Effect of citicoline on functional and cognitive status among patients with traumatic brain injury: Citicoline Brain Injury Treatment Trial (COBRIT).

CONTEXT Traumatic brain injury (TBI) is a serious public health problem in the United States, yet no treatment is currently available to improve outcome after TBI. Approved for use in TBI in 59 countries, citicoline is an endogenous substance offering potential neuroprotective properties as well as facilitated neurorepair post injury. OBJECTIVE To determine the ability of citicoline to positively affect functional and cognitive status in persons with complicated mild, moderate, and severe TBI. DESIGN, SETTING, AND PATIENTS The Citicoline Brain Injury Treatment Trial (COBRIT), a phase 3, double-blind randomized clinical trial conducted between July 20, 2007, and February 4, 2011, among 1213 patients at 8 US level 1 trauma centers to investigate effects of citicoline vs placebo in patients with TBI classified as complicated mild, moderate, or severe. INTERVENTION Ninety-day regimen of daily enteral or oral citicoline (2000 mg) or placebo. MAIN OUTCOME MEASURES Functional and cognitive status, assessed at 90 days using the TBI-Clinical Trials Network Core Battery. A global statistical test was used to analyze the 9 scales of the core battery. Secondary outcomes were functional and cognitive improvement, assessed at 30, 90, and 180 days, and examination of the long-term maintenance of treatment effects. RESULTS Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4% in the citicoline group and 35.6% in the placebo group. For all other scales the rate of improvement ranged from 37.3% to 86.5% in the citicoline group and from 42.7% to 84.0% in the placebo group. The citicoline and placebo groups did not differ significantly at the 90-day evaluation (global odds ratio [OR], 0.98 [95% CI, 0.83-1.15]); in addition, there was no significant treatment effect in the 2 severity subgroups (global OR, 1.14 [95% CI, 0.88-1.49] and 0.89 [95% CI, 0.72-1.49] for moderate/severe and complicated mild TBI, respectively). At the 180-day evaluation, the citicoline and placebo groups did not differ significantly with respect to the primary outcome (global OR, 0.87 [95% CI, 0.72-1.04]). CONCLUSION Among patients with traumatic brain injury, the use of citicoline compared with placebo for 90 days did not result in improvement in functional and cognitive status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00545662.

[1]  Harvey S. Levin,et al.  Mild head injury classification. , 1990, Neurosurgery.

[2]  Ron Dumont,et al.  California Verbal Learning Test, Second Edition , 2014 .

[3]  F. Cohadon,et al.  [A precursor of phospholipids in the treatment of severe traumatic comas]. , 1982, Neuro-Chirurgie.

[4]  R. Lozano.  CDP-choline in the treatment of cranio-encephalic traumata , 1991, Journal of the Neurological Sciences.

[5]  R. Zafonte,et al.  CDP‐Choline as a Biological Supplement During Neurorecovery: A Focused Review , 2011, PM & R : the journal of injury, function, and rehabilitation.

[6]  J. Habbema,et al.  Subgroup Analysis and Covariate Adjustment in Randomized Clinical Trials of Traumatic Brain Injury: A Systematic Review , 2005, Neurosurgery.

[7]  N L Geller,et al.  Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and Stroke t-PA Stroke Trial. , 1996, Stroke.

[8]  J. Langhinrichsen-Rohling,et al.  A Meta-Analysis of Neuropsychological Outcome After Mild Traumatic Brain Injury: Re-analyses and Reconsiderations of Binder et al. (1997), Frencham et al. (2005), and Pertab et al. (2009) , 2011, The Clinical neuropsychologist.

[9]  Ross Zafonte,et al.  The citicoline brain injury treatment (COBRIT) trial: design and methods. , 2009, Journal of neurotrauma.

[10]  J. J. Ryan,et al.  Wechsler Adult Intelligence Scale-III , 2001 .

[11]  Y. Arabi,et al.  Critical care management of severe traumatic brain injury in adults , 2012, Scandinavian Journal of Trauma, Resuscitation and Emergency Medicine.

[12]  D. Rubin.  Multiple imputation for nonresponse in surveys , 1989 .

[13]  S. Dikmen,et al.  Mild Head Injury: Facts and Artifacts , 2001, Journal of clinical and experimental neuropsychology.

[14]  J. Secades.  Citicoline: pharmacological and clinical review, 2010 update. , 2011, Revista de neurologia.

[15]  S. Pocock.  Clinical trials with multiple outcomes: a statistical perspective on their design, analysis, and interpretation. , 1997, Controlled clinical trials.

[16]  Issues of loss to follow-up in a population study of traumatic brain injury (TBI) followed to 3 years post-trauma , 2010, Brain injury.

[17]  A. Benton.  Contributions to Neuropsychological Assessment: A Clinical Manual , 1983 .

[18]  Harvey S. Levin,et al.  Mild head injury classification. , 1990, Neurosurgery.

[19]  J. A. Escario,et al.  Effects of CDP-choline on the recovery of patients with head injury , 1991, Journal of the Neurological Sciences.

[20]  H. Levin.  Treatment of postconcussional symptoms with CDP-choline , 1991, Journal of the Neurological Sciences.

[21]  Joan Machamer,et al.  Neuropsychological outcome at 1-year post head injury. , 1995 .

[22]  angesichts der Corona-Pandemie,et al.  UPDATE , 1973, The Lancet.

[23]  R. Reitan.  Trail Making Test: Manual for Administration and Scoring , 1992 .

[24]  P. O'Brien.  Procedures for comparing samples with multiple endpoints. , 1984, Biometrics.

[25]  D. Marion,et al.  Effects of CDP-choline treatment on neurobehavioral deficits after TBI and on hippocampal and neocortical acetylcholine release. , 1997, Journal of neurotrauma.

[26]  G. Teasdale,et al.  Structured interviews for the Glasgow Outcome Scale and the extended Glasgow Outcome Scale: guidelines for their use. , 1998, Journal of neurotrauma.

[27]  D. Rubin,et al.  Statistical Analysis with Missing Data , 1988 .

[28]  A. Benton,et al.  Mild head injury , 1990 .

[29]  R. Dempsey,et al.  Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. , 2003, Journal of neurosurgery.

[30]  Marcel Dijkers,et al.  Systematic bias in traumatic brain injury outcome studies because of loss to follow-up. , 2003, Archives of physical medicine and rehabilitation.

[31]  J. R. Pauly,et al.  Therapeutic targets for neuroprotection and/or enhancement of functional recovery following traumatic brain injury. , 2011, Progress in molecular biology and translational science.

[32]  T. Bell,et al.  Issues of Attrition in a Population Study of Tramatic Brain Injury (TBI) Followed to 3 years Post-Trauma , 2008 .

[33]  D. Rubin,et al.  Statistical Analysis with Missing Data. , 1989 .

[34]  R. Reitan,et al.  The Halstead-Reitan neuropsychological test battery: Theory and clinical interpretation , 1993 .

[35]  C. Dodrill.  A Neuropsychological Battery for Epilepsy , 1978, Epilepsia.

[36]  A. Harvey,et al.  Postconcussive symptoms and posttraumatic stress disorder after mild traumatic brain injury. , 1999, The Journal of nervous and mental disease.

[37]  Ramon Diaz-Arrastia,et al.  Measuring Outcome in Traumatic Brain Injury Treatment Trials: Recommendations From the Traumatic Brain Injury Clinical Trials Network , 2010, The Journal of head trauma rehabilitation.

[38]  J. Secades,et al.  Citicoline: pharmacological and clinical review, 2006 update. , 2006, Methods and findings in experimental and clinical pharmacology.

[39]  E. P. Kennedy.  The synthesis of cytidine diphosphate choline, cytidine diphosphate ethanolamine, and related compounds. , 1956, The Journal of biological chemistry.

[40]  R. M. Adibhatla,et al.  Citicoline mechanisms and clinical efficacy in cerebral ischemia , 2002, Journal of neuroscience research.

[41]  R. Dempsey,et al.  Neuroprotective effects of citicoline on brain edema and blood-brain barrier breakdown after traumatic brain injury. , 2000, Journal of Neurosurgery.