Gene defects obesity
Conditions
Interventions
A 2-Stage (Open-Label Followed by Randomized Double-Blind, Placebo-Controlled
Stage), Phase 2 Trial.
In stage 1 of the study, the patient injects setmelanotide daily for 16 weeks.
In stage 2 of the s
Sponsors
Rhythm Pharmaceuticals, Inc.
Eligibility
Age
2 Years to 64 Years
Inclusion criteria
Inclusion criteria: 1. Patients must have a pre-identified genetic variant in an established MC4R pathway gene that contributes to obesity Note: Genetic testing requirements and a list of genes which have variants that are eligible for enrollment into the trial are provided in Appendix 1 of the protocol. 2. Patients between the ages of 6 and 65, inclusive, at the time of signing Informed Consent or Assent. 3. Patients with obesity, defined as BMI >=40 kg/m2 for patients >=18 years of age or BMI >=97th percentile for age and gender for patients 6 to
Exclusion criteria
Exclusion criteria: 1. Patients with the following genetic variants: biallelic Bardet-Biedl Syndrome (BBS); biallelic Alström Syndrome 1 (ALMS1); homozygous, heterozygous, or compound heterozygous variants in MC4R, POMC, PCSK1, LEPR, nuclear receptor coactivator 1 (NCOA1; steroid receptor coactivator-1 [SRC1]) or SRC homology 2 B adapter protein 1 (SH2B1) genes as well as 16p11.2 chromosomal deletions that include the SH2B1 gene. 2. Weight loss >2% in the previous 3 months. Patients will not be excluded for using regimens for weight maintenance or to prevent weight gain, such as dietary and/or exercise regimens, or medications, supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide-1 [GLP-1] receptor agonists, etc.), provided: • 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 trial. 3. Bariatric surgery or procedure (e.g., 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. Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or documented worsening psychiatric condition that required changes in treatment regimen within the previous 2 years, or other psychiatric related risks that the Investigator believes may interfere with trial compliance or patient safety. 5. Clinically significant depression or suicidality, as defined by: any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt during the patient*s lifetime, any suicidal behavior in the last month, or a Patient Health Questionnaire-9 (PHQ-9) score of >=15 during Screening process. Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive impairment may be enrolled in the trial provided that there are no clinical signs or symptoms of significant depression or suicidal behavior in the opinion of the Investigator. 6. Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility. 7. Significant features of, or meeting the diagnostic criteria for, a genetic syndrome that is associated with obesity. Note: Although some of the genetic variants that are eligible to be enrolled into this trial are associated with specific syndromes, the intent of this trial is not to enroll children with significant cognitive impairment or other significant co-morbidities. Patients with eligible genetic variants, but who otherwise do not exhibit the syndrome, are eligible for enrollment. 8. HbA1C >10.0% at Screening. 9. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| • The proportion of patients by genotype who demonstrate a significant clinically meaningful response (defined below) to setmelanotide at the end of Stage 1: * For all patients: achieving a >=5% reduction in BMI from Baseline | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary: • Mean change and percent change in BMI from Baseline to end of Stage 1 in all patients and patients >=18 years old, per gene • Mean change and percent change in body weight from Baseline to end of Stage 1 in patients >=18 years old, per gene • Mean change in BMI Z-score from Baseline to end of Stage 1 in patients =12 years old, per gene • The proportion of patients >=12 years old, per gene, who achieve a >=2-point reduction (improvement) from Baseline to end of Stage 1 in the weekly average of the daily maximal hunger score. Exploratory: • Mean change from Baseline to end of Stage 1 in total score for the 5-level EuroQol 5 Dimension questionnaire (EQ-5D-5L in patients >=16 years old and EQ-5D-5L Proxy version in patients =18 years old and IWQOL-Kids in patients 11- =12 years old, per gene • Mean change from Baseline to the end of Stage 2, per gene, in metabolic parameters including: fasting glucose, HbA1C, lipid profiles (total-, high-density lipoprotein [HDL]-, and low-density lipoprotein [LDL]-cholesterol, triglycerides) in patients in the setmelanotide arm compared to placebo arm • Mean change from Baseline to the end of Stage 1 per gene, in metabolic parameters including: fasting glucose, HbA1C, lipid profiles (total-, HDL-, and LDL-cholesterol, triglycerides) • Proportion of setmelanotide-treated patients by genotype who achieve a >=5% reduction in BMI from Baseline at the end of Stage 2 compared to placebo • Mean change and percent change in BMI from Baseline to end of Stage 2 in all patients and patients >=18 years old, per gene, for the setmelanotide group compared with the placebo group • Mean change and percent change in body weight from Baseline to end of Stage 2 in patients >=18 years old, per gene, for the setmelanotide group compared with the placebo group • Mean change in BMI Z-score from Baseline to end of Stage 2 in patients =12 years old, per gene • Mean percent change in the weekly average of the daily maxi | — |
Countries
Netherlands
Outcome results
None listed