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.
FINDINGS: 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.
INTERPRETATION: 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.