Neuroprotective Effects of Citicoline in TBI Questioned

Megan Brooks

November 21, 2012

Citicoline did not improve functional or cognitive status in patients with traumatic brain injury (TBI) enrolled in the phase 3 randomized Citicoline for Brain Injury Treatment Trial (COBRIT).

Citicoline is an approved therapy for TBI in 59 countries, yet it hasn't been evaluated in a large randomized trial for TBI until now, the study team notes.

"The COBRIT study indicates that citicoline was not superior to placebo as an acute and postacute therapy among participants with a broad range of severity of TBI. The worldwide use of citicoline for TBI should now be questioned," they conclude.

"While we were disappointed at the results, [we] are heartened to have made a contribution that will impact care worldwide. This study highlights the need for rigorous clinical trials," study investigator Ross D. Zafonte, DO, Harvard Medical School, Spaulding Rehabilitation and Massachusetts General Hospital, Boston, told Medscape Medical News.

"Clinicians and researchers should be cautious about nutriceuticals, supplements, and other substances that are assumed to have efficacy. Agents that are strong enough to help may have no effect, or be strong enough to harm," he added.

Their findings are published in the November 21 issue of the Journal of the American Medical Association.

Favorable Improvement Similar

COBRIT involved 1213 patients with complicated mild, moderate, or severe TBI at 8 US level 1 trauma centers. They were randomly assigned to a 90-day regimen of daily enteral or oral citicoline (2000 mg) or placebo, initiated within 24 hours of injury.

At 90 days, the 2 groups did not differ with respect to the TBI Clinical Trials Network Core Battery (global odds ratio, 0.98; 95% confidence interval, 0.83 - 1.15), the researchers say.

Rates of favorable improvement in the Glasgow Outcome Scale-Extended also didn't differ significantly; they were 35.4% with citicoline and 35.6% with placebo. For all other scales, the rate of improvement ranged from 37.3% to 86.5% with citicoline and from 42.7% to 84.0% with placebo.

The researchers also didn't see any significant treatment effect in the 2 severity subgroups (moderate/severe and complicated mild TBI).

Evaluations performed at 180 days also showed no marked differences between the citicoline and placebo groups.

A total of 316 serious adverse events occurred among 234 patients. The overall proportion of patients reporting serious adverse events was similar between the placebo and citicoline groups.

There was also no statistically significant difference in survival between the citicoline and placebo groups. A total of 73 patients died during the study: 42 (6.9%) in the placebo group and 31 (5.1%) in the citicoline group. Most deaths occurred during the first 30 days.

'Great Hope' Dashed

There currently are no effective treatments to reduce the severity of TBI-related deficits, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, from Neurology and Polytrauma Services and Department of Neurology, Cleveland Veterans Affairs Medical Center, Ohio, note in an editorial published with the study. "Therefore, the results of the COBRIT study of citicoline therapy were anticipated with great hope."

Dr. Ruff and Dr. Riechers say there have been "encouraging findings" in animal studies and preliminary clinical pilot studies using citicoline to reduce cerebral injury caused by TBI, ischemia, and aging. However, similar to the COBRIT study, a multicenter placebo-controlled study published earlier this year found that citicoline did not improve the extent or speed of recovery after acute stroke, as previously reported by Medscape Medical News.

COBRIT demonstrates "conclusively" the lack of efficacy of citicoline monotherapy for TBI, Dr. Ruff and Dr. Riechers say, and it's "unlikely that this finding can be accounted for by limitations in the study design or conduct. The broader implication of the COBRIT study may be that no single therapeutic agent is likely to be sufficient to improve functional outcomes for patients with TBI."

"The diverse and complex nature of the pathological mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery. Future studies of TBI treatment should be designed to incorporate multiple treatment interventions and comprehensive TBI rehabilitation strategies, either as components of the intervention or standardized across study treatment groups," Dr. Ruff and Dr. Riechers conclude.

The COBRIT study was supported by the National Institute of Child Health and Human Development. The COBRIT investigators, and Dr. Ruff and Dr. Riechers, have disclosed no relevant financial relationships.

JAMA. 2012;308:1993-2000, 2032-2033. Abstract Editorial