration, as well as the 
presence of localized pain, tenderness, and itching. A sample injection site evaluation form is 
included in Appendix 4. 
In addition, unscheduled evaluations may also be recorded as warranted by clinical conditions. 


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8.9.9. 
Suicidal Ideation and Depression Monitoring 
As setmelanotide is considered to act through the central nervous system (CNS), suicidal 
ideation and risk will be assessed using the C-SSRS scale (Section 8.9.9.1) and depression will 
be assessed using the PHQ-9 or the Children’s Depressive Inventory-2 (CDI-2) (Section 8.9.9.2 
and 8.9.9.3). 
A patient should be referred to a mental health professional (MHP) if he/she has: 
• Any suicidal behavior 
• Any suicidal ideation of type 4 or 5 on the C-SSRS 
• A PHQ-9 score of ≥10 
• A CDI-2 score of >20 
A referral to a MHP should also be made if in the opinion of the Investigator it is necessary for 
the safety of the patient. If a patient’s psychiatric condition can be adequately treated with 
psychotherapy and/or pharmacotherapy, then the patient, at the discretion of the MHP, may be 
continued in the trial. 
In patients with cognitive impairment or pediatric patients, the ability to complete the C-SSRS or 
PHQ-9 may be limited. If in the clinical opinion of the Investigator a specific patient cannot 
complete the instrument(s), the following strategies may be employed: 
• Site staff may administer the questions directly to the patient or may ask for the 
information from a third party, such as a caregiver or family members, as appropriate. 
• The Investigator may use his/her clinical judgment to skip any questionnaires that 
he/she feels are not appropriate for a specific patient. 
Any deviation from the intended use of an instrument should be documented by the Investigator, 
along with the reason for the deviation. If the PHQ-9 and C-SSRS are not administered, the 
Investigator should document that the issues of depression and suicidality were assessed 
clinically (e.g., discussion with caregivers).  
8.9.9.1. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
Patients ≥6 years of age 
As required in the US by the Food and Drug Administration (FDA), for clinical trials of CNS-
acting medications, changes in suicidality as assessed by the C-SSRS will be monitored over the 
course of the trial to ensure patient safety.  
The C-SSRS is a tool used not only to predict suicide attempts but to assess the full range of 
evidence-based ideation and behavior items, with criteria for next steps (e.g., referral to a MPH). 
There are 2 versions of the C-SSRS that will be administered according to the SoA (Table 1 and 
Table 2): 
• The Baseline/Screening version of the scale is the initial form of the instrument to 
assess suicidality in a patient’s lifetime. This version can assess a patient’s lifetime 
suicidality for data collection purposes as well as eligibility based on 
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• The Since Last Visit version of the scale assesses suicidality since the patient’s last 
visit. This version is meant to assess patients who have completed at least 1 initial 
C-SSRS assessment and should be used in subsequent visits. The ‘Since Last Visit’ 
version of the C-SSRS is asking about any suicidal thoughts or behaviors the 
patient/participant may have had since the last time the C-SSRS was administered. 
To be eligible for the trial, a patient cannot have a suicidal ideation of type 4 or 5, a suicide 
attempt during the patient’s lifetime, or any suicidal behavior in the last month. 
Any patient with a suicidal behavior or a suicidal ideation of type 4 or 5 on the CSSRS will be 
referred to a mental health professional. 
8.9.9.2. 
Patient Health Questionnaire -9 (PHQ-9)  
The PHQ-9 is a 9-item depression scale of the Patient Health Questionnaire. The PHQ-9 is a tool 
for assisting clinicians in diagnosing depression as well as selecting and monitoring treatment. 
After the patient has completed the PHQ-9 questionnaire, it is scored by the trial staff. The 
PHQ-9 will be administered in patients ≥12 years of age or according to the SoA (Table 1 and 
Table 2). 
Any patient with a PHQ-9 score ≥10 will be referred to a mental health professional. 
8.9.9.3. 
Children’s Depression Inventory-2 
The CDI-2 has both a self-report and a parent version. The CDI-2: Self-Report Short version is 
an efficient screening measure that contains 12 items and takes about 5-10 minutes to administer. 
The self-report short version will be administered to patients <12 years of age according to the 
SoA (Table 1 and Table 2).  
Items on the CDI-2 Parent form correspond to items on the self-report version and are suitably 
rephrased. Item selection for the parent forms was guided to maximize validity, and thus focused 
on observable manifestations of depression. The CDI-2 parent form consists of 17 items and the 
4 choices provided for each item correspond to 4 levels of symptomatology: 0 (not at all), 
1 (some of the time), 2 (often), or 3 (most of the time). The CDI-2 parent version will be 
administered to caregivers of patients <12 years of age according to the SoA (Table 1 and 
Table 2). 
Any patient with a CDI-2 score >20 will be referred to a mental health professional. 
8.9.10. 
Overdose 
One accidental overdose has been reported in the clinical program in a pediatric patient receiving 
a 5-mg dose instead of a 0.5-mg dose. The patient had mild symptoms that resolved. 
In the event of an overdose, the Investigator should contact the Medical Monitor immediately. 
Appropriate supportive treatment should be initiated according to the patient’s clinical signs and 
symptoms. 
The quantity of the excess dose as well as the duration of the overdose are to be documented in 
the eCRF. 


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Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Sponsor based on the clinical evaluation of the patient. 
8.9.11. 
Adverse and Serious Adverse Events 
Adverse events will be reported by the patient (or, when appropriate, by a caregiver, surrogate, 
or the patient’s legally authorized representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following-up AEs 
that are serious, considered related to the trial treatment or trial procedures, or that caused the 
patient to discontinue trial treatment (see Section 6.3). 
Details on recording AEs and SAEs, including definitions, are provided in Appendix 5. 
8.9.11.1. Time Period and Frequency for Collecting AE and SAE Information 
All AEs, including SAEs, will be collected from the time informed consent is signed until the 
EOS visit at the time points designated in the SoA (Table 1 and Table 2). AEs reported after 
dosing on Day 1 will be considered TEAEs. 
Medical occurrences that begin before the start of trial treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF, not in the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours without 
undue delay but no later than within 24 hours, as indicated in Appendix 5. The Investigator will 
submit any updated SAE data to the Sponsor without undue delay but no later than within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information from former trial 
patients. However, if the Investigator learns of any SAE, including a death, at any time after a 
patient has been discharged from the trial, and he/she considers the event to be reasonably related 
to the trial treatment or trial participation, the Investigator must promptly notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 5. 
8.9.11.2. Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-
leading verbal questioning of the patient is the preferred method to inquire about AE 
occurrences. 
8.9.11.3. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 5. 


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8.9.11.4. Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of an SAE is essential so that 
regulatory obligations and ethical responsibilities towards the safety of patients and 
the safety of a trial treatment under clinical investigation are met. 
• The Sponsor has a legal responsibility to notify both the local regulatory authority 
and other regulatory agencies about the safety of a trial treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs, IECs, and Investigators. 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and Sponsor policy 
and forwarded to Investigators as necessary. 
• An Investigator who receives an Investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then file it along with the Investigator Brochure and will notify the 
IRB/IEC, if appropriate according to local requirements. 
9. 
SAFETY DATA MONITORING 
The Investigators will be responsible to review and evaluate safety data from their patients in a 
continuous manner. Cumulative safety data from the trial will be reviewed by the Sponsor on an 
ongoing basis for any safety signals or tolerability concerns. Additionally, this trial will be 
monitored by an independent Data Safety Monitoring Board (DSMB). The DSMB will operate 
under a separate charter and will meet periodically (e.g., every 3 months) to review the 
cumulative safety data from the trial and will make a recommendation to continue or modify the 
trial, if needed. 
10. 
STATISTICS 
This section describes the plans for analysis of the trial data. Details of the statistical 
methodology for summaries and statistical analyses will be provided in a separate statistical 
analysis plan (SAP), which will be maintained by the Sponsor. The SAP may modify the plans 
outlined in the protocol; however, any major modifications of the primary endpoint definition 
and/or its analysis will also be reflected in a protocol amendment. If, after the trial has 
completed, changes are made to the SAP, then these deviations to the plan will be listed, along 
with an explanation as to why they occurred, in the clinical study report for the trial, as 
appropriate. 


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10.1. 
Sample Size Determination 
The trial is a 2-stage design: Stage 1 is open-label treatment part, and Stage 2 is randomized, 
double blind, placebo-controlled part. It is planned to enroll 100-200 patients in the trial. Sample 
size is not based on any statistical considerations. 
10.2. 
Populations for Analyses 
There are 2 analysis populations defined in the protocol:  
• Full Analysis Set (FAS): all patients randomized in Stage 2 who received at least 
1 dose of trial medication (placebo or setmelanotide) in Stage 2 and have baseline 
data. Analyses performed on the FAS will be based on patients as randomized. 
• Safety Analysis Set: All patients who received at least 1 dose of trial medication. 
10.3. 
Statistical Analyses 
A separate SAP will be developed, which will include a more technical and detailed description 
of the statistical analyses described in this section.  
The primary efficacy endpoint of the trial is the proportion of patients by genotype who 
demonstrate a significant clinically meaningful response (defined below) to setmelanotide at the 
end of Stage 1: 
• For all patients: ≥5% reduction in BMI from Baseline 
The 95% exact confidence interval will be provided for the primary efficacy endpoint. The 
analyses of the efficacy endpoints in Stage 1 will be performed based on the safety analysis set, 
and the analyses of the efficacy endpoints in Stage 2 will be performed based on the FAS, which 
is defined as all patients randomized in Stage 2 who received at least 1 dose of trial medication 
(placebo or setmelanotide) in Stage 2 and have baseline data.  
AEs/SAEs will be summarized with frequencies and percentages. A by-patient AE data listing 
including onset and resolution dates, verbatim term, preferred term, treatment, severity, 
relationship to treatment, action taken, and outcome will be provided.  
Safety data including laboratory evaluations and vital signs assessments will be summarized by 
time of collection. In addition, change from baseline to any post-dose values will be summarized 
for vital signs and clinical laboratory results. Frequency of patients with abnormal safety 
laboratory results will be tabulated.  
All safety analyses and summary tables will be based on the safety analysis set. 
10.3.1. 
Interim Analyses 
There are no planned interim analyses. 
 


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11. 
LIST OF REFERENCES 
Farooqi IS, O’Rahilly S. Mutations in ligands and receptors of the leptin-melanocortin pathway 
that lead to obesity. Nat Clin Pract Endocrinol Metab. 2008;4(10):569-77. 
Fitzpatrick TB. Soleil et peau. J Med. 1975;2:33034. 
Jensen MD, Ryan DH, Apovian CM, Ard JD, Comuzzie AG, Donato KA, et al. 2013 
AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of 
the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines and The Obesity Society. Circulation. 2014;129(25 Suppl 2):S102-38. 
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. 
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Package Insert. U.S. Food and Drug 
Administration. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/213793s001lbl.pdf. 
Revised June 2022. Accessed 23 June 2022.  
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
European Medicines Agency. https://www.ema.europa.eu/en/documents/product-
information/imcivree-epar-product-information_en.pdf. Revised November 2021. Accessed 
22 July 2022.  
Rhythm Pharmaceuticals. IMCIVREE (setmelanotide) Summary of Product Characteristics. 
Medicines and Healthcare Products Regulatory Agency. 
https://mhraproducts4853.blob.core.windows.net/docs/f22032c92d5504e9a5c3270ba2dacde0cc1
7819b. Revised December 2021. Accessed 22 July 2022.  
 


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12. 
APPENDICES 


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APPENDIX 1. LIST OF GENES ELIGIBLE FOR ENROLLMENT 
AND GENETIC TESTING REQUIREMENTS 
Patients with genetic variants in the following genes that have been categorized by a Clinical 
Laboratory Improvement Amendment (CLIA)/College of American Pathologists 
(CAP)/ISO15189 certified laboratory using American College of Medical Genetics (ACMG) 
criteria as (1) pathogenic, (2) likely pathogenic, or (3) a variant of uncertain significance as 
potentially causing dysfunction in the melanocortin-4 receptor pathway and leading to obesity 
are eligible for this trial: 
LEP 
ISL1 
DNMT3A 
TRPC5 
PLXNA4 
NRP1 
SEMA3E 
SEMA3F 
MECP2 
SEMA3A 
SEMA3C 
PHIP 
NRP2 
MRAP2 
MC3R 
CPE 
SEMA3B 
SEMA3D 
SIM1 
HTR2C 
SEMA3G 
KSR2 
MAGEL2 
RPGRIP1L 
TBX3 
PLXNA1 
CREBBP 
PLXNA3 
PLXNA2 
TUB 
 


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GENETIC TESTING REQUIRMENTS:  
Eligibility per Inclusion Criterion #1 and assignment to the appropriate sub-study cohort will be 
based on either: 
a. genetic diagnosis made by a CLIA/CAP/ISO15189 laboratory, or  
b. genetic report available at screening from a non-CLIA/CAP/ISO15189 laboratory, 
sent for review and adjudication via Variant Interpretation Service (VIS) conducted 
by PreventionGenetics (PG), a CLIA/CAP/ISO15189 certified laboratory.  
In addition to the eligibility testing described above, all patients will have confirmatory 
diagnosis made based on the PG Uncovering Rare Obesity (URO) 3.0 panel (79 genes 
+1 chromosomal region).  
All randomized patients will be included in the safety and Full Analysis Set (FAS) analyses. The 
Per-Protocol (PP) analysis will only include patients whose confirmatory diagnosis testing 
matches the respective sub-study cohort assignment. There are 3 potential scenarios for sub-
study cohort assignment:  
• If at Screening the genetic diagnosis is derived from PG, a CLIA/CAP/ISO15189 
certified laboratory (URO 3.0 panel), the patient will be assigned to the cohort 
reported in the PG URO 3.0 genetic report. A genetic sample will be taken for 
confirmatory testing, unless waived by the Sponsor.  
• If the genetic diagnosis is derived from a non-CLIA/CAP/ISO15189 laboratory (such 
as a research academic center laboratory), the genetic report will be reviewed and 
adjudicated by PG for VIS before the patient enters Screening. The VIS result will be 
utilized for cohort assignment. A genetic sample will be taken either at the time of 
screening or at Study Visit 1 (V1) and confirmatory testing will be run using the PG 
laboratory. If the confirmatory genetic report does not confirm the initial genetic 
diagnosis and sub-study cohort assignment, then patients will be included in the 
safety and FAS analyses only, and not in the PP analysis.  
• If the genetic diagnosis is derived from a CLIA/CAP/ISO15189 laboratory, other than 
PG, no PG VIS review is required. A genetic sample will be taken either at the time 
of screening or at V1 and confirmatory testing will be run using the PG laboratory.  
All patients will have genetic samples processed for confirmatory genetic testing. Where 
permitted by law, all patients may provide additional informed consent to have genetic samples 
stored for future research purposes.  
 


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APPENDIX 2. CONSIDERATIONS FOR REDUCING PAIN AND 
DISTRESS IN THE PEDIATRIC POPULATION 
Although the trial procedures and assessments required per protocol are classified as “No or 
Minimal Risk” according to the 2008 Guidance Document “Ethical Considerations for Clinical 
Trials on Medicinal Products Conducted with the Paediatric Population”, considerations for 
reducing pain and distress in participants <18 years of age are suggested below. 
• The clinical trial may only be conducted if it exposes the person concerned to as little 
burden and other foreseeable risks as possible. 
• Physical and emotional pain should be prevented as much as possible, and effectively 
treated when unavoidable. 
• In order to minimize pain, distress, and fear, facilities should be appropriate to 
childcare, and the personnel should be trained to look after children and supervised by 
experienced health care professionals. Staff should be trained to communicate with 
both parents (or legal representative) and children. Generally, this would assume non- 
adult patients are being studied at experienced pediatric centers. 
• For most procedures, the child should always be accompanied by a trial-related staff 
member who could provide reassurance. At the sign of distress and/or dissent, the 
procedure should be stopped. A short pause to allow the child to feel in control, 
further explanation, and an assessment of the situation may be needed to reassure the 
child, or to decide to definitely abandon the procedure at the discretion of the 
Investigator. 
• In all situations, investigations/interventions should be limited to the minimum 
required for obtaining valid data and performed using size-/age-appropriate material 
and devices, including limiting in advance the number of attempts for sampling. 
• Trial medication injections should only be performed by caregiver (or home health 
care professionals), unless the child is of suitable age and competency, and desires the 
ability to do so. 
• Although almost all trial procedures are classified as low risk, risk should be 
continuously monitored and assessed by appropriate personnel. 
• For assessments in which there is a psychological component, measures should be 
taken to minimize distress. For example, Tanner Staging assessments could utilize a 
diagram for the child to point to and indicate what stage they currently are, vs. having 
to have an examination without clothes. 
A comment on benefit risk: Risk is very low, from procedures and/or known safety profile of 
the drug (both clinically and toxicologically, where large margins and preliminary data from 
juvenile toxicology studies have not identified any new or concerning safety concerns) and based 
on representative examples of rare genetic diseases of obesity impacting the MC4R pathway, 
there is the possibility of major benefit. 


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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 TB. Soleil et peau. J Med Esthet. 1975;2:33034. 




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APPENDIX 5. ADVERSE EVENTS: DEFINITIONS AND 
PROCEDURES FOR RECORDING, EVALUATING, FOLLOW-
UP, AND REPORTING 
Definition of Adverse Event (AE) 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical trial patient, temporally 
associated with the use of trial treatment, whether or not considered related to the trial treatment. 
• 
NOTE: 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 trial treatment. 
 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
Investigator (i.e., not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after trial treatment administration even though it may have 
been present before the start of the trial. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either trial treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE. 
 


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Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the Investigator to be more 
severe than expected for the patient’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the trial that do not worsen. 
Definition of Serious Adverse Event (SAE) 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term ‘life-threatening’ in the definition of ‘serious’ refers to an event in which the patient was 
at risk of death at the time of the event. It does not refer to an event, which hypothetically might 
have caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g., 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 


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A SAE is defined as any untoward medical occurrence that, at any dose: 
f. 
Important medical event 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in 
hospitalization, or development of drug dependency or drug abuse. 
Recording and AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the Investigator to review all documentation 
(e.g., hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The Investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the Investigator to send photocopies of the patient’s medical records in lieu 
of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested. In this case, 
all patient identifiers, with the exception of the patient number, will be redacted on the copies of 
the medical records before submission. 
• 
The Investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
 
Assessment of Intensity 
Intensity of all AEs including clinically significant treatment-emergent laboratory abnormalities, 
injection site reactions and potential systemic reactions will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. The CTCAE grade 
refers to the severity of the AE and ranges from Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 
(severe AE), and Grade 4 (life-threatening or disabling AE) to Grade 5 (death related to AE). 
Adverse events not listed by the CTCAE will be graded as follows: 
• 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities.  
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should 
not be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
 


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Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between trial treatment and each occurrence 
of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments 
to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The Investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to trial treatment administration will be considered 
and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 
• 
For each AE/SAE, the Investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the Investigator has minimal 
information to include in the initial report. However, it is very important that the Investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data. 
• 
The Investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to the use 
of the trial medication, 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 trial medication exposure and onset of the AE. 
• 
Whether the manifestations of the AE are consistent with known actions or toxicity of the trial 
medication. 
• 
The AE resolved or improved with decreasing the dose or stopping use of the trial medication 
(dechallenge). Judgment should be used if multiple products are discontinued at the same time. 
The causal relationship between the trial medication and the AE will be assessed using one of the 
following categories: 
• 
Not Related: Factors consistent with an assessment of Not Related include: 
− 
Temporal relationship is lacking (e.g., the event did not occur within a reasonable time frame 
following administration of the trial medication); or 
− 
Other causative factors more likely explain the event (e.g., a pre-existing condition, other 
concomitant treatments). 
• 
Related: Factors consistent with an assessment of Related include: 
− 
There is a "reasonable possibility" of a relationship; i.e., there are facts, evidence, and/or 
arguments to suggest a causal relationship (not just that “a relationship cannot be ruled out”); 
− 
There is a positive temporal relationship (e.g., the event occurred within a reasonable time 
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Assessment of Causality 
− 
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 trial medication). 
 
Follow-up of AEs and SAEs 
• 
The Investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested to elucidate the nature and/or causality of 
the AE or SAE as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals. 
• 
If a patient dies during participation in the trial or during a recognized follow-up period, the 
Investigator will provide a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The Investigator will submit any updated SAE data to the Sponsor within 24 hours without undue 
delay but no later than within 24 hours of receipt of the information. 
 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE will be the electronic data collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the trial is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a trial patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then 
the site can report this information on a paper SAE form (see next section) or by telephone. 
 
SAE Reporting via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information 
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier 
service. 
• 
Initial notification via telephone does not replace the need for the Investigator to complete 
and sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting will be provided to sites. 
 


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APPENDIX 6. GUIDANCE ON TRIAL CONDUCT DURING THE 
COVID-19 (CORONAVIRUS) PANDEMIC 
The Coronavirus Disease 2019 (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 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 Schedule of Assessments via a home visit, 
including but not limited to collection of body weight, vital signs, physical 
examinations, electrocardiograms (ECGs), recording of adverse events (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 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 caregiver 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 case report form (CRF). 
• If a patient is unable to attend a site visit, investigational product may be shipped to 
directly to the patient. 
Note that remote monitoring for COVID-19 will include source data verification.  
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 


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positive test results for SARS-COV-2 should have this recorded as an AE, and if hospitalized, 
this should be reported as a serious AE (SAE). 


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APPENDIX 7. TRIAL GOVERNANCE CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This trial will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, informed consent form (ICF), IB, and other 
relevant documents (e.g., advertisements) must be submitted to an Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC) by the Investigator and 
reviewed and approved by the IRB/IEC before the trial is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before 
implementation of changes made to the trial design, except for changes necessary to 
eliminate an immediate hazard to trial patients. 
• The Investigator will be responsible for the following: 
− Providing written summaries of the status of the trial to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
− Notifying the IRB/IEC of serious adverse events (SAEs) or other significant 
safety findings as required by IRB/IEC procedures 
− Providing oversight of the conduct of the trial at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the 
IRB/IEC, European regulation 536/2014 for clinical studies (if applicable), and all 
other applicable local regulations 
Financial Disclosure 
Investigators and sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the trial and for 
1 year after completion of the trial. 
Informed Consent Process 
• The Investigator or his/her representative will explain the nature of the trial to the 
patient or his/her legally authorized representative and answer all questions regarding 
the trial. 
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 


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meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB/IEC or trial center. 
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the trial and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the trial. 
• A copy of the ICF(s) must be provided to the patient or the patient’s legally 
authorized representative. 
• Patients who are rescreened are required to sign a new ICF and will retain their 
unique identifier. 
Data Protection 
• Patients will be assigned a unique identifier by the Sponsor. Any patient records or 
datasets that are transferred to the Sponsor will contain the 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/IEC members, and by inspectors from regulatory 
authorities. 
Data Quality Assurance 
All patient data relating to the trial will be recorded on printed or electronic case report forms 
(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/IEC 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. 


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The Sponsor or designee is responsible for the data management of this trial including quality 
checking of the data. 
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, 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 of patients and integrity of the patient data. 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 
• Remote Data Verification (rDV) visits 
• Audio Data Verification (ADV) visits: An alternative approach for remote data 
verification of critical patient data, when the CRA asks Investigator site staff member 
to read patient source documents during a telephone call while reviewing the 
electronic Case Report Form (eCRF) to verify patient safety is protected and the data 
reported by Investigator (e.g., in the CRF) is accurate and complete 
• Video Source Data Monitoring visits: Process for conducting SDM 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 (SMC) visits 
Depending on the local regulations, some of these types of rIMV may be allowed or not. 
Records and documents, including signed ICFs, 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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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 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. 
Trial, Site, or Cohort Closure 
The Sponsor reserves the right to close a trial cohort or 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 
sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a trial site by the Sponsor or Investigator may include but are not 
limited to: 
For trial termination: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Discontinuation of further trial intervention development.  
For site termination: 
• Failure of the Investigator to comply with the protocol, the requirements of the IRB 
or local health authorities, the Sponsor's procedures, or GCP guidelines. 
• Inadequate or no recruitment (evaluated after a reasonable amount of time) of 
participants by the Investigator. 
• Total number of participants enrolled earlier than expected. 
• Insufficiently complete and/or evaluable data 
For cohort termination: 
• Plans to modify, suspend or discontinue the cohort 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
Investigators, the IRBs/IECs, the regulatory authorities, and any contract research 
organization(s) involved in the trial of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The Investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up. 


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Publication Policy 
All information regarding setmelanotide supplied by the Sponsor to the Investigator or generated 
as a result of any clinical studies is privileged and confidential information belonging to the 
Sponsor. The Investigator agrees to use Sponsor’s 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 studies 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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APPENDIX 8. DEVICES USED FOR VIRTUAL VISITS 
Detailed information pertaining to each device used, including manufacturer and model number, 
are maintained within in the following trial documents: 
• Connected Device Operations Plan. 
• Investigator Manual for Weight Scale, Blood Pressure and Temperature Data 
Monitoring. 
• Subject Reference Guide for each device (adult and pediatric versions). 
All devices (including any new devices) outlined in trial documents will meet the same standards 
and requirements in accordance with the Food and Drug Administration’s (FDA’s) guidance for 
industry, Digital Health Technologies for Remote Data Acquisition in Clinical Investigations. If 
new devices are added due to regional considerations, the trial documents will be updated 
accordingly. 
Devices may vary by region and age of the participant; however, all devices are either calibrated 
at the time of manufacture or are self-calibrating with every use (weight scales). All trial 
participants will receive a device and a hot spot for data transmission. Devices are assigned by 
site to each participant using non-identifying trial participant information (date of birth, gender 
and Subject ID number). Data are transmitted to a dedicated and secure Carematix portal and are 
password protected for site access. Transmitted data are entered into the eCRF by delegated site 
staff, and are100% verified by clinical research associates (CRAs) during monitoring. Out-of-
range values are flagged to the site for follow-up and any queries are documented through a 
written data clarification form (DCF) process.  
 
 

SAP_001.pdf: 


















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Patients with genetic variants in the following genes that have been categorized by a Clinical 
Laboratory Improvement Amendment (CLIA)/College of American Pathologists 
(CAP)/ISO15189 certified laboratory using American College of Medical Genetics (ACMG) 
criteria as (1) pathogenic, (2) likely pathogenic, or (3) a variant of uncertain significance as 
potentially causing dysfunction in the melanocortin-4 receptor pathway and leading to obesity 
are eligible for this trial. The genes eligible for enrollments are as following: 
 
LEP, ISL1, DNMT3A, TRPC5, PLXNA4, NRP1, SEMA3E, SEMA3F, MECP2, SEMA3A, 
SEMA3C, PHIP, NRP2, MRAP2, MC3R, CPE, SEMA3B, SEMA3D, SIM1, HTR2C, SEMA3G, 
KSR2, MAGEL2, RPGRIP1L, TBX3, PLXNA1, CREBBP, PLXNA3, PLXNA2, TUB and 
OTHER. 
 
E. 
Assessment Schedule 
 
Refer to Appendix XII. 
 
IV. 
Interventions 
 
A. 
Treatment Administration 
 
Trial drug will be administered as a subcutaneous (SC) injection once daily (QD). 
Patients 12 years of age and older: Setmelanotide 2 mg QD for approximately 2 weeks, then 
increased to setmelanotide 3 mg QD for the remainder of the trial. Dose escalation should 
occur at the trial visit planned for Day 14 (±3 days) and should occur on the day of that visit. 
Note: if the starting dose of setmelanotide is not tolerated reduce to 1 mg QD; the lowest 
target dose in patients ≥12 years of age is 1.0 mg QD; however, in consultation with the 
Medical Monitor, the dose may be lowered to 0.5 mg QD if not tolerated. 
 
Patients 6 to <12 years of age: Setmelanotide 1 mg QD for approximately 1 week, then 
increased to setmelanotide 2 mg QD for approximately 1 week, then increased to 
setmelanotide 3 mg QD for the remainder of the trial. Dose escalation should occur during the 
phone call planned for Day 7 (±2 days) and at the trial visit planned for Day 14 (±3 days) and 
should occur on the day of that visit. Note: if the starting dose of setmelanotide is not tolerated 
reduce to 0.5 mg QD; the lowest target dose in patients 6 to <12 years of age is 0.5 mg QD. 
 
All changes in dose other than the per-protocol dose titration should be captured as a protocol 
violation, regardless of the rationale for the dose adjustment. Trial drug administration will be 
interrupted if certain safety parameter criteria are met, and additional assessments may be 
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V. 
General Analytical Considerations 
 
A. 
Data Sources 
 
All information requested in this protocol will be recorded on the electronic Case Report 
Forms (eCRFs) provided by the Sponsor or its designee (or via other data collection methods, 
eg, electronic laboratory data transfer or electronic patient reporting devices). 
 
B. 
Blinding Considerations 
 
Due to the nature of the study additional blinding considerations need to be made for Stage 2. 
The weight and BMI data in Stage 2 are considered blinding and therefore will be populated 
with dummy data for blinded outputs.   
 
All blinded team members will maintain the blind until the end of the study and the database is 
locked.   
 
C. 
Study Stage 
 
This study has two stages, open-label stage followed by a randomized double-blind, placebo-
controlled stage.  
In general, unless otherwise specified, events or measurements happen before the 
randomization date are in Stage 1 and happen on or after the randomization date are in Stage 
2. For patients who are not randomized, all events or measurements are in Stage 1. All events 
happening after visit 14 will not be considered as in Stage 2 for patients who enrolled into 
bridging visit unless otherwise specified. 
 
D. 
Definition of Baseline 
 
Baseline Definition 
 
Baseline will be defined as the last non-missing measurement taken prior to the start of stage 
1 open-label treatment administration. In the case where the last non-missing measurement 
and the reference start date coincide and time of measurement is not available, that 
measurement will be considered Baseline unless the assessment was scheduled to be post-
study drug administration in the SOA. Change from baseline is defined as the post-baseline 
value minus the baseline value, unless specified otherwise. Percent change from baseline = 
(Change from Baseline/Baseline) x 100. 
 
Study Day 
 
Study Day will be calculated from the reference start date within stage and will be used to 
show start/stop day of assessments and events. Reference start date is defined as the day of 
first dose (Day 1) in stage1. 
 
Study Day will be computed as follows: 
 




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For patients who do not have BMI value at the end of Stage 1 (Week 16), the unscheduled or 
early termination weight measurement mapped into Week 16 per visit window will be used for 
the primary analysis. If weights are measured in triplicate within a same date, the average of 
the triplicates will be calculated before the BMI calculation. The latest height value will be 
used together to derive the missing Week 16 BMI.  
 
For patients who still do not have BMI value after above imputation at Week 16, they are 
treated as non-responder for the primary. 
 
Missing or Partial Adverse Event and Medication Start or Stop Date: 
For partial start dates: 
 
• If the year is unknown, no imputation will occur.  
• If the year is known and the month and day is unknown, then: 
o If the year matches the year of the first dose date, then impute the month and the 
day the same as first dose date. 
o If the year is not the same year of the first dose, then month and day will be imputed 
as 01 January. 
• If the month and year is known and the day in unknown, then: 
o If the month and year match the month and year of the first dose date, then impute 
the day the same as first dose date. 
o If year and month is not the same as the first dose date, then the day will be 
imputed as “01”. 
 
For partial end-dates: 
 
• If the year is missing, no imputation will be performed, and the AE/CM will be assumed 
as ongoing. 
• If the year is present and both month and day are missing and the year is not the same 
as the last study date, then the month and day will be imputed as the last day of the 
year, 31 December. 
• If the year is present and both month and day are missing and the year is the same as 
the last study date, then the month and day will be imputed as the last study date. 
• If the year and month are present and only the day is missing, and the year and month 
is not the same as the last study day then the day will be imputed as the last day of the 
month. 
If the year and month are present and only the day is missing, and the year and month is the 
same as the last study day then the day will be imputed as the last day of the study. 
 
F. 
Genetic Diversity 
 
It is possible that a patient may enter the trial with more than one eligible gene. In this 
situation, all eligible genes will be captured in the database. For analysis purposes, a single 
gene will be considered the “primary gene” for that patient, and the patient will be analyzed 
within that gene cohort. The primary gene will be defined as the eligible gene with the most 


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significant American College of Medical Genetics (ACMG) categorization (e.g., 
Pathogenic>Likely Pathogenic>Variant of Uncertain Significance [VUS]). If two or more 
eligible genes share the same most significant ACMG categorization, then the “primary gene” 
will be defined as the least prevalent gene and the patient will be analyzed within that gene 
cohort. 
 
G. 
Multiple Study Centers 
 
The study is a multicenter trial. Data from all study sites will be pooled for the purpose of 
analyses. No adjustment for study center is planned.    
 
H. 
Covariate Adjustment in Primary Analysis 
 
Covariate adjustment is not applicable for this study as there is not statistical testing for the 
primary analysis. 
 
I. 
Data Safety Monitoring Board 
 
The Data Safety Monitoring Board (DSMB) will meet periodically (i.e., every 3 months) to 
review the cumulative safety data from the study and will make a recommendation to continue 
or modify the study, if needed. The following unblinded data will be presented to the DSMB 
members: 
 
• Demographics 
• Disposition 
• Adverse Events 
• 12-Lead ECG 
• Injection Site Evaluation 
• Skin Examination 
• Hyperpigmentation 
• Fitzpatrick Classification Scale 
• Inclusion/Exclusion Criteria 
• Sexual Function (Male) 
• Sexual Function (Female) 
• Safety Laboratory Data 
• Columbia-Suicide Severity Rating Scale 
• Patient Health Questionnaire-9 
 
J. 
Interim Analysis 
 
An interim analysis will be performed when all patients have completed Stage 1 or terminated 
before Stage 1. All Stage 1 related analyses on this SAP will be summarized. 
 
To avoid any potential bias due to patients still enrolled in the study at the time of the interim 
analysis, an unblinded team member at 
 will be involved in ensuring that any 
data of the Stage 2 are not included in the interim analysis.  
 


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K. 
Multiple Comparisons 
 
There is no statistical testing planned in this study. 
 
L. 
Analysis Set  
 
• Screened Population 
All patients who are screened (including screen failed). 
 
• Safety Analysis Set 
All patients who received at least one dose of trial medication. 
 
o Safety Analysis Set Enrolled in Stage 2 
All patients from Safety Analysis Set who enrolled in stage 2 and received at 
least one dose of trial medication in stage 2. 
 
• Full Analysis Set (FAS) 
All patients randomized in Stage 2 who received at least one dose of trial 
medication (placebo or setmelanotide) after randomization in Stage 2 and have 
baseline weight data. Analyses performed on the FAS will be based on patients as 
randomized. 
 
• Supplemental Analysis Set (SAS) 
All patients who are eligible after the re-confirmatory genetic diagnosis. 
 
M. 
Special Distribution Schedule 
 
Hunger Questions and 
 will be recorded as: 
 
Stage 1 
Daily [Scenario 1] during the Screening Period, [Scenario 2] for 7 consecutive dates after the 
enrollment visit, [Scenario 3] for 7 consecutive days starting at Study Days 28, 56, and 84, 
and [Scenario 4] up to 14 consecutive days starting at Study Day 98. These questionnaires 
should be completed prior to the morning meal (after an 8-hour fast) and prior to dosing in the 
morning. During the Screening Period, the patient must complete these questionnaires at 
least 4 of the 7 days prior to V1 (enrollment visit). If a patient completes V7 (Week 16), and is 
not continuing into Stage 2 of the trial, the patient will stop completing these questionnaires 
after completing V7 (and return the electronic diary, if applicable). 
 
Stage 2 
[Scenario 2] for 7 consecutive days starting at Study Days 140, 168, 196, 224, and 252, and 
[Scenario 4] up to 14 consecutive days starting at Study Day 266 (Week 38). These 


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questionnaires should be completed prior to the morning meal (after an 8-hour fast) and prior 
to dosing in the morning. All patients will stop completing these questionnaires after Visit 14 
(Study Day 280), regardless of whether they have completed the full 14 days of data entry 
(and return the e-diary, if applicable) or at their Early Termination Visit (if applicable).  
 
For continuous outcome measure analyses, a weekly average score will be calculated as an 
arithmetic mean. The baseline score for Stage 1 will still be arithmetic mean of the available 
score values within 7 days before or on the first dosing (Day 1). For visits in [Scenario 2], 
[Scenario 3] and [Scenario 4], arithmetic mean of up to 7 measurements that are closest to 
and before the scheduled visit date will be calculated. For example, measurements taken 
between Day 1 (V1) to Day 14 (V2) will be labeled as Day 14 (V2) measurement on the table 
display. 
 
N. 
Data Display Characteristics 
 
Data displays produced for this study will include three types—summary tables, data listings, 
and figures.  Unless stated otherwise, data listings will be produced for all recorded data.  
Summary tables will be produced as specified in following sections.  Additional data listings 
will be produced for outcome measures that involve extensive procedures to derive the 
analyzed outcomes.  Figures will be produced when specified in sections to follow. 
 
Listings in general will be presented by gene cohort, stage, then treatment (active and 
placebo) unless otherwise specified. 
 
Data listings will simply list the data recorded on the CRF or derived for each patient.  When 
expedient, additional levels of ordering hierarchy may reflect subsets of assessments within 
patient.  Data listings will not display patient initials. 
 
Tables in general will be presented by stage unless otherwise specified. In which stage 1 will 
be presented by overall, each gene in SEMA 3 gene cohort, and gene cohort, stage 2 will be 
present by overall, each gene in SEMA 3 gene cohort, gene cohort, and treatment (active and 
placebo). 
 
Tables may have either of two general layouts.  When the greatest interest is in direct 
comparison of one treatment group with the other at particular times, different columns of a 
summary table will display the statistics for the different treatment groups.  The placebo group 
statistics will be displayed to the left of the treatment group statistics.  When the evolution of 
statistics over time is of greater concern than comparison at particular moments, a group of 
rows may be designated for the placebo group; the table columns would be designated for 
different summary statistics of interest.  A subsequent group of rows would then be used for 
the treatment group.  In this layout, a group of rows that represent a treatment group would 
generally be ordered chronologically.  
 
The summary statistics displayed will be a function of the type of data associated with the 
summarized assessment.  Unless stated otherwise in relevant sections to follow, continuous 
data will be summarized with the number of nonmissing values, mean, standard deviation, 
minimum, first quartile (Q1), median, and maximum, third quartile (Q3). Categorical data will 


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be summarized with the number of nonmissing values and the numbers of values equal to 
each of the possible values.  Percentages of patients with each of the possible values will be 
calculated from the number of patients in the corresponding analysis population, unless stated 
otherwise.  Some continuous variables may also be grouped into categorical levels and 
evaluated in frequency tables. 
 
O. 
Blinded Review of Data 
 
After all study data have been collected but prior to examining any study outcome data by 
treatment group, the data will be reviewed by the study statistician to determine whether any 
clarifications or changes to the analysis plan are needed.  Any revisions made to the analysis 
plan as a result of the blinded review of the data will be documented. 
 
P. 
Software Version 
 
All analyses will be conducted using SAS Enterprise Guide 7.1 (64-bit) or SAS version 9.4 
(64-bit). 
 
Q. 
Gene Cohort Analysis 
 
Gene cohort in this SAP is defined as group of patients with specified primary gene(s). In 
details, please see below for the grouping: 
 
Gene Cohort 
Genotype 
SEMA3 Pathway 
NRP1, NRP2, PLXNA1, PLXNA2, PLXNA3, PLXNA4, SEMA3A, 
SEMA3B, SEMA3C, SEMA3D, SEMA3E, SEMA3F, SEMA3G 
PHIP 
PHIP 
SIM1 
SIM1 
MAGEL2 
MAGEL2 
Other 
TRPC5, MRAP2, HTR2C, KSR2, TBX3, LEP, ISL1, DNMT3A, 
MECP2, MC3R, CPE, RPGRIP1L, CREBBP, TUB 
 
After a patient enrolls in the trial, the pre-identified primary gene is reconfirmed or may be 
reclassified with the 
 and manual blind review 
during the trial.  A supplemental analysis with the re-confirmative classification of genes will 
be conducted.  
 
VI. 
Patient Accountability 
 
All patients in safety analysis set will be used for below analyses unless otherwise specified. 
The table and listing display for all analyses below will follow section V.N unless otherwise 
specified. 
 
A. 
Patient Demographic and Baseline Characteristics 
 
Patient demographic and baseline characteristics will include the patient’s age [6 to <12, 12 to 
<18, and 18 to ≤65 years of age], sex [Child-bearing potential if female], ethnicity, race, weight 


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at baseline, height at baseline, BMI at baseline, waist circumference at baseline, genotype, 
skin type from Fitzpatrick Classification Scale assessment.  
 
Demographic and baseline characteristics will be tabulated for stage 1 and stage 2 
separately, and listing will be included for all patients.  
 
B. 
Disposition 
 
Stage 1 
 
All screened patients will be included in this analysis. Patient disposition will include the 
number of patients screened and patients screen failed, number and percentage of patients in 
safety analysis set, number and percentage of completion status at end of treatment (with 
discontinuation reason) and at end of study (with discontinuation reason).  
 
Stage 2 
 
All patients randomized into stage 2 will be included in this analysis. Patient disposition will 
include number of patients in FAS, number and percentage of completion status at end of 
treatment (with discontinuation reason), at end of study (with discontinuation reason). Patients 
who have finished visit 14 and enrolled into bridging visit will be considered as Competed in 
the end of treatment in stage 2. 
 
Disposition listing will be included for all patients. 
 
C. 
Protocol Deviations  
 
Protocol deviations will be classified as major and minor.  
 
All protocol deviations will be listed for all patients.  
 
 
D. 
Historic Measurements and Interventions 
 
D.1. Medical History Weight Loss Interventions 
A listing will be included to provide information about weight loss intervention program and its 
start date, end date and outcome of the interventions collected on the “Medical History Weight 
Loss Interventions” eCRF form. 
 
D.2. Historic Height and Weight 
The records of historic height and weight measurements for each patient will be listed.  
 
D.3. Weight History 
All weight history data collected on “Weight History” eCRF form will be listed. 
 


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D.4. Prior Weight Loss Medication History  
All prior weight loss medication history data will be listed. 
 
D.5. Prior Surgery Weight Loss Intervention  
All prior surgeries intended to treat weight or hunger are recorded and will be listed. 
 
D.6. Prior Weight Loss Programs  
All prior treatments (dietary or exercise) intended to treat weight or hunger are recorded on 
the “Prior Weight Loss Medication History” eCRF page and will be listed. 
 
E. 
Medical History 
 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 24.1 Medical history will be tabulated by system organ class and preferred term. A 
listing of medical history will be provided. 
 
VII. Efficacy Analyses  
 
The analysis of the efficacy endpoints in Stage 1 will be performed based on the safety 
analysis set, and the analyses of the efficacy endpoints in Stage 2 will be performed based on 
the full analysis set (FAS). End of Stage 1 in below section will refer to the measurement 
collected at Week 16 and end of Stage 2 will refer to Week 40, unless otherwise specified. 
The tabulation and listing formats for all analyses below will follow section V.N unless 
otherwise specified. 
 
A. 
Efficacy Assessments 
 
A.1 Weight 
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 kg if reported with a digital scale, or half kg with a 
mechanical scale. Weight measurements will be collected in triplicate. Only in-person visits 
measurements will be summarized in tables. 
 
 
 
 
 
 
 
 


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A.3 Height 
For patients ≥21 years of age, height is to be measured at Screening only. For patients aged 
<21 years, height is to be measured at the time points listed in the SoA. Only in-person visits 
measurements will be summarized in tables. 
 
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. 
 
A.4 BMI and BMI Z-score calculation 
The Body Mass Index (BMI) will be calculated as weight (kg) / [height (m)]2. In the case where 
there are measurements in triplicate, the average of the triplicates will be calculated before 
the BMI calculation.  
 
BMI z-score for patients < 18 years will be calculated according to the Centers for Disease 
Control and Prevention (CDC) Growth Charts. The LMS-based BMI z-score is calculated as: 
 
BMI z-score = ((value / M)**L) – 1] / (S * L)  
 
where L, M, S are given in XII. Appendix 1 according to patients’ gender and age at 
screening. 
 
Only in-person visits measurements will be summarized in tables. 
 
B. 
Primary Efficacy Analysis 
 
The primary efficacy endpoint is the proportion of patients by gene cohort who demonstrate a 
significant clinically meaningful response (defined below) to setmelanotide at the end of Stage 
1: 
• For all patients: ≥5% reduction in BMI from Baseline  
A table with frequency count and percentage of patients who have met the meaningful 
response will be tabulated. The 95% exact confidence interval will also be included. 
 
C. 
Secondary Efficacy Analyses 
 
For the below list of secondary endpoints, summary statistics will be provided for the 
continuous endpoints while proportion and percentage will be provided for the categorical 
endpoint. The analyses of the continuous endpoints are presented by gene cohort and by visit 
unless otherwise specified.  
 


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• Mean change and percent change in BMI from Baseline to end of Stage 1 in all patients 
and patients ≥18 years old, per gene cohort  
o The 95% confidence interval with Student t-distribution will also be provided for 
the mean percent change in BMI from Baseline 
• Mean change and percent change in body weight from Baseline to end of Stage 1 in 
patients ≥18 years old, per gene cohort 
• Mean change in BMI Z-score from Baseline to end of Stage 1 in patients <18 years old, 
per gene cohort 
• Mean percent change in the weekly average of the daily maximal hunger score from 
Baseline to end of Stage 1 in patients ≥12 years old, per gene cohort 
• The proportion of patients ≥12 years old, per gene cohort, who achieve a ≥2-point 
reduction (improvement) from Baseline to end of Stage 1 in the weekly average of the 
daily maximal hunger score 
o Patients ≥12 years old with no measurement at the end of Stage 1 will be 
treated as a non-responder.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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VIII. Questionnaires 
 
All patients in safety analysis set will be used for below analyses in Stage 1 and FAS in Stage 
2 unless otherwise specified. The tabulation and listing formats for all analyses below will 
follow section V.N unless otherwise specified. 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 


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G. 
Nutrition and Exercise Counseling 
 
All nutrition and exercise counseling will be listed for all patients in Safety analysis set. 
 
IX. 
Safety Analyses 
 
All patients in safety analysis set will be used for below analyses in Stage 1 and in Stage 2 
unless otherwise specified. The tabulation and listing formats for all analyses below will follow 
section V.N unless otherwise specified.  
 
A. 
Exposure 
 
A.1 
Study Treatment Exposure 
 
Duration of study treatment (days) will be calculated within each of the two study stages 
(stages are defined in section V.C) based on below formula: 
 
Duration = Date of last administration – Date of first administration + 1 
 
Summary statistics will be provided. For patient enrolled in Stage 2, the date of last 
administration will be the latest record before randomization date in Stage 1 analysis. And the 
date of first administration will be the first record on or after randomization date in Stage 2 
analysis. The date of last administration in Stage 2 will be the record on visit 14 or last 
administration record before the first bridging visit (if visit 14 record is not available) for 
patients enrolled into bridging visit. 
 
A.2 
Study Treatment Compliance 
 
Compliance to dosing will be monitored throughout the trial by having the patient/caregiver 
complete a daily dosing log. 
 
Compliance will be calculated within each of the two study stages as: 
 
Compliance (%) = # of actual administration / # of expected administration*100 
 
Where: 
 
# of actual administration = number of administrations from daily dosing diary 
# of expected administration = (Date of last administration – date of first administration 
+1) = Duration 
 


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For patient enrolled in Stage 2, the number of dose administration will be derived from the 
records before randomization date in Stage 1 analysis. And the number of dose administration 
will be derived from the records on or after randomization date in Stage 2 analysis. The 
number of dose administration in Stage 2 or last administration record before the first bridging 
visit (if visit 14 record is not available) will be derived from the records before and on visit 14 
for patients enrolled into bridging visit. 
 
 
A.3 
Dose Level Changes 
 
The frequency and percentage of reasons for dose level change will be provided (excluding 
reason ‘Per Protocol Planned Escalation’). A patient could have more than one dose level 
changes. 
 
All study treatment administration and dose level changes data will be listed by stage. 
 
B. 
Adverse Events 
 
All adverse events will be coded according to the Medical Dictionary for Regulatory Activities 
(MedDRA) version MedDRA24.1.  
 
A treatment-emergent adverse event (TEAE) is defined as following: 
 
Stage 1 
 
An adverse event will be considered as treatment-emergent adverse event in Stage 1 period 
as following: 
• 
If the start date is completely missing and end date is on or after Stage 1 
treatment administration and before Stage 2 treatment administration and it is not 
ongoing. 
• 
Or the event start date is on or after the Stage 1 treatment administration but 
before the first Stage 2 treatment administration. 
 
Stage 2 
 
An adverse event will be considered as treatment-emergent adverse event in Stage 2 period 
as following: 
• 
If the start date is completely missing and end date is after Stage 2 treatment 
administration or ongoing. 
• 
Or the event start date is on or after the Stage 2 treatment administration. 
• 
Any events happening 30 days after the dosing date at visit 14 will not be 
considered as TEAE in stage 2 
 
The number and percent of patients experiencing a treatment-emergent adverse event will be 
summarized by stage. Patient who reports multiple treatment-emergent AEs within the same 
System Organ Class (SOC) and/or Preferred Term (PT) will be counted only once for that 
SOC and/or PT. The most severe PT will be counted if the patient has different severities 


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within same PT. AE missing relationship will be imputed as ‘Related’. AE missing CTCAE 
grade will be imputed as ‘Grade 3 - Severe’. 
 
An overall summary will be prepared for the following type of AEs : 
 
• Any TEAE 
• Any TEAE related to study drug 
• Any serious TEAE 
• Any serious TEAE related to study drug 
• Any TEAE with CTCAE grade 3 or higher 
• Any TEAE leading to drug permanently discontinued 
• Any TEAE leading to drug permanently discontinued and related to study drug 
 
Separate summaries will be prepared for the following types of treatment-emergent AEs by 
stage and treatment group: 
 
• By SOC and PT 
• By SOC and PT for study drug related events 
• By SOC and PT for serious events 
o By SOC and PT for treatment related serious events 
• By SOC, PT and maximum CTCAE grade 
o By SOC, PT and maximum CTCAE grade for study drug related events 
• By SOC and PT for event with CTCAE grade 3 or higher 
• By SOC and PT for events leading to drug permanently discontinued 
o By SOC and PT for study drug related events leading to drug permanently 
discontinued 
 
All AE data will be listed in one listing by cohort and treatment and a column to indicate the 
period of the AE occurs. Separate AE listings will be created for SAE, AE with CTCAE Grade 
3 or higher and AE leading to Drug Permanently Discontinued. 
 
C. 
Injection Site Evaluation 
 
Frequency and percentage of injection site reaction (including Erythema, Edema, Induration, 
Itching, Pain or Tenderness, Other) will be tabulated by no reaction or severity (mild, 
moderate, and serve) by stage and visit. Percentage is based on the number of patients with 
assessment performed within each visit. 
 
Injection site reaction data will be presented in listing by stage. 
 
D. 
 Clinical Laboratory Results 
 
Laboratory test results include hematology, coagulation, clinical chemistry, and urinalysis. 
 
Blood samples for a fasting glucose, 
 measurements will be obtained at the time points designated in the 


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SOA. They will follow the analysis in section VII.D and will be analyzed separately from 
laboratory data.  
 
Antidrug antibody will be summarized by visit and be listed separately from laboratory data. 
 
Summaries of actual values and changes from baseline within stage will be presented by 
stage and visit according to SOA. Similarly, summary statistics for the eGFR will be provided.  
 
Low/Normal/High shift from baseline tables within stage will also be provided for hematology, 
coagulation and clinical chemistry. Normal/Abnormal shift from baseline tables within stage 
will also be provided for urinalysis. 
  
Laboratory test results will be presented in data listings.  
 
Pregnancy test will be presented in data listings. 
 
E. 
 Vital Signs 
 
Vital signs include systolic and diastolic blood pressure (mmHg), heart rate (beats/min), 
respiration rate (breaths/min), 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. 
 
All blood pressure and heart rate measurements will be taken in triplicate, approximately 2 
minutes apart. The average of triplicate measurements will first be calculated within each 
patient then used in the summary statistics. 
 
Summary statistics for actual values and changes from baseline within stage will be 
presented. Only in-person visits measurements will be summarized in table. 
 
Vital sign data will also be presented in listing. 
 
F. 
Physical Examination 
 
Tanner staging data will be presented in listing. 
 
G. 
Prior and Concomitant Medications 
 
Prior and concomitant medications (CMs) will be coded using WHO-DD version September 
2021. 
 
G.1 
Prior Medications 
Prior medications are defined as medications with an end date prior to the first dose of study 
drug in Stage 1. Prior medications will be tabulated by Anatomic Therapeutic Chemical (ATC) 
Level 2 classification and Preferred Term (PT) by treatment group and overall. A patient 
having more than one medication within the same ATC Level 2 or preferred term will be 
counted only once for that ATC Level 2 or preferred term. 
 


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G.2 
Concomitant Medications 
Concomitant medications are defined as medications which are taken during the course of 
study stage. A detailed definition will be as following: 
 
Stage 1 
A medication will be considered a concomitant medication in Stage 1 as following: 
 
• If the end date is completely missing and the medication start date is before the Stage 
2. 
• Or the medication start date is before the Stage 2 treatment administration and end 
date is on or after Stage 1 treatment administration or it is ongoing. 
 
Stage 2 
A medication will be considered a concomitant medication in Stage 2 as following: 
 
• If the end date is completely missing  
• Or the medication is either ongoing or end date is on or after Stage 2 treatment 
administration. 
• Any medications happening after the dosing date at visit 14 will not be considered as 
concomitant medication in stage 2 
 
Concomitant medications will be tabulated by ATC Level 2 classification and PT by stage. A 
patient having more than one medication within the same ATC Level 2 or preferred term will 
be counted only once for that ATC Level 2 or preferred term. 
 
A listing of prior and concomitant medications will be provided. 
 
H. 
Concomitant Procedures  
 
Concomitant procedures data will be listed by stage. The definition of stage will follow adverse 
events in IX.B. 
 
I. 
Skin Examination  
 
A comprehensive skin examination will be performed by the Investigator at the time points 
designated in the SOA. 
 
The skin examination should include a full body (head-to-toe skin examination). 
 
Frequency count of most severe outcome across all skin regions within patients will - be 
provided by stage and visit. The severity of the outcome is rated as Abnormal, CS > Anormal, 
Not CS > Normal > Not Done. 
 
Also, the frequency count by skin region with abnormal result will be provided. 
 
All skin examination data will be presented in listing. 


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J. 
Hyperpigmentation  
 
Hyperpigmentation form will be administrated at postbaseline visits.  
 
 
All hyperpigmentation data will be presented in listing. 
 
K. 
Sexual Function  
 
Sexual function forms have different versions between male and female.  
All sexual function data will be presented in listing by version. 
 
L. 
Electrocardiogram 
 
A single 12-lead electrocardiogram (ECG) is performed at the visits designated in the SOA.  
 
ECG measurements include PR interval (msec), RR interval (msec), QRS interval (msec), QT 
uncorrected (msec), QT corrected with Bazzett’s formula (msec), QT corrected with Fridericia 
formula (msec). Summaries of actual values and changes from baseline of these 
measurements will be presented. 
 
A frequency and percentage table of normal, abnormal not clinically significant and abnormal 
clinically significant for overall ECG evaluation will be tabulated. 
 
ECG data will be presented in listing. 
  
M. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
 
The C-SSRS that will be administered to patients ≥6 years of age according to the SOA.  
 
There are two versions of the C-SSRS forms: 
 
1. The Baseline/Screening version of the scale is the initial form of the instrument to 
assess suicidality in a patient’s lifetime. This version can assess a patient’s lifetime 
suicidality for data collection purposes as well as eligibility based on inclusion/exclusion 
criteria. 
 
2. The ‘Since Last Visit’ version of the scale assesses suicidality since the patient’s last 
visit. This version is meant to assess patients who have completed at least 1 initial C-
SSRS assessment and should be used in subsequent visits. The ‘Since Last Visit’ 
version of the C-SSRS is inquiries about any suicidal thoughts or behaviors the 
patient/participant may have had since the last time the C-SSRS was administered. 
 
A frequency and percentage table and a shift from baseline by visit will be provided to display 
the number of patients who have answered at least one ‘Yes’ to: Suicidal Ideation (1-5), 


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Suicidal behavior (6-10), either have suicidal ideation or suicidal behavior (1-10), and the 
question “Non-Suicidal Self-Injurious Behavior”. 
 
In details, the Suicidal Ideation and Suicidal behavior will include questions as below: 
Suicidal Ideation (1-5) 
1. Wish to be dead 
2. Non-Specific thoughts 
3. Ideation without intent to act 
4. Ideation with some intent to act 
5. Ideation with specific plan  
 
Suicidal behavior (6-10) 
6. Preparatory acts or behavior 
7. Aborted attempt 
8. Interrupted attempt 
9. Actual attempt 
10. Completed suicide 
 
All C-SSRS data will be listed. 
 
N. 
Patient Health Questionnaire-9 (PHQ-9) 
 
The PHQ-9 is a 9-item depression scale of the Patient Health Questionnaire and will be used 
for patients ≥12 years of age. After the patient has completed the PHQ-9 questionnaire, it is 
scored by the trial staff. Any patient with a PHQ-9 score ≥10 will be referred to a mental health 
professional (MHP). The PHQ-9 will be administered according to the SOA. 
 
Summary statistics for the score of summation of the 9 items and changes from baseline will 
be provided. Frequency count and percentage of number of patients with score ≥10 will also 
be included. Only scores with all 9 items answered will be summarized.  
 
All PHQ-9 data will be listed. 
 
O. 
Children’s Depression Inventory-2 (CDI-2) 
 
The CDI-2 has both a self-report and a parent version.  
 
The CDI-2: Self-Report Short version is an efficient screening measure that contains 12 items 
and will be administered to patients <12 years of age according to the SoA. 
 
Items on the CDI-2 Parent form correspond to items on the self-report version and are suitably 
rephrased. Item selection for the parent forms was guided to maximize validity, and thus 
focused on observable manifestations of depression. The CDI-2 parent form consists of 17 
items and the 4 choices provided for each item correspond to 4 levels of symptomatology: 0 
(not at all), 1 (some of the time), 2 (often), or 3 (most of the time). The CDI-2 parent version 
will be administered to caregivers of patients <12 years of age according to the SoA. Any 
patient with a CDI-2 score >20 during the trial will be referred to an MHP. 


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Summary statistics for the score of summation of the items and changes from baseline will be 
provided by version. Frequency count and percentage of number of patients with score > 20 
will also be included. Only scores with all items answered will be summarized.  
 
All CDI-2 data will be listed by version. 
 
 


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X. 
Supplemental Analysis 
 
A supplemental analysis deriving from re-confirmatory genetic diagnosis is conducted for 
Primary endpoint, and Secondary endpoints of efficacy for patients in Supplemental Analysis 
Set. 
 
Patients who become ineligible for the trial after the re-confirmatory genetic diagnosis will be 
excluded from the supplemental analysis. 
 
XI. 
Pharmacokinetic Analysis 
 
The trough concentration values will be reported descriptively as mean, standard deviation 
(SD), maximum (Max), minimum (Min), median, and percent coefficient of variation (% CV) 
based on dose and visit. 
 
The PK concentration and ADA will be listed. 
 
 


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XII. References 
 
Altman DG, Dore CJ.  Randomisation and baseline comparisons in clinical trials.  
Lancet 1990; 335(8682): 149-53. 
 
Senn S.  Testing for baseline balance in clinical trials.  Stat Med 1994; 13(17): 1715-26. 




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XIV. Appendix 2:  Schedule of Assessments 
Table 1: 
Schedule of Assessments – Stage 1 
Assessment 
Screenin
g (In-
Person) 
Enrollment 
Visit (IP) 
Phone 
Call† 
Virtual Trial 
Visits 
In-Person 
Trial 
Visits 
Early 
Termination 
Visit (In-
Person) 
Visit Number 
V1 
V1c 
V2, V3, V4, V6 
V5, V7 
Study Week 
1 
2, 4, 6, 12, 
8, 16 
Study Day 
-56 to -
14 
1 
7 
14*, 28, 42, 84 
56, 
112 
Window 
+/-2 
+/-3 
+/-5 
+/-5 
Informed Consent/Assent (1) 
X 
Inclusion/Exclusion 
X 
X 
Genetic Sample (2) 
X 
X 
Optional WES (3) 
X 
X 
Medical History 
X 
X 
Nutrition and physical activity 
counseling and follow-up 
X 
X 
X 
X 
Physical Exam (4) 
X 
X 
X 
X 
Fitzpatrick Classification 
Scale 
X 
Comprehensive Skin Exam 
(5) 
X 
X 
X 
Weight (6) 
X 
X 
X 
X 
X 
Height (7) 
X 
X 
X 
X 
Vital Signs (9) 
X 
X 
X 
X 
X 
ECG (10) 
X 
X 
X 
Pregnancy (11) 
X 
X 
X 
X 
X 
Hunger Questions (12) 
X 
X 
X 
X 
X 




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Trough PK (18) 
X 
X 
X 
Anti-Drug Antibodies (19) 
X 
X 
X 
Biomarkers (20) 
X 
X 
X 
Daily Drug Compliance (21) 
X 
X 
X 
Dispense/Return Trial 
medication (22) 
X 
X 
X 
X 


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Abbreviations: ADA = anti-drug antibodies; CDI-2 = Children’s Depression Inventory -2; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = 
electrocardiogram; 
 
; IP = In Person; 
; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetic; QoL = quality of life; WES = Whole Exome 
Sequencing. 
†  A phone visit should occur on Day 7 (±2 days) for all patients <12 years of age; at this visit dose escalation should occur from 1 to 2 mg once 
daily (QD). 
* Dose escalation (from 2 mg QD to 3 mg QD) should occur at the trial visit planned for Day 14 (±3 days) and should occur on the day of 
that visit. NOTE: Additional assessments may be performed at the Investigator’s discretion as needed to ensure patient safety. 
1 
Although the trial procedures and assessments required per protocol are classified as “No or Minimal Risk” according to the 2008 Guidance 
Document “Ethical Considerations for Clinical Trials on Medicinal Products Conducted with the Pediatric Population,” considerations for 
reducing pain and distress in patients younger than 18 years of age are included in Appendix 2. 
2 
Patients will have a sample collected for confirmatory genetic testing either during Screening or at the Enrollment visit; this only needs to 
be completed 1 time. The Sponsor may waive this requirement for individual patients who have a genetic sample analysis from certain 
testing laboratories. 
3 
All patients will be offered the opportunity to opt-in to having WES performed; a separate blood sample is not required (testing to be 
completed from confirmatory genetic sample collected either during Screening or at the Enrollment visit). 
4 
A complete physical examination will be conducted at Screening and at Visit 7 or the early termination (ET) visit and include review of 
peripheral lymph nodes, head, eyes (including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, lungs, abdomen, 
musculoskeletal including back, extremities and neurologic. At other time points, 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. In addition, Tanner Staging for assessment of pubertal development will be conducted for those patients who have 
yet to reach Tanner Stage V. Whenever possible, the same trained health care professional will conduct the examination and Tanner 
Staging. 
5 
A comprehensive skin evaluation will be performed by the Investigator or designee. The skin examination should include a full body skin 
examination (head- to-toe skin examination). If any concerning lesions are identified during Screening, the patient should be referred to a 
dermatologist. Any concerning lesions identified during the Screening Period will be biopsied and results known to be benign prior to first dose 
of setmelanotide. If the pre-treatment biopsy results are of concern, the patient may be excluded from the trial. Additionally, any lesion or 
significant change in an existing lesion 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) 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 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 Kg if reported with a digital scale, or half 
Kg with a mechanical scale. Whenever possible, the scale should be calibrated on a regular basis per manufacturer’s specifications. 
7 
For patients ≥21 years of age, height is to be measured at Screening only. For patients aged <21 years, height is to be measured at the time 
points listed in the SoA. 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 
 
 


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9 
All vital signs measurements are to be obtained in the sitting position following at least 5 minutes of rest. All measurements will be taken in 
triplicate, approximately 2 minutes apart. When possible, blood pressure (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. For virtual visits, patients will be 
instructed on the proper use of and will be provided with WiFi/Bluetooth connected devices for measuring and transmitting data on blood 
pressure, and temperature during virtual trial visits. The data are stored and automatically transferred when connected to WiFi. 
10 A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest. 
11 A urine pregnancy test may be performed to expedite availability of results prior to dosing on Day 1. Except for virtual visits, all other pregnancy 
tests will be serum tests; dosing may continue with results pending. At sites where pregnancy tests are required for virtual visits, at Visit 1 
women of child-bearing potential will be given urine pregnancy kits for use at each of the virtual visits. 
 
 
 
 
 
 
 
 
 
 
 
 
14 Assessments will only be performed at Study Weeks 4, 8, and 12. 
 
 
16 The Baseline/Screening version of the scale is the initial form of the instrument to assess suicidality in a patient’s lifetime and is administered at 
Screening. In order to be eligible for the trial, a patient at Screening cannot have a suicidal ideation of type 4 or 5, a suicide attempt during the 
patient’s lifetime, or any suicidal behavior in the last month, as per the C-SSRS. After Screening, the ‘Since Last Visit’ version of the scale will be 
used to assess suicidality since the patient’s last visit. If at any time during the trial a patient has a suicidal ideation of type 4 or 5, or any suicidal 
behavior, the patient should be referred to a mental health professional (MHP). 
17 Safety laboratory tests will include: Complete blood count (CBC) with platelet count and standard indices, chemistry panel (includes sodium, 
potassium, chloride, CO2, albumin, total protein, glucose, blood urea nitrogen [BUN], creatinine (including eGFR), 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), and urinalysis with microscopic analysis if 
positive findings on dipsticks warrant further examination. Safety laboratories will also include a coagulation profile (prothrombin time [PT] or 
international normalized ratio [INR], and partial thromboplastin time [PTT] also referred to as activated PTT [aPTT]). 
18 A blood sample for PK will be drawn at the time points indicated before dosing, with dosing performed at the clinic. PK samples will be drawn 
with patients/caregivers being reminded there should be NO trial medication administration at home on the day of clinic visits; the drug will be 
administered in the clinic by the patient AFTER the PK sample is obtained. For the PK sample, the actual collection (clock) time will be recorded. 


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19 Any patient with a positive ADA will be followed every 3 months after the ADA sample analysis until resolution of the ADA. 
20 A biomarker blood sample will be collected for metabolic, inflammation, metabolomic and/or proteomic biomarker analysis. This sample 
may not be analyzed. All samples are sent to a central laboratory. Additional details are described in the laboratory manual. 
21 A daily question querying whether the patient completed their daily injection will be asked via electronic diary. Paper versions can be used, if 
needed. 
22 Dispensing will be made by site staff, using the dispensation function in the Interactive Response Technology (IRT) system, as outlined in the 
SoA. Dispensing may also be made directly to the patient if required and allowed by local regulations. At the Early Termination visit, only drug 
return will apply. 
23 If at any time during the trial an individual patient’s PHQ9 score is ≥10, the patient should be referred to a Mental Health Professional. 
24 The CDI-2 will be administered to patients <12 years of age (self-report short form) and to caregivers of patients <12 years of age (parent 
version). 


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Table 2: 
Schedule of Assessments – Stage 2 
Assessment 
Stage 2 
Entry 
Visit† (In-
Person) 
Virtual Trial 
Visits 
In-Person 
Clinic 
Visits 
End of 
Treatment 
Visit (In-
Person) 
End-of-
Study Visit 
(Telephone) 
22 
Early 
Termination 
Visit (In-
Person) 
Bridging 
Visits (if 
needed) (In-
Person) 
Visit Number 
V7 
V8, V9, V11, 
V13 
V10, V12 
V14 
V15 
Study Week 
16 
18, 20, 28, 
36 
24, 32 
40 
44 
Q12 
weeks 
Study Day 
112 
126, 140, 
196, 252 
168, 224 
280 
Window (1) 
+/-3 
+/- 5 
+/- 5 
+/-3 
+/- 5 
Nutrition and physical activity 
counseling and follow-up 
X 
X 
X 
X 
X 
Physical Exam (2) 
X 
X 
X 
X 
X 
Comprehensive Skin Exam 
(3) 
X 
X 
X 
X 
X 
Vital Signs (7) 
X 
X 
X 
X 
X 
X 
ECG (8) 
X 
X 
X 
X 
Pregnancy (9) 
X 
X 
X 
X 
X 
X 
C-SSRS (14) 
X 
X 
X 
X 
X 
X 
X 
PHQ-9 (21) 
X 
X 
X 
X 
X 
X 
X 


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CDI-2 (23) 
X 
X 
X 
X 
X 
X 
X 




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Abbreviations: ADA = anti-drug antibodies; CDI-2 = Children’s Depression Inventory -2; C-SSRS = Columbia Suicide Severity Rating Scale; ECG 
= electrocardiogram; EOS = end of study; EOT = end of treatment; 
 
; PHQ-9 = Patient Health Questionnaire-9; PK = pharmacokinetic; Q = every. 
†  The Stage 2 Entry visit is the same visit as the final visit from Stage 1. 
NOTE: Additional assessments may be performed at the Investigator’s discretion as needed to ensure patient safety. 
1 
For patients who qualify for Stage 2 at the Week 16 visit in Stage 1, the Stage 2 Baseline Visit (B1) is the same as Week 16 in Stage 1. 
2 
A complete physical examination will be conducted at the Stage 2 entry visit and at the End-of-Treatment Visit. At other time points, 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. In addition, Tanner Staging for assessment of pubertal 
development will be conducted for those patients who have yet to reach Tanner Stage V. Whenever possible, the same trained health care 
professional will conduct the examination and Tanner Staging. Assessment to be performed at Visit 15 only if that is an in-person visit. 
3 
A comprehensive skin evaluation will be performed by the Investigator or designee. The skin examination should include a full body skin 
examination (head- to-toe skin examination). Any lesion or significant change in an existing lesion during the course of the trial must be 
evaluated by a dermatologist and biopsied, if clinically indicated in the opinion of the dermatologist. Assessment to be performed at Visit 15 
only if that is an in-person visit. 
 
 
 
 
 
 
 
 
 
 
 
7 
All vital signs measurements are to be obtained in the sitting position following at least 5 minutes of rest. All measurements will be taken 
in triplicate, approximately 2 minutes apart. When possible, blood pressure (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. For virtual visits, patients 
will be instructed on the proper use of and will be provided with WiFi/Bluetooth connected devices for measuring and transmitting data on 
blood pressure, and temperature during virtual trial visits. The data are stored and automatically transferred when connected to WiFi. 
8 
A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest. 
9 
Except for virtual visits, all other pregnancy tests will be serum tests; dosing may continue with results pending. At sites where pregnancy 
tests are required for virtual visits, at Visit 7 women of child-bearing potential will be given urine pregnancy kits for use at each of the 
virtual visits. 


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12 Assessments will only be performed at Study Weeks 20, 28, and 36. 
 
 
 
 
14 The ‘Since Last Visit’ version of the scale will be used to assess suicidality since the last time the C-SSRS was administered. If at any time 
during the trial a patient has a suicidal ideation of type 4 or 5, or any suicidal behavior, the patient should be referred to a mental health 
professional (MHP). 
15 Safety laboratory tests will include: Complete blood count (CBC) with platelet count and standard indices, chemistry panel (includes sodium, 
potassium, chloride, CO2, albumin, total protein, glucose, blood urea nitrogen [BUN], creatinine (including eGFR), 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), and urinalysis with microscopic analysis if 
positive findings on dipsticks warrant further examination. Safety laboratories will also include a coagulation profile (prothrombin time [PT] or 
international normalized ratio [INR], and partial thromboplastin time [PTT] also referred to as activated PTT [aPTT]). 
16 A blood sample for PK will be drawn at the time points indicated before dosing, with dosing performed at the clinic. PK samples will be drawn 
with patients/caregivers being reminded there should be NO trial medication administration at home on the day of clinic visits; the drug will be 
administered in the clinic by the patient AFTER the PK sample is obtained. For the PK sample, the actual collection (clock) time will be 
recorded. 
17 Any patient with a positive ADA will be followed every 3 months after the ADA sample analysis until resolution of the ADA. 
18 A biomarker blood sample will be collected for metabolic, inflammation, metabolomic and/or proteomic biomarker analysis. This sample 
may not be analyzed. All samples are sent to a central laboratory. Additional details are described in the laboratory manual. 
19 A daily question querying whether the patient completed their daily injection will be asked via electronic diary. Paper versions can be used, if 
needed. 
20 Dispensing will be made by site staff, using the dispensation function in the Interactive Response Technology (IRT) system, as outlined in 
the SoA. Dispensing may also be made directly to the patient if required and allowed by local regulations. At the Early Termination visit, 
only drug return will apply. 
21 If at any time during the trial an individual patient’s PHQ9 score is ≥10, the patient should be referred to a Mental Health Professional. 
22 If required by local regulation or if deemed necessary to assess patient safety by physical examination or after a longer follow-up period, the 
visit may be converted to an in-person visit and/or can occur up to Day 336 (Week 48). If the EOS visit is converted to an in-person visit, a 


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physical examination and a comprehensive skin examination should be completed at that in-person visit. Patients who enroll in the long-term 
extension trial will have the EOS visit at the same time as the EOT visit. 
23 The CDI-2 will be administered to patients <12 years of age (self-report short form) and to caregivers of patients <12 years of age (parent 
version).