A Phase 2, Randomized, Double-Blind, Placebo-controlled Pilot Study to Assess the Effects of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist, in Obese Subjects With Prader-Willi Syndrome (PWS) on Safety, Weight Reduction, and Food-Related Behaviors
Phase: PHASE2
Conditions: Prader-Willi Syndrome
Sponsor: Rhythm Pharmaceuticals, Inc.

CONFIDENTIAL 
 
Rhythm Pharmaceuticals, Inc. 
CLINICAL STUDY PROTOCOL 
 
Protocol RM-493-010 
 
A Phase 2, Randomized, Double-Blind, Placebo-controlled Pilot Study to 
Assess the Effects of RM-493, a Melanocortin 4 Receptor (MC4R) Agonist, in 
Obese Subjects with Prader-Willi Syndrome (PWS) on Safety, Weight 
Reduction, and Food-Related Behaviors 
 
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. 
 
Study Sponsor:  
 
Rhythm Pharmaceuticals, Inc. 
855 Boylston Street 
Boston, MA 02 16, USA 
 
 
 
Sponsor Signatory: 
 
Medical Monitor: 
 
 
Document Version (Date):  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIALITY NOTE 
The information contained in this document is privileged and confidential. Any distribution, 
copying, or disclosure is strictly prohibited unless such disclosure is required by federal 
regulations or state law.  Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
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5.3. Method of Assigning Patients to Treatment 
Patients who qualify for the study will return to the site on Day -1 (e.g., randomization will 
formally take place at the end of the placebo-controlled run-in period, after compliance during 
the run-in period is assessed). Prior to randomization, the Investigator will ensure that the patient 
continues to meet inclusion and exclusion criteria, and perform all pre-dose procedures. Once a 
patient is determined to be eligible for randomization by the Investigator, the Investigator or the 
Investigator’s research staff will randomize the patient according to a centralized randomization 
process.   
Note all patients will be pre-randomized to their status/treatment group for the randomized 
withdrawal part of the protocol at the initial randomization.   
5.4. Blinding, Packaging, and Labeling 
5.4.1. Blinding and Breaking the Blind 
This is a randomized, double-blind, placebo-controlled study. Blinding and randomization will 
be accomplished so that all study-related staff remain blinded to patient assignation.   
The Investigator, study site staff, clinical research organization staff providing site management, 
and Medical Monitor will not have access to the randomization scheme during the study except 
in the case of an emergency.  Breaking the blind for a patient should be done only in the event of 
a medical emergency where the identity of study drug is necessary to appropriately treat the 
patient.  The request to break the blind should be discussed with the Medical Monitor and 
Rhythm, whenever possible.  If the blind is broken, the reason, when and how the blind was 
broken will be documented.  Every attempt will be made to maintain the blind throughout the 
study. 
5.4.2. Packaging and Labeling 
Study drug is provided in single-use vials.  The study drug is supplied in glass vials and is 
provided in kits according to the randomization schedule for patients enrolled in the study.  All 
study drugs, including placebo for practice, will be supplied by Rhythm. 
Packaging and labeling will be prepared to meet all regulatory requirements. 
5.5. Duration of Patient Participation 
The overall study duration will be approximately 12 months, as currently planned.  Individual 
patient participation in the study (Screening Period, Run-in, Treatment Period, withdrawal 
period, open label optional extension and Follow-up Period) will be approximately 5 months.   
Screening, inclusive of the placebo practice period, will occur within 30 days prior to entry into 
the single-blind placebo-run in period. 
5.6. Assessment of Treatment Compliance 
In order to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the 
study drug, it is critical that patients receive study drug as directed.  All used vials and syringes 
will be collected to assess compliance with the protocol. 
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Table 6-1: 
Schedule of Assessments (continued) 
1 
A complete physical examination will be conducted at Screening (or at the discretion of the site, at Day -1), and Day 90.    Height will be 
measured during the Screening Period only. 
2 
A comprehensive skin evaluation will be performed by a dermatologist.  Any concerning lesions identified during the screening period will 
be biopsied and results known to be benign prior to randomization.  If the pre-treatment biopsy results are of concern, the patient will be 
excluded from the study.   
3 
Randomization to occur after all pre-dose procedures completed on Day 15.   
4 
The screening and run in can be scheduled on the same day, as long as the lab results are back in time for the start of run-in phase.  Study 
procedures required to be performed in the Screening Visit and also required in the Baseline visit per the SOA should be performed in the 
Screening portion of the single visit and do not need to be repeated during the Baseline ortion of the visit..  Study personnel will still need to 
record two separate visits in required study documentation, but both visits will have the same date. 
5 
On Day 1, prior to the initial injection of run-in single blind study drug.  
6 
Clinic Visit Schedule:  For Days 1-14 (run-in) patients will receive a telephone ontact approximately 1 week into the Run-In; During the 
double blind 4-week treatment period (Days 15 to 42), there will be an optional in clinic or telephone contact visit at ~2 weeks into the 
treatment period (~Day 28 ± 2 days). There will be a clinic visit at the nset of  Withdrawal Period (~Day 42 ± 2 days); at the end of the 2-
week randomized withdrawal period (~Day 56 ± 2 days), at the end of th  optional open label period (~Day 70 - 2 days or +4 days) and at the 
poststudy visit (~1-3 months after last active dose).   
7 
The Fitzpatrick assessment will be performed. 
8 
Telephone contact weekly by site for any visit more than 1 week apart.  
10 Weight is to be measured using the same scale after patients have emptied their bladder and while fasting.  Patients are to wear scrubs or 
equivalent, no shoes, and will be weighed at approximately the same time of day.  Weight measurements are to be done in 
 
11 Extra retain samples (2 red top and 2 purple top vacutainer) will be taken pre-dose prior to double-blind study drug, and at the end of the 4-
week double blind treatment period before first dose of the withdrawal period. 
12 Study drug is administered by patients/caretakers beginning the morning of Day 1 through to Day 70 (-2 days, +4 Days); e.g., the last day of 
Optional Extension).  Patients/caretakers, including home health practitioners, will draw up and self-administer/administer the drug on a daily 
basis. Home health practitioners may draw up study drug into syringes for storage in refrigerator for up to 2-days in advance, if desired, for 
patient/caretaker self-administration.  On days with clinic visits, the patients/caretaker will administer the drug at the clinic in the presence of 
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the clinical staff.  Patients/caretakers will return all empty syringes and vials to the clinic when they visit (the number recorded) and both 
clinic administered study drug, as well as outpatient study drug administration will be recorded by the patient in a study diary.   
13 Injection site evaluations and scoring (by the clinical staff) will include identification and measurement of areas of erythema, edema and 
induration, as well as the presence of localized pain, tenderness and itching.  Additional evaluation data can be collected at any visit where 
there are injection site reactions even if not a timepoint for formal assessment.   
14 All BP and HR measurements are to be obtained in the sitting position following at least 5 minutes of rest.  All measurements will be taken in 
triplicate, approximately 2 minutes apart.  On Day 1 and Day 14, patients will have vitals obtained pre-dose.  When possible, BP should be 
taken in the same arm throughout the study, using the same methodology (automated or manual).  Body temperature (°C) and respiration rate 
(breaths/minute) will be obtained in the sitting position following at least 5 minutes of rest.   
15 On Treatment Day 15, at the end of the single-blind placebo run-in but prior to beginning dosing in the 4 week double blind treatment period. 
16 A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest, at Screening, on Day 42 and 
at poststudy. 
17 Safety laboratories to be collected at screening.  Safety laboratories also to be collected on Day 15, 28 (if clinic visit occurs) 42, Day 70 and 
at Poststudy.  CBC 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), urinalysis with microscopic analysis if positive findings on dipsticks warrant further examination.  Fasting samples (8 hr 
minimum) are required at all timepoints where feasible in this population  
18 A blood sample for PK will be drawn within 5 minutes before d sing on Day 42 and Day 70 (during the clinic visit) for each patient.  These 
PK samples will be drawn with patients/caretakers being reminded there should be NO study drug administration at home; the drug will be 
administered in the clinic AFTER the PK sample is obtain d.  For the PK sample, the actual collection (clock) time will be recorded, as well 
as the time of the previous day’s study drug injection time as reported by the patient/caretaker.   Exception: patients who participate in the PK 
substudy between Days 63 and 69 do not ne d to have PK repeated on Day 70 visit. 
19 Adverse events will be recorded from the time a p tien  provides informed consent.  Adverse events reported after randomization will be 
considered as treatment-emergent adverse events. 
20 Questionnaires and other assessments include the Dykens Hyperphagia, 
 Food-
Related Problems Questionnaire,
 and Symptom and Global 
Assessments.  
21 Basal metabolic rate for baseline should be obtained ONCE during screening or during the 14 day double-blind placebo-controlled run-in, but 
must be completed before initiation of the first dose of the 4-week double blind treatment period.  Post-dose basal metabolic rate should be 
assessed ONCE during the 4-week double blind treatment period, preferably on Day~ 42± 2 days and once during open label treatment 
period, preferably on day 70 (-2, +4 days). 
22  Performed or collected on visits where starting (or changing) the study drug treatment.  DEXA may be performed prior to or after treatment 
administration.   
23  To be performed only if visit performed in clinic; an in-clinic visit is recommended. 
24  Follow-up visit to be conducted 1- 3 months after completion of treatment 
25 Starting on any day from Day 63 through 69 (the second week of the optional open-label, active-dose extension period), a substudy of 
patients will have a 24-hour PK profile obtained (as outlined in a separate PK manual). Blood samples will be collected at 0 (within 5 minutes 
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BEFORE dosing), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing. The samples collected at 1 and 2 hours will be collected within 5 
minutes of the scheduled time; the samples at 4 to 12 hours will be collected within 10 minutes of the scheduled time, and the 24-hour sample 
will be collected within 10 minutes BEFORE the next dose of study drug. For each PK sample, the actual collection (clock) time will be 
recorded. 
26  On day 15, urine pregnancy test to be performed prior to dosing for the 4 week double blind treatment period; all other pregnancy testing 
time points will be obtained from serum. 
 
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6.2. Patient Requirements 
6.2.1. Contraception 
RM-493 has not been evaluated in any pre-clinical Developmental and Reproductive Toxicology 
Studies to date, therefore, the effects of RM-493 on embryo-fetal development are unknown at 
this time. It is imperative all study subjects adhere to the contraception requirements as outlined 
below.   
Females must not be pregnant and must have a negative serum pregnancy test result at the 
Screening Visit and Day 1 with results known prior to initiating the injection, and pregnancy 
testing will be monitored during the study. 
For females able to bear children, a hormonal (i.e., oral, implantable, or injectable) and single-
barrier method (i.e., sponge), or a double-barrier method of birth control (i.e., condom with 
spermicide) or abstinence must be used/ practiced throughout the study and for 90 days 
following 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. 
It is not known if this treatment will affect spermatogenesis.  Therefore, males with female 
partners of childbearing potential must agree o use contraception (e.g., if they ;have not had a 
vasectomy then should either (a) abstain from reproductive sexual intercourse or (b) use a 
condom and contraceptive foam during intercourse) if they become sexually active during the 
study and for 90 days following the study. Male subjects must not donate sperm for 90 days 
following their participation in the study  
6.2.2. Protection from Sun 
Skin hyperpigmentation, or ta ning, was observed in the cynomolgus monkey toxicology 
studies, and the human Phase 1/2 studies.  These events were reversible upon cessation of study 
drug.  However, it is still uncertain if exposure to sunlight might exacerbate the tanning effects of 
RM-493. 
It is also important that patients do not participate in any activities that will intentionally cause 
their skin to tan (e.g.; visit UV tanning salons, use spray tanners, self-tanning lotions, etc.). 
6.3. Efficacy Measurements 
6.3.1. Weight 
Weight (Kg) will be recorded as shown in the Schedule of Assessments (SOA), and generally 
will be assessed and recorded once weekly.  All measurements will be done in triplicate at each 
timepoint.  The same scale should be used throughout the study, including the Screening Visit, 
and should be calibrated on a regular basis.  Weight should be measured when patients are 
fasting and at approximately the same time at each visit.  Patients should be in underwear or 
scrubs (or equivalent), with no shoes and have emptied their bladder.    
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6.3.3. Body Composition DEXA 
Participants will have three DEXA procedures to measure body compositions over the course of 
the study.  DEXA uses low dose x-rays to non-invasively assess skeletal and soft tissue density.  
Half-body scans may be performed for subjects that extend beyond the scanning area. The risk 
associated with exposure to ionizing radiation is minimal and further minimized through the 
exclusion of pregnant women. 
6.4. Clinical Procedures and Safety Assessments 
6.4.1. Informed Consent 
A complete description of the study is to be presented to each potential patient and signed and 
dated informed consent is to be obtained before any study specific procedures are performed.   
6.4.2. Demographics and Medical History 
A complete medical history along with demographic data will be obtained for all patients during 
the Screening Period.  Data to be recorded in the source document and CRF include the patient’s 
gender, race, date of birth and concomitant medication use. 
A recent medical history will be obtained on Day 1 prior to randomization to assess continued 
study eligibility and adherence to final inclusion/exclusion criteria.  This recent medical history 
includes a review for changes from screening as well as a review of the patient’s recent 
medication use and to assess whether or not any changes have occurred since the previous visit. 
6.4.3. Physical Examination, Comprehensive Skin Examination, and Height 
Physical Examinations 
A complete physical examination will include review of peripheral lymph nodes, head, eyes 
(including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, lungs, abdomen, 
musculoskeletal including back, extremities and neurologic, will be performed during the 
Screening Period (or at the discretion of the site, can be performed at Day -1), and at the Final 
Study Visit.   
Abbreviated symptom-directed physical examinations (e.g., general, heart, lungs, abdomen, skin 
(not comprehensive), and extremities) will be performed during the Treatment Period, and follow 
up period as shown in the SOA.   
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 adverse event (AE) on the appropriate CRF. 
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Comprehensive Skin Examinations 
Comprehensive skin examinations will be performed by a Dermatologist.  Comprehensive skin 
exams will be performed according to the SOA.   
At screening, a specific focus of the comprehensive skin examination will be the identification of 
any skin lesions that appear to have dysplastic or malignant potential that could interfere with the 
interpretation of study outcomes regarding skin changes.  In such cases, the patient will be 
excluded from the study.  However, any lesions of concern can be biopsied and if confirmed to 
be benign prior to randomization, patients can be enrolled in the study.   
In the event a patient experiences changes to skin or skin lesions that are unresolved (or have not 
significantly improved or are close to resolution) at the Final Study Visit, the patient may be 
asked to return for additional follow up assessments to document progress towards resolution for 
~60-90 days after last treatment. 
Height 
Height (cm) will be measured  without shoes, during Screening using a wall-mounted 
stadiometer. 
6.4.4. Fitzpatrick Scale 
Each patient is to be categorized for skin type according to the Fitzpatrick scale [18] during the 
Screening Period.  The Fitzpatrick Scale is depicted in Appendix 11.5. 
6.4.5. Concomitant Medication Review 
A review of concomitant medications will be conducted during the Screening Period and at every 
study visit.  Any medications taken by study patients will be recorded in source documents and 
on the appropriate CRF. 
6.4.6. Vital Signs 
Vital signs will be obtained in the sitting position following at least 5 minutes of rest each time 
they are measured, at the times outlined in the SOA.   
Blood pressure and heart rate 
Blood pressure (BP; mmHg) and heart rate (HR; bpm) are to be measured according to the SOA.  
At each timepoint, BP and HR measurements will be performed in triplicate approximately 2 
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minutes apart, using the same methodology throughout the study (manual or automated).  
Careful attention should be paid to using an appropriately sized BP cuff.  
When possible, BP should be taken in the same arm throughout the entire study period. 
Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR.   
Body temperature and respiration rate 
Body temperature (°C) and respiration rate (breaths/minute) will be obtained in the sitting 
position following at least 5 minutes of rest according to the SOA. 
6.4.7. 12-Lead Electrocardiogram 
Single 12-lead electrocardiograms will be performed following a period of at least 10 minutes of 
rest in the supine position according to the SOA. 
6.4.8. Clinical Laboratory Tests 
Clinical safety laboratory tests are to be performed by the local laboratory as outlined in the 
Schedule of Assessments and patients are to be fasting for 8 hours.  Labs are to be drawn prior to 
dosing.  
All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated according to the judgment of the Investigator.   
Liver function test abnormalities will be evaluated in accordance with FDA Guidance (2009) as 
described in the Appendix 11.8.   
Specific tests are described below. 
6.4.8.1. 
Hematology  Clinical Chemistry and Urinalysis 
Hematology: 
Complete blood count with platel t count and standard indices will be obtained. 
Chemistry: 
Sodium, potassium, chloride, 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. 
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. 
6.4.8.2. 
Serum Samples for Storage 
Extra retain samples will be taken pre-dose prior to double-blind study drug, and at the end of the 
4-week double blind treatment period and will be used only in the event that unscheduled 
diagnostic tests are required for safety reasons, or for
that are currently not defined 
but are directly related to the aims of this study.  These samples will be retained until the study 
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has been completed, and until the Sponsor has notified the study site in writing that the samples 
can be discarded. 
6.4.9. Injection Site Evaluation and Scoring 
Injection sites will be carefully inspected, evaluated and scored during the study period. The 
injection site evaluation will include identification and measurement of areas of erythema, edema 
and induration, as well as the presence of localized pain, tenderness and itching.  A sample 
injection site evaluation form is included in the Appendix. 
Injection site evaluations and scoring will be conducted according to the SOA.  In addition, 
unscheduled evaluations may also be recorded as warranted by clinical conditions. 
6.4.10. Anti-RM-493 Antibody Measurements 
Blood samples for measurement of anti-RM-493 antibodies will be drawn pre-dose, and 
thereafter according to the SOA. 
6.4.11. Patient Questionnaires 
The patient questionnaires will be answered by the patient and/or caretaker after careful training. 
PWS Hyperphagia Questionnaire (Dykens, 2014) 
The PWS Hyperphagia Questionnaire is a tool for assessing hyperphagia-related behavior and 
will be a primary endpoint of the study, evaluated at both the end of the 4-week double-blind 
treatment phase, and again at the end of the 2-week randomized double-blind withdrawal phase.  
Food Related Problems Questionnaire (Russell 2003) 
The Food-Related Problems Questionnaire is a tool specifically designed for patients with 
Prader-Willi Syndrome to rate preoccupation with food, impairment of satiety, difficulty with 
self-control and other food-related ‘challenging’ behavior.  
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