Phase 2 Trial to Evaluate Safety and Efficacy of Setmelanotide (RM-493) in Obese Participants With Prader-Willi Syndrome

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

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

Conditions
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Prader-Willi Syndrome

Intervention / Treatment
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* Drug: Setmelanotide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: PWS due to chromosome 15 micro-deletion, maternal uniparental disomy, or imprinting defect, confirmed by fluorescent in situ hybridization, chromosomal microarray, and/or methylation studies. Obese male or female participants weighing at least 50 kilograms (kg) with body mass index (BMI) ≥ 27 kilogram per square meter (kg/m²) Age 16-65 years If a participant has diagnosis of type 2 diabetes, following criteria must be met: hemoglobin A1C (HbA1c) < 7.5% not being managed with insulin. Participants taking glucagon-like peptide-1 (GLP-1) analogues (exenatide or liraglutide) must have been on stable dose for greater than 3 months. Fasting plasma glucose < 140 milligrams per deciliter (mg/dL) No history of ketoacidosis or hyperosmolar coma Vital signs must be within the following ranges and stable. Systolic blood pressure, 90-150 millimeter of mercury (mm Hg) Diastolic blood pressure, 50-90 mm Hg Pulse rate, 40-100 beats per minute (bpm) Stable body weight at home for approximately 2 months (self or guardian-reported loss/gain within ± 5%). Blood pressure (≤ 150/90 mmHg); may include stable dose (≥ 30 days of use) of up to two anti-hypertensive medications that are intended to remain on a stable dose during the protocol Parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the study, and be able to understand and sign the written informed consent. Due to the significant intellectual disability with PWS, assent is to be provided by the participant who cannot consent for himself or herself. Results of screening clinical laboratory tests (complete blood count with differential and platelets and chemistry profile) must be within normal range or, if outside of the normal range, must be accepted by the investigator and sponsor as not clinically significant. Females of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone (FSH) level in the post-menopausal lab range), do not require contraception during the study. All other females of child-bearing potential must agree to use contraception as outlined in the protocol. Males with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study and for 90 days following the study. Male participants must not donate sperm for 90 days following their participation in the study. Participants must be on a stable dose of any allowed chronic concomitant medications while participating in the study. Exclusion Criteria: Recent use (within 3 month) of weight loss agents including herbal medication. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders, Third Edition (DSM-III) disorders which the investigator believes will interfere significantly with study compliance. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15. Any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS). Clinically significant illness in the 8 weeks before screening. History of clinically significant bleeding disorders. Current, clinically significant liver, renal, pulmonary, cardiac, oncologic, or gastrointestinal disease. Diagnosis of type 1 diabetes mellitus or other active endocrine disorders (e.g., Cushing syndrome, or thyroid dysfunction except if on adequate thyroid or glucocorticoid replacement supplement). Cardiovascular disease event including history of congestive heart failure, coronary artery disease, myocardial infarction, second degree or greater heart block or prolonged QT syndrome. Blood pressure > 150/90 mm Hg. Liver disease or liver injury as indicated by abnormal liver function tests, aspartate aminotransferase, alkaline phosphatase, or serum bilirubin (> 1.5 x upper limit of normal for any of these tests) or history of hepatic cirrhosis. History or presence of impaired renal function as indicated by clinically significantly abnormal creatinine, blood urea nitrogen, or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft-Gault equation (< 50 mL/min). History or close family history (parents or siblings) of melanoma. Oculocutaneous albinism (occurs at approximately 1% in PWS). Significant dermatologic findings as part of the Screening comprehensive skin evaluation performed by the dermatologist. Significant history of abuse of drugs or solvents in the year before screening or a positive Drugs of Abuse (DOA) test at screening. History of alcohol abuse in the past year before screening or currently drinks in excess of 21 units per week (3 servings or units/day). Caffeine consumption exceeding 6 cups of caffeinated tea/coffee (or equivalent) per day. Participant is, in the opinion of the Investigator, not suitable to participate in the study. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing. Positive history for human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C tests or tuberculosis. Serious adverse reaction or significant hypersensitivity to any drug. Clinically significant blood loss or blood donation > 500 milliliters (mL) within 3 months. Inadequate venous access. History of low blood counts or recurring infections.

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Setmelanotide 0.5 mg<br>Participants received setmelanotide 0.5 milligrams (mg) once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period) and Day 42 to Day 55 (2-week, randomized withdrawal period). | Drug: Setmelanotide<br>* subcutaneous injection<br>* Other names: RM-493;|
| Experimental: Setmelanotide 1.5 mg<br>Participants received setmelanotide 1.5 once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period), Day 42 to Day 55 (2-week, randomized withdrawal period), and Day 56 to Day 69 (optional 2-week, open-label extension period). | Drug: Setmelanotide<br>* subcutaneous injection<br>* Other names: RM-493;|
| Experimental: Setmelanotide 2.5 mg<br>Participants received setmelanotide 2.5 once daily as a subcutaneous injection from Day 15 to Day 41 (4-week, double-blind randomized treatment period), Day 42 to Day 55 (2-week, randomized withdrawal period), and Day 56 to Day 69 (optional 2-week, open-label extension period). | Drug: Setmelanotide<br>* subcutaneous injection<br>* Other names: RM-493;|
| Placebo Comparator: Placebo<br>Participants received placebo matched to setmelanotide once daily as a subcutaneous injection from Day 1 to Day 14 (2-week, single-blind run-in period), Day 15 to Day 41 (4-week, double-blind randomized treatment period), and Day 42 to Day 55 (2-week, randomized withdrawal period). | Drug: Placebo<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) - Period 2 | An adverse event (AE) was any untoward medical occurrence in a clinical trial participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE is considered to be treatment-emergent if the onset date/time is during or after administration of double-blind study drug or, in the event that onset time precedes double-blind study drug administration, the AE increases in severity during or after administration of double-blind study drug; in either case through 1-week after the last treatment dose. A serious adverse event (SAE) was any untoward medical occurrence that, at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent disability/incapacity; Was a congenital anomaly/birth defect | Days 15 to 41 | 
| Number of Participants Who Experienced a TEAE - Period 3 | An AE was any untoward medical occurrence in a clinical trial participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE is considered to be treatment-emergent if the onset date/time is during or after administration of double-blind study drug or, in the event that onset time precedes double-blind study drug administration, the AE increases in severity during or after administration of double-blind study drug; in either case through 1-week after the last treatment dose. An SAE was any untoward medical occurrence that, at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent disability/incapacity; Was a congenital anomaly/birth defect | Days 42 to 55 | 
| Number of Participants Who Experienced a TEAE - Period 4 | An AE was any untoward medical occurrence in a clinical trial participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE is considered to be treatment-emergent if the onset date/time is during or after administration of double-blind study drug or, in the event that onset time precedes double-blind study drug administration, the AE increases in severity during or after administration of double-blind study drug; in either case through 1-week after the last treatment dose. An SAE was any untoward medical occurrence that, at any dose: Resulted in death; Was life-threatening; Required inpatient hospitalization or prolongation of existing hospitalization; Resulted in persistent disability/incapacity; Was a congenital anomaly/birth defect | Days 56 to 69 | 
| Mean Body Weight - Period 2 |  | Baseline (Day 15) | 
| Percent Change From Baseline in Body Weight - Period 2 |  | Baseline (Day 15) and Day 42 | 
| Overall Score of Prader-Willi Syndrome (PWS) Hyperphagia Questionnaire - Period 2 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Three factors identified from this questionnaire are: Hyperphagic Drive, Hyperphagic Behaviors, and Hyperphagic Severity. Items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Raw scores for each factor were used in data analyses, and the 3 domains were summed for an overall summary index of hyperphagia. Possible scores on the questionnaire range from a minimum score of 10 (no hyperphagia) to a maximum score of 50 (greater hyperphagia). | Baseline (Day 15) | 
| Percent Change From Baseline in Overall Score of Prader-Willi Syndrome (PWS) Hyperphagia Questionnaire - Period 2 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Three factors identified from this questionnaire are: Hyperphagic Drive, Hyperphagic Behaviors, and Hyperphagic Severity. Items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Raw scores for each factor were used in data analyses, and the 3 domains were summed for an overall summary index of hyperphagia. Possible scores on the questionnaire range from a minimum score of 10 (no hyperphagia) to a maximum score of 50 (greater hyperphagia). Percent change from baseline in overall score of PWS hyperphagia questionnaire is presented. | Baseline (Day 15) and Day 42 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Hyperphagic Drive Score of PWS Hyperphagia Questionnaire - Period 2 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Hyperphagic drive score assesses the persistence in asking for food based on 4 items. All 4 items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Possible scores for hyperphagic drive range from a minimum score of 4 (no hyperphagic drive) to a maximum score of 20 (greater hyperphagic drive). Percent change from baseline in hyperphagic drive score of PWS hyperphagia questionnaire is presented. | Baseline (Day 15) and Day 42 | 
| Percent Change From Baseline in Hyperphagic Behaviors Score of PWS Hyperphagia Questionnaire - Period 2 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Hyperphagic behavior factor score assesses food seeking behaviors based on 4 items. All 4 items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Possible scores for hyperphagic behaviors range from a minimum score of 4 (no hyperphagic behavior) to a maximum score of 20 (greater hyperphagic behavior). Percent change from baseline in hyperphagic behaviors score of PWS hyperphagia questionnaire is presented. | Baseline (Day 15) and Day 42 | 
| Percent Change From Baseline in Hyperphagic Severity Score of PWS Hyperphagia Questionnaire - Period 2 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Hyperphagic severity factor score assesses the severity of hyperphagia based on 2 items. Both items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Possible scores for hyperphagic severity range from a minimum score of 2 (no hyperphagic severity) to a maximum score of 10 (greater hyperphagic severity). Percent change from baseline in hyperphagic severity score of PWS hyperphagia questionnaire is presented. | Baseline (Day 15) and Day 42 | 
| Percent Change From Baseline in Overall Score of PWS Hyperphagia Questionnaire - Period 3 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Three factors identified from this questionnaire are: Hyperphagic Drive, Hyperphagic Behaviors, and Hyperphagic Severity. Items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Raw scores for each factor were used in data analyses, and the 3 domains were summed for an overall summary index of hyperphagia. Possible scores on the questionnaire range from a minimum score of 10 (no hyperphagia) to a maximum score of 50 (greater hyperphagia). Percent change from baseline in overall score of PWS hyperphagia questionnaire is presented. | Baseline (Day 42) and Day 56 | 
| Percent Change From Baseline in Overall Score of PWS Hyperphagia Questionnaire - Period 4 | The hyperphagia questionnaire is a 10-item instrument designed to measure food-related preoccupations and problems in PWS, as well as the severity of these concerns. Three factors identified from this questionnaire are: Hyperphagic Drive, Hyperphagic Behaviors, and Hyperphagic Severity. Items are rated by care providers on a 5-point scale (1=not a problem to 5=a severe and/or frequent problem). Raw scores for each factor were used in data analyses, and the 3 domains were summed for an overall summary index of hyperphagia. Possible scores on the questionnaire range from a minimum score of 10 (no hyperphagia) to a maximum score of 50 (greater hyperphagia). Percent change from baseline in overall score of PWS hyperphagia questionnaire is presented. | Baseline (Day 56) and Day 70 | 
| Mean Setmelanotide Trough Concentrations | The average of setmelanotide trough concentrations values for both timepoints (5 minutes predose on Day 42 and Day 70) is presented. | 5 minutes predose on Day 42 and Day 70 | 
| Maximum Drug Concentration (Cmax) of Setmelanotide During a 24-Hour Steady-State Interval | Maximum drug concentration determined directly from individual concentration-time data. | Starting on any day from Day 63 through 69, a 24-hour PK profile obtained; blood samples were collected at 0 (within 5 minutes predose), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing | 
| Time to the Maximum Drug Concentration (Tmax) of Setmelanotide During a 24-Hour Steady-State Interval | Maximum drug concentration determined directly from individual concentration-time data. | Starting on any day from Day 63 through 69, a 24-hour PK profile obtained; blood samples were collected at 0 (within 5 minutes predose), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing | 
| Area Under the Drug Concentration-Time Curve From Time-Zero to 24 Hours Postdose (AUC24h) of Setmelanotide During a 24-Hour Steady-State Interval |  | Starting on any day from Day 63 through 69, a 24-hour PK profile obtained; blood samples were collected at 0 (within 5 minutes predose), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing | 
| Volume of Distribution (Vd) of Setmelanotide During a 24-Hour Steady-State Interval | Volume of distribution calculated as Dose/The observed terminal rate constant*AUC24h. | Starting on any day from Day 63 through 69, a 24-hour PK profile obtained; blood samples were collected at 0 (within 5 minutes predose), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing | 
| Total Clearance (CL) of Setmelanotide During a 24-Hour Steady-State Interval | Clearance after extravascular administration; calculated as Dose/AUC24h. | Starting on any day from Day 63 through 69, a 24-hour PK profile obtained; blood samples were collected at 0 (within 5 minutes predose), 1, 2, 4, 6, 7, 8, 9, 10, 12, and 24 hours after dosing | 
| Change From Baseline in Body Weight - Period 2 |  | Baseline (Day 15) and Day 42 | 
| Percent Change From Baseline in Body Weight - Period 3 |  | Baseline (Day 42) and Day 56 | 
| Percent Change From Baseline in Body Weight - Period 4 |  | Baseline (Day 56) and Day 70 | 
| Percent Change From Baseline in Body Weight for Continuous Active and Continuous Placebo Treatments - Period 2 and 3 |  | Baseline (Day 15), Day 42, Day 56 | 
| Percent Change From Baseline in Body Fat Measured Using Dual x-Ray Absorptiometry (DEXA) - Period 2 | Total body fat was assessed by DEXA scan. | Baseline (Day 15) and Day 42 | 
| Number of Participants With Clinically Significant Percent Change From Baseline in Body Fat Measured Using DEXA - Period 4 | Total body fat was assessed by DEXA scan. Number of participants with clinically significant percent change from baseline in body fat were judged by investigator. | Baseline (Day 56) and Day 70 | 
| Percent Change From Baseline in Body Mass Measured Using DEXA - Period 2 | Total body mass was assessed by DEXA scan. | Baseline (Day 15) and Day 42 | 
| Number of Participants With Clinically Significant Percent Change From Baseline in Body Mass Measured Using DEXA - Period 4 | Total body mass was assessed by DEXA scan. Number of participants with clinically significant percent change from baseline in body mass were judged by investigator. | Baseline (Day 56) and Day 70 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prader-Willi Syndrome, obesity, hyperphagia