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
Conditions
Interventions
Product Name: setmelanotide
Product Code: RM-493
Pharmaceutical Form: Solution for injection
INN or Proposed INN: setmelanotide
CAS Number: 920014-72-8
Current Sponsor code: RM-493
Concentration unit
Sponsors
Rhythm Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria 1. Patients aged 6 or older who 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. 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. Meaningful clinical benefit is defined as follows: • Patients up to 18 years of age or younger that have completed participation on active drug and demonstrated adequate safety and at least 3% body mass index (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. 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 study. 3. Patient must meet one of the following requirements: • 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 section 6.2.1 • 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 FSH level in the post-menopausal laboratory range), contraception is not required during the study. - Any female participant in this latter category of having failed to Younger female patients who have not reached menarche upon study 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. Are the trial subjects under 18? yes Number of subjects for this age range: 205 F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 101 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 3
Exclusion criteria
Exclusion criteria: ALL Patients: 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 (CSSRS). Any lifetime history of a suicide attempt, or any suicidal behavior 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 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)12 years of age(see Appendix11.5). 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary •To characterize safety and tolerability of setmelanotide in patients who have completed treatment in a previous trial with setmelanotide for obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway and obesity related to other abnormalities in MC4R pathway ;Secondary Objective: Exploratory To assess the effect of setmelanotide, long term, on: •Maintenance 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. ;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.;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. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Exploratory endpoints include: The yearly mean percent change from baseline in body weight=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 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 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;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. | — |
Countries
Belgium, Canada, European Union, France, Germany, Greece, Israel, Netherlands, Spain, United Kingdom, United States
Contacts
Public ContactCathy O'Connor
Rhythm Pharmaceuticals, Inc.
Outcome results
None listed