Clinical trial NCT03287960: Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity
Official title: An Open Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Leptin Receptor Deficiency Obesity
Keywords: LEPR deficiency obesity
setmelanotide
RM-493
Leptin receptor
Obesity
Melanocortin 4 receptor
Lead sponsor: Rhythm Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2017-09-19
Enrollment: 15
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
Primary purpose: TREATMENT

Brief summary: To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.


Eligibility criteria: Inclusion Criteria:

1. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for the LEPR gene, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.
2. Age 6 years and above. 6+: Germany, Netherlands, UK. 12+: France
3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kilograms per meters squared (kg/m\^2); if child or adolescent (\< 18 years of age), obesity with weight \> 97th percentile for age on growth chart assessment.
4. Study participant and/or parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the study, and is able to understand and sign the written informed consent/assent, after being informed about the study.
5. Female participants of child-bearing potential must agree to use contraception as outlined in the protocol. Female participants of non-childbearing potential, defined as surgically sterile (status post hysterectomy, bilateral oophorectomy, or bilateral tubal ligation) post-menopausal for at least 12 months (and confirmed with a screening FSH level in the post-menopausal lab range), or failure to have progressed to Tanner Stage V and/or failure to have achieved menarche, do not require contraception during the study.
6. Male participants with female partners of childbearing potential must agree to a double barrier method if they become sexually active during the study. Male participants must not donate sperm during and for 90 days following their participation in the study.

Exclusion Criteria:

1. Recent intensive (within 2 months) diet and/or exercise regimen with or without the use of weight loss agents including herbal medications, that has resulted in weight loss or weight stabilization.
2. Prior gastric bypass surgery resulting in \>10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
3. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders (DSM-III) disorders that the investigator believes will interfere significantly with study compliance.
4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
5. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
6. Current, severe stable restrictive or obstructive lung disease arising because of extreme obesity, evidence of significant heart failure (New York Heart Association \[NYHA\] Class 3 or greater), or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results.
7. History of significant liver disease or liver injury, or current liver assessment for a cause of abnormal liver tests \[as indicated by abnormal liver function tests, alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase, or serum bilirubin (\> 2.0 x upper limit of normal (ULN) for any of these tests)\] for an etiology other than non-alcoholic fatty liver disease (NAFLD).
8. History or presence of impaired renal function as indicated by clinically significant abnormal creatinine, blood urea nitrogen (BUN), or urinary constituents (e.g., albuminuria) or moderate to severe renal dysfunction as defined by the Cockcroft Gault equation \< 30 milliliter/minute (mL/min).
9. History or close family history (parents or siblings) of skin cancer or melanoma, or participant history of ocular-cutaneous albinism.
10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions, determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist.
11. Volunteer is, in the opinion of the study investigator, not suitable to participate in the study.
12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
13. Significant hypersensitivity to study drug.
14. Inability to comply with every day (QD) injection regimen.
15. Participants who have been placed in an institution through an official or court order, as well as those who are dependent on the sponsor, Investigator or study site.

Primary outcomes:
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
timeFrame: Week 52
Secondary outcomes:
measure: Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
timeFrame: Week 52
measure: Mean Percent Change From Baseline in Body Weight
timeFrame: Baseline and Week 52
measure: Mean Percent Change From Baseline in Hunger Score ('Most Hunger')
timeFrame: Baseline and Week 52
measure: Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline
timeFrame: Baseline and Week 52
measure: Absolute Change From Baseline in Waist Circumference
timeFrame: Baseline and Week 52
measure: Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
timeFrame: Baseline and Week 8 of withdrawal period
measure: Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period
timeFrame: Week 8 of withdrawal period
measure: Mean Percent Change From Baseline in Body Mass Index
timeFrame: Baseline and Week 52
measure: Change From Baseline in Glucose Parameters
timeFrame: Baseline and Week 52
Other outcomes:
Locations:
city: Markham
country: Canada
facility: Markham Stouffville Hospital
state: Ontario
city: Paris
country: France
facility: Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital
city: Ulm
country: Germany
facility: University of Ulm
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center
city: Saint Denis
country: Réunion
facility: Hôpital Félix GUYON
city: Cambridge
country: United Kingdom
facility: University of Cambridge Metabolic Research Laboratories
Study officials:
affiliation: Rhythm Pharmaceuticals, Inc.
name: David Meeker, MD
role: STUDY_CHAIR
References:
citation: Clement K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kuhnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators. Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials. Lancet Diabetes Endocrinol. 2020 Dec;8(12):960-970. doi: 10.1016/S2213-8587(20)30364-8. Epub 2020 Oct 30.