Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)

Background Citicoline is approved in some countries for the treatment of acute ischaemic stroke. The drug has shown some evidence of efficacy in a pooled analysis. We sought to confirm the efficacy of citicoline in a larger trial. Methods We undertook a randomised, placebo-controlled, sequential trial in patients with moderate-to-severe acute ischaemic stroke admitted at university hospitals in Germany, Portugal, and Spain. Using a centralised minimisation process, patients were randomly assigned in a 1: 1 ratio to receive citicoline or placebo within 24 h after the onset of symptoms (1000 mg every 12 h intravenously during the first 3 days and orally thereafter for a total of 6 weeks [2x500 mg oral tablets given every 12 h]). All study participants were masked. The primary outcome was recovery at 90 days measured by a global test combining three measures of success: National Institutes of Health Stroke Scale <= 1, modified Rankin score <= 1, and Barthel Index >= 95. Safety endpoints included symptomatic intracranial haemorrhage in patients treated with recombinant tissue plasminogen activator, neurological deterioration, and mortality. This trial is registered, NCT00331890. Results 2298 patients were enrolled into the study from Nov 26, 2006, to Oct 27, 2011. 37 centres in Spain, 11 in Portugal, and 11 in Germany recruited patients. Of the 2298 patients who gave informed consent and underwent randomisation, 1148 were assigned to citicoline and 1150 to placebo. The trial was stopped for futility at the third interim analysis on the basis of complete data from 2078 patients. The final randomised analysis was based on data for 2298 patients: 1148 in citicoline group and 1150 in placebo group. Global recovery was similar in both groups (odds ratio 1.03, 95% CI 0.86-1.25; p=0.364). No significant differences were reported in the safety variables nor in the rate of adverse events. Interpretation Under the circumstances of the ICTUS trial, citicoline is not efficacious in the treatment of moderate-to-severe acute ischaemic stroke.