Elsevier

The Lancet Neurology

Volume 10, Issue 2, February 2011, Pages 140-147
The Lancet Neurology

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Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: a randomised placebo-controlled trial

https://doi.org/10.1016/S1474-4422(10)70321-5Get rights and content

Summary

Background

Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease.

Methods

We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov, NCT00303446.

Findings

50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (−0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI −5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, −3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3% vs −3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events.

Interpretation

Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials.

Funding

US National Institutes of Health.

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.

Section snippets

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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