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    Summary
    EudraCT Number:2021-002873-24
    Sponsor's Protocol Code Number:RM-493-035
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2021-09-23
    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 number2021-002873-24
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study: 5 Independent Sub-studies of Setmelanotide in Patients with POMC, PCSK1, LEPR, SRC1, SH2B1, and PCSK1 N221D Gene Defects in the Melanocortin-4 Receptor Pathway
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of setmelanotide in obese patients with specific genetic defects
    A.3.2Name or abbreviated title of the trial where available
    Setmelanotide in patients with specific gene defects
    A.4.1Sponsor's protocol code numberRM-493-035
    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 pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street Address222 Berkeley Street, Suite 1200
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA02116
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 857 264 4280
    B.5.5Fax number+1 857 264 4299
    B.5.6E-mailoohayon@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 Yes
    D.2.1.1.1Trade name IMCVIREE
    D.2.1.1.2Name of the Marketing Authorisation holderRhythm Pharmaceuticals Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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
    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 CodeAS1
    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
    Specific Gene Defects in the Melanocortin-4 Receptor Pathway, responsible for improper functions of certain
    messenger materials in the body. E.g Melanocyte-Stimulating Hormone (MSH)
    E.1.1.1Medical condition in easily understood language
    Improper function of certain messenger materials in the body that control body weight and hunger in people
    Identify the therapeutic area
    E.1.1.2Therapeutic area Body processes [G] - Digestive System and Oral Physiological Phenomena [G10]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the proportion of obese patients who respond to setmelanotide at 52 weeks of treatment
    E.2.2Secondary objectives of the trial
    • To evaluate the change in body weight in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate changes in hunger score in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate change in BMI and waist circumference in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate the safety and tolerability of setmelanotide
    Other Secondary:
    • To evaluate quality of life parameters following treatment with setmelanotide
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The master protocol describes 5 independent, randomized, double-blind, placebo-controlled, sub-studies of setmelanotide in obese patients with 6 specific gene defects in the MC4R pathway:
    • POMC or PCSK1 (Sub-study 035a)
    • LEPR (Sub-study 035b)
    • SRC1 (Sub-study 035c)
    • SH2B1 (Sub-study 035d)
    • PCSK1 N221D (Sub-study 035e)
    wih same date and version and with high degree of similarities. The objectives and endpoints are identical for all 5 sub-studies in patients with POMC and/or PCSK1 (Sub-study 35a), LEPR (Sub-study 35b), SRC1 (Sub-study 35c), SH2B1 (Sub-study 35d), and PCSK1 N221D (Sub-study 35e) gene defects in the melanocortin-4 receptor (MC4R) pathway.
    E.3Principal inclusion criteria
    1. Patients must have a pre-identified:
    • Heterozygous genetic variant in the POMC gene or PCSK1 gene (Sub-study 35a)
    • Heterozygous genetic variant in the LEPR gene (Sub-study 35b),
    • Homozygous or heterozygous variant, compound heterozygous in the SRC1 (Sub-study 35c),
    • Homozygous or heterozygous variant, compound heterozygous in SH2B1 gene, or chromosomal16p11.2 deletion encompassing the SH2B1 gene (Sub-study 35d),
    • Heterozygous N221D (Sub-study 35e) variant in the PCSK1 gene.
    For POMC, PCSK1, LEPR, SRC1 and SH2B1 gene variants, to be considered for inclusion, the variant must either:
    • be categorized by a CLIA/CAP/ISO15189-certified laboratory using ACMG criteria as
    a) Pathogenic; or
    b) Likely Pathogenic; or
    c) a Variant of Uncertain Significance (VOUS)
    OR
    • be an N221D variant of the PCSK1 gene
    If a patient has composite heterozygous variants eligible for the study she/he will be accounted for the higher category based on ACMG classification.
    • For example, if a patient is a composite heterozygous for POMC pathogenic variant, and LEPR VOUS, the patient will be categorized as POMC pathogenic (Sub-study 35a).
    If the 2 variants have the same ACMG classification, adjudication will be assigned to the less prevalent gene sub-study.
    • For example, if a patient is a composite heterozygous for LEPR VOUS and SRC1 VOUS, the patient will be categorized as SRC1 (Sub-study35c).
    The final Sub-study assignment will follow this hierarchy: deletion> pathogenic> likely pathogenic> VOUS> RISK. Patients that harbor RISK variants are not eligible, with the exception of PCSK1 N221D .
    If a patient has two variants with the same ACMG classification, adjudication will be assigned following this arbitrary hierarchy: PCSK1>SRC1>SH2B1>LEPR>POMC>PCSK1 N221D.
    If the investigator has genetics results on a patient who may be eligible for the study, but the genetics have not yet been categorized by a CLIA/CAP/ISO15189 certified laboratory, then Rhythm may provide testing and/or categorization through a third-party laboratory.
    2. Between 6 and 65 years of age at the time of provision of informed consent/assent.
    3. Obese, defined as BMI ≥30 kg/m2 for patients ≥18 years of age or BMI ≥95th percentile for age and gender for patients 5 up to 17 years of age, based on based on the United States (US) Centers for Disease Control and Prevention criteria.
    4. Patient and/or parent or guardian is able to communicate well with the Investigator, understand and comply with the requirements of the study (including once daily [QD] injection regimen and all other study procedures), and is able to understand and sign the written informed consent/assent. Patients who are unable to comply with all study procedures due to cognitive limitations or any other reason should not be enrolled into the study.
    5. Patient and/or parent or guardian reports that patient experienced childhood obesity, defined as the patient and/or parent or guardian reporting that the patient was significantly overweight during childhood.
    6. For women of child-bearing potential (WOCBP), agrees to use a highly effective form of contraception throughout the study and for 90 days following the study.
    • Highly effective forms of contraception include:
    − Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal)
    − Progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable)
    − Intrauterine device (IUD)
    7. Sexual abstinence only if it is the preferred and usual lifestyle of the patient. Reported history of failed lifestyle intervention of diet and exercise.
    8. Reported history of hyperphagia.
    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.
    2. Use of any medication that is approved to treat obesity within 3 months of first dose of study (e.g., orlistat, phentermine-topiramate, naltrexone-bupropion, GLP-1 treatments) if >2% weight loss in the last 3 months.
    3. History of bariatric surgery with evidence of weight loss of >2% in the last 3 months.
    4. Documented diagnosis of schizophrenia, bipolar disorder, personality disorder, major depressive disorder or other significant psychiatric disorder(s) that the Investigator believes will interfere significantly with study compliance.
    5. Any suicidal ideation of type 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS) during Screening, any suicide attempt in the past 5 years, 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 Rhythm to determine eligibility.
    7. Glycated hemoglobin (HbA1C) >10% at Screening.
    8. History of significant liver disease other than non-alcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
    9. Glomerular filtration rate (GFR) <30 mL/min bat Screening.
    10. History or close family history (parents or siblings) of melanoma, or patient history of oculocutaneous albinism.
    11. Significant dermatologic findings relating to melanoma or pre-melanoma skin lesions (excluding non-invasive basal or squamous cell lesion), determined as part of a comprehensive skin evaluation performed by the Investigator during Screening. Any concerning lesions identified during Screening 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 study.
    12. Patient 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 or 5 half-lives, whichever is longer, prior to the first day of dosing.
    14. Previously enrolled in a clinical study involving setmelanotide or any previous exposure to setmelanotide.
    15. Significant hypersensitivity to any excipient in the study drug.
    16. If female, pregnant or breastfeeding.

    E.5 End points
    E.5.1Primary end point(s)
    To evaluate the proportion of obese patients who respond to setmelanotide at 52 weeks of treatment
    E.5.1.1Timepoint(s) of evaluation of this end point
    • Proportion of patients who are responders to active treatment compared to placebo:
    - For patients ≥18 years old at the time of enrollment, a responder is defined as achieving a ≥10% reduction in body weight at 52 weeks of treatment
    - For patients <18 years old at the time of enrollment, a responder is defined as reduction of body mass index (BMI) ≥5% at 52 weeks of treatment
    E.5.2Secondary end point(s)
    Key Secondary:
    • To evaluate the change in body weight in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate changes in hunger score in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate change in BMI and waist circumference in response to setmelanotide from baseline to 52 weeks of treatment
    • To evaluate the safety and tolerability of setmelanotide
    Other Secondary:
    • To evaluate quality of life parameters following treatment with setmelanotide
    E.5.2.1Timepoint(s) of evaluation of this end point
    • The mean change and mean percent change in body weight in patients in response to setmelanotide at 52 weeks of treatment compared to placebo
    • Change in % Centers for Disease Control and Prevention (CDC) 95th percentile in patients <18 with BMI >40 at 52 weeks of treatment compared to placebo
    • Mean body weight loss, and % body weight loss in responders (defined as patients with ≥5% body weight loss (if
    >18 years of age), and a decrease in % BMI by 3% (if <18 years of age) after 12 weeks of therapy on 3.0 mg/day or
    maximally tolerated dose, as compared to placebo responders
    • Mean percent change in the weekly average most hunger score at 52 weeks of setmelanotide treatment compared to placebo.

    See in protocol synopsis rest of Timepoints of evaluation due to lack of charchters
    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 Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    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) 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA33
    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
    Saudi Arabia
    Turkey
    United States
    Belgium
    Denmark
    France
    Germany
    Italy
    Netherlands
    Spain
    United Kingdom
    Greece
    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 years5
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months1
    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: 150
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 50
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 100
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 410
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 106
    F.4.2.2In the whole clinical trial 560
    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)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-01-25
    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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