E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with obesity caused by genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway. Human Genetics studies have identified several diseases that are the result of genetic defects affecting the MC4R pathway, for example: •POMC deficiency obesity due to mutations in the POMC gene •PCSK1 deficiency due to mutations in the PCSK1 gene •LEPR deficiency obesity due to mutations in the LEPR gene •Bardet-Biedl syndrome •Alström syndrome
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E.1.1.1 | Medical condition in easily understood language |
Obesity caused by rare genetic defects in patients causing extreme hunger. |
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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 characterize safety and tolerability of setmelanotide in patients who have completed treatment in a previous trial of setmelanotide for obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway. |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of setmelanotide, long term, on: • Maintained or continued weight loss • Hunger • Percent change in body fat mass • Waist circumference • Percent change in total body mass, non-bone lean mass, and bone density • Fasting lipid (cholesterol and triglyceride) panel • Changes in quality of life and health status • Biomarkers predictive of a setmelanotide response and/or that change when the rate of weight loss may change later in the treatment regimen. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients aged 6 or older that have completed participation on active drug and demonstrated adequate safety and meaningful clinical benefit (efficacy) in a previous setmelanotide study for obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway.
Note: The index study may have a primary endpoint relied on efficacy, safety or tolerability. Patient will be eligible for extension study if the Primary Investigator believes the patient exhibited a clinically meaningful benefit (i,e, efficacy) to setmelanotide treatment, and would benefit from continued treatment, after discussion with the Sponsor.
2. 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 to understand and sign the written informed consent/assent. The patient must assent/consent to participate in the trial.
3. 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), postmenopausal for at least 12 months (and confirmed with a screening FSH level in the post-menopausal lab range), or have delayed pubertal development and failure to have achieved menarche, do not require contraception during the study. Any female participant in this latter category of having failed to reach menarche upon study entry, that suspects this status may have changed should promptly inform the investigator and undergo pregnancy testing. If confirmed to be of child bearing potential, the participant must agree to use contraception as outlined in the protocol. 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 |
ALL Patients: 1. Pregnant and/or breastfeeding women 2. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), 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 pre-treatment biopsy results are of concern, the patient may need to be excluded from the study.
3. Patient is, in the opinion of the Study Investigator, not suitable to participate in the study. In addition, any patient who experiences a gap in treatment of at least one month between completing the Index study and Screening for this study, should have the following exclusion criteria evaluated:
4. Current, clinically significant disease, if 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
5. 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.
6. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
7. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (CSSRS). 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 enrolled in the study, as long as in the opinion of the Primary Investigator there are no clinical signs or symptoms of suicidal behavior.
8. History of significant liver disease or liver injury, or a current liver assessment due to abnormal liver tests (as indicated by abnormal liver function tests, alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin >1.5× the upper limit of normal [ULN] for any of these tests) for an etiology other than nonalcoholic 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 is exclusionary, but the presence of NAFLD is not be exclusionary.
9. Moderate to severe renal dysfunction as defined by a glomerular filtration rate (GFR) <30 mL/min.
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. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The safety and tolerability of setmelanotide, as assessed by the frequency and severity of AEs as well as changes in physical examinations, electrocardiograms (ECGs), vital signs (including resting BP and HR), laboratory evaluations, and injection site reactions. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The open label extension study and the analysis itself is exploratory so there is no specific time-point of the analysis (or statistical hypothesis) to define the success or failure of this study. All available study data will be summarized per patient population at each visit time point so we can evaluate the long-term safety and efficacy outcomes. |
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E.5.2 | Secondary end point(s) |
Exploratory endpoints include: The yearly mean percent change from baseline in body weight. Hunger, as assessed at each visit using a set of two global questions. Yearly change in body composition including total body weight loss, fat loss, and nonbone lean mass, as measured by DXA scan or BIA. Waist circumference, as measured by US National Heart Lung and Blood Institute criteria [2000 NHLBI] over time. Change from baseline in lipid values (e.g. fasting cholesterol and triglycerides) Change in Quality of life, as assessed by the following assessments: o Impact of Weight on Quality of Life-Lite (IWQOL-Lite) o 10-Item Short Form Health Survey for Children (SF-10) 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) Change from baseline in metabolic and hormonal assays and other exploratory biomarkers |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The open label extension study and the analysis itself is exploratory so there is no specific timepoint of the analysis (or statistical hypothesis) to define the success or failure of this study. All available study data will be surmised per patient population at each visit time point so we can evaluate the long term safety and efficacy outcomes. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 |
The primary objectives of this extension trial are to explore the long-term safety and tolerability of setmelanotide for up to 5 years or until drug is otherwise available through authorized use. |
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 18 |
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 | Yes |
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 |
Belgium |
Canada |
France |
Germany |
Netherlands |
Spain |
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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The end of the trial will be defined as the last patient last visit. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | |
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 | 5 |