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    Summary
    EudraCT Number:2017-002005-36
    Sponsor's Protocol Code Number:RM-493-015
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-07-03
    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 ConcernedGermany - BfArM
    A.2EudraCT number2017-002005-36
    A.3Full title of the trial
    An Open Label, 1-Year Trial, including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic mutations
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An Open Label, 1-Year Trial, including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic mutations
    A.4.1Sponsor's protocol code numberRM-493-015
    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 pointFred Fiedorek
    B.5.3 Address:
    B.5.3.1Street Address11th Floor, 500 Boylston Street
    B.5.3.2Town/ cityBoston
    B.5.3.3Post codeMA 02116
    B.5.3.4CountryUnited States
    B.5.4Telephone number+18572644288
    B.5.5Fax number+18572644299
    B.5.6E-mailffiedorek@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 (preserved formulation)
    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.3.9.3Other 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
    Early Onset Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
    E.1.1.1Medical condition in easily understood language
    Early Onset Leptin Receptor (LEPR) Deficiency Obesity due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
    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 statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in patients with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.
    E.2.2Secondary objectives of the trial
    To assess the effect of setmelanotide, over one year, on:
    • Safety and tolerability of setmelanotide (including blood pressure [BP] and heart rate [HR]).
    • Hunger in patients ≥ 12 year old
    • Percent change in body fat mass.
    • Glucose parameters: fasting glucose, glycated hemoglobin (HbA1c), oral glucose tolerate test (OGTT) with focus on parameters of insulin sensitivity.
    • Waist circumference.
    • During withdrawal from drug: reversal of weight and hunger reduction during the double-blind placebo- controlled withdrawal period.
    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 following are optional sub-studies:

    24-Hour PK Profile
    Ambulatory Blood Pressure Monitoring
    Energy Expenditure
    Quantitative Skin Color Measurement
    Photographic Skin Evaluation
    E.3Principal inclusion criteria
    1. Bi-allelic, homozygous or compound heterozygous (a
    different gene mutation on each allele) genetic status for either the LEPR genes, with the
    loss-of-function (LOF) variant for each allele conferring a severe obesity phenotype.
    2. Age 6 years and above.
    3. If adult age ≥18 years, obesity with body mass index (BMI)
    ≥ 30 kg/m2; if child or adolescent, obesity with BMI ≥ 95th percentile for age on growth chart assessment.
    4. Study participant and/or parent or guardian can communicate well with the investigator, to understand and comply with the requirements of the study, and can understand and sign the written
    informed consent/assent, after being informed about the study.
    5. Female participants of child-bearing potential must 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) or post- menopausal for at least 12 months (and confirmed with a screening FSH level in the post-menopausal lab range), or delayed pubertal development 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 weight loss or weight stabilization. Patients may be reconsidered approximately 1 month
    after cessation of such intensive regimens.
    2. 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
    Rhythm prior to enrollment.
    3. 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.
    4. A Patient Health Questionnaire-9 (PHQ-9) score of ≥ 15.
    5. 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.
    6. Current, severe stable restrictive or obstructive lung disease due to extreme obesity, evidence of significant heart failure (NYHA Class 3 or greater), 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.
    7. 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 (> 2.0 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.
    8. 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 the Cockcroft Gault equation < 30 mL/min.
    9. History or close family history (parents or siblings) of skin cancer or melanoma, or patient history of ocular-cutaneous albinism.
    10. 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 pre- treatment biopsy results are of concern, the patient may need to be excluded from the study.
    11. Volunteer 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. Previous history of significant hypersensitivity to exogenously injected peptides (e.g. urticaria, shortness of breath, or more severe responses including anaphylactoid reactions or anaphylaxis).
    14. Inability to comply with QD injection regimen.
    15. Patients who have been placed in an institution through and official or court order, as well as those who are dependent on the sponsor, Investigator, or study site.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the proportion of patients in the full analysis set (FAS) who meet the
    ≥10% weight loss threshold (responders) after ~1 year of treatment, compared to the proportion
    from historical data (at most 5% responders in the null population).
    E.5.1.1Timepoint(s) of evaluation of this end point
    End of 1 year treatment
    E.5.2Secondary end point(s)
    Supporting secondary, tertiary and exploratory endpoints will include:
    The safety and tolerability of setmelanotide QD SC injection will be assessed by the frequency and severity of adverse events (AEs) as well as changes in physical examinations, electrocardiograms (ECGs), vital signs (including resting BP and HR), laboratory evaluations, monitoring for changes in neurocognition in patients ≤16 years of age, and injection site reactions.

    Assessemnt of Hunger, Body composition, waist circumference, Glucose parameters, PK (adult an adolescent patients).

    Potential improvements in lipids (fasting cholesterol and triglycerides) as well as glucose parameters as measured by fasting glucose, HbA1c and OGTT with focus on parameters of insulin sensitivity will be assessed over time.

    Several questionnaires will be utilized throughout the study to assess quality of life (IWQOL-Lite and PedsQL) along with the SF-36 and SF-10 health survey. As required by Food and Drug Administration (FDA) for central nervous system (CNS)-active obesity medications, changes in depression/suicidality as assessed by the C- SSRS and PHQ-9 will be monitored over the entire course of the trial.

    Changes in pubertal development for those patients who have yet to reach Tanner Stage V will
    be assessed over the course of the study.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the course of the study and end of approximately 1 year 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) 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 No
    E.8.1.2Open No
    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
    The open-label trial includes a double-blind placebo-controlled withdrawal period.
    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 trial1
    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.8.5The 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
    France
    Germany
    Netherlands
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    The end of the trial will be defined as the last patient last visit.
    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 months6
    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 months6
    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: 5
    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: 2
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 3
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 13
    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 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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 18
    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 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 to allow for continued treatment.
    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 Decision2017-10-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-30
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-09-25
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