Setmelanotide (RM-493), Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström Syndrome (AS) Participants With Moderate to Severe Obesity

NCT ID: NCT03746522

Last Updated: 2023-12-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 52 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-11-23
• Study Completion Date: 2021-03-08

Brief Summary

This pivotal, phase 3 study is designed to confirm the efficacy and safety of setmelanotide, a potent melanocortin receptor type 4 (MC4R) agonist, for the treatment of obesity and hyperphagia in participants with Bardet Biedl syndrome (BBS) or Alström syndrome (AS). The study's primary efficacy endpoint is to evaluate the proportion of participants (≥ 12 years of age at baseline) who lose ≥ 10% of their baseline body weight following approximately (~) 52 weeks of treatment with setmelanotide compared to a historical control rate.

Detailed Description

Eligible participants will enter a 14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be followed by a 38-week open-label treatment period (Period 2) in which all participants will receive setmelanotide. Following Period 2, participants will continue receiving open-label setmelanotide for 14 weeks (Period 3), after which they could enroll into a separate treatment extension study.

Conditions

Bardet Biedl Syndrome (BBS); Alström Syndrome (AS)

Keywords

MC4R Pathway; Obesity; BBS; AS

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Setmelanotide (Double-Blind)

Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants \<16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg.

Group Type: EXPERIMENTAL

Setmelanotide

Intervention Type: DRUG

SC injection of setmelanotide

Placebo (Double-Blind)

Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1).

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

SC injection of placebo

Setmelanotide (Open-label)

After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).

Group Type: EXPERIMENTAL

Setmelanotide

Intervention Type: DRUG

SC injection of setmelanotide

Interventions

Setmelanotide

SC injection of setmelanotide

Intervention Type: DRUG

Placebo

SC injection of placebo

Intervention Type: DRUG

Other Intervention Names

SET; RM-493

Eligibility Criteria

Inclusion Criteria

1. BBS clinical diagnosis or AS diagnosis

2. Greater than or equal to (≥) 6 years of age.

3. Obese, defined as BMI ≥30 kilograms/meters^2 for participants ≥16 years of age or weight >97th percentile for age and sex on growth chart assessment for participants 6 to 15 years of age.

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.

5. Female participants of child-bearing potential must be confirmed non-pregnant and 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 follicle stimulating hormone (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 use a double barrier method contraception if they become sexually active during the study or within 90 days following their participation in the study. Male participants must also 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 >2% weight loss. These participants may be reconsidered approximately 1 month after cessation of such intensive regimens.

2. Current or prior (within prior 2 months) use of any medication, including those approved to treat obesity, that could impact the efficacy results of this study (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide). Participants on a stable dose and regimen (for at least 2 months) of medication to treat attention deficit hyperactivity disorder (ADHD) may be enrolled in the study as long as they agree to remain on the same dose and regimen during the study.

3. Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain. Specifically, participants may be considered if surgery was not successful, resulted in <10% weight loss compared to pre-operative baseline weight, or there is clear evidence of weight regain after an initial response to bariatric surgery. All participants with a history of bariatric surgery must be discussed with, and receive approval from, the Sponsor prior to enrollment.

4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-V) disorders that the Investigator believes will interfere significantly with study compliance. Neurocognitive disorders affecting ability to consent will not be disqualifying as long as an appropriate guardian able to give consent has been appointed.

5. In participants with no significant neurocognitive deficits:

• A Patient Health Questionnaire-9 (PHQ-9) score of ≥15 and/or
• 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, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any participant with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.

7. History of significant liver disease or liver injury, or a current liver assessment due to abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin >1.5x the 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 is exclusionary, but the presence of NAFLD is not exclusionary.

8. Moderate to severe renal dysfunction defined as <30 mL/min.

9. History or close family history (parents or siblings) of skin cancer or melanoma (excluding non-invasive basal or squamous cell lesion), or participant history of ocular-cutaneous albinism.

10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion).

11. Participant 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 once daily (QD) injection regimen.

• Minimum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Rhythm Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

David Meeker, MD

Role: STUDY_CHAIR

Rhythm Pharmaceuticals, Inc.

Locations

Wr-McCr, Llc

San Diego, California, United States

UMMS Baystate Health; BAYSTATE MEDICAL CENTER; Baystate Children's Specialty Center

Springfield, Massachusetts, United States

Columbia University Center

New York, New York, United States

M3 Wake Research

Raleigh, North Carolina, United States

University of Tennessee Health Science Center

Memphis, Tennessee, United States

Marshfield Clinic Research Foundation

Marshfield, Wisconsin, United States

Alberta Health Services

Edmonton, Alberta, Canada

Sorbonne University, Hôpital de la Pitié-Salpêtrière

Paris, , France

Centre Hospitalier Universitaire de Strasbourg

Strasbourg, , France

UPR Medical Sciences Campus

Rio Piedras, , Puerto Rico

Universidad Autónoma de Madrid University Hospital Niño

Madrid, , Spain

St. Thomas Hospital

London, , United Kingdom

Countries

United States; Canada; France; Puerto Rico; Spain; United Kingdom

References

Ervin C, Norcross L, Mallya UG, Fehnel S, Mittleman RS, Webster M, Haqq AM, Haws RM. Interview-Based Patient- and Caregiver-Reported Experiences of Hunger and Improved Quality of Life with Setmelanotide Treatment in Bardet-Biedl Syndrome. Adv Ther. 2023 May;40(5):2394-2411. doi: 10.1007/s12325-023-02443-y. Epub 2023 Mar 24.

Reference Type: DERIVED

PMID: 36961653 (View on PubMed)

Forsythe E, Haws RM, Argente J, Beales P, Martos-Moreno GA, Dollfus H, Chirila C, Gnanasakthy A, Buckley BC, Mallya UG, Clement K, Haqq AM. Quality of life improvements following one year of setmelanotide in children and adult patients with Bardet-Biedl syndrome: phase 3 trial results. Orphanet J Rare Dis. 2023 Jan 16;18(1):12. doi: 10.1186/s13023-022-02602-4.

Reference Type: DERIVED

PMID: 36647077 (View on PubMed)

Haqq AM, Chung WK, Dollfus H, Haws RM, Martos-Moreno GA, Poitou C, Yanovski JA, Mittleman RS, Yuan G, Forsythe E, Clement K, Argente J. Efficacy and safety of setmelanotide, a melanocortin-4 receptor agonist, in patients with Bardet-Biedl syndrome and Alstrom syndrome: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial with an open-label period. Lancet Diabetes Endocrinol. 2022 Dec;10(12):859-868. doi: 10.1016/S2213-8587(22)00277-7. Epub 2022 Nov 7.

Reference Type: DERIVED

PMID: 36356613 (View on PubMed)

Haws RM, Gordon G, Han JC, Yanovski JA, Yuan G, Stewart MW. The efficacy and safety of setmelanotide in individuals with Bardet-Biedl syndrome or Alstrom syndrome: Phase 3 trial design. Contemp Clin Trials Commun. 2021 May 3;22:100780. doi: 10.1016/j.conctc.2021.100780. eCollection 2021 Jun.

Reference Type: DERIVED

PMID: 34013094 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

2018-004058-11

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

RM-493-023

Identifier Type: -

Identifier Source: org_study_id