title: Efficacy and safety of rifampicin for multiple system atrophy: a randomised, double-blind, placebo-controlled trial.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  National Institutes of Health, Mayo Clinic Center for Translational Science Activities, and Mayo Funds.
authors: Mayo Clinic, Rochester, MN, USA. Electronic address: low@mayo.edu.
authors: Phillip A
authors: PA
authors: Low
authors: Vanderbilt University, Nashville, TN, USA.
authors: David
authors: D
authors: Robertson
authors: University of Michigan, Ann Arbor, MI, USA.
authors: Sid
authors: S
authors: Gilman
authors: New York University Medical Center, New York, NY, USA.
authors: Horacio
authors: H
authors: Kaufmann
authors: Mayo Clinic, Rochester, MN, USA.
authors: Wolfgang
authors: W
authors: Singer
authors: Vanderbilt University, Nashville, TN, USA.
authors: Italo
authors: I
authors: Biaggioni
authors: Beth Israel Deaconess Medical Center, Boston, MA, USA.
authors: Roy
authors: R
authors: Freeman
authors: University of California, Los Angeles Medical Center, Los Angeles, CA, USA.
authors: Susan
authors: S
authors: Perlman
authors: University of South Florida, Tampa, FL, USA.
authors: Robert A
authors: RA
authors: Hauser
authors: Mayo Clinic, Jacksonville, FL, USA.
authors: William
authors: W
authors: Cheshire
authors: University of California, San Diego, La Jolla, CA, USA.
authors: Stephanie
authors: S
authors: Lessig
authors: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors: Steven
authors: S
authors: Vernino
authors: Mayo Clinic, Rochester, MN, USA.
authors: Jay
authors: J
authors: Mandrekar
authors: Vanderbilt University, Nashville, TN, USA.
authors: William D
authors: WD
authors: Dupont
authors: Medical College of Wisconsin, Milwaukee, WI, USA.
authors: Thomas
authors: T
authors: Chelimsky
authors: National Institutes of Health, Bethesda, MD, USA.
authors: Wendy R
authors: WR
authors: Galpern
mesh_terms: D000368:Aged; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy / Q000175:diagnosis* / Q000188:drug therapy* / Q000453:epidemiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D012293:Rifampin / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D012293:Rifampin