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
Overview
- Phase
- Phase 2
- Intervention
- Setmelanotide
- Conditions
- Prader-Willi Syndrome
- Sponsor
- Rhythm Pharmaceuticals, Inc.
- Enrollment
- 40
- Locations
- 5
- Primary Endpoint
- Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) - Period 2
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
The purpose of this study was to evaluate the effects of a once daily subcutaneous injectable formulation of setmelanotide in obese participants with Prader-Willi syndrome on tolerability, weight loss, and hyperphagia-related behavior. The study drug (setmelanotide and placebo) was administered in a blinded fashion.
Investigators
Eligibility Criteria
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)
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 ≥
- •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.
Arms & Interventions
Setmelanotide 0.5 mg
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).
Intervention: Setmelanotide
Setmelanotide 1.5 mg
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).
Intervention: Setmelanotide
Setmelanotide 2.5 mg
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).
Intervention: Setmelanotide
Placebo
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).
Intervention: Placebo
Outcomes
Primary Outcomes
Number of Participants Who Experienced a Treatment-Emergent Adverse Event (TEAE) - Period 2
Time Frame: Days 15 to 41
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
Percent Change From Baseline in Overall Score of Prader-Willi Syndrome (PWS) Hyperphagia Questionnaire - Period 2
Time Frame: Baseline (Day 15) and Day 42
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.
Number of Participants Who Experienced a TEAE - Period 3
Time Frame: Days 42 to 55
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
Mean Body Weight - Period 2
Time Frame: Baseline (Day 15)
Number of Participants Who Experienced a TEAE - Period 4
Time Frame: Days 56 to 69
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
Overall Score of Prader-Willi Syndrome (PWS) Hyperphagia Questionnaire - Period 2
Time Frame: Baseline (Day 15)
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 Body Weight - Period 2
Time Frame: Baseline (Day 15) and Day 42
Secondary Outcomes
- Percent Change From Baseline in Overall Score of PWS Hyperphagia Questionnaire - Period 4(Baseline (Day 56) and Day 70)
- 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(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(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)
- Maximum Drug Concentration (Cmax) 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)
- Percent Change From Baseline in Body Mass Measured Using DEXA - Period 2(Baseline (Day 15) and Day 42)
- Percent Change From Baseline in Hyperphagic Drive Score of PWS Hyperphagia Questionnaire - Period 2(Baseline (Day 15) and Day 42)
- Percent Change From Baseline in Hyperphagic Behaviors Score of PWS Hyperphagia Questionnaire - Period 2(Baseline (Day 15) and Day 42)
- Percent Change From Baseline in Hyperphagic Severity Score of PWS Hyperphagia Questionnaire - Period 2(Baseline (Day 15) and Day 42)
- Mean Setmelanotide Trough Concentrations(5 minutes predose on Day 42 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(Baseline (Day 15) and Day 42)
- Number of Participants With Clinically Significant Percent Change From Baseline in Body Fat Measured Using DEXA - Period 4(Baseline (Day 56) and Day 70)
- Time to the Maximum Drug Concentration (Tmax) 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)
- Percent Change From Baseline in Body Weight - Period 4(Baseline (Day 56) and Day 70)
- Percent Change From Baseline in Overall Score of PWS Hyperphagia Questionnaire - Period 3(Baseline (Day 42) and Day 56)
- 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)
- Number of Participants With Clinically Significant Percent Change From Baseline in Body Mass Measured Using DEXA - Period 4(Baseline (Day 56) and Day 70)