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    Summary
    EudraCT Number:2017-005006-35
    Sponsor's Protocol Code Number:RM-493-022
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-01-19
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - BfArM
    A.2EudraCT number2017-005006-35
    A.3Full title of the trial
    Long Term Extension Trial of setmelanotide (RM-493) for patients who have completed a trial of Setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long Term Extension Trial of setmelanotide (RM-493) for patients who have completed a trial of Setmelanotide for the treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway
    A.4.1Sponsor's protocol code numberRM-493-022
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorRhythm Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportRhythm Pharmacueticals, Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRhythm Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointCathy O'Connor
    B.5.3 Address:
    B.5.3.1Street Address222 Berkeley Street, 12th Floor
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02116
    B.5.3.4CountryUnited States
    B.5.4Telephone number+14135194676
    B.5.5Fax number+16179097103
    B.5.6E-mailcoconnor@rhythmtx.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/18/2101 and EU/3/16/1703
    D.3 Description of the IMP
    D.3.1Product namesetmelanotide
    D.3.2Product code RM-493
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsetmelanotide
    D.3.9.1CAS number 920014-72-8
    D.3.9.2Current sponsor codeRM-493
    D.3.9.4EV Substance CodeSUB182686
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10.0
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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
    E.1.1.1Medical condition in easily understood language
    treatment of obesity associated with genetic defects upstream of the MC4 receptor in the leptin-melanocortin pathway
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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

    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 sub study involving a patient survey. Patients will be required to provide written informed consent to participate in this sub study.

    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.
    E.3Principal 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.
    E.4Principal 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)<30 mL/min / 1.73 m2 in patient >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.
    E.5 End points
    E.5.1Primary 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.5.1.1Timepoint(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.
    E.5.2Secondary 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
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other 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.

    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.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Extension Trial
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other 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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Netherlands
    Spain
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days18
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 205
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 31
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 70
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 101
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    6-17 year olds.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state31
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 96
    F.4.2.2In the whole clinical trial 109
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    It is planned for patients to receive the drug for up to 7 years or until drug is otherwise available through authorized use.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-05-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-05-30
    P. End of Trial
    P.End of Trial StatusOngoing
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