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Rimeporide in Patients With Duchenne Muscular Dystrophy (RIM4DMD)

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ClinicalTrials.gov Identifier: NCT02710591
Recruitment Status : Recruiting
First Posted : March 17, 2016
Last Update Posted : July 28, 2017
Sponsor:
Information provided by (Responsible Party):

Study Description
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).

Condition or disease Intervention/treatment Phase
Muscular Dystrophy, Duchenne Drug: Rimeporide Phase 1

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 In addition, blood samples will be withdrawn for the evaluation of Rimeporide in plasma.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

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : March 2016
Estimated Primary Completion Date : December 2017
Estimated Study Completion Date : December 2017


Arms and Interventions

Arm Intervention/treatment
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.

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


Outcome Measures

Primary Outcome Measures :
  1. 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

  2. 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

  3. 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


Secondary Outcome Measures :
  1. 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]

  2. 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]

  3. 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]

  4. 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]


Other Outcome Measures:
  1. To explore Pharmacodynamic biomarkers in blood to monitor muscle damages [ Time Frame: at 4 week study treatment ]
    plasma biomarkers

  2. Muscle composition as assessed by Magnetic Resonance Imaging [ Time Frame: at 4 week study treatment ]
    T2, T2 heterogenity, fat fraction and muscle-mass index


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   6 Years to 14 Years   (Child)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
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.).
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02710591


Locations
France
I-Motion - Hôpital Armand Trousseau Recruiting
Paris, Ile de France, France, 75012
Contact: Teresa GIDARO, MD    +33144736583 / +33171738042    t.gidaro@institut-myologie.org   
Principal Investigator: Teresa Gidaro, MD         
Sub-Investigator: Laurent Servais, Professor         
Sub-Investigator: Elena Gargaun, MD         
Italy
San Raffaele Hospital Recruiting
Milano, Italy, 20132
Contact: Stefano Carlo Previtali, MD    +39 0226433036 /+39 0226435080    previtali.stefano@hsr.it   
Principal Investigator: Stefano C Previtali, MD         
Sub-Investigator: Maria Grazia Natali Sora, MD         
Sub-Investigator: Alberto Zambon, MD         
Spain
Santa Creu i Sant Pau Hospital Recruiting
Barcelona, Spain, 08041
Contact: Jordi Diaz Manera, MD    +34 935 565 986    JDiazM@santpau.cat   
Contact: Nuria Vidal Fernández, Nurse    +34 935 537 115    MVidalF@santpau.cat   
Principal Investigator: Jordi Diaz Manera, MD         
Sub-Investigator: Ricardo Rojas García, MD         
United Kingdom
UCL Institute of Child Health and Great Ormond Street Hospital Recruiting
London, United Kingdom, WC1N 1EH
Contact: Ling Tang    02079052139    l.tang@ucl.ac.uk   
Contact: Anna Bellin    02079052139    a.bellin@ucl.ac.uk   
Principal Investigator: Francesco Muntoni, Professor         
Sub-Investigator: Joana Pisco Domingos, MD         
Sub-Investigator: Jacqueline Pitchforth, MD         
Sub-Investigator: Kate Maresh, MD         
Sponsors and Collaborators
EspeRare Foundation
Investigators
Study Director: Hanane Gheit, MSc EspeRare Foundation
More Information

Additional Information:
Responsible Party: EspeRare Foundation
ClinicalTrials.gov Identifier: NCT02710591     History of Changes
Other Study ID Numbers: EspeRare_RIM_001
2015-002530-50 ( EudraCT Number )
First Posted: March 17, 2016    Key Record Dates
Last Update Posted: July 28, 2017
Last Verified: July 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by EspeRare Foundation:
Rimeporide

Additional relevant MeSH terms:
Muscular Dystrophies
Muscular Dystrophy, Duchenne
Muscular Disorders, Atrophic
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Genetic Diseases, X-Linked