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    Summary
    EudraCT Number:2018-004058-11
    Sponsor's Protocol Code Number:RM-493-023
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-03-20
    Trial results View 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 number2018-004058-11
    A.3Full title of the trial
    A Phase 3 trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström syndrome (AS) Patients with Moderate to Severe Obesity
    Étude de phase 3 portant sur la setmélanotide (RM-493), un agoniste du récepteur 4 de la mélanocortine (MC4R), dans le syndrome de Bardet-Biedl (SBB) et le syndrome d’Alström (SA) chez des patients atteints d’obésité modérée à sévère
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Setmelanotide (RM-493) trial in Bardet-Biedl Syndrome (BBS) and Alström syndrome (AS) Patients with Moderate to Severe Obesity
    Traitement de l’obésité et de l’hyperphagie chez les patients atteints du SBB ou du SA
    A.4.1Sponsor's protocol code numberRM-493-023
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03746522
    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 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 pointMatthew Webster
    B.5.3 Address:
    B.5.3.1Street Address500 Boylston Street, 11th Floor
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02116
    B.5.3.4CountryUnited States
    B.5.4Telephone number001508 789 1527
    B.5.6E-mailmwebster@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 No
    D.2.5.1Orphan drug designation number
    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.3.9.2Current sponsor codeRM-493
    D.3.9.4EV Substance CodeSUB192416
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Obesity and hyperphagia in patients with Bardet-Biedl Syndrome or Alström syndrome
    E.1.1.1Medical condition in easily understood language
    Obesity and hyperphagia in patients with Bardet-Biedl Syndrome or Alström syndrome
    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 assess the effect of setmelanotide on the proportion of patients (≥12 years of age at baseline) treated with setmelanotide for approximately (~) 52 weeks who achieve a clinically meaningful reduction from baseline (ie, ≥10%) in body weight.
    E.2.2Secondary objectives of the trial
    Key Secondary
    • To assess the effect of setmelanotide on the proportion of all patients who achieve a ≥10% reduction from baseline in body weight after ~52 weeks of treatment with setmelanotide.
    • To assess the effect of setmelanotide on mean percent change in body weight (in patients ≥12 years of age at baseline) compared with baseline after ~52 weeks of treatment with setmelanotide..
    • To assess the effect of setmelanotide on the proportion of patients who achieve a ≥25% improvement in the weekly average of the daily hunger score (in patients ≥12 years of age at baseline) after ~52 weeks of treatment with setmelanotide.
    • To assess the effect of setmelanotide on the mean percent change from baseline in the weekly average of the daily hunger score (in patients ≥12 years of age at baseline) after ~52 weeks of treatment with setmelanotide.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. BBS clinical diagnosis as per Beales, 1999 (with either 4 primary features or 3 primary and 2 secondary features, as described below):
    - Primary Diagnostic Criteria
    • Rod cone dystrophy
    • Learning disabilities
    • Polydactyly
    • Hypogonadism in males
    • Obesity
    • Renal anomalies
    - Secondary Diagnostic Criteria:
    • Speech disorder/delay
    • Mild spasticity (especially lower limbs)
    • Strabismus/cataracts/astigmatism
    • Diabetes mellitus
    • Brachydactyly/syndactyly
    • Dental crowding/hypodontia/small roots/high arched palate
    • Developmental delay
    • Left ventricular hypertrophy/congenital heart disease
    • Polyuria/polydipsia (nephrogenic diabetes insipidus)
    • Hepatic fibrosis
    • Ataxia/poor coordination

    Or AS diagnosis as per Marshall, 2007 (using major and minor age adjusted criteria, as described below).
    For patients 6 to ≤14 years of age - Minimum Required: 2 major criteria or 1 major and 3 minor criteria, as follow:
    - Major Diagnostic Criteria
    • Mutation of ALMS1 and/or family history of AS
    • Vision (nystagmus, photophobia, diminished acuity, if old enough for testing: cone dystrophy by ERG)
    - Minor Diagnostic Criteria
    • Obesity and/or insulin resistance and/or T2DM
    • History of DCM/CHF
    • Hearing loss
    • Hepatic dysfunction
    • Renal failure
    • Advanced bone age

    For patients ≥15 years of age - Minimum Required: 2 major and 2 minor criteria or 1 major and 4 minor criteria, as listed below:
    - Major Diagnostic Criteria:
    • Mutation of ALMS1 and/or family history of AS
    • Vision (history of nystagmus in infancy/childhood, legal blindness, cone and rod dystrophy by ERG)
    - Minor Diagnostic Criteria:
    • Obesity and/or insulin resistance and/or T2DM
    • History of DCM/CHF
    • Hearing loss
    • Hepatic dysfunction
    • Renal failure
    • Short stature
    • Males: hypogonadism
    • Females: irregular menses

    Note: at least 90% of patients with BBS and 100% of patients with AS must have genetically confirmed diagnosis at the time of enrollment
    o A genetically confirmed diagnosis of BBS is defined as a homozygous or compound heterozygous loss-of-function mutation in BBS genes; patients without a genetically confirmed BBS diagnosis must be reviewed with the Sponsor’s medical monitor prior to enrollment.
    o A genetically confirmed diagnosis of AS is defined as a homozygous or compound heterozygous loss-of-function mutation in the ALMS1 gene.
    Once 10% of patients without a confirmed BBS diagnosis have been enrolled in the study, sites will be notified that only genetically confirmed BBS patients may be enrolled.

    2. ≥6 years of age.
    3. Obese, defined as BMI ≥30 kg/m2 for patients ≥16 years of age or weight >97th percentile for age and sex on growth chart assessment for patients 6 to 15 years of age.
    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 is able to understand and sign the written informed consent/assent.
    5. Female participants of child-bearing potential must be confirmed non-pregnant and 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), post-menopausal for at least 12 months (and confirmed with a screening follicle stimulating hormone (FSH) level in the post-menopausal lab range), orfailure to have progressed to Tanner Stage V and/or failure to have achieved menarche, do not require contraception during the study.
    6. Male participants with female partners of childbearing potential must agree to use a double barrier method contraception if they become sexually active during the study or within 90 days following their participation in the study. Male patients must also 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. These patients may be reconsidered approximately 1 month after cessation of such intensive regimens.
    2. Current or prior (within prior 2 months) use of any medication, including those approved to treat obesity, that could impact the efficacy results of this study (eg, orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion, liraglutide). Patients on a stable dose and regimen (for at least 2 months) of medication to treat attention deficit hyperactivity disorder (ADHD) may be enrolled in the study as long as they agree to remain on the same dose and regimen during the 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, resulted in <10% weight loss compared to pre-operative baseline weight, or there is 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, the Sponsor prior to enrollment.
    4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other Diagnostic and Statistical Manual of Mental Disorders fifth edition (DSM-V) 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. In patients with no significant neurocognitive deficits:
    • A PHQ-9 score of ≥15 and/or
    • Any suicidal ideation of type 4 or 5 on the C-SSRS, any lifetime history of a suicide attempt, or any suicidal behavior in the last month.
    6. Current, clinically significant pulmonary, cardiac, or oncologic disease considered severe enough to interfere with the study and/or confound the results. Any patient with a potentially clinically significant disease should be reviewed with the Sponsor to determine eligibility.
    7. 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 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 is exclusionary, but the presence of NAFLD is not be exclusionary. 8. Moderate to severe renal dysfunction defined as <30 mL/min (Appendix
    11.6).
    9. History or close family history (parents or siblings) of skin cancer or melanoma (excluding non-invasive basal or squamous cell lesion), or patient history of ocular-cutaneous albinism.
    10. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of comprehensive skin evaluation performed by a qualified dermatologist during screening. Any concerning lesions identified during the screening period will be biopsied and results must be known to be benign prior to enrollment. If the pre-treatment biopsy results are of concern, the patient should be excluded from the study.
    11. Patient is, in the opinion of the Study Investigator, not suitable to participate in the study.
    12. Participation in any clinical study with an investigational drug/device within 3 months prior to the first day of dosing.
    13. Significant hypersensitivity to study drug.
    14. Inability to comply with QD injection regimen.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients (≥12 years of age at baseline) who achieve a ≥10% reduction from baseline in body weight (ie, are ‘responders’) after ~52 weeks of treatment with setmelanotide.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after ~52 weeks of treatment with setmelanotide
    E.5.2Secondary end point(s)
    • The proportion of all patients, regardless of age at baseline, who achieve a ≥10% reduction from baseline in body weight (ie, are ‘responders’) after ~52 weeks of treatment with setmelanotide.
    • Mean percent change from baseline in body weight (in patients ≥12 years of age at baseline) after ~52 weeks of treatment with setmelanotide.
    • The proportion of patients who achieve a ≥25% improvement in the weekly average of the daily hunger score (in patients ≥12 years of age at baseline) after ~52 weeks of treatment with setmelanotide.
    • Mean percent change from baseline in the weekly average of the daily hunger score (in patients ≥12 years of age at baseline) after ~52 weeks of treatment with setmelanotide.
    E.5.2.1Timepoint(s) of evaluation of this end point
    after ~52 weeks of treatment with setmelanotide
    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 No
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 EEA4
    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
    France
    Germany
    Netherlands
    Spain
    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 years1
    E.8.9.1In the Member State concerned months9
    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: 15
    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: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 10
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) No
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2019-03-20. Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 10
    F.4.2.2In the whole clinical trial 30
    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)
    Patients may be entered into a separate extension study if they are benefitting from the IMP.
    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 StatusCompleted
    P.Date of the global end of the trial2021-03-08
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