Treatment of Duchenne Muscular Dystrophy with Cyclosporine A

INTERVENTION: Intervention 1: CSA will be applied in a daily dose of 3.5‐4 mg per kilogram body weight and applied as capsules or oral solution twice daily. For capsules and liquid solution placebo preparations identical in appearance, weight, and taste are used. Intervention 2: Placebo will be applied in a daily dose of 3.5‐4 mg per kilogram body weight and applied as capsules or oral solution twice daily. For capsules and liquid solution placebo preparations identical in appearance, weight, and taste are used. Intervention 3: After three months of monotherapy with CSA intermittent prednisone will be added for all patients (0.75 mg per kilogram bodyweight daily, 10 days on alternating with 10 days off medication) and the combined treatment will be continued for another 12 months. Intervention 4: After three months of monotherapy with placebo intermittent prednisone will be added for all patients (0.75 mg per kilogram bodyweight daily, 10 days on alternating with 10 days off medication) and the combined treatment will be continued for another 12 months. CONDITION: G71.0 ‐ Muscular dystrophy PRIMARY OUTCOME: Primary outcome will be manual muscle testing using an extended 11‐point version of the Medical Research Council (MRC) score. MRC is a validated instrument to assess muscle strength in DMD patients in 28 different muscle groups including neck, shoulder, elbow, wrist, hip, knee, and ankle in defined positions using an ordinal 11‐point scale. It has been used as primary outcome measure in various controlled trials for DMD. The MRC score is calculated as a percentage of a possible total score (%MRC) and the change of %MRC between baseline (M0) and month 3 (M3) was used to assess CSA monotherapy. Respectively, change between month 3 (M3) and month 15 (M15) was used to assess the combination of CSA with intermittent prednisone. INCLUSION CRITERIA: ‐ Male patients, minimum age 5 ‐ Ability to walk independently (minimum 50 meters) ‐ Proven diagnosis of duchenne muscular dystrophy: clinical symptoms, increase of CK (more than 10‐fold), together with at least one of the following criteria: dystrophine immunofluorescence and/or immunoblot negative muscle biopsy; positive gene deletion for duchenne; positive family history (with proven duchenne dystrophy) ‐ Cooperation concerning visits ‐ Able to swallow study medication (capsules) ‐ Parents´ written informed consent ‐ Child´s written informed consent if able to understand meaning of the study SECONDARY OUTCOME: In addition, quantitative muscle testing using the Citec© hand‐held dynamometry (C.I.T. Techniques, Haren, The Netherlands) is used as secondary outcome measure. The Citec© dynamometer is a small hand‐held device that is used to measure maximal isometric force in Newton (N). In this study shoulder abduction, elbow flexion, hip flexion, knee extension, and ankle dorsiflexion were assessed on the patient’s dominant site. According to a published protocol, defined positions and locations for each muscle group will be tested and the best of three consecutive measurements will be used for each muscle group. The total score for dynamometry measurement is calculated as the sum of the best value of each muscle group. For MRC and dynamometry scores, missing single items will be replaced by mean values of the remaining items. The time to walk 10 m independently and the time to stand up from supine position are used as functional outcome measures. Muscle strength assessment and timed tests will be performed by experienced physiotherapists at each site. A detailed manual and training material illustrating assessment of different muscle groups as well as central training sessions for all evaluators before and during the trial on an annual basis will be used to ensure inter‐ and intrarater reliability. The revised German KINDL© questionnaire will be used as a generic quality of life measure for children. Primary and secondary outcome assessments will be done at baseline and months 3, 9, and 15.; ; In parallel, safety of CSA will be monitored during and 30 days after discontinuation of study drug by adverse event reports and monthly physical examination, assessment of blood pressure, and central laboratory tests (biochemistry and haematology). As serum creatine level is not a reliable biomarker for renal function in DMD due to the low muscle mass, cystatin C will be measured when the creatine level increase. In the case of increase of blood pressure or cystatin C level above normal range a dose reduction of CSA by one fourth is prescribed in the protocol. Additionally, CSA serum concentrations will be analyzed by an external investigator to detect potentially toxic levels and to cause a dose reduction if appropriate. Random CSA serum level alerts with consecutive dose reduction are created in the placebo group to keep investigators blinded.