Rimeporide in patients with Duchenne Muscular Dystrophy

• Register: EUCTR
• Last refreshed on: 19 February 2018
• Main ID: EUCTR2015-002530-50-ES
• Date of registration: 25/08/2015
• Prospective Registration: Yes
• Primary sponsor: EspeRare
• Public title: Rimeporide in patients with Duchenne Muscular Dystrophy
• Scientific 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. - Rim4DMD
• Date of first enrolment: 04/11/2015
• Target sample size: 20
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-002530-50
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no; Randomised: no; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: yes; Other trial design description: sequential-group study of ascending oral doses of IMP; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: no
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

France, Italy, Spain, Switzerland, United Kingdom

Contacts

• Name: Clinical Trials Information
• Affiliation: QED Clinical Services

• Name: Clinical Trials Information
• Affiliation: QED Clinical Services

Key inclusion & exclusion criteria

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
Are the trial subjects under 18? yes
Number of subjects for this age range: 20
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

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.).


Age minimum:
Age maximum:
Gender:
Female: no
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Musculoskeletal Diseases [C05]

Duchenne Muscular Dystrophy (DMD)
MedDRA version: 18.1 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders

Intervention(s)

Product Name: Rimeporide
Product Code: EMD 87580
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: N(4,5Bis methanesulfonyl2methylbenzoyl) guanidine hydrochloride monohydrate
Current Sponsor code: EMD 87580
Other descriptive name: Rimeporide
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

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.

Secondary Objective: Secondary objectives:
•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).

Main Objective: To determine the preliminary safety and tolerability profile of multiple oral administrations of rimeporide.

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

Secondary Outcome(s)

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.

Pharmacodynetics: 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.

Secondary end point(s): Pharmacokinetic profile of rimeporide in plasma derived from modelling using sparse sampling

Pharmacodynamics: Changes of plasma/urine biomarkers:
- Plasma levels of Troponin I, myomesin, creatine kinase isoenzyme (MM fraction); miRNAs;
- Urine concentration of titin fragments ;
- Plasma levels of the inflammation markers: C - reactive protein (CRP), Tumor Necrosis Factor alfa (TNFa), Transforming Growth Factor beta (TGFß).
- Plasma level of fibrosis makers: MMP-9.

Exploratory endpoints:

Pharmacodynamics: Changes in NMRI and NMRS indices in skeletal muscle will be explored through:
- 3 NMRI indices (water T2, fat fraction);
- Nine 31P NMRS indices;
- 23Na NMRS indices may also be included.

Participation in MRI/MRS requires travel to the Institute of Myology in Paris and will be optional

Secondary ID(s)

EspeRare_RIM_001

Source(s) of Monetary Support

European Commission

Merck Serono

L?Association Française Contre les Myopathies (AFM)