A Trial of Setmelanotide in Acquired Hypothalamic Obesity

A Phase 3, Double Blind, Randomized, Placebo-Controlled Trial to Evaluate the Efficacy and Safety of Setmelanotide in Patients With Acquired Hypothalamic Obesity

The goal of this trial is to learn how well Setmelanotide works to improve weight reduction, hunger, and quality of life in patients 4 years of age and older with acquired Hypothalamic Obesity (HO). To determine how well setmelanotide works and how safe it is, patients with HO will take a daily injection of either setmelanotide or placebo and complete trial assessments for 52 weeks on a therapeutic regimen.

A separate sub-study in patients with congenital HO is detailed under NCT06760546.

Study Overview

• Status: Active, not recruiting
• Conditions: Hypothalamic Obesity
• Intervention / Treatment: Drug: Setmelanotide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 143
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • Hospital for Sick Children
• Germany
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf (UKE) - Ambulanzzentrum des UKE GmbH
  • München, Germany, 81667
    • Medicover Neuroendokrinologie
  • Oldenburg, Germany, 26133
    • University Children's Hospital, Klinikum Oldenburg
  • Ulm, Germany, 89075
    • Universitaetsklinikum Ulm - Klinik fuer Kinder- und Jugendmedizin
• Japan
  • Aichi-ken
    • Nagoya, Aichi-ken, Japan, 467-8602
      • Nagoya City University Hospital
  • Nagano
    • Azumino, Nagano, Japan, 399-8288
      • Nagano Children's Hospital
  • Tokyo
    • Minato, Tokyo, Japan, 105-8470
      • Toranomon Hospital
• Netherlands
  • Utrecht, Netherlands, 3584CS
    • Prinses Maxima Center for Pediatric Oncology
• United Kingdom
  • Birmingham, United Kingdom, B46NH
    • Birmingham Women and Children's Hospital NHS Trust
  • Hull, United Kingdom, HU32RW
    • Hull University Teaching Hospital
  • London, United Kingdom, WC1N 1EH
    • UCL Great Ormond Street Institute of Child Health
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233
      • UAN Pediatric Endocrinology
  • California
    • San Diego, California, United States, 92123
      • Rady Children's Hospital
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Gainesville, Florida, United States, 32610-0296
      • University of Florida
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Stead Family Department of Pediatrics
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital
    • Boston, Massachusetts, United States, 02115
      • Boston Children's Hospital
  • Minnesota
    • Saint Paul, Minnesota, United States, 55102
      • Children's Minnesota
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
    • New York, New York, United States, 100029
      • Icahn School of Medicine at Mount Sinai
  • Ohio
    • Columbus, Ohio, United States, 43203
      • Ohio State Wexner Medical Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73122
      • Lynn Health Science Institute
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University School of Medicine
  • Washington
    • Seattle, Washington, United States, 98101
      • Seattle Children's Hospital, Research and Foundation - Center for Integrative Brain Research

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Documented evidence of acquired hypothalamic obesity (HO)
2. Age 4 years and older
3. Weight gain associated with the hypothalamic injury and a BMI of ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and sex for patients 4 to <18 years of age
4. Agree to use a highly effective form of contraception throughout the study and for 90 days after the study

Key Exclusion Criteria:

1. Diagnosis of Prader-Willi syndrome (PWS) or Rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, neuroendocrine tumor syndrome (ROHHADNET)
2. Weight loss >2% in the previous 3 months for patients aged ≥18 years or >2% reduction in BMI for patients aged 4 to <18 years
3. Bariatric surgery or procedure within last 2 years
4. Diagnosis of severe psychiatric disorders; any suicidal ideation, attempt or behavior
5. Current, clinically significant pulmonary, cardiac, metabolic, or oncologic disease
6. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion)
7. History or close family history of skin cancer or melanoma
8. Participation in any clinical trial with an investigational drug/device within 3 months prior to the first trial dose
9. Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to setmelanotide
10. Inability to comply with once daily (QD) injection regimen
11. If female, pregnant and/or breastfeeding
12. Patients with obesity attributable to other genetic or syndromic conditions (eg, PPL [POMC, PCSK1, LEPR, collectively], BBS) prior to the hypothalamic injury.
13. If receiving hormone replacement therapy, dose has remained stable for at least 2 months before Screening

Other protocol defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Setemelanotide; Randomized 2:1 (Setmelanotide: Placebo)	Drug: Setmelanotide; Solution for daily subcutaneous injection; Other Names: RM-493; Imcivree
Placebo Comparator: Placebo; Randomized 2:1 (Setmelanotide: Placebo)	Drug: Placebo; Placebo matched to setmelanotide for daily subcutaneous injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pivotal Cohort: Mean Percent Change From Baseline in Body Mass Index (BMI) After 52 Weeks on a Therapeutic Regimen	BMI was calculated as weight (kg)/height (m^2). Least square (LS) mean and standard error (SE) were calculated using analysis of covariance (ANCOVA) model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pivotal Cohort: Percentage of Participants With ≥5% Reduction From Baseline in BMI (≥18 Years of Age) or ≥0.2-point Reduction From Baseline in BMI Z-score (<18 Years of Age)	BMI was calculated as weight (kg)/height (m^2). BMI Z-Score calculated for participants <18 years old only is a measure of relative weight adjusted for child's age, sex and height at the time of data collection. The Z-Scores were calculated using the World Health Organization's WHO 2007 BMI SAS Macro Package. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease in BMI Z-score (< 0) indicates a reduction in BMI from Baseline whereas an increase in BMI-Z score (> 0) indicated an increase in BMI from Baseline. Baseline was defined as the most recent measurement prior to the first administration of study drug. Results below represent the percentage of estimated participants with either ≥5% BMI reduction or ≥0.2 point reduction in BMI Z-score by age in each treatment arm as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants With ≥5% Reduction From Baseline in BMI	BMI was calculated as weight (kg)/height (m^2). Results below represent the percentage of estimated participants with ≥5% BMI reduction in each treatment arm as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Change From Baseline in Weekly Average Daily Most Hunger Score in Participants ≥12 Years of Age	Change from baseline in hunger scores for participants ≥12 years of age with acquired hypothalamic obesity was evaluated. Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on an 11-point numeric rating scale. On Daily Hunger Questionnaire, each of the 2 items (average hunger and most hunger) was scored separately and averaged on weekly basis. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants (≥12 Years of Age) With a ≥2-point Reduction From Baseline in the Weekly Average Daily Most Hunger Score	Hunger score ranged from 0= "not hungry at all" to 10= "hungriest possible" on an 11-point numeric rating scale. On Daily Hunger Questionnaire, each of the 2 items (average hunger and most hunger) was scored separately and averaged on weekly basis. Results below represent the percentage of estimated participants ≥12 years of age with ≥2-point reduction in each treatment arm as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in the Weekly Average of the Symptoms of Hyperphagia Composite Score in Participants ≥12 Years of Age	Participants ≥12 years of age who were able to self-report were administered the Symptoms of Hyperphagia: Patient (Version 1.0). The questionnaire consisted of 4 items related to the frequency of a participant's hunger symptoms on a scale (Never, 1 or 2 times, 3 or more times) over the past 24 hours. The scores on this scale range from 0 to 2 with higher scores indicating more hyperphagia. Daily composite score was derived as the sum of daily answered questions divided by the number of answered questions per day. The weekly average of the daily composite scores equals to the sum of daily composite scores divided by the number of days with a composite score within the 7 identified days prior to the visit. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants With a ≥10% Reduction From Baseline in BMI	BMI was calculated as weight (kg)/height (m^2). Results below represent the percentage of estimated participants with ≥10% BMI reduction in each treatment arm as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants With a ≥10% Reduction From Baseline in Body Weight	Body weight was captured for analysis in kilograms. Results below represent the percentage of estimated participants with ≥10% reduction in body weight in each treatment arm as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Mean Percent Change From Baseline in Body Weight in Participants ≥18 Years	Body weight was captured for analysis in kilograms. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in BMI Z-Score in Participants <18 Years of Age	BMI was calculated as weight (kg)/height (m^2). BMI Z-Score calculated for participants <18 years old only is a measure of relative weight adjusted for child's age, sex and height at the time of data collection. The Z-Scores were calculated using the World Health Organization's WHO 2007 BMI SAS Macro Package. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease in BMI Z-score (< 0) indicates a reduction in BMI from Baseline whereas an increase in BMI-Z score (> 0) indicates an increase in BMI from Baseline. Baseline was defined as the most recent measurement prior to the first administration of study drug. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in Percent of BMI 95th Percentile in Participants <18 Years of Age	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. BMI percentile scores are measures of relative weight adjusted for child's age and gender. The percent of the BMI 95th percentile score expresses the participant's BMI as a percentage of the Centers for Disease Control (CDC) 95th percentile reference population. Baseline was defined as the most recent measurement prior to the first administration of study drug. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants <18 Years of Age With ≥0.2-Point Reduction From Baseline in BMI Z-Score	BMI was calculated as weight (kg)/height (m^2). BMI Z-Score calculated for participants <18 years old only is a measure of relative weight adjusted for child's age, sex and height at the time of data collection. The Z-Scores were calculated using the World Health Organization's WHO 2007 BMI SAS Macro Package. A Z-score of 0 is equal to the mean of a reference population (i.e., healthy, age and sex-matched individuals). A decrease in BMI Z-score (< 0) indicates a reduction in BMI from Baseline whereas an increase in BMI-Z score (> 0) indicates an increase in BMI from Baseline. Baseline was defined as the most recent measurement prior to the first administration of study drug. Results below represent the percentage of estimated participants with ≥0.2 point reduction in BMI Z-score in each treatment arm and the difference between the treatment arms as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Percentage of Participants With BMI <30 kg/m^2 (Aged ≥18 Years) or <95th Percentile (Aged <18 Years) From Baseline	BMI was calculated using participant's weight and height assessments, using the following formula: BMI = kg/m^2. BMI Percentile scores are measures of relative weight adjusted for child's age and gender. The percent of the BMI 95th percentile score expresses the participant's BMI as a percentage of the CDC 95th percentile reference population. Baseline was defined as the most recent measurement prior to the first administration of study drug. Results below represent the percentage of estimated participants with either BMI <30 kg/m^2 (aged ≥18 years) or <95th percentile (aged <18 years) in each treatment arm and the difference between the treatment arms as calculated through the MIANALYZE SAS procedure.	After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in Physical Functioning Score and Total Score on the Impact of Weight on Quality of Life-Lite (IWQOL)	The IWQOL-Lite-Clinical Trials (administered to participants ≥18 years of age) is a validated 20-item self-report measure of obesity-specific quality of life questionnaire. It assessed 2 primary domains of obesity-related health-related quality of life (HRQoL): physical (7 items) and psychosocial (13 items). Each item was rated on a scale from 0 (worst) to 100 (best), with higher scores indicating better levels of functioning. It provided composite scores for each domain, as well as a total score, all ranging from 0 (worst) to 100 (best). Higher scores reflect better levels of functioning and quality of life. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in Total Score on the Impact of Weight on Quality of Life-Kids (IWQOL-Kids)	The IWQOL-Kids (administered to participants between the ages of 11 and <18 years) is a validated 27-item self-report measure of weight-related quality of life for youth. It provided a total score inclusive of 4 domains: physical comfort, body esteem, social life, and family relations. Results below represent the total score, which is rated on a scale from 0 (worst) to 100 (best), with higher scores indicating better levels of functioning. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Mean Change From Baseline in Waist Circumference	Waist circumference was captured for analysis in centimeters. LSM and SE were calculated using ANCOVA model.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)
Pivotal Cohort: Change From Baseline in Systolic and Diastolic Blood Pressure	Blood pressure was calculated in millimeters of mercury.	Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks)

Collaborators and Investigators

• Sponsor: Rhythm Pharmaceuticals, Inc.
• Investigators: Study Chair: David Meeker, MD, Rhythm Pharmaceuticals, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): April 26, 2023
• Primary Completion (Actual): March 18, 2025
• Study Completion (Estimated): April 16, 2027

Study Registration Dates

• First Submitted: March 1, 2023
• First Submitted That Met QC Criteria: March 16, 2023
• First Posted (Actual): March 20, 2023

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: melancortin 4 receptor, MC4R
• Additional Relevant MeSH Terms: Urogenital Diseases; Endocrine System Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Gonadal Disorders; Congenital Abnormalities; Disorders of Sex Development; Urogenital Abnormalities; Gonadal Dysgenesis; Hypogonadism; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Sexual Infantilism; setmelanotide
• Other Study ID Numbers: RM-493-040

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No