TBI is a serious public health problem and no treatment is yet able to improve functional outcome. Citicoline is an endogenous substance, which enhances phospholipid membrane function and impacts a wide variety of pathways after injury. The medication had been approved in 59 countries and was employed to provide neuroprotection and neurofacilitation. The plieotropic mechanisms of action of citicoline and its prior positive results in clinical trials of stroke made this medication an attractive target.

An eight site phase 3 randomized clinical trial was performed to evaluate the efficacy of 90 days of citicoline (200 mg) or placebo. Functional and clinical outcome was assessed at 30,90 and 180 days with a 9 scale combined clinical trials outcome metric. Those greater than age 18 ( > 19 in the state of Alabama) were enrolled, and the inclusion criteria included those with complicated mild (neuroimaging verified), moderate and severe TBI. All patients where treated according to established clinical protocols.

A total of 1213 subjects where randomized to the study with excellent balance between groups. Rates of favorable outcome based on the glasgow outcome scale extended as well as the clinical trials global metric where similar between treatment groups. At 90 days the groups did not significantly, while at 180 days some sub group differences are potentially observed.

The findings of the COBRIT study are surprising and suggest that this therapy is not effective. Of note issues related to subpopulation effects, lessons learned regarding method, outcome metric and recovery patters in subpopulations will be reviewed. Implications for future TBI clinical trials (especially those in the rehabilitation setting) will be discussed.