A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and Efficacy of Setmelanotide in Subjects With Hypothalamic Obesity
Phase: PHASE2
Conditions: Hypothalamic Obesity
Sponsor: Rhythm Pharmaceuticals, Inc.

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
1 of 67 
Confidential 
 
 
SETMELANOTIDE 
RM-493-030 
A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and Efficacy of Setmelanotide in 
Subjects with Hypothalamic Obesity 
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. 
IND No. 
 
Short Title:  
Open-Label Study of Setmelanotide in Hypothalamic Obesity 
Study Sponsor: 
Rhythm Pharmaceuticals, Inc. 
222 Berkeley Street 
12th Floor 
Boston, MA 02116 
Document Date (Version): 09 September 2021 (V2.0; Amendment 1) 
Previous Version: 
16 October 2020 (V1.0; Original) 
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. 

Protocol 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
2 of 67 
Confidential 
APPROVAL SIGNATURE PAGE 
Protocol Title: 
A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and 
Efficacy of Setmelanotide in Subjects with Hypothalmic Obesity 
Protocol Number: 
RM-493-030 
Document Version: 
Version 2.0 (Amendment 1) 
Document Date: 
09 September 2021 
REVIEWED/APPROVED BY: 
 
 
Rhythm Pharmaceuticals, Inc. 
Signature 
Date 
[Please see e-signature page
appended to this protocol]

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
3 of 67 
Confidential 
INVESTIGATOR STATEMENT 
 
Protocol Title: 
A Phase 2, Open-Label 20-Week Study to Evaluate the Safety and 
Efficacy of Setmelanotide in Subjects with Hypothalamic Obesity 
Protocol Number: 
RM-493-030 
Document Version: 
Version 2.0 (Amendment 1) 
Document Date: 
09 September 2021 
 
 
I understand that all documentation provided to me by Rhythm Pharmaceuticals, Inc. (Rhythm) 
or its designated representative(s) concerning this study that has not been published previously 
will be kept in the strictest confidence. This documentation includes the study protocol, 
Investigator Brochure (IB), case report forms, and other scientific data. 
This study will not commence without the prior written approval of a properly constituted 
Institutional Review Board. No changes will be made to the study protocol without the prior 
written approval of Rhythm and the Institutional Review Board, except where necessary to 
eliminate an immediate hazard to the subject. 
I have read, understood, and agree to abide by all the conditions and instructions contained in 
this protocol. 
 
Investigator Name 
 
Investigator Signature 
 
Date 
 
 
 
 
 
Investigational site (or name of institution) and location (printed) 
 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
5 of 67 
Confidential 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
Setmelanotide 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
Patients aged 6 to <16 years, inclusive 
• 
Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will receive 
setmelanotide 1.0 mg/day.  
• 
Starting at approximately Day 15 through 28, patients will receive setmelanotide 2.0 mg/day.  
Patients/caregivers will be contacted by study center personnel on Day 15 to ensure dose 
titration has occurred and to document any adverse events (AEs). 
• 
Starting on approximately Day 29 (Visit 3), patients will receive setmelanotide 3.0 mg/day; 
patients will continue to receive setmelanotide 3.0 mg/day for 12 weeks.  
The dose of setmelanotide should be titrated as explained in the SoA. 
Patients aged ≥16 years, inclusive 
• 
Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will receive 
setmelanotide 2.0 mg/day.  
• 
Starting at approximately Day 15, patients will receive setmelanotide 3.0 mg/day; patients will 
continue to receive setmelanotide 3.0 mg/day for 14 weeks. 
The dose of setmelanotide should be titrated as explained in the SoA.  
Patients will return to the study center for Visits 3, 4, and 5 (Weeks 4, 8, and 12, respectively), with 
each of these visits conducted approximately 4 weeks apart. All patients will return to the study center 
at Week 16 (Visit 6) and receive the last setmelanotide injection. Study endpoints are analyzed at 
Visit 6. After completion of Visit 6, participation in the current study will then conclude in one of the 
following 2 ways: 
• 
Patients meeting the primary endpoint may be eligible to be enrolled in a separate extension 
study, Rhythm Study RM-493-022, under which auspices the patient will continue to receive 
setmelanotide.  
• 
Patients who do not meet the primary endpoint or elect not to continue setmelanotide are to 
discontinue setmelanotide at Visit 6 and return for an End-of-Study Visit (Visit 7) 4 weeks 
thereafter for a final safety review under the auspices of the current study. 
Number of patients (planned):  
Approximately 15 patients are planned to be enrolled. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
6 of 67 
Confidential 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
Setmelanotide 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
Diagnosis and main criteria for inclusion:  
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study participation: 
1. Patient has documented evidence of HO, including: 
a. Recent (within the previous 8 months before Screening) evidence of hypothalamic injury 
on magnetic resonance imaging (MRI); AND 
b. Diagnosis of craniopharyngioma or other non-malignant brain tumor affecting the 
hypothalamic region; AND 
c. Has undergone surgery, or chemotherapy, or radiation ≥6 months and ≤15 years before 
Screening.  
2. Patient has either unilateral hypothalamic lesions (at least 6 patients) or bilateral hypothalamic 
lesions (at least 7 patients), as assessed by MRI. 
Note: Although the intention of the study is to enroll at least 6 patients with unilateral 
hypothalamic lesions, the Sponsor may decrease the required number during the course of the 
study. 
3. Aged 6 to 40 years, inclusive, at time of enrollment. (A maximum of 10 patients between the 
ages of 6 and 12 will be enrolled in the study.) 
4. Obesity, documented by a BMI ≥35 kg/m2 for patients ≥18 years of age or BMI ≥95th 
percentile for age and gender for patients 6 to <18 years of age based on the US Centers for 
Disease Control and Prevention criteria. 
5. Documented increase in BMI (change from pre-surgery baseline in BMI Z-score ≥0.2 for 
patients <18 years of age or BMI >5% for patients ≥18 years of age) either during the first 
6 months following surgery or within 1 year before surgery AND still present at Screening. 
6. More than 6 months after the end of post-tumor treatment, including chemotherapy, surgery, or 
radiation.  
7. Patient must meet one of the following contraception requirements: 
• 
If a female of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), must use a highly effective form of 
contraception as outlined in Section 9.19.5. 
• 
If a female of non-childbearing potential, defined as permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or post-menopausal for 
at least 12 months (and confirmed with a screening follicle-stimulating hormone [FSH] 
level in the post-menopausal laboratory range), contraception is not required during the 
study.  
• 
Younger female patients who have not reached menarche upon study entry will be 
assessed for Tanner staging and at first menarche will be required to comply with 
contraception requirements and pregnancy testing as outlined in the protocol.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
7 of 67 
Confidential 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
Setmelanotide 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
• 
If a male with female partner(s) of childbearing potential, must agree to a double barrier 
method if they become sexually active during the study. Furthermore, male patients must 
not donate sperm during and for 90 days following their participation in the study. 
8. Ability to communicate well with the Investigator, understand and comply with the 
requirements of the study, and understand and sign the written informed consent, or, for 
patients aged <18 years, a parent/legal guardian that can sign.  
9. If receiving hormone replacement therapy (ie, thyroid hormones, glucocorticoids, growth 
hormone or other medications known to affect metabolism or weight/body composition), the 
dose of such therapy has remained stable for at least 2 months prior to Screening. (Changes in 
dose of ≤15% may be permissible, with the Sponsor’s approval.) 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study participation: 
1. Weight gain >5% in the previous 3 months. 
2. Weight loss ≥2% in the previous 3 months. 
NOTE: Dietary and/or exercise regimens, with or without the use of medications, supplements 
or herbal treatments associated with weight loss (eg, orlistat, lorcaserin, phentermine, 
topiramate, naltrexone, bupropion, glucagon-like peptide-1 [GLP-1] receptor agonists, etc.) 
are allowed if: 
• 
the regimen and/or dose has been stable for at least 3 months prior to randomization 
• 
the patient has not experienced weight loss ≥2% during the previous 3 months, AND 
• 
the patient intends to keep the regimen and/or dose stable throughout the course of the 
study. 
3. Bariatric surgery or procedure (eg, gastric bypass/band/sleeve, duodenal switch, gastric 
balloon, intestinal barrier, etc) within the last 6 months. All patients with a history of bariatric 
surgery or procedures must be discussed with and receive approval from the Sponsor prior to 
enrollment. 
4. Diagnosis of severe psychiatric disorders (eg, schizophrenia, bipolar disorder, personality 
disorder), or Major Depressive Disorder (MDD) within the previous 2 years, or Screening 
Patient Health Questionnaire (PHQ)-9/PHQ-A score ≥15, or any suicidal ideation of type 4 
or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, or lifetime 
history of suicide attempts, or any suicidal behavior in the last month. 
5. Glycated hemoglobin (HbA1c) >10.0% at Screening. 
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe 
enough to interfere with the study and/or confound the results. Any patient with a potentially 
clinically significant disease should be reviewed with the Sponsor to determine eligibility.  
7. Glomerular filtration rate (GFR) <30 mL/min/1.73 m2 during Screening.  
8. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
8 of 67 
Confidential 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
Setmelanotide 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
skin evaluation performed by the Investigator during Screening. Any concerning lesions 
identified during Screening will be biopsied and results known to be benign prior to 
enrollment. If the pre-treatment biopsy results are of significant concern, the patient is not 
eligible for study participation. 
9. History or close family history (parents or siblings) of skin cancer or melanoma (not including 
noninvasive, infiltrative basal or squamous cell lesion), or patient history of ocular-cutaneous 
albinism. 
10. Participation in any clinical study with an investigational drug/device within 3 months or 
5 half-lives, whichever is longer, prior to the first setmelanotide dose.  
11. Previously enrolled in a clinical study involving setmelanotide or any previous exposure to 
setmelanotide. 
12. Inability to comply with once daily (QD) injection regimen.  
13. Pregnant and/or breastfeeding, or desiring to become pregnant during this trial. 
14. Cognitive impairment that, in the Investigator’s opinion, precludes participation to the study 
and completions of study procedures or questionnaires.  
15. Patient is, in Investigator’s opinion, otherwise not suitable to participate in the study. 
Investigational product, dosage, and mode of administration:  
Investigational product: Setmelanotide, 10 mg/mL in a sterile solution for injection.  
Dosage: 1.0, 2.0, 3.0 mg QD for patients 6 to <16 years of age, and 2.0 to 3.0 mg QD for patients 
≥16 years of age.  
Mode of administration: SC injection 
Duration of treatment:  
All patients will receive study treatment for 16 weeks. Total study participation will last between 
22 and 28 weeks, based on the variable length of the Screening Period. 
Reference therapy, dosage, and mode of administration:  
NA 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
10 of 67 
Confidential 
Name of Sponsor/Company: 
Rhythm Pharmaceuticals, Inc. 
Name of Investigational Product: 
Setmelanotide 
Name of Active Ingredient: 
Setmelanotide (RM-493; Melanocortin-4 Receptor Agonist) 
10 patients aged 6 to <12 years, at 1-sided 0.05 significance level, the study provides ~90% power to 
reject the null hypothesis that the true response rate is less than 5%, assuming a 40% target response 
rate in setmelanotide.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
11 of 67 
Confidential 
2. 
SCHEDULE OF ACTIVITIES 
The schedule of activities (SoA) is presented in Table 1. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
12 of 67 
Confidential 
Table 1: 
Schedule of Activities 
Study Period/Procedure 
Screening 
Study Treatment 
EOS 
Visit 
Treatment 
Discontinuation  
Visit 
Clinic Visit Number 
V1 
V2 
- 
V3 1 
V4 
V5 
V6 2 
V7 2 
Study Day 
-56 to -14 
1 
15 
29 
57 
85 
113 
141 
Visit Window (days) 
- 
- 
+3d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
Informed consent/assent 3 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria review 
X 
X 
 
 
 
 
 
 
 
Medical history review 
X 
 
 
 
 
 
 
 
 
Physical examination 4 
X 
X 
 
X 
X 
X 
X 
X 
X 
Comprehensive skin examination 5 
X 
 
 
 
 
 
X 
 
X 
Fitzpatrick classification scale 
X 
 
 
 
 
 
X 
X 
X 
Weight 6 
X 
X 
 
X 
X 
X 
X 
X 
X 
Waist circumference 7 
X 
X 
 
X 
X 
X 
X 
X 
X 
Height 8 
X 
 
 
X 
X 
X 
X 
X 
X 
Body composition assessment by DXA 9 
X 
 
 
 
 
 
X 
 
X 
Vital signs 10 
X 
X 
 
X 
X 
X 
X 
X 
X 
ECG (12-lead) 11 
X 
X 11 
 
X 11 
 
 
X 11 
 
X 
Pregnancy test 12 
X 
X13 
 
X 
X13 
X13 
X13 
 
X 
Daily hunger questionnaires 14, 15 
X 
Daily 
X 
Global hunger assessment 15 
 
X13 
 
X13 
X13 
X13 
X13 
X 
X 
PHQ-A or PHQ-9 16, 17 
X 
X13 
 
X13 
X13 
X13 
X13 
X 
X 
C-SSRS 18 
X 
X13 
 
X13 
X13 
X13 
X13 
X 
X 
SF-12 or SF-10 19 
X 
X13 
 
X13 
 
 
X13 
 
X 
IWQOL-Lite-CT 20 
X 
X13 
 
X13 
 
 
X13 
 
X 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
13 of 67 
Confidential 
Study Period/Procedure 
Screening 
Study Treatment 
EOS 
Visit 
Treatment 
Discontinuation  
Visit 
Clinic Visit Number 
V1 
V2 
- 
V3 1 
V4 
V5 
V6 2 
V7 2 
Study Day 
-56 to -14 
1 
15 
29 
57 
85 
113 
141 
Visit Window (days) 
- 
- 
+3d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
±4 d 
EQ-5D-5L or Y 21 
X 
X13 
 
X13 
 
 
X13 
 
X 
Safety laboratory tests 22 
X 
X 
 
X13 
X13 
X13 
X13 
X 
X 
FSH* 
X 
 
 
 
 
 
 
 
 
Injection site inspection 24 
 
X 
 
X 
X 
X 
X 
 
X 
Telephone call 25 
 
 
X 
 
 
 
 
 
 
Review lesion type on MRI 26 
X 
 
 
 
 
 
 
 
 
Study drug administration 27 
 
Daily dosing 
 
 
Dispense/Return study drug 28 
 
X 
 
X 
X 
X 
X 
 
 
Adverse event assessment 29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications review  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: C-SSRS = Columbia-Suicide Severity Rating Scale; D = Days; DXA = Dual-energy X-ray absorptiometry; ECG = electrocardiogram; EOS = End 
of Study; EQ-5D = EuroQol-5 Dimension; IWQOL-Lite-CT = Impact of Weight on Quality of Life-Lite Clinical Trials version; FSH = follicle-stimulating 
hormone; 
 MRI = magnetic resonance imaging; PHQ = Patient Health Questionnaire; SF= Short Form; V = Study Visit 
Number. 
1. Patients who are <16 years of age will receive first daily dose of 3.0 mg at V3, at the clinic.  
2. Study endpoints are analyzed at V6. After completing V6. Patients meeting the primary endpoint may be eligible to be enrolled in a separate extension study, 
Rhythm Study RM-493-022, under which auspices the patient will continue to receive setmelanotide. Patients who do not meet the primary endpoint or elect 
not to continue setmelanotide are to discontinue setmelanotide at Visit 6 and return for an End-of-Study Visit (Visit 7) 4 weeks thereafter for a final safety 
review under the auspices of the current study. 
3. Although the study procedures and assessments required per protocol are classified as “No or Minimal Risk” (with the exception of DXA which may be 
classified as “Minor Increase over Minimal Risk”) according to the 2008 Guidance Document “Ethical Considerations for Clinical Trials on Medicinal 
Products Conducted with the Pediatric Population,” considerations for reducing pain in distress in patients younger than 18 years of age are included in 
Appendix 2. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
14 of 67 
Confidential 
4. A complete physical examination will be conducted at Screening and at the EOS V7. At other time points, an abbreviated examination will be performed. 
The abbreviated examination should focus on heart, lungs, skin, neurologic exam, and any areas of previous abnormal findings, noting any changes from 
baseline. In addition, Tanner Staging for assessment of pubertal development will be conducted for those patients who have yet to reach Tanner Stage V. 
Whenever possible, the same trained health care professional will conduct the exam and Tanner Staging. 
5. A comprehensive skin examination will be performed by the Investigator. The skin examination should include a full body (head-to-toe skin examination). If 
any concerning lesions are identified during Screening, the patient should be referred to a dermatologist. Any concerning lesions will be biopsied by the 
dermatologist and results must be benign prior to the first dose of setmelanotide. If the pre-treatment biopsy results are of concern, the patient will be 
excluded from the study. Additionally, any concerning lesion or change in an existing lesion during the course of the study must be evaluated by the 
dermatologist and biopsied, if clinically indicated in the opinion of the dermatologist.  
6. Weight (kg) is to be measured at the clinic using the same scale throughout the study, including the Screening Visit, after patients have emptied their 
bladders and pockets and after fasting for at least 8 hours. Patients are to wear light clothing or underwear and no shoes, and will be weighed at 
approximately the same time of day. Weight should be recorded to the nearest tenth of a decimal place if reported by a digital scale or to the nearest half of a 
kg if reported by a mechanical scale. 
7. Waist circumference (cm) will be done in triplicate and recorded to the nearest half cm. Waist circumference should be measured after patients have fasted 
for at least 8 hours and at approximately the same time at each visit. Patients should be standing and in light clothing and have emptied their bladder. 
Whenever possible, the same study staff member should perform the measurement for a given patient to minimize variability. 
8. For patients ≥18 years of age, height needs to be measured at Screening only. Height (cm) will be measured, without shoes, socks, or hats, using a wall-
mounted stadiometer. All measurements will be done in triplicate at each time point and recorded to the nearest half cm.  
9. Body composition assessment will be performed using DXA. If DXA is not available at the clinic, this procedure may be skipped, with prior approval of the 
Sponsor.  
10. All blood pressure (BP) and heart rate (HR) measurements are to be obtained with the patient in the sitting position following at least 5 minutes of rest. All 
measurements will be taken in triplicate, approximately 2 minutes apart. When possible, BP should be taken in the non-dominant arm throughout the study, 
using the same methodology (automated or manual). Body temperature (°C) and respiration rate (breaths/minute) will be obtained in the sitting position 
following at least 5 minutes of rest. 
11. A single 12-lead ECG will be performed in the supine position following a period of at least 10 minutes of rest. At V2, the ECG will be performed before 
and 4 hours after dosing, and at V3 and V6, the ECG is to be performed at 4 hours after dosing. 
12. A urine pregnancy test may be performed to expedite availability of results prior to dosing on Day 1. All other pregnancy tests will be serum tests; dosing 
may continue with results pending. 
13. Collected prior to study drug administration. 
14. Daily hunger questionnaire scores will be recorded prior to the patient’s morning meal. During Screening, the patient must complete the daily hunger 
questionnaire in the electronic diary at least 4 of the 7 days prior to V2, paper version can be used if required. Patients who do not meet this requirement 
should not be enrolled into the study. V2 may be rescheduled if needed to fulfill this requirement with Sponsor approval.  
16. In order to be eligible for the study, an individual patient’s PHQ-A or PHQ-9 score must be <15 at Screening. If at any time during the study an individual 
patient’s PHQ-A or PHQ-9 score is ≥10, the patient should be referred to a Mental Health Professional (MHP). 
17. The PHQ-A will be administered to patients 11-17 years old and the PHQ-9 will be administered to patients ≥18.  
18. In order to be eligible for the study, a patient at Screening cannot have a suicidal ideation of type 4 or 5, any lifetime history of a suicide attempt, or any 
suicidal behavior in the last month. If at any time during the study a patient has a suicidal ideation of type 4 or 5, or any suicidal behavior, the patient should 
be referred to an MHP.  
19. The SF-12 will be administered to patients ≥18 years of age and the SF-10 will be administered to the parents/caregivers of patients <18 years of age. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
15 of 67 
Confidential 
20. IWQOL-Lite-CT will be administered to patients ≥18 years of age. 
21. The EQ-5D-5L will be administered to patients ≥16 years of age. The EQ-5D-Y will be administered to patients >8 up to <16 years of age. In patients under 
the age of 8 years of age will not complete the EQ-measures. 
22. Safety laboratory tests will include: complete blood count with differential (platelet count, red blood cell [RBC] count, hemoglobin, hematocrit, neutrophils, 
lymphocytes, monocytes, eosinophils, basophils) and standard indices (mean corpuscular volume, mean corpuscular hemoglobin, %reticulocytes), 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), and urinalysis with microscopic analysis if positive findings on dipsticks warrant further 
examination.  
23. Blood samples will be collected prior to dose administration in the fasting state for total cholesterol, high-density lipoprotein cholesterol, low-density 
lipoprotein cholesterol, and triglycerides.  
24. 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 in which there are injection site reactions, 
even if not a time point for formal assessment.  
25. Site personnel will call the patient on Day 15 to confirm the proper dose escalation has occurred and to collect AEs. 
26. All patients must have evidence of hypothalamic injury on MRI completed within 8 months of Screening. If no MRI is available, then it may be repeated 
during the Screening Period.  
27. Patients/caretakers will draw up and self-administer/administer the drug once daily in the morning beginning the morning of Day 1 and for the duration of 
dosing. On days with clinic visits, the patients/caretakers will administer the drug in the clinic in the presence of the clinical staff to assure proper technique.  
28. Patients/caretakers will return all (the number recorded) used vials to the clinic when they visit, and both clinic-administered study drug as well as outpatient 
study drug administration will be recorded in a study diary. 
29. AEs will be recorded from the time a patient provides informed consent. AEs reported after dosing on Day 1 will be considered TEAEs.  
* FSH should be measured in women who have been post-menopausal >12 months and should be in post-menopausal range.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
16 of 67 
Confidential 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
SCHEDULE OF ACTIVITIES ..................................................................................11 
3. 
INTRODUCTION ......................................................................................................20 
3.1. 
Rationale for the Study ...............................................................................................20 
3.2. 
Setmelanotide .............................................................................................................21 
3.3. 
Benefit/Risk Assessment ............................................................................................22 
4. 
OBJECTIVES AND ENDPOINTS ............................................................................24 
5. 
STUDY DESIGN .......................................................................................................25 
5.1. 
Overall Design ............................................................................................................25 
5.2. 
Patient and Study Completion ....................................................................................26 
5.3. 
Scientific Rationale for Study Design ........................................................................27 
5.4. 
Justification for Dose ..................................................................................................27 
5.5. 
Study Conduct During the COVID-19 (Coronavirus) Pandemic ...............................28 
6. 
STUDY POPULATION .............................................................................................28 
6.1. 
Inclusion Criteria ........................................................................................................28 
6.2. 
Exclusion Criteria .......................................................................................................29 
6.3. 
Lifestyle Restrictions ..................................................................................................31 
6.4. 
Screen Failures ............................................................................................................31 
7. 
TREATMENTS ..........................................................................................................31 
7.1. 
Treatments Administered ............................................................................................31 
7.2. 
Method of Treatment Assignment ..............................................................................31 
7.3. 
Dose Modification ......................................................................................................32 
7.4. 
Blinding ......................................................................................................................32 
7.5. 
Preparation/Handling/Storage/Accountability ............................................................32 
7.6. 
Assessment of Treatment Compliance and Study Drug Accountability ....................33 
7.7. 
Concomitant Therapy .................................................................................................33 
7.7.1. 
Prohibited Medications ...............................................................................................33 
7.8. 
Treatment after the End of the Study ..........................................................................34 
8. 
DISCONTINUATION/WITHDRAWAL CRITERIA ...............................................34 
9. 
PATIENT ASSESSMENTS .......................................................................................35 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
17 of 67 
Confidential 
9.1. 
Informed Consent/Assent ...........................................................................................35 
9.2. 
Inclusion/Exclusion Review .......................................................................................35 
9.3. 
Demographics, Concomitant Medications and Medical History Review ..................35 
9.4. 
Type of Lesions on Magnetic Resonance Imaging .....................................................35 
9.5. 
Height .........................................................................................................................36 
9.6. 
Weight .........................................................................................................................36 
9.7. 
Waist Circumference ..................................................................................................36 
9.8. 
Body Composition Assessment by DXA ...................................................................36 
9.9. 
Physical Examination and Comprehensive Skin Examination ...................................37 
9.9.1. 
Physical Examinations ................................................................................................37 
9.9.2. 
Comprehensive Skin Examinations ............................................................................37 
9.10. 
Fitzpatrick Classification Scale ..................................................................................37 
9.11. 
Vital Signs ..................................................................................................................38 
9.12. 
Electrocardiograms .....................................................................................................38 
9.13. 
Clinical Laboratory Tests ...........................................................................................38 
9.13.1. 
Pregnancy Testing ......................................................................................................38 
9.14. 
Injection Site Examination .........................................................................................38 
9.15. 
Patient Questionnaires ................................................................................................39 
9.15.1. 
Hunger Scores .............................................................................................................39 
9.15.2. 
Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-
Lite-CT) ......................................................................................................................39 
9.15.3. 
Patient Health Questionnaire-9 (PHQ-9 or PHQ-A) ..................................................40 
9.15.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) ...................................................40 
9.15.5. 
Short Form-12/Short Form-10 (SF-12/SF-10) ............................................................41 
9.15.6. 
EuroQol-Five Dimension ............................................................................................41 
9.16. 
Telephone Call ............................................................................................................41 
9.17. 
Study Drug Administration .........................................................................................41 
9.18. 
Dispensing/Return of Study Drug ..............................................................................41 
9.19. 
Adverse Events ...........................................................................................................41 
9.19.1. 
Time Period and Frequency for Collecting AE and SAE Information .......................42 
9.19.2. 
Method of Detecting AEs and SAEs ..........................................................................42 
9.19.3. 
Follow-up of AEs and SAEs .......................................................................................42 
9.19.4. 
Regulatory Reporting Requirements for SAEs ...........................................................42 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
18 of 67 
Confidential 
9.19.5. 
Pregnancy and Contraception .....................................................................................43 
9.19.6. 
Overdose .....................................................................................................................44 
9.19.7. 
Depression or Suicidality ............................................................................................44 
9.20. 
Pharmacokinetics ........................................................................................................44 
9.21. 
Pharmacodynamics .....................................................................................................44 
9.22. 
Genetics ......................................................................................................................44 
9.23. 
Biomarkers ..................................................................................................................44 
10. 
STATISTICAL CONSIDERATIONS .......................................................................45 
10.1. 
Sample Size Determination ........................................................................................45 
10.2. 
Populations for Analyses ............................................................................................45 
10.3. 
Statistical Analyses .....................................................................................................45 
10.3.1. 
Interim Analyses .........................................................................................................46 
11. 
REFERENCES ...........................................................................................................47 
12. 
APPENDICES ............................................................................................................49 
APPENDIX 1. ABBREVIATIONS AND TRADEMARKS ......................................................50 
APPENDIX 2. CONSIDERATIONS FOR REDUCING PAIN AND DISTRESS IN 
THE PEDIATRIC POPULATION .............................................................................52 
APPENDIX 3. FITZPATRICK SCALE .....................................................................................53 
 
APPENDIX 5. INJECTION SITE EVALUATIONS .................................................................57 
APPENDIX 6. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................58 
APPENDIX 7. STUDY GOVERNANCE CONSIDERATIONS ..............................................63 
Regulatory and Ethical Considerations ..........................................................................................63 
Financial Disclosure .......................................................................................................................63 
Informed Consent Process .............................................................................................................63 
Data Protection...............................................................................................................................64 
Data Quality Assurance .................................................................................................................64 
Source Documents .........................................................................................................................65 
Study and Site Closure ...................................................................................................................65 
Publication Policy ..........................................................................................................................66 
APPENDIX 8. GUIDANCE ON STUDY CONDUCT DURING THE COVID-19 
(CORONAVIRUS) PANDEMIC ...............................................................................67 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
19 of 67 
Confidential 
 
LIST OF TABLES 
Table 1: 
Schedule of Activities .................................................................................................12 
Table 2: 
Objectives and Endpoints ...........................................................................................24 
 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
20 of 67 
Confidential 
3. 
INTRODUCTION 
3.1. 
Rationale for the Study 
Central melanocortin signaling is the central element of energy homeostasis [Holland 2019]. In 
patients with hypothalamic lesions, leptin signaling is often disturbed and as a result 
melanocortin signalling is reduced [Enriori 2016; Roth 2010; Roth 1998; Patel 2002; 
Shaikh 2008]. Imaging studies  in humans and rodents models show that lesions of the 
ventromedial nucleus of the hypothalamus (VMN) and the region of the arcuate nucleus (ARC), 
are more often associated with hyperphagia and excessive weight gain [Ahmet 2006; DeVile 
1996; Roth 2011; Daousi 2005; Holmer 2010; Elfers 2011].  
Hypothalamic obesity (HO) is a severe obesity that arises from mechanical hypothalamic insults 
(eg, tumors, tumor resections, radiotherapy treatment). Lesions of hypothalamus can derive from 
various types of tumors (craniopharyngiomas, gliomas, pituitary adenomas, hamartomas) and 
surgeries and radiotherapies for the treatments of the tumor itself. Literature reports that patients 
with craniopharyngioma are less physically active than controls with comparable body mass 
indices (BMIs) [Harz 2003]. Moreover, they display higher degree of hyperleptinemia and 
hyperinsulinemia when compared to individuals with normal BMIs. Alpha-melanocortin-
stimulating hormone (α-MSH) can be detectable in blood, and its levels can change depending 
on different energy states [Enriori 2016]; however, in patients with craniopharyngioma or post-
surgical treatment for it, α-MSH levels are significantly reduced [Roth 2010; Roth 2011]. 
Reduced serum α-MSH levels suggest melanocortin pathway deficiency, which might explain 
lower energy expenditure in peripheral tissues due to reduced fat and muscle fatty acid oxidation 
[Roth 2010; Roth 2011; An 2007].  
In a rat model of “combined medial hypothalamic lesion” or CMHL rat model for HO [Roth 
2011], Roth et al found that the characteristic metabolic changes of human HO were 
recapitulated when the lesion included the rat ARC. In this rat model, α-MSH levels are reduced 
[Roth 2011], similar to patients with craniopharyngioma [Roth 2010].  
Additionally, an MC3/4 receptor agonist, MTII 1mg/kg/d intraperitoneally over a period of 
14 days, resulted in a robust reduction of weight gain in CMHL rats without 
rebound/tachyphylaxia (-17.2% vs. saline injected controls) [Roth 2012]. Taken together, these 
preclinical and clinical findings offer a rationale for a novel melanocortin treatment in patients 
with HO to compensate for potentiate the defective leptin signaling.  
Setmelanotide, a potent agonist of the human melanocortin 4 receptor (MC4R) [Sharma 2019], 
has been studied in relevant genetic models of obesity, and in clinical studies. In mice, leptin-
receptor deficient Zucker fa/fa rats (a rodent model of genetic obesity impacting the MC4R 
pathway) and Magel2-null mice (a mouse model for Prader-Willi syndrome), treatment with a 
melanocortin receptor agonist reduced both body weight and food intake [Bischof 2016; Hwa 
2001]. These data demonstrate that setmelanotide is effective in these models of monogenic and 
syndromic obesity. In humans, homozygous mutations of the proopiomelanocortin (POMC) and 
leptin receptor (LEPR) obesity were successfully treated by setmelanotide [Kuhnen 2016; 
Clement 2018]. Overall, nonclinical and clinical data demonstrate that setmelanotide restores 
normal hunger, satiety, and energy expenditure regulation, leading to profound reduction of 
excess weight, in essence as a form of “replacement therapy”.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
21 of 67 
Confidential 
Putting together these results, MC4Rs expressed in the paraventricular nucleus (PVN) of the 
hypothalamus play a paramount role for body-weight regulation and for the leptin–melanocortin 
weight regulatory pathway of the hypothalamus [Kuhnen 2019]. Although setmelanotide has not 
been tested in a model of HO, given its role in restoring POMC pathway in POMC/LEPR 
deficient patients and the reported damage of the POMC pathway in the HO syndrome, this 
proposed study will investigate whether setmelanotide can be employed to recover melanocortin 
signaling and reduce body weight and/or hunger in patients with HO.  
3.2. 
Setmelanotide 
Setmelanotide is a synthetic, cyclic octapeptide (8-amino acid-containing peptide) that functions 
as a potent MC4R agonist. Setmelanotide is an 8-amino acid, cyclic peptide that binds with high 
affinity (inhibitory constant = 2.1 nM) to the human MC4R and is efficient in activating MC4R 
(50% effective concentration = 0.27 nM). While not an analog, it retains the specificity and 
functionality of the naturally occurring POMC-derived neuropeptide, α-MSH, which is the 
endogenous ligand for the MC4R. Setmelanotide is more potent and has a much longer half-life 
(~10-12 hours in humans) than the short-lived α-MSH ligand. 
The setmelanotide peptide was initially selected for clinical development based on its acceptable 
circulating half-life as a saline formulation (2.8-3.5 hours in non-human primates) and the ability 
to decrease body weight gain and suppress food intake in normal rats. Subsequent studies 
demonstrated the efficacy of setmelanotide in suppressing food intake and body weight gain in 
diet-induced obese mice, rats, dogs, and monkeys, as well as in genetic models of obesity, 
including leptin-deficient ob/ob mice and leptin receptor deficient obese Zucker rats. Later 
studies in obese monkeys showed that setmelanotide did not increase blood pressure (BP) or 
heart rate (HR), a potential concern observed with other MC4R agonist compounds. 
To support clinical studies, the toxicological profile of setmelanotide formulations has been 
evaluated in repeated-dose continuous SC infusion toxicity studies up to 13 weeks in duration in 
rats and monkeys. The formulation used in almost all of these studies, including the pivotal 
28-day and 13-week toxicology studies, was setmelanotide in 0.9% sodium chloride for injection 
(setmelanotide-saline formulation), tested over a range of concentrations. An International 
Council for Harmonisation (ICH)-compliant battery of in vitro and in vivo genetic toxicity 
studies that included a bacterial mutation assay, a chromosomal aberration assay in cultured 
human peripheral blood lymphocytes and a rat micronucleus study has been completed with this 
formulation. In addition, a 7-day repeat dose local tolerability bridging study was conducted with 
the current clinical formulation, setmelanotide-mPEG/DSPE (N-[Carbonyl-methoxypolyethylene 
glycol 2000]-1,2-distearoyl- glycero-3-phosphoethanolamine sodium salt) in rodents.  
Finally, chronic toxicology, reproductive, and juvenile toxicology studies using the RM-493-
mPEG/DSPE formulation are completed and reports are in preparation.  
The most significant potential safety issue for MC4R agonist compounds is the concern about 
potential mechanism-based increases in HR and BP. An MC4R agonist, LY2112688 (Eli Lilly 
and Company), had been studied in the clinic and caused HR and BP increases at all doses 
(eg, up to a mean 9.4 mm Hg increase in systolic BP [SBP] at the highest dose) [Greenfield 
2009, Kievit et al 2013]. While the increases were not an immediate safety concern for the 
healthy volunteers in the Lilly study, similar but chronic increases in a patient population with 
obesity would have been problematic. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
22 of 67 
Confidential 
Setmelanotide was developed in nonclinical studies to analyze and obviate these cardiovascular 
(CV) effects. A large number of nonclinical studies were performed to demonstrate that 
setmelanotide did not cause similar CV effects as LY2112688, while still delivering equal or 
greater efficacy in animal models. The underlying premise of the development program was that 
setmelanotide in humans would deliver efficacy on weight loss without unacceptable CV effects. 
A review of the clinical effects of setmelanotide revealed little if any evidence of BP or HR 
change from baseline versus placebo in any study, nor evidence of a 
pharmacokinetic/pharmacodynamic relationship [Gottesdiener 2015].  
Other potential safety and/or tolerability issues that have been reported from published literature 
for some MC4R agonists in clinical and animal studies have included nausea and vomiting, male 
penile erections, increases in female sexual arousal, and off-target activity at the closely related 
MC1R (which mediates melanin deposition in the skin, producing tanning). In addition to careful 
CV monitoring, the setmelanotide program was designed to include careful monitoring for these 
potential mechanism-based effects in the initial clinical studies. 
Overall, ~600 subjects have been exposed to setmelanotide or matching placebo at doses ranging 
from 0.0025 to 0.1 mg/kg/24 hours (0.12-9.12 mg total daily dose) in the setmelanotide clinical 
development program. (The exact number is not known, due to ongoing double-blinded clinical 
studies.) Overall, setmelanotide has been well tolerated by subjects who have received it in 
clinical studies. Regardless of formulation, setmelanotide has demonstrated a mostly similar set 
of adverse events (AEs) in both short-term and long-term clinical studies. Treatment-emergent 
adverse events (TEAEs) associated with setmelanotide include injection site reactions, 
intermittent and short-duration gastrointestinal AEs (mostly mild in grade, including reduced 
appetite, nausea, diarrhea, and vomiting), gradual and reversible increases in skin and nevi 
pigmentation, and short duration, intermittent male penile erections. 
Data obtained to date in the setmelanotide clinical program demonstrate robust weight reduction 
and hunger suppression efficacy in obesity disorders impacting the leptin-melanocortin pathway, 
with proof-of-concept established for obesity associated with POMC deficiency, LEPR 
deficiency, Bardet-Biedl syndrome, and Alström syndrome. By restoring impaired signaling in 
this pathway, setmelanotide can serve as an indirect form of replacement therapy for patients 
with hypothalamic deficiencies leading to extreme obesity, with the potential for dramatic 
improvements in body weight and appetite control.  
3.3. 
Benefit/Risk Assessment 
Setmelanotide has not been investigated previously in patients with HO, a population of patients 
with no effective long-term therapeutic options [Abuzzahab 2019]. However, in patients with 
rare genetic forms of obesity, setmelanotide has been associated with clinically meaningful 
reductions in weight and improvement in hunger. In particular, in patients with POMC or LEPR 
deficiency obesity, who are characterized by early onset obesity, severe hunger and progressive 
weight gain, setmelanotide has demonstrated clinically meaningful and statistically significant 
weight reduction, often bringing patients with very high morbid obesity BMI (>40 kg/m2) to 
BMI ranges in the overweight or normal range (<30 kg/m2). In addition to weight loss, 
setmelanotide has demonstrated clinically meaningful and statistically significant decreases in 
hunger. Both the decreased hunger and the weight loss continue over 52 weeks of treatment and 
are maintained with continued setmelanotide treatment. Furthermore, following the significant 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
23 of 67 
Confidential 
weight loss with setmelanotide treatment, there were improvements in glycated hemoglobin 
(HbA1c), glucose and lipids, as well as body composition with decreased fat mass and decreased 
waist circumference. These weight loss changes were accompanied by improvements in quality 
of life. 
Setmelanotide is well tolerated. Side effects of setmelanotide are predictable, well understood 
and do not present significant safety concerns. Collectively, safety data obtained to date show 
that AEs commonly associated with setmelanotide include injection site reactions and skin 
hyperpigmentation. Less commonly, nausea and vomiting were reported and rarely, sexual 
events have been observed. Potential mechanistic-based events such as hypertension have been 
assessed throughout the setmelanotide clinical development program and have not been 
observed. Events associated with severe obesity such as depression and suicidal ideation 
occurred infrequently and were assessed as not related to setmelanotide. 
Overall, the substantial weight loss, reduction of hunger, and improvement in cardiometabolic 
parameters, as well as quality of life, represents a clinically significant benefit with minimal 
safety risk to patients with rare forms of obesity treated with setmelanotide. 
In conclusion, it is considered that setmelanotide will have a positive benefit-risk profile in 
patients with HO who have no long-term successful therapeutic options. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of setmelanotide may be found in the Investigator’s Brochure. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
24 of 67 
Confidential 
4. 
OBJECTIVES AND ENDPOINTS 
The objectives and endpoints are summarized in Table 2. 
Table 2: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
 
• 
The primary objective of this study is to 
evaluate the change in body weight in 
response to setmelanotide administered 
subcutaneously (SC) daily in patients with 
HO.  
• 
Proportion of patients with ≥5% reduction 
from baseline in BMI after 16 weeks of 
setmelanotide treatment compared to a 
historic control of <5% in this patient 
population. 
Secondary 
 
• 
The secondary objectives of this study are 
to evaluate changes in parameters of body 
weight, body mass index (BMI), waist 
circumference, and hunger in response to 
setmelanotide in patients with HO and to 
evaluate the safety and tolerability of 
setmelanotide in patients with HO. 
Key Secondary 
• 
Composite proportion of patients aged 
≥6 to <18 years with ≥0.2 reduction of 
BMI Z-score and patients aged ≥18 years 
with 5% reduction of body weight from 
baseline after 16 weeks of setmelanotide 
• 
Proportion of patients aged ≥6 to 
<18 years with ≥0.2 reduction of BMI 
Z-score from baseline after 16 weeks of 
setmelanotide 
• 
Proportion of patients aged ≥18 years 
with ≥5% reduction of body weight from 
baseline after 16 weeks of setmelanotide 
Other Secondary 
• 
Change from baseline in waist 
circumference in patients aged ≥18 years 
after 16 weeks setmelanotide treatment. 
• 
Change in hunger in response to 16 weeks 
of setmelanotide treatment as measured 
by change from baseline in daily and 
global hunger scores.  
• 
Safety and tolerability assessed by the 
frequency and severity of AEs, vital 
signs, and laboratory evaluations.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
26 of 67 
Confidential 
Patients aged 6 to <16 years, inclusive 
• Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will 
receive setmelanotide 1.0 mg/day.  
• Starting at approximately Day 15 through 28, patients will receive setmelanotide 
2.0 mg/day.  
Patients/caregivers will be contacted by study center personnel on Day 15 to ensure 
dose titration has occurred and to document any AEs. 
• Starting on approximately Day 29 (Visit 3), patients will receive setmelanotide 
3.0 mg/day; patients will continue to receive setmelanotide 3.0 mg/day for 12 weeks.  
The dose of setmelanotide should be titrated as explained in the SoA.  
Patients aged ≥16 years, inclusive 
• Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will 
receive setmelanotide 2.0 mg/day.  
• Starting at approximately Day 15, patients will receive setmelanotide 3.0 mg/day; 
patients will continue to receive setmelanotide 3.0 mg/day for 14 weeks. 
Patients/caregivers will be contacted by study center personnel on Day 15 to ensure 
dose titration has occurred and to document any AEs. 
The dose of setmelanotide should be titrated as explained in the SoA.  
Patients will return to the study center for Visits 3, 4, and 5 (Weeks 4, 8, and 12, respectively), 
with each of these visits conducted approximately 4 weeks apart. All patients will return to the 
study center at Week 16 (Visit 6) and receive the last setmelanotide injection. Study endpoints 
are analyzed at Visit 6. After completion of Visit 6, participation in the current study will then 
conclude in one of the following 2 ways: 
• Patients meeting the primary endpoint may be eligible to be enrolled in a separate 
extension study, Rhythm Study RM-493-022, under which auspices the patient will 
continue to receive setmelanotide.  
• Patients who do not meet the primary endpoint or elect not to continue setmelanotide 
are to discontinue setmelanotide at Visit 6 and return for an End-of-Study (EOS) Visit 
(Visit 7) 4 weeks thereafter for a final safety review under the auspices of the current 
study. 
5.2. 
Patient and Study Completion 
The study is planned to enroll ~15 patients, with ~5 to 10 patients aged >12 years, and up to 
10 patients between 6 and 12 years.  
A patient is considered to have completed the study if he/she has either: 
• Receives the last planned setmelanotide dose at Week 16 (Visit 6), meets the primary 
endpoint, and elects to enroll in a separate extension study, Rhythm Study RM-493-
022, under which auspices the patient will continue to receive setmelanotide. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
27 of 67 
Confidential 
• Receives the last planned setmelanotide dose at Week 16 (Week 6) and completes the 
EOS Visit (Visit 7) for a final safety review under the auspices of the current study. 
Patients who discontinue before completing the 16-week treatment period are to attend a 
Treatment Discontinuation visit within 7 days (±4 days) after the last setmelanotide dose for final 
study assessments. 
The end of the study is defined as the date of the last visit of the last patient under the auspices of 
the current study. 
5.3. 
Scientific Rationale for Study Design 
Setmelanotide is being evaluated as a potential treatment for obesity in rare mechanistically 
induced populations with hypothalamic injury and subsequent obesity.  
Given the rarity of the condition under study, no placebo control group is planned. Placebo 
comparisons with so few patients with HO existing, all of whom are expected to demonstrate a 
very high need for therapy, are not considered feasible. 
5.4. 
Justification for Dose 
Based on the results of previous studies in patients with rare genetic forms of obesity, the 
recommended setmelanotide dose for adults is a starting dose of 2 mg once daily (QD), with, if 
tolerated for 2 weeks, an increase to 3 mg QD, aiming to achieve a normal BMI.  
For adolescents 12 to 15 years of age and pediatric patients 6 to 11 years of age, the 
recommended starting setmelanotide dose is 1 mg QD, with, if tolerated for 2 weeks, an increase 
to 2 mg, aiming to achieve a healthy weight 50-90th centile per charts/guidelines. A further 
escalation to 3 mg QD is required at the end of Week 4 (Day 28). There are 2 main factors 
supporting this regimen.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
28 of 67 
Confidential 
5.5. 
Study Conduct During the COVID-19 (Coronavirus) Pandemic 
The worldwide Coronavirus Disease 2019 (COVID-19) pandemic may impact the conduct of 
clinical studies due to the challenges from quarantines, site closures, travel limitations, and other 
considerations if site personnel or study participants become potentially exposed to or infected 
with COVID-19. To assure the safety of study participants, maintain compliance with Good 
Clinical Practice (GCP), and minimize risks to study integrity, if necessary, in consultation with 
the Sponsor, the method of assessment may be changed (eg, paper assessments replaced by 
electronic assessments). In addition, site visits may be replaced with telephone, internet-based 
video‑conferencing applications, or home visits by qualified health care professionals. Normal 
procedures, as detailed in this protocol, will be resumed as soon as possible thereafter. 
More detailed guidance on study conduct during the COVID-19 pandemic is provided in 
Appendix 8. 
6. 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria (ie, protocol 
waivers or exemptions) is not permitted. 
6.1. 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for study participation: 
1. Patient has documented evidence of HO, including: 
a. Recent (within the previous 8 months before Screening) evidence of hypothalamic 
injury on magnetic resonance imaging (MRI); AND 
b. Diagnosis of craniopharyngioma or other non-malignant brain tumor affecting the 
hypothalamic region; AND 
c. Has undergone surgery, or chemotherapy, or radiation ≥6 months and ≤15 years 
before Screening.  
2. Patient has either unilateral hypothalamic lesions (at least 6 patients) or bilateral 
hypothalamic lesions (at least 7 patients), as assessed by MRI. 
Note: Although the intention of the study is to enroll at least 6 patients with unilateral 
hypothalamic lesions, the Sponsor may decrease the required number during the course 
of the study. 
3. Aged 6 to 40 years, inclusive, at time of enrollment. (A maximum of 10 patients between 
the ages of 6 and 12 will be enrolled in the study.) 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
29 of 67 
Confidential 
4. Obesity, documented by a BMI ≥35 kg/m2 for patients ≥18 years of age or BMI ≥95th 
percentile for age and gender for patients 6 to <18 years of age based on the US Centers 
for Disease Control and Prevention criteria. 
5. Documented increase in BMI (change from pre-surgery baseline in BMI Z-score ≥0.2 for 
patients <18 years of age or BMI >5% for patients ≥18 years of age) either during the 
first 6 months following surgery or within 1 year before surgery AND still present at 
Screening. 
6. More than 6 months after the end of post-tumor treatment, including chemotherapy, 
surgery, or radiation.  
7. Patient must meet one of the following contraception requirements:  
• If a female of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy), must use a highly effective form of 
contraception as outlined in Section 9.19.5. 
• If a female of non-childbearing potential, defined as permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or post-
menopausal for at least 12 months (and confirmed with a screening follicle-
stimulating hormone [FSH] level in the post-menopausal laboratory range), 
contraception is not required during the study. 
• Younger female patients who have not reached menarche upon study entry will be 
assessed for Tanner staging and at first menarche will be required to comply with 
contraception requirements and pregnancy testing as outlined in the protocol. 
• If a male with female partner(s) of childbearing potential, must agree to a double 
barrier method if they become sexually active during the study. Furthermore, male 
patients must not donate sperm during and for 90 days following their participation in 
the study. 
8. Ability to communicate well with the Investigator, understand and comply with the 
requirements of the study, and understand and sign the written informed consent, or, for 
patients aged <18 years, a parent/legal guardian that can sign.  
9. If receiving hormone replacement therapy (ie, thyroid hormones, glucocorticoids, growth 
hormone or other medications known to affect metabolism or weight/body composition), 
the dose of such therapy has remained stable for at least 2 months prior to Screening. 
(Changes in dose of ≤15% may be permissible, with the Sponsor’s approval.) 
6.2. 
Exclusion Criteria 
Patients meeting any of the following criteria are not eligible for study participation: 
1. Weight gain >5% in the previous 3 months. 
2. Weight loss ≥2% in the previous 3 months. 
NOTE: Dietary and/or exercise regimens, with or without the use of medications, 
supplements or herbal treatments associated with weight loss (eg, orlistat, lorcaserin, 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
30 of 67 
Confidential 
phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide-1 [GLP-1] 
receptor agonists, etc.) are allowed if: 
• the regimen and/or dose has been stable for at least 3 months prior to randomization 
• the patient has not experienced weight loss ≥2% during the previous 3 months, AND 
• the patient intends to keep the regimen and/or dose stable throughout the course of the 
study. 
3. Bariatric surgery or procedure (eg, gastric bypass/band/sleeve, duodenal switch, gastric 
balloon, intestinal barrier, etc.) within the last 6 months. All patients with a history of 
bariatric surgery or procedures must be discussed with, and receive approval from, the 
Sponsor prior to enrollment. 
4. Diagnosis of severe psychiatric disorders (eg, schizophrenia, bipolar disorder, personality 
disorder), or Major Depressive Disorder (MDD) within the previous 2 years, or Screening 
Patient Health Questionnaire (PHQ)-9/PHQ-A score ≥15, or any suicidal ideation of 
type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, 
or lifetime history of suicide attempts, or any suicidal behavior in the last month. 
5. HbA1c >10.0% at Screening. 
6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe 
enough to interfere with the study and/or confound the results. Any patient with a 
potentially clinically significant disease should be reviewed with the Sponsor to 
determine eligibility.  
7. Glomerular filtration rate (GFR) <30 mL/min/1.73 m2 during Screening.  
8. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions 
(excluding non-invasive basal or squamous cell lesion), determined as part of a 
comprehensive skin evaluation performed by the Investigator during Screening. Any 
concerning lesions identified during Screening will be biopsied and results known to be 
benign prior to enrollment. If the pre-treatment biopsy results are of significant concern, 
the patient is not eligible for study participation. 
9. History or close family history (parents or siblings) of skin cancer or melanoma (not 
including noninvasive, infiltrative basal or squamous cell lesion), or patient history of 
ocular-cutaneous albinism. 
10. Participation in any clinical study with an investigational drug/device within 3 months or 
5 half-lives, whichever is longer, prior to the first setmelanotide dose. 
11. Previously enrolled in a clinical study involving setmelanotide or any previous exposure 
to setmelanotide. 
12. Inability to comply with QD injection regimen.  
13. Pregnant and/or breastfeeding, or desiring to become pregnant during this trial. 
14. Cognitive impairment that, in the Investigator’s opinion, precludes participation to the 
study and completions of study procedures or questionnaires.  
15. Patient is, in Investigator’s opinion, otherwise not suitable to participate in the study. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
31 of 67 
Confidential 
6.3. 
Lifestyle Restrictions 
There are no lifestyle restrictions during study participation.  
6.4. 
Screen Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently enrolled. A minimal set of screen failure information is required to ensure 
transparent reporting of screen failure patients to meet the Consolidated Standards of Reporting 
Trials publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
eligible for rescreening at a later date, depending on the reason for the initial screen failure and 
provided enrollment is still open. Rescreening of a patient must be approved by the Sponsor prior 
to rescreening. If a patient is approved for rescreening by the Sponsor, the rescreened patients 
should be assigned the same Screening number as for the initial screening. Up to 3 screenings 
per patient are allowed (2 screening failures). 
7. 
TREATMENTS 
Study treatment is defined as any investigational treatment(s), marketed product(s), placebo, or 
medical device(s) intended to be administered to a study patient according to the study protocol. 
7.1. 
Treatments Administered 
All patients will receive open-label setmelanotide in this study.  
Setmelanotide will be supplied by Rhythm. 
Setmelanotide drug product is a preserved, multidose solution for injection to be administered 
SC, QD. It is formulated as a 10 mg/mL sterile, preserved, clear to slightly opalescent, colorless 
to slightly colored solution, practically free of visible particles. The drug product solution (1 mL) 
is presented in a clear 2R glass vial with a rubber stopper.  
Packaging and labeling will be prepared to meet all regulatory requirements. 
Setmelanotide will be administered as SC injection QD.  
7.2. 
Method of Treatment Assignment 
All patients will receive setmelanotide in this study. The starting setmelanotide dose is dependent 
on patient age at the time of Visit 2 (Day 1); however, for all patients, the setmelanotide dose 
will be titrated to a final dose of 3.0 mg/day (initial titration phase), as follows:  
Patients aged 6 to <16 years 
• Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will 
receive setmelanotide 1.0 mg/day.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
32 of 67 
Confidential 
• Starting at approximately Day 15 through 28, patients will receive setmelanotide 
2.0 mg/day.  
• Patients/caregivers will be contacted by study center personnel on Day 15 to ensure 
dose titration has occurred and to document any AEs. 
• Starting on approximately Day 29 (Visit 3), patients will receive setmelanotide 
3.0 mg/day; patients will continue to receive setmelanotide 3.0 mg/day for 12 weeks.  
The dose of setmelanotide should be titrated as explained in the SoA. 
Patients aged ≥16 years 
• Starting at Baseline (Day 1; Visit 2) through approximately Day 14, patients will 
receive setmelanotide 2.0 mg/day.  
• Starting at approximately Day 15, patients will receive setmelanotide 3.0 mg/day; 
patients will continue to receive setmelanotide 3.0 mg/day for 14 weeks. 
The dose of setmelanotide should be titrated as explained in the SoA.  
7.3. 
Dose Modification 
The intention of the study is for all patients to reach a dose of 3.0 mg per day. If a patient 
experiences tolerability or safety issues during the dose titration phase, a lower maintenance dose 
may be used during the trial, with approval by the Sponsor. Additionally, after titration to a dose 
of 3.0 mg is complete, the setmelanotide dose should not be lowered unless discussed and 
approved by the Sponsor. No dose greater than 3.0 mg per day will be used in this study. 
7.4. 
Blinding 
This is an open-label study; no blinding methods will be employed. 
7.5. 
Preparation/Handling/Storage/Accountability 
Only patients enrolled in the study may receive study treatment and only authorized site staff 
may supply or administer study treatment. All study treatments must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the Investigator and authorized site staff. 
All study drug must be kept in a secure, limited-access storage area at a temperature between 
2°C to 8°C. Setmelanotide is stable at room temperature for a short time period that will allow 
patients to transport study drug home; ice packs and cooler bags will be provided for patients and 
caretakers who will travel long distances from the clinic. Once home, the un-opened study drug 
must be stored in the patient’s refrigerator. Opened study drug may be stored at room 
temperature for up to 30 days.  
There will be extensive training of patients in drug administration including educational 
materials. Study specific training materials will be provided to both the investigative staff and 
study patients and caregivers.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
33 of 67 
Confidential 
7.6. 
Assessment of Treatment Compliance and Study Drug 
Accountability  
Accountability for the study drug at the study site is the responsibility of the Investigator. The 
Investigator will ensure that the study drug is used only in accordance with this protocol. Where 
allowed, the Investigator may choose to assign drug accountability responsibilities to a 
pharmacist or other appropriate individual. Drug accountability records indicating the delivery 
date to the site, inventory at the site, use by each patient, return of all used study drug to the 
study center, and return to Rhythm (or disposal of the drug, if approved by Rhythm) will be 
maintained by the clinical site. Reasons for departure from the expected dispensing regimen must 
also be recorded. The Sponsor or its designee will review drug accountability at the site during 
monitoring visits. 
Compliance to dosing will be monitored throughout the study by having the patient complete a 
daily dosing log that records daily dosing information, including whether the dose was 
administered, and if not administered, the rationale for why it was not administered. If a patient 
is non-compliant with the dosing schedule, the Sponsor may implement steps to ensure 
compliance, eg, sending a nurse to the patient’s home for retraining or having a nurse administer 
the study drug. 
7.7. 
Concomitant Therapy 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Reason for use 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
7.7.1. 
Prohibited Medications 
Unless concomitant medications are likely to present a strong potential safety concern, the 
general goal of this protocol is to allow as many patients with this rare condition to participate in 
the study as possible. 
However, patients are not permitted to enter the study if they have had weight gain >5% during 
the previous 3 months or >2% weight loss during the prior 3 months. It should be noted that 
dietary and/or exercise regimens, with or without the use of medications, supplements or herbal 
treatments associated with weight loss (eg, orlistat, lorcaserin, phentermine, topiramate, 
naltrexone, bupropion, glucagon-like peptide1 [GLP1] receptor agonists, etc.) are allowed if:  
• the regimen and/or dose has been stable for at least 3 months prior to randomization  
• the patient has not experienced weight loss ≥2% during the previous 3 months, AND  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
34 of 67 
Confidential 
• the patient intends to keep the regimen and/or dose stable throughout the course of the 
study.   
GLP-1 receptor agonists may be used up to the dose approved for the treatment of diabetes 
mellitus (eg, liraglutide up to a daily dose of 1.8 mg) as long as (1) it is not being prescribed for 
the treatment of obesity, (2) the dose has been stable for at least 3 months prior to enrollment, 
(3) the patient has not experienced >3% weight loss during the previous 3 months, AND (4) the 
patient intends to keep the dose stable throughout the course of the study. 
Other medications that may cause weight loss (eg, stimulants) are allowed as long as the patient 
(1) has used a stable dose for at least 3 months prior to enrollment, (2) has not lost weight during 
the previous 3 months, and (3) intends to keep the dose of the medication stable through the 
course of the study. 
All concomitant medications should be kept at a stable dose throughout the course of the study, 
unless a dose change is necessary to treat an AE. 
7.8. 
Treatment after the End of the Study 
After the EOS Visit, no further treatment is planned under the auspices of this protocol. Patients 
who meet the primary endpoint of this study may be eligible to enroll in a separate long-term 
extension study under which auspices the patient would continue to receive setmelanotide.  
8. 
DISCONTINUATION/WITHDRAWAL CRITERIA  
Given this rare patient population, every effort will be made to encourage and keep patients 
enrolled in the study until completion, unless there are any safety concerns necessitating 
withdrawal of the patient. Rhythm will provide assistance for any patient and caregiver travel, 
will make available visiting home health care professionals, and any other necessary logistical 
support to ease the burden on the patient in order to facilitate compliance.  
If the patient withdraws consent for disclosure of future information, the Sponsor may retain and 
continue to use any data collected before such a withdrawal of consent. 
If a patient withdraws from the study, he/she may request destruction of any samples taken and 
not tested, and the Investigator must document this in the site study records. 
Patients will be informed that they have the right to withdraw from the study at any time for any 
reason, without prejudice to their medical care. The Investigator also has the right to withdraw 
patients from the study, after discussion with the Sponsor, for reasons such as: 
• AEs, which justify treatment or study withdrawal. For specific predefined events, 
additional monitoring and guidance for the Investigator is provided in Appendix 6. 
• Non-adherence to study drug regimen or protocol requirements. 
• Non-compliance with instructions or failure to return for follow-up. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
35 of 67 
Confidential 
9. 
PATIENT ASSESSMENTS 
Study procedures and their timing are summarized in the SoA (Table 1). Adherence to the study 
design requirements, including those specified in the SoA, is essential and required for study 
conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain a screening log to record details of all 
patients screened and to confirm eligibility or record reasons for screening failure, as applicable.  
When scheduled at the same time point, the order of procedures should be as follows: obtain 
vital signs, perform 12-lead electrocardiogram (ECG), and perform blood draws (at the specified 
time point, if applicable). Adjustments may be made depending upon specific circumstances and 
in consultation with the Sponsor. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the patient should continue or discontinue study treatment. 
9.1. 
Informed Consent/Assent  
A complete description of the study is to be presented to each potential patient, and signed and 
dated informed consent and/or assent is to be obtained before any study-specific procedures are 
performed.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count) and 
obtained before signing of the informed consent form (ICF) may be utilized for Screening or 
Baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
9.2. 
Inclusion/Exclusion Review  
Inclusion and exclusion criteria are to be reviewed per the SoA (Table 1) to ensure the patient is 
eligible for the study.  
9.3. 
Demographics, Concomitant Medications and Medical History 
Review  
Medical history and demographic data including the patient’s gender, race, date of birth, and 
concomitant medication use will be obtained for all patients during the Screening Period 
(Table 1). 
The medical history should be updated on Day 1 prior to first dose of study drug, to assess 
continued study eligibility and adherence to final inclusion/exclusion criteria. This medical 
history update includes a review for changes from Screening as well as a review of the patient’s 
recent medication use to assess whether any changes have occurred since the previous visit. 
9.4. 
Type of Lesions on Magnetic Resonance Imaging 
All patients must have evidence of hypothalamic injury on MRI completed within 8 months of 
Screening. If no MRI is available, then it may be repeated during the Screening Period. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
36 of 67 
Confidential 
Hypothalamic Lesion score [Roth 2015] will be noted and collected for each patient when 
possible.  
9.5. 
Height 
For patients ≥18 years of age, height needs to be measured at Screening only. For patients aged 
<18 years, height is to be measured at the time points designated in the SoA (Table 1). 
Height (cm) will be measured, without shoes, socks, or hats, using a wall-mounted stadiometer. 
All measurements will be done in triplicate at each time point and recorded to the nearest half 
cm. 
9.6. 
Weight 
Weight (kg) will be recorded at the time points designated in the SoA (Table 1). Weight (kg) is 
to be measured at the clinic using the same scale throughout the study, including the Screening 
Visit, after patients have emptied their bladders and pockets and after fasting for at least 8 hours. 
Patients are to wear light clothing or underwear and no shoes, and will be weighed at 
approximately the same time of day. Weight should be recorded to the nearest tenth of a decimal 
place if reported by a digital scale or to the nearest half of a kg if reported by a mechanical scale. 
The scale should be calibrated on a regular basis per the manufacturer’s specifications.  
9.7. 
Waist Circumference 
Waist circumference (cm) will be measured according to the National Heart, Lung, and Blood 
Institute (NHLBI) criteria [NHLBI 2000] during the study at the time points designated in the 
SoA (Table 1). All measurements will be done in triplicate at each time point and recorded to the 
nearest half cm.  
Waist circumference should be measured after patients have fasted for at least 8 hours and at 
approximately the same time at each visit. Patients should be standing and in light clothing and 
have emptied their bladder. Whenever possible, the same study staff member should perform the 
measurement for a given patient to minimize variability. 
9.8. 
Body Composition Assessment by DXA 
Patients will have body composition measurements performed by dual-energy X-ray 
absorptiometry (DXA) at the time points designated in the SoA (Table 1). If DXA is not 
available at the clinic, this procedure may be skipped, with prior approval of the Sponsor. 
For DXA methodology, which uses low dose x-rays to non-invasively assess skeletal and soft 
tissue density, half-body scans may be performed for patients 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. If patients have severe obesity and cannot be 
measured in the DXA scanner available due to practical limitations (size of DXA machine), then 
this assessment can be skipped. If DXA is available but patients are too large to enter at 
Screening, DXA should be added to assessments (in addition to the methods used at study entry) 
at a time when patients may have lost enough weight to do adequate DXA measurements (as 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
37 of 67 
Confidential 
DXA may provide additional information above BIA, for example). If DXA is begun in the 
middle of the study, it will be considered supplemental to the methodology used at Baseline.  
9.9. 
Physical Examination and Comprehensive Skin Examination 
9.9.1. 
Physical Examinations 
A complete physical examination will be conducted at Screening and at the EOS visit (Visit 7). 
At other time points, as designated in the SoA, an abbreviated examination will be performed 
(Table 1).  
• A complete physical examination will include review of peripheral lymph nodes, 
head, eyes (including conjunctiva), ears, nose, mouth and oropharynx, neck, heart, 
lungs, abdomen, musculoskeletal including back, extremities and neurologic.  
• The abbreviated examination should focus on heart, lungs, skin, neurologic 
examination, and any areas of previous abnormal findings, noting any changes from 
baseline.  
• Tanner Staging for assessment of pubertal development will be conducted for those 
patients who have yet to reach Tanner Stage V.  
Whenever possible, the same trained health care professional will conduct the exam and Tanner 
Staging. 
All physical examinations are to be conducted in adequate light.  
Changes from baseline in any physical examination findings identified by the Investigator as 
clinically significant must be recorded as an AE on the appropriate electronic case report form 
(eCRF). 
9.9.2. 
Comprehensive Skin Examinations 
A comprehensive skin examination will be performed by the Investigator at the time points 
designated in the SoA (Table 1).  
A comprehensive skin examination will be performed by the Investigator. The skin examination 
should include a full body (head-to-toe skin examination). If any concerning lesions are 
identified during Screening, the patient should be referred to a dermatologist. Any concerning 
lesions will be biopsied by the dermatologist and results must be benign prior to the first dose of 
setmelanotide. If the pre-treatment biopsy results are of concern, the patient will be excluded 
from the study. Additionally, any concerning lesion or change in an existing lesion during the 
course of the study must be evaluated by the dermatologist and biopsied, if clinically indicated in 
the opinion of the dermatologist. 
9.10. 
Fitzpatrick Classification Scale 
Each patient is to be categorized for skin type according to the Fitzpatrick scale [Fitzpatrick]. 
The Fitzpatrick Scale is presented in Appendix 3. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
38 of 67 
Confidential 
9.11. 
Vital Signs 
Vital signs include systolic and diastolic BP, HR, respiration rate (RR), and body temperature 
(°C). Vital signs will be obtained in the sitting position following at least 5 minutes of rest each 
time point designated in the SoA (Table 1).  
All BP and HR measurements will be taken in triplicate, approximately 2 minutes apart. When 
possible, BP should be taken in the non-dominant arm throughout the study, using the same 
methodology (automated or manual).  
Repeat measures and more frequent monitoring can be implemented for significant increases in 
BP or HR.  
9.12. 
Electrocardiograms 
A single 12-lead ECG will be performed at the time points designated in the SoA (Table 1). 
ECGs are to be performed with the patient in the supine position following a period of at least 
10 minutes of rest. At Visit 2, the ECG will be performed before and 4 hours after dosing, and at 
Visit 3 and Visit 6, the ECG will be performed at 4 hours after dosing. 
9.13. 
Clinical Laboratory Tests 
Blood and urine samples for clinical laboratory tests are to be collected at the time points 
designated in the SoA (Table 1). Clinical safety laboratory tests are to be performed by the local 
laboratory and patients are to be fasting for 8 hours. Samples are to be collected prior to 
setmelanotide administration.  
All clinically significant laboratory abnormalities will be followed-up by repeat testing and 
further investigated according to the judgment of the Investigator.  
Clinical laboratory parameters to be evaluated, including hematology, clinical chemistry,
 
as well as urine analysis, are identified in the SoA (Table 1). 
9.13.1. 
Pregnancy Testing 
Pregnancy testing is to be performed for female patients of childbearing potential, as defined in 
Section 9.19.5. 
A urine pregnancy test may be performed to expedite availability of results prior to dosing on 
Day 1. At all other time points designated in the SoA (Table 1), serum pregnancy tests may be 
performed; setmelanotide dosing may continue with results pending. 
9.14. 
Injection Site Examination 
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 Appendix 5. 
In addition, unscheduled evaluations may also be recorded as warranted by clinical conditions. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
39 of 67 
Confidential 
9.15. 
Patient Questionnaires 
The patient questionnaires will be answered by the patient and/or caretaker after careful training.  
9.15.1. 
Hunger Scores 
Hunger will be assessed as shown in the SoA (Table 1).  
For all patients, the daily hunger questionnaire will be completed prior to the morning meal 
(fasted) and prior to dosing each day in the morning.  
The Global Hunger Questions and Daily Hunger Questionnaire are described in Appendix 4. The 
Global Hunger Questions will be completed during specified study visits at the clinic and the 
Daily Hunger Questionnaire will be recorded each day directly into an electronic data capture 
device (paper version can be used if needed). 
9.15.2. 
Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-
CT) 
The Impact of Weight on Quality of Life-Lite Clinical Trials (IWQOL-Lite-CT) is a validated 
20-item self-report measure of obesity-specific quality of life questionnaire [Kolotkin 2019]. The 
IWQOL-Lite-CT yields a Total score and 3 composite scores: Physical (7 items), including 
Physical Function (5 items) and Psychosocial (13 items). The IWQOL-Lite will be conducted in 
patients 18 years of age and older at the time points designated in the SoA (Table 1).  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
40 of 67 
Confidential 
9.15.3. 
Patient Health Questionnaire-9 (PHQ-9 or PHQ-A) 
The PHQ-9 is a 9-item depression scale of the Patient Health Questionnaire. The PHQ-9 is a tool 
for assisting clinicians in diagnosing depression as well as selecting and monitoring treatment. 
The PHQ-A is a modification of the PHQ-9 for adolescents. After the patient has completed the 
PHQ-9 or PHQ-A questionnaire, it is scored by the study staff.  
The PHQ-A will be administered to patients 11-17 years of age and the PHQ-9 will be 
administered to patients ≥18 years of age. 
The PHQ-9 or PHQ-A will be implemented at the time points designated in the SoA at the time 
points designated in the SoA (Table 1). 
In order to be eligible for the study, the patient must have a Screening PHQ-9/PHQ-A score <15. 
9.15.4. 
Columbia-Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a tool used not only to predict suicide attempts but to assess the full range of 
evidence-based ideation and behavior items, with criteria for next steps (eg, referral to an MPH). 
There are 2 versions of the C-SSRS that will be administered according to the SoA (Table 1): 
1. The Baseline/Screening version of the scale combines the Baseline and Screening forms 
to assess suicidality in a patient’s lifetime and during a predefined time. This version can 
assess a patient’s lifetime suicidality for data collection purposes as well as eligibility 
based on inclusion/exclusion criteria. 
2. The Since Last Visit version of the scale assesses suicidality since the patient’s last visit. 
This version is meant to assess patients who have completed at least 1 initial C-SSRS 
assessment and should be used in every subsequent visit. The ‘Since Last Visit’ version 
of the C-SSRS is asking about any suicidal thoughts or behaviors the patient/participant 
may have had since the last time the C-SSRS was administered.  
To be eligible for the study, a patient cannot have a suicidal ideation of type 4 or 5, any lifetime 
history of a suicide attempt, or any suicidal behavior in the last month. 
Significantly cognitively impaired patients may not be able to complete the PHQ-9 or C-SSRS as 
intended. If in the clinical opinion of the Primary Investigator a specific patient cannot complete 
either or both of these instruments, the following strategies may be employed: 
• Regardless of the patient’s actual age, the site staff may administer the pediatric 
version of the C-SSRS, which may be more appropriate to the cognitive age of the 
patient. 
• Site staff may administer the questions directly to the patient or may ask for the 
information from a third party, such as a caregiver or family members, as appropriate. 
• The Primary Investigator may use his/her clinical judgment to skip any questionnaires 
that he/she feels are not appropriate for a specific patient. 
Any deviation from the intended use of an instrument should be documented by the Primary 
Investigator, along with the reason for the deviation. If the PHQ-9 or C-SSRS are not 
administered, the Primary Investigator should document that the issue of suicidality was assessed 
clinically (eg, discussion with caregivers). 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
41 of 67 
Confidential 
9.15.5. 
Short Form-12/Short Form-10 (SF-12/SF-10) 
The Short Form-12 (SF-12) is a self-reported outcome measure assessing the impact of health on 
an individual’s everyday life that is often used as a quality of life measure. It is a 12-item 
shortened form of the 36-item SF-36 that can be completed by the patient or through interview. 
The SF-10 is a modified 10-item questionnaire that is to be completed by caregivers rather than 
the patient. The scoring method yields 2 summary measures: a physical summary score and a 
psychosocial summary score. 
The SF-12 will be administered to patients ≥18 years of age and the SF-10 will be administered 
to the parents/caregivers of patients <18 years of age. The SF-12 or SF-10 is to be conducted at 
the time points designated in the SoA (Table 1). 
9.15.6. 
EuroQol-Five Dimension 
Patients will complete either the EuroQol-5 Dimension (EQ-5D)-5L or the EQ-5D-Y. 
• EQ-5D-5L 
Used for patients ≥16 years of age, the EQ-5D-5L is a standardized instrument to measure 
health-related quality of life that can be used in a wide range of health conditions and treatments. 
The EQ-5D-5L consists of a descriptive system and the EQ VAS. The EQ-5D instrument will be 
administered according to the SoA (Table 1). 
• EQ-5D-Y 
Used for patients 8 to 16 years of age, the EQ-5D-Y is a standardized instrument to measure 
health-related quality of life that can be used in a wide range of health conditions and treatments. 
It is the child-friendly version of the EQ-5D. The EQ-5D-Y consists of a descriptive system and 
the EQ VAS. The EQ-5D-Y instrument will be administered according to the SoA (Table 1). 
Patients between 6 and 8 years of age will not complete this questionnaire. 
9.16. 
Telephone Call 
The site will call a patient’s home on Day 15 to assess AEs and ensure the patient escalated to 
the appropriate dose, depending on age, as outlined in the SoA (Table 1).  
9.17. 
Study Drug Administration 
Study drug will be administered daily as outlined in the SoA (Table 1).  
9.18. 
Dispensing/Return of Study Drug 
Study drug will be dispensed as outlined in the SoA (Table 1) and Section 7.5. Any unused drug 
will be returned to the clinic site and the Sponsor as described in Section 7.6.  
9.19. 
Adverse Events 
The definitions of an AE or SAE can be found in Appendix 6. 
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
42 of 67 
Confidential 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or study procedures, or that caused the 
patient to discontinue study treatment (see Section 8).  
9.19.1. 
Time Period and Frequency for Collecting AE and SAE Information  
All AEs, including SAEs, will be collected from the provision of informed consent until the EOS 
visit (Visit 7) at the time points designated in the SoA (Table 1). AEs reported after dosing on 
Day 1 will be considered TEAEs. 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the 
eCRF not the AE section. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 6. The Investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient has been 
discharged from the study, and he/she considers the event to be reasonably related to the study 
treatment or study participation, the Investigator must promptly notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 6. 
9.19.2. 
Method of Detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
9.19.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event is 
otherwise explained, or the patient is lost to follow-up. Further information on follow-up 
procedures is given in Appendix 6. 
9.19.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the Investigator to the sponsor of a SAE is essential so that 
regulatory obligations and ethical responsibilities towards the safety of patients and 
the safety of a study treatment under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study treatment under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB), and investigators. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
43 of 67 
Confidential 
• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary. 
• An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will 
review and then file it along with the Investigator’s Brochure and will notify the IRB, 
if appropriate according to local requirements. 
9.19.5. 
Pregnancy and Contraception 
Setmelanotide has not been completely evaluated in any preclinical Developmental and 
Reproductive Toxicology Studies to date, therefore, the effects of setmelanotide on embryo-fetal 
development are unknown at this time.  
Females must not be pregnant and must have a negative pregnancy test result at each visit.  
Furthermore, it is imperative that all study patients adhere to the contraception requirements as 
outlined below.  
Female patients of childbearing potential, defined as fertile, following menarche and until 
becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy), must use a highly effective form of contraception throughout the study 
and for 90 days following the study. Highly effective forms of contraception include:  
• Combined (estrogen and progestogen) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal)  
• Progestogen-only hormonal contraception associated with inhibition of ovulation 
(oral, injectable, implantable)  
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system  
• Bilateral tubal occlusion  
• Vasectomized partner (provided that the vasectomized partner is the sole sexual 
partner of the woman of childbearing potential (WOCBP), and the vasectomized 
partner has received medical assessment of surgical success)  
• Sexual abstinence, only if it is the preferred and usual lifestyle of the patient 
Females of non-childbearing potential, defined as permanently sterile (status post 
hysterectomy, bilateral oophorectomy, or bilateral salpingectomy) or post-menopausal for at 
least 12 months (and confirmed with a screening FSH level in the post-menopausal range) do not 
require contraception during the study. Younger female patients who are not sexually mature at 
study entry will be assessed for Tanner staging and required to comply with contraception and 
pregnancy testing requirements at first menarche. 
Male patients with female partner(s) of childbearing potential must agree to use contraception 
(eg, if they have not had a vasectomy then should either (a) abstain from reproductive sexual 
intercourse or (b) use a single barrier method in combination with a female partner using a highly 
reliable method (ie, hormonal or IUD) if they become sexually active during the study and for 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
44 of 67 
Confidential 
90 days following the study. Male patients must not donate sperm for 90 days following their 
participation in the study.  
If a pregnancy should occur while a male or female patient is on study drug, relevant pregnancies 
will be followed up on to determine birth and neonatal outcomes. 
9.19.6. 
Overdose 
One accidental overdose has been reported in the clinical program in a pediatric patient receiving 
a 5 mg dose instead of a 0.5-mg dose. The patient had mild symptoms which resolved. 
In the event of an overdose, the Investigator should contact the Medical Monitor immediately. 
Appropriate supportive treatment should be initiated according to the patient’s clinical signs and 
symptoms. 
The quantity of the excess dose as well as the duration of the overdose are to be documented in 
the eCRF. 
Decisions regarding dose interruptions or modifications will be made by the Investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the patient. 
9.19.7. 
Depression or Suicidality 
A patient should be referred to a mental health professional (MHP) if he/she has: 
• A PHQ-9/PHQ-A score ≥10.  
• Any suicidal behavior. 
• Any suicidal ideation of type 4 or 5 on the C-SSRS. 
A referral to a MHP should also be made if in the opinion of the Investigator it is necessary for 
the safety of the patient. If a patient’s psychiatric disorder can be adequately treated with psycho- 
and/or pharmacotherapy, then the patient, at the discretion of the MHP, should be continued in 
the study. 
9.20. 
Pharmacokinetics 
Pharmacokinetic parameters are not evaluated in this study. 
9.21. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
9.22. 
Genetics 
Genetics are not evaluated in this study. 
9.23. 
Biomarkers 
Biomarkers are not evaluated in this study. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
45 of 67 
Confidential 
10. 
STATISTICAL CONSIDERATIONS 
This section describes the plans for analysis. Details of the statistical methodology for summaries 
and statistical analyses will be provided in a separate statistical analysis plan (SAP), which will 
be maintained by the Sponsor. The SAP may modify the plans outlined in the protocol; however, 
any major modifications of the primary endpoint definition and/or its analysis will also be 
reflected in a protocol amendment. If, after the study has completed, changes are made to the 
statistical analysis plan, then these deviations to the plan will be listed, along with an explanation 
as to why they occurred, in the Clinical Study Report for the study, as appropriate.  
10.1. 
Sample Size Determination  
The study is a Phase 2, Proof-of-Concept study. The objective of this study is to evaluate safety 
and preliminary efficacy on weight loss in patients with HO. The primary endpoint is the 
proportion of patients who achieve at least 5% reduction from baseline in BMI at ~16 weeks of 
treatment with setmelanotide. Given the exploratory nature of the study, the sample size is 
primarily driven by clinical considerations, with the considerations of statistical testing. It is 
planned to enroll ~5 to 10 patients aged >12 years, and up to 10 patients between 6 and 12 years. 
With 10 patients aged >12 years and up to 10 patients aged 6 to 12 years, at 1-sided 
0.05 significance level, the study provides ~90% power to reject the null hypothesis that the true 
response rate is less than 5%, assuming a 40% target response rate in setmelanotide. 
10.2. 
Populations for Analyses 
There are 3 analysis population defined in the protocol:  
• Full Analysis Set: All patients who received at least 1 dose of setmelanotide and have 
baseline data. 
• Per-Protocol Set: All patients in FAS without any major protocol violations that will 
result in exclusion of the patients from the analysis 
• Safety Analysis Set: All patients who received at least 1 dose of study drug. 
10.3. 
Statistical Analyses 
A separate statistical analysis plan will be developed, which will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a summary 
of the planned statistical analyses of the most important endpoints including primary and other 
endpoints 
The primary endpoint is defined as the proportion of patients who achieve at least 5% BMI 
reduction from baseline, at ~16 weeks of treatment with setmelanotide. The primary statistical 
hypothesis will be tested with an exact binomial test at 1-sided 0.05 significant level, compared 
to a historical control rate of 5%. The 2-sided 90% Clopper-Pearson confidence interval will be 
provided.  
For the primary endpoint, and all other endpoints, the last value obtained prior to the first dose of 
active treatment will be considered the baseline value for statistical analyses.  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
46 of 67 
Confidential 
AEs will be coded by using the most current version of Medical Dictionary for Regulatory 
Activities and summarized by system organ class, preferred term, and treatment group for the 
number and percent of AEs reported, the number of patients reporting each AE, and the number 
of patients with any AE.  
A by-patient AE data listing including onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided.  
Safety data including laboratory evaluations and vital signs assessments will be summarized by 
time of collection and by treatment group. In addition, change from baseline to any post-dose 
values will be summarized for vital signs and clinical laboratory results. Frequency of patients 
with abnormal safety laboratory results will be tabulated by treatment.  
10.3.1. 
Interim Analyses  
There is no planned interim analysis for the purposes of modifying the study. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
47 of 67 
Confidential 
11. 
REFERENCES 
Abuzzahab MJ, Roth CL, Shoemaker AH. Hypothalamic Obesity: Prologue and Promise. Horm 
Res Paediatr 2019;91(2):128-136. 
Ahmet A, Blaser S, Stephens D, Guger S, Rutkas JT, Hamilton J. Weight gain in 
craniopharyngioma--a model for hypothalamic obesity. J Pediatr Endocrinol Metab 2006;19:121-
7.  
An JJ, Rhee Y, Kim SH, et al. Peripheral effect of alpha-melanocyte-stimulating hormone on 
fatty acid oxidation in skeletal muscle. J Biol Chem 2007;282:2862-70. 
Bischof JM, Van Der Ploeg LH, Colmers WF, Wevrick R. Magel2-null mice are hyper-
responsive to setmelanotide, a melanocortin 4 receptor agonist. Br J Pharmacol 2016;173:2614-
21.  
Clement K, Biebermann H, Farooqi IS, et al. MC4R agonism promotes durable weight loss in 
patients with leptin receptor deficiency. Nat Med 2018;24:551-5. 
Daousi C, Dunn AJ, Foy PM, MacFarlane IA, Pinkney JH. Endocrine and neuroanatomic 
features associated with weight gain and obesity in adult patients with hypothalamic damage. 
Am J Med 2005;118:45-50.  
DeVile CJ, Grant DB, Hayward RD, Stanhope R. Growth and endocrine sequelae of 
craniopharyngioma. Arch Dis Child 1996;75:108-14.  
Elfers C, Ralston M, Roth CL. Studies of different female rat models of hypothalamic obesity. 
J Pediatr Endocrinol Metab 2011;24:131-7. 
Enriori PJ, Chen W, Garcia-Rudaz MC, et al. alpha-Melanocyte stimulating hormone promotes 
muscle glucose uptake via melanocortin 5 receptors. Mol Metab 2016;5:807-22.  
Gottesdiener K, Connors H, Van der Ploeg L, et al. Analysis of the synthetic peptide RM-493, a 
melanocortin-4 receptor (MC4R) agonist, on cardiovascular parameters in three Phase1b/2a 
studies. Poster - Obesity Society, 2015. 
Greenfield JR, Miller JW, Keogh JM, et al. Modulation of blood pressure by central 
melanocortinergic pathways N Engl J Med 2009;360(1):44-52.  
Holland J, Sorrell J, Yates E, et al. A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue 
Expansion Independently of Energy Intake. Cell Rep 2019;27:2399-410 e6.  
Holmer H, Pozarek G, Wirfalt E, et al. Reduced energy expenditure and impaired feeding-related 
signals but not high energy intake reinforces hypothalamic obesity in adults with childhood onset 
craniopharyngioma. J Clin Endocrinol Metab 2010;95:5395-402.  
Hwa JJ, Ghibaudi L, Gao J, Parker EM. Central melanocortin system modulates energy intake 
and expenditure of obese and lean Zucker rats. Am J Physiol Regul Integr Comp Physiol 
2001;281:R444-51.  
Kievet P, Halem H, Marks D, et al. Chronic treatment with a melanocortin-4 receptor agonist 
causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-
induced obese rhesus macaques. Diabetes 2013;62:490-497. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
48 of 67 
Confidential 
Kolotkin RL, Williams VSL, Ervin CM, et al. Validation of a new measure of quality of life in 
obesity trials: Impact of Weight on Quality of Life-Lite Clinical Trials Version. Clin Obes 
2019;9(3):e12310. 
Kuhnen P, Clement K, Wiegand S, et al. Proopiomelanocortin Deficiency Treated with a 
Melanocortin-4 Receptor Agonist. N Engl J Med 2016;375:240-6.  
Kuhnen P, Krude H, Biebermann H. Melanocortin-4 Receptor Signalling: Importance for Weight 
Regulation and Obesity Treatment. Trends Mol Med 2019;25:136-48. 
NHLBI. The Practical Guide Identification, Evaluation, and Treatment of Overweight and Obese 
in Adults. NIH Publication No. 00-4084, October 2000. 
Patel L, Cooper CD, Quinton ND, et al. Serum leptin and leptin binding activity in children and 
adolescents with hypothalamic dysfunction. J Pediatr Endocrinol Metab 2002;15:963-71.  
Roth C, Wilken B, Hanefeld F, Schroter W, Leonhardt U. Hyperphagia in children with 
craniopharyngioma is associated with hyperleptinaemia and a failure in the downregulation of 
appetite. Eur J Endocrinol 1998;138:89-91.  
Roth CL, Blevins JE, Ralston M, et al. A novel rodent model that mimics the metabolic sequelae 
of obese craniopharyngioma patients. Pediatr Res 2011;69:230-6.  
Roth CL, Elfers CT, Morton GJ. A Model of Disturbed Weight Regulatory Pathways in 
Hypothalamic Obesity Abstract NIH NIDDK Scientific Workshop- Rare Syndromic Body Fat 
Disorders, March 1 and 2, 2012.  
Roth CL, Enriori PJ, Gebhardt U, et al. Changes of peripheral alpha-melanocyte-stimulating 
hormone in childhood obesity. Metabolism 2010;59:186-94.  
Roth CL, Gebhardt U, Muller HL. Appetite-regulating hormone changes in patients with 
craniopharyngioma. Obesity (Silver Spring) 2011;19:36-42.  
Roth CL, Eslamy H, Werny D, et al. Semiquantitative analysis of hypothalamic damage on MRI 
predicts risk for hypothalamic obesity. Obesity (Silver Spring) 2015;23(6):1226-33.  
Shaikh MG, Grundy RG, Kirk JM. Hyperleptinaemia rather than fasting hyperinsulinaemia is 
associated with obesity following hypothalamic damage in children. Eur J Endocrinol 
2008;159:791-7.  
Sharma S, Garfield AS, Shah B, et al. Current Mechanistic and Pharmacodynamic 
Understanding of Melanocortin-4 Receptor Activation. Molecules 2019;24.  
US Department of Health and Human Services, Food and Drug Administration, Center for Drug 
Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER). 
Guidance for Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation. Silver 
Spring, MD. July 2009. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
49 of 67 
Confidential 
12. 
APPENDICES 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
50 of 67 
Confidential 
APPENDIX 1. ABBREVIATIONS AND TRADEMARKS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase 
ARC 
Arcuate nucleus 
AST 
Aspartate aminotransferase 
BMI 
Body mass index 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CMHL 
Combined medial hypothalamic lesion 
COVID-19 
Coronavirus Disease 2019 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
Cardiovascular 
DXA 
Dual-energy X-ray absorptiometry 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EOS 
End-of-Study 
EQ-5D 
EuroQol-5 Dimension 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
GLP-1 
Glucagon-like peptide-1 
HDL 
High-density lipoprotein 
HO 
Hypothalamic obesity 
HR 
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IRB 
Institutional Review Board 
IUD 
Intrauterine device 
IWQOL-Lite-CT 
Impact of Weight on Quality of Life-Lite Clinical Trials Version  

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
51 of 67 
Confidential 
Abbreviation 
Definition 
LEPR 
Leptin receptor 
MC4R 
Melanocortin 4 receptor 
MDD 
Major Depressive Disorder 
MHP 
Mental health professional 
mPEG/DSPE 
N-[Carbonyl-methoxypolyethylene glycol 2000]-1,2-distearoyl- 
glycero-3-phosphoethanolamine sodium salt 
MRI 
Magnetic resonance imaging 
MSH 
Melanocortin stimulating hormone 
NHLBI 
National Heart, Lung, and Blood Institute 
PGIC 
Patient global impression of change 
PGIS 
Patient global impression of severity 
PHQ 
Patient Health Questionnaire 
POMC 
Proopiomelanocortin 
PVN 
Paraventricular nucleus 
QD 
Once daily 
RBC 
Red blood cell 
RR 
Respiration rate 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous(ly) 
SF 
Short Form 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reaction 
TEAE 
Treatment-emergent adverse event 
US 
United States 
VMN 
Ventromedial nucleus of the hypothalamus 
WOCBP 
Woman of childbearing potential 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
52 of 67 
Confidential 
APPENDIX 2. CONSIDERATIONS FOR REDUCING PAIN AND 
DISTRESS IN THE PEDIATRIC POPULATION 
Although the study procedures and assessments required per protocol are classified as “No or 
Minimal Risk” (with the exception of DXA which may be classified as “Minor Increase over 
Minimal Risk”) according to the 2008 Guidance Document “Ethical Considerations for Clinical 
Trials on Medicinal Products Conducted with the Paediatric Population”, considerations for 
reducing pain in distress in participants <18 years of age are suggested below. 
• The clinical trial may only be conducted if it patients the person concerned to as little 
burden and other foreseeable risks as possible. 
• Physical and emotional pain should be prevented as much as possible, and effectively 
treated when unavoidable. 
• In order to minimize pain, distress, and fear, facilities should be appropriate to 
childcare, and the personnel should be trained to look after children and supervised by 
experienced health care professionals. Staff should be trained to communicate with 
both parents (or legal representative) and children. Generally, this would assume non-
adult patients are being studied at experienced pediatric centers.  
• For most procedures, the child should always be accompanied by a trial-related staff 
member who could provide reassurance. At the sign of distress and/or dissent, the 
procedure should be stopped. A short pause to allow the child to feel in control, 
further explanation, and an assessment of the situation may be needed to reassure the 
child, or to decide to definitely abandon the procedure at the discretion of the 
Investigator. 
• In all situations, investigations/interventions should be limited to the minimum 
required for obtaining valid data and performed using size-/age-appropriate material 
and devices, including limiting in advance the number of attempts for sampling. 
• Study drug injections should only be performed by parents (or home health care 
professionals), unless the child is of suitable age and competency, and desires the 
ability to do so. 
• Although almost all study procedures are classified as low risk (with the exception of 
DXA which may be classified as “minor increase over minimal risk”), risk should be 
continuously monitored and assessed by appropriate personnel.  
• For assessments in which there is a psychological component, measures should be 
taken to minimize distress. For example, Tanner Staging assessments could utilize a 
diagram for the child to point to and indicate what stage they currently are, vs. having 
to have an exam without clothes. 
A comment on benefit risk: Risk is very low, from procedures and/or known safety profile of the 
drug (both clinically and toxicologically, where large margins and preliminary data from juvenile 
toxicology studies have not identified any new or concerning safety concerns), and based on one 
representative example of rare genetic disorder of obesity impacting the MC4 pathway, there is 
the possibility of major benefit. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
53 of 67 
Confidential 
APPENDIX 3. FITZPATRICK SCALE 
Skin 
Type 
Skin Color 
Characteristics 
I 
White; very fair; red or blond hair; blue eyes; freckles 
Always burns, never tans 
II 
White; fair; red or blond hair; blue, hazel, or green eyes 
Usually burns, tans with difficulty 
III 
Cream white; fair with any eye or hair color; very 
common 
Sometimes mild burn, gradually 
tans 
IV 
Brown; typical Mediterranean Caucasian skin 
Rarely burns, tans with ease 
V 
Dark Brown; mid-eastern skin types 
Very rarely burns, tans very easily 
VI 
Black 
Never burns, tans very easily 
Fitzpatrick TB: Soleil et peau. J Med Esthet 1975;2:33034. 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
54 of 67 
Confidential 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
55 of 67 
Confidential 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
56 of 67 
Confidential 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
58 of 67 
Confidential 
APPENDIX 6. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES 
FOR RECORDING, EVALUATING, FOLLOW-UP, AND 
REPORTING 
Definition of Adverse Event (AE) 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study patient, temporally 
associated with the use of study treatment, whether or not considered related to the study treatment. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use 
of study treatment. 
 
Events Meeting the AE Definition  
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (eg, ECG, radiological scans, vital signs measurements), including those that worsen 
from baseline, considered clinically significant in the medical and scientific judgment of the 
investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study treatment administration even though it may 
have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
“Lack of efficacy” or “failure of expected pharmacological action” per se will not be reported as an 
AE or SAE. Such instances will be captured in the efficacy assessments. However, the signs, 
symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as AE or SAE if 
they fulfil the definition of an AE or SAE.  
 
Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the patient’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the patient’s condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at 
the start of the study that do not worsen. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
59 of 67 
Confidential 
Definition of Serious Adverse Event (SAE) 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
• 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the patient was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
• 
In general, hospitalization signifies that the patient has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not 
have been appropriate in the physician’s office or outpatient setting. Complications that occur 
during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other 
serious criteria, the event is serious. When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious. 
• 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline 
is not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance such 
as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, 
sprained ankle) which may interfere with or prevent everyday life functions but do not constitute a 
substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. 
Important medical event 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately life-
threatening or result in death or hospitalization but may jeopardize the patient or may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above definition. 
These events should usually be considered serious. 
Examples of such events include invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that do not 
result in hospitalization, or development of drug dependency or drug abuse. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
60 of 67 
Confidential 
Recording and AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the patient’s medical records in lieu 
of completion of the AE/SAE CRF page. 
• 
There may be instances when copies of medical records for certain cases are requested. In this case, 
all patient identifiers, with the exception of the patient number, will be redacted on the copies of 
the medical records before submission. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information. Whenever possible, the diagnosis (not the individual signs/symptoms) 
will be documented as the AE/SAE. 
 
Assessment of Intensity 
Intensity of all AEs including clinically significant treatment-emergent laboratory abnormalities, 
injection site reactions and potential systemic reactions will be graded according to the National Cancer 
Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. The CTCAE grade 
refers to the severity of the AE and ranges from Grade 1 (mild AE), Grade 2 (moderate AE), Grade 3 
(severe AE) and Grade 4 (life-threatening or disabling AE) to Grade 5 (death related to AE). 
Adverse events not listed by the CTCAE will be graded as follows:  
• 
Mild: An event that is easily tolerated by the patient, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficiently discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe should 
not be confused with a SAE. Severe is a category utilized for rating the intensity of an event; and 
both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as described in 
the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study treatment and each 
occurrence of each AE/SAE. 
• 
A “reasonable possibility” of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as 
well as the temporal relationship of the event to study treatment administration will be considered 
and investigated. 
• 
The investigator will also consult the Investigator’s Brochure (IB) and/or Product Information, for 
marketed products, in his/her assessment. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
61 of 67 
Confidential 
Assessment of Causality 
• 
For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed 
the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report. However, it is very important that the investigator 
always make an assessment of causality for every event before the initial transmission of the 
SAE data. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and send 
a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
A medically qualified Investigator must assess the relationship of any AE (including SAEs) to the use 
of the study drug, as related or not related, based on clinical judgment and using all available 
information, and may include consideration of the following factors: 
• 
Possible alternative causes of the AE, including the disease under treatment, pre-existing 
conditions, concomitant use of other drugs, and presence of environmental or genetic factors.  
• 
The temporal association between study drug exposure and onset of the AE.  
• 
Whether the manifestations of the AE are consistent with known actions or toxicity of the study 
drug. 
• 
The AE resolved or improved with decreasing the dose or stopping use of the study drug 
(dechallenge). Judgment should be used if multiple products are discontinued at the same time. 
The causal relationship between the study drug and the AE will be assessed using one of the following 
categories: 
• 
Not Related: Factors consistent with an assessment of Not Related include: 
− 
Temporal relationship is lacking (eg, the event did not occur within a reasonable time frame 
following administration of the study drug); or 
− 
Other causative factors more likely explain the event (eg, a pre-existing condition, other 
concomitant treatments).  
• 
Related: Factors consistent with an assessment of Related include: 
− 
There is a “reasonable possibility” of a relationship; i.e. there are facts, evidence, and/or 
arguments to suggest a causal relationship (not just that “a relationship cannot be ruled out”); 
− 
There is a positive temporal relationship (eg, the event occurred within a reasonable time frame 
following administration of study drug); 
− 
The AE is more likely explained by the investigational product than by another cause (ie, the 
AE shows a pattern consistent with previous knowledge of the investigational product or the 
class of the study drug). 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
62 of 67 
Confidential 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested to elucidate the nature and/or causality 
of the AE or SAE as fully as possible. This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. 
• 
If a patient dies during participation in the study or during a recognized follow-up period, the 
investigator will provide a copy of any post-mortem findings including histopathology. 
• 
New or updated information will be recorded in the originally completed CRF. 
• 
The investigator will submit any updated SAE data to the Sponsor within 24 hours of receipt of 
the information. 
 
Reporting of SAEs 
SAE Reporting via an Electronic Data Collection Tool 
• 
The primary mechanism for reporting an SAE will be the electronic data collection tool. 
• 
If the electronic system is unavailable for more than 24 hours, then the site will use the paper 
SAE data collection tool (see next section). 
• 
The site will enter the SAE data into the electronic system as soon as it becomes available. 
• 
After the study is completed at a given site, the electronic data collection tool will be taken off-
line to prevent the entry of new data or changes to existing data. 
• 
If a site receives a report of a new SAE from a study patient or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then the 
site can report this information on a paper SAE form (see next section) or by telephone. 
 
SAE Reporting to via Paper CRF 
• 
Facsimile transmission of the SAE paper CRF is the preferred method to transmit this 
information   
• 
In rare circumstances and in the absence of facsimile equipment, notification by telephone is 
acceptable with a copy of the SAE data collection tool sent by overnight mail or courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to complete and 
sign the SAE CRF pages within the designated reporting time frames. 
• 
Contacts for SAE reporting will be provided to sites. 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
63 of 67 
Confidential 
APPENDIX 7. STUDY GOVERNANCE CONSIDERATIONS 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
− Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
− Applicable ICH Good Clinical Practice (GCP) Guidelines 
− Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB by the investigator and 
reviewed and approved by the IRB before the study is initiated.  
• Any amendments to the protocol will require IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study patients.  
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB 
− Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures 
− Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, 
European regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
patient or his/her legally authorized representative and answer all questions regarding 
the study.  
• Patients must be informed that their participation is voluntary. Patients or their legally 
authorized representative will be required to sign a statement of informed consent that 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
64 of 67 
Confidential 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health 
Insurance Portability and Accountability Act requirements, where applicable, and the 
IRB or study center.  
• The medical record must include a statement that written informed consent was 
obtained before the patient was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign 
the ICF. 
• Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the patient or the patient’s legally 
authorized representative.  
Patients who are rescreened are required to sign a new ICF. 
Data Protection 
• Patients will be assigned a unique identifier by the sponsor. Any patient records or 
datasets that are transferred to the sponsor will contain the identifier only; patient 
names or any information which would make the patient identifiable will not be 
transferred.  
• The patient must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the patient who will be required to give consent for their data to 
be used as described in the informed consent.  
• The patient must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB members, and by inspectors from regulatory authorities. 
Data Quality Assurance 
All patient data relating to the study will be recorded on printed or eCRF unless transmitted to 
the sponsor electronically (eg, electronic diary). The Investigator is responsible for verifying that 
data entries are accurate and correct by physically or electronically signing the eCRF. 
The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The Investigator must permit study-related monitoring, audits, IRB review and regulatory agency 
inspections and provide direct access to source data documents. 
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality such 
as Risk Management and Mitigation Strategies and Analytical Risk-Based Monitoring), methods, 
responsibilities and requirements, including handling of noncompliance issues and monitoring 
techniques (central, remote or on-site monitoring) are provided in the Monitoring Plan. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
65 of 67 
Confidential 
The Sponsor assumes accountability for actions delegated to other individuals (eg, Contract 
Research Organizations). 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is being 
conducted in accordance with the currently approved protocol and any other study agreements, 
ICH GCP, and all applicable regulatory requirements. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for at least 2 years after the last marketing application approval 
or 2 years after formal discontinuation of the clinical development of the investigational product 
or according to applicable regulatory requirement(s). If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person willing to 
accept the responsibility. The Sponsor must be notified immediately by telephone or e-mail and 
the notification confirmed in writing if a custodial change occurs. 
Source Documents 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the Investigator’s site. 
Data entered in the eCRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The Investigator may need to 
request previous medical records or transfer records, depending on the study. Also, current 
medical records must be available. 
Any electronic study data are to be entered into a secure, validated data processing system 
and a backup maintained. Any changes to electronic study data will be documented. 
Study and Site Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
For study termination: 
• Discontinuation of further study intervention development. 
For site termination: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB or 
local health authorities, the sponsor's procedures, or GCP guidelines. 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
66 of 67 
Confidential 
Inadequate or no recruitment (evaluated after a reasonable amount of time) of participants by the 
investigator. 
• Total number of participants included earlier than expected. 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research organization(s) 
used in the study of the reason for termination or suspension, as specified by the applicable 
regulatory requirements. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up. 
Publication Policy 
All information regarding setmelanotide supplied by the Sponsor to the Investigator or generated 
as a result of any clinical studies is privileged and confidential information belonging to the 
Sponsor. The Investigator agrees to use Sponsor’s confidential information solely to accomplish 
the study and will not use such information for any other purposes without the prior written 
consent of Rhythm. It is understood that there is an obligation to provide the Sponsor with 
complete and accurate data obtained during the study. The information obtained from the clinical 
study will be used towards the development of setmelanotide and may be disclosed by Rhythm 
to regulatory authority(ies), other investigators, corporate partners, or consultants as required.  
It is anticipated that the results of this study may be presented at scientific meetings and/or 
published in a peer reviewed scientific or medical journal. The Sponsor generally supports 
publication of multicenter studies initially in their entirety and not as individual site data. A 
coordinating investigator will be designated. 
Subsequently, individual Investigators may publish results from the study in compliance with 
their agreement with the Sponsor. 
A pre-publication manuscript is to be provided to Rhythm at least 30 days prior to the 
submission of the manuscript to a publisher. Similarly, the Sponsor will provide any company-
prepared manuscript to the Investigators for review at least 30 days prior to submission to a 
publisher. All publications and presentations must be approved in writing by Rhythm before 
public disclosure. 
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
 

Protocol 
 
RM-493-030 
Rhythm Pharmaceuticals, Inc. 
67 of 67 
Confidential 
APPENDIX 8. GUIDANCE ON STUDY CONDUCT DURING THE 
COVID-19 (CORONAVIRUS) PANDEMIC 
The Coronavirus Disease 2019 (COVID-19) pandemic could impact the conduct of this clinical 
study for several reasons, including: self-isolation/quarantine by patients and study-site 
personnel; travel restrictions/limited access to public places, including hospitals; and 
reassignment of site personnel to critical tasks. 
In accordance with recent health authority guidance, the Sponsor is providing temporary 
considerations for study conduct in the event of disruption of the study. This guidance does not 
supersede any local or government requirements or the clinical judgment of the investigator. If at 
any time a patient’s safety is considered to be at risk, study intervention will be discontinued, and 
study follow-up will be conducted. 
If COVID restrictions are imposed on or by the study site and the site cannot fully carry out 
normal operations, the following measures are recommended on a temporary basis during the 
COVID-19 pandemic: 
• Where possible, every effort should be made to complete all protocol-required 
assessments. In place of a required site visit, a qualified healthcare provider could 
perform study-related procedures as per the Schedule of Events via a home visit, 
including but not limited to collection of body weight, vital signs, physical 
examinations, electrocardiograms (ECGs), recording of adverse events (AEs), 
collection of blood and urine samples. Most efficacy assessments could potentially be 
done off site. Investigators should use their clinical judgment to determine whether a 
patient can continue study treatment in the absence of on-site clinic visits, or consider 
alternatives such as temporary treatment interruption or study discontinuation. 
• All protocol-required assessments missed due to COVID restrictions should be 
documented in detail within the patients’ source documents and should be clearly 
designated as “COVID-19 RELATED”. It must be documented if a site visit is 
instead conducted remotely. Source documentation should detail how each 
assessment was collected (eg, remote vs. on-site, central vs. local laboratory, vital 
signs taken at home by caretaker vs. delegated in-home nursing, etc). 
• If applicable, discontinuations of study interventions and withdrawal from the study 
due to disruption of study conduct by the pandemic should be documented with the 
prefix “COVID-19 RELATED” in the case report form (CRF). 
COVID-19 Infection in Study Patients: 
There is currently no available data suggesting that patients treated with setmelanotide should 
have treatment interrupted during the COVID-19 pandemic. If a patient develops symptoms 
associated with coronavirus infection, it is recommended to confirm the diagnosis using locally 
approved laboratory kits and report it to the local health authorities, as required. Patients with 
positive test results for SARS-COV-2 should have this recorded as an AE, and if hospitalized, 
this should be reported as a serious adverse event (SAE).