E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
- POMC/PCSK1/LEPR heterozygous - POMC/PCSK1/LEPR compound heterozygous or homozygous deficiency obesity - POMC/PCSK1/LEPR composite heterozygous deficiency obesity - Smith-Magenis Syndrome - SH2B1 deficiency obesity - Chromosomal rearrangement of the 16p11.2 locus causing obesity - CPE compound heterozygous or homozygous deficiency obesity - Leptin deficiency obesity with loss of response to metreleptin - SRC1 deficiency obesity - MC4R deficiency obesity |
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E.1.1.1 | Medical condition in easily understood language |
Treatment of the obesity and hyperphagia of rare genetic disorders of obesity |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
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 explore the impact of setmelanotide on obesity in patients with various specific rare genetic mutations. |
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E.2.2 | Secondary objectives of the trial |
To assess the effects of setmelanotide on: - Safety and tolerability - Hunger - Waist circumference |
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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 |
Optional sub-study to further evaluate the PK profile. participating in the 24-hour sub-study, 4 additional blood samples will be collected after the same dose: • 9, 10, and 12 hours (± 10 min) after dosing, and •At approximately 24 hours after dosing; specifically, within 10 minutes BEFORE the next dose of study drug. |
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E.3 | Principal inclusion criteria |
1. Patients with the following genotypes and/or clinical diagnosis: a. POMC/PCSK1/LEPR heterozygous b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity c. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more genes) deficiency obesity d. Smith-Magenis Syndrome (SMS) e. SH2B1 deficiency obesity f. Chromosomal rearrangement of the 16p11.2 locus causing obesity g. CPE compound heterozygous or homozygous deficiency obesity h. Leptin deficiency obesity with loss of response to metreleptin i. SRC1 deficiency obesity j. MC4R deficiency obesity
Note: The specific genotype for all patients must be reviewed by the Sponsor prior to study enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment of patients in some subgroups may be prioritized by the Sponsor in order to ensure enrollment of patients with (1) well described, loss-of-function genetic mutations, (2) a variety of genetic variants, or (3) genetic variants likely to respond to setmelanotide. 2. Age 12 years and above. 3. Obese, defined as Body Mass Index (BMI) ≥ 30 kg/m2 for patients ≥16 years of age or BMI ≥ 95th percentile for age and gender for patients 12 up to 16 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), and 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 patients must not donate sperm during and for 90 days following their participation in the study.
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E.4 | Principal 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, naltrexone-bupropion). 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, patients 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 patients 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 PHQ-9 score of ≥ 15 or any suicidal ideation of type 4 or 5 on the C-SSRS during Screening, any lifetime history of a suicide attempt, or any suicidal behavior in the last month. Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive defects may be allowed to enroll in the study, as long as in the opinion of the Primary Investigator there are no clinical signs or symptoms of suicidal behavior. 6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or 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 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: Patients entering the study with SRC1 haploinsufficiency obesity must be evaluated during the Screening Period for hepatic fibrosis by appropriate imaging techniques (e.g., transient elastography or magnetic resonance elastography). Any patient with moderate or greater fibrosis (e.g., the equivalent of a METAVIR score ≥ 2) will be excluded from the study. 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 non-invasive/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 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. Patient 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. Patients 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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E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of patients in each subgroup of RGDO who achieve at least 5% body weight reduction from baseline, at ~3 months treatment with setmelanotide. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
At the end of ~3 months of treatment. |
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E.5.2 | Secondary end point(s) |
Secondary endpoints: • Safety and tolerability of setmelanotide injection, assessed by the frequency and severity of AEs, vital signs, and laboratory evaluations • Change and percentage change from baseline in body weight • Change from baseline in Daily and Global Hunger scores • Change from baseline in waist circumference
Exploratory Endpoints • Change from baseline in total body mass, including body fat and nonbone lean mass,as measure by either dual-energy x-ray absorptiometry (DXA) or bioelectrical impedance (BIA) • Change from baseline in fasting lipids (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides) • Change from baseline in metabolic and hormonal assays and other exploratory biomarkers • Change from baseline in glycated hemoglobin (HbA1c) • Evaluation of plasma pharmacokinetic (PK) parameters • Change from baseline in quality of life as measured by the following assessments: − Impact of Weight on Quality of Life-Lite (IWQOL-Lite) − EuroQoL-Five Dimension-5L (EQ-5D-5L) or EuroQoL-Five Dimension-Y (EQ-5D-Y) − The 12-Item Short Form Health Survey (SF-12) or 10-Item Short Form Health Survey for Children (SF-10) − Patient-Reported Behavioral Disturbance Questionnaire • Change from baseline in mental health status as measured by the Patient Health Questionnaire-9 (PHQ-9) and Columbia-Suicide Severity Rating Scale (C-SSRS) • Tanner Staging for patients who have yet to reach Tanner Stage V
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points are assessed from baseline to end of treatment. |
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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 | Yes |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | 12 |
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 States |
France |
Germany |
Netherlands |
Spain |
United Kingdom |
Greece |
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E.8.7 | Trial has a data monitoring committee | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |