Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial

Maggie C Walter, Peter Reilich, Simone Thiele, Joachim Schessl, Herbert Schreiber, Karlheinz Reiners, Wolfram Kress, Clemens Müller-Reible, Matthias Vorgerd, Peter Urban, Bertold Schrank, Marcus Deschauer, Beate Schlotter-Weigel, Ralf Kohnen, Hanns Lochmüller, Maggie C Walter, Peter Reilich, Simone Thiele, Joachim Schessl, Herbert Schreiber, Karlheinz Reiners, Wolfram Kress, Clemens Müller-Reible, Matthias Vorgerd, Peter Urban, Bertold Schrank, Marcus Deschauer, Beate Schlotter-Weigel, Ralf Kohnen, Hanns Lochmüller

Abstract

Background: Dysferlinopathies are autosomal recessive disorders caused by mutations in the dysferlin (DYSF) gene encoding the dysferlin protein. DYSF mutations lead to a wide range of muscular phenotypes, with the most prominent being Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B).

Methods: We assessed the one-year-natural course of dysferlinopathy, and the safety and efficacy of deflazacort treatment in a double-blind, placebo-controlled cross-over trial. After one year of natural course without intervention, 25 patients with genetically defined dysferlinopathy were randomized to receive deflazacort and placebo for six months each (1 mg/kg/day in month one, 1 mg/kg every 2nd day during months two to six) in one of two treatment sequences.

Results: During one year of natural course, muscle strength declined about 2% as measured by CIDD (Clinical Investigation of Duchenne Dystrophy) score, and 76 Newton as measured by hand-held dynamometry. Deflazacort did not improve muscle strength. In contrast, there is a trend of worsening muscle strength under deflazacort treatment, which recovers after discontinuation of the study drug. During deflazacort treatment, patients showed a broad spectrum of steroid side effects.

Conclusion: Deflazacort is not an effective therapy for dysferlinopathies, and off-label use is not warranted. This is an important finding, since steroid treatment should not be administered in patients with dysferlinopathy, who may be often misdiagnosed as polymyositis.

Trial registration: This clinical trial was registered at http://www.ClincalTrials.gov, identifier: NCT00527228, and was always freely accessible to the public.

Figures

Figure 1
Figure 1
Description of the study population.
Figure 2
Figure 2
Flow chart of the clinical trial.
Figure 3
Figure 3
Manual muscle strength assessed by CIDD in both groups in 18 patients (sequence deflazacort-placebo, and placebo-deflazacort, completer population). a) Average course%CIDD sum score from natural history until end of both sequences. b) Pooled sequences for absolute change%CIDD from natural history until end of both sequences. c) Mutation-related CIDD subgroup analysis. Correlation between the type of mutation, resulting in residual dysferlin protein versus total loss of dysferlin protein, assessed by Western Blot and mutation prediction, and outcomes during treatment phases with a sample size of 4 patients in 3 subgroups (sequence deflazacort-placebo, protein present / sequence deflazacort-placebo, protein absent / sequence placebo-deflazacort, protein present) and 6 patients in the remaining subgroup (sequence placebo-deflazacort, protein absent).
Figure 4
Figure 4
Hand-held dynamometry (HHD) in both groups in 18 patients (sequence deflazacort-placebo, and placebo-deflazacort, completer population). a) Average course%HHD sum score from natural history until end of both sequences. b) Pooled sequences for absolute change%HHD from natural history until end of both sequences. c) Mutation-related HHD subgroup analysis. Correlation between the type of mutation, resulting in residual dysferlin protein versus total loss of dysferlin protein, assessed by Western Blot and mutation prediction, and outcomes during treatment phases with a sample size of 4 patients in 3 subgroups (sequence deflazacort-placebo, protein present / sequence deflazacort-placebo, protein absent / sequence placebo-deflazacort, protein present) and 6 patients in the remaining subgroup (sequence placebo-deflazacort, protein absent).
Figure 5
Figure 5
Neuromuscular Symptom Score (NSS) in both groups in 18 patients (sequence deflazacort-placebo, and placebo-deflazacort, completer population). a) Average course%NSS sum score from natural history until end of both sequences. b) Mutation-related NSS subgroup analysis. Correlation between the type of mutation, resulting in residual dysferlin protein versus total loss of dysferlin protein, assessed by Western Blot and mutation prediction, and outcomes during treatment phases with a sample size of 4 patients in 3 subgroups (sequence deflazacort-placebo, protein present / sequence deflazacort-placebo, protein absent / sequence placebo-deflazacort, protein present) and 6 patients in the remaining subgroup (sequence placebo-deflazacort, protein absent).

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