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 [2×500 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.
FUNDING: Ferrer Grupo.