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Rimeporide in Patients With Duchenne Muscular Dystrophy (RIM4DMD)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02710591
Recruitment Status : Completed
First Posted : March 17, 2016
Results First Posted : July 18, 2019
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
EspeRare Foundation

Tracking Information
First Submitted Date  ICMJE January 26, 2016
First Posted Date  ICMJE March 17, 2016
Results First Submitted Date  ICMJE December 21, 2018
Results First Posted Date  ICMJE July 18, 2019
Last Update Posted Date July 18, 2019
Study Start Date  ICMJE March 2016
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 6, 2019)
Number of Participants With Adverse Events [ Time Frame: up to 6 weeks from first administration ]
Observations are given for the safety population (all patients who received at least one dose of study drug). Categorical data are presented with the number of subjects with at least one event for the following selections:
  • treatment-emergent AEs (TEAEs)
  • study drug-related TEAEs (ADRs)
  • serious TEAEs
  • study drug-related serious TEAEs (serious ADRs)
  • TEAEs leading to withdrawal
  • study drug-related TEAEs (ADRs) leading to withdrawal
  • serious TEAEs leading to withdrawal
  • TEAEs leading to death as outcome
Original Primary Outcome Measures  ICMJE
 (submitted: March 11, 2016)
  • To evaluate the incidence of the Adverse Events [AEs] and Serious adverse event [SAEs] which might occur after multiple oral administrations of rimeporide in pediatric patients with DMD [ Time Frame: at 4 weeks of treatment ]
    Number of patients with AEs and SAEs related or not to the study treatment
  • To evaluate the causality of the Adverse Events [AEs] and Serious adverse event [SAEs] which might occur after multiple oral administrations of rimeporide in pediatric patients with DMD [ Time Frame: at 4 weeks of treatment ]
    Number of patients with AEs and SAEs possibly or probably related to study treatment
  • To evaluate the outcome of the Adverse Events [AEs] and Serious adverse event [SAEs] which might occur after multiple oral administrations of rimeporide in pediatric patients with DMD [ Time Frame: at 4 weeks of treatment ]
    Outcomes of AEs and SAEs possibly or probably related to study treatment
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: March 11, 2016)
  • To evaluate the Maximum Plasma Concentration of rimeporide in plasma in pediatric patients with DMD [ Time Frame: at 4 week study treatment ]
    Maximum Plasma Concentration [Cmax]
  • To evaluate the Area Under the Curve of rimeporide in plasma in pediatric patients with DMD [ Time Frame: at 4 week study treatment ]
    Area Under the Curve [AUC]
  • To evaluate the Time to concentration peak of rimeporide in plasma in pediatric patients with DMD [ Time Frame: at 4 week study treatment ]
    Time to concentration peak [Tmax]
  • To evaluate the Elimination half- life of rimeporide in plasma in pediatric patients with DMD [ Time Frame: at 4 week study treatment ]
    Elimination Half life [T1/2]
Current Other Pre-specified Outcome Measures
 (submitted: May 6, 2019)
PK Profile of Rimeporide - Cmax [ Time Frame: 4 week study treatment ]
PK samples were collected according to the following schedule:
  • At Day 1: for half of the patients: just before first administration, and one sample in each of the following time frames after the first dose:
    • 0.5 to 1h after dosing,
    • 1 to 2h after dosing,
    • 2.5 to 3.5h after dosing,
    • 6h after dosing
  • At Day 1: for the other half of the patients: just before first administration, and one sample in each of the following time frames after the second dose:
    • 0.5 to 1h after dosing,
    • 1 to 2h after dosing,
    • 2.5 to 3.5h after dosing,
    • 6h after dosing
Finally, at week 4 (Day 28) after the last dose:
  • 0.5 to 1h after dosing,
  • 6h after dosing
Original Other Pre-specified Outcome Measures
 (submitted: March 11, 2016)
  • To explore Pharmacodynamic biomarkers in blood to monitor muscle damages [ Time Frame: at 4 week study treatment ]
    plasma biomarkers
  • Muscle composition as assessed by Magnetic Resonance Imaging [ Time Frame: at 4 week study treatment ]
    T2, T2 heterogenity, fat fraction and muscle-mass index
 
Descriptive Information
Brief Title  ICMJE Rimeporide in Patients With Duchenne Muscular Dystrophy
Official Title  ICMJE 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
Brief Summary In Duchenne Muscular Dystrophy (DMD) there is an imbalance between the levels of calcium and sodium in the muscles cells which is thought to be important in the damage which occurs overtime. Sodium/proton type 1 exchanger (NHE-1) inhibition is an innovative pathway that has proved to efficiently prevent the accumulation of muscle damage (inflammation and fibrosis) in animal models of muscular dystrophies and heart failure. Based on prior safety and efficacy results in animal and humans, NHE-1 inhibition with Rimeporide represents a new therapeutic approach with no restriction on age and on genetic subtypes which could be combined to other treatments that restore or augment dystrophin.This study examines the safety and tolerability and effects on the muscles of rimeporide, in patients aged 6 to 14 years with Duchenne Muscular Dystrophy (DMD).
Detailed Description

This study is designed as a phase Ib, multicenter, european, open label study to evaluate the safety and tolerability and biomarkers of a new drug, rimeporide, in boys aged 6 to 14 years with Duchenne Muscular Dystrophy (DMD).

Rimeporide will be taken orally for 4 weeks, three times a day. Dose will be adapted to body weight. The study will enrol 20 patients with DMD, aged 6 to 14 years. 4 dose levels will be tested, in 4 different cohorts with 5 patients taking the drug at each dose level.

During the study, there will be 6 visits in the Hospital over a maximum of 10 weeks. At each visit, patients will undergo safety examinations including vital signs, physical and neurological examinations, ECG, safety and hematology, biochemistry and urinalysis, concomitant treatments review, and any symptoms and side effects review. In addition, blood samples will be withdrawn for the evaluation of Rimeporide in plasma. Finally, additional blood & urine samples will be collected to explore efficacy markers. Patients will also undergo 2 NMR (at screening and End of study) to develop non invasive biomarkers for further investigations in DMD patients.

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 SMC and determined that it is safe to proceed to the next dose level.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Muscular Dystrophy, Duchenne
Intervention  ICMJE Drug: Rimeporide

Cohort 1:

50 mg TID in patients with a body weight ≤ 30kg at Baseline and 75 mg TID in patients with a body weight > 30kg at Baseline

Cohort 2:

100mg TID in patients with a body weight ≤ 30kg at baseline and 150 mg TID in patients with a body weight > 30kg at Baseline

Cohort 3:

150 mg TID in patients with a body weight ≤ 30kg at baseline and 200 mg TID in patients with a body weight > 30kg at Baseline

Cohort 4:

200 mg TID in patients with a body weight ≤ 30kg at Baseline and 300 mg TID mg TID in patients with a body weight > 30kg at Baseline

Other Name: EMD 87580
Study Arms  ICMJE Experimental: Rimeporide

Multiple oral doses of rimeporide ranging from 50 to 300 mg will be administered three times a day (TID) for a total of 4 weeks. 4 ascending dose levels will be studied sequentially in ascending order. Rimeporide is provided as hard gel 25 mg or 50 mg capsules.

Each patient will participate in only 1 dose cohort. 5 patients are expected to be recruited in each cohort through all participating sites.

Intervention: Drug: Rimeporide
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: March 11, 2016)
20
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE February 2018
Actual Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Duchenne muscular dystrophy genetically confirmed;
  • Males between 6 and 14 years old;
  • Able to walk independently at least 75 meters;
  • Patients on a stable dose of corticosteroids at least 6 months prior to baseline;
  • Patients able to swallow capsules size 4 according to the parents and investigator opinion;
  • Willing and able to comply with all protocol requirements and procedures;
  • Signed informed consents by the parent(s)/legal guardian(s);
  • France only: Affiliated to or a beneficiary of a social security system

Exclusion Criteria:

  • 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
  • Current or history of liver disease or impairment,
  • 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
  • Acute illness within 4 weeks of the first administration of study medication which may interfere with study assessments;
  • Significant change of dosage and/or dosing regimens for corticosteroids planned for the duration of study medication;
  • Use of beta blockers / and ACEI or ARB unless at stable dose for at least 3 months prior to baseline;
  • Use of Proton Pump Inhibitors unless at a stable dose for at least 3 months prior to baseline
  • Use of aldosterone antagonists (i.e. spironolactone, eplerenone) within 3 months prior to first administration of study medication;
  • Use of anticoagulants, antithrombotics or antiplatelet agents,
  • Use of antibiotics with predominant renal secretion (e.g., cephalosporins), immunosuppressive agents exception corticosteroids, continuous treatment with non-steroidal, anti-inflammatory drugs (NSAIDs), or lithium;
  • Previous treatment with idebenone or other forms of Coenzyme Q10 within 1 month of the first administration of study medication;
  • 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;
  • A baseline QTc>450msec,or history of risk factors for torsades de pointes (eg, heart failure, hypokalaemia, family history of long QT syndrome);
  • LVEF≤ 45% at screening or within the past 6 months and/or history of acute heart failure;
  • Ventilator dependent;
  • Known individual hypersensitivity to any of the ingredients/excipients of the study medication;
  • Patients with specific contraindication to MRI (e.g.: metallic foreign body, claustrophobia, etc.).
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 6 Years to 14 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   Italy,   Spain,   United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02710591
Other Study ID Numbers  ICMJE EspeRare_RIM_001
2015-002530-50 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party EspeRare Foundation
Study Sponsor  ICMJE EspeRare Foundation
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Florence Porte-Thomé R&D Director EspeRare
PRS Account EspeRare Foundation
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP