Hypothalamic Obesity
Conditions
Keywords
melancortin 4 receptor, MC4R
Brief summary
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.
Interventions
DRUGSetmelanotide
Solution for daily subcutaneous injection
DRUGPlacebo
Placebo matched to setmelanotide for daily subcutaneous injection
Sponsors
Rhythm Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pivotal Cohort: Mean Percent Change From Baseline in Body Mass Index (BMI) After 52 Weeks on a Therapeutic Regimen | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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) | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants With ≥5% Reduction From Baseline in BMI | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Change From Baseline in Weekly Average Daily Most Hunger Score in Participants ≥12 Years of Age | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants (≥12 Years of Age) With a ≥2-point Reduction From Baseline in the Weekly Average Daily Most Hunger Score | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Change From Baseline in the Weekly Average of the Symptoms of Hyperphagia Composite Score in Participants ≥12 Years of Age | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants With a ≥10% Reduction From Baseline in BMI | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants With a ≥10% Reduction From Baseline in Body Weight | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Percent Change From Baseline in Body Weight in Participants ≥18 Years | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | Body weight was captured for analysis in kilograms. LSM and SE were calculated using ANCOVA model. |
| Pivotal Cohort: Mean Change From Baseline in BMI Z-Score in Participants <18 Years of Age | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Change From Baseline in Percent of BMI 95th Percentile in Participants <18 Years of Age | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants <18 Years of Age With ≥0.2-Point Reduction From Baseline in BMI Z-Score | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Percentage of Participants With BMI <30 kg/m^2 (Aged ≥18 Years) or <95th Percentile (Aged <18 Years) From Baseline | After approximately 52 Weeks on a Therapeutic Regimen (baseline up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Change From Baseline in Physical Functioning Score and Total Score on the Impact of Weight on Quality of Life-Lite (IWQOL) | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Change From Baseline in Total Score on the Impact of Weight on Quality of Life-Kids (IWQOL-Kids) | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | 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. |
| Pivotal Cohort: Mean Change From Baseline in Waist Circumference | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | Waist circumference was captured for analysis in centimeters. LSM and SE were calculated using ANCOVA model. |
| Pivotal Cohort: Change From Baseline in Systolic and Diastolic Blood Pressure | Baseline, after approximately 52 Weeks on a Therapeutic Regimen (up to approximately 60 weeks) | Blood pressure was calculated in millimeters of mercury. |
Countries
Canada, Germany, Japan, Netherlands, United Kingdom, United States
Contacts
STUDY_CHAIRDavid Meeker, MD
Rhythm Pharmaceuticals, Inc.
Participant flow
Pre-assignment details
As planned, the analysis of the primary and secondary efficacy endpoints were done only in the pivotal cohort. Pivotal cohort: defined as the first 120 participants dosed in any region who had completed the trial and any participants who discontinued after receiving their first dose of study drug.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 22.9 years STANDARD_DEVIATION 16.31 |
| Body Mass Index | 35.73 kilograms (kg)/square meter (m^2) STANDARD_DEVIATION 9.173 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 16 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 12 Participants |
| Race (NIH/OMB) White | 107 Participants |
| Region of Enrollment Canada | 8 participants |
| Region of Enrollment Germany | 12 participants |
| Region of Enrollment Japan | 4 participants |
| Region of Enrollment Netherlands | 12 participants |
| Region of Enrollment United Kingdom | 1 participants |
| Region of Enrollment United States | 31 participants |
| Sex: Female, Male Female | 85 Participants |
| Sex: Female, Male Male | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 95 | 0 / 48 |
| other Total, other adverse events | 94 / 94 | 46 / 48 |
| serious Total, serious adverse events | 26 / 94 | 3 / 48 |
Outcome results
None listed