Fast track — ArticlesEfficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial
Introduction
Spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is an uncommon neurodegenerative disease that is characterised by muscle weakness.1 The disease is progressively disabling and can be fatal. There is currently no effective treatment. In addition to bulbar and extremity muscle weakness, patients with SBMA can have manifestations of androgen insensitivity.2 The cause of SBMA is a repeat expansion in the androgen receptor gene, which results in a toxic gain of function in the receptor protein and leads to a loss of spinal and bulbar motor neurons.3
The toxic effects of the mutant androgen receptor in SBMA depend on androgens. This ligand dependence is shown by prevention of the SBMA phenotype with castration in male transgenic mice and by induction of the phenotype in female mice with androgen administration.4 These findings led to recent randomised clinical trials of leuprorelin, which reduces androgen concentrations. At 48 weeks, leuprorelin was associated with significantly improved swallowing function in a phase 2 study,5 but not in a subsequent phase 3 trial.6
Inhibitors of 5α-reductase have not been tested before in SBMA. These agents block the conversion of the androgen testosterone to dihydrotestosterone7 and offer the opportunity to decrease the toxic effects of dihydrotestosterone while sparing the anabolic effects of testosterone. We investigated the safety and efficacy of the 5α-reductase inhibitor dutasteride in patients with SBMA. Another aim of this study was to evaluate outcome measures for future studies of the disease.
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Patients
We undertook a randomised, double-blind, placebo-controlled, single-site study at the National Institutes of Health (NIH) Clinical Center in Bethesda, MD, USA. Patients with SBMA were recruited between May and November, 2006, with the help of a patient organisation, the Kennedy's Disease Association. Inclusion criteria were genetically confirmed SBMA with neurological symptoms, ability to walk 100 feet (30 m), willingness to participate in the trial design, and male sex. Exclusion criteria
Results
57 patients were recruited, of whom seven were excluded from the trial because of raised blood liver enzyme concentrations or haemoglobin concentrations below the lower limit of normal. Table 1 summarises the baseline characteristics of the 50 patients randomly allocated to placebo or dutasteride. The treatment groups were balanced with respect to age, CAG repeat length, disease duration, and body-mass index. Six patients did not complete the study (figure 1); the remaining 44 patients were
Discussion
In our study, dutasteride had no significant effect on muscle strength at 2 years' follow-up. Several findings implicating androgens in SBMA provided the rationale for the study. First, dihydrotestosterone caused neurodegeneration in a fly model of SBMA.21 Second, male transgenic mice developed progressive weakness, whereas female mice were comparatively unaffected; furthermore, motor function improved in the male mice with androgen reduction, and their female counterparts developed weakness
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