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    EudraCT Number:2015-002530-50
    Sponsor's Protocol Code Number:EspeRare_RIM_001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-09-07
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-002530-50
    A.3Full title of the trial
    A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending oral doses of Rimeporide in patients with Duchenne Muscular Dystrophy
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rimeporide in patients with Duchenne Muscular Dystrophy
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberEspeRare_RIM_001
    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 SponsorEspeRare
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Commission
    B.4.1Name of organisation providing supportL’Association Française Contre les Myopathies (AFM)
    B.4.1Name of organisation providing supportMerck Serono
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation QED Clinical Services
    B.5.2Functional name of contact pointDirector of Clinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressSnowdon Drive / Winterhill
    B.5.3.2Town/ cityMilton Keynes
    B.5.3.3Post codeMK6 1BP
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number44 1908 251 480
    B.5.5Fax number44 1908 251 499
    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 numberEU/3/15/1478
    D.3 Description of the IMP
    D.3.1Product nameRimeporide
    D.3.2Product code EMD 87580
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN-(4,5-Bis methanesulfonyl-2-methyl-benzoyl)guanidine hydrochloride monohydrate
    D.3.9.2Current sponsor codeEMD 87580
    D.3.9.3Other descriptive nameRimeporide
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN-(4,5-Bis methanesulfonyl-2-methyl-benzoyl)guanidine hydrochloride monohydrate
    D.3.9.2Current sponsor codeEMD 87580
    D.3.9.3Other descriptive nameRimeporide
    D.3.9.4EV Substance CodeAS2
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Duchenne Muscular Dystrophy (DMD)
    E.1.1.1Medical condition in easily understood language
    Duchenne Muscular Dystrophy (DMD)
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10013801
    E.1.2Term Duchenne muscular dystrophy
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the preliminary safety and tolerability profile of multiple oral administrations of rimeporide.
    E.2.2Secondary objectives of the trial
    • Pharmacokinetics: To evaluate the pharmacokinetic profile of rimeporide in pediatric patients with DMD.

    • Pharmacodynamics:
    - To measure inflammatory and muscular injury biomarkers;
    - To explore the PK/PD relationship of a 4-week rimeporide treatment on those surrogate biomarkers.

    Exploratory objectives:
    • To explore the relationship between safety endpoints and pharmacokinetic parameters
    • To explore using Nuclear Magnetic Resonance (NMR) Spectroscopy and imaging the effect of a 4-week treatment with rimeporide on biomarkers including intracellular pH and intracellular Na, and degree of inflammation, oedema, fat fraction, muscle composition.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Duchenne muscular dystrophy genetically confirmed;
    2. Males between 6 and 14 years old;
    3. Able to walk independently at least 75 meters;
    4. Patients on a stable dose of corticosteroids at least 6 months prior to baseline;
    5. Willing and able to comply with all protocol requirements and procedures;
    6. Signed informed consents by the parent(s)/legal guardian(s);
    7. France only: Affiliated to or a beneficiary of a social security system
    E.4Principal exclusion criteria
    1. Patients with significant renal disease or impairment, with Glomerular Filtration Rate estimated using plasma cystatin C level using the Filler formula less than 90ml/min/1.73m2
    2. Current or history of liver disease or impairment,
    3. History of any significant medical disorder which may confound the interpretation of either efficacy or safety data e.g. inflammatory, coagulation disease, unstable cardiac or respiratory disease
    4. Acute illness within 4 weeks of the first administration of study medication which may interfere with study assessments;
    5. Significant change of dosage and/or dosing regimens for corticosteroids planned for the duration of study medication;
    6. Use of beta blockers / and ACEI or ARB unless at stable dose for at least 3 months prior to baseline;
    7. Use of protocol pump inhibitors unless at a stable dose for at least 3 months prior to baseline
    8. Use of aldosterone antagonists (i.e. spironolactone, eplerenone) within 3 months prior to first administration of study medication;
    9. Use of anticoagulants, antithrombotics or antiplatelet agents,
    10. Previous treatment with idebenone or other forms of Coenzyme Q10 within 1 month of the first administration of study medication;
    11. Previous treatment with investigational drugs within 4 weeks (or 7 half-life if longer than 4 weeks) of the first administration of study medication including placebo;
    12. A baseline QTc>450msec,or history of risk factors for torsades de pointes (eg, heart failure, hypokalaemia, family history of long QT syndrome);
    13. LVEF≤ 45% at screening or within the past 6 months and/or history of acute heart failure;
    14. Ventilator dependent;
    15. Known individual hypersensitivity to any of the ingredients/excipients of the study medication;
    16. For patients willing to undergo MRI/MRS assessments: Patients with specific contraindication to MRI (e.g.: metallic foreign body, claustrophobia, etc.).
    E.5 End points
    E.5.1Primary end point(s)
    Each subject will participate in only 1 dose cohort and will receive rimeporide for a total of 4 weeks.

    Safety assessment will be done on data collected in each cohort and during the 4 weeks treatment and 2 weeks of follow-up. The decision to progress to the next higher dose will be made after safety and tolerability data are reviewed for the preceding dose for 5 patients by a data Safety Monitoring Committee and determined that it is safe to proceed to the next dose level.

    Safety and tolerability of rimeporide will be assessed as follows:
    - Incidence, severity, causality and outcomes of AE and SAE
    - Vital signs, Supine and standing blood pressure, heart rate and respiratory rate
    - Evolution of laboratory parameters from blood and urine samples including gastrin levels: substantial changes in laboratory parameters and gastrin;
    - Monitoring of heart function (ECG evolution parameters including QTc)
    - Number of patients withdrawn for safety issues
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety endpoints will be assessed druning on site visit at Baseline, day 14, day 28 and via a phone call at day 7 and day 21 (fexibility window for each visit or call is +/-2 days) during treatment period and 2 weeks after the last rimeporide dose.

    Safety endpoints will be also assessed if unplanned visit(s) may occur should the patient need to be assessed or treated for any clinical condition that arises during the study.
    E.5.2Secondary end point(s)
    A physiologically based pharmacokinetic (PBPK) modeling is proposed. Blood samples will be obtained to determine the pharmacokinetic profile of orally administered rimeporide (spare sampling).

    Exploratory evaluation of the early biological response of a 4 week treatment by rimeporide in skeletal muscles will be assessed through change observed from baseline to Week 4 of plasma/urine biomarkers:
    - Plasma levels of Troponin I, myomesin, creatine kinase (CK) total, creatine kinase isoenzyme (MM fraction); miRNAs
    - Urine concentration of titin fragments (additional interim urine sample will be collected to W2)
    - Plasma levels of the inflammation markers: C-Reactive Protein (CRP), Tumor Necrosis Factor alfa (TNFα), Transforming Growth Factor beta (TGFβ)

    Exploratory enpoints (optional)::
    Changes in NMRI and NMRS indices in skeletal muscle will be explored through
    o 3 NMRI indices (water T2, fat fraction);
    o Nine 31P NMRS indices: 8 metabolic ratios combining: adenosine triphosphate (ATP), phosphocreatine (PCr), phospho mono- and di-esters (PME, PDE) and two pools of inorganic phosphate: cytosolic (Pia) and the remarkable alkaline pool present in dystrophic muscle (Pib), and corresponding weighted pH values for the two Pi pools.
    o 23Na NMRS indices may also be included.
    E.5.2.1Timepoint(s) of evaluation of this end point
    At day 1, for half of the patients, samples will be taken at screening or D1 and at (0.5 – 1h), (1 – 2h), (2.5 – 3.5h), 6h after the first dose. For the other half of the patients, samples will be taken before at screening or D1 and at (0.5 – 1h), (1 – 2h), (2.5 – 3.5h), 6h after the second dose. In this way, samples will be taken up to 12h after the first dose, corresponding to approximately 3 half-lives. At week 4, samples will be taken at (0.5 – 1h), 6h after the last dose.

    Pharmacodynamics: Blood samples will be collected at D1 before rimeporide administration and then at week 4 after the last rimeporide dose.

    Exploratory enpoints: Just before first dose of rimeporide and at the end of treatment, between day 21 and day 27, patient will undergo to a MRI/MRS.
    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 No
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E. trial type description
    First administration in Children with DMD (tested in phase 1 in healthy subject and CHF patients)
    E.7.2Therapeutic exploratory (Phase II) No
    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 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 No
    E. trial design description
    sequential-group study of ascending oral doses of IMP
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 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
    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
    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 months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days22
    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: 20
    F.1.1.1In Utero No
    F. of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F. of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F. of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F. of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F. of subjects for this age range: 15
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 5
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female No
    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 No
    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. of subjects incapable of giving consent
    DMD is characterized by a progressive loss of skeletal muscle and degeneration that lead to a loss of independent ambulation before 13y without disease modifying treatment. For this reason, to satisfy inclusion criteria, this age range is required.
    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 20
    F.4.2.2In the whole clinical trial 20
    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)
    In this pilot study, no further treatment beyond Week 4 is planned as no efficacy is claimed by this study. Subject who has ended the participation in the trial, will be treated according to the standard of care at the site as specific rescue therapy is foreseen for DMD. However in case of positive data that will allow the sponsor to move forward with a pivotal study, participation of patients already enrolled in this study will be prioritized in the pivotal study, if the patient wish so.

    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation Action Duchenne & Muscular Dystrophy Campaign
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-10-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-20
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