Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy

A randomised placebo-controlled trial

Lindsay Fernandez-Rhodes, Angela D. Kokkinis, Michelle J. White, Charlotte A. Watts, Sungyoung Auh, Neal O. Jeffries, Joseph A. Shrader, Tanya J. Lehky, Li Li, Jennifer E. Ryder, Ellen W. Levy, Beth I. Solomon, Michael O. Harris-Love, Alison La Pean, Alice B. Schindler, Cheun Ju Chen, Nicholas A. Di Prospero, Kenneth H. Fischbeck

Research output: Contribution to journalArticle

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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. Funding: US National Institutes of Health.

Original languageEnglish (US)
Pages (from-to)140-147
Number of pages8
JournalThe Lancet Neurology
Volume10
Issue number2
DOIs
StatePublished - Feb 1 2011

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Atrophic Muscular Disorders
Randomized Controlled Trials
Placebos
Safety
Outcome Assessment (Health Care)
Muscle Strength
Muscles
Quality of Life
Therapeutics
Dutasteride
Neural Conduction
Muscle Weakness
National Institutes of Health (U.S.)
Androgen Receptors
Creatine Kinase
Activities of Daily Living
Androgens
Disease Progression
Oxidoreductases
Animal Models

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Fernandez-Rhodes, Lindsay ; Kokkinis, Angela D. ; White, Michelle J. ; Watts, Charlotte A. ; Auh, Sungyoung ; Jeffries, Neal O. ; Shrader, Joseph A. ; Lehky, Tanya J. ; Li, Li ; Ryder, Jennifer E. ; Levy, Ellen W. ; Solomon, Beth I. ; Harris-Love, Michael O. ; La Pean, Alison ; Schindler, Alice B. ; Chen, Cheun Ju ; Di Prospero, Nicholas A. ; Fischbeck, Kenneth H. / Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy : A randomised placebo-controlled trial. In: The Lancet Neurology. 2011 ; Vol. 10, No. 2. pp. 140-147.
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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. Funding: US National Institutes of Health.",
author = "Lindsay Fernandez-Rhodes and Kokkinis, {Angela D.} and White, {Michelle J.} and Watts, {Charlotte A.} and Sungyoung Auh and Jeffries, {Neal O.} and Shrader, {Joseph A.} and Lehky, {Tanya J.} and Li Li and Ryder, {Jennifer E.} and Levy, {Ellen W.} and Solomon, {Beth I.} and Harris-Love, {Michael O.} and {La Pean}, Alison and Schindler, {Alice B.} and Chen, {Cheun Ju} and {Di Prospero}, {Nicholas A.} and Fischbeck, {Kenneth H.}",
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Fernandez-Rhodes, L, Kokkinis, AD, White, MJ, Watts, CA, Auh, S, Jeffries, NO, Shrader, JA, Lehky, TJ, Li, L, Ryder, JE, Levy, EW, Solomon, BI, Harris-Love, MO, La Pean, A, Schindler, AB, Chen, CJ, Di Prospero, NA & Fischbeck, KH 2011, 'Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy: A randomised placebo-controlled trial', The Lancet Neurology, vol. 10, no. 2, pp. 140-147. https://doi.org/10.1016/S1474-4422(10)70321-5

Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy : A randomised placebo-controlled trial. / Fernandez-Rhodes, Lindsay; Kokkinis, Angela D.; White, Michelle J.; Watts, Charlotte A.; Auh, Sungyoung; Jeffries, Neal O.; Shrader, Joseph A.; Lehky, Tanya J.; Li, Li; Ryder, Jennifer E.; Levy, Ellen W.; Solomon, Beth I.; Harris-Love, Michael O.; La Pean, Alison; Schindler, Alice B.; Chen, Cheun Ju; Di Prospero, Nicholas A.; Fischbeck, Kenneth H.

In: The Lancet Neurology, Vol. 10, No. 2, 01.02.2011, p. 140-147.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Efficacy and safety of dutasteride in patients with spinal and bulbar muscular atrophy

T2 - A randomised placebo-controlled trial

AU - Fernandez-Rhodes, Lindsay

AU - Kokkinis, Angela D.

AU - White, Michelle J.

AU - Watts, Charlotte A.

AU - Auh, Sungyoung

AU - Jeffries, Neal O.

AU - Shrader, Joseph A.

AU - Lehky, Tanya J.

AU - Li, Li

AU - Ryder, Jennifer E.

AU - Levy, Ellen W.

AU - Solomon, Beth I.

AU - Harris-Love, Michael O.

AU - La Pean, Alison

AU - Schindler, Alice B.

AU - Chen, Cheun Ju

AU - Di Prospero, Nicholas A.

AU - Fischbeck, Kenneth H.

PY - 2011/2/1

Y1 - 2011/2/1

N2 - 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.

AB - 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.

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