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Setmelanotide for the Treatment of LEPR Deficiency Obesity

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03287960
Recruitment Status : Recruiting
First Posted : September 19, 2017
Last Update Posted : February 26, 2020
Information provided by (Responsible Party):
Rhythm Pharmaceuticals, Inc.

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 10 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
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

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

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

Information from the National Library of Medicine

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

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03287960

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Contact: Jim Murray 857-264-4289

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United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Wendy Chung, MD   
Contact: Joanne Carroll   
Principal Investigator: Wendy Chung, MD         
Canada, Ontario
Markham Stouffville Hospital Recruiting
Markham, Ontario, Canada, L3P 7P3
Contact: Susan Kirsch, MD    905.472.7373 ext 2279   
Contact: Kim Zetazate    905.472.7373 ext 2279   
Principal Investigator: Susan Kirsch, MD         
Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital Recruiting
Paris, France, 75013
Contact: Karine Clement, MD PhD    +33 (0)142 177 928   
Contact: Prof. Jean Sébastien Hulot, MD/PhD         
Principal Investigator: Karine Clement, MD/PhD         
University of Ulm Recruiting
Ulm, Germany
Contact: Martin Wabitsch, MD    +49 731 500 57400   
Contact: Stephanie Laviani   
Principal Investigator: Martin Wabitsch, MD         
Erasmus Medical Center Recruiting
Rotterdam, Netherlands
Contact: Annemieke Van Der Zwaan-Meijer    +31 10 703 66 43   
Contact: Esther Hofland    +31 10 703 66 43   
Principal Investigator: Erica Van Den Akker, MD         
Hôpital Félix GUYON Recruiting
Saint Denis, Réunion, 97405
Contact: Julie Amandine Gonneau-Lejeune, MD    0262 90 61 95 ext 202   
Contact: Hajar Harmachi    +262 (0)2 62 90 68 87   
Principal Investigator: Julie Amandine Gonneau-Lejeune, MD         
United Kingdom
University of Cambridge Metabolic Research Laboratories Recruiting
Cambridge, United Kingdom, CB2 0QQ
Contact: Sadaf Farooqi, PhD    +44 (0)1223 762 634   
Contact: Julia Keogh, BSc    +44 (0)1223 762 634   
Principal Investigator: Sadaf Farooqi, PhD         
Sponsors and Collaborators
Rhythm Pharmaceuticals, Inc.
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Study Chair: Liz Stoner Rhythm Pharmaceuticals, Inc.

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Responsible Party: Rhythm Pharmaceuticals, Inc. Identifier: NCT03287960    
Other Study ID Numbers: RM-493-015
First Posted: September 19, 2017    Key Record Dates
Last Update Posted: February 26, 2020
Last Verified: February 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Leptin receptor
Melanocortin 4 receptor
Additional relevant MeSH terms:
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Nutrition Disorders
Body Weight
Signs and Symptoms
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs