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).

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.

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.

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.