Setmelanotide for the Treatment of LEPR Deficiency Obesity

Sponsor

Rhythm Pharmaceuticals, Inc. (Industry)

Overall Status

Completed

CT.gov ID

NCT03287960

Collaborator

(none)

Enrollment

Locations

Arms

31.8

Actual Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

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

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 PeriodOpen-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 :

Jan 30, 2018

Actual Primary Completion Date :

Sep 25, 2020

Actual Study Completion Date :

Sep 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: setmelanotide setmelanotide subcutaneous injection once daily	Drug: setmelanotide Once daily subcutaneous injection Other Names: 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

Arm

Intervention/Treatment

Experimental: setmelanotide

setmelanotide subcutaneous injection once daily

Drug: setmelanotide

Once daily subcutaneous injection

Other Names:

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

Weight loss [1 year]
Percent change in body weight from baseline

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.
Age 6 years and above. 6+: Germany, Netherlands,UK 12+France
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.
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.
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.
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:

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.
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.
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.
A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
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.
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.
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.
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.
History or close family history (parents or siblings) of skin cancer or melanoma, or patient history of ocular-cutaneous albinism.
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.
Volunteer is, in the opinion of the Study Investigator, not suitable to participate in the study.
Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
Significant hypersensitivity to study drug.
Inability to comply with QD injection regimen.
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

	Site	City	State	Country	Postal Code
1	Columbia University	New York	New York	United States	10032
2	Markham Stouffville Hospital	Markham	Ontario	Canada	L3P 7P3
3	Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital	Paris		France	75013
4	University of Ulm	Ulm		Germany
5	Erasmus Medical Center	Rotterdam		Netherlands
6	Hôpital Félix GUYON	Saint Denis		Réunion	97405
7	University of Cambridge Metabolic Research Laboratories	Cambridge		United Kingdom	CB2 0QQ