PDF: ICTUS
(2012)Objective
ICTUS trial tested whether citicoline improves recovery at 90 days in patients with moderate-to-severe acute ischaemic stroke.
Study Summary
• Primary outcome (OR 1.03, 95% CI 0.86–1.25, p=0.364) was neutral
• No significant safety concerns identified
Intervention
Patients were randomized within 24 hours of stroke onset to receive 2000 mg/day citicoline IV and orally for 6 weeks or matching placebo. All received standard stroke care including rt-PA when indicated.
Inclusion Criteria
Age ≥18, MCA territory stroke, NIHSS ≥8, symptom onset ≤24h, pre-stroke mRS 0–1
Study Design
Arms: Citicoline vs Placebo
Patients per Arm: 1148 citicoline, 1150 placebo
Outcome
• Mortality: 19% (citicoline) vs 21% (placebo), p=0.31
• No significant differences in adverse events
Bottom Line
Citicoline did not improve global functional recovery at 90 days vs placebo (OR 1.03; 95% CI 0.86-1.25; P=0.364). Stopped for futility after 2078 patients. No secondary endpoint showed benefit. Safety was equivalent. Subgroup analyses suggested possible heterogeneity by age (P=0.001), rt-PA use (P=0.041), and NIHSS severity (P=0.021) — hypothesis-generating only.
Major Points
- Global recovery (NIHSS ≤1 + mRS ≤1 + Barthel ≥95) OR 1.03 (0.86-1.25; P=0.364) — convincingly null.
- Stopped for futility at 3rd interim analysis after 2078 patients with complete data.
- All secondary endpoints null: mRS ≤1 OR 1.07, NIHSS ≤1 OR 1.09, Barthel ≥95 OR 0.95, mRS shift OR 1.02.
- Mortality numerically lower but NS: 19.2% vs 21.0% (P=0.31).
- Safety excellent: sICH in rt-PA patients 6.0% vs 7.9% (P=0.25). No increase in any adverse event.
- 46% received rt-PA (vs 13% in prior citicoline trials) — may have created ceiling effect.
- Significant subgroup heterogeneity: benefit trend in age >70 (P=0.001 interaction), non-rt-PA (P=0.041), moderate NIHSS 8-14 (P=0.021) — but must accept harm in complementary subgroups.
- Updated meta-analysis (all citicoline trials): fixed-effect OR 1.14 (1.00-1.30) but I²=73%. Excluding Tazaki 1988: OR 1.07 (0.93-1.22), NS.
- Definitive negative trial for citicoline in contemporary stroke care including thrombolysis.
- 2298 patients, 59 centers, Spain/Portugal/Germany. Double-blind, placebo-controlled.
Study Design
- Study Type
- Randomized, placebo-controlled, sequential, double-blind, superiority trial
- Randomization
- Yes
- Blinding
- Double-blind. Centralized 1:1 via IVRS with minimization balancing NIHSS (8-14/15-22/≥23), window (≤12h/>12h), rt-PA intent (yes/no), age (≤70/>70), stroke side, center.
- Sample Size
- 2298
- Follow-up
- 90 days
- Centers
- 59
- Countries
- Spain, Portugal, Germany
Primary Outcome
Definition: Global recovery at 90 days: composite requiring NIHSS ≤1 AND mRS ≤1 AND Barthel ≥95 simultaneously
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| — | — | - (0.86-1.25) | 0.364 |
Limitations & Criticisms
- Industry funded by Ferrer Grupo (citicoline manufacturer); one author was company employee.
- 46% rt-PA use (vs 13% in prior trials) may have created ceiling effect.
- Older/more severe population than prior trials (mean age 73, median NIHSS 15).
- 24-hour randomization window may be too late for neuroprotection.
- No upper infarct size limit — large irreversible infarcts included.
- 24% protocol deviations; 164+160 excluded from per-protocol for poor compliance.
- Failed to replicate prior pooled analysis (OR 1.26); updated meta-analysis I²=73%.
- Multiple subgroup interactions may represent chance findings.
Citation
Lancet. 2012;380(9839):349-357.