Efficacy and safety of rifampicin for multiple system atrophy: A randomised, double-blind, placebo-controlled trial

Phillip A. Low, David Robertson, Sid Gilman, Horacio Kaufmann, Wolfgang Singer, Italo Biaggioni, Roy Freeman, Susan Perlman, Robert A. Hauser, William Cheshire, Stephanie Lessig, Steven Vernino, Jay Mandrekar, William D. Dupont, Thomas Chelimsky, Wendy R. Galpern

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Background: No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. Methods: In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings: Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI -0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation: Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. Funding: National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

Original languageEnglish (US)
Pages (from-to)268-275
Number of pages8
JournalThe Lancet Neurology
Volume13
Issue number3
DOIs
StatePublished - Mar 2014

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Multiple System Atrophy
Rifampin
Placebos
Safety
Medical Futility
Synucleins
Time and Motion Studies
Riboflavin
National Institutes of Health (U.S.)
Financial Management
Random Allocation
Nervous System Diseases
Capsules
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Low, P. A., Robertson, D., Gilman, S., Kaufmann, H., Singer, W., Biaggioni, I., ... Galpern, W. R. (2014). Efficacy and safety of rifampicin for multiple system atrophy: A randomised, double-blind, placebo-controlled trial. The Lancet Neurology, 13(3), 268-275. https://doi.org/10.1016/S1474-4422(13)70301-6

Efficacy and safety of rifampicin for multiple system atrophy : A randomised, double-blind, placebo-controlled trial. / Low, Phillip A.; Robertson, David; Gilman, Sid; Kaufmann, Horacio; Singer, Wolfgang; Biaggioni, Italo; Freeman, Roy; Perlman, Susan; Hauser, Robert A.; Cheshire, William; Lessig, Stephanie; Vernino, Steven; Mandrekar, Jay; Dupont, William D.; Chelimsky, Thomas; Galpern, Wendy R.

In: The Lancet Neurology, Vol. 13, No. 3, 03.2014, p. 268-275.

Research output: Contribution to journalArticle

Low, PA, Robertson, D, Gilman, S, Kaufmann, H, Singer, W, Biaggioni, I, Freeman, R, Perlman, S, Hauser, RA, Cheshire, W, Lessig, S, Vernino, S, Mandrekar, J, Dupont, WD, Chelimsky, T & Galpern, WR 2014, 'Efficacy and safety of rifampicin for multiple system atrophy: A randomised, double-blind, placebo-controlled trial', The Lancet Neurology, vol. 13, no. 3, pp. 268-275. https://doi.org/10.1016/S1474-4422(13)70301-6
Low, Phillip A. ; Robertson, David ; Gilman, Sid ; Kaufmann, Horacio ; Singer, Wolfgang ; Biaggioni, Italo ; Freeman, Roy ; Perlman, Susan ; Hauser, Robert A. ; Cheshire, William ; Lessig, Stephanie ; Vernino, Steven ; Mandrekar, Jay ; Dupont, William D. ; Chelimsky, Thomas ; Galpern, Wendy R. / Efficacy and safety of rifampicin for multiple system atrophy : A randomised, double-blind, placebo-controlled trial. In: The Lancet Neurology. 2014 ; Vol. 13, No. 3. pp. 268-275.
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T2 - A randomised, double-blind, placebo-controlled trial

AU - Low, Phillip A.

AU - Robertson, David

AU - Gilman, Sid

AU - Kaufmann, Horacio

AU - Singer, Wolfgang

AU - Biaggioni, Italo

AU - Freeman, Roy

AU - Perlman, Susan

AU - Hauser, Robert A.

AU - Cheshire, William

AU - Lessig, Stephanie

AU - Vernino, Steven

AU - Mandrekar, Jay

AU - Dupont, William D.

AU - Chelimsky, Thomas

AU - Galpern, Wendy R.

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N2 - Background: No available treatments slow or halt progression of multiple system atrophy, which is a rare, progressive, fatal neurological disorder. In a mouse model of multiple system atrophy, rifampicin inhibited formation of α-synuclein fibrils, the neuropathological hallmark of the disease. We aimed to assess the safety and efficacy of rifampicin in patients with multiple system atrophy. Methods: In this randomised, double-blind, placebo-controlled trial we recruited participants aged 30-80 years with possible or probable multiple system atrophy from ten US medical centres. Eligible participants were randomly assigned (1:1) via computer-generated permuted block randomisation to rifampicin 300 mg twice daily or matching placebo (50 mg riboflavin capsules), stratified by subtype (parkinsonian vs cerebellar), with a block size of four. The primary outcome was rate of change (slope analysis) from baseline to 12 months in Unified Multiple System Atrophy Rating Scale (UMSARS) I score, analysed in all participants with at least one post-baseline measurement. This study is registered with ClinicalTrials.gov, number NCT01287221. Findings: Between April 22, 2011, and April 19, 2012, we randomly assigned 100 participants (50 to rifampicin and 50 to placebo). Four participants in the rifampicin group and five in the placebo group withdrew from study prematurely. Results of the preplanned interim analysis (n=15 in each group) of the primary endpoint showed that futility criteria had been met, and the trial was stopped (the mean rate of change [slope analysis] of UMSARS I score was 0·62 points [SD 0·85] per month in the rifampicin group vs 0·47 points [0·48] per month in the placebo group; futility p=0·032; efficacy p=0·76). At the time of study termination, 49 participants in the rifampicin group and 50 in the placebo group had follow-up data and were included in the final analysis. The primary endpoint was 0·5 points (SD 0·7) per month for rifampicin and 0·5 points (0·5) per month for placebo (difference 0·0, 95% CI -0·24 to 0·24; p=0·82). Three (6%) of 50 participants in the rifampicin group and 12 (24%) of 50 in the placebo group had one or more serious adverse events; none was thought to be related to treatment. Interpretation: Our results show that rifampicin does not slow or halt progression of multiple system atrophy. Despite the negative result, the trial does provide information that could be useful in the design of future studies assessing potential disease modifying therapies in patients with multiple system atrophy. Funding: National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.

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