Clinical trial NCT02311673
Conditions: Prader-Willi Syndrome
Keywords: Prader-Willi Syndrome obesity hyperphagia
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2015-03-19; Completion date: 2016-10-26
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to evaluate the effects of a once daily subcutaneous injectable formulation of setmelanotide in obese participants with Prader-Willi syndrome on tolerability, weight loss, and hyperphagia-related behavior. The study drug (setmelanotide and placebo) was administered in a blinded fashion.

Detailed description:

Arms: arm 1: Participants received setmelanotide 0.5 milligrams (mg) once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period) and Day 42 to Day 55 (2-week, randomized withdrawal period). arm 2: Participants received setmelanotide 1.5 once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period), Day 42 to Day 55 (2-week, randomized withdrawal period), and Day 56 to Day 69 (optional 2-week, open-label extension period). arm 3: Participants received setmelanotide 2.5 once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period), Day 42 to Day 55 (2-week, randomized withdrawal period), and Day 56 to Day 69 (optional 2-week, open-label extension period). arm 4: Participants received placebo matched to setmelanotide once daily as a subcutaneous injection from Day 1 to Day 14 (2-week, single-blind run-in period), Day 15 to Day 41 (4-week, double-blind randomized treatment period), and Day 42 to Day 55 (2-week, randomized withdrawal period).
Interventions: intervention 1: Setmelanotide intervention 2: Placebo
Intervention descriptions: intervention 1: subcutaneous injection intervention 2: Subcutaneous injection

Protocol documents:
Prot_000.pdf: 
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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SAP_001.pdf: 
   
Rhythm Pharmaceuticals, Inc. 
 
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 
Statistical Analysis Plan 
Final Version 2.1 
Date: June 2, 2016 




Protocol RM-493-010 
 
Statistical Analysis Plan 
 
 
 
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TABLE OF CONTENTS 
 
1 
INTRODUCTION ................................................................................................ 7 
2 
STUDY OBJECTIVES ........................................................................................ 7 
2.1  Primary Objectives ............................................................................................... 7 
2.2  Secondary Objectives ........................................................................................... 8 
2.3  Exploratory Objectives ......................................................................................... 8 
3 
INVESTIGATIONAL PLAN ............................................................................... 8 
3.1  Overall Study Design and Plan ............................................................................. 8 
3.2  Randomization Methodology ............................................................................. 10 
3.3  Efficacy Endpoints and Safety Parameters ......................................................... 12 
3.3.1 Primary Efficacy Endpoint ....................................................................... 12 
3.3.2 Secondary Efficacy Endpoints .................................................................. 12 
3.3.2.1  Key secondary efficacy endpoint: ............................................... 12 
3.3.2.2  Additional Secondary endpoints are: .......................................... 12 
3.3.4 Safety Endpoints ....................................................................................... 13 
3.3.5 Pharmacokinetic Endpoints ...................................................................... 14 
3.4  Analysis Populations .......................................................................................... 14 
4 
STATISTICAL METHODS ............................................................................... 15 
4.1  Sample Size Justification .................................................................................... 15 
4.2  General Considerations ....................................................................................... 15 
4.2.1 Derived Data ............................................................................................. 16 
4.2.2 Handling of Missing Data ......................................................................... 17 
4.2.3 Visit Windows .......................................................................................... 18 
4.2.4 Multiplicity ............................................................................................... 18 
4.2.5 Baseline Definition ................................................................................... 18 
4.3  Statistical Hypothesis .......................................................................................... 19 
4.4  Study Patients ..................................................................................................... 19 
4.4.1 Disposition of Patients .............................................................................. 19 
4.4.2 Summary of Populations and Protocol Deviations ................................... 20 
4.4.3 Demographic and Disease Characteristics ................................................ 20 
4.4.4 Study Drug Administration ....................................................................... 20 
4.4.5 Medical History ........................................................................................ 20 
4.4.6 Concomitant Medications ......................................................................... 20 
4.5  Efficacy Endpoints and Analyses ....................................................................... 21 
4.5.1 Primary Efficacy Endpoints ...................................................................... 21 
4.5.1.1  Primary Analysis ......................................................................... 21 
4.5.2 Secondary Efficacy Endpoints .................................................................. 22 
4.5.2.1  Key secondary efficacy endpoints ............................................... 22 
4.5.2.2  Secondary endpoints .................................................................... 23 
4.6  Subgroup Analyses ............................................................................................. 27 
4.7  Correlation and
4.8  Safety Analyses .................................................................................................. 28 


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4.8.1 Adverse Events (AEs) ............................................................................... 28 
4.8.2 Clinical Laboratory Evaluations ............................................................... 29 
4.8.3 Vital Signs ................................................................................................. 30 
4.8.4 Physical Examinations .............................................................................. 30 
4.8.5 ECG........................................................................................................... 30 
4.9  Pharmacokinetic Evaluation ............................................................................... 30 
4.10 
Interim Analysis ........................................................................................ 30 
4.11 
Patient Profiles .......................................................................................... 30 
5 
REPORTING OUTPUT ..................................................................................... 31 
6 
APPENDICES .................................................................................................... 33 
Appendix 1: 
Schedule of Assessments .......................................................................... 34 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
°C 
Degrees Celsius 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BID 
bis in die or twice a day 
BUN 
Blood urea nitrogen 
CBC 
Complete blood count 
cm 
Centimeter 
CPK 
Creatine Phosphokinase 
CRO 
Contract Research Organization 
DEXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
FAS 
Full Analysis Set 
FRPQ 
Food related problems questionnaire 
GGT 
Gamma-glutamyltranspeptidase  
IA 
Interim analysis 
iSAP 
Interim statistical analysis plan 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LFT 
Liver function test 
MAD 
Multiple ascending dose 
MC4R 
Melanocortin 4 receptor 
MedDRA 
Medical dictionary for regulatory activities 
mg 
Milligram 
ORO 
Observer reported outcome 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PWS 
Prader-Willi Syndrome 
QD 
qua´que di´e or every day 
QoL 
Quality of life 
SAE 
Serious adverse event 
SAF 
Safety Set 


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SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
WBC 
White blood count 
 


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1 
INTRODUCTION 
This document presents the statistical analysis plan (SAP) for Rhythm Pharmaceuticals, Inc. 
(Rhythm), Protocol No.  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. 
It contains the details and methods to be used to perform the proposed efficacy and safety 
analyses, including planned summary tables and by-patient listings. 
This SAP was based on 
.  The 
reader of this SAP is encouraged to also read the clinical protocol, and other relevant 
documents for details on the planned conduct of this study.  Other than the schedule of study 
procedures which is provided in Appendix 1, operational aspects related to collection and 
timing of planned clinical assessments are not repeated in this SAP unless relevant to the 
planned analyses. 
The objectives listed below (primary, secondary and exploratory) are found in the protocol.   
Study RM-493-010 is a Phase 2 study designed to provide the basis for pivotal data in a 
Phase 3 study or studies to follow.  The PWS population is very rare, and patients are 
difficult to identify and recruit.  Therefore the number of participants studied will be small.   
In addition, there is no precedent for an approved effective treatment for the hyperphagia and 
obesity of PWS.  As a consequence, endpoints have not been well studied, and key questions 
on tools, endpoints, populations, age-related effects, and other parameters remain to be 
answered.  This study has been designed to explore these questions, and to provide a 
rationale for a more robust Phase 3 study design.  As a result of the small number of patients 
and the lack of clarity on clinically important endpoints for PWS, this study includes 
numerous endpoints for which no multiplicity adjustment is planned.  It will also include an 
interim analysis when approximately half the patients have been randomized, with the 
likelihood that study parameters may be altered and adjusted to reflect additional 
understanding of the effects of setmelanotide in this population.  This approach is justified 
given the evolving understanding of PWS and any information and/or conclusions will be 
confirmed in a prospective, rigorous Phase 3 study or studies to follow.   
2 
STUDY OBJECTIVES 
2.1 
Primary Objectives 
After 4 weeks of double-blind study drug treatment, the primary objectives of this study are 
to: 
 To assess safety and tolerability of RM-493  
 To assess the effect of RM-493 on weight loss 
 To assess the effect of RM-493 on hyperphagia-related behavior using the PWS 


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Hyperphagia Questionnaire 
2.2 
Secondary Objectives 
The key secondary objectives are to: 
 Evaluate the changes in quality of life, other hyperphagia- and food-related behavior, 
and/or psychiatric status 
 To evaluate the pharmacokinetics of RM-493 in Prader-Willi patients (substudy) 
 To assess the effect of RM-493 during a 2-week, double-blind, randomized 
withdrawal period 
 To assess the percent change in body mass by DEXA in the active treatment group 
compared to the placebo group 
 To assess the percent change in fat content by DEXA in the active treatment group 
compared to the placebo group 
 
3 
INVESTIGATIONAL PLAN 
3.1 
 Overall Study Design and Plan 
This will be a randomized, double-blind, placebo-controlled, parallel group study.  It will 
consist of 4 sequential periods:  
(1)  
2-week single-blind, placebo-controlled baseline period; and 
(2) 
4-week, double blind, placebo-controlled, randomized parallel group period (primary 
analysis time point) where patients will be randomized 2:1:3 to placebo or one of two dose 
levels of RM-493; and  


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(3)  
2-week, double-blind, randomized withdrawal period where half of each RM-493 
group will remain on the same dose of active drug and the other half will receive placebo, and 
half of the placebo group will receive RM-493; and   
(4)  
an optional 2-week open label extension period where every patient can participate and 
receive open label RM-493. 
 
The active doses to be studied in the trial are RM-493 1.5 mg and RM-493 0.5 mg QD 
(administered in the morning) by SC injection. 
 
Approximately 20 subjects will be randomized to a placebo arm or one of 2 dosing arms.  
Subjects will initiate with 2 weeks of single blind placebo lead-in phase (period 1), after which 
they will be randomized 2:1:3 to receive daily SC doses of RM 493 or placebo for 4 weeks. 
Based on the results of the interim analysis, in the second half of the study, for approximately 
16 subjects, active doses will be increased to 1.5 mg of RM-493 and 2.5 mg of RM-493 with 
matching placebo in a 2:1:3 allocation (Placebo/low dose/high dose). 
After completion of the primary 4-week, double-blind treatment period (period 2), a double-
blind randomized placebo withdrawal period (period 3) will initiate:  patients in each of the 
RM-493 groups will be randomized 1:1 to either continue with the same dose or begin 
placebo treatment.  The patients in the placebo group during the 4 week primary treatment 
period would also be randomized 1:1 during the randomized withdrawal phase (period 3) to 
continue on placebo or to receive RM-493 at the corresponding dose/volume established 
during periods 1 and 2.   
A follow-up open label extension phase of the trial (after the initial 4 weeks of study duration 
and the 2-weeks of randomized withdrawal) will be available for patients who completed the 
trial and wish to continue in the 2-week open label extension.  For this final treatment period, 
all subjects will receive 2.5 mg (150 mcl) of RM-493 for 2 weeks. 
The overall study duration will be approximately 12 months; individual patient participation 
will be approximately 5 months (from Screening period through OL follow-up period).   
Study patients will receive study drug by SC injection for up to 10 weeks (either RM-493 or 
placebo, if including the single-blind placebo run in, the 4 week double blind treatment 
period, the 2-week randomized withdrawal period, and the optional open label active drug 
extension).  Patients and/or their caretakers will be responsible for all procedures for study 
drug administration at all times, i.e., drawing up, and self-administering the study drug once 
daily (including during the practice periods (see below).   
In addition, a substudy of up to N=8 patients may participate in a pharmacokinetic substudy. 
Patients who participate in this substudy would be required to spend ~12 hours in the clinic 


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(during second week of the optional open-label, active-dose 2-week extension period), and 
return the next day for one additional assessment for pharmacokinetics. 
Two study diagrams are presented 
 Figure A: First Half of Study Schema of Dose Allocation (original protocol through 
Amendment 4) 
 
 
Figure B: Second Half of Study Schema of Dose Allocation (after Interim Analysis) 
 
 
3.2 
Randomization Methodology 
In the first half of the study, approximately 20 subjects will be randomized to a placebo arm 
or one of 2 dosing arms in a 2:1:3 allocation.  Based on the results of the interim analysis, in 
the second half of the study, for approximately 16 subjects, active doses will be increased to 
1.5 mg of RM-493 and 2.5 mg of RM-493 with matching placebo.  After completion of the 
primary 4-week, double-blind treatment (period 2), a double-blind, randomized placebo 




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maintain balance between treatment groups having a small sample size, replacements will 
have the same treatment as the original randomized patient being replaced, via a system 
(IWRS) randomization.  Patients who discontinue from the study or study treatment 
prematurely after receiving at least one dose of the study drug will not be replaced. 
Study drug will be packaged in kits with approximately a weekly supply, and uniquely 
identified to allow blinded assignment by the study staff.  Note that everyone will receive 
placebo during the run-in period, and everyone will receive active drug during the optional 
open label active drug extension. 
   
3.3 
Efficacy Endpoints and Safety Parameters      
All primary and key secondary endpoints are analysed during Period 2, the 4-week double 
blind period of the study.  Other secondary endpoints (for which data are available) are 
assessed during Period 3 (the randomized withdrawal) and Period 4 (open label active 
extension).   
3.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoints are the: 
 Body weight (kg): Percent change from baseline (Period 2) 
 PWS Hyperphagia Questionnaire: Percent Change from baseline (Period 2) 
Overall Score 
3.3.2 Secondary Efficacy Endpoints 
3.3.2.1 Key secondary efficacy endpoint: 
 Body weight (kg): Change from baseline (Period 2)  
 PWS Hyperphagia Questionnaire: Percent Change/Change from baseline (Period 
2)  
o Overall Score (Change from Baseline only – Period 2) 
o 3 domains 
 Hyperphagic Drive 
 Hyperphagic Behaviors 
 Hyperphagic Severity 
o Individual Questions 
 DEXA (body fat): Percent Change/Change from Baseline (Period 2)  
 DEXA (body mass): Percent Change/Change from Baseline (Period 2)  
3.3.2.2 Additional Secondary endpoints are: 
 Body weight (kg): Percent Change/Change from baseline (Period 3) (Period 4) 


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 Body weight (kg): Percent Change/Change from baseline (Period 2/3) for 
continuous active and continuous placebo treatments 
 PWS Hyperphagia Questionnaire: Percent Change/Change from baseline (Period 
3) (Period 4) 
 DEXA (body fat): Percent Change/Change from Baseline (Period 4)  
 DEXA (body mass): Percent Change/Change from Baseline (Period 4) 
3.3.4 Safety Endpoints 
Safety and tolerability of RM-493 will be assessed throughout the study.   
Safety and tolerability endpoints include: 
 AE review 
 Injection Site Evaluation 
 Clinical laboratory safety tests (subset) including: 
o Hematology:  Hemoglobin, Hematocrit, WBC, Platelets 
o Chemistry: Bun, Creatinine,  Potassium, ALT, AST, Total Bilirubin, 
Alkaline phosphatase, GGT, CPK, Glucose 
 Vital signs 


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 ECG evaluations 
 Physical examination, Comprehensive Skin Examination, and Height 
 Concomitant medication  
 
3.3.5 Pharmacokinetic Endpoints 
Blood samples for measurement of plasma RM-493 will be collected from all patients on 
Day 1 pre-dose and within 5 minutes before study drug is administered on Day 42. 
Additionally, in a subset of patients participating in the optional PK substudy, (any day from 
Day 63 through Day 69), PK samples may be collected pre-dose and at selected time points 
for up to 24 hours post-dose.  Samples will be assayed for RM-493 levels.  PK analysis will 
be included in a separate PK analysis plan. 
 
3.4 
Analysis Populations 
The following patient populations will be evaluated and used for presentation and analysis of 
the data. 
 Safety Set (SAF):  All subjects who were randomized and received at least 1 dose of study 
medication and have at least one post-dose safety assessment (within Period 2) will comprise 
the SAF.  Subjects will be classified into groups based on actual treatment received.  The 
SAF will be used for all safety analyses. 
 
Intent to Treat (ITT):  All randomized subjects.  If there is a greater than 15% difference 
from the FAS, efficacy tables for the ITT population will also be generated. 
 
Full Analysis Set (FAS): All randomized subjects who have received at least 1 dose of 
randomized study medication with a baseline and at least 1 post-baseline efficacy observation 
within Period 2 will comprise the FAS.  Subjects will be classified based on randomized 
treatment group, regardless of the actual treatment taken. The FAS will be used for analyses 
of all efficacy endpoints.   
 
Per Protocol Set (PP): A subset of the FAS who completed the 4-week double blind treatment 
period (Period 2) with no major protocol violations. The list of deviations that will exclude 
data from the PP population will be finalized by the Sponsor and documented prior to any 
unblinding of data for analysis. 
Major protocol violations may include, among others: 
1. Violation of key inclusion/exclusion criteria, as reviewed by study clinician. 
2. Violation of legal documents including, but may not be limited to informed consent 
and patient privacy. 
3. Subjects who received the wrong treatment or incorrect dose. 
4. Non-compliance on study withdrawal criteria: 


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a. Non-adherence to study drug regimen (must be at least 67% compliant with 
study medication) or protocol requirements. 
b. Non-compliance with instructions or failure to return for follow-up. 
 
Subjects will be classified based on randomized treatment group, regardless of the actual 
treatment taken.  
The FAS Population is the primary population for the analysis of efficacy parameters.  The 
PP subset is also used for the primary and key secondary endpoint analyses. The SAF is the 
primary population for the analysis of safety endpoints. 
 
4 
STATISTICAL METHODS 
This SAP may not describe all analyses that will be performed for this study.  Additional 
analyses may be requested by the Sponsor and performed to supplement the results outlined 
in this SAP.  All post-hoc analyses that have not been identified in this plan but are included 
in the clinical study report (CSR) will be clearly identified in the text of the CSR. 
4.1 
Sample Size Justification 
Prior data from the 4 week Phase 1b treatment arms of Study RM493-002 (MAD study) 
yielded the following summary statistics for mean change from baseline after 4 weeks: 
Pooled SD for Placebo:  
SD=1.1, N=12 
Pooled SD for RM493:  
SD=2.3, N=18 
Assuming SD=1.1 for placebo and SD=2.3 for RM-493, if the true mean difference in 1-
month weight loss between treatments is 2.5 kg in this study (N=12 placebo and N=12 
RM493), there would be 94% power to yield a statistically significant (alpha=0.05, 1-sided) 
difference between treatments (83% power if true difference is 2 kg). The minimum observed 
difference in mean weight loss after 4 weeks of treatment, between RM493 and placebo that 
would be statistically significant is 1.3 kg. 
4.2 
General Considerations 
Data will be described and analyzed using the Statistical Analysis System (SAS), version 9.2 
or higher on a Windows platform (SAS Institute Inc., Cary, NC).  Adverse events and 
medical history will be coded using MedDRA Version 18.1.  Prior and concomitant 
medications will be coded to provide Anatomical Therapeutic Chemical (ATC) levels 2 
(therapeutic main groups) and 4 (chemical subgroups) using the December 2014 version of 
the World Health Organization (WHO) Drug Dictionary. 
Individual patient data will be presented in by-patient data listings.  Descriptive statistics 
(number of patients [n], mean, standard deviation [SD], median, minimum [Min] and 
maximum [Max]) will be presented for continuous data.  For categorical data, the frequency 
and percentage of patients in each category will be presented; percentages will be based on 
the number of patients with non-missing observations. 


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Unscheduled visits will not be used, unless they meet the criteria for a baseline observation 
(e.g. last observation prior to initial double-blind drug administration). 
A by-patient listing will be provided which includes all derived efficacy data for which the 
derivation is not otherwise provided.  The data as collected will be provided in the relevant 
by-patient listing of the raw data.   
Unless specified otherwise, by-patient listings will be provided for all data as contained in 
the raw database. 
Reporting of treatment groups in summary tables will be performed with placebo groups 
(high and low dose groups) combined.  The primary focus for the treatment group analysis 
will be on Period 2 (the 4-week double blind period).  Additional analyses will focus on 
specific intervals (Period 3; effect of randomized change in treatment from active to placebo, 
and placebo to active); Period 4 (the open label, 1.5 mg dose 2-week active extension), and 
Period 1 (the double-blind, placebo controlled run-in period).   
The final study analysis will include summaries from pooled data using identical active doses 
(e.g., 0.5 mg, 1.5 mg, 2.5 mg) across the whole study, including data from before and after 
any interim analysis.  As mentioned above, all placebo data will be pooled as well.   
Supplemental exploratory analyses will be done for Period 1 (run-in) data to help in 
understanding of the variability of PWS subjects in a clinical trial; this data will complement 
the placebo data obtained later in the trial.   
Lastly, if the data support that all active groups show similar efficacy, a pooled “active” vs 
placebo exploratory analysis will also be conducted.   
The design of this study raises additional questions on data analysis, as patients may have 
alternating period of active and placebo treatment after beginning double-blind treatment in 
Period 2.  Data may be summarized by periods and treatment sequences (e.g., within the 
“withdrawal” phase of Period 3 and/or the open label active extension of Period 4), by focus 
on patients who remain on the same treatment vs. those whose treatment changes (e.g., to 
evaluate the difference in hyperphagia in those who remain on an active dose in both Period 
2 and 3, vs those that receive active in Period 2 but are withdrawn to placebo in Period 3).  It 
is anticipated that some of these exploratory analyses will be informed by the interim 
analysis.  
 
4.2.1 Derived Data 
The following implementations will be made for derived data: 




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 If the start time and day are missing but the start month and year are complete, an AE 
will only be excluded as being treatment-emergent if the start month/year is before 
the month/year of study drug administration or if the stop date/time is before study 
drug administration.  
 
 If the start day and month are missing but the start year is complete, an AE will only 
be excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration.  
 
 If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date/time is before study drug administration.  
 
4.2.3 Visit Windows 
Visit windows will not be employed in the analysis, i.e., data will not be excluded from the 
analysis based on whether the data fell outside of visit windows.   
4.2.4 Multiplicity 
There will be no multiplicity adjustments in this Phase 2a pilot study.  
4.2.5 Baseline Definition 
Baseline will be determined separately for each efficacy endpoint and safety parameter. That 
is, a missing baseline for one endpoint/parameter does not mean that the baseline will be 
missing for the other endpoints/parameters.  For endpoints with discrete visits, baseline will 
use the last observation prior to dosing. 
 
 The baseline for each of the analysis periods is specified below: 
Period 1 Baseline = Screening/Day 1 (based on assessment) 
Period 2 Baseline = Day 15 
Period 3 Baseline = Day 42 
Period 4 Baseline = Day 56 
where Days 15, 42, and 56 refer to the baseline of  the respective period and not the actual 
study day for any one patient. 
 
Change from baseline is defined as: 
 
Period 1 (Day 15 value – Day 1 value) 
 
Period 2 (Day 42 value – Day 15 value) 
 
Period 3 (Day 56 value – Day 42 value) 
 
Period 4 (Day 70 value  - Vay 56 value) 
 
For patients with either a continuous active or a continuous placebo dosing over time, 
information may be summarized using the following intervals: 
 
Period 2/3: 
 
   Day 15 through Day 56 
Continuous low dose:    Day 15 through Day 56 
Continuous high dose:   Day 15 through Day 70 
Continuous placebo:      Day 1 through Day 56 


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4.3 
Statistical Hypothesis 
For the co-primary efficacy endpoint, the null hypothesis is that the mean percent change 
from baseline (Period 2) in Weight (kg) for patients taking RM-493 is the same as for those 
taking placebo. That is, 
 
Hp0: µpA  = µpP 
 
Hp1: µpA ് µpP 
where µpA and µpP is the mean percent change in weight (kg) at Day 42 (Week 6),  for 
patients on active treatment (RM-493 0.5 mg and placebo 50 uL) and (RM-493 1.5 mg and 
placebo150 uL), respectively.  
Likewise, for the co-primary efficacy endpoint for the PWS, the null hypothesis is that the 
mean percent change from baseline (Period 2) in the Overall Score for the Dykens PWS 
assessment for patients taking RM-493 is the same as for those taking placebo. That is, 
 
Hs0: µsA  = µsP 
 
Hs1: µsA ് µsP 
where µsA and µsP is the mean percent change in the PWS Overall score at Day 42 (Week 6),  
for patients on active treatment (RM-493 0.5 mg and placebo 50 uL) and (RM-493 1.5 mg 
and placebo150 uL), respectively.  
 
4.4 
Study Patients 
Screen Failure: A patient screened for participation in the RM-493-010 study who does not 
meet all of the inclusion and/or who meets any of the exclusion criteria for enrolment will be 
deemed a screen failure and will not be randomized.     
Patients may also be considered screen failures during the 14-day, single-blind, placebo run-
in phase. After an initial screening and confirmation of eligibility, volunteers will enter a 
two-week single blind placebo run-in period (period 1). Those who are compliant in study 
drug administration and have demonstrated willingness to complete study procedures 
(weighing, questionnaire and diary completion), will be randomized to receive subcutaneous 
doses of RM-493 or placebo for 4 weeks of double-blind treatment (primary efficacy 
timepoint) (period 2).   
4.4.1 Disposition of Patients 
Summary data will be presented by dose group and overall, based on the number of patients 
enrolled as well as defined by the analysis populations. Patient disposition will be tabulated 
and include the number screened and the number who participated in the placebo run-in 
period.  Screen failure data during the placebo run-in period as well as screen failures prior to 
the placebo run-in period will also be summarized.  The number of patients in the ITT Set, 
Safety Set, the Full Analysis Set, and the Per Protocol Set, and the number who withdrew 
prior to completing the study along with their primary reason for withdrawal, and the Period 


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in which they discontinued, will be presented.   A breakdown of patients by site and 
treatment group, within the Safety Set will be provided.  
A by-patient listing including the details of the study disposition will be provided for all 
patients (including screen failures that are prior to or during the single blind run-in period). 
4.4.2 Summary of Populations and Protocol Deviations 
A summary of the populations and associated defining criteria will be presented in a tabular 
format for selected populations (ITT, SAF, FAS, PP).   
For the ITT population, the number of patients with a protocol violation (determined through 
joint clinical / statistical review prior to data base lock), as well as a summary of protocol 
deviation categories will be presented.  Protocol deviation categories will be summarized by 
category and center. 
The list of important protocol deviations related to study inclusion/exclusion criteria, patient 
management/assessment, or conduct of the study will be finalized by the Sponsor and 
documented prior to database lock or any unblinding of data.  Specific criteria will be 
reviewed prior to database lock, and will include such criteria as contraindicated concomitant 
medications or incorrect dose group and other items as deemed appropriate by the Sponsor. 
All important protocol deviations will be summarized and presented in a by-patient data 
listing. 
4.4.3 Demographic and Disease Characteristics 
Demographic data will include patient age, gender, race, and ethnicity. Baseline characteristics 
include weight, height, BMI, and waist circumference. Demographic and baseline 
characteristics will be tabulated for all patients in the SAF population by dose group and 
overall. 
 
A by-patient listing will be presented for all patients in the SAF population. 
4.4.4 Study Drug Administration 
Study drug exposure will be presented for all patients in the SAF. Injection information will 
include total study drug exposure, individual administering dose, quantity of dose administered 
(full or partial), and reason for dose interruption or modification and will be tabulated by period 
2 and 3.   
 
Exposure data will be presented in a by-patient data listing for all patients in the SAF 
population. 
4.4.5 Medical History 
A by-patient listing of medical history data will be provided in a data listing. 
4.4.6 Concomitant Medications 
By-patient listings of all concomitant medications will be provided.  


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4.5 
Efficacy Endpoints and Analyses 
4.5.1 Primary Efficacy Endpoints 
There will be 2 co-primary endpoints analysed. 
Percent change from baseline in body weight, and percent change from baseline in the 
Overall score for the PWS Hyperphagia questionnaire over the 4-week double-blind dosing 
period (Period 2) will be assessed as co-primary efficacy endpoints.   
The Hyperphagia Questionnaire is a 10-item instrument designed to measure food-related 
preoccupations and problems in PWS, as well as the severity of these concerns.  Three factors 
identified from this questionnaire are: 
 Hyperphagic Drive (e.g. how persistent in asking for food; how easy to direct away 
from food; items 1,3,6,9) 
 Hyperphagic Behaviors (e.g. how fast or clever in obtaining food; how often steal 
food; items 2,4,5,8) 
 Hyperphagic Severity (time spent talking about food; extent that food interferes with 
everyday functioning; items 7,10) 
 
Items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or 
frequent problem).  The questionnaire can be found in Appendix 2.   Raw scores for each factor 
will be used in data analyses, and the three domains will be summed for an overall summary 
index of hyperphagia (maximum overall score of 50).  Missing values will not be imputed.  If 
a single item in a factor is missing for a patient, that factor will be missing. 
These endpoints will be tabulated by dose group for the FAS and PP populations.  There will 
be no adjustment for multiplicity. 
4.5.1.1 Primary Analysis 
 
The primary analysis involves comparison of percent change from baseline during Period 2 
between the RM-493 active treatment groups and placebo. A mixed model repeated measures 
analysis of variance with fixed terms for treatment, time, treatment-by-time interaction and 
baseline covariate as well as a random effect for subjects will be used to assess the primary 
efficacy endpoint. An unstructured covariance matrix will be used to model the expected 
different variances among the treatments. T-tests derived from the model will use 
Satterthwaite's degrees of freedom estimates. 
 
The assumption of normality will be assessed via the Shapiro-Wilk statistic as a diagnostic of 
closeness to normality, not as a conditional test associated with efficacy endpoint analyses. 
Other graphical assessments of residuals from the model fit may be examined. If a substantial 
departure from normality is observed, a transformation such as log (post/pre) or rank may be 
used to analyze the data as a sensitivity analysis; however, the analysis on the original scale 
of observation will be reported. 
 
The comparison of each dose of RM-493 with placebo will be carried out via 1-sided 
statistical test at alpha=0.05, with no adjustment for multiplicity for comparisons with two 
dose regimens. Of note, the 0.5 mg dose was included in the study as an anticipated no-effect 
or minimal effect dose for dose ranging.   


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Least square (LS) mean changes from baseline for each treatment group, and LS mean 
difference between each active RM-493 dose group and placebo, and the associated 95% 
confidence intervals for the difference will be provided, along with the reported p-values 
(one-sided).  In addition change from baseline will be tested using a 2-sided statistical test at 
alpha=0.05. 
 
Sample SAS code that can be used to implement the MMRM analysis is provided below: 
 
proc mixed data=adef  method=reml; 
  class subjid trtpn visitnum; 
  model pcgresn = trtpn visitnum trtpn*visitnum base / solution ddfm=satterthwaite; 
  repeated visitnum / type=un subject=subjid; 
  lsmeans trtpn*avisitn  / cl alpha=0.05; 
  lsmeans trtpn*avisitn / diff=control ('1' ‘Day x’) cl;  *[where '1' represents group=placebo]; 
run; 
 
In an effort to examine the robustness of the results obtained from the analysis of the co-
primary endpoints, sensitivity analyses will be performed. The sensitive analysis will be 
undertaken by imputing missing data from subjects who do not adhere to therapy with the 
mean value from those subjects on the same arm that also did not adhere to therapy, but had 
the measurement for the primary endpoint. 
 
By-patient data listings will be provided. 
  
4.5.2 Secondary Efficacy Endpoints 
4.5.2.1 Key secondary efficacy endpoints 
 
Key secondary efficacy endpoints will be analysed for Period 2 for 3 treatment groups (see 
Table C, Period 2) for both the FAS and PP populations.  Endpoints include: 
 Change from baseline to end of Period 2 in body weight (kg), and 
 Percent change/change from baseline in PWS Hyperphagia questionnaire for each of 
Overall Score (change from baseline only), 3 domains and individual scores (Period 
2).  
 Percent change/change from baseline in DEXA (Body Fat) and (Body Mass) for 
Period 2 
 
Change from baseline in body weight over the 4-week double-blind dosing period will be 
assessed as a key secondary efficacy endpoint.  Change in body weight during Period 2 will be 
tabulated by dose group. 
 
Percent Change/Change from baseline in PWS Hyperphagia Questionnaire for each of 
Overall score (Change from baseline only), 3 domains and individual scores will be 
assessed as key secondary efficacy endpoints.  Change and percent change in PWS during 
Period 2 will be tabulated by dose group. 


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Analyses for the key secondary endpoints will employ the similar methods used for the primary 
analyses (see Section 4.5.1.1). 
 
4.5.2.2 Secondary endpoints 
 
Additional secondary efficacy endpoints will be analysed for the FAS population only.  
Endpoints include: 
 Body weight (kg): Percent Change/Change from baseline (Period 3) (Period 4) 
 Body weight (kg): Percent Change/Change from baseline (Period 2/3) for 
continuous active and Placebo treatments 
 PWS Hyperphagia Questionnaire: Percent Change/Change from baseline (Period 
3) (Period 4) 
 DEXA (body fat): Percent Change/Change from Baseline (Period 4) 
 DEXA (body mass): Percent Change/Change from Baseline (Period 4) 
 
The Body weight (kg) percent change and change from baseline (Period 3) (Period 4), will 
be assessed for Period 3 and for Period 4. 
 
The Body weight (kg) percent change and change from baseline (Period 2/3) for continuous 
active and Placebo treatments only (e.g. 4 treatment groups), will be assessed for Period 2 
through Period 3. 
 
The PWS Hyperphagia Questionnaire percent change/change from baseline (Period 3) 
(Period 4), will be assessed for Period 3 and Period 4 with treatment groups corresponding to 
each period.  Summaries will be generated for the Overall score, the 3 PWS domains, and 
individual questions. 
 
The DEXA (body fat) percent change/change from baseline (Period 4), will be assessed 
from end of Period 2 (Day 42) to end of Period 4 (Day 70), with treatment groups 
corresponding to these periods.   
 
The DEXA (body fat) percent change/change from baseline (Period 4) will be assessed 
from end of Period 2 (Day 42) to end of Period 4 (Day 70), with treatment groups 
corresponding to these periods. 
 
A similar model to that used for the primary endpoint analysis will be used for analysis of all 
secondary endpoints. 
 
By-patient data listings will be provided. 
 


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The food related problem questionnaire Percent change/change from baseline (Period 2) 
(Period 3) (Period 4) will be assessed for each of these time periods between baseline and end 
of Periods 2, 3, and 4 for the respective treatment groups found in those time periods.  
 
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.  There are 16 questions on this 7-
point Likert scale, with responses from 0 (never) to 6 (always), with a response of 7 (does not 
apply) included for 6 items on the scale.  There are 3 open-ended questions.  The maximum 
possible score is 96 for the total FRPQ, where a higher score indicates a ‘worse’ condition.  
See Appendix 3. 
 
Along with the total item score, three (3) subscales will be presented for: 
1. Preoccupation (items 1,5,15) 
2. Impairment of satiety (items 8,9,13,14,16) 
3. Composite negative behavior (2,4,8; 12,15; 3,7,14) 
 
The individual item score and each subscale will be analyzed by each of the 3 periods, using 
descriptive statistics for visit and mean changes from baseline for each treatment group. If a 
single item in a factor is missing for a patient, that factor will be missing. 


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4.6 
Subgroup Analyses 
An additional subgroup DEXA analysis will be conducted for the first 8 subjects enrolled prior 
to 
who received DEXA testing at Day 0 and Day 15, using the mean of these 
two values as baseline (with Day 15 data alone serving as the baseline for the analysis of the 
entire study population). 
 
In addition, pre-specified subgroup analysis may be performed based on the following: 
 
 Age (16-40; 41-64; >65 years; in addition, if patients between 12-16 are included in 
the trial, an additional age group analysis will be include for these patients to support 
inclusion of younger and pediatric patients into future studies.  


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 Gender 
 BMI (greater vs less than the median BMI) 
 Overall hyperphagia score (greater vs less than the median hyperphagia score) 
 By growth hormone usage (yes or no) 
 By institutionalized care situation (if permitted in the study; yes or no) 
 
4.7 
Correlation and
An exploratory analysis may be done with correlations between pharmacokinetics and/or 
efficacy endpoints (weight loss, change in hyperphagia scores) and between different 
instruments will be explored.  
4.8 
Safety Analyses 
4.8.1  Adverse Events (AEs) 
Adverse events are to be recorded from signing the informed consent through the Final Study 
Visit (~ 2 weeks post treatment).  All AEs (serious and non-serious) spontaneously reported 
by the patient and/or in response to an open question from study personnel or revealed by 
observation, physical examination or other diagnostic procedures will be recorded.  An 
adverse event is considered to be treatment-emergent if the onset date/time is during or after 
administration of double-blind study drug or, in the event that onset time precedes double-
blind study drug administration, the adverse event increases in severity during or after 
administration of double-blind study drug; in either case through 1-week after the last 
treatment dose.    
Imputations will be used for determining treatment emergence for adverse events with partial 
dates (see Section 4.2.2); the unimputed partial dates will be included in the data listings. 
A top line summary of AE incidence will be presented by treatment group.  The number and 
percentage of patients with any treatment-emergent AE (TEAE), with any TEAE leading to 
study drug discontinuation, serious TEAE, and with any AE based on an injection site 
assessment will be summarized by dose group and period.  In addition, the TEAE and SAE 
tables will be analysed by AE severity.   
The following AE summaries will be produced by SOC and preferred term, by period: 
 
Incidence of TEAEs  
 
Incidence of TEAEs by severity 
 
Incidence of SAEs  
 
Incidence of SAEs by severity 
A frequency of injection site reactions (Erythema, Edema, Induration, Itching, Pain or 
Tenderness, Other) will also be produced by each period, summarized by dose group.   
All AEs will be provided in a by-patient listing which will include both the term reported on 
the CRF (verbatim term) and the preferred term and SOC to which it is coded.  Relative start 
and stop days will be included along with the actual onset and resolution dates and times.  
AEs that are not considered treatment-emergent will be provided in a separate listing. 


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In addition, separate listings will be provided for the following, whether or not considered to 
be treatment-emergent (non treatment-emergent AEs will be flagged): 
 
Serious adverse events (SAEs) 
 
Adverse events leading to death or discontinuation of study drug (treatment-
emergent) 
 
Adverse events of potential special interest:  hypertension, tachycardia, penile 
erections, changes in female sexual arousal, skin and lesion pigmentation changes 
(tanning), thromboembolic events.  All AEs will be designated AEs of special interest 
(yes/no and assigned to a category) by blinded review of the study team prior to 
locking the data base and any unblinding.   
 
4.8.2 Clinical Laboratory Evaluations 
Laboratory evaluations are performed at Screening, Days 1, 15, 28, 42, 70-163.  A subset of 
lab parameters that have been collected will be summarized for Period 1 (Screening, Day 1, 
and Day 15) and Period 2 (Days 15, 28, 42): 
 
 Hematology:  Hemoglobin, Hematocrit, WBC, Platelets 
 Chemistry: Bun, Creatinine,  Potassium, ALT, AST, Total Bilirubin, Alkaline 
phosphatase, GGT, CPK, Glucose 
Change from baseline (Day 15) to Day 28 and end of Period 2 (Day 42) (and during 
screening and Period 1) in selected Hematology and Chemistry laboratory parameters will be 
summarized by dose group for all patients in the SAF population. If a Day 15 assessment is 
missing, the last non-missing assessment prior to Day 15 should be used. By-patient data 
listings will be presented and in addition, a listing of all abnormal laboratory data values will 
be presented.  
Laboratory values for Hematology or Chemistry tests that are normally numeric, but are 
presented with a character string (e.g.’<1’) will take the numeric value without the symbol 
(e.g. ‘<1’ would be ‘1’) for use in the analysis tables.  Listings will present the original data. 
 Laboratory values will be tabulated (n %) with observed value and change from 
baseline over time and presented by dose group.   
 
By-patient listings of all laboratory results will be provided.  These listings will report the 
laboratory results in SI units.  Laboratory values that are clinically significantly abnormal 
will be identified in the data listings. 
 
Plots of change from baseline (or percent change from baseline, as appropriate) will be 
provided including all pre-baseline (screening and Period 1), Period 2 baseline (Day 15) and 
all post-dose values for placebo and active dose groups through Period 2.   
 


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4.8.3 Vital Signs 
Vital signs measures for blood pressure (systolic and diastolic) and heart rate will be 
tabulated (n %) with observed value and change from baseline over time for Period 2 
(Screening values and Days 15 (baseline), 28, and 42) and presented by dose group.  The 
average of blood pressure and heart rate values for any one timepoint will be taken; if only 1 
value is present for a timepoint, this value will be used in the analysis. 
By-patient listings of vital signs results will be provided.   
 
4.8.4 Physical Examinations 
A by-patient listing of physical examination details will be provided; a summary table is not 
planned.  Significant findings (new or worsening after baseline findings) from the physical 
examination are to be recorded as AEs. 
4.8.5 ECG 
ECG measurements are to be taken at screening, Day 42 and follow-up.   A by-patient listing 
of ECG evaluations will be provided. 
4.9 
Pharmacokinetic Evaluation 
Plasma concentrations of RM-493 will be reported separately from these analyses.  
4.10 Interim Analysis 
See separate iSAP 
4.11 Patient Profiles 
No patient profiles will be provided. 


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5 
REPORTING OUTPUT 
All outputs will be produced using SAS version 9.2 or higher.  The REPORT procedure will 
be used to produce all tables and listings whenever possible.  All statistical appendices 
(supportive SAS output) will be output directly from the appropriate SAS procedure. 
All table and listing outputs will stand on their own by being appropriately titled, footnoted 
and labelled such that the contents of their output are clear without reference to other study 
documents.  All outputs will contain a footer indicating the name of the program used to 
produce the output and the date and time the output was generated; pages will be numbered 
‘x of y’.  The block of information containing notes, footnotes, and listing/table/figure 
generation will be flush with the bottom margin. 
Tables, listings, and figures will be numbered according to ICH Guidelines E3, Structure and 
Content of Clinical Study Reports.  
All tables, listings, and statistical appendices will be produced to landscape orientation and 
will be incorporated into a Word document (margins 1.5” at the top and 1” at the left, right, 
and bottom) using Courier New 8 point font or higher.   
All adverse event and concomitant medication listings will contain relative study days for the 
start and end dates of events being reported in addition to the actual dates and times of the 
events.  Day 1 is the day study drug is administered.  Day -1 is the day immediately 
preceding Day 1; there is no Day 0 in this study.  Formulae for calculating the relative study 
days are provided in Table 1.   
Unless indicated otherwise in the shells, listings of efficacy data will contain the relative time 
for the evaluation.  The formula for calculating the relative time is provided in Table 1.   


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Listings will include all patients with data relevant to the particular listing and will be 
ordered by patient and visit within each treatment arm   
Unless specified otherwise, percentages will be based on the number of non-missing 
observations (which will not always be the same as the number of patients in the treatment 
arm).  The header will contain the number of patients in the treatment arm.   
All percentages will be rounded and reported to a single decimal point (xx.x%) except for a 
percentage of 100% which will be reported as 100%.  A value of 0% will be reported as a 
blank. 
Analyses that include P values will report the P value to 3 decimal places with a leading zero 
(e.g., 0.023).  P values <0.0005 will be reported as <0.001 not 0.000; p-values greater than 
0.9995 will be reported as >0.999 not 1.000. 
Unless it is not practical, mean and median values will be formatted to one more decimal 
place from the measured value.  The standard deviation will be formatted to two more 
decimal places than the measured value.  Minimum and maximum values will be presented 
with the same number of decimal places as the measured value.  The number of decimal 
places in the measured value will not necessarily be reflected in the table and listing shells. 
 
 


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6 
APPENDICES 
 


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Appendix 1: Schedule of Assessments 
Study Period 
 
 
 
Study Day 
Screening  
 
 
 
Days -30 to -1 
Onset Single-
Blind Treatment 
Run-in 
 
Days 1-14 
Double Blind Treatment 
 
 
 
Days 15-41 
End Double Blind 
/ Onset 
Withdrawal 
Period  
 
Days 42-55 
End Withdrawal / 
Onset Optional 
Open Label 
Extension  
Days 56-69 
End Open Label 
Extension 
Post-Study 
Follow Up  
 
 
Days 90 to 16324 
Procedure 
 
Run-In 
 
 
Day 16, 
Onset 
Treatment 
Period  
Day 15±2- 
Treatment  Period
Interim Visit 
 
~Day 284,6 
Treatment Period 
End, Onset 
Withdrawal  
Day 42±2  
Onset Optional 
Expansion 
 
~Day 56±2 
Final Visit 
 
 
Day 70 -2 or +4  
Follow up Visit 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion review 
X 
X5 
 
 
 
 
 
 
Medical history review 
X 
X5 
X15 
 
 
 
 
 
Pregnancy test  
X 
X5 
X15, 26 
 
X 
X 
 
X 
Physical examination1 
X 
 
X15 
 
X 
 
 
X 
Height 
X 
 
 
 
 
 
 
 
Comprehensive skin exam2 
X 
 
 
 
 
 
 
X 
Fitzpatrick scale7 
X 
 
 
 
 
 
 
 
Weight/
 
X 
X5 
X15 
X23 
X 
X 
X 
X 
DEXA 
 
 
X22 
 
X22 
 
X 
 
Archive sample for storage11 
 
X5 
 
 
X 
 
X 
 
Single-Blind placebo practice 
 
X 
 
 
 
 
 
 
Randomization to treatment3 
 
 
X3 
 
 
 
 
 
Study treatment administration12 
 
X 
X6 
X6,23 
X6 
X 
X 
Injection site inspection13 
 
X 
X 
X23 
X 
X 
X 
X
Vital signs14 
X 
X5 
X15 
X23 
X 
X 
X 
X 
ECG (12-lead)16 
X 
 
 
 
X16 
 
 
X 
Safety laboratory tests17 
X 
 
X15 
X23 
X 
 
X 
X 
Questionnaires/Assessments 
 
X5 
X15 
X 
X 
X 
X 
X 


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Appendix 1: Schedule of Assessments 
Study Period 
 
 
 
Study Day 
Screening  
 
 
 
Days -30 to -1 
Onset Single-
Blind Treatment 
Run-in 
 
Days 1-14 
Double Blind Treatment 
 
 
 
Days 15-41 
End Double Blind 
/ Onset 
Withdrawal 
Period  
 
Days 42-55 
End Withdrawal / 
Onset Optional 
Open Label 
Extension  
Days 56-69 
End Open Label 
Extension 
Post-Study 
Follow Up  
 
 
Days 90 to 16324 
Procedure 
 
Run-In 
 
 
Day 16, 
Onset 
Treatment 
Period  
Day 15±2- 
Treatment  Period
Interim Visit 
 
~Day 284,6 
Treatment Period 
End, Onset 
Withdrawal  
Day 42±2  
Onset Optional 
Expansion 
 
~Day 56±2 
Final Visit 
 
 
Day 70 -2 or +4  
Follow up Visit 
 
PK blood sampling18 
 
X5 
 
 
X18 
X25 
X18 
 
Basal Metabolic Rate21 
 
X21 
 
 
X21 
 
X 
 
Anti-RM-493 antibody samples 
 
X5 
 
 
 
X 
 
X 
Adverse Event assessment19 
X 
X5 
X15 
X 
X 
X 
X 
X 
Concomitant meds review 
X 
X5 
X15 
X 
X 
X 
X 
X 
Telephone contact8 
 
X 
 
X 
X 
X 
 
X 
 
 
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 consecutive days, as long as the lab results are back in time for the start of run-in phase. 
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 contact 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 onset 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 the 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.  


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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 triplicate,
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 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 14, 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 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 dosing 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 obtained.  For the PK sample, the actual collection 
(clock) time will be recorded, as well as the time of the previous day’s study drug injection time as reported by the patient/caretaker.   Exception: patients who participate in the PK substudy 
between Days 63 and 69 do not need to have PK repeated on Day 70 visit. 
19 
Adverse events will be recorded from the time a patient 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 
.  
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 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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