Patients with traumatic brain injury (TBI) who were treated with citicoline failed to show improvements in functional and cognitive status, according to results of a multicenter phase III trial reported in the November 21, 2012, issue of JAMA. Citicoline proved to be no better than placebo at improving function or cognition after TBI in the first large randomized clinical trial to test it in this patient population.
Citicoline, an endogenous compound that is an intermediate in the biosynthesis of phosphatidylcholine from choline, is thought to have a range of neuroprotective properties and has been approved as a treatment for TBI in 59 countries other than the United States. But it is widely available in the US as a nutraceutical used for various neurologic disorders, said lead author Ross D. Zafonte, DO, of the Department of Physical Medicine and Rehabilitation at Harvard Medical School in Boston, and his associates.
Given these new findings, “the worldwide use of citicoline for TBI should now be questioned,” the investigators wrote.
It’s likely that no single therapeutic agent will ever be sufficient to improve functional outcomes in TBI, because so many pathologic mechanisms are at work, including hematoma, edema, infarction, contusions, and inflammation, Robert L. Ruff, MD, PhD, and Ronald G. Riechers II, MD, of the Neurology and Polytrauma Services and the Department of Neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an accompanying editorial. “The diverse and complex nature of the pathologic mechanisms activated by TBI suggests that multimodal treatment interventions may be needed to improve recovery.”
Dr. Zafonte and his colleagues conducted the Citicoline Brain Injury Treatment Trial (COBRIT), the first large, phase III, double-blind study to compare citicoline with placebo in the acute and postacute phases after TBI. They enrolled patients with a broad range of severity of injury who had presented to eight level I trauma centers across the country.
The 1,213 study subjects ranged in age from 18 to 70, and the study population was ethnically and demographically diverse. As is typical for TBI patients, three-quarters of the study subjects were male, and more than half were younger than 45.
These patients were randomly assigned to receive 90 days of either citicoline (607 patients) or identical-looking placebo (606) through an enteral route; those who could not swallow the regular oral tablets received the compound as crushed tablets mixed with water or saline and administered through a nasogastric or percutaneous endoscopic gastrostomy tube. The dosage was 2,000 mg per day. Treatment commenced within 24 hours of sustaining the injury.
The primary outcome of the study was functional status and cognitive performance at 90 days, as measured by all nine components of the TBI Clinical Trials Network Core Battery. These components included the Glasgow Outcome Scale-Extended (GOS-E) instrument.
COBRIT was halted early when an interim analysis indicated that further accrual would not change the main outcome: Patients given citicoline did not differ from those given placebo when tested using the combined battery (odds ratio, 0.98) or when tested on any of the individual elements of the battery.
In particular, rates of improvement on the GOS-E were almost exactly the same: 35.4% among subjects given citicoline and 35.6% among those given placebo, the researchers reported. These findings did not change when the data were adjusted to account for patients’ results on the Abbreviated Injury Score at baseline or when the subjects were categorized by the severity of their TBI. The results also did not change when the analysis was restricted to only subjects who took at least 75% of their assigned study medication. There also were no significant differences between the groups in any measure at 180 days postinjury.
A total of 73 subjects died during the study, with no significant difference in survival between the groups.
Similarly, there were no differences between the groups in the overall rates of adverse events or in the rates of serious adverse events.
Mary Ann Moon