| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway |
|
| E.1.1.1 | Medical condition in easily understood language |
| treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway |
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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 |
Primary
• To characterize safety and tolerability of setmelanotide in patients who have completed a previous trial on treatment with setmelanotide for obesity associated with genetic defects upstream of the MC4R in the leptin-melanocortin pathway and with obesity related to other abnormalities in the MC4R pathway..
|
|
| E.2.2 | Secondary objectives of the trial |
Exploratory
To assess the effect of setmelanotide, long term, on:
• Maintained or continued improvement in weight-related parameters
• 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 potentially predictive of a setmelanotide response and/or that change due to improvement in weight-related parameters.
PK parameters will be calculated for a subset of patients with hypothalamic obesity participating in the study at selected trial centers in the US. |
|
| 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 |
Chart review sub-study - Investigators may be asked by the Sponsor to perform a chart review and a detailed analysis and collection of the clinical history of a specific patient population (e.g., selected based on indication, genetics, age group, duration of participation in the current study [e.g., at least 6 months]). Patients must provide written informed consent to participate in this substudy. Specifically, at a minimum, the following parameters will be collected:
• Growth charts and/or weight records for age of onset of obesity and weight trajectory
• Previous records of treatments or interventions for obesity or weight management (e.g., timing, duration and efficacy; related to lifestyle, behavioral, herbal/supplements, pharmacological, and/or surgical/endoscopic)
• Hunger/hyperphagia history 6.4.4. Patient Survey Substudy
Specific patient populations (e.g., selected based on indication, genetics, age group, duration of participation in the current study [e.g., at least 6 months]), at the discretion of the Sponsor, after an agreement with the investigator will be offered the opportunity to participate in a substudy involving a patient survey. Patients will be required to provide written informed consent to participate in this substudy.
6.4.5. Pharmacokinetic Substudy
For a subset of approximately 6 patients with hypothalamic obesity participating in the study at selected centers, additional blood samples for PK analysis will be collected; see Section 6.4.14 for details. |
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| E.3 | Principal inclusion criteria |
1. Patients aged 2 or older (or aged >2 years as per local regulations; only patients aged 12 years or older may be enrolled in the trial in Greece; only patients 6 years or older may be enrolled in the trial in Germany) who have completed participation in a previous setmelanotide clinical trial.
2. If patient received setmelanotide on an open-label basis in a previous setmelanotide clinical trial, patient demonstrated adequate safety and meaningful clinical benefit (efficacy) in the previous setmelanotide trial. Meaningful clinical benefit is defined as follows:
• Patients 18 years of age or younger that have completed participation on active drug and demonstrated adequate safety and at least 3% BMI reduction or reduction in BMI Z-score of 0.2 compared to baseline.
• Patients over 18 years of age should show reduction of 3% BMI compared to baseline.
If the patient received trial drug in a double-blind basis in the previous placebo-controlled clinical trial, patient tolerated trial drug in the previous clinical trial.
3. Patient and/or parent or guardian is able to communicate well with the investigator, to understand and comply with the requirements of the trial, and to understand and sign the written informed consent/assent. The patient must assent/consent to participate in the trial.
4. Patient must meet one of the following requirements regarding contraception:
• If a female of childbearing potential, defined as fertile, following menarche and until becoming post-menopausal unless permanently sterile (hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), must use a highly effective form of contraception as outlined in the protocol
• If a female 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 (FSH) level in the post-menopausal laboratory range), contraception is not required during the trial.
- Younger female patients who have not reached menarche upon trial entry will be assessed for Tanner staging and at first menarche will be required to comply with contraception requirements and pregnancy testing as outlined in the protocol.
• If a male with female partner(s) of childbearing potential, must agree to a double barrier method if they become sexually active during the study. Furthermore, male patients must not donate sperm during and for 90 days following their participation in the trial. |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Pregnant and/or breastfeeding women
2. Significant dermatologic findings relating to melanoma or premelanoma 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 trial.
3. Patient is, in the opinion of the Study Investigator, not suitable to participate in the trial.
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 enrollment in the trial.
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 trial 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 (C-SSRS). Any lifetime history of a suicide attempt, or any suicidal behavior in since the last visit in the index study.
Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive defects may be enrolled in the trial, 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. Severe renal dysfunction as defined by a glomerular filtration rate (GFR) <30 mL/min/1.73 m2 in patients >12 years of age.
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. |
|
| 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. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Since this is a OLE study and the analysis itself is really exploratory in nature. So there is no specific timepoint of the analysis (or statistical hypothesis) defines success/failure of the study. so in this case, we will summarized all the available data at each visit time points planned in the protocol. |
|
| E.5.2 | Secondary end point(s) |
Exploratory endpoints include:
• The yearly mean percent change from baseline in body weight in patients ≥18 years of age.
• Mean change from baseline in BMI Z-score and percent of 95th BMI percentile in patients <18 years of age.
• Mean change in BMI and mean percent change in BMI from baseline in all patients.
• Change in hunger from baseline, as assessed at each visit using a set of 2 global questions.
• Change from baseline in waist circumference, as measured by US National Heart Lung and Blood Institute criteria [2000 NHLBI] over time.
• 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 from baseline in Quality of life, as assessed by the following instruments:
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.
PK parameters will be calculated for a subset of patients with hypothalamic obesity participating in the trial at selected trial centers in the US. PK parameters to be calculated may include the following, based on sample availability:
Cmax The maximum concentration determined directly from individual concentration-time data
Tmax Time to reach maximum concentration
AUC0-8 The area under the plasma concentration-time curve from time-zero to 8 hours; calculated using the linear trapezoidal rule and allowing for extrapolation to 8 h if applicable.
AUC0-24 The area under the plasma concentration-time curve from time-zero to 24 hours; calculated using the linear trapezoidal rule and allowing for extrapolation to 24 h if applicable.
AUClast The area under the plasma concentration-time curve from time-zero to the time of the last quantifiable concentration; calculated using the linear trapezoidal rule.
Clast The last quantifiable concentration determined directly from individual concentration-time data.
Tlast Time of the last quantifiable concentration.
λZ The apparent terminal elimination rate constant, based on linear regression through the long concentration-time data using at least 3 data points.
The data points used in the regression is to be based on goodness of fit (adjusted R2).
T1/2 The apparent terminal elimination half-life, calculated as T1/2 = ln(2)/λz;
reported for informational purposes only.
Ctrough The concentration at the end of the 24-hour dosing interval (equal to the predose concentration for the next dose). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Since this is a OLE study and the analysis itself is really exploratory in nature. So there is no specific timepoint of the analysis (or statistical hypothesis) defines success/failure of the study. so in this case, we will summarized all the available data at each visit time points planned in the protocol. |
|
| 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 | 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 longterm safety and tolerability of setmelanotide for up to 5 years or until drug is otherwise available through authorized use.
Patients in the study may also leave to participate in other Rhythm studies studying the same drug. If they do this a transition visit will occur and they are able to transition back into 022 after. |
|
| 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Belgium |
| European Union |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 13 |
| 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 | 18 |
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