Setmelanotide for the Treatment of LEPR Deficiency Obesity

• ClinicalTrials.gov Identifier: NCT03287960
• Recruitment Status: Completed
• First Posted: September 19, 2017
• Last Update Posted: January 27, 2021
• Sponsor: Rhythm Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Rhythm Pharmaceuticals, Inc.

Study Description

Brief Summary:

This study is assessing the effect of setmelanotide (RM-493) on weight and other factors in patients with Leptin Receptor (LEPR) deficiency obesity due to rare bi-allelic loss-of-function LEPR genetic mutation.

Condition or disease	Intervention/treatment	Phase
Leptin Receptor Deficiency Obesity	Drug: setmelanotide; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Early Onset Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
• Actual Study Start Date: January 30, 2018
• Actual Primary Completion Date: September 25, 2020
• Actual Study Completion Date: September 25, 2020

Arms and Interventions

Arm	Intervention/treatment
Experimental: setmelanotide; setmelanotide subcutaneous injection once daily	Drug: setmelanotide; Once daily subcutaneous injection; Other Name: RM-493
Placebo Comparator: Placebo; Placebo subcutaneous injection once daily	Drug: Placebo; During the double blind placebo withdrawal period, patients will receive RM-493 or placebo at variable times over an 8 week period

Outcome Measures

Primary Outcome Measures :

1. Weight loss [ Time Frame: 1 year ]
   Percent change in body weight from baseline

Secondary Outcome Measures :

1. Incidence of Treatment-Emergent Adverse Events [ Time Frame: 1 year ]
   Assessment of Adverse Events related to treatment
2. Body Fat Mass [ Time Frame: 1 year ]
   Assessment of body composition as measured by bioelectrical impedance (BIA) or Dual-energy x-ray absorptiometry (DXA)
3. Hunger [ Time Frame: 1 year ]
   Assessment of hunger using a hunger questionnaire
4. Improvements in insulin resistance [ Time Frame: 1 year ]
   Assessment of fasting glucose, glycated hemoglobin (HbA1c) and oral glucose tolerance test (OGTT)
5. Waist circumference [ Time Frame: 1 year ]
   Assessment of waist circumference
6. Reversal of weight during the double-blind placebo controlled withdrawal phase [ Time Frame: 8 weeks ]
   Assessment of weight regain during the double-blind withdrawal phase

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 BMI ≥ 30 kg/m2; if child or adolescent, 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 patients 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. Patients may be reconsidered approximately 1 month after cessation of such intensive regimens.
2. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. Specifically, patients may be considered if surgery was not successful, or resulted in <10% weight loss compared to pre-operative baseline weight or clear evidence of weight regain after an initial response to bariatric surgery. All patients with a history of bariatric surgery must be discussed with, and receive approval from Rhythm prior to enrollment.
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 (NYHA Class 3 or greater), or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results. Any such patients should be discussed with the sponsor prior to inclusion.
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). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis will be exclusionary, but the presence of NAFLD would not be exclusionary.
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 mL/min.
9. History or close family history (parents or siblings) of skin cancer or melanoma, or patient 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. Any concerning lesions identified during the screening period will be biopsied and results known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
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 QD injection regimen.
15. Patients 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.

Contacts and Locations

Locations

United States, New York

Columbia University

New York, New York, United States, 10032

Canada, Ontario

Markham Stouffville Hospital

Markham, Ontario, Canada, L3P 7P3

France

Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital

Paris, France, 75013

Germany

University of Ulm

Ulm, Germany

Netherlands

Erasmus Medical Center

Rotterdam, Netherlands

Réunion

Hôpital Félix GUYON

Saint Denis, Réunion, 97405

United Kingdom

University of Cambridge Metabolic Research Laboratories

Cambridge, United Kingdom, CB2 0QQ

Sponsors and Collaborators

Rhythm Pharmaceuticals, Inc.

Investigators

• Study Chair: Murray Stewart, BM/DM; Rhythm Pharmaceuticals, Inc.

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Clément 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, Kühnen 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.

• Responsible Party: Rhythm Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03287960
• Other Study ID Numbers: RM-493-015
• First Posted: September 19, 2017
• Last Update Posted: January 27, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rhythm Pharmaceuticals, Inc.:

LEPR deficiency obesity; setmelanotide; RM-493; Leptin receptor; Obesity; Melanocortin 4 receptor

Additional relevant MeSH terms:

Obesity; Obesity, Morbid; Overnutrition; Nutrition Disorders; Overweight; Body Weight