Leptin Receptor Deficiency ObesityPhase 3NCT03287960
Setmelanotide for the Treatment of Leptin Receptor (LEPR) Deficiency Obesity
A Phase 3 study testing Setmelanotide in people with Leptin Receptor Deficiency Obesity, run by Rhythm Pharmaceuticals, Inc. at 6 sites in 6 countries.
Trial summary
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment. Read more about this study
- Who is it for?
- Ages 6 years and older
- Conditions the study is for
- Leptin Receptor Deficiency Obesity
- What is being tested?
- Setmelanotide
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 15 participants
- Where
- 6 sitesin 6 countries
- Study dates
- 30 Jan 2018to 25 Sep 2020
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 6 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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 body mass index (BMI) ≥ 30 kilograms per meters squared (kg/m^2); if child or adolescent (< 18 years of age), 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 participants must not donate sperm during and for 90 days following their participation in the study.
Who cannot join
- 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.
- Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
- 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 (New York Heart Association [NYHA] Class 3 or greater), or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results.
Show all 15Show fewer
- 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).
- 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 milliliter/minute (mL/min).
- History or close family history (parents or siblings) of skin cancer or melanoma, or participant 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.
- 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 every day (QD) injection regimen.
- Participants 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.
Trial locations and contacts
6 sites in 6 countries.
6 sites in 6 countries
France1 site
Institute of Cardiometabolism and Nutrition / Pitié-Salpêtrière Hospital
Paris, 75013
United Kingdom1 site
University of Cambridge Metabolic Research Laboratories
Cambridge, CB2 0QQ
About this study
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 Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.
- Conditions
- Leptin Receptor Deficiency Obesity
- Being tested
- Setmelanotide, Placebo
- Keywords
- LEPR deficiency obesity, setmelanotide, RM-493, Leptin receptor, Obesity, Melanocortin 4 receptor
- Medical subject headings
- Obesity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SetmelanotideDrug
Also called RM-493
Once daily subcutaneous injection
PlaceboDrug
Once daily subcutaneous injection
| Study group | Role | What they receive |
|---|---|---|
| Setmelanotide | Experimental | Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose. Receives: Drug: Setmelanotide; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.
Measured: Week 52
Secondary outcomes (9)
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.
Measured: Week 52
Mean Percent Change From Baseline in Body Weight
The mean percent change from baseline in body weight at 52 weeks was analyzed.
Measured: Baseline and Week 52
Mean Percent Change From Baseline in Hunger Score ('Most Hunger')
The mean percent change in hunger scores for participants ≥12 years of age with leptin receptor (LEPR) deficiency obesity in treatment with setmelanotide was evaluated. Hunger score ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.
Measured: Baseline and Week 52
Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline
The percentage of participants (≥12 years of age) achieving a ≥25% improvement from baseline in hunger score at Week 52 (i.e., after treatment with setmelanotide for 52 weeks at the therapeutic dose) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis.
Measured: Baseline and Week 52
Absolute Change From Baseline in Waist Circumference
Waist circumference (cm) was measured according to the National Heart, Lung, and Blood Institute (NHLBI) criteria. Waist circumference was measured when participants were fasting at approximately the same time at each visit. The absolute change from baseline in waist circumference was assessed.
Measured: Baseline and Week 52
Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
A comparison of weight change was evaluated during the 8 week placebo-controlled withdrawal period for each participant, during which each participant received 4 weeks of placebo and 4 weeks active therapy in a blinded fashion.
Measured: Baseline and Week 8 of withdrawal period
Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period
The absolute score in daily hunger reduction during the double-blind placebo-controlled withdrawal period (≥12 Years of Age) was assessed. Hunger ranged from 0 - 10 on a Likert-type scale; 0 = not hungry at all and 10 = hungriest possible. On the Daily Hunger Questionnaire, each of the 3 items (average hunger, most/worst hunger, and morning hunger) was scored separately and averaged on a weekly basis. The weekly average hunger score of the daily worst (most) hunger score in 24 hours is the hunger score used to assess this study endpoint. Lower scores represent lower hunger, higher scores represent greater hunger.
Measured: Week 8 of withdrawal period
Mean Percent Change From Baseline in Body Mass Index
The mean percent change from baseline in body mass index (BMI) was assessed.
Measured: Baseline and Week 52
Change From Baseline in Glucose Parameters
Glucose parameters included glucose, glycated hemoglobin (HbA1c) and Oral glucose tolerance test (OGTT). Data is planned to be reported only for change from baseline in glucose levels.
Measured: Baseline and Week 52
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted19 Sep 2017
- Study start30 Jan 2018
- Primary completion25 Sep 2020
- Study completion25 Sep 2020
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Leptin Receptor Deficiency ObesityStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rhythm Pharmaceuticals, Inc.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- David Meeker, MD, Study chair, Rhythm Pharmaceuticals, Inc.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03287960
- Sponsor's protocol ID
- RM-493-015
- Other IDs
- 2017-002005-36, 2017
- Status last verified
- May 2023
- First submitted
- 14 Sep 2017
- Last updated
- 23 May 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Clement K, Roth CL, Kuhnen P, Haqq AM, Mallya UG, Ervin C, Norcross L, Bhargava S, Argente J, Miller JL. Measuring Hunger Severity in Rare MC4R Pathway Diseases: Development and Psychometric Evaluation of the Most Hunger Item. Adv Ther. 2026 Oct 1. doi: 10.1007/s12325-026-03741-x. Online ahead of print.
PubMed 42821228Clement 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, Kuhnen 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.
PubMed 33137293
Study at a glance
From the registry record, last updated by the sponsor on 23 May 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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 Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
- ClinicalTrials.gov ID
- NCT03287960
- Acronym / sponsor ID
- RM-493-015
- Conditions
- Leptin Receptor Deficiency Obesity
- Keywords
- LEPR deficiency obesity, setmelanotide, RM-493, Leptin receptor, Obesity, Melanocortin 4 receptor
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- Rhythm Pharmaceuticals, Inc.Industry (pharma, biotech, devices)
- Study start
- 30 Jan 2018 (actual)
- Primary completion
- 25 Sep 2020 (actual)
- Study completion
- 25 Sep 2020 (actual)
- First posted
- 19 Sep 2017 (actual)
- Results
- Posted 23 May 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Open-label with an 8 week Double-Blind Placebo-Controlled Withdrawal Period
| Arm | Type | Receives |
|---|---|---|
| Setmelanotide | Experimental | Drug: Setmelanotide, Drug: PlaceboParticipants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was <100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (~1 year) of treatment at a therapeutic dose. |
Who may qualify
- Ages
- 6 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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 body mass index (BMI) ≥ 30 kilograms per meters squared (kg/m^2); if child or adolescent (< 18 years of age), 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.
Key exclusion criteria (15 listed)
- 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.
- Prior gastric bypass surgery resulting in >10% weight loss durably maintained from the baseline pre-operative weight with no evidence of weight regain.
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SetmelanotideAlso: RM-493Once daily subcutaneous injection | Drug | Setmelanotide |
| PlaceboOnce daily subcutaneous injection | Drug | Setmelanotide |
Primary outcome
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort)
Time frame: Week 52
The percentage of participants who met the ≥10% weight loss threshold (responders) after approximately Week 52 (~1 year) of treatment were analyzed.
9 secondary outcomes
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal + Supplemental Cohort)
Time frame: Week 52
Mean Percent Change From Baseline in Body Weight
Time frame: Baseline and Week 52
Mean Percent Change From Baseline in Hunger Score ('Most Hunger')
Time frame: Baseline and Week 52
Percentage of Participants Achieving at Least 25% Improvement in Daily Hunger From Baseline
Time frame: Baseline and Week 52
Absolute Change From Baseline in Waist Circumference
Time frame: Baseline and Week 52
Absolute Change in Body Weight (Reversal of Weight Loss) During Double-Blind Placebo-Controlled Withdrawal Period
Time frame: Baseline and Week 8 of withdrawal period
Absolute Daily Hunger Reduction Score During the Double-Blind Placebo-Controlled Withdrawal Period
Time frame: Week 8 of withdrawal period
Mean Percent Change From Baseline in Body Mass Index
Time frame: Baseline and Week 52
Change From Baseline in Glucose Parameters
Time frame: Baseline and Week 52
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 23 May 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 42821228Clement K, Roth CL, Kuhnen P, Haqq AM, Mallya UG, Ervin C, Norcross L, Bhargava S, Argente J, Miller JL. Measuring Hunger Severity in Rare MC4R Pathway Diseases: Development and Psychometric Evaluation of the Most Hunger Item. Adv Ther. 2026 Oct 1. doi: 10.1007/s12325-026-03741-x. Online ahead of print.
- Derived from this study: PubMed 33137293Clement 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, Kuhnen 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David Meeker, MD study chair
Rhythm Pharmaceuticals, Inc.
6 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Setmelanotide in people with Leptin Receptor Deficiency Obesity, run by Rhythm Pharmaceuticals, Inc. at 6 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 15 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 23 May 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in Canada, France, Germany, Netherlands, Reunion and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 23 May 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Participants Who Reached ≥10% Weight Loss Threshold After 1 Year (Pivotal Cohort) (time frame: Week 52). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03287960, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 May 2023.