Clinical trial NCT05194124
Conditions: Bardet-Biedl Syndrome POMC Deficiency
Keywords: Melanocortin-4 Receptor Pathway Genetic Obesity Hunger Hyperphagia
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2021-12-21; Completion date: 2023-10-19
Enrollment: 19 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A trial to compare the weekly and daily formulations of setmelanotide in participants with genetic defects in the melanocortin-4 receptor pathway.

Detailed description:
This study is designed to compare the safety, pharmacokinetics, and efficacy of weekly and daily formulations of setmelanotide in participants with obesity associated with biallelic or heterozygous POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase subtilisin/kexin Type 1), LEPR (leptin receptor) genetic variants, and participants with Bardet-Biedl Syndrome (BBS).

Arms: arm 1: Participants received subcutaneous (SC) injection of 2 mg setmelanotide once daily (QD) for 1 week in the run-in period. arm 2: Participants received SC injection of 2.5 mg setmelanotide QD for 1 week in the run-in period. arm 3: Participants received SC injection of 3 mg setmelanotide QD for 1 week in the run-in period. arm 4: Participants who received 2 mg setmelanotide QD in the run-in period, received SC injection of 20 mg setmelanotide once weekly (QW) and placebo matched to setmelanotide QD for 13 weeks in the DB period. arm 5: Participants who received 2.5 mg setmelanotide QD in the run-in period, received SC injection of 25 mg setmelanotide QW and placebo matched to setmelanotide QD for 13 weeks in the DB period. arm 6: Participants who received 3 mg setmelanotide QD in the run-in period, received SC injection of 3 mg setmelanotide QD and placebo matched to setmelanotide QW for 13 weeks in the DB period. arm 7: Participants who received 3 mg setmelanotide QD in the run-in period, received SC injection of 30 mg setmelanotide QW and placebo matched to setmelanotide QD for 13 weeks in the DB period. arm 8: Participants who received 2 mg setmelanotide QD in the run-in period and 20 mg setmelanotide QW in the DB period, received SC injection of 20 mg setmelanotide QW for 13 weeks in the OL period. arm 9: Participants who received 2.5 mg setmelanotide QD in the run-in period and 25 mg setmelanotide QW in the DB period, received SC injection of 25 mg setmelanotide QW for 13 weeks in the OL period. arm 10: Participants who received 3 setmelanotide QD in the run-in period and 3 mg setmelanotide QD or 30 mg setmelanotide QW in the DB period, received SC injection of 30 mg setmelanotide QW for 13 weeks in the OL period.
Interventions: intervention 1: Setmelanotide 2 mg intervention 2: Setmelanotide 2.5 mg intervention 3: Setmelanotide 3 mg intervention 4: Setmelanotide 20 mg intervention 5: Setmelanotide 25 mg intervention 6: Setmelanotide 30 mg
Intervention descriptions: intervention 1: Administered as SC injection intervention 2: Administered as SC injection intervention 3: Administered as SC injection intervention 4: Administered as SC injection intervention 5: Administered as SC injection intervention 6: Administered as SC injection

Protocol documents:
Prot_000.pdf: 
Protocol 
 
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SETMELANOTIDE (RM-493) 
RM-493-037 
A Phase 3, Randomized, Double-Blind Trial of Two Formulations of Setmelanotide (Daily and 
Weekly) with a Crossover to Open-Label Once Weekly Setmelanotide in Patients with Specific 
Gene Defects in the Melanocortin-4 Receptor Pathway Who Are Currently on a Stable Dose of 
the Once Daily Formulation  
 
This trial will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
 
 
IND No. 
 
 
EudraCT 
2021-004597-65 
 
 
 
Trial Sponsor:  
Rhyththm P
m Pharma
rmaceutiticals, Inc. 
 
 
 
 
Document Date (Version):  
07 July 2022 (Version 4.0) 
 
 
 
 
 
 
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APPROVAL SIGNATURE PAGE 
Protocol Title:  
A Phase 3, Randomized, Double-Blind Trial of Two Formulations 
of Setmelanotide (Daily and Weekly) with a Crossover to Open-
Label Once Weekly Setmelanotide in Patients with Specific Gene 
Defects in the Melanocortin-4 Receptor Pathway Who Are 
Currently on a Stable Dose of the Once Daily Formulation 
Protocol Number: 
RM-493-037 
Document Version: 
Version 4.0  
Document Date: 
07 July 2022 
 
REVIEWED/APPROVED BY: 
 
 
 
 
 
 
 
Signature  
Date 
 
 
 
Rhythm Pharmaceuticals, Inc. 
 
 
 
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INVESTIGATOR STATEMENT 
Protocol Title: 
A Phase 3, Randomized, Double-Blind Trial of Two Formulations 
of Setmelanotide (Daily and Weekly) with a Crossover to Open-
Label Once Weekly Setmelanotide in Patients with Specific Gene 
Defects in the Melanocortin-4 Receptor Pathway Who Are 
Currently on a Stable Dose of the Once Daily Formulation 
Protocol Number: 
RM-493-037 
Document Version: 
Version 4.0  
Document Date: 
07 July 2022 
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm) 
or its designated representative(s) concerning this trial that has not been published previously 
will be kept in the strictest confidence. This documentation includes the trial protocol, 
Investigator’s Brochure, 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)/Ethics Committee (EC). No changes will be made to the trial 
protocol without the prior written approval of Rhythm and the IRB/EC, 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 (printed) 
 
Investigator Signature 
 
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: 
Setetmelelan
anotide (RM-493): 
 f for daily administration and 
 
 for weekly adm
dmininistration
on 
Title of Trial:  
A Phase 3, Randomized, Double-Blind Trial of Two Formulations of Setmelanotide (Daily and Weekly) 
with a Crossover to Open-Label Once Weekly Setmelanotide in Patients with Specific Gene Defects in 
the Melanocortin-4 Receptor Pathway Who Are Currently on a Stable Dose of the Once Daily 
Formulation 
Trial center(s): This trial will be conducted at multiple trial centers located in the United States (US), 
Canada, and Europe 
Phase of development: 3 
Objectives:  
Primary: 
• 
To compare the pharmacokinetics (PK) of the once daily (QD) and once weekly (QW) formulations 
of setmelanotide 
Secondary: 
• 
To assess the safety of the QW formulation of setmelanotide with up to 6 months (26 weeks) of drug 
administration 
 
 
 
 
 
 
 
  
Methodology:  
This trial is designed to compare the safety, PK, and 
nd 
 of the QW and QD formulations of 
setmelanotide, as well as to evaluate the safety and 
 of
of up to 6 months of QW setmelanotide 
administration in patients with Bardet-Biedl syndrome ( (BBS)
S), biallelic PPL (POMC [pro-
opiomelanocortin], PCSK1 [proprotein convertase subtilisin/kexin Type 1], LEPR [leptin receptor]), or 
heterozygous PPL. Eligible patients are those who are currently taking QD setmelanotide in 
Trial RM-493-022, referred to as the long-term extension (LTE) trial, for at least 6 months with 
acceptable safety and tolerability, and who wish to continue with setmelanotide treatment, and who 
otherwise meet all inclusion and exclusion criteria. Approximately 30 patients will be targeted in 3 age 
groups as follows: approximately 20 patients who are ≥18 years old; approximately 6 patients ≥12 to 
<18 years old; and approximately 4 patients ≥6 to <12 years old at the time of trial entry. 
The trial consists of a Screening Period for transition from the LTE trial, a Run-in Period of up to 1 week 
of continuation on the patient’s current dose level of QD setmelanotide (2, 2.5, or 3 mg), a 13-week 
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double-blind phase in which the patients will be randomized to either QD or QW setmelanotide, a 
13-week non-randomized open-label phase where all patients will receive open-label QW setmelanotide, 
and a 3-week follow-up period in which all patients will return to their run-in dose of QD setmelanotide 
to prepare for re-enrollment into Trial RM-493-022 or to resume the QD formulation in some other way.  
Dur
uring t
ng the
he S
 Screenining P
ng Period,
od, pa
 patientnts w
 will unde
 undergo m
o medidical e eva
valua
uation a
on and 
nd otothe
her trtrial proced
cedures,
es, 
 
 T
 To 
ens
nsur
ure c cont
ontinui
nuity of
y of t treatmentnt, i inf
nfor
ormed c
d cons
onsentnt f for
or t thihis trtriaial will b
ill be o obtatainined a and e elig
ligibibilility
ity of th
 the patient 
will be confirmed before the patient is withdrawn from the LTE trial.  
The patient will have a Run-in Period of 1 day to 1 week on QD setmelanotide at the dose they were on in 
the LTE trial. The first day of the Run-in Period (Visit 2) should coincide with the patient’s last visit in 
the LTE trial to avoid an interruption of treatment. On the first day of the Run-in Period, patients will 
have serial blood samples taken for measurement of setmelanotide concentrations (QD formulation) and 
24-hour PK profiles will be performed. 
On Day 1 (Visit 3), patients will be randomized 1:1 to receive either QD or QW setmelanotide. Patients 
who were on QD setmelanotide at a dose of 2 mg at the time of trial entry will be randomized to receive 
either QD setmelanotide 2 mg or QW setmelanotide at a dose of 20 mg, whereas patients who were on 
QD setmelanotide at a dose of 2.5 mg will be randomized to receive either QD setmelanotide 2.5 mg or 
QW setmelanotide at a dose of 25 mg, and finally patients who were on QD setmelanotide at a dose of 
3 mg will be randomized to receive either QD setmelanotide 3 mg or QW setmelanotide at a dose of 
30 mg. Study medication will be administered in a double-dummy fashion in order to maintain the double 
blind. Patients will receive the first QW dose on Day 1 of the randomized treatment period (Visit 3). The 
randomization will be stratified by age group.  
• Patients randomized to QW setmelanotide will receive blinded QW setmelanotide and QD placebo 
injections until the Week 14 visit (ie, completion of 13 weeks of blinded dose administration). 
Starting with Week 14, patients will continue with open-label QW injections of setmelanotide 
during the 13-week non-randomized phase.  
• Patients randomized to QD setmelanotide will receive blinded QD setmelanotide and QW placebo 
injections until the Week 14 visit (ie, completion of 13 weeks of blinded dose administration). 
Starting with Week 14, patients will continue with open-label QW injections of setmelanotide 
during the 13-week non-randomized phase.  
Prior to the QW dose of study drug at prespecified time points during the double-blind treatment phase, 
predose blood samples will be collected for trough plasma drug concentrations in all patients. At 
Week 14, serial blood samples (including a predose blood sample) will be taken for measurement of 
steady-state setmelanotide concentrations (QD and QW formulations) for a 24-hour PK profile.  
For the 3-week Follow-up Period, all patients will return to their run-in dose of QD setmelanotide. The 
trial design is depicted in the figure below. 
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Abbreviations: PK = pharmacokinetic, QD = once daily; QW = once weekly. 
 
The safety and tolerability of setmelanotide will be assessed by the frequency and severity of adverse 
events (AEs)/serious adverse events (SAEs) and injection site reactions (ISRs), as well as changes in 
physical examination (to include comprehensive skin examination), electrocardiograms (ECGs), vital 
signs (including resting blood pressure [BP] and heart rate [HR]), routine laboratory evaluations, 
development of anti-drug antibodies, and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
 
Number of patients (planned):  
It is intended that a total of ~30 patients will be enrolled in the trial. Patients will come from 3 targeted 
age groups: ≥18 years old (~20 patients), ≥12 to <18 years old (~6 patients), and ≥6 to <12 years old 
(~4 patients). 
Diagnosis and main criteria for inclusion: 
Patients with BBS, biallelic PPL, and heterozygous PPL who have been on open-label QD setmelanotide 
treatment for at least 6 months with acceptable safety and tolerability, and the dose level must have been 
stable at 2, 2.5, or 3 mg of setmelanotide for at least the last 3 months. 
Investigational product, dosage and mode of administration: 
The setmelanotide QW formulation 
 will be provided as a sterile solution at a 
concentration of 30 mg/mL for admininistration of
on of d dos
ose l leve
vels of
 of 20, 25, and 30 mg by subcutaneous (SC) 
injection.  
Setetmelelan
anotide QD 
e QD dr
drug pr
ug produc
oduct 
 wi
will b be p
e provided
ed as a st
 as a stererile so
e solution 
at a a c conc
oncentntration of
on of 10
10 mg/mL f for
or a adm
dmininistration of
on of dos
dose l leve
vels of
 of 2 2, 2.5 and 3 mg by SC injection. The 
product will be provided in clear glass vials. 
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Duration of treatment:  
Total duration of treatment with setmelanotide in this trial will be ~30 weeks: a Run-in Period of 1 day to 
1 week on QD setmelanotide, 13 weeks on randomized setmelanotide treatment (QD or QW), 13 weeks 
on non-randomized QW setmelanotide, followed by 3 weeks on the QD formulation. 
Reference therapy, dosage and mode of administration:  
QD or QW matching placebo for SC injection. Placebo is vehicle only and is identical in appearance to 
active treatment. 
Criteria for evaluation: 
Primary Endpoint: 
• 
Comparison of steady-state PK parameters (maximum plasma concentration [Cmax,], time to 
maximum plasma concentration [Tmax], trough plasma concentration [Ctrough], area under the 
plasma concentration-time curve over the dosing interval [AUC0-tau]) for QW compared with QD 
setmelanotide 
Secondary Endpoint:  
• 
Safety outcomes, including AEs/SAEs, ISRs, and changes in laboratory parameters, vital signs, 
ECG recordings, and physical examination findings, etc.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Statistical methods: 
The primary objective is to assess steady-state PK parameters (Cmax, Tmax, Ctrough, AUC0-tau) for QW 
compared with QD setmelanotide. The sample size is based on availability of the patients enrolled in the 
LTE trial and is not driven by formal statistical hypothesis testing on non-inferiority/similarity. 
The PK profile of the 2 formulations of setmelanotide will be characterized and the steady-state PK 
parameters (Cmax, Tmax, Ctrough, and AUC0-tau) will be summarized for QD and QW setmelanotide by dose 
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level and prior treatment regimen (QW or QD) during the double-blind phase of the trial using descriptive 
statistics (e.g., n, mean, standard deviation, geometric mean, minimum, median, maximum, % coefficient 
of variation [CV], geometric mean CV, and confidence intervals [CI]). 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs, including ISRs, as well as discontinuations due to AEs will be summarized descriptively with 
frequencies and percentages. By-patient AE data listings including onset and resolution dates, verbatim 
term, preferred term, treatment, severity, relationship to treatment, action taken, and outcome will be 
provided. Injection site reactions for the QD and QW formulations will be summarized separately. 
Safety data including laboratory evaluations, ECGs, physical examinations, and vital signs assessments 
will be summarized by time of collection. In addition, change from baseline to any postdose values will 
be summarized for vital signs, ECGs, and clinical laboratory results. Frequency of patients with abnormal 
safety laboratory results will be tabulated. Continuous outcomes (e.g., vital signs, safety laboratory 
parameters) will be summarized using n, mean, median, standard deviation, etc. 
 
2. 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities (SoA) to be conducted are depicted in Table 1.  
Any patient withdrawing from the trial will complete the Early Termination Visit, if possible.  
Screening Period: To ensure continuity of treatment, informed consent for this trial will be 
obtained and eligibility of the patient will be confirmed before the patient is withdrawn from the 
long-term extension (LTE) trial. Visit procedures from the last visit of the LTE trial and first 
visit of this trial are not intended to be duplicated. Thus, any repeat assessments do not need to 
be conducted and data from the last visit of the LTE trial will be used as Visit 1 data in this trial, 
as applicable. 
Run-in Period: Day 1 of the Run-in Period should coincide with the patient’s last visit in the LTE 
trial to avoid an interruption of treatment. The patient will have a Run-in Period of 1 day to 
1 week on QD setmelanotide at the dose they were on in the LTE trial.  
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Table 1: 
Schedule of Activities 
Trial Period 
Screening* 
(up to 
21 days) 
Run-In∆ 
(up to 
1 week) 
Randomized, Double-Blind Treatment (QD and QW) 
Open-Label 
Non-Randomized 
QW Administration 
Restart 
QD 
Follow-
up on 
QD 
(EoS) 
Early 
Termin
ation 
Visit (V) 
Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 
10 
V 
11 
V 
12 
V 
13 
V 
14 
V 
15 
V 
16 
V 
17 
V 
18 
V 
19 
V 
20 
V 
21 
 
Trial Week 
-4 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
18 
22 
27 
30 
 
Trial Day  
± Visit Window 
-28 to -8 
-7 to -1 
1 
8 
± 1 
15 
± 1 
22 
± 1 
29 
± 3 
36 
± 1 
43 
± 1 
50 
± 1 
57 
± 3 
64 
± 1 
71 
± 1 
78 
± 1 
85 
± 1 
92 
± 0 
106 
± 1 
120 
± 3 
148 
± 3 
183 
± 3 
204 
± 3 
(n/a) 
In Person Visit 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Telehealth 
Visit†† 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Informed 
consent/assent1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusi
on review 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
& prior 
medication 
review 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Fitzpatrick scale 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
Comprehensive 
skin exam2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test3 
X 
X 
X† 
 
 
 
X† 
 
 
 
X† 
 
 
 
 
X† 
 
X† 
X† 
X† 
X† 
X† 
Study drug: 
administer4 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study drug 
didispe
pens
nse4 
 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
 
 
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Table 1: 
Schedule of Activities 
Trial Period 
Screening* 
(up to 
21 days) 
Run-In∆ 
(up to 
1 week) 
Randomized, Double-Blind Treatment (QD and QW) 
Open-Label 
Non-Randomized 
QW Administration 
Restart 
QD 
Follow-
up on 
QD 
(EoS) 
Early 
Termin
ation 
Visit (V) 
Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 
10 
V 
11 
V 
12 
V 
13 
V 
14 
V 
15 
V 
16 
V 
17 
V 
18 
V 
19 
V 
20 
V 
21 
 
Trial Week 
-4 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
18 
22 
27 
30 
 
Trial Day  
± Visit Window 
-28 to -8 
-7 to -1 
1 
8 
± 1 
15 
± 1 
22 
± 1 
29 
± 3 
36 
± 1 
43 
± 1 
50 
± 1 
57 
± 3 
64 
± 1 
71 
± 1 
78 
± 1 
85 
± 1 
92 
± 0 
106 
± 1 
120 
± 3 
148 
± 3 
183 
± 3 
204 
± 3 
(n/a) 
In Person Visit 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Telehealth 
Visit†† 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
Height6 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
C-SSRS10 
X 
X† 
X† 
 
 
 
X† 
 
 
 
X† 
 
 
 
 
X† 
 
X† 
X† 
X† 
X† 
X† 
PHQ-921 
X 
X† 
X† 
 
 
 
X† 
 
 
 
X† 
 
 
 
 
X† 
 
X† 
X† 
X† 
X† 
X† 
Dosing Diary 11 
 
X 
For each dose administered (QW or QD) 
 
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Table 1: 
Schedule of Activities 
Trial Period 
Screening* 
(up to 
21 days) 
Run-In∆ 
(up to 
1 week) 
Randomized, Double-Blind Treatment (QD and QW) 
Open-Label 
Non-Randomized 
QW Administration 
Restart 
QD 
Follow-
up on 
QD 
(EoS) 
Early 
Termin
ation 
Visit (V) 
Number 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
V 
10 
V 
11 
V 
12 
V 
13 
V 
14 
V 
15 
V 
16 
V 
17 
V 
18 
V 
19 
V 
20 
V 
21 
 
Trial Week 
-4 
-1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
16 
18 
22 
27 
30 
 
Trial Day  
± Visit Window 
-28 to -8 
-7 to -1 
1 
8 
± 1 
15 
± 1 
22 
± 1 
29 
± 3 
36 
± 1 
43 
± 1 
50 
± 1 
57 
± 3 
64 
± 1 
71 
± 1 
78 
± 1 
85 
± 1 
92 
± 0 
106 
± 1 
120 
± 3 
148 
± 3 
183 
± 3 
204 
± 3 
(n/a) 
In Person Visit 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
X 
X 
X 
X 
Telehealth 
Visit†† 
 
 
 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
 
 
PK blood 
sampling 
(trough)13 
 
 
X† 
 
 
 
X† 
 
 
 
X† 
 
 
 
 
X† 
 
X† 
X† 
X† 
 
 
PK profile14 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X† 
 
 
 
 
 
 
Injection site 
inspection15 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Safety laboratory 
tests16 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Anti-drug 
antibodies17 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
Vital signs18 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG (12-lead)19 
X 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
X 
X 
Physical exam20 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Adverse event 
assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Abbreviations: BP = blood pressure; C-SSRS = Columbia-Suicide Severity Rating Scale; ECG = electrocardiogram; EoS = End of Study; 
 
 HR = heart rate; min = minute; n/a = not applicable; LTE = long-term extension; PHQ-9=Patient Health Questionnaire– 9; PK = pharmacokinetic; 
QD = 
= once
ce daily; QW = once weekly; V = visit. 
* Due to the rarity of these patients and difficulty associated with travel to the trial site, the Screening Period may be extended beyond 3 weeks, if necessary, 
after discussion with the Sponsor. 
∆ The patient will have a Run-in Period of 1 day to 1 week on QD setmelanotide at the dose they were on in the LTE trial. The first day of the Run-in Period 
(V2) should coincide with the patient’s last visit in the LTE trial to avoid an interruption of treatment. 
† Assessment/sample should be performed/obtained prior to administration of study drug. 
†† Any telehealth visit may optionally be converted to an in-person visit.  
1 Patients who reach the age of consent during the trial must be re-consented, as applicable. 
2 
A comprehensive skin evaluation will be performed by the Investigator. Any concerning lesions identified during the Screening Period will be biopsied and 
results known to be benign prior to trial entry. If the pretreatment biopsy results are of concern, the patient will be excluded from the trial.  
3 
A urine pregnancy test may be performed in order to expedite availability of results prior to the first dose at Run-in (V2). All other pregnancy tests will be 
serum; dosing may continue with results pending. 
4 For the QD doses of study drug, patients/caretakers will draw up and self-administer/administer the study drug each morning beginning with the first dose of 
Run-in (V2) and for the duration of the 13-week double-blind period. In addition, once each week the QW dose of study drug will be prepared and 
administered at the trial center or self-administered/administered by the patient/caretaker in between visits. A home healthcare provider can optionally be 
made available at the patient’s home to administer or supervise administration of the QW dose. The patient will receive the first QW dose on Day 1 (V3) at 
the trial center. On the days of in-person clinic visits, the patients/caretakers will self-administer/administer the QD dose of study drug in the clinic in the 
presence of the clinical staff to assure proper technique. For accountability, patients/caretakers will return all used vials to the clinic when they visit; the trial 
staff will record the number returned; and both study drug administration at the clinic, as well as outpatient study drug administration will be recorded in a 
trial didiary.y. 
 
 
 
 
 
 
  
6 For patients ≥21
21 ye
years of age
ge, he
heightht will be
be measured onlnly du
during g the
he Screenining g Period.d. For
or pa
patientnts age
ged d <21
21 ye
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. All measurements will be done in 
triplicat
cate e atat each
each timep
epoint an
and reco
ecorded to the e near
eares
est halalf cm
 cm. The e stadiometeterer should be e cal
calibratated
ed on n a da
daily y ba
basis p prior
or to o he
heightht assessmentnt.  
 
 
 
 
 
  
 
 
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10 
10 The e Bas
aseleline/e/Scrcreen
eening version of the e C-SSR
SSRS shoululd o onlnly be
be adm
dmininistered d to pa
patientnts who
ho ha
have
ve ne
neve
ver com
omplpleted d an n initial C-SSRS assessment prior to 
entering this trial; however, this version is expected to have been completed in the index trial for all patients prior to entry into this trial.  The Screening 
version of the C-SSRS is to be completed at the Screening visit. At all subsequent visits, the Since Last Version is to be completed. If at any time during the 
trial a patient has suicidal ideation of type 4 or 5, or any suicidal behavior, the patient should be referred to a mental health professional. 
11 The dosing diary will be completed for all QD and QW dose administration. 
 
  
13 A blblood
od samplple for
or trough plasma levels of setmelanotide will be drawn within 30 minutes prior to dosing of QD or QW study drug. On the days when PK 
profiles are done, the predose (trough) PK sample will be drawn within 30 minutes prior to any study drug administration. No visit window is allowed for 
Week 14, which must occur exactly 7 days after the Week 13 (V15) dose administration. (i.e., if the Week 13 (V15) visit occurs on Day 86, the Week 14 
(V16) visit must occur on Day 93). Patients/caretakers will be reminded that there should be NO study drug administration at home on the day of clinic visits; 
the drug will be administered in the clinic AFTER the predose PK sample is obtained. For the PK sample, the actual collection (clock) time will be recorded, 
as well as the time of the previous day’s study drug injection as reported by the patient/caretaker.  
14 Patients will undergo serial blood samples taken for measurement of steady-state setmelanotide concentrations (both QD and QW) and PK profiles will be 
performed. On the first day of the Run-in Period, blood samples for the QD PK profile will be drawn within 30 minutes prior to dose administration. Postdose 
samples will be collected at: 0.5, 1, 2 (±5 mins), 6, 8, 12, and 24 hours (±30 min). At minimum, mandatory postdose samples must be collected at: 6 and 
8 hours (±30 min) and at 24 hours (±30 min). At Week 14, blood samples for the PK profiles will be drawn within 30 minutes prior to dose administration. 
Postdose samples will be collected at: 0.5, 1, 2 (±5 mins), 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours (±30 min). At minimum, mandatory postdose samples 
must be collected at: 6 and 8 hours (±30 min), 24 hours (±30 min), 48, 72, 96, 120 hours (±30 min), and 168 hours (±30 min) In case of significant challenges 
with the collection of  any PK sample, the investigator should confirm sample prioritization with the sponsor. Patients/caretakers will be reminded that there 
should be NO study drug administration at home on the day of clinic visits and that the predose (trough) blood draw must occur PRIOR to study drug 
administration. The blood draws for the Week 14 PK sampling must occur exactly 7 days after the prior visit. The Investigators will adhere to the site-specific 
blood volume limits for safety laboratory and PK analyses both to ensure minimal distress and reduce the number of venipunctures in pediatric patients. For 
patients <18 years of age, it may not be possible to collect all labs at every trial visit, though efforts should be made to collect as many PK samples per 
protocol. Venipuncture reduction is allowed should a patient <18 years of age experience unacceptable discomfort as deemed by the Investigator. 
15 Injection site evaluations and scoring (by the clinical staff) will include identification of areas of erythema, edema, and induration, as well as the presence of 
localized pain, tenderness, and itching. At in-person trial visits, the clinical staff will also record measurements of areas of erythema, edema, and induration if 
possible. Unscheduled evaluations may also be recorded as warranted by clinical conditions. 
16 Safety laboratory tests will include: complete blood count with platelet count and standard indices, chemistry panel, coagulation, and urinalysis with 
microscopic analysis (if positive findings on dipsticks warrant further examination). For patients <18 years of age, it may not be possible to collect all 
laboratory samples at every trial visit. Screening may be performed over multiple days, to complete the required assessments. After enrollment, if not all lab 
tests a are possible, then the tests should be collected in the following descending order of priority: safety, anti-drug antibodies, trough PK, 
 
 
17 Any
ny patient with a positive ADA at the end of trial or early termination will be followed every 3 months after the sample analysis until resolution (ie, no 
measurable ADA response). 
18 All BP and HR 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, BP should be taken in the non-dominant arm throughout the trial, using the same methodology (automated or 
manual). Body temperature (°C) and respiration rate (breaths/minute) will be obtained in the sitting position following at least 5 minutes of rest. Note that for 
virtual visits, BP will be collected.  
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19 A single 12-lead ECG will be performed with the patient in the supine position following a period of at least 10 minutes of rest.  
20 A complete physical examination will be conducted at Screening and at the end of trial (Week 30). At other time points, an abbreviated examination, noting 
any changes from baseline will be performed. 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. 
21 
 If at any time during the trial an individual patient’s PHQ-9 score is ≥10, the patient should be referred to a Mental Health Professional.   
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TABLE OF CONTENTS 
SUMMARY OF CHANGES TO THE PROTOCOL ......................................................................2 
APPROVAL SIGNATURE PAGE .................................................................................................4 
INVESTIGATOR STATEMENT ...................................................................................................5 
1. 
SYNOPSIS ...................................................................................................................6 
2. 
SCHEDULE OF ACTIVITIES ..................................................................................10 
TABLE OF CONTENTS ...............................................................................................................17 
LIST OF TABLES .........................................................................................................................19 
LIST OF FIGURES .......................................................................................................................20 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................21 
3. 
INTRODUCTION ......................................................................................................24 
3.1. 
Rationale for the Trial .................................................................................................24 
3.2. 
Setmelanotide Benefit/Risk Assessment ....................................................................25 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................27 
5. 
INVESTIGATIONAL PLAN .....................................................................................29 
5.1. 
Overall Trial Design ...................................................................................................29 
5.1.1. 
Screening Period .........................................................................................................30 
5.1.2. 
Run-In Period ..............................................................................................................30 
5.1.3. 
Double-Blind and Open-Label Treatment Periods .....................................................31 
5.1.4. 
Follow-up Period ........................................................................................................31 
5.1.5. 
Patient and Trial Completion ......................................................................................31 
5.2. 
Discussion of Trial Design .........................................................................................31 
5.3. 
Dosing Rationale ........................................................................................................32 
5.4. 
Trial Termination ........................................................................................................32 
5.5. 
Trial Conduct During the Coronavirus Pandemic ......................................................33 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................33 
6.1. 
Patient Inclusion Criteria ............................................................................................33 
6.2. 
Patient Exclusion Criteria ...........................................................................................34 
6.3. 
Re-Screening ...............................................................................................................35 
6.4. 
Patient Withdrawal Criteria ........................................................................................35 
7. 
TREATMENT OF PATIENTS ..................................................................................36 
7.1. 
Description of Study Medication ................................................................................36 
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7.2. 
Randomization and Blinding ......................................................................................36 
7.2.1. 
Blinding and Unblinding ............................................................................................36 
7.3. 
Administration ............................................................................................................37 
7.4. 
Treatment Compliance ................................................................................................38 
7.5. 
Preparation/Handling/Storage/Accountability ............................................................38 
7.6. 
Concomitant Medications ...........................................................................................39 
7.6.1. 
Prohibited Medications ...............................................................................................39 
8. 
ASSESSMENTS .........................................................................................................39 
8.1. 
Informed Consent/Assent ...........................................................................................40 
8.2. 
Inclusion/Exclusion Review .......................................................................................40 
8.3. 
Demographics, Concomitant Medications and Medical History ................................40 
8.4. 
Height .........................................................................................................................40 
8.5. 
Fitzpatrick Classification Scale ..................................................................................41 
8.6. 
Pharmacokinetic Assessments ....................................................................................41 
8.6.1. 
Blood sampling ...........................................................................................................41 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.8. 
Safety Assessments .....................................................................................................43 
8.8.1. 
Vital Signs ..................................................................................................................43 
8.8.2. 
Physical Examination .................................................................................................43 
8.8.3. 
Comprehensive Skin Examination .............................................................................44 
8.8.4. 
Electrocardiogram .......................................................................................................44 
8.8.5. 
Laboratory Assessments .............................................................................................44 
8.8.6. 
Anti-Drug Antibodies .................................................................................................45 
8.8.7. 
Pregnancy and Contraception .....................................................................................45 
8.8.8. 
Injection Site Examination .........................................................................................46 
8.8.9. 
Suicidal Ideation and Depression Monitoring ............................................................47 
8.8.9.1. 
Columbia-Suicide Severity Rating Scale ....................................................................47 
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8.8.9.2. 
PHQ-9 .........................................................................................................................48 
8.8.10. 
Overdose .....................................................................................................................48 
8.8.11. 
Adverse and Serious Adverse Events .........................................................................49 
8.8.11.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................49 
8.8.11.2. 
Method of Detecting AEs and SAEs ..........................................................................49 
8.8.11.3. 
Follow-up of AEs and SAEs .......................................................................................49 
8.8.11.4. 
Regulatory Reporting Requirements for SAEs ...........................................................50 
9. 
STATISTICS ..............................................................................................................50 
9.1. 
Sample Size Determination ........................................................................................50 
9.2. 
Populations for Analyses ............................................................................................50 
9.3. 
Statistical Analyses .....................................................................................................51 
9.3.1. 
Primary Analysis of PK Parameters ...........................................................................51 
 
 
9.3.3. 
Safety Analyses ..........................................................................................................51 
9.3.4. 
Interim Analysis ..........................................................................................................52 
10. 
LIST OF REFERENCES ............................................................................................53 
11. 
APPENDICES ............................................................................................................54 
APPENDIX 1. GUIDANCE ON TRIAL CONDUCT DURING THE 
CORONAVIRUS PANDEMIC ..................................................................................55 
APPENDIX 2. INJECTION SITE EVALUATIONS .................................................................57 
APPENDIX 3. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................58 
APPENDIX 4. CONSIDERATIONS FOR REDUCING PAIN AND DISTRESS IN 
THE PEDIATRIC POPULATION .............................................................................63 
APPENDIX 5. TRIAL GOVERNANCE CONSIDERATIONS ................................................64 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................11 
Table 2: 
Objectives and Endpoints ...........................................................................................28 
Table 3: 
Fitzpatrick Classification Scale ..................................................................................41 
 
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LIST OF FIGURES 
Figure 1: 
Trial Design ................................................................................................................30 
 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Specialist Term 
Explanation 
ADA 
Anti-drug antibodies 
ADV 
Audio Data Verification 
AE 
Adverse event 
AUC0-tau 
Area under the plasma concentration-time curve over the dosing 
interval 
BBS 
Bardet-Biedl syndrome 
 
 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIOMS 
Council for International Organizations of Medical Sciences 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
Maximum plasma concentration 
CNS 
Central nervous system 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRF 
Case report form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
Ctrough 
Trough plasma concentration 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-like peptide-1 
 
 
HR 
Heart rate 
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Abbreviation or Specialist Term 
Explanation 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ISR 
Injection site reaction 
IUD 
Intrauterine device 
LEPR 
Leptin receptor 
LTE 
Long-term extension 
MC4R 
Melanocortin-4 receptor 
MHP 
Mental health professional 
MSH 
Melanocyte-stimulating hormone 
NAFLD 
Nonalcoholic fatty liver disease 
NASH 
Nonalcoholic steatohepatitis 
NHLBI 
National Heart, Lung, and Blood Institute 
NIH 
National Institutes of Health 
PCSK1 
Proprotein convertase subtilisin/kexin type 1 
PHQ-9 
Patient Health Questionnaire-9 
PK 
Pharmacokinetic 
PKAS 
Pharmacokinetic analysis set 
P/LP 
Pathogenic, likely pathogenic 
PPL 
POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase 
subtilisin/kexin type 1), LEPR (leptin receptor) 
POMC 
Pro-opiomelanocortin 
QD 
Once daily 
QW 
Once weekly 
rDV 
Remote Data Verification 
RGDO 
Rare genetic disorders of obesity 
rIMV 
Remote Interim Monitoring Visit 
rSDM 
Remote Source Data Monitoring 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
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Abbreviation or Specialist Term 
Explanation 
SARS-COV-2 
Severe acute respiratory syndrome coronavirus-2  
SC 
Subcutaneous 
SMC 
Site Monitoring Visit 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reaction 
Tmax 
Time to maximum plasma concentration 
US 
United States 
VUS 
Variant of uncertain significance 
 
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3. 
INTRODUCTION 
3.1. 
Rationale for the Trial 
Obesity is a multifactorial disease caused by various environmental, neurobehavioral, 
immunological, endocrine, medical, and genetic/epigenetic factors or a complex interplay 
between 2 or more of these factors (Maes 1997; Schousboe 2003; Silventoinen 2010; Hall 2012; 
Pigeyre 2016; Sheikh 2017; Thaker 2017). In a subset of individuals with obesity, rare genetic 
variants may result in severe obesity. The identification of key genetic determinants of the 
neuronal pathways and signaling molecules (e.g., leptin) regulating appetite and body weight has 
led to the discovery of multiple rare genetic disorders of obesity (RGDO) (van der Klaauw 
2015). A key neuronal pathway, the central melanocortin and melanocortin-4 receptor (MC4R) 
pathway, plays an important role in appetite, hunger, and energy utilization. The melanocortins 
are a family of peptide hormones (including adrenocorticotropic hormone, α-melanocyte-
stimulating hormone [MSH], β-MSH, and γ-MSH) derived from the common precursor, pro-
opiomelanocortin (POMC). Originating in the hypothalamus, the MC4R pathway concertedly 
modulates appetite (feelings of hunger and satiety), 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 defects in the MC4R pathway, such as POMC deficiency, 
result in severe forms of early-onset obesity and hyperphagia (Farooqi 2008). Patients with rare 
genetic variants in leptin receptor (LEPR) and patients with Bardet-Biedl syndrome (BBS, a rare 
pleiotropic autosomal recessive disorder caused by mutations in as many as 24 different genes) 
also present with unremitting hunger and severe obesity caused in part by a lack of activation of 
the MC4R pathway. As a result of hyperphagia, individuals with RGDO have increased calorie 
intake leading to early-onset, severe obesity, and obesity-related comorbidities such as type 2 
diabetes. The Sponsor is developing setmelanotide (also known as RM-493), an MC4R agonist, 
as a treatment for patients with RGDO. Setmelanotide bypasses upstream signaling defects to 
directly activate MC4R. 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). 
Thus, setmelanotide, has the potential to restore reduced activity in the MC4R pathway in 
patients with these and other genetic defects and may serve as a form of “replacement” therapy 
to re-establish weight and appetite control in patients with these disorders. 
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The purpose of this trial is to compare the QW and QD formulations of setmelanotide in patients 
with biallelic PPL, heterozygous PPL, and patients with BBS. QW dosing is expected to provide 
a more convenient dosing regimen for these patients and would be more suitable for younger 
patients than QD dosing. In addition, QW dosing would be expected to improve compliance, 
especially given the long-term requirement for continued dose administration in order to achieve 
sustained benefits. 
3.2. 
Setmelanotide Benefit/Risk Assessment 
In patients with RGDO, setmelanotide has been associated with clinically meaningful reductions 
in weight and improvement in hunger. In particular, in patients with POMC or LEPR deficiency 
obesity, who are characterized by early-onset obesity, severe hunger and progressive weight 
gain, setmelanotide has demonstrated clinically meaningful and statistically significant weight 
reduction, often bringing patients with very high morbid obesity body mass index (BMI) 
(>40 kg/m2) to BMI ranges in the overweight or normal range (<30 kg/m2). In addition to weight 
loss, setmelanotide has demonstrated clinically meaningful and statistically significant decreases 
in hunger. Both the decreased hunger and the weight loss continued over 52 weeks of treatment 
and are maintained with continued setmelanotide treatment. Furthermore, following the 
significant weight loss with setmelanotide treatment, there were improvements in lipids and 
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other parameters, 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 (ISRs) and skin hyperpigmentation. Less commonly, nausea and vomiting were 
reported and rarely, sexual AEs 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. 
Specifically, regarding children less than 12 years old, the AEs reported in this population were 
consistent with those reported in other studies of setmelanotide. Adverse events reported as 
related to setmelanotide treatment were consistent with the known safety profile. No evidence for 
concern regarding bone development has been observed.  
Daily injection of setmelanotide is technically challenging for pediatric patients and patients with 
poor coordination/vision or other physical challenges, thus, the Sponsor is developing the weekly 
formulation 
on to i
o improve compliance and to address user limitations, with the hypothesis that 
safety and 
 b between the two formulations will be comparable. 
In summary, the QD setmelanotide formulation has a positive benefit-risk profile in patients with 
genetic defects upstream of the MC4R pathway and the QW formulation may have the added 
advantage of a more convenient dosing regimen. 
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. 
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4. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints are described in Table 2. 
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Table 2: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• To compare the PK of the QD and QW 
formulations of setmelanotide  
• Comparison of steady-state PK parameters (Cmax, Tmax, 
Ctrough, AUC0-tau) for QW compared with QD 
setmelanotide 
Secondary 
• To assess the safety of the QW 
formulation of setmelanotide with up to 
6 months (26 weeks) of drug 
administration  
• Safety outcomes, including AEs/SAEs, ISRs, and 
changes in laboratory parameters, vital signs, ECG 
recordings, and physical examination findings, etc.  
Abbreviations: AE = adverse event; AUC0-tau = area under the plasma concentration-time curve over the dosing 
interval; 
; Cmax
max = 
= maximum plas
asma co
concentration; Ctrough = trough plasma concentration; 
ECG = elelect
ectrocar
cardiogram
am; 
 ISR = injection site reaction; PK = pharmacokinetic; 
QD = once daily; QW = once
ce wee
eekly; SAE = 
= sererious ad
advererse e ev
event; Tmax = time to maximum plasma concentration. 
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5. 
INVESTIGATIONAL PLAN 
5.1. 
Overall Trial Design 
This trial is designed to compare the safety, pharmacokinetics (PK), and 
nd 
 of the QW and 
QD formulations of setmelanotide, as well as to evaluate the safety and 
 of
 of up to 
6 months of QW setmelanotide administration in patients with BBS, biaiallllelic
lic P
 PPL, or 
heterozygous PPL. Eligible patients are those who are currently taking QD setmelanotide in 
Trial RM-493-022, referred to as the long-term extension (LTE) trial, for at least 6 months with 
acceptable safety and tolerability, and who wish to continue with setmelanotide treatment, and 
who otherwise meet all inclusion and exclusion criteria. Approximately 30 patients will be 
targeted in 3 age groups as follows: approximately 20 patients ≥18 years old; approximately 
6 patients ≥12 to <18 years old; and approximately 4 patients ≥6 to <12 years old at the time of 
trial entry. 
The trial consists of a Screening Period for transition from the LTE trial, a Run-in Period of up to 
1 week of continuation on the patient’s current dose level of QD setmelanotide (2, 2.5, or 3 mg), 
a 13-week double-blind phase in which the patients will be randomized to either QD or QW 
setmelanotide, a 13-week non-randomized open-label phase where all patients will receive open-
label QW setmelanotide, and a 3-week follow-up period in which all patients will return to their 
run-in dose level of QD setmelanotide to prepare for re-enrollment into Trial RM-493-022 or to 
resume the QD formulation in some other way. 
The safety and tolerability of setmelanotide will be assessed by the frequency and severity of 
AEs/serious adverse events (SAEs) and ISRs, as well as changes in physical examinations (to 
include comprehensive skin examinations), electrocardiograms (ECGs), vital signs (including 
resting blood pressure [BP] and heart rate [HR]), routine laboratory evaluations, development of 
anti-drug antibodies (ADA), and the Columbia-Suicide Severity Rating Scale (C-SSRS). 
 
 
  
The trial design is depicted graphically in Figure 1. 
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Figure 1: 
Trial Design 
 
Abbreviations: PK = pharmacokinetic; QD = once daily; QW = once weekly. 
5.1.1. 
Screening Period 
Upon providing informed consent, 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 Activities (SoA) (Section 2). During
ng t the
he S
 Screenining P
ng Period, p
od, patients w
 will unde
undergo 
go 
medidical e eva
valua
uation a
on and o
nd othe
her tri
trial pr
 procedur
dures, 
 
 To e ensurere c contitinuity
ity o of f tre
treatme
tment,t, 
ininfo
forme
med c consent fo
t for th
r this tri
 trial will b
ll be obtatainined a and e elig
ligibibililitity of the patient will be confirmed 
before the patient is withdrawn from the LTE trial. 
5.1.2. 
Run-In Period 
The patient will have a Run-in Period of 1 day to 1 week on QD setmelanotide at the dose they 
were on in the LTE trial. The first day of the Run-in Period (Visit 2) should coincide with the 
patient’s last visit in the LTE trial to avoid an interruption of treatment. The first dose of QD 
setmelanotide as part of the RM-493-037 trial will occur in clinic on the first day of the run-in 
period. 
On the first day of the Run-in Period, patients will have serial blood samples taken for 
measurement of setmelanotide concentrations (QD formulation) and 24-hour PK profiles will be 
performed. 
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5.1.3. 
Double-Blind and Open-Label Treatment Periods 
On Day 1 (Visit 3) patients will be randomized 1:1 to receive either QD or QW setmelanotide. 
Patients who were on QD setmelanotide at a dose of 2 mg at the time of trial entry will be 
randomized to receive either QD setmelanotide 2 mg or QW setmelanotide at a dose of 20 mg, 
whereas patients who were on QD setmelanotide at a dose of 2.5 mg will be randomized to 
receive either QD setmelanotide 2.5 or QW setmelanotide at a dose of 25 mg, and finally patients 
who were on QD setmelanotide at a dose of 3 mg will be randomized to receive either QD 
setmelanotide 3 mg or QW setmelanotide at a dose of 30 mg. Study medication will be 
administered in a double-dummy fashion in order to maintain the double blind. Patients will 
receive the first QW dose on Day 1 of the randomized treatment period (Visit 3). The 
randomization will be stratified by age group.  
• Patients randomized to QW setmelanotide will receive blinded QW setmelanotide and 
QD placebo injections until the Week 14 visit (ie, completion of 13 weeks of blinded 
dose administration). Starting with Week 14, patients will continue with open-label 
QW injections of setmelanotide during the 13-week non-randomized phase.  
• Patients randomized to QD setmelanotide will receive blinded QD setmelanotide and 
QW placebo injections until the Week 14 visit (ie, completion of 13 weeks of blinded 
dose administration). Starting with Week 14, patients will continue with open-label 
QW injections of setmelanotide during the 13-week non-randomized phase.  
Prior to the QW dose of study drug at prespecified time points during the double-blind treatment 
phase, predose blood samples will be collected for trough plasma drug concentrations in all 
patients. At Week 14, serial blood samples (including a predose blood sample) will be taken for 
measurement of steady state setmelanotide concentrations (QD and QW formulations) for 
24-hour PK profiles.  
5.1.4. 
Follow-up Period 
For the 3-week Follow-up Period, all patients will return to their run-in dose of QD 
setmelanotide to prepare for re-enrollment into Trial RM-493-022 or to resume the QD 
formulation in some other way. 
5.1.5. 
Patient and Trial Completion 
A patient is considered to have completed the trial if he/she has completed the trial through the 
3-week follow-up period. 
A patient who discontinues before completing all planned visits is to attend an Early Termination 
visit within 14 days (±7 days) after their last dose of study 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. 
5.2. 
Discussion of Trial Design 
Patients to be enrolled in this trial will be those who have been on open-label QD setmelanotide 
treatment in the LTE trial for at least 6 months with acceptable safety and tolerability, and the 
dose level must have been stable at 2, 2.5, or 3 mg of setmelanotide for at least the last 3 months. 
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Switching these patients from the daily to the weekly formulation will allow intra-patient 
com
ompa
parison of the PK profiles of the 2 formulations as well as comparisons of safety and 
 b between the 2 formulations. 
For
or pa
 patientnts randomized to QW setmelanotide, this trial design will allow the pattern of 
 
 t to be observed for 6 months on the QW formulation as a patient switches fro
rom th
m the 
daily
ily for
ormulation during the Run-in Period to the weekly formulation of setmelanotide.  
To maintain n the
he bl
 blind dur
nd during t
ng the
he randomized treatment period, a all p
ll patie
tientsts will r
ill receive placebo 
injections 
 from the QD formulation or 
 fr
 from the QW 
formulation)
on) i in a
n addi
ddition t
on to t
o the
he s setmelanotide injections in a doubl
ouble-du
dummy f
y fashihion. P
on. Placebo and 
active study drug will be visually indistinguishable. 
A formal non-inferiority trial design for the QD vs QW formulation is not feasible because a 
large sample size would be required, which is unachievable in RGDO. Therefore, the sample size 
is primarily driven by availability of patients on stable doses of setmelanotide and by other 
clinical considerations. 
5.3. 
Dosing Rationale 
Patients to be enrolled in this trial will be those who are on open-labelel QD
QD set
setmelanotide 
treatment at a dose level of 2, 2.5, or 3 mg. Given the PK, safety, and 
 r results for 
otherwise healthy patients with obesity in Tria
rial RM
RM-493-026, it is anticicipipateted t that 30 mg QW 
setmelanotide will provide PK, safety, and 
 co
 comparable to the 3 mg QD setmelanotide 
dose.  
Likewise, it is anticipated that 25 mg QW setmelanotide will provide PK, safety, and 
 
comparable to the
he 2.5 
2.5 mg
mg QD setmelanotide dose and that 20 mg QW setmelanotide will
ill pr
 prov
ovide 
PK, safety, and 
 comparable to the 2 mg QD setmelanotide dose.  
5.4. 
Trial Termination 
This trial may be terminated, if in the opinion of the Investigator (at a participating site) or the 
Sponsor, there is sufficiently reasonable cause. The terminating party will provide written 
notification documenting the reason for termination to either the Investigator(s) or Sponsor. 
Circumstances that may warrant termination include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to patients 
• Failure to enter patients at an acceptable rate  
• Insufficient adherence to protocol requirements 
• Insufficient complete and/or evaluable data 
• Plans to modify, suspend, or discontinue the development of the study drug 
Should the trial be closed/terminated, all trial materials must be returned to the Sponsor or 
designee. 
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5.5. 
Trial Conduct During the 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, to maintain compliance with Good 
Clinical Practice (GCP), and to 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 1. 
6. 
SELECTION AND WITHDRAWAL OF PATIENTS 
6.1. 
Patient Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for trial participation: 
1. All patients must have met the criteria for diagnosis of a gene defect in the MC4R 
pathway (BBS, biallelic PPL, heterozygous PPL), for which they are being treated with 
QD setmelanotide. 
2. Patients must be ≥6 years old at screening.  
3. Patients must have been taking the setmelanotide QD formulation for at least 6 months in 
the LTE trial with acceptable safety and tolerability, and the dose level must have been 
stable at 2, 2.5 or 3 mg of setmelanotide for at least the last 3 months prior to starting the 
Run-in Period. 
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 and is able to understand and 
sign the written informed consent/assent.  
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 8.8.7: 
- Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal) 
- Progestin-only hormonal contraception associated with inhibition of ovulation (oral, 
implantable, or injectable) 
- Intrauterine device (IUD) 
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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 
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 (FSH) level in the post-menopausal lab range) 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 of 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. 
6.2. 
Patient Exclusion Criteria 
A patient who meets any of the following criteria will be excluded from this trial. 
1. HbA1C >9.0% at screening. 
2. Has taken a medication that is approved to treat obesity (e.g., orlistat, lorcaserin, 
phentermine-topiramate, naltrexone-bupropion) within 3 months prior to starting the 
Run-in Period. Glucagon-like peptide-1 (GLP-1) receptor agonists being prescribed 
for the treatment of obesity are not allowed. 
3. History of significant liver disease or liver injury, or a current liver assessment due to 
abnormal liver tests for an etiology other than nonalcoholic fatty liver disease 
(NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed 
nonalcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic 
cirrhosis is exclusionary, but the presence of NAFLD is not exclusionary.  
4. Moderate to severe renal dysfunction as defined by a glomerular filtration rate 
<30 mL/min (based upon the Chronic Kidney Disease Epidemiology Collaboration 
[CKD-EPI] creatinine equation 2021 from the National Kidney Foundation). In 
patients <18 years of age the Bedside Schwartz Equation should be used to calculate 
estimated glomerular filtration rate (eGFR). 
5. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of 
comprehensive skin evaluation performed by the Investigator during screening. Any 
concerning lesions identified during the Screening Period will be biopsied and results 
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must be known to be benign prior to enrollment. If the pretreatment biopsy results are 
of concern, the patient should be excluded from the trial.  
6. Diagnosis of schizophrenia, bipolar disorder, personality disorder, or other psychiatric 
disorders that the Investigator believes will interfere significantly with trial 
compliance. Neurocognitive disorders affecting ability to consent will not be 
disqualifying as long as an appropriate guardian able to give consent has been 
appointed. 
7. Clinically significant depression or suicidality as defined by: any suicidal ideation of 
type 4 or 5 on the C-SSRS, any lifetime history of a suicide attempt, or any suicidal 
behavior in the last month or a Patient Health Questionnaire-9 (PHQ-9) score of 
≥15 during Screening in patients with no significant neurocognitive deficits. 
8. Patient is not suitable, in the opinion of the Investigator, to participate in the trial.  
9. Hypersensitivity to the active substance or to any of the excipients of the 
investigational products (active or placebo). 
10. Inability to comply with the QW and QD injection regimens. 
11. Participation in any clinical trial with an investigational drug/device within 3 months 
prior to the first day of dosing, with the exception of a setmelanotide clinical trial. 
12. Legally protected persons per local regulations (e.g., those that fall under the L1121-6 
article of the Public Health code in France) or other applicable local laws. 
13. The patient or a relative of the patient is the investigator or a sub-investigator, 
research assistant, pharmacist, trial coordinator, or other staff directly involved with 
the conduct of the trial. 
6.3. 
Re-Screening 
Patients may be re-screened once if the screen failure is due to an entry criterion result that may 
change over time (e.g., HbA1c >9.0%). In this situation, the patient may be re-screened after at 
least 1 month and no more than 6 months. Re-screening of a patient is up to the discretion of the 
Sponsor and must be approved by the Sponsor prior to any re-screening procedures. Re-screened 
participants must be informed and provide consent again at re-screening. All screening 
procedures and assessments must be performed at re-screen. 
6.4. 
Patient Withdrawal Criteria 
Given this rare patient population, every effort will be made to encourage and keep patients 
enrolled in the trial until completion, regardless of premature study drug discontinuation, 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. 
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. 
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. 
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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 the opinion of the Investigator, justifies treatment or trial withdrawal. 
Appendix 3 
• Non-adherence to the study drug regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 
7. 
TREATMENT OF PATIENTS 
7.1. 
Description of Study Medication 
All study medication is for investigational use only and is to be used only within the context of 
this protocol. All investigational study medication (setmelanotide QW formulation, QD 
formulation, and vehicle placebos) will be supplied by the Sponsor. 
Setmelanotide QW formulation will be provided as a sterile solution at a concentration of 
30 mg/mL for administration at dose levels of 20, 25, and 30 mg by SC injection. Setmelanotide 
QW drug product consists of setmelanotide dissolved in a liquid lipid phase consisting of key 
excipients, soy phosphatidylcholine and glycerol dioleate. The solution is a clear, pale yellow to 
yellow solution, practically free from particles. The placebo for the QW formulation will consist 
of the vehicle only (no active ingredient) and will be visually indistinguishable from the QW 
drug product. 
Setmelanotide QD drug product ( (
) w
) will be provided as a 
sterile solution at a concentration o
on of 10 
10 mg
mg/mL
/mL f for r admininisistrtratio
tion atat dos
 dose levels of 2, 2.5, and 
3 mg by SC injection. Setmelanotide is a clear to slightly opalescent, colorless to pale yellow 
solution essentially free of visible particulates. The QD formulation will be provided in clear 
glass vials. The placebo for the QD formulation will consist of the vehicle only (no active 
ingredient), will be visually indistinguishable from the drug product, and will be provided in 
clear glass vials. 
7.2. 
Randomization and Blinding 
Patients will be randomized on Day 1 (Visit 3) to treatment with either QD or QW 
setmelanotide. The trial staff will utilize an interactive response technology (IRT) system to 
obtain the randomization number for each patient.  
No randomization or blinding will be done for the 13-week open-label phase or for the 3-week 
QD follow-up phase. 
7.2.1. 
Blinding and Unblinding 
To maintain the blind dur
nd during t
ng the
he 13
 13-week r
k randomized treatment period, a
od, all p patie
tientsts w
 wilill re
l receive 
placebo injections 
 from the QD formulation or 
 fro
 from 
the QW formulation)
on) in a addi
ddition t
on to t
o the
he s setmelanotide injections in a dou
 doublble-du
dummy f
y fashihion.
on. 
Blinded randomization will occur via an IRT system. 
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Emergency unblinding for AEs may be performed through an IRT system. The IRT system 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 intervention 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 intervention 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 intervention 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, Ethics Committees, and/or Institutional 
Review Boards (IRBs). Investigators will receive only blinded information unless unblinded 
information is judged necessary for safety reasons. 
7.3. 
Administration 
Details on preparation and administration of setmelanotide for dosing are provided in the 
Pharmacy Manual. Extensive training on drug administration, including educational materials, 
will be provided to the patients/caregivers. Trial-specific training materials will be provided to 
both the investigative staff and trial participants and caregivers. Both the QW and QD 
formulations of setmelanotide will be administered by SC injection. A home healthcare provider 
may be contracted to observe or perform the administration of injections of the QW study drug to 
the patient at the patient’s home.  
All patients will receive QD setmelanotide injections during the Screening (supplied by the LTE 
trial) and during the Run-in Periods (supplied under this protocol). For the QD doses of study 
drug supplied under this protocol, patients/caretakers will draw up and self-administer/administer 
the study drug each morning during the Run-in Period. 
Starting on Day 1 (Visit 3) of the trial and throughout the duration of the double-blind period, 
study medication will be administered in a double-dummy fashion. P
on. Patien
ents r
s ran
andomized
zed t to QW 
setmelanotide will concurrently receive QD injections of placebo 
 
Patie
tientsts ra
 randomiz
mized toto QD setmelanotide will concurrently receivive Q
 QW ininjejectio
tions o of p plalacebo 
 F
 For the QD doses of study drug, patients/caretakers will draw up and self-
admin
minisisteter/a
r/admin
minisisteter th
r the study drug each morning during the double-blind period. On the days 
of in-person clinic visits, the patients/caretakers will administer the QD dose of study drug in the 
clinic in the presence of the clinical staff to assure proper technique. In addition, once each week, 
the QW dose of study drug will be prepared and administered by the trial staff at the trial center 
or by the patient, caretaker, or home healthcare provider, if applicable, at the patient’s home. The 
patient will receive the first QW dose on Day 1 (Visit 3) at the trial center. The QD study drug 
and QW study drug should not be administered in the same location. The location of each 
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injection will be documented so that any ISRs resulting from QD study drug will be 
differentiated from those resulting from QW study drug. 
During the non-randomized phase, all patients will receive open-label QW setmelanotide 
prepared and administered by the trial staff at the trial center or by the patient, caretaker, or 
health home care provider, as applicable, at the patient’s home. During the follow-up period, all 
patients will return to QD setmelanotide (self-administered or administered by the patient’s 
caretaker) at the dose they were on at the time of trial entry. 
Dose adjustment is not permitted during the trial. Any change in dose must be captured as a 
protocol violation, regardless of the rationale for the dose adjustment. 
7.4. 
Treatment Compliance 
Accountability for the study drug (including placebo) at the trial site is the responsibility of the 
Investigator. The Investigator will ensure that the study drug 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 
study drug to the trial center, and return to the Sponsor (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 
capture dosing in an electronic diary, and by accounting for vials dispensed and returned (used 
and partially used). 
7.5. 
Preparation/Handling/Storage/Accountability 
Only patients enrolled in the trial may receive study medication and only authorized site staff 
may supply study medication. All study medication must be stored at the trial center 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 study drug accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records). 
All study medication must be kept at a temperature between 2°C to 8°C. Both formulations are 
stable at room temperature for a short time period that will allow patients to transport study drug 
home; ice packs and cooler bags will be provided for patients and caretakers who have to travel a 
long distance from the clinic. Once at home, the unopened study medication must be stored in 
the patient’s refrigerator. 
For accountability, patients/caretakers will return all used vials to the clinic when they visit, the 
trial staff will record the number returned, and both study drug administration in the clinic and 
outpatient study drug administration will be recorded in a trial diary. 
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7.6. 
Concomitant Medications 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the trial must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
GLP-1 receptor agonists may be used up to the dose approved for the treatment of diabetes 
mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) it is not being prescribed for 
the treatment of obesity, (2) the dose has been stable for at least 3 months prior to enrollment, 
(3) the patient has not experienced weight loss during the previous 3 months, AND (4) the 
patient intends to keep the dose stable throughout the course of the trial. 
All concomitant medications should be kept at a stable dose throughout the course of the trial, 
unless a dose change is necessary to treat an AE. 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Patients should not make significant changes to their diet or exercise routines during the course 
of the trial. 
7.6.1. 
Prohibited Medications 
Medications that are approved to treat obesity (e.g., orlistat, lorcaserin, phentermine-topiramate, 
naltrexone-bupropion) are not allowed within 3 months prior to the first dose of study medication 
(e.g., enrollment) and are prohibited during the course of the trial. GLP-1 receptor agonists being 
prescribed for the treatment of obesity are not allowed. 
8. 
ASSESSMENTS 
Trial procedures and their timing are summarized in the SoA (Section 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 ECG, and perform blood draws (at the specified time point, if 
applicable). Adjustments may be made depending upon specific circumstances and in 
consultation with the Sponsor. 
For patients <18 years of age, it may not be possible to perform all planned assessments at each 
visit. Thus, as described in the SoA (Section 2), the Investigator will be given latitude to adjust 
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the planned assessments and blood draws as appropriate for the optimal medical care of the 
patients. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
8.1. 
Informed Consent/Assent 
The method of obtaining and documenting the informed consent and assent (if applicable) and 
the contents of the consent will comply with current International Council for Harmonisation 
(ICH) E6 GCP Guidelines and all applicable laws and regulations. A complete description of the 
trial is to be presented to each potential patient or parent/legal guardian and a signed and dated 
informed consent form (ICF) and/or assent form 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 ICFs during their participation in the trial, and a copy of the ICF(s) must 
be provided to the patient or their legally authorized representative. Patients who reach the age of 
consent during the trial must be re-consented, as applicable, per local laws. 
Procedures conducted as part of the LTE trial or patient’s routine clinical management (e.g., 
laboratory tests) 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 (Section 2). 
8.2. 
Inclusion/Exclusion Review 
Inclusion and exclusion criteria must be carefully reviewed 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. 
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 (Visit 3) prior to the first dose of randomized 
study drug, to assess continued trial eligibility and adherence to final inclusion/exclusion criteria. 
This medical history update includes a review for changes from screening and 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 should be measured at Screening only. For patients aged 
<21 years, height is to be measured at the time points designated in the SoA (Section 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 centimeter.  
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8.5. 
Fitzpatrick Classification Scale 
Each patient is to be categorized for skin type according to the Fitzpatrick classification scale 
(Table 3). 
Table 3: 
Fitzpatrick Classification 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 
Source: Fitzpatrick TB. Soleil et peau. J Med Esthet. 1975;2:33034. 
8.6. 
Pharmacokinetic Assessments 
For all blood samples collected for PK analysis, the actual (clock) time the blood sample is 
drawn will be recorded in the source documents and electronic case report form (eCRF). Plasma 
will be harvested from each blood sample and the plasma will be frozen, shipped to a 
bioanalytical laboratory designated by the Sponsor, and analyzed for setmelanotide 
concentrations. A temporary indwelling catheter may be placed to obtain serial blood samples for 
the PK profiles.  
Patients/caretakers will be reminded that there should be no study drug administration at home 
on the day of clinic visits so that samples for trough (predose) concentrations can be drawn 
within 30 minutes prior to dosing at the clinic. 
8.6.1. 
Blood sampling 
Blood samples will be collected from all patients according to the SoA (Table 1) instructions for 
PK sampling. All efforts will be made to obtain all PK samples relative to dosing. The exact time 
of sample collection will be noted. 
In case of significant challenges with the collection of any PK sample, the investigator should 
confirm sample prioritization with the sponsor. 
 
 
 
 
 
 
 
 
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8.8. 
Safety Assessments 
8.8.1. 
Vital Signs 
Vital signs include systolic and diastolic BP, HR, respiration rate, and body temperature (°C). 
Vital signs will be obtained in the sitting position following at least 5 minutes of rest. Note that 
for virtual visits, BP will be collected. 
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). 
Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR. In addition, if results from outpatient measurement of vital signs indicate clinically 
significant abnormalities, these results should be re-checked either by the patient’s primary care 
physician or at the investigative site. 
8.8.2. 
Physical Examination  
A complete physical examination will be conducted at screening and at the end of trial visit 
(Week 30). At other time points, an abbreviated examination will be performed. All physical 
examinations are to be conducted in adequate lighting. 
• 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 neurologic. 
• 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. 
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Whenever possible, the same trained health care professional will conduct the examination and 
Tanner Staging. 
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. 
8.8.3. 
Comprehensive Skin Examination 
A comprehensive skin examination will be performed by the Investigator or qualified designee. 
The skin examination should include a full body (head-to-toe) 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 classified as benign 
prior to the first dose of setmelanotide. If the pretreatment biopsy results are of concern, the 
patient will be excluded from the trial.  
During the course of the trial, any concerning lesion or change in an existing lesion must be 
evaluated by the dermatologist and biopsied, if clinically indicated in the opinion of the 
dermatologist. The decision to continue the patient on setmelanotide treatment or to discontinue 
treatment will be decided by the Investigator after discussion with the Medical Monitor. 
8.8.4. 
Electrocardiogram 
Single 12-lead ECGs will be performed with the patient in the supine position following a period 
of at least 10 minutes of rest.  
8.8.5. 
Laboratory Assessments 
Blood and urine samples for clinical laboratory tests are to be collected after patients have been 
fasting for 8 hours. Samples are to be collected prior to setmelanotide administration. 
The Investigators will adhere to the site-specific blood volume limits for safety laboratory and 
PK analyses to ensure minimal distress to pediatric patients. Due to the age of the children 
potentially eligible for participation in this trial, it may not be possible to collect all labs at every 
trial visit in this patient population, though efforts should be made to collect as many PK samples 
per protocol. Screening may be completed over multiple days to complete the required 
assessments. Venipuncture reduction is allowed should a patient experience unacceptable 
discomfort as deemed by the Investigator. After enrollment, if not all lab tests are possible, then 
the tests should be collected in the following descending order of priority: safety, anti-drug 
antibodies, trough PK, hemoglobin A1c, and then lipid panel. 
All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated according to the judgment of the Investigator. 
The routine clinical laboratory parameters to be evaluated are as follows: 
Hematology 
Complete blood count with platelet count and standard indices will be obtained. 
Chemistry 
Sodium, potassium, chloride, carbon dioxide, albumin, total protein, glucose, blood urea 
nitrogen, creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, gamma-
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glutamyltranspeptidase, creatine phosphokinase, alkaline phosphatase, total bilirubin, direct 
bilirubin, lactate dehydrogenase, calcium and phosphorus. 
Coagulation Profile 
Prothrombin time or international normalized ratio, and partial thromboplastin time, also referred 
to as activated partial thromboplastin time. 
Urinalysis 
Urine pH, glucose, protein, ketones, bilirubin, blood, urobilinogen, specific gravity, nitrite, and 
leukocytes by dipstick analysis or machine urinalysis. Urine microscopic examination will be 
performed if positive findings on dipsticks warrant further examination. 
8.8.6. 
Anti-Drug Antibodies 
Blood samples for measurement of ADA will be collected according to the SoA in Table 1. Any 
patient with a positive titer will be followed until resolution. 
8.8.7. 
Pregnancy and Contraception 
In animal reproduction studies, setmelanotide was not teratogenic at doses >10 times the 
maximum recommended human dose of 3 mg. No evidence of embryo-fetal toxicity was 
observed. Pre-and post-natal development studies in rats showed no adverse setmelanotide-
related effects. Please refer to the Investigator’s Brochure for additional information. 
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; however, setmelanotide 
dosing may continue with results pending. 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  
• 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. 
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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 FSH 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 if 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 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. True 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 and should follow the SAE reporting procedures outlined in 
Appendix 3. 
Details of all pregnancies in female patients and female partners of male patients will be 
collected after the start of study 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. 
8.8.8. 
Injection Site Examination 
Injection sites will be carefully inspected, evaluated, and scored by the clinical staff during each 
in-person and telehealth trial visit. It is important to distinguish injection sites for the QW 
formulation from those with the QD formulation. It is recommended to use a dedicated part of 
the body (such as a single quadrant of the abdomen) for the QW injections to facilitate this 
process.  
The injection site evaluation will include identification of areas of erythema, edema, and 
induration, as well as the presence of localized pain, tenderness, and itching. At in-person trial 
visits, the clinical staff will also record measurements of areas of erythema, edema, and 
induration. A sample injection site evaluation form is included in Appendix 2. 
In addition, unscheduled evaluations may also be recorded as warranted by clinical conditions. 
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8.8.9. 
Suicidal Ideation and Depression Monitoring 
As setmelanotide is considered to act through the central nervous system (CNS), 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 ≥10 
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 disorder can be adequately treated with psycho- 
and/or pharmacotherapy, then the patient, at the discretion of the MHP, should be continued in 
the trial. 
In cognitively impaired patients or pediatric patients, the ability to complete the following 
Mental Health Assessment instruments as intended may be limited. If in the clinical opinion of 
the Investigator a specific patient cannot complete the instrument, 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 C-SSRS is not administered, the Investigator 
should document that the issue of suicidality was assessed clinically (e.g., discussion with 
caregivers). 
8.8.9.1. 
Columbia-Suicide Severity Rating Scale 
As required in the US by the Food and Drug Administration (FDA), for clinical trials of CNS-
acting medications, changes in depression/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 MHP). 
There are 2 versions of the C-SSRS that will be administered: 
• The Screening version of the scale documents recent (within the past month) scores 
from the screening C-SSRS scale. This version can assess a patient’s eligibility based 
on inclusion/exclusion criteria.  
[Note that patients will have completed the Baseline/Screening version of the 
C-SSRS scale during the index trial and are therefore not expected to complete this 
version in the current trial. Thus, the baseline assessment that was collected at the 
beginning of the index trial should continue to be used as the baseline for this 
trial. (The Baseline/Screening version of the scale combines the Baseline and 
Screening forms to assess suicidality in a patient’s lifetime and during a predefined 
time period. This version can assess a patient’s lifetime suicidality for data collection 
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purposes as well as eligibility, based on inclusion/exclusion criteria, for the index 
trial.)] 
• 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 every subsequent visit. 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 you have administered the 
C-SSRS. 
To be eligible for the trial, a patient cannot have suicidal ideation of type 4 or 5, any lifetime 
history of suicide attempt, or any suicidal behavior in the last month in patients with no 
significant neurocognitive deficits. 
Pediatric patients may not be able to complete the C-SSRS as intended. If in the clinical opinion 
of the Investigator a specific patient cannot complete the instrument, 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 C-SSRS is not administered, the Investigator 
should document that the issue of suicidality was assessed clinically (e.g., discussion with 
caregivers). 
A patient should be referred to an MHP if he/she has: 
• Any suicidal behavior. 
• Any suicidal ideation of type 4 or 5 on the C-SSRS. 
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 disorder can be adequately treated with psycho- 
and/or pharmacotherapy, then the patient, at the discretion of the MHP, should be continued in 
the trial. 
8.8.9.2. 
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. 
8.8.10. 
Overdose 
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. 
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The quantity of the excess dose and the duration of the overdose are to be documented in the 
eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
8.8.11. 
Adverse and Serious Adverse Events 
AEs 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 study treatment or trial procedures, or that caused the 
patient to discontinue study treatment (see Section 6.4). 
Details on recording AEs and SAEs, including definitions, are provided in Appendix 3. 
8.8.11.1. Time Period and Frequency for Collecting AE and SAE Information 
All AEs, including SAEs, will be collected from the start of the Run-in Period to the end-of-trial 
visit (Week 30). AEs reported after starting the Run-in Period will be considered treatment-
emergent AEs. 
Medical occurrences that begin before the start of the Run-in Period but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours from the 
point in time when the Investigator becomes aware of the SAE. All SAEs must be reported 
whether or not considered causally related to the study drug. The Investigator will submit any 
updated SAE data to the Sponsor within 24 hours of it being available. 
Investigators are not obligated to actively seek AEs or SAEs in 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 AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3. 
8.8.11.2. 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. 
8.8.11.3. 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 3. 
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8.8.11.4. Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the Sponsor of a SAE is essential so that 
regulatory obligations and ethical responsibilities toward the safety of patients and the 
safety of a study 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 study treatment under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs, 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’s Brochure and will notify the IRB, 
if appropriate according to local requirements. 
9. 
STATISTICS 
This section describes the plans for analysis. 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 trial report for the trial, as appropriate. 
9.1. 
Sample Size Determination 
The primary objective is to assess steady-state PK parameters (maximum plasma concentration 
[Cmax,], time to maximum plasma concentration [Tmax], trough plasma concentration [Ctrough], 
area under the plasma concentration-time curve over the dosing interval [AUC0-tau]) for QW 
compared with QD setmelanotide. The sample size is based on availability of the patients 
enrolled in the LTE trial and is not driven by formal statistical hypothesis testing on non-
inferiority/similarity. 
9.2. 
Populations for Analyses 
The analysis populations are defined as follows:  
• Pharmacokinetic Analysis Set (PKAS): All patients who receive at least 1 dose of 
setmelanotide and who have a sufficient number of measurable plasma concentrations 
to permit assessment of noncompartmental parameters. 
• Full Analysis Set (FAS): All patients who receive at least 1 dose of setmelanotide. 
Patients will be analyzed according to their randomly assigned treatment. 
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• Per Protocol Set: All patients in FAS without any major protocol violations that 
would result in exclusion of the patients from the analysis. Patients will be analyzed 
according to their randomly assigned treatment. 
• Safety Analysis Set: All patients who are randomized and receive at least 1 dose of 
protocol-specified study drug. Patients will be analyzed according to the treatment 
they actually received. 
9.3. 
Statistical Analyses 
9.3.1. 
Primary Analysis of PK Parameters 
The PK profile of the 2 formulations of setmelanotide will be characterized and the steady-state 
PK parameters (Cmax, Tmax, Ctrough, and AUC0-tau) will be summarized for QD and QW 
setmelanotide by dose level and prior treatment regimen (QW or QD) during the double-blind 
phase of the trial using descriptive statistics (e.g., n, mean, standard deviation, geometric mean, 
minimum, median, maximum, % coefficient of variation [CV], geometric mean CV, and 
confidence interval [CI]). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
9.3.3. 
Safety Analyses 
AEs/SAEs including ISRs, as well as discontinuations due to AEs will be summarized with 
frequencies and percentages. By-patient AE data listings including onset and resolution dates, 
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verbatim term, preferred term, treatment, severity, relationship to treatment, action taken, and 
outcome will be provided. Injection site reactions for the QD and QW formulations will be 
summarized separately. 
Safety data including laboratory evaluations, ECGs, physical examinations, and vital signs 
assessments will be summarized by time of collection. In addition, change from baseline to any 
postdose values will be summarized for vital signs, ECGs, and clinical laboratory results. 
Frequency of patients with abnormal safety laboratory results will be tabulated. Continuous 
outcomes (e.g., vital signs, safety laboratory parameters) will be summarized using n, mean, 
median, standard deviation, etc. 
All safety analyses and summary tables will be based on Safety Analysis Set. 
9.3.4. 
Interim Analysis 
No unblinded interim analysis is planned. Blinded interim analyses may be conducted during the 
course of the trial to facilitate scientific monitoring and business needs. 
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10. 
LIST OF REFERENCES 
Bardet G. On congenital obesity syndrome with polydactyly and retinitis pigmentosa (a 
contribution to the study of clinical forms of hypophyseal obesity). Thesis. Obes Res. 
1995;3(4):387-99. 
Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of 
Bardet-Biedl syndrome: results of a population survey. J Med Genet. 1999;36(6):437-46. 
Biedl A. A pair of siblings with adiposo-genital dystrophy. Obes Res. 1995;3(4):404. 
CKD-EPI creatinine equation 2021. National Kidney Foundation from 
https://www.kidney.org/professionals/kdoqi/gfr_calculator. Accessed 09 November 2021. 
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. 
Forsythe E, Beales PL. Bardet-Biedl syndrome. Eur J Hum Genet. 2013;21:8-13. 
Forsythe E, Sparks K, Hoskins BE, Bagkeris E, McGowan BM, Carroll PV, et al. Genetic 
predictors of cardiovascular morbidity in Bardet-Biedl syndrome. Clin Genet. 2015;87(4):343-9.  
Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR. Energy balance 
and its components: implications for body weight regulation. Am J Clin Nutr. 2012;95(4):989-
94. 
Maes HH, Neale MC, Eaves LJ. Genetic and environmental factors in relative body weight and 
human adiposity. Behav Genet. 1997;(4):325-51. 
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. 
Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and 
metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond). 
2016;130(12):943-86. 
Schousboe K, Willemsen G, Kyvik KO, Mortensen J, Boomsma DI, Cornes BK, et al. Sex 
differences in heritability of BMI: a comparative study of results from twin studies in eight 
countries. Twin Res. 2003;6(5):409 21. 
Silventoinen K, Rokholm B, Kaprio J, Sorensen TI. The genetic and environmental influences on 
childhood obesity: a systematic review of twin and adoption studies. Int J Obes (Lond). 
2010;34(1):29-40.  
Sheikh A, Nasrullah A, Haq S, Akhtar A, Ghazanfar H, Nasir A, et al. The interplay of genetics 
and environmental factors in the development of obesity. Cureus. 2017;9(7):e1435.  
Thaker V. Genetic and epigenetic causes of obesity. Adolesc Med State Art Rev. 
2017;28(2):379-405. 
van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161(1):119-
32. 
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11. 
APPENDICES 
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APPENDIX 1. GUIDANCE ON TRIAL CONDUCT DURING THE 
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-19 restrictions are imposed on or by the trial site and the site cannot fully carry out 
normal operations, the following measures are recommended on a temporary basis during the 
COVID-19 pandemic:  
• Where possible, every effort should be made to complete all protocol-required 
assessments. In place of a required site visit, a qualified healthcare provider could 
perform trial-related procedures as per the Schedule of Activities (Section 2) via a 
home visit, including but not limited to collection of body weight, vital signs, 
physical examinations, electrocardiograms (ECGs), r
, recordiding
ng of adverse events 
(AEs), collection of blood and urine samples. Most 
 a assessments could 
potentially be done off site. Investigators should use t the
heir c 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 caretaker vs. delegated in-home nursing, etc.). 
• If applicable, discontinuations of trial interventions and withdrawal from the trial due 
to disruption of trial conduct by the pandemic should be documented with the prefix 
“COVID-19 RELATED” in the electronic case report form (eCRF). 
• If a patient is unable to attend a site visit, investigational product may be shipped 
directly to the patient. 
COVID-19 Infection in Trial Patients: 
There is currently no available data suggesting that patients treated with setmelanotide should 
have treatment interrupted during the COVID-19 pandemic. If a patient develops symptoms 
associated with coronavirus infection, it is recommended to confirm the diagnosis using locally 
approved laboratory kits and report it to the local health authorities, as required. Patients with 
positive test results for severe acute respiratory syndrome coronavirus-2 (SARS-COV-2) should 
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have this recorded as an AE, and if hospitalized, this should be reported as a serious adverse 
event (SAE). 
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APPENDIX 2. INJECTION SITE EVALUATIONS 
Injection sites will be assessed (by the clinical staff) using a form similar to the depiction below 
at the time points outlined in the Schedule of Activities (Section 2), and in the setting of any 
injection site reaction adverse experience. 
Local Skin Tolerability Assessment 
Reaction 
NONE 
Mild 
Moderate 
Severe 
Measurement 
(if applicable) 
Erythema* 
□ 
□ 
□ 
□ 
 
Edema* 
□ 
□ 
□ 
□ 
 
Induration* 
□ 
□ 
□ 
□ 
 
Itching 
□ 
□ 
□ 
□ 
 
Pain or Tenderness 
□ 
□ 
□ 
□ 
 
Other:  
 
□ 
□ 
□ 
□ 
 
* If present, region will be measured, length and width as appropriate during in-clinic visits and if possible during 
telehealth visits.  
Initials:  
 
 
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APPENDIX 3. 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 study treatment, whether or not considered related to the study 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 study 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 study 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 study 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. 
• 
 or “failure of expected phararmac
acological action” per se will not be reported as an AE or 
SAE. Such instan
ances
ces will be cap
aptured
ed in the e 
 assessments. However, the signs, symptoms, and/or 
clinical sequelae resulting from 
 will be reported as AE or SAE if they fulfill the definition of 
an AE or SAE. 
 
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. 
 
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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 trial, 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 
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. 
 
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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 eCRF 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 one of the predefined outcomes as described in the 
definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The Investigator is obligated to assess the relationship between study 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 study treatment administration will be considered and investigated. 
• 
The Investigator will also consult the Investigator’s Brochure 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. 
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Assessment of Causality 
• 
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 
study drug, 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 study drug exposure and onset of the AE. 
• 
Whether the manifestations of the AE are consistent with known actions or toxicity of the study drug. 
• 
The AE resolved or improved with decreasing the dose or stopping use of the study drug (dechallenge). 
Judgment should be used if multiple products are discontinued at the same time. 
The causal relationship between the study drug 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 study drug); 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 frame 
following administration of study drug); 
− 
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 study 
drug). 
 
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 postmortem 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 of receipt of the 
information. 
 
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Reporting of SAEs 
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours from the 
point in time when the investigator becomes aware of the SAE. All SAEs must be reported 
whether or not considered causally related to the study drug. 
SAE & Pregnancy Reporting to Sponsor 
• 
All SAEs will be reported via the SAE Re
Report Form within 24 hours of the Investigators awareness to 
RhythmSafety.SM@ppdi.com  or via fax x 
 
• 
If a pregnancy is reported by a patient or patient partner, the Investigator should inform the Sponsor by 
completing a Pregnancy Reporting Form withihin n 24 4 ho
hours and sending via 
RhythmSafety.SM@ppdi.com  or via fax x 
 
• 
The site will also enter the SAE data into the electronic data collection system as soon as it becomes 
available. 
 
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APPENDIX 4. 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”, which may be classified as “Minor Increase over 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 
patients <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. This includes adherence to site-specific blood volume 
limits for safety laboratory and PK analyses (as applicable) to ensure minimal distress 
and reduce the number of excessive venipunctures in pediatric patients. 
• 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. 
• Study drug injections should only be performed by parents (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 exam 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 one representative example of rare genetic disorder of obesity impacting the MC4R pathway, 
there is the possibility of major benefit. 
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APPENDIX 5. 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), Investigator 
Brochure, and other relevant documents (e.g., advertisements) must be submitted to 
an Institutional Review Board (IRB) by the Investigator and reviewed and approved 
by the IRB before the trial is initiated. 
• Any amendments to the protocol will require IRB 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 
− Notifying the IRB of serious adverse events (SAEs) or other significant safety 
findings as required by IRB 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, 
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 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. 
• Patients who reach the age of consent during the trial must be re-consented, as 
applicable, per local laws. 
• 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. 
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 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 form 
(eCRF) unless transmitted to the Sponsor electronically (e.g., e-diary). The Investigator is 
responsible for verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit trial-related monitoring, audits, IRB review and regulatory agency 
inspections and provide direct access to source data documents. 
Monitoring details describing strategy (e.g., risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote or on-site monitoring) are provided in the Monitoring Plan. 
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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 (e.g., due to COVID-19), the Clinical Research Associate (CRA) 
will perform routine scheduled Remote Interim Monitoring Visits (rIMV) for active sites. The 
aim of the remote activities is to ensure adequate ongoing oversight of trial activities to identify 
and eliminate any immediate risk to the safety and integrity of the patients. Each individual 
RMV 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 Monitor asks Investigator site staff member 
to read patient source documents during a telephone call while reviewing the Case 
Report Form (CRF) 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 regulation, 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 and Site Closure 
The trial is to be discontinued if the required approval or favorable approval is revoked. 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: 
• 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 patients by the 
Investigator. 
• Total number of patients included earlier than expected. 
If the trial is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the trial of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The Investigator shall promptly inform the patient and should assure 
appropriate patient therapy and/or follow-up. 
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 the 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 
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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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Statistical Analysis Plan; Effective 24 July 2023, v2.0 
 
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TABLES INCLUDED IN THE TEXT 
 
Page 
Table 1 
Schedule of Assessments ............................................................................................... 16 
Table 2              Fitzpatrick Classification Scale ................................................................................... 29 
 
 




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Abbreviation 
Definition 
PPL 
POMC (pro-opiomelanocortin), PCSK1 (proprotein convertase 
subtilisin/kexin type 1), LEPR (leptin receptor) 
PPS 
Per Protocol Set 
PR 
PR interval  
PT 
Preferred term 
QD 
Once daily Setmelanotide 
QRS 
Interval between Q, R, and S waves 
QT 
Interval between Q and T waves 
QW 
Once weekly Setmelanotide 
Rel Day 
Relative study day 
RGDO 
Rare genetic disorder of obesity 
RM-493 
Setmelanotide 
SA 
Safety analysis set 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SI 
International System of Units 
SoA 
Schedule of Assessments 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
US 
United States 
VC 
Vital capacity 
WHO 
World Health Organization 
 
 








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randomized to receive either QD setmelanotide 2 mg or QW setmelanotide at a dose of 20 mg, 
whereas patients who were on QD setmelanotide at a dose of 2.5 mg will be randomized to 
receive either QD setmelanotide 2.5 or QW setmelanotide at a dose of 25 mg, and finally 
patients who were on QD setmelanotide at a dose of 3 mg will be randomized to receive either 
QD setmelanotide 3 mg or QW setmelanotide at a dose of 30 mg. Study medication will be 
administered in a double-dummy fashion in order to maintain the double blind. Patients will 
receive the first QW dose on Day 1 of the randomized treatment period (Visit 3). The 
randomization will be stratified by age group. 
 Patients randomized to QW setmelanotide will receive blinded QW setmelanotide and QD 
placebo injections until the Week 14 visit (i.e., completion of 13 weeks of blinded dose 
administration). Starting with Week 14, patients will continue with open-label QW 
injections of setmelanotide during the 13-week non-randomized phase of the study. 
 
 Patients randomized to QD setmelanotide will receive blinded QD setmelanotide and QW 
placebo injections until the Week 14 visit (i.e., completion of 13 weeks of blinded dose 
administration). Starting with Week 14, patients will continue with open-label QW 
injections of setmelanotide during the 13-week non-randomized phase of the study. 
 
For the 3-week Follow-up Period, all patients will return to their allocated run-in 
medication of QD setmelanotide to prepare for re-enrollment into Study RM-493-
022 or to resume the QD formulation in some other way. 
 
The study design is depicted graphically in Figure 1. 
 




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patient. The date and reason for the unblinding by the Investigator must be recorded. If a 
patient’s intervention assignment is unblinded, the Sponsor must be notified by the 
Investigator within 24 hours that an unblinding occurrence. 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 serious adverse event (SAE) that is treatment-related (e.g., possibly or 
probably related), 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 study (such as 
the monitors, investigators, etc.) and those responsible for data analysis and interpretation of 
results at the conclusion of the study (such as biometrics personnel). Unblinded information 
will only be accessible to those who need to be involved in the safety reporting to Health 
Authorities, Ethics Committees, and/or Institutional Review Boards (IRBs). Investigators will 
receive only blinded information unless unblinded information is judged necessary for safety 
reasons. 
This study may be prematurely terminated, if in the opinion of the Investigator (at a 
participating site) or Rhythm (for the whole study), there is sufficiently reasonable cause. The 
terminating party will provide written notification documenting the reason for study termination 
to either the Investigator or Rhythm. Circumstances that may warrant termination include, but 
are not limited to:  
 Discontinuation of further study intervention development 
 Inadequate or no recruitment (evaluated after a reasonable amount of time) of patients by 
the Investigator 
 Total number of patients enrolled earlier than expected 
If the study is prematurely terminated or suspended, the Sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The Investigator shall promptly inform the patient and 
should ensure appropriate patient therapy and/or follow-up. 
Every attempt will be made to maintain the blind through the end of the study. Breaking the 
blind for a patient should be done only in the event of a medical emergency where the identity 
of study drug is necessary to appropriately treat the patient. As noted above, the Primary 
Investigator will be provided with access to the IRT system to unblind their patients, but, if 
possible, the decision to break the blind should first be discussed with the Sponsor. If the blind 
is broken, the reason, when, and how the blind was broken will be documented. 


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1.2.4. 
Study Procedures 
The schedule of assessments, as outlined in the study protocol, is provided in Error! Reference 
source not found.. 












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18 All BP and HR 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, BP should be taken in the non-dominant arm throughout the study, using the same methodology 
(automated or manual). Body temperature (°C) and respiration rate (breaths/minute) will be obtained in the sitting position following at least 5 minutes 
of rest. 
19 A single 12-lead ECG will be performed with the patient in the supine position following a period of at least 10 minutes of rest. 
20 A complete physical examination will be conducted at Screening and at the end of study (Week 30). At other time points, an abbreviated examination, 
noting any changes from baseline will be performed. 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. 
21 If at any time during the study an individual patient’s PHQ9 score is ≥10, the patient should be referred to a Mental Health Professional. 




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1.2.5.3. 
Safety Parameters 
The safety endpoints include AEs, SAEs, and injection site reactions (ISRs), and laboratory 
parameters (including pregnancy testing), vital signs, ECG recordings, physical examination 
findings, skin examination, and the Columbia-Suicide Severity Rating Scale (C-SSRS) 
questionnaire results. 










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3.12. 
Interim Analyses 
No unblinded interim analysis is planned. Blinded interim analyses may be conducted during 
the course of the trial to facilitate scientific monitoring and business needs. 










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geometric mean, minimum, median, maximum, % coefficient of variation (CV), geometric 
mean CV, and 95% confidence intervals (CIs). 
A separate tabulation will be created for the same analysis by subgroup (age category and 
genetic subgroup).  
4.5. 
Safety Analyses 
Safety analyses will be conducted using the SA Set. 
4.5.1. 
Drug Exposure 
Drug exposure will be summarized by QD/QW treatment group across the entire length of the 
study. The number of doses administered, total dose received in mg, treatment duration in 
weeks, and percentage of dosing compliance will be summarized using descriptive statistics (N, 
mean, SD, median, minimum, maximum, and 95% confidence intervals). Treatment duration 
will be defined in weeks as (date of last dose – date of first dose + 1) / 7. Dosing compliance 
percentage will be defined as ([number of doses administered] / [duration of treatment in days]) 
* 100 for QD treatment and ([number of doses administered * 7] / [duration of treatment in 
days]) * 100 for QW treatment. A by-patient listing for dosing will be created.  
4.5.2. 
Adverse Events 
All AEs will be coded using the MedDRA coding system (Version 24.0 or later) and displayed 
in tables and data listings by SOC and PT. Adverse events will also be graded using the 
National Cancer Institute Common Terminology Criteria for AEs (NCI-CTCAE) on a scale of 
Grades 1 to 5 in which Grade 1 is a mild AE, Grade 2 a moderate AE, Grade 3 a severe AE, 
Grade 4 a life-threatening or disabling AE, and Grade 5 a fatal AE). Those not listed by CTCAE 
will be graded as either mild, moderate, or severe.  
Analyses of AEs will be performed for those events that are considered treatment-emergent, 
where treatment-emergent is defined as any AE with onset after the administration of 
randomized study medication at the start of the Run-in period through the end of the study (at 
the end of the 3-week follow-up period), any event that was present at baseline (beginning of 
Run-in period) but worsened in intensity or was subsequently considered drug-related by the 
Investigator through the end of the study, or any event deemed to be related to study drug 
exposure.  
The number and percentage of patients with any treatment-emergent adverse event (TEAE), 
with any TEAE assessed by the Investigator as related to treatment (definite, probable, or 
possible relationship), with any serious TEAE, any serious related TEAE, with any TEAE 
resulting in study drug withdrawal, with any TEAE leading to death will be summarized by 
QD/QW treatment group and overall. All TEAE analyses will have separate tabulations for two 
time frames: the beginning of the randomized, double-blind period (Day 1) to Week 14 and the 
beginning of the Run-in period through the end of the 3-week follow-up period (end of study). 
Since visits are not collected for AEs, the dates that each patient started and ended treatment at 


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each of these periods will be used to compare to the AE start and end dates for each patient in 
order to subset on the AEs specific to the randomized, double-blind period.   
In these tabulations, each patient will contribute only once (i.e., the most related occurrence or 
the most intense occurrence) to each of the incidence rates in the descriptive analysis, regardless 
of the number of episodes.  
No formal hypothesis-testing analysis of AE incidence rates will be performed. 
All AEs occurring on study will be listed in patient data listings. By-patient listings also will be 
provided for the following: patient deaths, serious TEAEs, serious related TEAEs, TEAEs 
leading to withdrawal, TEAEs related to the drug, and TEAEs of CTCAE Grade 3 or higher.  
4.5.3. 
Injection Site Evaluations 
Injection site evaluations will be summarized for all visits over time by QD/QW treatment 
received according to severity (none, mild, moderate, severe), and type of reaction (erythema, 
edema, induration, itching, pain or tenderness, or other reaction). For patients reporting more 
than one occurrence of the same type of reaction, the most severe reaction will be included in 
the summary.  
A by-patient listing will be provided for all injection site evaluations and will also include 
measurement (if applicable). 
4.5.4. 
Laboratory Data 
Clinical laboratory values will be expressed in the International System of Units. 
The actual value and change from baseline to each on-study evaluation will be summarized for 
each continuous clinical laboratory parameter by visit and QD/QW treatment received. 
Categorical results will be summarized by counts and percentages of patients in each category. 
In the event of repeat values, the last non-missing value per study day/time will be used. 
Clinical laboratory parameters include: 
Hematology 
Complete blood count with platelet count and standard indices 
Chemistry 
Sodium, potassium, chloride, carbon dioxide, albumin, total protein, glucose, blood urea 
nitrogen, creatinine, uric acid, aspartate aminotransferase, alanine aminotransferase, gamma- 
glutamyl transpeptidase, creatine phosphokinase, alkaline phosphatase, total bilirubin, direct 
bilirubin, lactate dehydrogenase, calcium, and phosphorus. 
Coagulation Profile 
Prothrombin time or international normalized ratio, and partial thromboplastin time, also 
referred to as activated partial thromboplastin time. 




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4.5.8. 
Prior and Concomitant Medications 
A prior medication is defined as any medication that was used and stopped before the start of 
the trial (Day -1 or before). A concomitant medication is defined as any medication with a stop 
date that is on or after the date of first dose of study drug.  
Prior and concomitant medications will be coded using the WHO Drug Dictionary, version 
March 1, 2021, or later. Results will be tabulated by anatomic therapeutic class (ATC) and PT. 
Prior and concomitant medications over the full study will be tabulated by QD/QW treatment 
group as well as by ATC level and PT in frequency tables. Patients with more than 1 medication 
at a given ATC level and PT will be counted only once in that category. If an end date is 
missing or the medication is ongoing, the medication will be included. Medications starting after 
the treatment withdrawal date will be listed but will not be classified or summarized. Partial 
dates will not be imputed.  
The use of prior and/or concomitant medications will be included in a by-patient data listing. 
4.5.9. 
Columbia Suicide Severity Rating Scale 
The C-SSRS will be measured as shown in the SoA (Table 1) according to the age of the patient 
(child <12 or adult ≥12). Results of the C-SSRS will be provided in a shift table assessing shifts 
from the baseline most severe ideation to most severe ideation during follow-up. A by-patient 
listing including the ideation, intensity of ideation, behavior, and number of attempts will be 
provided. 
4.5.10. 
Patient Health Questionnaire-9 
The Patient Health Questionnaire-9 will be measured as shown in the SoA (Table 1). The actual 
values, change, and percent change from baseline of the total scores will be summarized with 
descriptive statistics by visit. A by-patient listing of the results of the individual 9 questions will 
be provided. 
4.5.11. 
Anti-RM Antibody 
Anti-RM Antibody will be measured as shown in the SoA (Table 1). A by-patient listing, 
including the date of the assessment and result, will be provided. 


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5. 
CHANGES TO PLANNED ANALYSES 
All changes from procedures outlined in the protocol and procedures outlined in this SAP will 
be summarized in the CSR. Decisions to deviate from planned analyses will be documented at 
the time they are made. 
If any modifications in the experimental design, dosages, parameters, patient selection, or any 
other sections of the protocol are indicated or required, the Investigator will consult with the 
Sponsor before such changes are instituted. Modifications will be accomplished through formal 
amendments to this protocol by the Sponsor and approval from the appropriate IRB or IEC. 


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6. 
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Thaker V. Genetic and epigenetic causes of obesity. Adolesc Med State Art Rev. 2017;28(2):379-405. 
van der Klaauw AA, Farooqi IS. The hunger genes: pathways to obesity. Cell. 2015;161(1):119- 32.