Clinical Question

Does 90 days of citicoline (CDP-choline) 2000 mg/day improve global functional and cognitive outcomes in patients with complicated mild, moderate, or severe traumatic brain injury (TBI) when started within 24 hours of injury?

Inclusion Criteria

• Non-penetrating traumatic brain injury.
• Age 18 years (19 in Alabama) to 70 years.
• GCS criteria — patients OFF paralytics: GCS 3–12 with GCS motor score ≤5; OR GCS 3–12 with GCS motor score=6 AND meeting ANY of the following CT criteria: (a) ≥10 mm total diameter intraparenchymal hemorrhage; (b) acute extra-axial hematoma thickness ≥5 mm; (c) contiguous subarachnoid hemorrhage visible on two or more contiguous CT slices; (d) intraventricular hemorrhage present on two slices; (e) midline shift ≥5 mm.
• GCS 13–15 meeting the above CT criteria.
• GCS criteria — patients ON paralytics: GCS 3TP (intubated and paralyzed) meeting the above CT criteria.
• Reasonable expectation of completing outcome measures at a network center at 6 months post-injury.
• Able to swallow oral medication, OR if unable to swallow, a gastric tube or PEG is placed by 23 hours after injury.
• Reasonable expectation of enrollment within the 24-hour time window.
• English-speaking.

Exclusion Criteria

• Intubated patients with GCS motor score=6 who do NOT meet CT criteria.
• Bilaterally fixed and dilated pupils.
• Positive pregnancy test, known pregnancy, or current breastfeeding.
• Evidence of pre-existing disease that interferes with outcome assessment.
• Current use of acetylcholinesterase inhibitors.
• Current citicoline use and unwilling to discontinue.
• Imminent death or current life-threatening disease.
• Current enrollment in another clinical study.
• Prisoner status.

Arms

Outcomes

Criticisms

• This publication reports only design and methods — no efficacy or safety results are presented. The actual COBRIT results (published JAMA 2012) showed no benefit of citicoline over placebo on any outcome measure.
• The enrolled severity distribution at interim report (67% complicated mild, 4% moderate, 29% severe) diverged substantially from the planned distribution (46% complicated mild, 16% moderate, 38% severe), potentially reducing power to detect effects in the more severely injured subgroups.
• Use of a global composite endpoint across 9 heterogeneous cognitive/functional measures may mask differential effects on individual domains — if citicoline affects only one measure, the global test will not detect efficacy.
• The assumption that treatment effect is constant across all 9 battery measures (required by the global logit model) may not hold for a drug targeting specific neurotransmitter systems (cholinergic, dopaminergic).
• Restriction to English-speaking patients limits generalizability to non-English-speaking TBI populations, who may constitute a significant fraction of urban TBI admissions.
• 24-hour enrollment window is broader than some prior trials (8–12 hours) — earlier administration might be necessary for maximal neuroprotection, and the broad window may dilute effect.
• Loss to follow-up of 15% was anticipated but not yet observed — actual loss may differ and affect power.
• No a priori plan to test pharmacogenomic interactions (e.g., APOE-4 status), though DNA banking for future secondary analyses was included.
• Prior positive trials of citicoline in TBI were small, used lower doses, and showed benefit only on secondary endpoints — the evidentiary basis for expecting efficacy at 2000 mg/day over 90 days in this broad population was modest.

Funding

National Center for Medical Rehabilitation Research (NCMRR), National Institute of Child Health and Human Development (NICHD), NIH. Grant numbers: U01HD042823, U01HD042738, U01HD042687, U01HD042736, U01HD042678, U01HD042686, U01HD042653, U01HD042689, U01HD042652.