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    Summary
    EudraCT Number:2017-000387-14
    Sponsor's Protocol Code Number:RM-493-014
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2019-03-14
    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 ConcernedFrance - ANSM
    A.2EudraCT number2017-000387-14
    A.3Full title of the trial
    Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients with rare genetic disorders of obesity
    Essai thérapeutique de phase 2 portant sur la setmélanotide (RM-493) chez des patients atteints de maladies génétiques rares de l’obésité
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Setmelanotide (RM-493) Phase 2 Treatment Trial in Patients with rare genetic disorders of obesity
    A.3.2Name or abbreviated title of the trial where available
    Basket Study
    A.4.1Sponsor's protocol code numberRM-493-014
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03013543
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/164/2018
    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 Pharmaceuticals, 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 pointSarah Pilley
    B.5.3 Address:
    B.5.3.1Street Address11th Floor, 500 Boylston Street
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA02116
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18572644281
    B.5.5Fax number+18572644299
    B.5.6E-mailspilley@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 numberEMA/OD/063/16
    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.3.9.3Other descriptive nameRM-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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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
    E.1.1.1Medical condition in easily understood language
    Treatment of the obesity and hyperphagia of rare genetic disorders of obesity
    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
    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.
    E.2.2Secondary 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.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full 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.
    E.3Principal 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.
    E.4Principal 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the mean percent change from baseline for body weight.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At the end of ~3 months of treatment.
    E.5.2Secondary 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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Over time.
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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 concerned1
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA11
    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
    Australia
    Canada
    France
    Germany
    Greece
    Ireland
    Israel
    Netherlands
    Portugal
    Spain
    Turkey
    United Kingdom
    United States
    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 years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 32
    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) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 32
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 62
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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
    Children under the age of 18.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 25
    F.4.2.2In the whole clinical trial 100
    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)
    At the end of the Treatment and Evaluation Period, patients who have had a positive response to setmelanotide after 1 year of treatment will have the opportunity to enroll in a future, separate, extension protocol, in order to allow for continued treatment.
    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 Decision2019-05-27
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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