Table 1.
Major clinical trials of citicoline in ischemic stroke
| Study | Design | Size (citicoline/controls) | Daily dose/delivery mode/duration | Time to treatment in citicoline group (hours) | Baseline NIHSS in citicoline group | Primary outcome measure/time/result | Secondary outcome measures and post hoc analysis |
|---|---|---|---|---|---|---|---|
| Tazaki et al37 | Randomized, placebo-controlled, multicenter | 272 (133/139) | 1,000 mg/iv/2 wk | 11.4% <24 hours | Not performed | Global improvement rating/2 wk/positive Global usefulness rating/2 wk/positive | Not performed |
| Clark et al38,* | Randomized, placebo-controlled, multicenter | 259 (194/65) | Mean – 14.7 | Mean – 12.8 | BI (5 strata)/12 wk/positive in 500 mg and 2,000 mg groups | Complete functional recovery (BI ≤95) and global recovery score (mRS ≤1 and NIHSS ≤1) better in 500 mg vs placebo (P<0.05) | |
| 62 (500 mg) | 500 mg/orally/6 wk | Mean – 14.7 | Mean – 11.6 | ||||
| 66 (1,000 mg) | 1,000 mg/orally/6 wk | Mean – 14.6 | Mean – 13.2 | ||||
| 66 (2,000 mg) | 2,000 mg (1,000 mg ×2)/orally/6 wk | Mean – 14.6 | Mean – 13.6 | ||||
| Clark et al39 | Randomized, placebo-controlled, multicenter | 394 (267/127) | 500 mg/orally/6 wk | Mean – 11.7 | Mean – 13.3 | BI (5 strata)/12 wk/primary planned analysis unreliable and not completed | Post hoc analysis: global recovery test (BI ≤95, mRS ≤1, NIHSS ≤1) and complete functional recovery (BI ≤95) better in citicoline patients with baseline NIHSS ≤8 (P<0.05) |
| Clark et al40 | Randomized, placebo-controlled, multicenter | 899 (453/446) | 2,000 mg (1,000 mg ×2)/orally/6 wk | Mean – 13.0 | Mean – 13.9 | NIHSS score change ≤7 points/12 wk/citicoline not effective (52% citicoline vs 51% placebo) | Post hoc analysis: mRS ≤1, NIHSS ≤1, global recovery test (BI ≤95, mRS ≤1, NIHSS ≤1) better in citicoline (P≤0.05)** |
| Davalos et al41 (ICTUS trial) | Randomized, placebo-controlled, multicenter | 2,298 (1,148/1,150) | a. 2,000 mg (1,000 mg ×2)/iv/first 3 days b. 2,000 mg (1,000 mg ×2)/orally/from the 4th day for a total of 6 wk | Median – 6.5 | Median – 15 | Global recovery test (BI ≤95, mRS ≤1, NIHSS ≤1)/12 wk/citicoline not effective | Post hoc analysis: citicoline more effective in patients >70 years, not treated with r-tPA, and with baseline NIHSS <14 (P≤0.041)*** |
Notes:
*
The proportion of patients with preexisting medical conditions was highest in the 1,000 mg group;
**
P=0.06, difference between citicoline and placebo groups in NIHSS score;
***
P=0.096 in patients not treated with r-tPA in per-protocol study. ≤1
Abbreviations: NIHSS, National Institute of Health Stroke Scale; iv, intravenous; wk, weeks; BI, Barthel Index; mRS, modified Rankin Scale; r-tPA, recombinant-tissue plasminogen activator.