JFK Johnson Rehabilitation Institute Announces Multi-National Clinical Study To Focus on Effectiveness of Drug For Treating Severe Traumatic Brain Injuries.

EDISON, N.J. -- -- Improvement Sought in Patients in Vegetative and Minimally Conscious States

Patients with severe traumatic brain injuries may be eligible to participate in an international clinical study funded by a 5-year, $3-million grant from the National Institute on Disability and Rehabilitation Research. The study is designed to test the effectiveness of a drug called amantadine hydrochloride for treating patients in vegetative and minimally conscious states.

Joseph T. Giacino, Ph.D., of the JFK-Johnson Rehabilitation Institute in Edison, NJ, who is directing the study, said: "Many drugs are used to try to speed the recovery of consciousness in individuals with severe brain injuries, but there is very little research available to help physicians select a drug that is effective in treating patients with prolonged impairments of consciousness."

"Amantadine hydrochloride, introduced in the 1960's as an antiviral agent, has been shown to enhance the transmission of nerve impulses in the brain," said project co-director John Whyte, M.D., Ph.D., of MossRehab in Philadelphia. The encouraging results of earlier pilot studies using this drug in patients recovering from disturbances in consciousness paved the way for this major study in which as many as 180 patients are expected to be enrolled at multiple sites throughout the United States and Germany.

Eight rehabilitation institutions are participating in the study as members of the Consciousness Consortium. In addition to the JFK-Johnson Rehabilitation Institute and MossRehab, the consortium includes HealthSouth Braintree Rehabilitation Hospital in Braintree, MA.; Bryn Mawr Rehabilitation Hospital in Malvern, PA; Fachkrankenhaus Neresheim Hospital in Neresheim, Germany; Methodist Rehab Center in Jackson, MS; Sunnyview Rehabilitation Hospital in Schenectady, NY; and Texas Neurorehab Center in Austin, TX. The department of Biostatistics in the Mailman School of Public Health at Columbia University in New York City will function as the Data Coordinating Center for this study.

Scope of the Problem

Between 15,000 and 45,000 Americans survive severe traumatic brain injury each year. "Survival rates have improved considerably during the last 25 years as the result of better emergency room care and surgical procedures," Dr. Giacino said. Yet the average lifetime per-patient cost for care after a severe traumatic brain injury remains very high at about $2 million, according to a 1999 National Institutes of Health survey. In addition, the family disruption caused by involuntary role changes is often overwhelming.

Those with the most severe injuries may survive in the vegetative state (commonly but inaccurately referred to as a long-term "coma") or the minimally conscious state (in which there are inconsistent but definite signs of consciousness) for prolonged periods and sometimes permanently, Dr. Whyte noted.

In the first phase of the earlier pilot study -- funded in 1997 through the Irving I. and Felicia F. Rubin Family Brain Injury Research Grant -- the Consciousness Consortium assessed the rate of spontaneous recovery of 149 patients who were in either vegetative or minimally conscious states of awareness. All patients were enrolled in the study between four and 16 weeks after brain injury and assessed using the Disability Rating Scale (DRS). The pilot study showed that scores during their first two weeks in the study were highly significant predictors of how well the patients would recover four months after injury.

During the second phase of the pilot study, focus shifted from spontaneous recovery rates to the impact of several rehabilitation treatments on recovery. Researchers noted that of all the medications patients received in the first month of treatment, only amantadine hydrochloride had a significantly positive relationship to outcome at four months post-injury. These and other promising findings from similar studies of the drug led to this successful proposal for a larger, double-blind clinical study designed to rule out the possibility that physicians in the earlier studies were more inclined to give the drug to patients already showing signs of improvement.

How the Drug May Help

"Among patients with prolonged disorders of consciousness, regions of the brain important in the transmission of a chemical called dopamine are prominently involved," Dr. Giacino explained. "Dopamine plays a critical role in the central nervous system by influencing arousal, movement, perception, and behavior. Amantadine hydrochloride may help patients in vegetative and minimally conscious states by stimulating dopamine transmission," he said.

To be eligible to enroll in the study, a patient must be between the ages of 16 and 65, must be admitted to one of the eight participating clinical facilities for brain injury care and rehabilitation, and be between four to 16 weeks post-injury with no or inconsistent ability to follow commands or communicate. Each patient will receive either amantadine hydrochloride or placebo, determined at random (as in flipping a coin) for four weeks in a double-blind study, which means that neither the patient nor attending physician will know the group to which the patient has been assigned.

Results will be measured after the fourth and sixth weeks of the study using two well-established behavioral rating scales to gauge recovery and measure whether improvements persist after the drug is stopped. All patients will have CT scans before entering the study to help determine whether the location and extent of brain injury influence response to amantadine hydrochloride.

For more information about the study, contact Dr. Giacino, JFK, [phone] or Dr. Whyte [phone]. In Germany, contact Dr. Eifert at 07326/960820.

Facts About Amantadine Hydrochloride (AH)

--Introduced in the 1960's as an antiviral agent against influenza A and used later to treat neurological disorders such as Parkinson's disease, AH has been shown to enhance the transmission of nerve impulses in the brain.

--A number of studies suggest AH is useful in treating cognitive and behavioral symptoms of developmental disorders and autism.

--Studies of AH's effectiveness in treating traumatic brain injury have been small and inconclusive, especially regarding whether improvements persist after treatment ends.

--AH may help patients in vegetative and minimally conscious states by stimulating dopamine transmission. Dopamine plays a critical role in the central nervous system by influencing arousal, movement, perception and behavior.

--AH is generally well-tolerated and adverse reactions are generally mild and reversible. Side-effects include insomnia, poor concentration, depression, swollen ankles and gastrointestinal effects such as upset stomach.