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    Summary
    EudraCT Number:2017-000387-14
    Sponsor's Protocol Code Number:RM-493-014
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-11-01
    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 ConcernedGreece - EOF
    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
    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.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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    - POMC/PCSK1/LEPR heterozygous
    - POMC/PCSK1/LEPR compound heterozygous or homozygous deficiency obesity
    - POMC/PCSK1/LEPR composite heterozygous deficiency obesity
    - Smith-Magenis Syndrome
    - SH2B1 deficiency obesity
    - Chromosomal rearrangement of the 16p11.2 locus causing obesity
    - CPE compound heterozygous or homozygous deficiency obesity
    - Leptin deficiency obesity with loss of response to metreleptin
    - SRC1 deficiency obesity
    - MC4R deficiency 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 explore the impact of setmelanotide on obesity in patients with
    various specific rare genetic mutations.
    E.2.2Secondary objectives of the trial
    To assess the effects of setmelanotide on:
    - Safety and tolerability
    - Hunger
    - Waist circumference
    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-study to further evaluate the PK profile.
    participating in the 24-hour sub-study, 4 additional blood samples will
    be collected after the same dose:
    • 9, 10, and 12 hours (± 10 min) after dosing, and
    •At approximately 24 hours after dosing; specifically, within 10 minutes
    BEFORE the next dose of study drug.
    E.3Principal inclusion criteria
    1. Patients with the following genotypes and/or clinical diagnosis: a. POMC/PCSK1/LEPR heterozygous
    b. POMC/PCSK1/LEPR compound heterozygous (two different mutations in gene) or homozygous deficiency obesity
    c. POMC/PCSK1/LEPR composite heterozygous (two or more mutations in two or more genes) deficiency obesity
    d. Smith-Magenis Syndrome (SMS)
    e. SH2B1 deficiency obesity
    f. Chromosomal rearrangement of the 16p11.2 locus causing obesity
    g. CPE compound heterozygous or homozygous deficiency obesity
    h. Leptin deficiency obesity with loss of response to metreleptin
    i. SRC1 deficiency obesity
    j. MC4R deficiency obesity

    Note: The specific genotype for all patients must be reviewed by the Sponsor prior to study enrollment to confirm that the patient meets Inclusion Criterion #1. In addition, enrollment of patients in some subgroups may be prioritized by the Sponsor in order to ensure enrollment of patients with (1) well described, loss-of-function genetic mutations, (2) a variety of genetic variants, or (3) genetic variants likely to respond to setmelanotide.
    2. Age 12 years and above.
    3. Obese, defined as Body Mass Index (BMI) ≥ 30 kg/m2 for patients ≥16 years of age or BMI ≥ 95th percentile for age and gender for patients 12 up to 16 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), 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.
    2. Use of any medication that is approved to treat obesity within three months of first dose of study drug (e.g., orlistat, lorcaserin, phentermine-topiramate, naltrexone-bupropion). Note: Glucagon-like peptide-1 (GLP-1) receptor agonists may be used up to the dose approved for the treatment of diabetes mellitus (e.g., liraglutide up to a daily dose of 1.8 mg) as long as (1) is it not being prescribed for the treatment of obesity, (2) the dose has been stable for at least three months prior to enrollment, (3) the patient has not experienced weight loss during the previous three months, AND (4) the patient intends to keep the dose stable throughout the course of the study.
    3. Gastric bypass surgery within the previous six months or any 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 pre-operative 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 the Sponsor prior to enrollment.
    4. Diagnosis of schizophrenia, bipolar disorder, personality disorder or other psychiatric disorder(s) 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 PHQ-9 score of ≥ 15 or any suicidal ideation of type 4 or 5 on the C-SSRS during Screening, any lifetime history of a suicide attempt, or any suicidal behavior in the last month. Note: Patients who are unable to complete the PHQ-9 or C-SSRS due to significant neurocognitive defects may be allowed to enroll in the study, as long as in the opinion of the Primary Investigator there are no clinical signs or symptoms of suicidal behavior.
    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. HbA1c >9.0% at Screening

    8. History of significant liver disease or abnormal liver tests on Screening (i.e. > 1.5 x upper limit of normal [ULN] for alanine transaminase [ALT], aspartate transaminase [AST], alkaline phosphatase, or serum bilirubin ). Note: Patients entering the study with SRC1 haploinsufficiency obesity must be evaluated during the Screening Period for hepatic fibrosis by appropriate imaging techniques (e.g., transient elastography or magnetic resonance elastography). Any patient with moderate or greater fibrosis (e.g., the equivalent of a METAVIR score ≥ 2) will be excluded from the study. Note: A patient with a diagnosis of non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH) may be allowed to enroll in the study, after consultation with the Sponsor. Other significant liver disease, such as cirrhosis, are exclusionary.

    9. Glomerular filtration rate (GFR) <30 mL/min at Screening.
    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.
    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 a qualified dermatologist during Screening. 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 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 prior to the first day of dosing.
    14. Patients 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. Inability to comply with QD injection regimen.
    17. Females who are breastfeeding or nursing.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients in each subgroup of RGDO who achieve at
    least 5% body weight reduction from baseline, at ~3 months treatment
    with setmelanotide.
    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)
    Secondary endpoints:
    • Safety and tolerability of setmelanotide injection, assessed by the
    frequency and severity of AEs, vital signs, and laboratory evaluations
    • Change and percentage change from baseline in body weight
    • Change from baseline in Daily and Global Hunger scores
    • Change from baseline in waist circumference

    Exploratory Endpoints
    • Change from baseline in total body mass, including body fat and nonbone lean mass,as measure by either dual-energy x-ray absorptiometry (DXA) or bioelectrical impedance (BIA)
    • Change from baseline in fasting lipids (total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and triglycerides)
    • Change from baseline in metabolic and hormonal assays and other exploratory biomarkers
    • Change from baseline in glycated hemoglobin (HbA1c)
    • Evaluation of plasma pharmacokinetic (PK) parameters
    • Change from baseline in quality of life as measured by the following
    assessments:
    − Impact of Weight on Quality of Life-Lite (IWQOL-Lite)
    − EuroQoL-Five Dimension-5L (EQ-5D-5L) or EuroQoL-Five Dimension-Y
    (EQ-5D-Y)
    − The 12-Item Short Form Health Survey (SF-12) or 10-Item Short Form
    Health Survey for Children (SF-10)
    − Patient-Reported Behavioral Disturbance Questionnaire
    • 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)
    • Tanner Staging for patients who have yet to reach Tanner Stage V
    E.5.2.1Timepoint(s) of evaluation of this end point
    End points are assessed from baseline to end of treatment.
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 EEA15
    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
    Greece
    Israel
    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 years6
    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 years6
    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: 48
    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: 14
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 41
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 86
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 9
    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 aged 6+
    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 40
    F.4.2.2In the whole clinical trial 150
    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 Period patients and choose to end the study or move onto Bridging Visits which occur every 12 weeks for up
    to one year, until the extension study opens at the site.
    If the extension study is already available at the site the patient can move directly to the extension study.
    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 Decision2020-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-11-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-03-01
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