E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
-LepR Deficiency Obesity -POMC Heterozygous Deficiency Obesity -POMC Epigenetic Deficiency Obesity -Bardet-Biedl syndrome -Alström syndrome -LEPR Heterozygous Deficiency Obesity -Bi-allelic, homozygous or compound heterozygous genetic status for either the POMC, PCSK1, or LEPR genes, with the loss-of-function variant for each allele conferring a severe obesity phenotype -Smith-Magenis Syndrome -SH2B1 Haploinsufficiency -Carboxypeptidase E deficiency -Leptin deficient 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 demonstrate clinically meaningful effects of setmelanotide, after 3 months of treatment, on percent body weight change in each type of these rare genetic disorders of obesity included in this protocol. |
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E.2.2 | Secondary objectives of the trial |
To assess setmelanotide effect after 3 months of treatment on: Safety and tolerability of setmelanotide (including blood pressure [BP] and heart rate [HR]), Hunger, Percent change in body fat mass, Glucose parameters: fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), oral glucose tolerate test (OGTT) with focus on parameters of insulin sensitivity, Waist circumference.
For patients who continue into the long term extension: To assess the effect of setmelanotide after 6 and 12 months of treatment on: Safety and tolerability of setmelanotide (including blood pressure [BP] and heart rate [HR]), Hunger, Percent change in body fat mass, Glucose parameters: fasting glucose, fasting insulin, glycated hemoglobin (HbA1c), oral glucose tolerate test (OGTT) with focus on parameters of insulin sensitivity, Waist circumference.
For consenting patients who agree to participate in a withdrawal phase: during withdrawal from drug, evaluate reversal of weight and hunger reduction. |
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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-studies to evaluate robust PK, energy expenditure, skin coloration changes by spectrophotometer, and blood pressure/heart rate by ambulatory blood pressure monitoring. |
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E.3 | Principal inclusion criteria |
1. Rare genetic disease patients genetically confirmed diagnoses (may be confirmed by test at Screening) of: a. Homozygous or compound heterozygous (different gene mutation on both alleles) LepR mutations b. Heterozygous POMC mutations c. POMC hypermethylation (epigenetic) variants (>51.92 % POMC methylation intensity at the specific analyzed POMC region) d. Bardet-Biedl Syndrome e. Alström Syndrome f. LEPR Heterozygous Deficiency Obesity g. Bi-allelic, homozygous or compound heterozygous (a different gene mutation on each allele) genetic status for either the POMC, PCSK1, or LEPR genes, with the loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype. h) Smith-Magenis Syndrome (SMS) i) SH2B1 Haploinsufficiency j) Carboxypeptidase E deficiency k) Leptin deficient obesity 2. Age 12 years and above. 3. If adult age ≥18 years, obesity with body mass index (BMI) ≥ 30 kg/m2; if age 12 and above, obesity with weight > 97th 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 be able to understand and sign the written informed consent/assent. 5. Female participants of child-bearing potential must 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 FSH level in the postmenopausal 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. Patients may be reconsidered approximately 1 month after cessation of such intensive regimens. 2. Recent (within 1 month) participation in another clinical trial that would confound the results of this study. 3. 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 preoperative 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 Rhythm prior to enrollment. 4. 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. 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 ≥ 15 in subjects with no significant neurocognitive deficits. 6. 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, again in patients without evidence of significant neurocognitive impairment. 7. Current, clinically significant pulmonary, cardiac, or oncologic disease, if these were severe enough to interfere with the study and/or would confound the results. Any such patients should be discussed with the sponsor prior to inclusion. 8. 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 (> 1.5 x upper limit of normal (ULN) for any of these tests)] for an etiology other than non-alcoholic fatty liver disease (NAFLD). Thus, any underlying etiology besides NAFLD, including diagnosed non-alcoholic steatohepatitis (NASH), other causes of hepatitis, or history of hepatic cirrhosis will be exclusionary, but the presence of NAFLD would not be exclusionary. 9. 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 ta glomerular filtration rate (GFR) <30 mL/min 10. History or close family history (parents or siblings) of skin cancer or melanoma, or patient history of ocularcutaneous albinism. 11. 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. Any concerning lesions identified during the screening period will be biopsied and results known to be benign prior to enrollment. If the pretreatment biopsy results are of concern, the patient may need to be excluded from the study. 12. Volunteer 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 or patients with a hypersensitivity to any of the excipients of the investigational medicinal product. 15. Inability to comply with QD injection regimen. 16. Females who are breastfeeding or nursing.
Inclusion criteria for extensions after 3 months of treatment: 1. Patient completes the initial ~3 months of treatment period without evidence of severe or clinically relevant adverse events, changes in vital signs, or changes in safety laboratories or ECGs 2. Patient loses ~5 kg (or 5% if baseline body weight < 100 kg) of weight over the treatment period. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the mean percent change from baseline for body weight. |
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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) |
Supporting secondary, tertiary and exploratory endpoints will include: safety and tolerability of setmelanotide, hunger assessed daily by a questionnaire using a Likert-type scale for each patient over time, including during the Screening Period; body composition assessments including total body weight loss, fat loss, and non-bone lean mass, measured in kg as well as percent change from baseline; glucose parameters as measured by fasting glucose, HbA1c and OGTT with focus on parameters of insulin sensitivity over time, and waist circumference; potential improvement in lipids, PK of setmelanotide, quality of life as assessed by IWQOL-Lite, PedsQL and SF-36; change in pubertal development; biomarkers predictive of setmelanotide response; changes in depression/suicidality as assessed by the C-SSRS and PHQ-9. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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
| 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 | 11 |
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 |
Australia |
Canada |
France |
Germany |
Greece |
Ireland |
Israel |
Netherlands |
Portugal |
Spain |
Turkey |
United Kingdom |
United States |
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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 | 2 |
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 | 2 |
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 |