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Protocol Details

Setmelanotide (RM-493; Rhythm Pharmaceuticals, Inc.) Phase 2 Open-Label Treatment Trials in Patients with Rare Genetic Disorders of Obesity

This study is NOT currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

17-CH-0078

Sponsoring Institute

National Institute of Child Health and Human Development (NICHD)

Recruitment Detail

Type: Completed Study; data analyses ongoing
Gender: Male & Female
Min Age: 6 Years
Max Age: 100 Years

Referral Letter Required

No

Population Exclusion(s)

None

Keywords

Obesity;
Pharmacotherapy

Recruitment Keyword(s)

None

Condition(s)

SRC1 Deficiency;
Bardet Biedl Syndrome;
CPE Deficiency;
POMC Deficiency;
Leptin Deficiency

Investigational Drug(s)

Setmelanotide

Investigational Device(s)

None

Intervention(s)

Drug: Setmelanotide

Supporting Site

National Institute of Child Health and Human Development

Background:

Messenger substances (MSH) affect how some genes work. Low MSH is thought to make people not feel full. This can cause them to eat too much and become overweight. Setmelanotide (RM-493) mimics MSH. Researchers want to see if it can help control body weight in people with conditions that lower MSH.

Objective

To test if RM-493 is safe, well tolerated, and effective for treating people with severe obesity caused by conditions that lower MSH.

Eligibility:

People ages 12 and older who have obesity due to particular conditions.

Design:

Participants will be screened with:

-Medical history

-Questionnaires

-Physical exam

-Skin exam

-Dual energy X-ray absorptiometry: Participants lie on a table while X-rays measure body composition.

-MRI: Participants lie on a table that slides into a tube that takes pictures of the body.

-Blood, heart, and urine tests

-Lunch: They will be given lunch and eat until they are full.

Participants will get RM-493 by injection under the skin once a day. They will be taught how to do it themselves at home. They will continue treatment for 3-15 months.

Participants will have visits every 2 weeks for the first 12 weeks. Then they will have 3 visits over 10 months, then 8 visits over 52 weeks. Visits include repeats of the screening tests. They may also include:

-Blood pressure monitoring

-Energy expenditure: Participants rest in a bed. Then they wear a plastic hood to measure breathing.

-Skin color measurement: A device pressed on the skin measures darkness of the skin.

-Photographs to assess skin

Participants may join a longer study after completing this trial.

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Eligibility

INCLUSION CRITERIA:

1. Individuals with the following genotypes and/or clinical diagnosis:

a. POMC/PCSK1/LEPR heterozygous deficiency obesity

b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity

c. POMC/PCSK1/LEPR composite heterozygous (two different mutations in gene) deficiency obesity

d. Smith-Magenis Syndrome (SMS)

e. SH2B1 deficiency obesity

f. Chromosomal rearrangement of the 16p11.2 locus causing obesity

g. Carboxypeptidase E (CPE) compound heterozygous or homozygous deficiency obesity

h. Leptin Deficiency Obesity with loss of response to exogenous leptin

i. SRC1 deficiency obesity

j. MC4R deficiency obesity

Note: The specific genotype for all participants must be reviewed by the Sponsor prior to study enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment of participants in some subgroups may be prioritized by the Sponsor in order

to ensure enrollment of participants with (1) well described, loss of function genetic variants, (2) a variety of genetic variants, or (3) genetic variants likely to respond to setmelanotide.

2. Age 6 years and above.

3. Obesity: If adult age greater than or equal to 16 years, body mass index (BMI) greater than or equal to 30 kg/m2; if age 6 - <16 years, obesity with weight > 95th percentile for age and sex 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.

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 nonchildbearing 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 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 > 2% weight loss.

2. Use of any medication that is approved to treat obesity within three months of first dose of study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexonebupropion). Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) is it not being prescribed for the treatment of obesity, (2) the dose has been stable for at least three months prior to enrollment, (3) the patient has not experienced weight loss during the previous three months, AND (4) the patient intends to keep the dose stable throughout the course of the study.

3. Gastric bypass surgery within the previous six months or any 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, 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 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 psychiatric disorder(s) 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. A Patient Health Questionnaire-9 (PHQ-9) score of greater than or equal to 15 or any suicidal ideation of type 4 or 5 on the Columbia

Suicide Severity Rating Scale (C-SSRS) during screening, 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 would confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine

eligibility.

7. HbA1c >9.0% at Screening

8. History of significant liver disease or abnormal liver function tests on screening (i.e. > 1.5 x upper limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin)

Note: A patient with a diagnosis of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) may be allowed to enroll in the study, after consultation with the Sponsor. Other significant liver disease, such as cirrhosis, are exclusionary.

9. Glomerular filtration rate (GFR) < 30 mL/min at screening.

10. History or close family history (parents or siblings) of skin cancer or melanoma (not including noninvasive/ infiltrative basal or squamous cell lesion), or patient history of ocular-cutaneous albinism.

11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a screening comprehensive skin evaluation performed by a qualified dermatologist during Screening. 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.

12. Participant is, in the opinion of the Study Investigator, not suitable to participate in the study.

13. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.

14. Participants previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide

15. Significant hypersensitivity to any excipient in the study drug.

16. Inability to comply with QD injection regimen.

17. Females who are breastfeeding or nursing.


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Citations:

Haws R, Brady S, Davis E, Fletty K, Yuan G, Gordon G, Stewart M, Yanovski J. Effect of setmelanotide, a melanocortin-4 receptor agonist, on obesity in Bardet-Biedl syndrome. Diabetes Obes Metab. 2020 Jul 6. doi: 10.1111/dom.14133. Epub ahead of print. PMID: 32627316.

Cl(SqrRoot)(Copyright)ment K, Biebermann H, Farooqi IS, Van der Ploeg L, Wolters B, Poitou C, Puder L, Fiedorek F, Gottesdiener K, Kleinau G, Heyder N, Scheerer P, Blume-Peytavi U, Jahnke I, Sharma S, Mokrosinski J, Wiegand S, M(SqrRoot) ller A, Wei(SqrRoot) K, Mai K, Spranger J, Gr(SqrRoot) ters A, Blankenstein O, Krude H, K(SqrRoot) hnen P. MC4R agonism promotes durable weight loss in patients with leptin receptor deficiency. Nat Med. 2018 May;24(5):551-555. doi: 10.1038/s41591-018-0015-9. Epub 2018 May 7.

K(SqrRoot) hnen P, Cl(SqrRoot)(Copyright)ment K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, Blume-Peytavi U, Gr(SqrRoot) ters A, Krude H. Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist. N Engl J Med. 2016 Jul 21;375(3):240-6. doi: 10.1056/NEJMoa1512693.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Jack A. Yanovski, M.D.
National Institute of Child Health and Human Development (NICHD)
NIHBC 10 - CRC BG RM 2-3142
10 CENTER DR
BETHESDA MD 20892
(301) 496-0858
jy15i@nih.gov

Julia Lazareva
National Institute of Child Health and Human Development (NICHD)
National Institutes of Health
Building 10
Room 2-3152
10 Center Drive
Bethesda, Maryland 20892
(301) 496-6726
julia.lazareva@nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT03013543

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