ICTUS
Citicoline in the treatment of acute ischaemic stroke: an international, randomised, multicentre, placebo-controlled study (ICTUS trial)
Year of Publication: 2012
Authors: Antoni Dávalos, José Alvarez-Sabín, José Castillo, ..., for the ICTUS trial investigators
Journal: The Lancet
Citation: Lancet. 2012;380(9839):349-357.
PDF: Clinical Question
Does citicoline 2000 mg daily for 6 weeks improve functional recovery at 90 days compared to placebo in patients with moderate-to-severe acute ischaemic stroke?
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.
Design
Study Type: Randomized, placebo-controlled, sequential, double-blind, superiority trial
Randomization: 1
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.
Enrollment Period: November 26, 2006 to October 27, 2011
Follow-up Duration: 90 days
Centers: 59
Countries: Spain, Portugal, Germany
Sample Size: 2298
Analysis: ITT primary; per-protocol secondary. LOCF for missing data. Group sequential modified triangular test. 80% power for OR 1.26.
Inclusion Criteria
- Age ≥18 years.
- Acute ischaemic stroke of MCA territory with compatible neuroimaging.
- Onset within previous 24 hours.
- NIHSS ≥8, with ≥2 points from motor items (sections 5+6).
- Pre-stroke mRS 0 or 1.
- Hospital admission to randomization ≤12 hours.
- Randomization to first dose ≤1 hour.
Exclusion Criteria
- Protocol deviations including: poor compliance (<80% doses), missing outcome scales at week 12, not-permitted procedures, commercial citicoline use, crossover between arms.
- rt-PA >4.5 hours from onset.
Baseline Characteristics
| Characteristic | Citicoline (N=1,148) | Placebo (N=1,150) |
|---|---|---|
| Age (mean±SD) | 72.9±11.8 | 72.8±12.1 |
| Age >70 | 774 (67.4%) | 777 (67.6%) |
| Female | 560 (48.8%) | 596 (51.8%) |
| NIHSS median (IQR) | 15 (11-19) | 15 (11-19) |
| NIHSS 8-14 | 540 (47.0%) | 538 (46.8%) |
| NIHSS 15-22 | 552 (48.1%) | 556 (48.3%) |
| NIHSS >22 | 56 (4.9%) | 56 (4.9%) |
| Received rt-PA | 532 (46.3%) | 532 (46.3%) |
| Time onset to treatment median (IQR) | 6.5h (4.0-12.3) | 6.8h (4.0-12.0) |
| Cardioembolic etiology | 533 (47.3%) | 534 (47.6%) |
| Large artery atherosclerosis | 258 (22.9%) | 229 (20.4%) |
| Hypertension | 841 (73.3%) | 830 (72.2%) |
| Diabetes | 273 (23.8%) | 290 (25.2%) |
| AF | 405 (35.3%) | 417 (36.3%) |
| Previous stroke | 162 (14.1%) | 147 (12.8%) |
Arms
| Field | Citicoline | Control |
|---|---|---|
| Intervention | Days 1-3: citicoline 1000 mg IV q12h (2000 mg/day) infused over 30-60 min in 100 mL saline. Days 4-42: citicoline 500 mg PO q12h (2000 mg/day). Dysphagia: tablets dissolved in 30-60 mL tepid water via NG tube. Total 6 weeks. | Identical matching placebo in IV (ampoule) and oral (tablet) formats. Same schedule and duration. |
| Duration | 6 weeks (42 days) | 6 weeks (42 days) |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Global recovery at 90 days: composite requiring NIHSS ≤1 AND mRS ≤1 AND Barthel ≥95 simultaneously | Primary | — | — | 0.364 | |
| mRS ≤1 at 90 days | 95% CI: 0.85-1.36 | Secondary | 208/1,150 (18.1%) | 211/1,148 (18.4%) | OR 1.07 | |
| NIHSS ≤1 at 90 days | 95% CI: 0.87-1.36 | Secondary | 260/1,150 (22.6%) | 264/1,148 (23.0%) | OR 1.09 | |
| Barthel ≥95 at 90 days | 95% CI: 0.77-1.17 | Secondary | 321/1,150 (27.9%) | 307/1,148 (26.7%) | OR 0.95 | |
| mRS shift analysis | 95% CI: 0.88-1.19 | Secondary | — | — | OR 1.02 | |
| Mortality | Adverse | 242/1,150 (21.0%) | 221/1,148 (19.2%) | 0.31 | |
| sICH in rt-PA patients | Adverse | 40/506 (7.9%) | 30/497 (6.0%) | 0.25 | |
| Any hemorrhagic transformation (rt-PA patients) | Adverse | 113/506 (22.3%) | 112/497 (22.5%) | 0.98 | |
| Neurological worsening (NIHSS ≥4 in 1st week) | Adverse | 204/1,150 (17.7%) | 184/1,148 (16.0%) |
Subgroup Analysis
Significant interactions: age (P=0.001) — trend benefit >70yr, trend harm ≤70yr. rt-PA (P=0.041) — trend benefit without rt-PA (OR 1.11), trend harm with rt-PA (OR 0.86). NIHSS (P=0.021) — NIHSS 8-14 OR 1.08, NIHSS 15-22 OR 0.82, NIHSS >22 OR 0.34. Stroke side and time window: NS.
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.
Funding
Ferrer Grupo, Barcelona, Spain (citicoline manufacturer).
Based on: ICTUS (The Lancet, 2012)
Authors: Antoni Dávalos, José Alvarez-Sabín, José Castillo, ..., for the ICTUS trial investigators
Citation: Lancet. 2012;380(9839):349-357.
Content summarized and formatted by NeuroTrials.ai.