Clinical trial NCT05046132
Conditions: Healthy
Keywords: Healthy Volunteers
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2021-08-05; Completion date: 2022-04-07
Enrollment: 77 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a double-blind, randomized, placebo- and positive-controlled, parallel group, 3-arm study that assessed the potential for therapeutic and supratherapeutic concentrations of setmelanotide to affect the QTc corrected by the Fredericia method (QTcF) interval.

Detailed description:

Arms: arm 1: Participants received titrated doses of 2-7 milligrams (mg) setmelanotide once daily by subcutaneous (SC) injection, starting with a dose of 2 mg from Days 1 to 7, 3 mg from Days 8 to 10, 5 mg from Days 11 to 13 and 7 mg from Days 14 to 16. Participants also received single oral dose of placebo matching moxifloxacin on Days 10 and 16. arm 2: Participants received placebo matching setmelanotide once daily by SC injection from Days 1 to 16. Participants also received a single oral dose of 400 mg moxifloxacin on Day 10 and a single oral dose of placebo matching moxifloxacin on Day 16. arm 3: Participants received placebo matching setmelanotide once daily by SC injection from Days 1 to 16. Participants also received a single oral dose of placebo matching moxifloxacin on Day 10 and a single oral dose of 400 mg moxifloxacin on Day 16.
Interventions: intervention 1: Setmelanotide intervention 2: Moxifloxacin intervention 3: Oral Placebo intervention 4: SC Placebo
Intervention descriptions: intervention 1: Administered once daily via SC injection. intervention 2: Moxifloxacin capsules via oral administration. intervention 3: Placebo capsules via oral administration. intervention 4: Placebo via SC injection.

Protocol documents:
SAP_002.pdf: 
 
Rhythm Pharmaceuticals, Inc. 
RM-493-032 
Statistical Analysis Plan 
 
 
Project Document Version No. 3.0 
Project Document Effective Date: 11 May 2022 
Page 1 of 47 
 
 
 
 
 
 
 
 
 
 
 
Rhythm Pharmaceuticals, Inc. 
 
 
 
 
RM-493-032 
 
 
 
 
A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and Positive-controlled Study to 
Investigate the Effects of Setmelanotide on QTc Interval in Healthy Subjects 
 
 
 
 
Statistical Analysis Plan 
 
 
 
 
 
Version: 3.0 
 
 
 
 
 


 
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SPONSOR SIGNATURE PAGE 
Approved by: 
_______________ 
          Date 
Rhythm Pharmaceuticals, Inc. 


 
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4.11.1 
Adverse Events ........................................................................................................... 33 
4.11.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events .................. 34 
4.11.3 
Clinical Laboratory Evaluation ................................................................................... 34 
4.11.4 
Vital Signs ................................................................................................................... 35 
4.11.5 
12-Lead Electrocardiogram (ECG) ............................................................................. 36
4.11.6 
12-Lead Holter ECG ................................................................................................... 36
4.11.7 
Physical Examination ................................................................................................. 37 
4.12 Other Analysis ................................................................................................................. 37 
4.12.1 
Columbia Suicide Severity Rating Scale (C-SSRS) ................................................... 37 
4.13 Determination of Sample Size ......................................................................................... 37 
4.14 Changes in the Conduct of the Study or Planned Analysis ............................................. 37 
5 
REFERENCES .................................................................................................................37 
6 
APPENDICES ..................................................................................................................39 
6.1 
Schedule of Assessments ................................................................................................. 39 
List of Tables 
Table 3-1 
Plasma Pharmacokinetic Parameters after Multiple Dose Administration of 
Setmelanotide .................................................................................................... 15 
Table 3-2 
Plasma Pharmacokinetic Parameters After Single Dose Administration of 
Moxifloxacin Administration ............................................................................ 16 
Table 4-1 
Graphical exploration analysis .......................................................................... 22 
Table 4-2 
Thresholds for abnormalities and corresponding flags for listings ................... 28 
Table 4-3 
Pharmacokinetic Parameter and Estimation ..................................................... 32 
Table 6-1 
Schedule of Assessments .................................................................................. 39 
Table 6-2 
Algorithm for Treatment-Emergent Adverse Events: ....................................... 43 
Table 6-3 
Algorithm for Prior/Concomitant Medications: ................................................ 44 
List of Figures 
Figure 3-1 
Study Design Schematic ................................................................................... 12 


 
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REVISION HISTORY 
 


 
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LIST OF ABBREVIATIONS 
Abbreviation/Acronym 
Definition/Expansion 
Change from baseline 
Placebo-corrected change from baseline 
AE 
Adverse event 
ATC 
Anatomical Therapeutic Chemical 
AUCtau 
Area under the plasma concentration-time curve during the dosing 
interval 
AUCinf 
AUC from time zero extrapolated to infinity 
AUClast 
AUC from time zero to the last quantifiable concentration 
BLQ 
Below the lower limit of quantification 
BMI 
Body mass index 
BP 
Blood pressure 
bpm 
Beats per minute 
CI 
Confidence interval 
C-SSRS
Columbia Suicide Severity Rating Scale 
Cl/F 
Apparent clearance  
Cmax 
Maximum observed concentration 
CPMS 
Clinical Pharmacology, Modelling and Simulation 
CRU 
Clinical Research Unit 
CS 
Clinically significant 
CS 
Clinically significant 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
EOS 
End of study 
BLQ 
Below the limit of quantification 
ET 
Early termination 
eCFR 
Electronic Case Report Form 
H 
High 


 
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Abbreviation/Acronym 
Definition/Expansion 
HR 
Heart rate 
ICF 
Informed consent form 
IMP 
Investigational medicinal product 
L 
Low 
LEPR 
Leptin receptor 
LLOQ 
Lower limit of quantification 
MC4R 
Melanocortin-4 receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Normal 
NCA 
Noncompartmental analysis 
NCS 
Not clinically significant 
NR 
Not reportable 
NS 
No sample 
PCS 
Potentially clinically significant 
PK 
Pharmacokinetics 
POMC 
Pro-opiomelanocortin 
PCSK1 
Proprotein convertase subtilisin/kexin type 1 
PT 
Preferred Term 
QD 
Once daily dosing 
QTc 
corrected QT interval 
QTcF 
QT corrected using Fridericia’s formula 
RGDO 
Rare genetic disorders of obesity 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SI 
Standard international 
SoA 
Schedule of Assessments 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TEMA 
Treatment-emergent markedly abnormal 


 
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Abbreviation/Acronym 
Definition/Expansion 
Tmax 
Time of the maximum observed plasma concentration 
Vd/F 
Apparent volume of distribution  
WHO-DD 
World Health Organization - Drug Dictionary 


 
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1 
INTRODUCTION 
Human genetics studies have identified several diseases that are the result of genetic defects affecting 
the melanocortin-4 receptor (MC4R) pathway, including, but not limited to, pro-opiomelanocortin 
(POMC) deficiency obesity due to mutations in the POMC gene; heterozygous proprotein convertase 
subtilisin/kexin type 1 (PCSK1) deficiency due to mutations in the PCSK1 gene, leading to a hormone 
processing defect that also causes POMC deficiency obesity; and leptin receptor (LEPR) deficiency 
obesity due to mutations in the LEPR gene. These MC4R pathway mutations cause rare genetic 
disorders of obesity (RGDO) that start early in childhood, progress over time, and can become life-
threatening in severity. 
Setmelanotide (also known as RM-493) is a synthetic, cyclic octapeptide (8-amino acid containing 
peptide) that functions as a potent MC4R agonist. Setmelanotide is an 8-amino acid, cyclic peptide 
that binds with high affinity (inhibitory constant [Ki] = 2.1 nM) to the human MC4R and is efficient 
in activating MC4R (50% effective concentration [EC50] = 0.27 nM). Setmelanotide is indicated for 
chronic weight management in adult and pediatric patients 6 years of age and older with obesity due 
to POMC, PCSK1, or LEPR deficiency confirmed by genetic testing demonstrating variants in 
POMC, PCSK1, or LEPR genes that are interpreted as pathogenic, likely pathogenic, or of uncertain 
significance. 
This study is being conducted to evaluate the effects of therapeutic and supratherapeutic 
setmelanotide concentrations on QTc corrected by the Fridericia method (QTcF) interval in healthy 
subjects. 
This Statistical Analysis Plan (SAP) describes the rules and conventions to be used in the presentation 
and analysis of PK and Safety data for Clinical Study Report (CSR) of Study RM-493-032. It 
describes the data to be analysed, including details of the statistical analyses to be performed. Should 
circumstances arise during the study rendering these analyses inappropriate, or if improved methods 
of analysis arise, updates to the analyses may be made. Any deviations from the final SAP before 
database lock and all alternative or additional statistical analyses that may be performed may be 
described in an updated SAP version and/or will be discussed in the CSR. 
The content of this SAP is based on following study documents: 
Study protocol, Version 2.0 (Nov 24, 2021). 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
The primary objective of this study is: 
To evaluate the effects of therapeutic and supratherapeutic setmelanotide concentrations on 
QTc corrected by the Fridericia method (QTcF) interval in healthy subjects. 
2.2 
Secondary Objectives 
The secondary objectives of this study are: 
To assess the effects of therapeutic and supratherapeutic setmelanotide concentrations on 
Heart rate (HR), PR interval, QRS interval, T-wave morphology, and cardiac safety in healthy 
subjects. 
To evaluate assay sensitivity and the effect of a positive control, a single 400 mg oral dose of 
moxifloxacin, on the QT/QTcF interval in healthy subjects. 


 
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To assess the pharmacokinetics (PK) of setmelanotide following administration of therapeutic 
and supratherapeutic doses of subcutaneous (SC) setmelanotide in healthy subjects.  
To evaluate the safety and tolerability of therapeutic and supratherapeutic doses of SC 
setmelanotide in healthy subjects. 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is a double-blind, randomized, placebo- and positive-controlled, parallel group, 3-arm study to 
assess the potential for therapeutic and supratherapeutic concentrations of SC setmelanotide 
administered as IMCIVREE to affect the QTcF interval compared with placebo. Approximately 72 
healthy subjects aged 18 to 50 years of age, inclusive, are planned to be enrolled in the United States. 
Subjects will be enrolled into 1 of 3 groups as follows: 
Group 1: SC setmelanotide; oral placebo on Days 10 and 16 
Group 2: SC placebo; oral moxifloxacin on Day 10 and oral placebo on Day 16 
Group 3: SC placebo; oral placebo on Day 10 and oral moxifloxacin on Day 16. 
The study design is presented in Figure 3-1. 
Figure 3-1 
Study Design Schematic 




 
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Adverse events (AEs), 12-lead safety ECGs, Columbia Suicide Severity Rating Scale (C-SSRS) score, 
clinical laboratory tests, vital signs, and concomitant medication monitoring will be collected 
throughout the study for safety assessments as described in the SoA (Table 6-1). 
3.2 
Endpoints and Associated Variables 
Triplicate values for HR (bpm), RR (msec), PR (msec), QRS (msec) and QT (msec) will be extracted 
by the ECG core lab at Day -1 and on Days 10 and 16 at the following timepoints: pre-dose and 0.5, 
1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, and 24 hours post-dose. The Day -1 extractions will begin 
at 7:30 AM (the time of anticipated dosing on Days 10 and 16).  
Heart rate corrected QT intervals will be derived from the QT and RR intervals for each replicate at 
each time point: 
o
Fridericia’s cube-root corrected QT(1): QTcF (msec) = QT (msec) / (RR(msec)/1000)1/3
o
Bazett’s square-root corrected QT(2): QTcB (msec) = QT (msec) / (RR(msec)/1000)1/2
At each time point, the triplicate values will be averaged in order to obtain 1 single value per 
subject and time point. The averaged values will be rounded to the nearest integer. Changes from 
baseline and percent changes from baseline will be computed as: 
o
i,k,j  = Yi,k,j - Yi, D-1, j
o
relYi,k,j(%) = 100 x (Yi,k,j- Yi, D-1, j) / Yi, D-1, j
o
With i=Subject, j=time, k=Day


 
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3.2.1 Primary Cardiac Endpoint 
The primary cardiac endpoint of the study is: 
3.2.2 Secondary Cardiac Endpoints 
The secondary cardiac endpoints of the study are: 
QTcF, QTcB, PR, and QRS intervals after administration of SC setmelanotide or oral 
moxifloxacin 
Categorical outliers for QTcF, QTcB, HR, PR, QRS, QTcF, QTcB, 
relHR, 
relPR and 
relQRS intervals after administration of SC setmelanotide 
Frequency of treatment-emergent changes of T-wave morphology and U-wave presence after 
administration of SC setmelanotide 
3.2.3 Pharmacokinetic Endpoints 
Pharmacokinetic concentration data will be obtained at time point(s) described in the protocol as 
follows: 
Plasma PK concentrations will be determined at the following nominal times: pre-dose, 0.5 (±2min), 
1 (±5min), 1.5 (±5min), 2 (±5min), 2.5 (±5min), 3 (±10min), 4 (±10min), 5 (±10min), 6 (±10min), 7 
(±10min), 8 (±10min), 9 (±10min), 10 (±10min), 12 (±20min), 16 (±20min) and 24 (±20min) hours 
post-dose 
Unless otherwise stated, derivation of PK parameters will be the responsibility of Clinical 
Pharmacology, Modeling and Simulation (CPMS) group, 
   
If calculable, the following PK parameters listed in Table 3-1 will be determined for setmelanotide 
in plasma  following repeated SC administration. 
Table 3-1 
Plasma Pharmacokinetic Parameters after Multiple Dose Administration of 
Setmelanotide 
Parameter
WNL Name 
CDISC Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration in a 
dosing interval after last dose administration 
Tmax 
Tmax 
TMAX 
Time corresponding to occurrence of Cmax 
after last dose administration 
AUCtau 
AUC_TAU 
AUCTAU 
AUC over the dosing interval after last dose 
administration 
AUClast 
AUClast 
AUCLST 
AUC from time zero to the last quantifiable 
concentration 


 
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Parameter
WNL Name 
CDISC Name 
Definition 
Cl/F 
CLss_F 
CLFTAU 
Apparent 
clearance 
following 
oral 
administration 
at 
after 
last 
dose 
administration 
Vd/F 
Vz_F 
VZFTAU 
Apparent volume of distribution during 
terminal phase after last dose administration 
If calculable, the following PK parameters listed in Table 3-2 will be determined for moxifloxacin in 
plasma following single oral administration. 
Table 3-2 
Plasma Pharmacokinetic Parameters After Single Dose Administration of 
Moxifloxacin Administration 
Parameter 
WNL  
Name 
CDISC 
Name 
Definition 
Cmax 
Cmax 
CMAX 
Maximum observed concentration 
Tmax 
Tmax 
TMAX 
Time corresponding to occurrence of Cmax
AUClast 
AUClast 
AUCLST 
AUC from time zero to the last 
quantifiable concentration 
AUCinf 
AUCINF_obs 
AUCIFO 
AUC from time zero extrapolated to 
infinity 
3.2.4 Safety Endpoints 
The safety endpoints are: 
Frequency and severity of AEs (assessed separately for relation to setmelanotide and/or 
moxifloxacin) 
Changes from baseline in clinical laboratory evaluations, vital signs, 12-lead safety ECGs, C-
SSRS score, and physical examinations 
 


 
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4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures, and data listings to be included in the report will be independently checked for 
consistency, integrity, and in accordance with standard 
procedures. 
4.2 
General Presentation Considerations 
This section is not applicable to PK data. 
4.2.1 Treatment 
The following treatments will be administered as follows: 
SC setmelanotide: SC injection: 2 mg × 7 days followed by 3, 5, and 7 mg × 3 days per dose 
level 
SC placebo (matched to active setmelanotide): SC placebo injection × 16 days 
Oral moxifloxacin: single oral dose of 400 mg moxifloxacin 
Oral placebo (matched to oral moxifloxacin): single oral placebo dose 
4.2.2 Study Day 
Study days will be numbered relative to the first day of study drug administration. 
If the date of event is before the study drug administration, then: 
Study day = (Date of measurement – Date of study drug administration in each group) 
If the date of event is on or after the study drug administration, then:  
Study day = (Date of measurement – Date of study drug administration in each group) + 1 
4.2.3 End of Study 
The end of the study is defined as the date of the last visit of the last subject under the auspices of the 
current study.   
4.2.4 Baseline 
Baseline is defined as the last non-missing measurement recorded before first dose of the study drug 
administration for res. 
Time-matched Measurements: 
For Continuous 12-lead ECG using Holter’s readings for Cardiac endpoints, baseline is defined as 
the time-matched measurements on Day -1.  
No imputation will be done for missing baseline value for derivation of change from baseline or 
summary tables and shift tables. 


 
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4.2.5 Summary and Representation of Data 
Continuous data will be summarized in terms of mean, standard deviation (SD), median, minimum, 
maximum and number of observations, unless otherwise stated.  
Categorical data will be summarized in terms of the number of participants providing data at the 
relevant time point (n), frequency counts, and percentages.   
The minimum and maximum will be reported to the same number of decimal places as the raw data 
recorded in the database. The mean and median will be reported to one more decimal place than the 
raw data recorded in the database.  The SD will be reported to two more decimal places than the raw 
data recorded in the database.  In general, the maximum number of decimal places reported shall be 
four for any summary statistics. 
Percentages will be presented to one decimal place. Percentages will not be presented for zero counts. 
Percentages will be calculated using N as the denominator.  If sample sizes are small, the data displays 
will show the percentages, but any textual report will describe frequencies only. Percentage will be 
presented as whole number if percentage is 100.  
If for any summary table, n is less than three then only n, minimum, and maximum should be 
presented, and other summary statistics will be left blank. 
All ECG data recorded during the course of the study or derived during the programming phase will 
be presented in the individual data listings. All listings will be presented sorted by treatment group, 
subject number, visit number, date and time point. 
Abnormality on ECG parameters will be flagged using the flag system defined in Table 4-2. 
Unless specified otherwise, quantitative ECG parameters will be described per treatment group, day 
and time point using the following statistics: N (number of observations), mean, median, standard 
deviation (SD), minimum (Min), and maximum (Max) for raw and change from baseline values. 95% 
confidence interval (CI) of the mean will be added on changes from baseline. 
4.3 
Software 
All report outputs will be produced using SAS® version 9.4 or later in a secure and validated 
environment.  
The PK analyses will be conducted using Phoenix® WinNonlin (WNL) version 8.2 or later in a secure 
and validated environment.  
All report outputs will be provided to the Sponsor in Microsoft RTF format. 
4.4 
Study Participants 
4.4.1 Disposition of Participants 
A clear accounting of the disposition of all subjects who enter the study will be provided, from 
randomization to study completion. 
Subject disposition will be summarized by treatment group for the randomized analysis population. 
This display will show the number and percentage of subjects who have completed the study or have 
discontinued study treatment and a summary of the primary reasons for discontinuation of study 
treatment.   
Primary reason for discontinuation of subjects are: 
Adverse event 


 
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Withdrew consent 
Protocol deviation 
Loss to follow up 
Death 
Pregnancy  
Study terminated by sponsor 
Investigator decision  
Other 
Disposition data will be presented for the Randomized Analysis Population. 
Subject discontinuations will be listed including the date of study exit, details of IMP and reason for 
discontinuation in the randomized analysis population. 
Listing of screening failure data will be provided including reason for screen failure in screened 
subjects. A disposition table during screening phase will also be provided in all screened subjects.  
4.4.2 Protocol Deviations 
All protocol deviations are predefined in the separate document, Protocol Deviation Specification. 
4.4.2.1 Protocol Deviations with Non-PK Implications 
The defined protocol deviations will be collected during the study period by site monitor/clinical team 
and programming team. All deviations related to study inclusion or exclusion criteria, conduct of the 
study, participant management or participant assessment, and handling of the participant’s rights will 
be described.  
4.4.2.2 Protocol Deviations with PK Implications 
Protocol deviations that may potentially impact PK parameter derivations include, but are not limited 
to: 
Emetic episode in case of orally administered study drug 
IV administration deviations – interruption of administration, etc. 
Missed PK samples that impact estimation of PK parameter(s) 
Concomitant medications not authorized by protocol 
PK samples obtained out of allowance window that may impact the estimation of PK 
parameter(s) 
Protocol deviations (mentioned in Sections 4.4.2.1 and 4.4.2.2) and analysis population will be 
reviewed in the data review meeting to decide inclusion or exclusion of participant(s) from analyses 
Population. Decisions regarding the exclusion of participants and/or participant data from analyses 
will be made after database lock and receipt of PK data, and will be documented and approved. 
A by-participant listing of major and minor protocol deviations will be provided including participant 
identifier; exclusion from specific analysis population; and protocol deviation classification, and 
protocol deviation description and exclusion from specific analysis Population. 


 
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4.5 
Analysis Populations 
The following populations are defined for this study: 
Randomized Population: All participants who signed Informed Consent Form (ICF) and are 
assigned a randomization number are included in the randomized population. 
Safety Population: all subjects who received at least one dose of study drug (SC 
setmelanotide, SC placebo, oral moxifloxacin, or oral placebo). 
Pharmacokinetic Population: all subjects who received at least 1 dose of setmelanotide or 
moxifloxacin and have at least one quantifiable concentration of setmelanotide or 
moxifloxacin. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2 times the median Tmax 
during moxifloxacin dosing. 
ECG Population: all subjects in the Safety Population with measurements at baseline as well 
as on-treatment with at least one post-dose timepoint with a valid value. The ECG population 
will be used for the by-timepoint and categorical analyses of the cardiodynamic ECG 
parameters. 
PK/QTc Population: all subjects who are in both the ECG and PK populations with at least 
1 pair of post-dose PK and QTcF data from the same timepoint as well as subjects in the ECG 
population who received placebo. The PK/QTc population will be used for the C-QTc 
analysis. The PK/QTc population will be defined for setmelanotide and for moxifloxacin. 
Placebo subjects will be included in the C-QTc analysis set by setting their concentrations to 
0. 
A summary table with the number of participants in each of the analysis population will be provided 
and this table will be displayed by treatment group and overall, for randomized population. A listing 
of subjects excluded from analysis population will also be provided including reason of exclusion for 
randomized analysis population.  
4.6 
Demographics and Baseline Characteristics 
The demographic characteristics (age, race, ethnicity, sex, height, body weight, body mass index 
[BMI]) will be summarized by treatment group and listed by participant for the Safety Population.  
Age, height, BMI and weight will be summarized using the mean, SD, minimum, median, and 
maximum. The count and percentage will be computed for sex, race, and ethnicity. The summary 
table will be displayed by treatment group and overall, for the Safety Population. 
4.7 
Medical History 
Based on the Safety Population, all subjects who had prior medical history will be presented in a by-
subject listing including but not limited to subject ID, group, description of disease/procedure, 
MedDRA System Organ Class (SOC), MedDRA Preferred Term (PT), start date and stop date (or 
ongoing if applicable) of disease/procedure. All medical history will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA). The version used for coding will be identified in 
the Data Management Plan. 
4.8 
Concomitant Medications 
Medications will be considered as concomitant if they are taken at least once in the treatment period 


 
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starting with the first study administration and ending after the last study drug administration during 
the study.  
Medications will be coded using the latest version of World Health Organization-Drug Dictionary (WHO-
DD) and will be classified by Anatomical Therapeutic Chemical (ATC) categories. 
By-participant listings of prior and concomitant medications will be provided for the Safety 
Population . 
4.9 
Treatment Exposure and Compliance 
4.9.1 Treatment Exposure  
A by-participant listing of participant exposure to study drug will be generated. The listing will 
include dose, date and time, unit, formulation, route, and frequency. 
4.9.2 Compliance  
Not applicable. 
4.10 Efficacy Evaluation 
Not Applicable. 
4.10.1 Analysis and Data Conventions 
Not Applicable. 
 
4.10.2 Primary Cardiac Variable 
4.10.2.1.1 Cardiodynamic ECG Assessment (Concentration-QTc analysis) 
Primary concentration-response relationship will be investigated between QTcF measurements and 
setmelanotide concentration. The same methodology can be used to analyze other ECG parameters 
(HR, PR, QRS) if an effect was evidenced from the central tendency analysis. 
The C-QTc analysis will be performed according to the methodology detailed in Garnett et al.( ) white 
paper. 
 
4.10.2.1.1 Graphical exploratory analysis 
As a preliminary step, graphical exploration supporting model assumptions will be performed as 
detailed in Table 4-1. 
 






 
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4.10.2.1.2 
Study specific QT correction 
For all analyses performed on healthy volunteers, the preferred, a priori, heart-rate correction method 
is the Fridericia -corrected QT interval (QTcF). 
In the case that the individual correction factor is poorly estimated (due to narrow range of RR/HR 
intervals within each subject) or that setmelanotide has a chronotopic effect (resulting in change of 
HR after drug administration and a relationship between QT and RR that may differ between on- and 
off-treatment) it might be necessary to determine an alternative correction method for the QT interval 
in order to limit the bias in the assessment of QT/QTc prolongation. 
In such case, an individual QT correction, QTcI, will be obtained from data recorded at baseline (Day 
-1) and from placebo subjects by modelling the QT/RR relationship (general power model) using a
mixed model. The formula obtained for the QT/RR relation will then be converted to individual heart
rate correction formulae.
The individual prediction of model parameters will be then applied to the QT and RR parameters at 
each time point to form the QTcI intervals. 
The general power model relating QT and RR intervals can be written as follows: 
QT= (RR/1000) ,  and  being the model parameters to be estimated. 
After log transformation the model can be expressed as: 
Log(QT)= ’+ log(RR/1000), where ’=log( ). 
In order to estimate the parameters, log(QT) and log(RR/1000) obtained at baseline and in placebo 
subjects will be submitted to a mixed regression model where the slope and the intercept will be 
considered as random terms. 
The statistical expression of the mixed model is: 
Log(QTij)= ai + bilog(RRij/1000) +eij 
Where: 
log(QTij) and log(RRij) are respectively, the jth log QT/RR measurements performed on subject i 
ai and bi are the random intercept and slope, respectively 
4.10.2.1.3 
Model development 
The model development will start with the pre-specified mixed linear model as detailed in Garnett 
etal considering QTcF as dependent variable. In case of the graphical exploration suggests that 
Fridericia correction does not account properly for HR/RR variations, alternative corrections should 
be investigated if possible (refer to previous Section 4.10.2.1.2). 
The fixed effect parameters of the pre-specified model will be intercept, slope for linear effect of 
setmelanotide concentrations, influence of baseline (centered on mean) covariate, treatment specific 
intercept (0=placebo, 1= setmelanotide) and time (as factor). 
Subject-specific random effects (between subject variability) will be added on intercept and slope 
parameters with an unstructured covariance matrix. In case of the unstructured covariance matrix is 
not supported by the data, other simplified or reduced structures will be investigated (ex. variance 
components). 




 
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Any marked bias in residual plots may suggest model misspecification. Moreover, a large and 
significant treatment specific intercept (TRT term in the model) may also indicate model 
misspecification (i.e. lack of linearity or hysteresis). 
Evaluation of the final model will be performed using: 
- 
selected and generated by binning the concentrations into deciles. VPC will be performed to 
assess the adequacy of the structural model. 
-
Mean observed and predicted QTc by deciles of concentrations (quantile plot) with model
slope and 90% CI.
4.10.2.1.5 
Alternative to direct linear model 
Nonlinear model 
an alternative model such as saturable model will be considered: 
(Eq.2) 
In Eq.2, the parameter 1 is the maximum asymptotic effect due to treatment, and the parameter 
2 is 
the concentration at which the effect is half 
1. 
with subject identifier used as the unit for resampling. Resampling should be stratified by dose level 
from each of the replicate bootstrapped datasets. Two-sided 90% CIs are computed from the 5th and 
95th
Indirect relationship 
If the effect cannot be directly related (time-matched) to exposure to setmelanotide, it will be 
investigated whether any metabolite can explain the delayed effect. 
In that case, a multivariate model combining parent and metabolite, as a linear or non-linear 
contribution, will be investigated using the same methodology as described above.  
max GM 
of each compound, setting the components for the other compounds at the mean value obtained at 
time of occurrence of Cmax (tmax) of the compound of interest. 
If the inclusion of the metabolite is not sufficient to explain the indirect/delayed effect and a hysteresis 
phenomenon cannot be ruled out, alternative models such as effect compartment or turn over models 
combining population PK and PKPD models should be envisaged. Such kind of modelling is out of 
the scope of this analysis plan and if it must be implemented will be detailed in a specific modelling 
plan. 
4.10.2.1.6 
Display of results 
Parameters estimated from the selected model will be tabulated with their standard errors and 95% 


 
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be provided. 
4.10.2.1.7 
Decision rule 
The impact of setmelanotide on QT/QTc prolongation will be considered as below the threshold of 
dose Cmax is below 10 ms. 
4.10.3 Secondary Cardiac Variables 
4.10.3.1 Central tendency analysis  
The holter extracted ECG parameters will be summarized separately using descriptive statistics, on 
raw values and changes from baseline ( ). Descriptive statistics will be computed per treatment 
group, day, dose level and time points.  
Mean changes with their 95% CI will be plotted over time per treatment. 
For all parameters, the changes from baseline ( ) will be analysed using an analysis of variance model 
(ANOVA) including treatment, time and their interaction as main factors and structuring the residual 
matrix in order to account for the repeated measurement pattern of the data. The baseline value 
(centered on population mean) will be considered as covariate. This analysis will be performed by 
day in order to evaluate the therapeutic setmelanotide dose at day 10 and the supra-therapeutic 
setmelanotide dose at day 16.  
At each time point, estimates (LSmeans) of treatment effects and differences between setmelanotide 
dose levels and placebo (
) will be obtained with their 2-sided 90% CIs. 
For moxifloxacin vs. placebo evaluations, the changes from baseline will be analysed per time point, 
for each parameter separately, using analysis of variance model including terms for treatment and 
considering the subject as random effect. The analysis will be performed by day (day 10 vs. day 16). 
At each time point, estimates (LSmeans) of treatment effects and differences between moxifloxacin 
and placebo (
) will be obtained with their 2-sided 90% CIs. 
4.10.3.2 Categorical analyses 
For the analyses described in this section, a treatment-emergent abnormality/finding will be defined 
as any abnormality/finding not already reported on any of the ECGs collected before the 
administration. 
The analysis will be performed for setmelanotide and moxifloxacin evaluation. 
4.10.3.2.1 
Incidence of abnormal values 
Average of the replicates extracted at each time point will be considered for this categorical analysis 
consisting on the display of the number and percentage of subjects by day and treatment group 
presenting at least one treatment emergent abnormality according to pre-defined thresholds presented 
in Table 4-2. 




 
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abnormal not clinically significant or abnormal clinically significant. Then a global conclusion will 
be drawn on the whole ECG as the worst case reported over all findings.  
Number and percentage of subjects presenting at least one treatment emergent abnormality, grouped 
according to the categories defined above, will be computed. The notion of abnormality in this 
analysis will refer to each individual finding for which the interpretation according to the charter is 
abnormal (either clinically or not clinically significant) and not ECG global conclusion which can 
mix normal and abnormal finding for the same ECG. 
4.10.3.3 Assay sensitivity 
The moxifloxacin C-QTc model will follow the same methods as described for setmelanotide model 
from Section 4.10.2.1.1 to 4.10.2.1.4. The sensitivity analysis will be performed separately for day 
10 and day 16, due to the different baseline for moxifloxacin in group 2 and 3.  
The assay sensitivity will be accepted if the slope for the relationship is significant at the 5% level 
max is above 5 ms. 
4.10.4 Pharmacokinetics 
4.10.4.1  Pharmacokinetic Concentrations 
Setmelanotide and moxifloxacin plasma concentration versus time data will be summarized by 
treatment group and nominal time using descriptive statistics (number of observations [n], mean, 
median, CV%, SD, minimum, and maximum). Individual and mean concentration versus time plots 
will be presented. 
Concentration Listings: 
Pharmacokinetic concentration data for setmelanotide and moxifloxacin, will be listed by treatment 
group, and participant for the Safety Population. Concentration listings will include nominal PK 
sampling time, actual sampling times relative to dose administration, deviation from nominal time, 
and percent deviation from nominal time, and concentrations.  Setmelanotide and moxifloxacin 
plasma concentrations below the lower limit of quantification (LLOQ) will be presented as below the 
limit of quantification (BLQ) in the listings and the LLOQ value presented as a footnote. Missing PK 
samples will be reported as no sample (NS) and/or not reportable (NR) and considered excluded from 
PK analysis.   
Concentration Summary Tables: 
Source data as reported from the laboratory will be used for calculation of concentration summary 
statistics.  Tabular summaries for concentration-time data will report N (number of subjects who 
received treatment), n (number of subjects with non-missing values), and n (BLQ) (the number of 
subjects with BLQ samples). 
Concentration for setmelanotide and moxifloxacin will be summarized by treatment group and 
nominal timepoint for the Pharmacokinetic Population.  The following descriptive statistics will be 
presented for plasma setmelanotide and moxifloxacin concentrations obtained at each nominal time 
point: N, n, n(BLQ), arithmetic mean, SD, coefficient of variation (CV%), geometric mean, geometric 
CV% (calculated as: gCV% =SQRT(es²-1)*100; where s is the SD of the log-transformed values), 
median, minimum, and maximum values. 


 
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For summary tables, all BLQs will be considered zero, and the number of BLQs and non-BLQs at 
each scheduled time point will be reported.  Summary Statistics will not be calculated if non-BLQ 
concentrations at a scheduled time point are <3 and will be reported as NC. 
The rules followed for calculation and presentation of concentration data with regards to the number 
of decimal places/significant digits for the listings of participant level concentrations and summary 
tables of concentration are as follows:  
Concentration Listings and Tables 
Rounding 
Individual concentrations
n s f. as supplied by bioanalytical laboratory 
Minimum and Maximum
n s.f. capped at 4 
Mean/SD/Median/Geomean
n+1 s f. capped at 4 
CV%/gCV%
1 d.p. 
N/n
Whole number 
s.f = significant figures, d.p. = decimal place
Concentration Figures: 
For arithmetic mean linear/linear graphs, all BLQ values will be substituted with zero for calculation 
of arithmetic mean and for log/linear graphs the log transformed arithmetic mean will be displayed 
(this should not include zero). 
For individual linear/linear and log/linear graphs all BLQ values will be substituted as follows: 
BLQs at the beginning of a participant profile (ie, before the first incidence of a measurable 
concentration) will be assigned to zero (except for intravenous administration when these 
BLQs should not be displayed). When using log/linear scale, these timepoints will be 
considered missing. 
BLQs at the end of a participant profile (ie, after the last incidence of a measurable 
concentration) will be set to missing. 
Single BLQs which fall between two measurable concentrations will be set to missing. 
Consecutive BLQs which fall between measurable concentrations will be set to missing. 
Measurable concentrations after consecutive BLQs will be set to missing. 
To visualize participant-level concentrations and the comparison between groups for each treatment, 
the descriptive PK graphs listed below will be generated.   
Figure x.x.x: Individual participant profiles for Setmelanotide Plasma Concentration Time Data 
– (Linear Scale and Semi-Logarithmic Scale) (Safety Population)
Figure x.x.x : Overlaid individual participant profiles for Setmelanotide Plasma Concentration 
Time Data – (Linear Scale and Semi-Logarithmic Scale) (Safety Population)  
Figure x.x.x : Mean (± SD) Setmelanotide Plasma Concentration Time Data – (Linear Scale and 
Semi-Logarithmic Scale) (PK Population)  
Figure x.x.x: Individual participant profiles for Moxifloxacin Plasma Concentration Time Data 
– (Linear Scale and Semi-Logarithmic Scale) (Safety Population)
Figure x.x.x : Overlaid individual participant profiles for Moxifloxacin Plasma Concentration 
Time Data – (Linear Scale and Semi-Logarithmic Scale) (Safety Population)  


 
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Figure x.x.x : Mean (± SD) Moxifloxacin Plasma Concentration Time Data – (Linear Scale and 
Semi-Logarithmic Scale) (PK Population) 
Figures will be generated in black and white or color using unique line style and marker for each plot 
in the graph. For all PK concentration-time plots, linear scale will be used for x-axis (eg, do not use 
an ordinal scale).  
4.10.4.2 Pharmacokinetic Parameters 
PK parameters for setmelanotide will be calculated by NCA methods from the concentration-time 
data using Phoenix® WinNonlin® Version 8.2 or higher following these guidelines: 
Actual time from dose/injection will be used in the calculation of all derived pharmacokinetic 
parameters, except when parameters are calculated for safety/dose escalation meetings when 
nominal times may be used to calculate PK parameters.   
There will be no imputation of missing data.  
Handling of BLQ samples for derivation of plasma PK parameters 
o
BLQs at the beginning of a participant profile (ie, before the first incidence of a measurable
concentration) will be assigned to zero.
o
BLQs at the end of a participant profile (ie, after the last incidence of a measurable
concentration) will be set to missing.
o
Single BLQs which fall between two measurable concentrations will be set to missing.
o
Consecutive BLQs which fall between measurable concentrations will be set to missing.
Measurable concentrations after consecutive BLQs will also be set to missing.
Pharmacokinetic parameters will be estimated according to the guidelines presented in Table 4-3. 






 
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Descriptive statistics for calculated PK parameters will include N, n, arithmetic mean, SD, CV%, geometric mean, median, minimum, and maximum 
values. For tmax, only N, n, median, minimum and maximum values will be presented. No descriptive statistics will be determined when fewer than three 
individual PK parameters are available. 
The rules followed for presentation of PK parameters data with regards to the number of decimal places/significant digits for the listings of participant 
level PK parameters and summary tables of PK parameters are as follows:  
PK Parameter Listings and Tables 
Rounding  
Derived Individual parameters 
4 s f. 
Directly Derived Individual parameters (Cmax) 
n s.f. as supplied by the analytical laboratory but not 
more than 4 s f. 
Minimum and Maximum 
4 s f. 
Mean/SD/Median/Geomean 
4 s f. 
CV% 
1 d.p. 
N/n 
Whole number 
Exceptions for PK Tables 
tmax individuals and min/max 
2 d.p 
tmax median only 
2 d.p 
s.f = significant figures, d.p. = decimal place
4.11 Safety Evaluation 
All safety summaries and analyses will be based upon the Safety Population as defined in Section 4.4 of this document. 
All summaries will be provided by treatment group. 
Placebo across treatment group will be pooled. 
4.11.1 Adverse Events 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in severity after at least one dose of the study drug has been 
administered. 


 
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Any AEs with incomplete start and end dates/times will be treated as per 




 
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Chemistry: sodium, potassium, chloride, carbon dioxide (CO2), albumin, total protein, 
glucose, blood urea nitrogen (BUN), creatinine, uric acid, aspartate aminotransferase (AST), 
alanine 
aminotransferase 
(ALT), 
gamma-glutamyltranspeptidase 
(GGT), 
creatine 
phosphokinase (CPK), alkaline phosphatase, total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), calcium and phosphorus. 
Coagulation Profile: prothrombin time (PT) or international normalized ratio (INR), and 
partial thromboplastin time (PTT), also referred to as activated partial thromboplastin time 
(aPTT). 
Urinalysis: 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. 
Clinical laboratory test results of hematology, chemistry, coagulation profile and urinalysis will be 
provided by treatment group.  
All TLFs will display only the standard international (SI) units after conversion by means of standard 
conversion factors.  
Quantitative clinical laboratory variables, ie, hematology, chemistry, coagulation profile, and 
urinalysis will be summarized using descriptive statistics (n, mean, SD, minimum, maximum and 
median) by treatment group and time-point. Additionally, a within-participant change will be 
calculated as the post-baseline measurement minus the baseline measurement and summarized in the 
same way.  
Baseline definition will be defined in section 4.2.4. 
Any quantitative laboratory parameters that are given as '<xx' or '>xx' in the database will be imputed 
with the absolute value of the number without the sign (e.g., <2.2 will be imputed as 2.2) for the 
calculation of the changes from baseline and for the descriptive statistics. In the listings, no 
imputations will be performed, and all data will be displayed as recorded in the database. 
Each laboratory result will be classified as low (L), normal (N), or high (H) at each time point 
according to the laboratory supplied reference ranges. For hematology and biochemistry, shift tables 
will be presented showing the number and percentage of subjects with shifts from baseline to each 
postdose time point. Tabulations will be presented by treatment group.  
Measurements obtained at Screening and End of Study (EOS) will not be included in the shift tables. 
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period. 
Frequency tabulations of qualitative clinical laboratory variables (urinalysis) will be presented by 
treatment group and time-point. 
All laboratory data will be displayed in listings. 


 
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Laboratory abnormalities that are considered clinically significant (CS) are recorded in the database 
as AEs. Therefore, no tabulation of laboratory values meeting any CS criteria (except liver chemistry) 
will be presented as all relevant information will be presented in the AE summaries. 
Results of pregnancy tests (females only), urine drugs screen tests will be listed only. 
4.11.4 Vital Signs 
Vital signs will be performed as shown in Table 6-1. The following vital signs measurements will be 
obtained: 
Supine Systolic blood pressure (SBP) [mmHg]. 
Supine Diastolic blood pressure (DBP) [mmHg]. 
Supine Heart rate (beats per minute [bpm]) 
Pulse rate (bpm). 
Tympanic (ear) Body temperature [°C]. 
Vital signs data will be listed by subject including changes from baseline. The baseline for the vital 
signs measurements will be the measurement on Day -1. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes 
from baseline will be summarized descriptively in tabular format by time of collection and by 
treatment group. 
4.11.5 12-Lead Electrocardiogram (ECG) 
Standard safety 12-lead ECGs will be performed as shown in Table 6-1. 
The following ECG parameters will be recorded: 
PR interval (msec) 
QRS interval (msec) 
QT interval (msec) 
QTc interval (msec) 
QT interval corrected using the Fridericia correction formula (QTcF) (msec). 
HR (beats per minute [bpm]). 
The ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, Not clinically significant 
(NCS)’ or ‘Abnormal, CS’. 
All ECG parameters will be listed by participant for each treatment group and time point including 
changes from baseline.  


 
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Baseline is defined in section 4.2.4. 
Descriptive statistics for absolute values and changes from baseline will be presented by treatment 
group. A categorical QTc analysis will also be performed. 
Measurements obtained at Screening and EOS will not be included in the shift tables. 
Measurements obtained prior to dosing in each period will be included in the tabulations for the 
treatment received in that specific treatment period. 
4.11.6 12-Lead Holter ECG 
A 12-lead Holter ECG recording will be performed for 24 hours on Day -1, Day 10, and Day 16 of 
each treatment group. The Holter recording will be used to obtain a measurement of mean HR per 
hour on each day. 
Mean HR per hour on Day -1, Day 10, and Day 16 will be summarized (mean, SD, minimum, 
maximum and median) by time point (each hour) and treatment. 
Day -1 measurements will be considered as baseline. 
Individual measurements of mean HR per hour will be displayed in a listing including the time-
matched changes from baseline from Day -1 to Day 1 and the placebo-corrected time-matched 
changes and Holter’s comment. 
4.11.7 Physical Examination 
Physical examinations will be performed as shown in Table 6-1. 
The full physical examination includes an assessment of general appearance and a review of systems 
(dermatologic, head, eyes, ears, nose, mouth/throat/neck, thyroid, lymph nodes, respiratory, 
cardiovascular, gastrointestinal, extremities, musculoskeletal, neurologic systems). 
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. 
Clinically significant physical examination, with respect to number frequencies and percentage, will 
also be tabulated by time of collection and treatment group Clinically significant physical 
examination findings will be listed. 
Other safety evaluations of comprehensive skin examination and Fitzpatrick scale will be listed. 


 
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4.12.1 Columbia Suicide Severity Rating Scale (C-SSRS) 
C-SSRS will be summarized by time of collection and treatment group.
C-SSRS score will be listed.
4.13 Determination of Sample Size 
Using a 2-sample t-test with a 1-sided 0.05 significance level, a sample size of 60 evaluable subjects 
who complete the study (20 subjects in Group 1 receiving SC setmelanotide and 20 subjects each in 
Groups 2 and 3 receiving SC placebo) will provide at least 85% power to exclude that setmelanotide 
causes more than a 10 msec QTc effect at clinically relevant plasma levels, as shown by the upper 
the observed geometric mean Cmax of setmelanotide on Day 10 and Day 16 in the study individually. 
To demonstrate assay sensitivity using moxifloxacin with a 1-sided 0.05 significance level, a sample 
size of 20 evaluable subjects receiving moxifloxacin and 20 evaluable subjects receiving placebo at 
each ECG assessment day (Days 10 and 16) will provide at least 81% power to demonstrate assay 
sensitivity with a 1-sided 0.05 significant level. The power to detect the effect of moxifloxacin on 
QTc over the entire crossover period is at least 86%.  
As such, a total of approximately 72 subjects are planned for enrollment to achieve 60 completers, 
accounting for dropouts. 
4.14 Changes in the Conduct of the Study or Planned Analysis 
Not Applicable. 
5 
REFERENCES 
i. Fridericia LS. Die systolendauer im elektrokardiogramm bei normalen menchen und bei
herzkranken. Acta Med Scand 1920; 15: 335-642
ii. Bazett HC. An analysis of the time-relations of electrocardiogram. Heart 1920; 7: 353-70
iii. Garnett, Christine, Peter L. Bonate, Qianyu Dang, Georg Ferber, Dalong Huang, Jiang Liu,
Devan Mehrotra, et al. « Scientific White Paper on Concentration-QTc Modeling ». Journal of
https://doi.org/10.1007/s10928-017-9558-5 
iv. ICH E14 Guideline (2005) The Clinical evaluation of QT/QTc interval prolongation and
proarrhythmic 
potential 
for 
non-antiarrhythmic 
drugs.
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E14/E14_
Guideline.pdf


 
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v. Shah RR et al (2015) Establishing assay sensitivity in QT studies: experience with the use of
moxifloxacin in an early phase clinical pharmacology study and comparison with its effect in a
thorough QT study. Eur J Clin Pharmacol 71(12):1451–1459
vi. SAS® Version 9.4 of the SAS System for Personal Computers. Copyright©®2002-2003. SAS
Institute Inc. SAS and all other SAS Institute Inc. product or service names are registered
trademarks or trademarks of SAS Institute Inc., Cary, NC, USA.
vii.
Phoenix®WinNonlin® Professional Software Version 8.2. https://www.certara.com






 
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c Height will only be collected at Screening. 
d Supine blood pressure, supine heart rate, pulse rate, and tympanic (ear) body temperature. Heart rate and blood pressure will be measured using the same arm for each reading after 
the subject has been resting in the supine position for at least 5 minutes. For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be collected, ECGs should be 
collected first followed by vital signs then PK samples, with the timing of the PK sample to occur at the nominal time. 
e Serum pregnancy test will be performed at Screening. Urine pregnancy test will be performed on all other designated days. 
f On the evening before continuous ECG sampling, subjects will undergo a 10-hour overnight fast. 
g Breakfast is to be administered at approximately 7:00 AM every day in the CRU (30 minutes pre-dose). Lunch, dinner, and a snack will be administered at approximately 12:00 PM 
(after 4-hour assessments), 6:00 PM (after 10-hour assessments), and 9:00 PM, respectively. 
h Group 1 will receive SC setmelanotide QD (approximately 7:30 AM) at a dose of 2 mg from Days 1 to 7; 3 mg from Days 8 to 10; 5 mg from Days 11 to 13; and 7 mg from Days 
14 to 16. 
Groups 2 and 3 will receive SC placebo QD (approximately 7:30 AM) from Days 1 through 16. 
All doses will be double-blinded. 
i Group 1 will receive oral placebo with their SC setmelanotide dose on Days 10 and 16. 
Group 2 will receive oral moxifloxacin 400 mg on Day 10 and oral placebo on Day 16. 
Group 3 will receive oral placebo on Day 10 and oral moxifloxacin 400 mg on Day 16. 
All doses will be double-blinded. On Days 10 and 16, subjects should receive SC setmelanotide/placebo first. Oral moxifloxacin/placebo should then be administered within 2 minutes 
of the SC dose. 
j Blood samples for quantification of setmelanotide and moxifloxacin concentrations will be collected at pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, and 24 hours post-
dose on Days 10 and 16. The PK samples collected at 0.5 hours post-dose will have a sampling window of ± 2 minutes, samples collected from 1 hour though 2.5 hours post-dose will 
have a sampling window of ± 5 minutes, samples collected from 3 hours through 10 hours post-dose will have a sampling window of ± 10 minutes, and samples collected from 12 
through 24 hours postdose will have a sampling window of ± 20 minutes; however, collection of samples outside of the window will not be considered protocol deviations. The timing 
of all PK samples should be recorded to the nearest minute. For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be collected, ECGs should be collected first 
followed by vital signs then PK samples, with the timing of the PK sample to occur at the nominal time. 
k ECGs will be extracted at Day -1 and on Days 10 and 16 at the following timepoints: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, and 24 hours post-dose. The Day -
1 extractions will begin at 7:30 AM (the time of anticipated dosing on Days 10 and 16). 
l For ECG collection, subjects will rest in the supine position for at least 10 minutes before and 5 minutes after each timepoint. For timepoints at which vital, PK blood samples, and/or
ECGs are all to be collected, ECGs should be collected first followed by vital signs then PK samples, with the timing of the PK sample
to occur at the nominal time.
m Safety ECGs will be collected at the Screening visit, CRU Baseline (Day -1), final CRU discharge, and the Follow-up visit.
n Safety clinical laboratory tests will include: hematology with platelet count and standard indices, chemistry panel (includes sodium, potassium, chloride, CO2, albumin, total protein,
glucose, BUN, creatinine, uric acid, AST, ALT, GGT, CPK, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, calcium, phosphorus, magnesium), and urinalysis with
microscopic analysis if positive findings on dipsticks warrant further examination. Safety laboratories will also include a coagulation profile (PT or INR, and PTT also referred to as
aPTT).
o In order to be eligible for the study, at Screening, a subject cannot have a suicidal ideation of type 4 or 5, a history of a suicide attempt in the past 20 years, or any suicidal behavior
in the last month. If at any time during the study a subject has a suicidal ideation of type 4 or 5, or any suicidal behavior, the subject should be referred to a mental health professional.


 
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P





Prot_000.pdf: 
Rhythm Pharmaceuticals, Inc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
Protocol 
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Confidential 
SETMELANOTIDE 
RM-493-032 
A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and Positive-controlled Study to 
Investigate the Effects of Setmelanotide on QTc Interval in Healthy Subjects 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
 
Short Title: 
Double-Blind Study of Setmelanotide Effects on QTc Interval in 
Healthy Subjects 
Study Sponsor: 
Rhythm Pharmaceuticals, Inc. 
 
 
Document Date (Version): 
24 NOV 2021 (V2.0; Amendment 1) 
CONFIDENTIALITY NOTE
The information contained in this document is privileged and confidential. Any distribution, copying, or disclosure 
is strictly prohibited unless such disclosure is required by federal regulations or state law. Persons to whom the 
information is disclosed must know that it is confidential and that it may not be further disclosed by them.
PPD
PPD


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Protocol 
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Confidential 
APPROVAL SIGNATURE PAGE 
Protocol Title: A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and 
Positive-controlled Study to Investigate the Effects of Setmelanotide on QTc Interval in Healthy 
Subjects 
Protocol Number: RM-493-032 
Document Version: Version 2.0; Amendment 1 
Document Date: 24 NOV 2021 
Sponsor’s Approval: 
The protocol has been approved by Rhythm Pharmaceuticals, Inc. 
Responsible Medical Officer:  
 
 
Rhythm Pharmaceuticals, Inc.
Sponsor’s Authorized Officer: 
 
Date 
PPD
PPD


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INVESTIGATOR STATEMENT 
Protocol Title: A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and Positive-
controlled Study to Investigate the Effects of Setmelanotide on QTc Interval in Healthy Subjects 
Protocol Number: RM-493-032 
Document Version: Version 2.0; Amendment 1  
Document Date: 24 NOV 2021 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm) 
or its designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
Investigator Brochure (IB), case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board. No changes will be made to the study protocol without the prior 
written approval of Rhythm and the Institutional Review Board, except where necessary to 
eliminate an immediate hazard to the subject. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
Printed Name of Investigator 
Signature of Investigator 
Date 
Investigational site (or name of institution) and location (printed)


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviations and specialist terms are used in this study protocol. 
Abbreviation or 
Specialist Term 
Explanation 
Δ 
Change from baseline 
ΔΔ 
Placebo-corrected change from baseline 
ADR  
Adverse drug reaction 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
aPTT 
Activated partial thromboplastin time 
AST 
Aspartate aminotransferase 
AUC 
Area under the plasma concentration-time curve 
AUClast 
AUC from time zero to the time of last measurable concentration 
AUCtau 
AUC during the dosing interval 
BMI 
Body mass index 
BP 
Blood Pressure 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
Cl/f 
Apparent clearance 
Cmax 
Maximum observed concentration 
CO2
Carbon dioxide 
CPK 
Creatine phosphokinase 
C-QTc 
Concentration-QTc 
CRA 
Clinical Research Associate 
CRU 
Clinical Research Unit 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBP 
Diastolic blood pressure 
EC50
50% effective concentration 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 


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Abbreviation or 
Specialist Term 
Explanation 
GFR 
Glomerular filtration rate 
GGT 
Gamma-glutamyltranspeptidase 
HBsAG 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
hERG 
Human ether-à-go-go-related gene 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
Ki
Inhibitory constant 
LDH 
Lactate dehydrogenase 
LEPR 
Leptin receptor 
MC4R 
Melanocortin-4 receptor 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHP 
Mental health professional 
NCA 
Noncompartmental analysis 
PCSK1 
proprotein convertase subtilisin/kexin type 1 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
POMC 
Pro-opiomelanocortin 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
Once daily dosing 
QTcF 
QTc interval corrected by the Fridericia method 
RGDO 
Rare genetic disorders of obesity 
SAE 
Serious adverse event 
SBP 
Systolic blood pressure 
SC 
Subcutaneous 


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Abbreviation or 
Specialist Term 
Explanation 
SD  
Standard Deviation 
SoA 
Schedule of Assessments  
TdP 
Torsades de Pointes 
TEAE 
Treatment-emergent adverse events  
Tmax 
Time of the maximum observed plasma concentration 
Vd 
Apparent volume of distribution 
VUS 
Gene variants interpreted as pathogenic, likely pathogenic, or of uncertain 
significance 
WHO 
World Health Organization 


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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2
INVESTIGATOR STATEMENT ...................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................4
1.
SYNOPSIS .................................................................................................................11
2.
SCHEDULE OF ASSESSMENTS.............................................................................18
3.
INTRODUCTION ......................................................................................................23
3.1.
Background .................................................................................................................23
3.1.1.
Rare Genetic Disorders of Obesity .............................................................................23
3.1.2.
Setmelanotide .............................................................................................................23
3.2.
Study Rationale ...........................................................................................................24
3.3.
Benefit/Risk Assessment ............................................................................................24
4.
TRIAL OBJECTIVES ................................................................................................25
4.1.
Primary Objective .......................................................................................................25
4.2.
Secondary Objectives .................................................................................................25
5.
INVESTIGATIONAL PLAN .....................................................................................26
5.1.
Overall Study Design ..................................................................................................26
5.2.
Study Endpoints ..........................................................................................................28
5.2.1.
Primary Cardiac Endpoint ..........................................................................................28
5.2.2.
Secondary Cardiac Endpoints .....................................................................................28
5.2.3.
Pharmacokinetic Endpoints ........................................................................................28
5.2.4.
Safety Endpoints .........................................................................................................29
5.3.
Justification of Study Design ......................................................................................29
5.4.
Dose Rationale ............................................................................................................29
5.5.
Number of Subjects and Study Completion ...............................................................30
5.6.
Dose Adjustment Criteria ...........................................................................................30
5.7.
Criteria for Study Termination ...................................................................................30
5.8.
Replacement of Early Termination Subjects ..............................................................31
6.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................32
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6.1.
Subject Inclusion Criteria ...........................................................................................32
6.2.
Subject Exclusion Criteria ..........................................................................................32
6.3.
Subject Withdrawal Criteria .......................................................................................33
7.
TREATMENT OF SUBJECTS ..................................................................................35
7.1.
Administration of Treatments .....................................................................................35
7.2.
Administration of Food...............................................................................................35
7.3.
Concomitant Medications and Prohibited Therapies ..................................................35
7.4.
Randomization ............................................................................................................35
7.5.
Study Blind and Breaking the Blind ...........................................................................36
8.
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................37
8.1.
Description of Study Drugs ........................................................................................37
8.2.
Study Drug Packaging and Labeling ..........................................................................37
8.3.
Preparation, Handling, and Storage ............................................................................37
8.4.
Study Drug Accountability, Handling, and Disposal .................................................38
9.
PHARMACOKINETIC ASSESSMENTS .................................................................39
10.
ASSESSMENT OF SAFETY .....................................................................................40
10.1.
Safety Parameters .......................................................................................................40
10.1.1.
Demographic, Medical History, and Concomitant Medication Review .....................40
10.1.2.
Physical Examination .................................................................................................40
10.1.3.
Comprehensive Skin Examination .............................................................................40
10.1.4.
Fitzpatrick Scale .........................................................................................................40
10.1.5.
Weight and Height ......................................................................................................41
10.1.6.
Vital Signs ..................................................................................................................41
10.1.7.
12-Lead Electrocardiogram (ECG) .............................................................................41
10.1.8.
Columbia Suicide Severity Rating Scale (C-SSRS) ...................................................41
10.1.9.
Laboratory Assessments .............................................................................................42
10.1.9.1.
Clinical Laboratory Tests ...........................................................................................42
10.1.9.2.
Virus Serology ............................................................................................................43
10.1.9.3.
Urine Drug Screen ......................................................................................................43
10.1.9.4.
Pregnancy Testing and Contraception ........................................................................43
10.2.
Adverse Events ...........................................................................................................44
10.2.1.
Definition of Adverse Events and Serious Adverse Events .......................................44
10.2.1.1.
Adverse Event .............................................................................................................44


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10.2.1.2.
Serious Adverse Event ................................................................................................44
10.2.1.3.
Unexpected Adverse Drug Reaction ..........................................................................44
10.2.2.
Relationship to Study Drug ........................................................................................45
10.2.3.
Severity of Adverse Events ........................................................................................45
10.2.4.
Procedures for AE and SAE Reporting ......................................................................46
10.2.5.
Adverse Event Monitoring and Follow-up .................................................................46
10.2.6.
Depression or Suicidality ............................................................................................47
11.
STATISTICS ..............................................................................................................48
11.1.
Sample Size Determination ........................................................................................48
11.1.1.
Sample Size for Setmelanotide C-QTc Analysis ........................................................48
11.1.2.
Sample Size for Assay Sensitivity of C-QTc Analysis ..............................................48
11.2.
Analysis Populations ..................................................................................................48
11.3.
Planned Analysis ........................................................................................................49
11.3.1.
Cardiodynamic ECG Assessment ...............................................................................49
11.3.2.
Assay Sensitivity ........................................................................................................49
11.3.3.
Pharmacokinetic Analysis ..........................................................................................49
11.3.4.
Safety Analysis ...........................................................................................................50
12.
ADMINISTRATIVE REQUIREMENTS ..................................................................51
12.1.
Good Clinical Practice ................................................................................................51
12.2.
Ethical Considerations ................................................................................................51
12.3.
Subject Information and Informed Consent ...............................................................51
12.4.
Subject Confidentiality ...............................................................................................51
12.5.
Protocol Compliance ..................................................................................................51
12.6.
Data Management .......................................................................................................52
12.6.1.
Data Handling .............................................................................................................52
12.6.2.
Computer Systems ......................................................................................................52
12.6.3.
Data Entry ...................................................................................................................52
12.6.4.
Medical Information Coding ......................................................................................52
12.6.5.
Data Validation ...........................................................................................................52
12.7.
Direct Access to Source Data .....................................................................................52
12.8.
Source Document/Case Report Form Completion .....................................................53
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12.9.
Record Retention ........................................................................................................53
12.10.
Liability Insurance ......................................................................................................54
12.11.
Publication of Study Findings and Use of Information ..............................................54
13.
LIST OF REFERENCES ............................................................................................55
14.
APPENDICES ............................................................................................................56
14.1.
Appendix 1: Fitzpatrick Classification Scale .............................................................56
LIST OF TABLES 
Table 1: 
Schedule of Assessments ............................................................................................19
Table 2:
Description of Study Drugs ........................................................................................37
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................26
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1.
SYNOPSIS 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
IMCIVREE™ (setmelanotide) injection 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
Protocol Number:  
RM-493-032
Phase: 4
Country: USA
Title of Study: A Randomized, Double-Blind, 3-arm, Parallel Group, Placebo- and 
Positive -controlled Study to Investigate the Effects of Setmelanotide on QTc Interval in Healthy 
Subjects 
Study center(s):  
 
 
 
Principal Investigator:  
 
 
 
 
Studied period (years):  
Estimated date first subject enrolled: September, 2021 
Estimated date last subject completed: March, 2022 
Objectives:  
Primary: 

To evaluate the effects of therapeutic and supratherapeutic setmelanotide concentrations on 
QTc corrected by the Fridericia method (QTcF) interval in healthy subjects.
Secondary: 

To assess the effects of therapeutic and supratherapeutic setmelanotide concentrations on 
heart rate (HR), PR interval, QRS interval, T-wave morphology, and cardiac safety in healthy 
subjects. 

To evaluate assay sensitivity and the effect of a positive control, a single 400 mg oral dose of 
moxifloxacin, on the QT/QTcF interval in healthy subjects. 

To assess the pharmacokinetics (PK) of setmelanotide following administration of therapeutic 
and supratherapeutic doses of subcutaneous (SC) setmelanotide in healthy subjects. 
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
To evaluate the safety and tolerability of therapeutic and supratherapeutic doses of SC 
setmelanotide in healthy subjects. 
 
 
 
 
 
Methodology:  
This is a double-blind, randomized, placebo- and positive-controlled, parallel group, 3-arm study to 
assess the potential for therapeutic and supratherapeutic concentrations of setmelanotide to affect the 
QTcF interval compared with placebo. SC setmelanotide doses will be titrated throughout the study (2 
mg × 7 days, 3 mg × 3 days, 5 mg × 3 days, and 7 mg × 3 days) to reduce the potential of 
experiencing gastrointestinal effects previously observed at initiation of treatment and to titrate to 
higher doses. Oral moxifloxacin will be used as a positive control to establish the assay sensitivity of 
this study. 
Approximately 72 healthy adult male and female subjects will be enrolled and randomized 1:1:1 to 
1 of 3 groups: 

Group 1: SC setmelanotide; oral placebo on Days 10 and 16 

Group 2: SC placebo; oral moxifloxacin on Day 10 and oral placebo on Day 16 

Group 3: SC placebo; oral placebo on Day 10 and oral moxifloxacin on Day 16. 
The following treatments will be administered according to the figure below: 

SC setmelanotide: SC injection: 2 mg × 7 days followed by 3, 5, and 7 mg × 3 days per dose 
level 

SC placebo (matched to active setmelanotide): SC placebo injection × 16 days 

Oral moxifloxacin: single oral dose of 400 mg moxifloxacin  

Oral placebo (matched to oral moxifloxacin): single oral placebo dose  
 
 
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After a 28-day Screening period, subjects will check-in to the Clinical Research Unit (CRU) on the 
morning of Day −2 and will begin an overnight fast in the evening of Day −2. On Day −1, subjects 
will receive a standard breakfast at approximately 7:00 AM, followed by 24-hour Holter monitor 
electrocardiogram (ECG) collection (to begin at 7:30 AM, the same time as the anticipated daily 
dosing), baseline assessments. On the morning of Day 1, subjects will receive their first SC dose (SC 
setmelanotide or SC placebo). 
From Days 2 through 16, the assigned SC treatment (SC setmelanotide or SC placebo) will be 
administered to each group at approximately the same time every morning. On Days 10 and 16, 
subjects in Group 1 will receive an oral placebo with their SC setmelanotide dose. Subjects in Group 
2 will receive oral moxifloxacin 400 mg on Day 10 and oral placebo on Day 16, while Subjects in 
Group 3 will receive oral placebo on Day 10 and oral moxifloxacin 400 mg on Day 16. Oral 
treatments on Days 10 and 16 (oral moxifloxacin or oral placebo) will be administered within 2 
minutes after the SC placebo dose. All treatments (SC setmelanotide versus SC placebo and oral 
placebo versus oral moxifloxacin) will be administered in a double-blinded manner. 
Subjects will remain in the CRU through the morning of Day 17 and will be discharged after 
completion of all study assessments if safety parameters are acceptable to the Investigator. Subjects 
will return to the CRU for a Follow-up visit 7 ± 2 days after receiving the last SC dose (Day 23 ± 2). 
Subjects will be instructed to fast overnight (at least 10 hours) prior to all continuous Holter ECG 
dosing days (Days -1, 10, and 16). A standard breakfast will be provided to subjects at approximately 
7:00 AM each day. Treatments will be administered 30 minutes after the start of the meal, between 
5:30 AM to 9:30 AM. Lunch, dinner, and a snack will be provided at approximately 12:00 PM (after 
4-hour assessments), 6:00 PM (after 10-hour assessments), and 9:00 PM, respectively. All meals 
should be administered at the same time every day throughout the treatment period. 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
Continuous Holter ECG monitoring and PK samples will be collected up to 24 hours post-dose on 
Days 10 and 16. Continuous Holter ECGs (obtained on Days -1, 10, and 16) will be read with manual 
adjudication at a central laboratory. The Holter ECG laboratory and cardiologist responsible for 
reading the Holter ECGs will be blinded to treatment, timepoint, and subject.  
Safety will be assessed throughout the study via collection of adverse events (AEs), 12-lead safety 
ECGs, Columbia Suicide Severity Rating Scale (C-SSRS), clinical laboratory tests, vital signs, 
physical examinations, and concomitant medication monitoring. 
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Number of subjects (planned):  
Approximately 72 subjects are planned to be enrolled to achieve study completion of 60 subjects, 
accounting for dropouts. Dropouts may be replaced, at the Sponsor’s discretion. 
 
Sample Size Justification: 
Using a 2-sample t-test with a 1-sided 0.05 significance level, a sample size of 60 evaluable subjects 
who complete the study (20 subjects in Group 1 receiving SC setmelanotide and 20 subjects each in 
Groups 2 and 3 receiving SC placebo) will provide at least 85% power to exclude that setmelanotide 
causes more than a 10 msec QTc effect at clinically relevant plasma levels, as shown by the upper 
bound of the 2-sided 90% confidence interval (CI) of the model-predicted QTc effect (∆∆QTcF) at 
the observed geometric mean Cmax of setmelanotide on Day 10 and Day 16 in the study individually. 
To demonstrate assay sensitivity using moxifloxacin with a 1-sided 0.05 significance level, a sample 
size of 20 evaluable subjects receiving moxifloxacin and 20 evaluable subjects receiving placebo at 
each Holter ECG assessment day (Days 10 and 16) will provide at least 81% power to demonstrate 
assay sensitivity with a 1-sided 0.05 significant level. The power to detect the effect of moxifloxacin 
on QTc over the entire crossover period is at least 86%.  
As such, a total of approximately 72 subjects are planned for enrollment to achieve 60 completers, 
accounting for dropouts. 
Inclusion Criteria:  
Subjects must meet all of the following criteria to be eligible for study participation: 
1.
Males or females between 18 and 50 years of age, inclusive. 
2.
Subject has body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive. 
3.
Subject is in good health, as confirmed by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, vital signs measurements, clinical laboratory 
evaluations, and liver function tests at Screening, Check-in (Day −2) and baseline (Day −1). 
4.
Female participants of childbearing potential must be confirmed non-pregnant and agree to 
use contraception. Female participants of non-childbearing potential, defined as: surgically 
sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), 
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 study.   
5.
Male participants with female partners of childbearing potential must agree to use 
contraception (e.g., if not vasectomized, should either abstain from sexual intercourse or use a 
highly reliable method of contraception such as condom and diaphragm with spermicide 
during intercourse) if they become sexually active during the study or within 90 days 
following their participation in the study. Male subjects must also not donate sperm during 
and for 90 days following their participation in the study.  
6.
Subject is a nonsmoker (for at least 3 months) with negative urinary cotinine test at Screening 
and agrees to abstain from alcohol, recreational drugs (including marijuana), and tobacco- or 
nicotine-containing products for the duration of the study. 
7.
Subject is able to comprehend and is willing to sign an informed consent form and abide by 
the study restrictions. 
Exclusion criteria:  
Subjects meeting any of the following criteria are not eligible for study participation: 
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1.
Subject has sustained systolic blood pressure (SBP) >150 mmHg or <90 mmHg or a diastolic 
blood pressure (DBP) >100 mmHg or <60 mmHg in the supine position at Screening. 
2.
Subject has supine pulse rate of <45 beats per minute (bpm) or >100 bpm. 
3.
Subject has abnormal screening ECG indicating a second- or third-degree atrioventricular 
block, or one or more of the following: QRS>110 msec, QTcF >450 msec for males and 
>470 msec for females, PR interval >200 msec.  
4.
Subject has a history of risk factors for Torsades de Pointes (TdP), including unexplained 
syncope, diagnosis or family history of Brugada syndrome or long QT syndrome, heart 
failure, myocardial infarction, angina, or clinically significant abnormal laboratory 
assessments including hypokalemia, hypercalcemia, or hypomagnesaemia. 
5.
Glomerular filtration rate (GFR) <60 mL/min at Screening. 
6.
Subject has 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.  If any 
concerning lesions are identified during Screening, the subject should be referred to a 
dermatologist for evaluation prior to enrollment. If the pre-treatment evaluation results are of 
significant concern, the subject is not eligible for study participation. 
7.
Subject has history or close family history (parents or siblings) of melanoma or subject 
history of ocular-cutaneous albinism. 
8.
Subject has significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, or psychiatric disorder (as determined by the Investigator).
9.
Subject has suicidal ideation of type 4 or 5 on the C-SSRS at Screening, a history of a suicide 
attempt in their lifetime, or any suicidal behavior in the last month. 
10. Subject has participated in any clinical study with an investigational drug/device within 30 
days (or 5 half-lives) prior to the first day of dosing. 
11. Subject was previously enrolled in a clinical study involving setmelanotide or any previous 
exposure to setmelanotide. 
12. Subject has inability to comply with QD injection regimen. 
13. Female subjects who are breastfeeding or nursing. 
14. Subject has cognitive impairment that, in the Investigator’s opinion, precludes participation to 
the study. 
15. Subject is, in Investigator’s opinion, otherwise not suitable to participate in the study. 
Note: Exclusion criteria #1, 2, 3 and 5 can be repeated at the discretion of the Investigator. Vital signs 
will be limited to 3 repeats. Safety laboratory tests and ECGs will be limited to 1 repeat.
Investigational product, dosage, and mode of administration:  
IMCIVREE (setmelanotide), 10 mg/mL solution in 1 mL multiple-dose vial for SC injection (2, 3, 5, 
and 7 mg doses) 
Placebo for SC injection (vehicle only; identical in appearance to SC setmelanotide treatment) 
Reference therapy, dosage and mode of administration:  
Moxifloxacin 400 mg capsules for oral administration 
Placebo capsules for oral administration (identical in appearance to oral moxifloxacin treatment) 


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Duration of treatment:  
All subjects will receive study treatment for a total of 16 days. Total study participation will be 
between 23 and 53 days, based on the variable length of the Screening Period and the Follow-up visit. 
Criteria for evaluation: 
Primary cardiac endpoint: 

Setmelanotide concentration-related change from baseline (Δ) in QTc and placebo-adjusted 
change from baseline (ΔΔ) in QTc corrected for HR using QTcF (ΔQTcF and ΔΔQTcF)  
Secondary cardiac endpoints: 

Change from baseline (Δ) and placebo-corrected change from baseline (ΔΔ) in HR, QTcF, 
PR, and QRS intervals after administration of SC setmelanotide or oral moxifloxacin 

Categorical outliers for QTcF, HR, PR, and QRS intervals after administration of SC 
setmelanotide 

Frequency of treatment-emergent changes of T-wave morphology and U-wave presence after 
administration of SC setmelanotide 

Relationship between moxifloxacin concentrations and ΔΔQTcF 
Pharmacokinetic endpoints: 
The following PK endpoints will be calculated for setmelanotide: 

Area under the plasma concentration-time curve during the dosing interval (AUCtau)  

AUC from time zero to the time of last measurable concentration (AUClast) 

Maximum observed concentration (Cmax) 

Time of the maximum observed plasma concentration (Tmax) 

Apparent clearance (Cl/F) 

Apparent volume of distribution (Vd/F) 
The following PK endpoints will be calculated for moxifloxacin: 

AUCinf 

AUClast 

Tmax 

Cmax 
Safety endpoints: 

Frequency and severity of AEs (assessed separately for relation to SC setmelanotide and/or 
oral moxifloxacin), clinical laboratory evaluations, safety ECGs, C-SSRS score, vital signs, 
and physical examinations 
 
 
 
 
 
 
 
 
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Statistical methods: 
Cardiodynamic Holter ECG Assessment: 
The primary analysis will be based on C-QTc modeling of the relationship between plasma 
concentrations of setmelanotide (or placebo) and ΔQTcF (using Day -1 time-matched Holter ECGs as 
baseline) with the intent to exclude an effect of ΔΔQTcF >10 msec at clinically relevant plasma 
levels, using the concepts presented in the “Scientific White Paper on C-QTc modeling” (Garnett 
2018b, Garnett 2018a). After development of the C-QTc model and assessment of model performance 
through nonparametric bootstrapping, the ΔΔQTcF associated with the Cmax of therapeutic and 
supratherapeutic doses will be computed using bias-corrected 90% CI. An increase in QTc of 10 msec 
or greater can be ruled out if the upper 90% CI is <10 msec.    
The change from baseline (Δ) and placebo-corrected change from baseline (ΔΔ) QTcF, HR, PR, and 
QRS will be summarized by nominal time and treatment using descriptive statistics. An analysis of 
categorical outliers will be performed for changes in QTcF, HR, PR, and QRS, and T-wave 
morphology, and U-wave presence and results will be summarized.  
Assay sensitivity will be evaluated by C-QTc analysis of the effect on ΔΔQTcF of moxifloxacin using 
a similar model as for the primary analysis. Assay sensitivity will be deemed as met if the predicted 
QT effect (i.e., the lower bound of the 2-sided 90% CI of ΔΔQTcF) is above 5 msec at the observed 
geometric mean Cmax of 400 mg oral moxifloxacin. 
Pharmacokinetics: 
Setmelanotide and moxifloxacin concentration data will be summarized by nominal time point and 
treatment using descriptive statistics. PK parameters for setmelanotide and moxifloxacin (as listed in 
the PK endpoints section) will be calculated using noncompartmental methods (NCA) and 
summarized by treatment.  
Safety: 
All AEs will be listed and TEAEs will be summarized using descriptive methodology (setmelanotide 
and moxifloxacin AEs reported separately). Each AE will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). Observed values for clinical laboratory test data, 12-lead safety 
ECGs, C-SSRS score, vital signs measurements, and physical examination findings will be listed. 
No formal statistical analysis of safety data is planned. 
 
 
 
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2.
SCHEDULE OF ASSESSMENTS 
The Schedule of Assessments (SoA) is presented in Table 1.


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Table 1:  
Schedule of Assessments 
Study Period 
Screenin
g 
Check-
In 
Baselin
e 
Treatment 
Follow-up 
Treatment 
Discontinuatio
n 
Study Day
Assessment 
-28 to -2 
-2 
-1 
1 
2-6 
7 
8 
9 
10 
11-
14 
15 
16 
17 
23 ± 2 
7 ± 4 days 
after last SC 
dose 
Informed consent 
X 
Inclusion/exclusion 
review 
X 
X 
Medical history 
review 
X 
Physical exam a
X 
X 
 
X 
X 
X 
Comprehensive 
skin exam b
X 
Fitzpatrick 
classification scale 
X 
Height and weight c
X 
X 
 
X 
X 
X 
Vital signs d
X 
X 
 
X 
X 
X 
Pregnancy test e
X 
X 
X 
X 
FSH test 
X 
X 
Urine drug screen 
X 
X 
CRU confinement 
X 
X 
X 
X 
X 
X
X
X 
X 
X 
X 
 
CRU discharge 
 
X 
Fasting f
X 
 
 
X
X 
 
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Study Period 
Screenin
g 
Check-
In 
Baselin
e 
Treatment 
Follow-up 
Treatment 
Discontinuatio
n 
Study Day
Assessment 
-28 to -2 
-2 
-1 
1 
2-6 
7 
8 
9 
10 
11-
14 
15 
16 
17 
23 ± 2 
7 ± 4 days 
after last SC 
dose 
Meal 
administration g
X 
X
X
X 
X 
X 
X 
Setmelanotide 
administration h
X 
X 
X 
X
X
X 
X 
X 
X 
 
Moxifloxacin 
administration i
X 
X 
 
PK sampling j
 
 
 
X 
 
X 
 
Continuous 12-lead 
ECGs (Holter 
monitor) k, l
X 
X 
X 
 
Safety 12-lead 
ECGs l, m
X 
X 
 
X 
 
 
X 
X 
X 
Clinical labs n
X 
X 
 
X 
 
 
 
X 
X 
X 
Adverse events 
X 
Continuous 
X 
Concomitant 
medication review 
X 
Continuous 
X 
C-SSRS o
X 
X 
 
X 
X 
 
 
 
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Study Period 
Screenin
g 
Check-
In 
Baselin
e 
Treatment 
Follow-up 
Treatment 
Discontinuatio
n 
Study Day
Assessment 
-28 to -2 
-2 
-1 
1 
2-6 
7 
8 
9 
10 
11-
14 
15 
16 
17 
23 ± 2 
7 ± 4 days 
after last SC 
dose 
CRU = Clinical Research Unit; C-SSRS = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; FSH = follicle stimulating hormone;  INR = 
international normalized ratio; PK = pharmacokinetic; PT = prothrombin time; PTT (or aPTT) = partial thromboplastin time.  
a A full physical exam will be conducted at Screening. A brief physical exam will be conducted at each check-in, baseline, study discharge, and follow-up. 
b A comprehensive skin evaluation will be performed by the Investigator at Screening. If any concerning lesions are identified during the screening period, the 
subject should be referred to a dermatologist for assessment and potential biopsy and results should be confirmed as to whether the lesion is benign prior to first 
dose of setmelanotide. If the pre-treatment biopsy results are of concern, the subject will be excluded from the study. 
c Height will only be collected at Screening. 
d Supine blood pressure, supine heart rate, pulse rate, and tympanic (ear) body temperature. Heart rate and blood pressure will be measured using the same arm 
for each reading after the subject has been resting in the supine position for at least 5 minutes. For timepoints at which vital signs, PK blood samples, and/or 
ECGs are all to be collected, ECGs should be collected first followed by vital signs then PK samples, with the timing of the PK sample to occur at the nominal 
time.    
e Serum pregnancy test will be performed at Screening. Urine pregnancy test will be performed on all other designated days. 
f On the evening before continuous Holter ECG sampling, subjects will undergo a 10-hour overnight fast. 
g Breakfast is to be administered at approximately 7:00 AM every day in the CRU (30 minutes pre-dose). Lunch, dinner, and a snack will be administered at 
approximately 12:00 PM (after 4-hour assessments), 6:00 PM (after 10-hour assessments), and 9:00 PM, respectively. 
h Group 1 will receive SC setmelanotide QD (approximately 7:30 AM) at a dose of 2 mg from Days 1 to 7; 3 mg from Days 8 to 10; 5 mg from Days 11 to 13; 
and 7 mg from Days 14 to 16.  
Groups 2 and 3 will receive SC placebo QD (approximately 7:30 AM) from Days 1 through 16.  
All doses will be double-blinded. 
i Group 1 will receive oral placebo with their SC setmelanotide dose on Days 10 and 16.
Group 2 will receive oral moxifloxacin 400 mg on Day 10 and oral placebo on Day 16. 
Group 3 will receive oral placebo on Day 10 and moxifloxacin 400 mg on Day 16.  
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All doses will be double-blinded. On Days 10 and 16, subjects should receive SC setmelanotide/placebo first. Oral moxifloxacin/placebo should then be 
administered within 2 minutes of the SC dose.  
j Blood samples for quantification of setmelanotide and moxifloxacin concentrations will be collected at pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 
16, and 24 hours post-dose on Days 10 and 16. The PK samples collected at 0.5 hours post-dose will have a sampling window of ± 2 minutes, samples 
collected from 1 hour though 2.5 hours post-dose will have a sampling window of ± 5 minutes, samples collected from 3 hours through 10 hours post-dose will 
have a sampling window of ± 10 minutes, and samples collected from 12 through 24 hours postdose will have a sampling window of ± 20 minutes; however, 
collection of samples outside of the window will not be considered protocol deviations. The timing of all PK samples should be recorded to the nearest minute. 
For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be collected, ECGs should be collected first followed by vital signs then PK 
samples, with the timing of the PK sample to occur at the nominal time.    
k Holter ECGs will be extracted at Day -1 and on Days 10 and 16 at the following timepoints: pre-dose and 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 16, and 
24 hours post-dose. The Day -1 extractions will begin at 7:30 AM (the time of anticipated dosing on Days 10 and 16). 
l For ECG collection, subjects will rest in the supine position for at least 10 minutes before and 5 minutes after each timepoint. For timepoints at which vital, PK 
blood samples, and/or ECGs are all to be collected, ECGs should be collected first followed by vital signs then PK samples, with the timing of the PK sample 
to occur at the nominal time. 
m Safety ECGs will be collected at the Screening visit, CRU baseline (Day−1), final CRU discharge, and the Follow-up visit. 
n Safety clinical laboratory tests will include: hematology with platelet count and standard indices, chemistry panel (includes sodium, potassium, chloride, CO2, 
albumin, total protein, glucose, BUN, creatinine, uric acid, AST, ALT, GGT, CPK, alkaline phosphatase, total bilirubin, direct bilirubin, LDH, calcium, 
phosphorus, magnesium), and urinalysis with microscopic analysis if positive findings on dipsticks warrant further examination. Safety laboratories will also 
include a coagulation profile (PT or INR, and PTT also referred to as aPTT).
o In order to be eligible for the study, at Screening, a subject cannot have a suicidal ideation of type 4 or 5, a history of a suicide attempt in the past 20 years, or 
any suicidal behavior in the last month. If at any time during the study a subject has a suicidal ideation of type 4 or 5, or any suicidal behavior, the subject 
should be referred to a mental health professional. 
 
 
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3.
INTRODUCTION 
3.1.
Background 
3.1.1.
Rare Genetic Disorders of Obesity 
Human genetics studies have identified several diseases that are the result of genetic defects 
affecting the melanocortin-4 receptor (MC4R) pathway, including, but not limited to, 
pro-opiomelanocortin (POMC) deficiency obesity due to mutations in the POMC gene; 
heterozygous proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency due to mutations 
in the PCSK1 gene, leading to a hormone processing defect that also causes POMC deficiency 
obesity; and leptin receptor (LEPR) deficiency obesity due to mutations in the LEPR gene. These 
MC4R pathway mutations cause rare genetic disorders of obesity (RGDO) that start early in 
childhood, progress over time, and can become life-threatening in severity. 
3.1.2.
Setmelanotide 
Setmelanotide (also known as RM-493) is a synthetic, cyclic octapeptide (8-amino acid-
containing peptide) that functions as a potent MC4R agonist. Setmelanotide is an 8-amino acid, 
cyclic peptide that binds with high affinity (inhibitory constant [Ki] = 2.1 nM) to the human 
MC4R and is efficient in activating MC4R (50% effective concentration [EC50] = 0.27 nM). 
Setmelanotide is indicated for chronic weight management in adult and pediatric patients 6 years 
of age and older with obesity due to POMC, PCSK1, or LEPR deficiency confirmed by genetic 
testing demonstrating variants in POMC, PCSK1, or LEPR genes that are interpreted as 
pathogenic, likely pathogenic, or of uncertain significance (IMCIVREE (setmelanotide) 
Prescribing Information 2020).  
Setmelanotide was evaluated extensively in nonclinical studies for cardiovascular parameters, 
primarily because of the potential concern for effects on blood pressure (BP) and heart rate (HR). 
The IC50 for the effect of setmelanotide on human ether-à-go-go-related gene (hERG) potassium 
current was estimated to be greater than 300 μg/mL, the maximum concentration tested. In 
addition, an extensive, multi-day cardiovascular telemetry study with setmelanotide administered 
by subcutaneous (SC) continuous infusion was performed in cynomolgus monkeys. No 
setmelanotide-related effects were noted on the electrocardiogram (ECG) parameters (PR, QRS, 
QT, and QTc intervals) following the administration at doses of 2.5, 12, and 25 mg/kg/day. In 
both these studies, there were extremely large exposure/concentration margins to the 
approximate Cmax of the maximum therapeutic 3 mg SC injection dose (~40.0 ng/mL) and the 
anticipated Cmax of the supratherapeutic 7 mg SC injection dose (~93.3 ng/mL, assuming dose 
proportionality). 
QTc evaluations were additionally conducted in 3 initial Phase 1 and Phase 2 clinical studies, as 
well as in 57 patients with monogenic obesity in 3 Phase 2 and Phase 3 studies. Mean and 
median data for QTcF demonstrate no effect of setmelanotide on QTc interval at doses up to 
3 mg QD.  


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3.2.
Study Rationale 
This study is being conducted to fulfill Postmarketing Requirement 
 
 to assess the risk of QT interval prolongation by SC setmelanotide. Oral moxifloxacin 
will be used as a positive control to determine the assay sensitivity of this study, with an 
expected peak QTcF effect (ΔΔQTcF) of 10 to 15 msec. Continuous Holter ECG measurements 
will be collected at baseline, after administration of SC and oral placebo, after SC setmelanotide 
administration, and after oral moxifloxacin administration; these ECGs will be read with manual 
adjudication at a central laboratory. The effect of setmelanotide and moxifloxacin on placebo- 
and baseline-corrected (ΔΔ) QTcF will be determined.  
 
 
 
 
3.3.
Benefit/Risk Assessment 
This study will be conducted according to the protocol and in compliance with Good Clinical 
Practice, the ethical principles stated in the Declaration of Helsinki, and other applicable 
regulatory requirements. 
Healthy subjects in the current study will not receive any health benefit (beyond that of an 
assessment of their medical status) from participating in the study. The risks of participation are 
primarily those associated with adverse reactions to the study treatments, in addition to the 
possibility of mild discomfort due to blood sampling and other study procedures. Further 
information about the known and expected benefits, risks, and reasonably anticipated adverse 
events (AEs) associated with SC setmelanotide are found in the Investigator’s Brochure (IB) and 
IMCIVREE (setmelanotide) Prescribing Information (2020).  
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4.
TRIAL OBJECTIVES  
4.1.
Primary Objective 
The primary objective of this study is: 

To evaluate the effects of therapeutic and supratherapeutic setmelanotide concentrations 
on QTc corrected by the Fridericia method (QTcF) interval in healthy subjects. 
4.2.
Secondary Objectives 
The secondary objectives of this study are: 

To assess the effects of therapeutic and supratherapeutic setmelanotide concentrations on 
HR, PR interval, QRS interval, T-wave morphology, and cardiac safety in healthy 
subjects. 

To evaluate assay sensitivity and the effect of a positive control, a single 400 mg oral 
dose of moxifloxacin, on the QT/QTcF interval in healthy subjects. 

To assess the pharmacokinetics (PK) of setmelanotide following administration of 
therapeutic and supratherapeutic doses of SC setmelanotide in healthy subjects. 

To evaluate the safety and tolerability of therapeutic and supratherapeutic doses of SC 
setmelanotide in healthy subjects. 
 
  
 
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5.
INVESTIGATIONAL PLAN 
5.1.
Overall Study Design 
This is a double-blind, randomized, placebo- and positive-controlled, parallel group, 3-arm study 
to assess the potential for therapeutic and supratherapeutic concentrations of SC setmelanotide 
administered as IMCIVREE to affect the QTcF interval compared with placebo. Approximately 
72 healthy subjects aged 18 to 50 years of age, inclusive, are planned to be enrolled in the United 
States. Subjects will be enrolled into 1 of 3 groups as follows: 

Group 1: SC setmelanotide; oral placebo on Days 10 and 16 

Group 2: SC placebo; oral moxifloxacin on Day 10 and oral placebo on Day 16 

Group 3: SC placebo; oral placebo on Day 10 and oral moxifloxacin on Day 16. 
The study design is presented in Figure 1. 
Figure 1:  
Study Design Schematic 
 
Upon providing informed consent, subjects will enter a 28-day Screening period, during which 
they will be assessed for eligibility and complete all screening procedures as described in the 
Schedule of Assessments (SoA) (Table 1).  
Following the Screening period, eligible subjects will check-in to the Clinical Research Unit 
(CRU) on the morning of Day −2. Subjects will be randomized 1:1:1 into Group 1, 2, or 3 and 
will be fasted overnight (for at least 10 hours). On the morning of Day -1 following a standard 
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breakfast, subjects will undergo 24-hour continuous ECG Holter monitoring beginning 
30 minutes after the meal (at the time of anticipated dosing on Days 10 and 16). Baseline 
assessments (Table 1) will occur on Day -1.  
On the morning of Day 1, subjects will receive SC setmelanotide 2 mg (Group 1) or SC placebo 
(Groups 2 and 3) in a double-blinded fashion.  
From Days 2 to 16 following a standardized breakfast, subjects will continue receiving SC 
setmelanotide (3 mg QD from Days 8 to 10; 5 mg QD from Days 11 to 13; 7 mg QD from 
Days 14 to 16) or SC placebo according to their assigned group. On Days 10 and 16, oral 
placebo or oral moxifloxacin 400 mg will be administered with the SC dose according to the 
assigned dose group. Continuous Holter ECGs and PK sampling will be conducted on Days 10 
and 16 pre-dose and for up to 24 hours post-dose according to the SoA (Table 1). All treatments 
administered in the CRU will be double-blinded and will be given at the same time every day 
(approximately 30 minutes after the start of breakfast). 
Subjects will remain in the CRU through the morning of Day 17 and will be discharged after 
completion of all study assessments if safety parameters are acceptable to the Investigator. 
Subjects will return to the CRU for a Follow-up visit 7 ± 2 days after receiving the last SC dose 
(Day 23 ± 2). 
Adverse events (AEs), 12-lead safety ECGs, Columbia Suicide Severity Rating Scale (C-SSRS) 
score, clinical laboratory tests, vital signs, and concomitant medication monitoring will be 
collected throughout the study for safety assessments as described in the SoA (Table 1). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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5.2.
Study Endpoints 
5.2.1.
Primary Cardiac Endpoint 
The primary cardiac endpoint of the study is: 

Setmelanotide concentration-related change from baseline in QTc (Δ) and placebo-
adjusted change from baseline in QTc (ΔΔ) corrected for HR using QTcF (ΔQTcF and 
ΔΔQTcF)  
5.2.2.
Secondary Cardiac Endpoints 
The secondary cardiac endpoints of the study are: 

Change from baseline (Δ) and placebo-corrected change from baseline (ΔΔ) in HR, 
QTcF, PR, and QRS intervals after administration of SC setmelanotide or oral 
moxifloxacin 

Categorical outliers for QTcF, HR, PR, and QRS intervals after administration of SC 
setmelanotide 

Frequency of treatment-emergent changes of T-wave morphology and U-wave presence 
after administration of SC setmelanotide 

Relationship between moxifloxacin concentrations and ΔΔQTcF 
5.2.3.
Pharmacokinetic Endpoints 
The following PK endpoints will be calculated for setmelanotide: 

Area under the plasma concentration-time curve during the dosing interval (AUCtau)  

AUC from time zero to the time of last measurable concentration (AUClast) 

Maximum observed concentration (Cmax) 

Time of the maximum observed plasma concentration (Tmax) 

Apparent clearance (Cl/F) 

Apparent volume of distribution (Vd/F) 
The following PK endpoints will be calculated for moxifloxacin: 

AUCinf 

AUClast 

Tmax 
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
Cmax 
5.2.4.
Safety Endpoints 
The safety endpoints are: 

Frequency and severity of AEs (assessed separately for relation to setmelanotide and/or 
moxifloxacin) 

Changes from baseline in clinical laboratory evaluations, vital signs, 12-lead safety 
ECGs, C-SSRS score, vital signs, and physical examinations 
 
 
 
 
 
  
 
  
 
 
5.3.
Justification of Study Design 
This study will be randomized and double-blinded. Randomization eliminates confounding by 
baseline variables, while blinding eliminates confounding by concomitant interventions and 
biased safety findings. These measures therefore eliminate the possibility that the observed 
effects of intervention are due to differential use of other treatments or biased expectations 
regarding safety. 
Subjects in Groups 2 and 3 will receive both oral placebo and oral moxifloxacin in order to serve 
as their own controls, thus reducing the variability between treatments.  
Healthy subjects will be used for this study to eliminate variables that are known to have effects 
on ECG parameters, such as concomitant drugs and disease. Both male and female subjects will 
be included to eliminate similar known ECG variability effects. 
As non-drug-related increases in HR and shortening of QT and QTcF within 4 hours of a meal 
(maximal effect at 2 hours post-meal) have been reported in the literature (Taubel 2012), meals 
will be administered at the same time each day during the study (Section 7.2) to control for the 
effect of food on QTc interval.  
5.4.
Dose Rationale 
Setmelanotide effect on QTcF will be evaluated at doses of 3 mg (maximum therapeutic dose) 
and 7 mg (supratherapeutic dose). The dose of SC setmelanotide will be titrated to these doses in 
a manner similar to that used for therapeutic dosing to alleviate gastrointestinal symptoms 
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previously observed with SC setmelanotide dosing (IMCIVREE (setmelanotide) Prescribing 
Information 2020). 
5.5.
Number of Subjects and Study Completion 
This study is planned to enroll 72 subjects to achieve a total of 60 completed subjects (Section 
11.1).  
A subject is considered to have completed the study after completion of the Follow-up visit on 
Day 23 ± 2. 
Subjects who discontinue before completing the Follow-up visit are to attend a Treatment 
Discontinuation visit within 7 days (± 4 days) after the last SC dose for final study assessments. 
Subjects who discontinue the study early may be replaced, at the discretion of the Sponsor, in 
order to assure that the final sample size is large enough to maintain sufficient statistical power. 
 
 
The end of the study is defined as the date of the last visit of the last subject under the auspices 
of the current study. 
5.6.
Dose Adjustment Criteria 
If a subject experiences gastrointestinal side effects (e.g., nausea or vomiting), a dose may be 
delayed or decreased, or dose escalation may be postponed, at the discretion of the Principal 
Investigator. If a subject has not received at least 4 consecutive days of SC treatment by Day 7, 
the subject’s enrollment should be discussed with the Sponsor prior to his/her continuation in the 
study.  
In general, all subjects in this study are intended to complete the study at the highest dose of SC 
setmelanotide that they can tolerate.  If >30% of the proposed patients cannot escalate SC 
setmelanotide up to a dose of at least 5 mg/day, additional subjects may be enrolled to ensure 
appropriate statistical power. If this occurs, a Note to File will be issued to explain the rationale 
for enrolling additional patients and the statistical justification for the change in sample size. 
5.7.
Criteria for Study Termination 
This study or a clinical site may be prematurely terminated, if in the opinion of the Sponsor, 
there is sufficiently reasonable cause. The Sponsor will provide written notification documenting 
the reason for study or site termination.  
Circumstances that may warrant termination include, but are not limited to: 

Determination of unexpected, significant, or unacceptable risk to subjects. 

Failure to enroll subjects into the study. 

Insufficient adherence to protocol requirements. 

Insufficient complete and/or evaluable data. 

Plans to modify, suspend, or discontinue the development of the study drug. 
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Should the study be closed prematurely, all study materials must be returned to the Sponsor or 
designee. 
5.8.
Replacement of Early Termination Subjects 
If a subject is replaced in attempt to limit completer bias, the replaced subject should have a new 
unique subject ID, and a new randomization number with the same treatment group by the pre-
specified randomization schedule, which will remain blinded until the study database is locked 
and unblinded. All the procedures of the replacement will be documented and kept in the study 
electronic trial master file (eTMF). 


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6.
SELECTION AND WITHDRAWAL OF SUBJECTS 
6.1.
Subject Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for study participation: 
1. Males or females between 18 and 50 years of age, inclusive. 
2. Subject has body mass index (BMI) between 18.0 and 30.0 kg/m2, inclusive. 
3. Subject is in good health, as confirmed by no clinically significant findings from medical 
history, physical examination, 12-lead ECG, vital signs measurements, clinical laboratory 
evaluations, and liver function tests at Screening, Check-in (Day −2) and baseline (Day 
−1). 
4. Female participants of childbearing potential must be confirmed non-pregnant and agree 
to use contraception (Section 10.1.9.4). Female participants of non-childbearing potential, 
defined as: surgically sterile (status post hysterectomy, bilateral oophorectomy, or 
bilateral tubal ligation), 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 study.   
5.
Male participants with female partners of childbearing potential must agree to use 
contraception (e.g., if not vasectomized, should either abstain from sexual intercourse or 
use a highly reliable method of contraception such as condom and diaphragm with 
spermicide during intercourse) if they become sexually active during the study or within 
90 days following their participation in the study. Male subjects must also not donate 
sperm during and for 90 days following their participation in the study. 
6. Subject is a nonsmoker (for at least 3 months) with negative urinary cotinine test at 
Screening and agrees to abstain from alcohol, recreational drugs (including marijuana), 
and tobacco- and nicotine-containing products for the duration of the study. 
7. Subject is able to comprehend and is willing to sign an informed consent form and abide 
by the study restrictions. 
6.2.
Subject Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for study participation: 
1. Subject has sustained systolic blood pressure (SBP) >150 mmHg or <90 mmHg or a 
diastolic blood pressure (DBP) >100 mmHg or <60 mmHg in the supine position at 
Screening. 
2. Subject has supine pulse rate of <45 beats per minute (bpm) or >100 bpm. 
3. Subject has abnormal screening ECG indicating a second- or third-degree atrioventricular 
block, or one or more of the following: QRS >110 msec, QTcF >450 msec for males and 
>470 msec for females, PR interval >200 msec.  
4. Subject has a history of risk factors for Torsades de Pointes (TdP), including unexplained 
syncope, diagnosis or family history of Brugada syndrome or long QT syndrome, heart 


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failure, myocardial infarction, angina, or clinically significant abnormal laboratory 
assessments including hypokalemia, hypercalcemia, or hypomagnesaemia. 
5. Glomerular filtration rate (GFR) <60 mL/min at Screening. 
6. Subject has 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.  If any 
concerning lesions are identified during Screening, the subject should be referred to a 
dermatologist for evaluation prior to enrollment. If the pre-treatment evaluation results 
are of significant concern, the subject is not eligible for study participation. 
7. Subject has history or close family history (parents or siblings) of melanoma or subject 
history of ocular-cutaneous albinism. 
8. Subject has significant history or clinical manifestation of any metabolic, allergic, 
dermatological, hepatic, renal, hematological, pulmonary, cardiovascular, 
gastrointestinal, neurological, or psychiatric disorder (as determined by the Investigator). 
9. Subject has suicidal ideation of type 4 or 5 on the C-SSRS at Screening, a history of a 
suicide attempt in their lifetime, or any suicidal behavior in the last month. 
10. Subject has participated in any clinical study with an investigational drug/device within 
30 days (or 5 half-lives) prior to the first day of dosing. 
11. Subject was previously enrolled in a clinical study involving setmelanotide or any 
previous exposure to setmelanotide. 
12. Subject has inability to comply with QD injection regimen. 
13. Female subjects who are breastfeeding or nursing. 
14. Subject has cognitive impairment that, in the Investigator’s opinion, precludes 
participation to the study. 
15. Subject is, in Investigator’s opinion, otherwise not suitable to participate in the study. 
Note: Exclusion criteria #1, 2, 3 and 5 can be repeated at the discretion of the Investigator. Vital 
signs will be limited to 3 repeats. Safety laboratory tests and ECGs will be limited to 1 repeat. 
6.3.
Subject Withdrawal Criteria 
Subjects will be informed that they have the right to withdraw their consent to participate in the 
study at any time for any reason, without prejudice to their medical care. The Investigator also 
has the right to withdraw subjects from the study, after discussion with the Sponsor, for any of 
the following reasons: 

Non-adherence to study drug regimen or protocol requirements. 

Non-compliance with instructions or failure to return for follow-up. 

Subject safety. 
If a subject is withdrawn or discontinued from the study, the primary reason for withdrawal from 
the study is to be recorded in the source documents/electronic case report form (eCRF). 


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Any subject that discontinues treatment prior to completing the study should be strongly 
encouraged to attend a Treatment Discontinuation visit within 7 days (± 4 days) after the last SC 
dose to complete all remaining visits and procedures as outlined in the SoA (Table 1), even if 
they are no longer receiving study drug.  
In case of discontinuation, all AEs should be followed as described in Section 10.2.5. 


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7.
TREATMENT OF SUBJECTS 
7.1.
Administration of Treatments 
Subjects will receive SC setmelanotide or SC placebo as an injection QD for the duration of the 
study. Doses will be administered in the CRU by study staff.  
On Days 10 and 16, oral placebo or oral moxifloxacin will be administered within 2 minutes of 
SC setmelanotide or SC placebo based on the assigned dose group (Section 5.1). Subjects will be 
instructed to take oral doses with 240 mL of water at room temperature. Dosing will be 
conducted by study staff. 
7.2.
Administration of Food 
Subjects will be instructed to fast overnight prior to all continuous Holter ECG sampling days 
(Days -1, 10, and 16), with water permitted 
. A standard breakfast will be provided in 
the CRU every morning at approximately 7:00 AM, with study drug dosing to occur 30 minutes 
after the start of the meal (between 5:30 AM to 9:30 AM). Lunch, dinner, and a snack will be 
provided at approximately 12:00 PM, 6:00 PM, and 9:00 PM, respectively. On Days -1, 10, and 
16, lunch and dinner should be provided after completion of the 4-hour and 10-hour assessments, 
respectively. 
Prior to the 
 energy intake assessment periods, subjects will be provided a 
standardized evening meal on Day −3 and Day 12.
 
 
 
. 
7.3.
Concomitant Medications and Prohibited Therapies 
With the exception of contraceptives or the occasional use of acetaminophen, naproxen, and 
ibuprofen, subjects should not take any other prescription or non-prescription drugs, including 
individual vitamins, herbal and dietary supplements, within 7 days or 5 half-lives (whichever is 
longer) prior to CRU admission and for the duration of the study, unless in the opinion of the 
Investigator and Sponsor’s Medical Monitor the medication is not expected to interfere with the 
study procedures or compromise subject safety. 
7.4.
Randomization 
Upon entering the CRU on Day -2, subjects will be assigned a unique randomization number 
based on a randomization code that will be generated prior to the start of the study. The 
randomization number codes the subject’s assignment to Group 1, 2, or 3 to receive the 
following treatments: 
Group 
SC Treatment  
Days 1 to 16 
Oral Treatment  
Day 10 
Oral Treatment 
Day 16 
1 
SC setmelanotide 
oral placebo 
oral placebo 
2 
SC placebo 
oral moxifloxacin 
oral placebo 
PPD
PPD
PPD


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3 
SC placebo 
oral placebo 
oral moxifloxacin 
The randomization scheme will assign subjects in a 1:1:1 ratio.  
7.5.
Study Blind and Breaking the Blind 
The Investigator, study site staff, clinical research organization staff providing site management, 
and Medical Monitor will not have access to the actual treatment assignment administered during 
the study, except in the case of emergency. Every attempt will be made to maintain the blind 
through the study (i.e., until the database snapshot prior to completing the primary statistical 
analysis). Breaking the blind for a subject should be done only in the event of a medical 
emergency where the identity of study drug is necessary to appropriately treat the subject. The 
Principal Investigator will be provided with access to a system to unblind, but if possible, the 
decision to break the blind should first be discussed with the Medical Monitor. If the blind is 
broken, the reason, when, and how the blind was broken will be documented. 


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8.
STUDY DRUG MATERIALS AND MANAGEMENT 
8.1.
Description of Study Drugs 
SC setmelanotide, SC placebo, oral moxifloxacin, and oral placebo will be provided as detailed 
in Table 2. 
Table 2: 
Description of Study Drugs 
Product Name 
SC Setmelanotide 
(IMCIVREE) 
SC placebo 
Moxifloxacin 
HCl 
Oral placebo 
Dosage Form 
Solution for 
injection 
Solution for 
injection 
Tablets 
Tablet 
Unit Dose 
10.0 mg/mL 
solution in a 1 mL 
multiple-dose vial 
1 mL multiple-
dose vial 
400 mg 
N/A 
Route of 
Administration
SC 
SC 
Oral 
Oral 
Physical 
Description 
Clear, colorless to 
slightly opalescent 
solution essentially 
free of visible 
particulates 
Identical in 
appearance to 
active 
setmelanotide 
Pink/beige hard 
tablet 
Identical in appearance 
to oral moxifloxacin 
SC setmelanotide and SC placebo will be manufactured by Recipharm (Monts, France).  
8.2.
Study Drug Packaging and Labeling 
SC setmelanotide and SC placebo will be supplied by Rhythm (manufactured by Recipharm). 
Oral moxifloxacin and oral placebo will be supplied by the CRU.  
Setmelanotide packaging and labeling will be prepared according to the IMCIVREE 
(setmelanotide) Prescribing Information (2020).  
To ensure that the subject and site are blinded with respect to subject’s randomized treatment 
assignment, SC placebo and SC setmelanotide are identical in appearance and are supplied in 
identical packaging. Each package and vial will contain a code that identifies the contents as 
either SC placebo or SC setmelanotide. For each dose the study pharmacist will select the correct 
study drug based on the package code and will provide the blinded study medication to the 
subject for administration. 
8.3.
Preparation, Handling, and Storage 
All study treatments must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access limited 
to the Investigator and authorized site staff. 
SC setmelanotide and SC placebo should be stored at a temperature between 2°C to 8°C. Both 
SC setmelanotide and SC placebo are stable at room temperature for a short time period. 


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Oral moxifloxacin and oral placebo should be stored at 25°C, with excursions are permitted to 
15-30°C. 
8.4.
Study Drug Accountability, Handling, and Disposal 
Accountability for the study drug at the study 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 subject, and return to Rhythm (or disposal of 
the drug, if approved by Rhythm) 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. 
All unused study drug supplies and equipment will either be returned to Rhythm or destroyed 
after the site close-out visit. The Sponsor, or designee, will verify study drug disposition at the 
site close-out visit. If the study drug is returned to Rhythm, documentation of the shipment will 
be provided. If the study drug is destroyed by the site, a Certificate of Destruction will be 
provided to Rhythm, or designee, by the site to document the disposal. 


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9.
PHARMACOKINETIC ASSESSMENTS 
Serial blood samples for determination of setmelanotide and moxifloxacin concentrations in 
plasma will be collected at the timepoints indicated in the SoA (Table 1). All efforts should be 
made to collect samples within the sampling windows specified in Table 1; however, collection 
of samples outside of the window will not be considered protocol deviations. For all PK blood 
samples, the actual (clock) time that the sample is collected will be recorded in source documents 
and the eCRF. For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be 
collected, ECGs should be collected first followed by vital signs then PK samples, with the 
timing of the PK sample occurring at the nominal time.    
Plasma will be harvested from PK samples and will be frozen, shipped to a bioanalytical 
laboratory designated by the Sponsor. Plasma samples will be analyzed for setmelanotide and 
moxifloxacin concentrations using validated analytical methods, as detailed in the laboratory 
manual. Samples collected after placebo dosing will not be analyzed. 


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10.
ASSESSMENT OF SAFETY 
10.1.
Safety Parameters 
Safety and tolerability of setmelanotide will be assessed by monitoring and recording of all AEs 
throughout the study (setmelanotide and moxifloxacin AEs reported separately). Regular 
monitoring of 12-lead safety ECGs, C-SSRS, clinical laboratory assessments, vital signs, 
physical examinations, and concomitant medications will be conducted as detailed in the SoA 
(Table 1) and below. Subjects will return to the CRU for a Follow-up visit 7 ± 2 days after 
receiving the last SC dose to assess for AEs and other safety parameters as described in the SoA 
(Table 1).  
10.1.1.
Demographic, Medical History, and Concomitant Medication Review 
Medical history and demographic data including the subject’s sex, race, date of birth, and 
concomitant medication use will be obtained for all subjects during the Screening period (Table 
1). 
The medical history should be updated on when the subject enters the CRU on Day -2 (prior to 
first dose of study drug on Day 1), to assess continued study eligibility and adherence to final 
inclusion/exclusion criteria. This medical history update includes a review for changes from 
Screening as well as a review of the subject’s recent medication use to assess whether any 
changes have occurred since the previous visit. 
A review of concomitant medications will be conducted during the Screening Period and 
throughout the study. Any medications taken by study subjects will be reviewed by the 
Investigator or Sponsor’s Medical Monitor to determine whether it is expected to interfere with 
study procedures or compromise subject safety and will be recorded in source documents and on 
the appropriate eCRF. 
10.1.2.
Physical Examination 
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 and extremities), and neurologic assessments. All physical 
examinations are to be conducted in adequate light. 
Changes from baseline in any physical examination findings identified by the Investigator as 
clinically significant must be recorded as an AE on the appropriate eCRF. 
10.1.3.
Comprehensive Skin Examination 
Each subject will receive a complete, comprehensive skin exam as part of Screening, prior to any 
treatment. If any concerning lesions are identified, the subject will be referred to a dermatologist 
for assessment and potential biopsy prior to study start. If the pre-treatment biopsy results are of 
concern, the subject will be excluded from the study. 
10.1.4.
Fitzpatrick Scale 
Each subject is to be categorized for skin type according to the Fitzpatrick scale (Fitzpatrick 
1975). The Fitzpatrick Scale is depicted in Appendix 14.1. 


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10.1.5.
Weight and Height 
Weight and height will be recorded at the time points designated in the SoA (Table 1) for the 
calculation of body mass index (BMI) as follows: 
ܤܯܫ(݇݃݉ଶ
⁄
) = ݓ݁݅݃ℎݐ (݇݃)
ℎ݁݅݃ℎݐ (݉)ଶ
10.1.6.
Vital Signs 
Vital signs include systolic and diastolic BP, HR, pulse rate, and tympanic (ear) body 
temperature (°C). BP and HR will be obtained in the supine position following at least 5 minutes 
of rest in the supine position at each timepoint designated in the SoA (Table 1). BP and HR will 
be measured using the same arm for each reading. Repeat measures and more frequent 
monitoring can be implemented for significant increases in BP or HR. 
For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be collected, 
ECGs should be collected first followed by vital signs then PK samples, with the timing of the 
PK sample occurring at the nominal time.    
10.1.7.
12-Lead Electrocardiogram (ECG) 
Continuous Holter 12-lead ECGs (for C-QTc analysis; collected by Holter monitors) and single 
12-lead safety ECGs will be obtained at the timepoints detailed in the SoA (Table 1). The 
following guidelines will be applied for ECG measurements obtained using a Holter monitor: 

ECG technicians should be thoroughly trained in the administration of a 12-lead ECG, 
the institution’s specific protocols and procedures for ECG tests and the requirements of 
the study protocol. 

ECG analysts will be blinded to the treatment, timepoint, and subject. 

The same make and model of ECG machine with the same style of leads should be used 
for all subjects. Such equipment should be recently serviced and calibrated. Machine 
calibration records and performance data should be maintained on file. 

Subjects should be in a supine position and have rested for 10 minutes before and 
5 minutes after each timepoint. 

For Holter ECG extractions, the ECG will be captured for 5 minutes after the subject has 
been supine for 10 minutes. The subject will remain supine for additional 5 minutes after 
the end of Holter extraction. 
Continuous Holter ECGs will be read with manual adjudication at a central laboratory. 
For timepoints at which vital signs, PK blood samples, and/or ECGs are all to be collected, 
ECGs should be collected first followed by vital signs then PK samples, with the timing of the 
PK sample to occur at the nominal time. 
10.1.8.
Columbia Suicide Severity Rating Scale (C-SSRS) 
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 mental 


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health professional [MHP]). Two versions of the C-SSRS will be administered according to the 
SoA (Table 1): 
1. The baseline/Screening version of the scale combines the Baseline and Screening forms 
to assess suicidality in a subject’s lifetime and during a predefined time. This version can 
assess a subject’s lifetime suicidality for data collection purposes as well as eligibility 
based on inclusion/exclusion criteria. 
2. The Since Last Visit version of the scale assesses suicidality since the subject’s last visit. 
This version is meant to assess subjects who have completed at least one 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 subject/participant 
may have had since the last time the C-SSRS was administered. 
To be eligible for the study, a subject cannot have a suicidal ideation of type 4 or 5 on the 
C-SSRS at Screening, a history of suicide attempt in the last 20 ears, or any suicidal behavior in 
the last month. 
Any deviation from the intended use of the instrument should be documented by the Investigator, 
along with the reason for the deviation.  
10.1.9.
Laboratory Assessments 
10.1.9.1.
Clinical Laboratory Tests 
Blood samples will be collected prior to dosing according to the SoA (Table 1). 
All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated per the judgment of the Investigator. 
Specific tests are described below: 

Hematology: complete blood count with platelet count and standard indices will be 
obtained. 

Chemistry: sodium, potassium, chloride, carbon dioxide (CO2), albumin, total protein, 
glucose, blood urea nitrogen (BUN), creatinine, uric acid, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), gamma-glutamyltranspeptidase (GGT), creatine 
phosphokinase (CPK), alkaline phosphatase, total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), calcium, phosphorus and magnesium. 

Coagulation Profile: prothrombin time (PT) or international normalized ratio (INR), and 
partial thromboplastin time (PTT), also referred to as activated partial thromboplastin 
time (aPTT). 

Urinalysis: 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. 


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10.1.9.2.
Virus Serology 
At Screening approximately 8 mL of blood will be withdrawn into a plain vacutainer for 
standard serological tests for the presence of human immunodeficiency virus infection (HIV), 
hepatitis B virus infection (HBsAg), and hepatitis C virus infection (anti-HCV). 
10.1.9.3.
Urine Drug Screen 
Urine screens will be conducted at Screening and at each CRU admission for drugs of abuse (at a 
minimum amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates), 
alcohol, and cotinine. A positive result for drugs of abuse or alcohol, or cotinine levels indicative 
of active smoking at any time will result in subject exclusion from the study. 
10.1.9.4.
Pregnancy Testing and Contraception 
Females of childbearing potential must not be pregnant and must have a negative serum 
pregnancy test result at the Screening Visit and negative urine pregnancy test on CRU admission 
days, with results known prior to initiating dosing; pregnancy testing will be monitored during 
the study. 
Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, 
bilateral oophorectomy, or bilateral tubal ligation), or post-menopausal for at least 12 months 
(and confirmed with a screening FSH level in the post-menopausal range) do not require 
contraception during the study. 
For females of childbearing potential, a highly reliable form of contraception must be 
used/practiced throughout the study and for 90 days following the study. Highly reliable 
acceptable forms of contraception include hormonal (i.e., oral, implantable, or injectable) and 
single-barrier method (i.e., condom), or an intrauterine device (IUD) and single-barrier method 
(i.e., condom) or vasectomized partner. True abstinence is acceptable only if it is the preferred 
and usual lifestyle of the subject. 
It is not known if setmelanotide 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 highly 
reliable method such as condom and diaphragm with spermicide during intercourse) if they 
become sexually active during the study and for 90 days following the study. True abstinence is 
acceptable only if it is the preferred and usual lifestyle of the subject. Male subjects must not 
donate sperm for 90 days following their participation in the study. 
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 procedures outlined in Section 10.2.4. 
Details of all pregnancies in female subjects and female partners of male subjects will be 
collected after the start of study treatment through 30 days after the last SC setmelanotide dose. 
Note that pregnancy itself is not considered a serious adverse event (SAE). However, abnormal 
pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, 
ectopic pregnancy) are considered SAEs. 


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10.2.
Adverse Events 
10.2.1.
Definition of Adverse Events and Serious Adverse Events 
10.2.1.1.
Adverse Event 
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether 
or not considered drug related. An adverse event (also referred to as an adverse experience) can 
be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a drug, without any judgment about causality. An 
AE can arise from any use of the drug (e.g., off-label use, use in combination with another drug) 
and from any route of administration, formulation, or dose, including an overdose. 
10.2.1.2.
Serious Adverse Event 
An AE or suspected adverse reaction is considered an SAE if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes: 

Death. 

Life-threatening. Life-threatening means that the subject was at immediate risk of death 
from the reaction as it occurred, ie, it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe form. 

In-patient hospitalization or prolongation of existing hospitalization. Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period but 
planned prior to study entry are not considered AEs if the illness or disease existed before 
the subject was enrolled in the study, provided that it did not deteriorate in an unexpected 
manner during the study (eg, surgery performed earlier than planned). 

A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 

Congenital anomaly/birth defect. 

Important medical event. An important medical event is an event that may not result in 
death, be life-threatening, or require hospitalization but may be considered an SAE when, 
based upon appropriate medical judgment, it may jeopardize the subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in the definitions 
for SAEs. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions 
that do not result in in-patient hospitalization, or the development of drug dependency or 
drug abuse. 
10.2.1.3.
Unexpected Adverse Drug Reaction 
An unexpected adverse drug reaction (ADR) is a reaction for which the nature or severity is not 
consistent with the product information (i.e., IMCIVREE (setmelanotide) Prescribing 
Information (2020)). Until product information is amended, expedited reporting is required for 
additional occurrences of the reaction. Reports that add significant information on specificity or 
severity of a known, already documented SAE constitute unexpected events. For example, an 


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event more specific or more severe than described in product label would be considered 
“unexpected”. 
10.2.2.
Relationship to Study Drug 
Relationship to study drug administration (setmelanotide or moxifloxacin, assessed separately) 
will be determined by the Investigator according to the following criteria. 

None: No relationship between the event and the administration of study drug. The event 
is related to other etiologies, such as concomitant medications or subject’s clinical state. 

Unlikely: The current state of knowledge indicates that a relationship to study drug is 
unlikely, the temporal relationship is such that study drug would not have had any 
reasonable association with the observed event or another reasonable explanation for the 
event (e.g., a pre-existing clinical condition or other concomitant treatment) is more 
likely. 

Possible: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The 
reaction might have been produced by the subject’s clinical state or other modes of 
therapy administered to the subject. 

Probable: A reaction that follows a plausible temporal sequence from administration of 
the study drug and follows a known response pattern to the suspected study drug. The 
reaction cannot be reasonably explained by the known characteristics of the subject’s 
clinical state or other modes of therapy administered to the subject. 
For the purpose of safety analyses, all AEs that are classified as possible or probable will be 
considered treatment-related events. 
10.2.3.
Severity of Adverse Events 
For both serious and non-serious AEs, the Investigator must determine both the intensity of the 
event and the relationship of the event to study drug administration. Only those injection site 
reactions considered clinically significant by the Investigator will be recorded as AEs. 
Intensity of all AEs including clinically significant treatment-emergent laboratory abnormalities, 
injection site reactions, and potential systemic reactions, where appropriate, will be guided per 
the Common Terminology Criteria for Adverse Events (CTCAE). 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). 
AEs not listed by the CTCAE will be graded as follows: 

Mild: discomfort noticed but no disruption of normal daily activity. 

Moderate: discomfort sufficient to reduce or affect daily activity. 

Severe: inability to work or perform normal daily activity. 

Life-threatening: represents an immediate threat to life. 


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10.2.4.
Procedures for AE and SAE Reporting 
Each subject must be carefully monitored for the development of any AEs. This information 
should be obtained in the form of non-leading questions (e.g., “How are you feeling?”) and from 
signs and symptoms detected during each examination, observations of study personnel, and 
spontaneous reports from subjects. 
All AEs (serious and non-serious) spontaneously reported by the subject and/or in response to an 
open question from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded on the appropriate eCRF. Any clinically relevant 
deterioration in laboratory assessments or other clinical findings is considered an AE and must 
be recorded on the appropriate eCRF. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event. 
All SAEs that occur during the study must be reported by the Investigator to the Medical 
Monitor 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 forms will be completed, and the information collected will include subject number, a 
narrative description of the event, and an assessment by the Investigator as to the severity of the 
event and relatedness to study drug. Follow-up information on the SAE may be requested by the 
Sponsor or its designee. 
If there are serious, unexpected adverse drug reactions associated with the use of the study drug, 
the Sponsor or designee will notify the appropriate regulatory agency(ies), Independent Ethic 
Committees (IECs) and all participating investigators on an expedited basis. It is the 
responsibility of the Investigator to promptly notify the Institutional Review Board (IRB)/IEC 
where required by the IRB/IEC of all unexpected serious adverse drug reactions involving risk to 
human subjects.  
10.2.5.
Adverse Event Monitoring and Follow-up 
Monitoring of AEs will be conducted throughout the study. AEs will be recorded in the eCRFs 
from Screening through the Follow-up visit. AEs that occur after the start of study drug 
administration will be considered treatment-emergent adverse events (TEAEs). SAEs will be 
recorded through the Follow-up visit. All AEs should be monitored until they are resolved. 
After the initial AE/SAE report, the Investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the subject is lost to follow-up. 
Any SAE that occurs at any time after completion of the study, which the Investigator considers 
to be related to study drug, must be reported to the Sponsor or designee. 
In the event a subject is withdrawn from treatment due to an AE, the subject should be 
encouraged to complete the final study/early termination visit to monitor the event to resolution 
and obtain additional protocol defined safety assessments. 


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10.2.6.
Depression or Suicidality 
A subject 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 subject. If a subject’s psychiatric disorder can be adequately treated with 
psycho- and/or pharmacotherapy, then the subject, at the discretion of the MHP, should be 
continued in the study. 
 
 
 
 
  
PPD


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11.
STATISTICS 
11.1.
Sample Size Determination 
11.1.1.
Sample Size for Setmelanotide C-QTc Analysis 
A sample size of 60 evaluable subjects who complete the study (20 subjects in Group 1 receiving 
SC setmelanotide and 20 subjects each in Groups 2 and 3 receiving SC placebo) will provide at 
least 85% power to exclude that setmelanotide causes more than 10 msec QTc effect at clinically 
relevant plasma levels, as shown by the upper bound of the 2-sided 90% confidence interval (CI) 
of the model-predicted QTc effect (∆∆QTcF) at the observed geometric mean Cmax of 
setmelanotide on Day 10 and Day 16 in the study individually. This power is estimated 
approximately using a 2-sample t-test using nQuery 8 (www.statsols.com). The calculation 
assumes a 1-sided 0.05 significance level, a small underlying effect of setmelanotide of 3 msec 
and a standard deviation (SD) of the ΔQTcF of 8 msec for both SC setmelanotide and SC 
placebo. Note that this calculation is conservative, since it does not take into account any gain in 
precision due to the use of all data from each subject with the help of a linear mixed effects 
model. The concentration-QTc analysis method is supported by Darpo (2015) and Ferber (2015). 
11.1.2.
Sample Size for Assay Sensitivity of C-QTc Analysis  
To demonstrate assay sensitivity with C-QTc analysis, it must be shown that the ΔΔQTcF of a 
single dose of 400 mg moxifloxacin exceeds 5 msec (i.e., the lower bound of the 2 sided 90% CI 
of the predicted QTcF effect [ΔΔQTcF] should exceed 5 msec) at the observed geometric mean 
Cmax of 400 mg moxifloxacin. Under the assumption that the predicted moxifloxacin QTc effect 
is 10 msec with a SD of ∆QTcF of 8 msec for both oral moxifloxacin and oral placebo, a sample 
size of 40 evaluable subjects in a crossover of moxifloxacin and placebo will provide at least 
81% power to demonstrate assay sensitivity with a 1-sided 0.05 significant level.  The power to 
detect the effect of moxifiloxicin on QTc over the entire crossover period is at least 86%.  This 
power is estimated approximately using a 2-sample t-test in nQuery 8 (www.statsols.com).  The 
number of 20 evaluable subjects in each sequence on moxifloxacin (40 over both Day 10 and 16) 
also agrees with recent recommendations of the FDA, which proposes at least 20 subjects 
(Huang 2019). 
11.2.
Analysis Populations 
The following populations are defined for this study: 

Safety Population: all subjects who received at least one dose of study drug (SC 
setmelanotide, SC placebo, oral moxifloxacin, or oral placebo). 

Pharmacokinetic Population: all subjects who received at least 1 dose of setmelanotide 
or moxifloxacin and have at least one quantifiable concentration of setmelanotide or 
moxifloxacin. A subject may be excluded from the PK summary statistics and statistical 
analysis if the subject has an AE of vomiting that occurs at or before 2 times the median 
Tmax during moxifloxacin dosing. 

QT/QTc Population: all subjects in the Safety Population with measurements at baseline 
as well as on-treatment with at least one post-dose timepoint with a valid ΔQTcF value. 


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The QT/QTc population will be used for the by-timepoint and categorical analyses of the 
cardiodynamic ECG parameters.  

PK/QTc Population: all subjects who are in both the QT/QTc and PK populations with 
at least 1 pair of post-dose PK and QTcF data from the same timepoint as well as subjects 
in the QT/QTc population who received placebo. The PK/QTc population will be used 
for the C-QTc analysis. The PK/QTc population will be defined for setmelanotide and for 
moxifloxacin.  
11.3.
Planned Analysis 
Separate statistical and PK analysis plans will be developed, which will include more technical 
and detailed descriptions of the statistical and PK analyses described in this section. This section 
is a summary of the planned statistical analyses of the most important endpoints, including 
primary and other endpoints. 
11.3.1.
Cardiodynamic ECG Assessment 
The primary analysis will be based on C-QTc modeling of the relationship between plasma 
concentrations of setmelanotide (or placebo) and ΔQTcF (using Day -1 time-matched Holter 
ECGs as baseline) with the intent to exclude an effect of ΔΔQTcF >10 msec at clinically relevant 
plasma levels, using the concepts presented in the “Scientific White Paper on C-QTc modeling” 
(Garnett 2018b, Garnett 2018a). After development of the C-QTc model and assessment of 
model performance through nonparametric bootstrapping, the ΔΔQTcF associated with the 
Cmax of therapeutic and supratherapeutic doses will be computed using bias-corrected 90% CI. 
An increase in QTc of ≥10 msec can be ruled out if the upper 90% CI is <10 msec.    
The change from baseline (Δ) and placebo-corrected change from baseline (ΔΔ) QTcF, HR, PR, 
and QRS will be summarized by nominal time and treatment using descriptive statistics. An 
analysis of categorical outliers will be performed for changes in QTcF, HR, PR, and QRS, and T-
wave morphology, and U-wave presence and results will be summarized.  
11.3.2.
Assay Sensitivity 
Assay sensitivity will be evaluated by C-QTc analysis of the effect on ΔΔQTcF of moxifloxacin 
using a similar model as for the primary analysis. Assay sensitivity will be deemed as met if the 
predicted QT effect (i.e., the lower bound of the 2-sided 90% CI of ΔΔQTcF) is above 5 msec at 
the observed geometric mean Cmax of 400 mg oral moxifloxacin. 
11.3.3.
Pharmacokinetic Analysis 
Setmelanotide and moxifloxacin plasma concentration versus time data will be summarized by 
treatment and nominal time using descriptive statistics (number of observations [n], mean, 
median, CV%, SD, minimum, and maximum). Individual and mean concentration versus time 
plots will be presented. 
PK parameters for setmelanotide will be calculated using noncompartmental methods and will 
include: Cmax, Tmax, AUClast, AUCtau, CL/F, and V/F. PK parameters from the PK 
populations will be summarized by treatment using descriptive statistics (including n, arithmetic 
and geometric mean, arithmetic and geometric CV%, SD, median, minimum, and maximum). 


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11.3.4.
Safety Analysis 
AEs will be coded by using the most current version of Medical Dictionary for Regulatory 
Activities (MedDRA) and summarized by system organ class, preferred term, and treatment 
group for the number and percent of AEs reported, the number of subjects reporting each AE, 
and the number of subjects with any AE. 
A by-subject AE data listing including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided. 
Safety data, including 12-lead safety ECGs, C-SSRS, clinical laboratory evaluations, vital signs, 
and concomitant medication monitoring will be summarized by time of collection and by 
treatment group. In addition, change from baseline to any post-dose values will be summarized 
for safety ECGs, C-SSRS, clinical laboratory results, and vital signs. Frequency of subjects with 
abnormal safety laboratory results will be tabulated by treatment. 
No formal statistical analysis of safety data is planned. 
 
 
 
 
 
 
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12.
ADMINISTRATIVE REQUIREMENTS  
12.1.
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on Harmonization 
for Good Clinical Practice (ICH-GCP) and the appropriate regulatory requirement(s). The 
Investigator will be thoroughly familiar with the appropriate use of the study drug as described in 
the protocol, IB, and labeling documents. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. Master files should 
be established at the beginning of the study, maintained for the duration of the study, and 
retained according to the appropriate regulations. 
12.2.
Ethical Considerations 
The study will be conducted in accordance with ethical principles founded in the Declaration of 
Helsinki. The IRB/IEC will review all appropriate study documentation in order to safeguard the 
rights, safety, and well-being of the subjects. The study will only be conducted at sites where 
IRB/IEC approval has been obtained. The protocol, IB, informed consent, advertisements (if 
applicable), written information given to the subjects, safety updates, annual progress reports, 
and any revisions to these documents will be provided to the IRB/IEC by the Investigator. 
12.3.
Subject Information and Informed Consent 
After the study has been fully explained, written informed consent will be obtained from the 
subject prior to study participation. The method of obtaining and documenting the informed 
consent and the contents of the consent will comply with ICH-GCP and all applicable regulatory 
requirement(s). 
12.4.
Subject Confidentiality 
In order to maintain subject privacy, all source documents/eCRFs, study drug accountability 
records, study reports, and communications will identify the subject by initials and the assigned 
subject number. The Investigator will grant monitor(s) and auditor(s) from the Sponsor or its 
designee and regulatory authority(ies) access to the subject’s original medical records for 
verification of data gathered on the source documents/eCRFs and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly available 
to the extent permitted by the applicable laws and regulations. 
12.5.
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol provided by the Sponsor 
and given approval/favorable opinion by the IRB/IEC and the appropriate regulatory 
authority(ies). Modifications to the protocol should not be made without agreement of both the 
Investigator and the Sponsor. Changes to the protocol will require written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is needed to 
eliminate an immediate hazard(s) to subjects. The IRB/IEC may provide, if applicable regulatory 
authority(ies) permit, expedited review and approval/favorable opinion for minor change(s) in 
ongoing studies that have the approval /favorable opinion of the IRB/IEC. The Sponsor or 


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designee will submit all protocol modifications to the regulatory authority(ies) in accordance 
with the governing regulations. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor, if circumstances permit, to discuss the 
planned course of action. Any departures from the protocol must be fully documented in the 
source documents/eCRF. 
12.6.
Data Management 
12.6.1.
Data Handling 
Data will be recorded at the site on source documents and reviewed by the Clinical Research 
Associate (CRA) during monitoring visits. The CRA will verify data recorded in the eCRF 
system with source documents. All corrections or changes made to any study data must be 
appropriately tracked in an audit trail in the eCRF system. eCRFs will be considered complete 
when all missing, incorrect, and/or inconsistent data have been accounted for. 
12.6.2.
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory 
requirements. 
12.6.3.
Data Entry 
Data must be recorded using the eCRF system as the study is in progress. All study site 
personnel must log into the system using their secure username and password in order to enter, 
review, or correct study data. These procedures must comply with Title 21 of the Code of 
Federal Regulations (21 CFR Part 11). All passwords will be strictly confidential. 
12.6.4.
Medical Information Coding 
For medical information the following thesauri will be used: 

Medical Dictionary for Regulatory Activities (MedDRA) for AEs 

World Health Organization (WHO) Drug for concomitant medications 
12.6.5.
Data Validation 
Validation checks programmed within the eCRF system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure 
accurate, consistent, and reliable data. Data identified as erroneous, or data that are missing, will 
be referred to the investigative site for resolution through data queries. 
Electronic CRFs must be reviewed and electronically signed by an Investigator who signed the 
protocol. 
12.7.
Direct Access to Source Data 
Monitoring and auditing procedures developed or reviewed and approved by the Sponsor will be 
followed, to comply with GCP guidelines. 


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The study will be monitored by the Sponsor or its designee. Monitoring will be done by personal 
on-site or remote visits from a representative of the Sponsor (site monitor) and will include 
review of the source documents/CRFs for completeness and clarity and cross-checking with 
source documents. Clarification of administrative matters will be performed, if necessary. The 
review of medical records will be performed in a manner to ensure that subject confidentiality is 
maintained. 
The site monitor will ensure that the investigation is conducted according to protocol design and 
regulatory requirements by frequent communications (letter, telephone, and fax). 
All unused study drug and other study materials are to be returned to the Sponsor or destroyed 
after the site close-out visit (see Section 8.4). 
Regulatory authorities, the IRB/IEC, and/or the Sponsor’s clinical quality assurance group or 
designee may request access to all source documents, CRFs, and other study documentation for 
on-site audit or inspection. Direct access to these documents must be guaranteed by the 
Investigator, who must provide support at all times for these activities. 
12.8.
Source Document/Case Report Form Completion 
Source documents/CRFs will be completed for each study subject. It is the Investigator’s 
responsibility to ensure the accuracy, completeness, and timeliness of the data reported in the 
subject’s source document/CRF. The source document/CRF should indicate the subject’s 
participation in the study and should document the dates and details of study procedures, AEs, 
and subject status. 
The Investigator, or designated representative, should complete the source document/CRF as 
soon as possible after information is collected, preferably on the same day that a study subject is 
seen for an examination, treatment, or any other study procedure. Any outstanding entries must 
be completed immediately after the final examination. An explanation should be given for all 
missing data. 
The Investigator must sign and date the Investigator’s Statement at the end of the source 
document/CRF to endorse the recorded data. 
The Sponsor will retain the originals of all CRFs. The Investigator will retain all completed 
source documents/CRFs. 
12.9.
Record Retention 
The Investigator will maintain all study records according to ICH-GCP and applicable regulatory 
requirement(s). Records will be retained for at least two years after the last marketing application 
approval or two 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 study records, custody must be transferred to a 
person willing to accept the responsibility. The Sponsor must be notified in writing if a custodial 
change occurs. 


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12.10.
Liability Insurance 
The Sponsor has subscribed to an insurance policy covering, in its terms and provisions, its legal 
liability for injuries caused to participating persons and arising out of this research performed 
strictly in accordance with the scientific protocol as well as with applicable law and professional 
standards. 
12.11.
Publication of Study Findings and Use of Information 
All information regarding setmelanotide supplied by the Sponsor to the Investigator is privileged 
and confidential information. The Investigator agrees to use this information to accomplish the 
study and will not use it for other purposes without consent from the Sponsor. It is understood 
that there is an obligation to provide the Sponsor with complete data obtained during the study. 
The information obtained from the clinical study will be used towards the development of 
setmelanotide and may be disclosed to regulatory authority(ies), other investigators, corporate 
partners, or consultants as required. 
It is the intention of the Sponsor and the academic investigators to publish the results of this 
study. 


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13.
LIST OF REFERENCES 
Darpo B, Benson C, Dota C, et al. Results from the IQ-CSRC prospective study support 
replacement of the thorough QT study by QT assessment in the early clinical phase. Clin 
Pharmacol Ther. 2015;97(4):326-335. 
Ferber G, Zhou M, Darpo B. Detection of QTc effects in small studies--implications for 
replacing the thorough QT study. Ann Noninvasive Electrocardiol. 2015;20(4):368-377. 
Fitzpatrick TB. Soleil et Peau. J Med Esthet. 1975: 33-34. 
Garnett C, Bonate PL, Dang Q, et al. Correction to: Scientific white paper on concentration-QTc 
modeling. J Pharmacokinet Pharmacodyn. 2018a;45(3):399. 
Garnett C, Bonate PL, Dang Q, et al. Scientific white paper on concentration-QTc modeling. J 
Pharmacokinet Pharmacodyn. 2018b;45(3):383-397. 
Huang DP, Chen J, Dang Q, Tsong Y. Assay sensitivity in "Hybrid thorough QT/QTc (TQT)" 
study. J Biopharm Stat. 2019;29(2):378-384. 
IMCIVREE (setmelanotide) Prescribing Information. Rhythm Pharmaceuticals, Inc. 2020. 
Accessed: May 3, 2021; 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213793s000lbl.pdf.  
Taubel J, Wong AH, Naseem A, Ferber G, Camm AJ. Shortening of the QT interval after food 
can be used to demonstrate assay sensitivity in thorough QT studies. J Clin Pharmacol. 
2012;52(10):1558-1565. 


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14.
APPENDICES 
14.1.
Appendix 1: 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; Middle Eastern skin types 
Very rarely burns, tans very easily 
VI 
Black 
Never burns, tans very easily 
Source: Fitzpatrick (1975)


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