Rimeporide in Patients With Duchenne Muscular Dystrophy

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).

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 In addition, blood samples will be withdrawn for the evaluation of Rimeporide in plasma.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.

Eligibility Criteria:
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.).