Widely-Used Citicoline Found to Be Ineffective in TBI Treatment

By Brenda L. Mooney

BOSTON – A compound approved for treating traumatic brain injury (TBI) in nearly 60 countries does not appear to approve function or cognitive status in patients, according to a new study.

The report was on a randomized trial of more than 1,200 participants with TBI that looked at the effectiveness of citicoline, an endogenous compound available as a dietary supplement in the United States but sold as a prescription medication in some other countries.1

“The COBRIT study indicates that citicoline was not superior to placebo as an acute and post-acute therapy among participants with a broad range of severity of TBI. The worldwide use of citicoline for TBI should now be questioned,” writes lead author Ross D. Zafonte, DO, of Harvard Medical School, Spaulding Rehabilitation and Massachusetts General Hospital, Boston, and colleagues. Their report was published last month in the Journal of the American Medical Association.

Citicoline was developed in Japan to treat stroke but now is frequently prescribed in Europe for cognitive issues related to circulation problems in the brain. In addition to TBI, it is used for Alzheimer’s disease and other types of dementia, cerebrovascular disease such as stroke, age-related memory loss, Parkinson’s disease, attention deficit-hyperactive disorder (ADHD) and glaucoma.

Its mechanism of action appears to be increasing a brain chemical called phosphatidylcholine, and some proponents have suggested citicoline also can decrease brain tissue damage after injury.

“Despite considerable advances in emergency and critical care management of TBI, as well as decades of research on potential agents for neuroprotection or enhanced recovery, no effective pharmacotherapy has yet been identified,” according to background information contained in the article.

The study reported in JAMA, the Citicoline Brain Injury Treatment Trial (COBRIT), was a phase 3, randomized clinical trial conducted between July 2007 and February 2011. Researchers examined the effects of 90 days of enteral or oral citicoline (2,000 mg) vs. placebo initiated within 24 hours of injury in 1,213 patients with complicated mild, moderate and severe TBI at eight U.S. level 1 trauma centers.

Citicoline and placebo groups did not differ significantly at the 90-day evaluation on measures of cognitive and functional status, according to the results.

“Rates of favorable improvement for the Glasgow Outcome Scale-Extended were 35.4% in the citicoline group and 35.6%,” the authors note. With other measurement tools,” 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.”

Treatment effect with citicoline didn’t differ between the moderate/severe and complicated mild TBI subgroups. Nor was much difference observed between placebo and citicoline in the overall proportion of patients reporting serious adverse events.

Although prior meta-analyses suggest that neuropsychological function might return to normal by three months in the majority of patients with uncomplicated mild TBI, this is untrue for those with so-called mild injury complicated by cerebral injuries visible on CT,” the authors suggest.

“The TBI Clinical Trials Network Core Battery includes sensitive measures of cognition, chosen because ceiling effects were unlikely. Thus, the COBRIT study appears to support the lack of utility of citicoline in the treatment of TBI across a broad spectrum of injury severity,” the report said.

In an accompanying editorial, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, both of the Louis Stokes Cleveland VA Medical Center and Case Western Reserve University, said the primary importance of the trial “is that it conclusively demonstrated the lack of efficacy of citicoline monotherapy for TBI.”2

Ruff and Riechers add, “it is 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.”

They suggest that future studies of TBI treatment focus on multiple treatment interventions and comprehensive TBI rehabilitation strategies.

The editorial writers point out that “reducing the severity of TBI morbidity once trauma has occurred and improving the rate and extent of recovery from TBI are major challenges,” saying that the results of the COBRIT study had been anticipated with “great hope.”

1. Zafonte RD; DO, Bagiella E; Ansel BM; Novack TA, et al. Effect of Citicoline on Functional and Cognitive Status Among Patients With Traumatic Brain Injury: Citicoline Brain Injury Treatment Trial (COBRIT). JAMA. 2012;308(19):1993-2000. doi:10.1001/jama.2012.13256

2. Ruff RL, Richers RG. Effective Treatment of Traumatic Brain Injury: Learning From Experience. JAMA. 2012;308(19):2032-2033. doi:10.1001/jama.2012.14008

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