Exelon for Traumatic Brain Injury

NEW YORK, Sept. 12 -- Investigators looking to see whether an Alzheimer's drug could help the memory of patients after a traumatic brain injury had to mine the data hard for a faint light at the end of the tunnel.

Mostly, however, the use of Exelon (rivastigimine) did not meet minimal expectations for patients with moderate to severe memory deficits following a traumatic brain injury, researchers here and elsewhere reported.

A year or more after a traumatic brain injury resulting in persistent cognitive impairment, patients who were then given Exelon daily for 12 weeks fared no better overall than those on placebo in objective measures of verbal or visual memory, wrote psychiatrist Jonathan M. Silver, M.D., of New York University, and colleagues, in the Sept. 11 issue of Neurology.

Although there were no differences between the active drug group and a placebo group as a whole in either the primary or secondary study endpoints, patients with more severe memory deficits did have significant improvement on some measures of verbal memory and visual processing tasks, the authors reported.

The benefits of Exelon, a cholinesterase inhibitor, "may not become apparent unless there is significant depletion of cholinergic activity in relevant brain regions causing a more profound impairment in memory or attention," Dr. Silver said. "This is an area where more research will be required to confirm these findings and to better define who may have the best response with rivastigmine."

The study was funded by Novartis, maker of Exelon, and all but two of the 11 authors have received honoraria or educational support from Novartis, or are current or former employees of the company.

The investigators conducted a randomized controlled trial comparing the efficacy and safety of rivastigmine at doses of 3 mg/day to 6 mg/day to placebo over 12 weeks in patients with traumatic brain injury.

A total of 157 patients (mean age 37.1 + 10.5 years) were enrolled. All patients had suffered a traumatic brain injury at least 12 months earlier, and had persistent cognitive impairments.

The authors chose for their primary measures of efficacy the Cambridge Neuropsychological Test Automated Battery (CANTAB) Rapid Visual Information Processing A? subtest, and the Hopkins Verbal Learning Test.

The primary efficacy endpoint was the proportion of patients who demonstrated at 12 weeks an improvement of one or more standard deviations on either the visual-processing or verbal-learning test.

Secondary endpoints included change from baseline at week 12 in the CANTAB subtests measuring spatial working memory, paired associates learning, and reaction time subtests. Other secondary measures included tests for verbal fluency and word-finding ability, short-term auditory and verbal memory, working memory, sequencing, mental flexibility, depression, attention, and aggression.

The authors found that percentages of responders at week 12 on either the rapid visual information processing test or verbal learning test were virtually identical, at 48.7% for the Exelon group, and 49.3% for those on placebo (P=0.940).

"Furthermore, for the overall study population, there were no significant differences for any of the secondary efficacy variables," they wrote.

They did find, however, that among 81 patients with moderate to severe memory impairment, defined as 25% impairment or greater on the Hopkins Verbal Learning Test at baseline, Exelon was significantly better than placebo for some measures, the authors reported.

Specifically, they found a significant change from baseline at weeks four and 12 (but not at week eight) favoring Exelon for mean latency on the CANTAB Rapid Visual Information Processing test.

In addition, about 33% of patients with severe impairment who were taking Exelon had at least a five-word improvement over baseline on the Hopkins Verbal Learning test, compared with about 13% of those on placebo (P<0.05).

One patient in each treatment group experienced at least one severe adverse event. One patient in the Exelon group had severe noncardiac chest pain, and one in the placebo group reported severe aggression, anger, and irritability.

The most common adverse events were nausea, upper respiratory tract infection, headache, dizziness, and vomiting, each of which reported in at least 10% of patients taking Exelon.

"It is possible that the improvement observed in various cognitive tests reflects a 'medication-enhanced' practice effect," the authors acknowledged.

"Nonetheless, cognitive improvements in patients with persistent impairments after traumatic brain injury are an important treatment goal, whether the result of a direct medication effect on memory or an indirect influence on a practice effect," they wrote.