Citicoline Failed to Improve Function or Cognition in TBI Patients

Citicoline proved to be no better than placebo at improving function or cognition after traumatic brain injury 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 traumatic brain injury (TBI) in 59 countries other than the United States. But it is widely available in the United States as a nutraceutical used for a range of neurological disorders, Dr. Ross D. Zafonte of the department of physical medicine and rehabilitation at Harvard Medical School, Boston, and his associates said in the November 21 issue of JAMA.

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 there is such a variety of pathological mechanisms at work, including hematoma, edema, infarction, contusions, and inflammation, Dr. Robert L. Ruff and Dr. Ronald G. Riechers II of the neurology and polytrauma services and the department of neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an editorial (JAMA 2012;308:2032-3). "The diverse and complex nature of the pathological 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 (JAMA 2012;308:1993-2000).

The 1,213 study subjects were aged 18-70 years, 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 age 45 years.

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 via 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. This 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 [95% confidence interval, 0.83-1.15]) 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 didn’t 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 post injury.

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.

This study was supported by the National Institute of Child Health and Human Development. Ferrer Grupo provided the citicoline and identical placebo used in the study. No financial conflicts of interest were reported.

Citicoline proved to be no better than placebo at improving function or cognition after traumatic brain injury 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 traumatic brain injury (TBI) in 59 countries other than the United States. But it is widely available in the United States as a nutraceutical used for a range of neurological disorders, Dr. Ross D. Zafonte of the department of physical medicine and rehabilitation at Harvard Medical School, Boston, and his associates said in the November 21 issue of JAMA.

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 there is such a variety of pathological mechanisms at work, including hematoma, edema, infarction, contusions, and inflammation, Dr. Robert L. Ruff and Dr. Ronald G. Riechers II of the neurology and polytrauma services and the department of neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an editorial (JAMA 2012;308:2032-3). "The diverse and complex nature of the pathological 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 (JAMA 2012;308:1993-2000).

The 1,213 study subjects were aged 18-70 years, 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 age 45 years.

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 via 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. This 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 [95% confidence interval, 0.83-1.15]) 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 didn’t 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 post injury.

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.

This study was supported by the National Institute of Child Health and Human Development. Ferrer Grupo provided the citicoline and identical placebo used in the study. No financial conflicts of interest were reported.

Citicoline proved to be no better than placebo at improving function or cognition after traumatic brain injury 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 traumatic brain injury (TBI) in 59 countries other than the United States. But it is widely available in the United States as a nutraceutical used for a range of neurological disorders, Dr. Ross D. Zafonte of the department of physical medicine and rehabilitation at Harvard Medical School, Boston, and his associates said in the November 21 issue of JAMA.

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 there is such a variety of pathological mechanisms at work, including hematoma, edema, infarction, contusions, and inflammation, Dr. Robert L. Ruff and Dr. Ronald G. Riechers II of the neurology and polytrauma services and the department of neurology at the Cleveland (Ohio) Veterans Affairs Medical Center said in an editorial (JAMA 2012;308:2032-3). "The diverse and complex nature of the pathological 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 (JAMA 2012;308:1993-2000).

The 1,213 study subjects were aged 18-70 years, 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 age 45 years.

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 via 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. This 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 [95% confidence interval, 0.83-1.15]) 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 didn’t 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 post injury.

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.

This study was supported by the National Institute of Child Health and Human Development. Ferrer Grupo provided the citicoline and identical placebo used in the study. No financial conflicts of interest were reported.