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

Abstract

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.

Conflict of interest statement

Conflicts of interest

ADK owns stock in GlaxoSmithKline, Inc.. MJW’s stipend was paid by a fellowship from the NIH Clinical Research Training Program, which is supported in part by funds paid to the NIH Foundation by Pfizer, Inc.. NADP is currently employed by and receives stock options from Johnson & Johnson. KHF serves as an unpaid member of advisory boards for Biogen Idec and Prosensa.

Copyright © 2011 Elsevier Ltd. All rights reserved.

Figures

Figure 1. Study profile

Four subjects dropped out of the study in the first 6 months due to travel difficulties in coming to the NIH from elsewhere in the United States and Canada. One subject died between his 3 and 6 month visits; an autopsy was consistent with a cardiac cause of death. One subject developed respiratory distress and declined rapidly during his 6 months of enrollment. He was removed from the study and hospitalized until his vital capacity and symptoms stabilized. No other cause for his respiratory failure was identified. He subsequently continued to decline and died about one year later. Thus, while the safety analysis was done on 25 subjects in each group, the efficacy analysis at 24 months was done on 23 subjects in the placebo group and 21 subjects in the dutasteride group.

Figure 2. Percent change from baseline in QMA, the primary outcome measure

The difference between placebo (blue) and dutasteride (red) was not significant. Bars indicate standard error of the mean.