SETMELANOTIDE for Obesity | Monogenic obesity (POMC/PCSK1/LEPR/NCOA1 (SRC1)/SH2B1 variants)

Inclusion criteria

• {"criterion_text":"- Patients must have a pre-identified: •Heterozygous gene variant in the POMC gene or PCSK1 gene (Sub-study 035a), •Heterozygous gene variant in the LEPR gene (Sub-study 035b), •Homozygous, heterozygous, or compound heterozygous variant in the NCOA1 (SRC1) gene (Sub study 035c), •Homozygous, heterozygous, or compound heterozygous variant in the SH2B1 gene, or chromosomal 16p11.2 deletion encompassing the SH2B1 gene (Sub-study 035d), For POMC, PCSK1, LEPR, NCOA1 (SRC1), and SH2B1 gene variants, to be considered for inclusion, the variant must either: • Be categorized by a Clinical Laboratory Improvement Amendments (CLIA)/College of American Pathologists (CAP)/International Organisation for Standardization (ISO) 15189 certified laboratory using ACMG criteria as a)\\tPathogenic (P); or b)\\tLikely pathogenic (LP); or c) Variant of uncertain significance (VUS); or d) For POMC, PCSK1, and LEPR, in addition to P/LP, only the sub-category of VUS variants that are suspected to be pathogenic (VUS-SP) will be eligible for inclusion. If a patient has 2 or more variants eligible for the trial, she/he will be assigned to a sub-study according to the following 2 rules: 1) To the highest ACMG pathogenicity category according to the following hierarchy: P > LP > VUS-SP > VUS •\\tFor example, if a patient carries both a POMC Pathogenic (P) variant and a LEPR VUS SP variant, the patient will be assigned as a POMC Pathogenic (P) patient (Sub study 035a). 2) If the 2 variants have the same ACMG classification, the patient will be assigned to the sub-study with lower overall frequency of gene variants according to the following hierarchy (least frequent to most frequent): LEPR > POMC/PCSK1 > NCOA1 (SRC1) > SH2B1. • For example, if a patient carries both a LEPR Pathogenic (P) variant and a SH2B1 Pathogenic (P) variant, the patient will be assigned as a LEPR Pathogenic (P) patient (Sub-study 035b)."}
• {"criterion_text":"- Between 6 and 65 years of age at the time of provision of informed consent/assent."}
• {"criterion_text":"- Obesity, with reported onset in childhood, and BMI ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and gender for patients 6 to 17 years of age, based on the United States (US) CDC criteria, at screening."}
• {"criterion_text":"- Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the trial (including once daily [QD] injection regimen and all other trial procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all trial procedures due to cognitive limitations or any other reason should not be enrolled into the trial."}
• {"criterion_text":"- Patient and/or parent or guardian reports that the patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient had obesity or was significantly overweight prior to the age of 6 years old."}
• {"criterion_text":"- Patient must meet one of the following requirements: Female participants of childbearing potential, defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must be confirmed non-pregnant and agree to use a highly effective form of contraception throughout the trial and for 90 days following the trial. Highly effective forms of contraception are detailed below and in Section 7.2.6: • Combined (estrogen and progestin) hormonal contraception associated with inhibition of ovulation (i.e., oral, intravaginal, or transdermal) • Progestin-only hormonal contraception associated with inhibition of ovulation (oral, implantable, or injectable) • Intrauterine device (IUD) •\\t Intrauterine hormone-releasing system • Bilateral tubal occlusion • Vasectomy/vasectomized partner (provided that the vasectomized partner is the sole sexual partner of the female participant, and the vasectomized partner has received medical assessment of surgical success) • Sexual abstinence, only if it is the preferred and usual lifestyle of the patient Female participants of non-childbearing potential, defined as: permanently sterile (status post hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or post-menopausal for at least 12 months (and confirmed with a screening follicle-stimulating hormone level in the post-menopausal lab range) do not require contraception during the trial. Younger female patients who have not achieved sexual maturity at trial entry will be assessed for Tanner Staging and required to comply with contraception requirements at first menarche. Male participants with female partners of childbearing potential must agree to use a highly effective method of contraception if they become sexually active during the trial or within 90 days following their participation in the trial. Male patients must also not donate sperm during and for 90 days following their participation in the trial."}
• {"criterion_text":"- Reported history of lifestyle intervention with diet and exercise."}
• {"criterion_text":"- Symptoms or behaviors of hyperphagia persistent during the patient’s life, including manifestations in childhood, as determined by the Investigator at screening."}

Exclusion criteria

• {"criterion_text":"- Bariatric surgery or procedure (e.g., gastric bypass/band/sleeve, duodenal switch, gastric balloon, intestinal barrier, etc.) within the last 6 months. All patients with a history of bariatric surgery or procedures must be discussed with, and receive approval from, the Sponsor prior to enrollment."}
• {"criterion_text":"- Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during screening. Any concerning lesions identified during screening 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 trial."}
• {"criterion_text":"- Patient is, in the opinion of the Investigator, not suitable to participate in the trial"}
• {"criterion_text":"- Participation in any clinical trial with an investigational drug/device within 3 months or 5 half-lives, whichever is longer, prior to the first day of dosing."}
• {"criterion_text":"- Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to setmelanotide."}
• {"criterion_text":"- Hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products (active and placebo)."}
• {"criterion_text":"- Females who are pregnant or breastfeeding, or planning or desiring to become pregnant during the duration of the trial."}
• {"criterion_text":"- Patients with the following gene variants: biallelic BBS (and/or clinical diagnosis of Bardet-Biedl syndrome [BBS]), biallelic ALMS1, or any MC4R variants"}
• {"criterion_text":"- Legally protected persons per local regulations (e.g., those that fall under the L1121-6 article of the Public Health code in France) or other applicable local laws."}
• {"criterion_text":"- Weight loss >2% in the previous 3 months. Patients will not be excluded for using regimens for weight maintenance or to prevent weight gain, such as dietary and/or exercise regimens, or medications, supplements or herbal treatments (e.g., orlistat, lorcaserin, phentermine, topiramate, naltrexone, bupropion, glucagon-like peptide 1 [GLP 1] receptor agonists, etc.), provided: • the regimen and/or dose has been stable for at least 3 months prior to randomization • the patient has not experienced weight loss >2% during the previous 3 months, AND • the patient intends to keep the regimen and/or dose stable throughout the course of the trial."}
• {"criterion_text":"- Documented diagnosis of current unstable major psychiatric disorder(s) (e.g., major depressive disorder, bipolar disorder, schizophrenia, etc.) or documented worsening psychiatric condition that required changes in treatment regimen within the previous 2 years, or other psychiatric-related risks that the Investigator believes may interfere with trial compliance or patient safety."}
• {"criterion_text":"- Clinically significant depression or suicidality as defined by: any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C SSRS) during screening, any suicide attempt during the patient’s lifetime, or any suicidal behavior in the last month, or a Patient Health Questionnaire 9 (PHQ 9) score of ≥15 during screening."}
• {"criterion_text":"- Current, clinically significant pulmonary, cardiac, endocrine/metabolic, hepatic, or oncologic disease considered severe enough to interfere with the trial and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility."}
• {"criterion_text":"- HbA1c >10% at screening."}
• {"criterion_text":"- History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH). (Patients with NAFLD or NASH will not be excluded based on this criterion.)"}
• {"criterion_text":"- Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 at screening. In patients ≥18 years of age the Modification of Diet in Renal Disease (MDRD) Equation should be used to calculate eGFR. In patients <18 years of age the Bedside Schwartz Equation should be used to calculate eGFR."}
• {"criterion_text":"- History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism."}

Primary endpoints

• {"endpoint_text":"- The difference in mean change in body weight from baseline at 52 weeks in patients treated with setmelanotide compared to placebo, assessed as percent change from baseline body mass index (BMI)","definition_or_measurement_approach":"Assessed as percent change from baseline body mass index (BMI) at 52 weeks comparing setmelanotide versus placebo."}

Secondary endpoints

• {"endpoint_text":"- The proportion of patients who achieve at least 5% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo","definition_or_measurement_approach":"Proportion achieving ≥5% reduction in baseline BMI at 52 weeks comparing setmelanotide versus placebo."}
• {"endpoint_text":"- The difference in mean change in body weight from baseline at 52 weeks in adult patients (age ≥18 years at baseline) treated with setmelanotide compared to placebo, assessed as percent change in baseline body weight","definition_or_measurement_approach":"Assessed as percent change in baseline body weight at 52 weeks in adults (≥18 years)."}
• {"endpoint_text":"- The difference in mean percent change in the weekly average most hunger score at 52 weeks in patients treated with setmelanotide compared to placebo, utilizing the Hunger Questions for Patients ≥12 years of Age","definition_or_measurement_approach":"Assessed as mean percent change in the weekly average 'most hunger' score at 52 weeks using the Hunger Questions for Patients ≥12 years of age."}
• {"endpoint_text":"- The proportion of patients who achieve at least 10% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo","definition_or_measurement_approach":"Proportion achieving ≥10% reduction in baseline BMI at 52 weeks comparing setmelanotide versus placebo."}
• {"endpoint_text":"- The difference in mean change in BMI from baseline at 52 weeks in pediatric patients (age <18 years at baseline) treated with setmelanotide compared to placebo assessed as change in baseline BMI Z-score","definition_or_measurement_approach":"Assessed as change in baseline BMI Z-score at 52 weeks in pediatric patients (<18 years)."}
• {"endpoint_text":"- The difference in change from baseline at 52 weeks in % of the 95th BMI percentile, as defined by the Centers for Disease Control and Prevention (CDC), in patients <18 years at baseline treated with setmelanotide compared to placebo","definition_or_measurement_approach":"Assessed as change in percentage of the 95th BMI percentile per CDC definitions at 52 weeks in patients <18 years."}
• {"endpoint_text":"- The difference from baseline at 52 weeks in mean change in waist circumference in patients treated with setmelanotide compared to placebo","definition_or_measurement_approach":"Assessed as mean change in waist circumference from baseline to 52 weeks."}
• {"endpoint_text":"- The overall safety and tolerability of setmelanotide in patients with genetic variants in the MC4R pathway •\tThe difference in mean change from baseline at 52 weeks in physical functioning score and total score for Impact of Weight on Quality of Life in adults (IWQOL-Lite) and in children (IWQOL-Kids-Parent Proxy) in patients treated with setmelanotide compared to placebo","definition_or_measurement_approach":"Safety and tolerability assessed via standard safety reporting; QoL assessed by mean change in IWQOL-Lite (adults) and IWQOL-Kids-Parent Proxy (children) from baseline to 52 weeks."}
• {"endpoint_text":"- The difference in mean body weight loss, and % body weight loss at 52 weeks in setmelanotide responders (defined as patients with ≥5% body weight loss if ≥18 years of age, or a decrease in BMI by ≥3% if <18 years of age, after 0 weeks of therapy at 0 mg/day or at the maximally tolerated dose) as compared to the placebo group","definition_or_measurement_approach":"Assessed as mean absolute and percent body weight loss at 52 weeks in the responder population; responders defined as ≥5% body weight loss in ≥18 years or BMI decrease ≥3% in <18 years (definition as provided)."}

Methods

• Physician referral letters (Dr to Adult Patient Letter; Dr to Parent Letter) — recruitment via treating clinicians
• Patient-facing materials (Patient Brochure, Patient Flyer) — direct-to-patient informational materials
• Parent-facing materials (Parent Brochure) — materials targeting parent/guardian of pediatric candidates
• Physician referral/physician brochures (Physician Referral Brochure) — materials to support clinician referral pathways

France

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

26-11-2025

Processing Time Days

406

Number Of Sites

5

Number Of Participants

15

Germany

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

26-11-2025

Processing Time Days

406

Number Of Sites

3

Number Of Participants

25

Greece

Earliest CTIS Part Ii Submission Date

17-12-2024

Latest Decision Or Authorization Date

27-11-2025

Processing Time Days

345

Number Of Sites

1

Number Of Participants

10

Netherlands

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

28-11-2025

Processing Time Days

408

Number Of Sites

1

Number Of Participants

25

Spain

Earliest CTIS Part Ii Submission Date

16-10-2024

Latest Decision Or Authorization Date

27-11-2025

Processing Time Days

407

Number Of Sites

5

Number Of Participants

10

Primary sponsor

Full Name

Rhythm Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

PPD (UK) Limited

Responsibilities

Pharmacovigilance

Name

Iqvia Biotech Limited

Responsibilities

patient recruitment, connected devices, virtual trials, mobile research nursing, central labs (and other operational roles as listed)

Name

IQVIA RDS Hellas Single Member S.A.

Responsibilities

Operational support roles (codes listed in sponsor duties)

Name

Syneos Health Clinique Inc.

Responsibilities

PK and ADA testing

Name

Q2 Solutions LLC

Responsibilities

Central labs

Third parties

• {"country":"United Kingdom","full_name":"Q Squared Solutions Limited","duties_or_roles":"Central Labs","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"PPD (UK) Limited","duties_or_roles":"Pharmacovigilance","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Q2 Solutions LLC","duties_or_roles":"Central Labs","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United Kingdom","full_name":"Iqvia Biotech Limited","duties_or_roles":"patient recruitment, connected devices, virtual trials, mobile research nursing, central labs","organisation_type":"Pharmaceutical company"}
• {"country":"Greece","full_name":"IQVIA RDS Hellas Single Member S.A.","duties_or_roles":"Duties include roles with codes 1, 12, 2 (as listed)","organisation_type":"Pharmaceutical company"}
• {"country":"Canada","full_name":"Syneos Health Clinique Inc.","duties_or_roles":"PK and ADA test","organisation_type":"Hospital/Clinic/Other health care facility"}