| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| POMC/PCSK1, LEPR, SRC1, SH2B1, and PCSK1 N221D Gene Defects in the Melanocortin-4 Receptor Pathway |
|
| E.1.1.1 | Medical condition in easily understood language |
| Improper function of certain messenger materials in the body that control body weight and hunger in people |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Digestive System and Oral Physiological Phenomena [G10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of setmelanotide on changes in body weight. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary:
• To evaluate the efficacy of setmelanotide based on the portion of patients with a clinically meaningful decrease in body weight defined as ≥5% decrease from baseline
• To evaluate the efficacy of setmelanotide on changes in body weight in adult patients with obesity
• To evaluate changes in hunger score in response to setmelanotide from baseline to 52 weeks of treatment
• To evaluate the efficacy of setmelanotide on the portion of patients with at least 10% decrease in body weight
Other Secondary:
• To evaluate the efficacy of setmelanotide on changes in BMI in pediatric patients with obesity
• To evaluate change in waist circumference in response to setmelanotide from baseline to 52 weeks of treatment
• To evaluate the safety and tolerability of setmelanotide
• To evaluate quality of life parameters following treatment with setmelanotide
• To evaluate the ability of an initial response to setmelanotide (defining a responder population) to predict long-term benefit. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
This master protocol describes multiple, independent, randomized, double-blind, placebo-controlled, sub-studies of setmelanotide in patients with obesity with 6 specific gene defects in the melanocortin-4 receptor (MC4R) pathway:
• pro-opiomelanocortin (POMC) or proprotein convertase subtilisin/kexin type 1 (PCSK1) (Sub-study 035a)
• leptin receptor (LEPR) (Sub-study 035b)
• nuclear receptor coactivator-1 (NCOA1), also referred to as steroid receptor coactivator-1 (SRC1) (Sub-study 035c)
• SRC homology 2 B adapter protein 1 (SH2B1) (Sub-study 035d)
These multiple sub-studies have a high degree of similarities. The objectives and endpoints are identical for all sub-studies in patients with POMC and/or PCSK1 (Sub-study 035a), LEPR (Sub-study 035b), NCOA1 (SRC1) (Sub-study 035c) and SH2B1 (Sub-study 035d) gene variants in the MC4R pathway. |
|
| E.3 | Principal inclusion criteria |
1. 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) pathogenic (P); or
b) likely pathogenic (LP); or
c) Variant of uncertain significance (VUS); or FOR POMC, PCSK1
d) and LEPR, in addition to P/LP, only the subcategory 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 (see Appendix 1 for further examples).
• For 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 (see Appendix 2. for further examples).
For example:
• If a patient carries both a LEPR Pathogenic (P) variant and SH2B1 Pathogenic (P) variant, the patient will be assigned as a LEPR Pathogenic (P) patient (Sub-study 035b).
See Appendix 3 for genetic testing requirements to be enrolled in the trial.
2. Between 6 and 65 years of age at the time of provision of informed consent/assent.
3. 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.
4. 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.
5. 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.
Refer to the protocol for inclusion criteria 6, 7, and 8 due character limit. |
|
| E.4 | Principal exclusion criteria |
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. HbA1c >10% at Screening.
7. 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.)
8. 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 (see Section 7.2.5).
9. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
10. 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.
11. Patient is, in the opinion of the Investigator, not suitable to participate in the trial.
12. 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.
13. Previously enrolled in a clinical trial involving setmelanotide or any previous exposure to setmelanotide.
14. Hypersensitivity to the active substance or to any of the excipients of the investigational medicinal products (active and placebo).
15.Females who are, pregnant or breastfeeding, or planning or desiring to become pregnant during the duration of the trial.
16. Patients with the following gene variations: biallelic BBS (and/or clinical diagnosis of Bardet-Biedl syndrome [BBS]) or biallelic ALMS1, or any MC4R variants.
17. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
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)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key Secondary:
• The proportion of patients who achieve at least 5% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo
• 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
• 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
• The proportion of patients who achieve at least 10% reduction in baseline BMI at 52 weeks, in patients treated with setmelanotide compared to placebo
Other Secondary:
• 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
• 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
• The difference from baseline at 52 weeks in mean change in waist circumference in patients treated with setmelanotide compared to placebo.
• The overall safety and tolerability of setmelanotide in patients with genetic variants in the MC4R pathway.
• The 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
• 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 12 weeks of therapy at 3.0 mg/day or at the maximally tolerated dose) as compared to the placebo group
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| United Kingdom |
| United States |
| France |
| Germany |
| Greece |
| Netherlands |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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