title: Treatment of Duchenne muscular dystrophy with ciclosporin A: a randomised, double-blind, placebo-controlled multicentre trial.
abstract: BACKGROUND
  Duchenne muscular dystrophy is a rare X-linked progressive disease characterised by loss of ambulation at about age 10 years, with death in early adulthood due to respiratory and cardiac insufficiency. Steroids are effective at slowing the progression of muscle weakness; however, their use is limited by side-effects, prompting the search for alternatives. We assessed the effect of ciclosporin A as monotherapy and in combination with intermittent prednisone for the treatment of ambulant patients with this disorder.
  
  
  METHODS
  Our study was a parallel-group, placebo-controlled, double-blind, multicentre trial at trial sites of the German muscular dystrophy network, MD-NET, over 36 months. Ambulant patients with Duchenne muscular dystrophy who were aged 5 years or older were randomly assigned to receive either ciclosporin A (3·5-4·0 mg/kg per day) or matching placebo. Allocation was done centrally with computer-generated random numbers. Patients and investigators were masked to the allocated treatment. After 3 months of treatment, both groups were also given intermittent prednisone for a further 12 months (0·75 mg/kg, alternating 10 days on with 10 days off). All patients who received at least one dose of study drug or placebo were included in the primary analysis. The primary outcome measure was manual muscle strength measured on the Medical Research Council (MRC) scale. This trial is registered with the German clinical trial register DRKS, number DRKS00000445.
  
  
  RESULTS
  77 patients were randomly assigned to the ciclosporin A group and 76 to the placebo group; 73 patients on ciclosporin A and 73 on placebo received at least one dose and were available for efficacy analyses. 3 months of treatment with ciclosporin A alone did not show any significant improvement in primary outcome measures (mean change in the proportion of a possible total MRC score [%MRC] was -2·6 [SD 6·0] for patients on ciclosporin A and -0·8 [4·9] for patients on placebo; adjusted group difference estimate -0·88, 97·5% CI -2·6 to 0·9; p=0·26). The combination of ciclosporin A with intermittent steroids was not better than intermittent steroids alone over 12 months (mean change in %MRC was 0·7 [7·1] for patients on ciclosporin A and -0·3 [7·9] for patients on placebo; adjusted group difference estimate -0·85, -3·6 to 1·9; p=0·48). Numbers of adverse events (75 in patients on ciclosporin A and 74 on placebo) and serious adverse events (four with ciclosporin A and four with placebo) did not differ significantly between groups.
  
  
  CONCLUSIONS
  Ciclosporin A alone or in combination with intermittent prednisone does not improve muscle strength or functional abilities in ambulant boys with Duchenne muscular dystrophy, but is safe and well tolerated.
  
  
  BACKGROUND
  German Federal Ministry of Education and Research, Action Benni and co eV, Novartis Pharma AG, and Deutsche Gesellschaft für Muskelkranke eV.
authors.affiliation: University Medical Centre, Freiburg, Germany. janbernd.kirschner@uniklinik-freiburg.de
authors.forename: Janbernd
authors.initials: J
authors.lastname: Kirschner
authors.forename: Joachim
authors.initials: J
authors.lastname: Schessl
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Bernd
authors.initials: B
authors.lastname: Reitter
authors.forename: Georg M
authors.initials: GM
authors.lastname: Stettner
authors.forename: Elke
authors.initials: E
authors.lastname: Hobbiebrunken
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Wilichowski
authors.forename: Günther
authors.initials: G
authors.lastname: Bernert
authors.forename: Simone
authors.initials: S
authors.lastname: Weiss
authors.forename: Florian
authors.initials: F
authors.lastname: Stehling
authors.forename: Gert
authors.initials: G
authors.lastname: Wiegand
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Müller-Felber
authors.forename: Simone
authors.initials: S
authors.lastname: Thiele
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grieben
authors.forename: Maja
authors.initials: M
authors.lastname: von der Hagen
authors.forename: Jürg
authors.initials: J
authors.lastname: Lütschg
authors.forename: Claudia
authors.initials: C
authors.lastname: Schmoor
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ihorst
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
mesh_terms: D002648:Child; D016572:Cyclosporine / Q000627:therapeutic use*; D004311:Double-Blind Method; D006801:Humans; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000188:drug therapy* / Q000503:physiopathology; D012196:Review Literature as Topic; D016896:Treatment Outcome
chemical_list: D016572:Cyclosporine