title: Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial.
abstract: BACKGROUND
  Minocycline has anti-apoptotic and anti-inflammatory effects in vitro, and extends survival in mouse models of some neurological conditions. Several trials are planned or are in progress to assess whether minocycline slows human neurodegeneration. We aimed to test the efficacy of minocycline as a treatment for amyotrophic lateral sclerosis (ALS).
  
  
  METHODS
  We did a multicentre, randomised placebo-controlled phase III trial. After a 4-month lead-in phase, 412 patients were randomly assigned to receive placebo or minocycline in escalating doses of up to 400 mg/day for 9 months. The primary outcome measure was the difference in rate of change in the revised ALS functional rating scale (ALSFRS-R). Secondary outcome measures were forced vital capacity (FVC), manual muscle testing (MMT), quality of life, survival, and safety. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00047723.
  
  
  RESULTS
  ALSFRS-R score deterioration was faster in the minocycline group than in the placebo group (-1.30 vs -1.04 units/month, 95% CI for difference -0.44 to -0.08; p=0.005). Patients on minocycline also had non-significant tendencies towards faster decline in FVC (-3.48 vs -3.01, -1.03 to 0.11; p=0.11) and MMT score (-0.30 vs -0.26, -0.08 to 0.01; p=0.11), and greater mortality during the 9-month treatment phase (hazard ratio=1.32, 95% CI 0.83 to 2.10; p=0.23) than did patients on placebo. Quality-of-life scores did not differ between the treatment groups. Non-serious gastrointestinal and neurological adverse events were more common in the minocycline group than in the placebo group, but these events were not significantly related to the decline in ALSFRS-R score.
  
  
  CONCLUSIONS
  Our finding that minocycline has a harmful effect on patients with ALS has implications for trials of minocycline in patients with other neurological disorders, and for how potential neuroprotective agents are screened for use in patients with ALS.
authors.affiliation: Department of Neurology, Columbia University, New York, NY, USA. phg8@columbia.edu
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gordon
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Robert G
authors.initials: RG
authors.lastname: Miller
authors.forename: Julaine M
authors.initials: JM
authors.lastname: Florence
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Verheijde
authors.forename: Carolyn
authors.initials: C
authors.lastname: Doorish
authors.forename: Joan F
authors.initials: JF
authors.lastname: Hilton
authors.forename: G Mark
authors.initials: GM
authors.lastname: Spitalny
authors.forename: Robert B
authors.initials: RB
authors.lastname: MacArthur
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Hans E
authors.initials: HE
authors.lastname: Neville
authors.forename: Kevin
authors.initials: K
authors.lastname: Boylan
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: Jerry M
authors.initials: JM
authors.lastname: Belsh
authors.forename: John
authors.initials: J
authors.lastname: Ravits
authors.forename: Richard S
authors.initials: RS
authors.lastname: Bedlack
authors.forename: Michael C
authors.initials: MC
authors.lastname: Graves
authors.forename: Leo F
authors.initials: LF
authors.lastname: McCluskey
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Barohn
authors.forename: Rup
authors.initials: R
authors.lastname: Tandan
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D016001:Confidence Intervals; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008911:Minocycline / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects; D017063:Outcome Assessment, Health Care / Q000379:methods; D011597:Psychomotor Performance / Q000187:drug effects; D011788:Quality of Life; D016019:Survival Analysis; D014797:Vital Capacity / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D008911:Minocycline