E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Duchenne Muscular Dystrophy (DMD) |
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E.1.1.1 | Medical condition in easily understood language |
Duchenne Muscular Dystrophy (DMD) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Musculoskeletal Diseases [C05] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10013801 |
E.1.2 | Term | Duchenne muscular dystrophy |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To determine the preliminary safety and tolerability profile of multiple oral administrations of rimeporide. |
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E.2.2 | Secondary 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.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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.). |
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E.5 End points |
E.5.1 | Primary 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
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E.5.1.1 | Timepoint(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. |
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E.5.2 | Secondary end point(s) |
Pharmacokinetics: A physiologically based pharmacokinetic (PBPK) modeling is proposed. Blood samples will be obtained to determine the pharmacokinetic profile of orally administered rimeporide (spare sampling).
Pharmacodynamics: 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.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Pharmacokinetics: 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. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
First administration in Children with DMD (tested in phase 1 in healthy subject and CHF patients) |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.1.7.1 | Other trial design description |
sequential-group study of ascending oral doses of IMP |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 22 |