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News from the AAN Annual Meeting: In Placebo-Controlled Trial, Amantadine Improves Recovery from Consciousness Disorders

ARTICLE IN BRIEF

DR. DOUGLAS KATZ: “Even if the only impact of the drug is to accelerate rather than magnify gains, I think that's an important benefit. Time is so short in the current reimbursement environment. If the patients manage to get into rehab in the first place, which a lot [of people] with disorders of consciousness don't, they [facility administrators] will try to get them out as soon as possible if they aren't making any gains.”

Investigators reported that in a placebo-controlled trial, the patients with consciousness disorders who received amantadine had significantly better functional recovery on two tests of disability.

Amantadine speeds consciousness recovery after traumatic brain injury (TBI), according to a new study. Results from this large, placebo-controlled, multicenter study — the first of its size for this condition — will be described at the AAN annual meeting in Hawaii next week.

“Rehabilitation programs treating patients with prolonged disorders of consciousness typically employ pharmacologic strategies to promote recovery, but with limited evidence to support efficacy,” according to one of the study leaders, John Whyte, MD, PhD, director of Moss Rehabilitation Research Institute in Elkins Park, PA, and professor of rehabilitation medicine at Thomas Jefferson University in Philadelphia.

Amantadine has been used off-label for TBI patients with disorders of consciousness for years, and “people have had the feeling that it works,” but the combination of variable response and spontaneous recovery in this population has made it difficult to interpret its effect, he said. “We felt there needed to be a bigger trial.”

Putting that trial together took some time, to put it mildly. “It's been 14 years in the making,” Dr. Whyte said. Patients with such disorders tend to be quickly moved out of rehabilitation and into chronic care facilities, which rarely have the academic affiliations that aid in patient recruitment and monitoring. And drug companies have shied away from funding such trials, since most of the likely drugs are off-patent. Over the 14 years, the core group of researchers put together a network of facilities, conducted a natural history study, and ran a pilot trial of amantadine. That study, published in 2005 in the Archives of Physical Medicine and Rehabilitation, indicated the drug had promise. The investigators suggested a larger, placebo-controlled and randomized trial would be practical and could offer more definitive evidence of amantadine's effects.

STUDY PROTOCOLS

The investigators enrolled 184 patients in the vegetative or minimally conscious state at five centers in the United States and three in Europe. Patients were between four and 16 weeks post-TBI, and received treatment with either amantadine or placebo for four weeks, followed by a two-week washout. Amantadine was dosed at 200 to 400 milligrams per day. While the researchers would have preferred a longer study, the six-week period was felt to be the longest practical length for two reasons: Six weeks is the average length of a reimbursed stay in a rehabilitation facility, and families were unlikely to approve a longer treatment period when their family member had a 50 percent risk of receiving placebo.

The primary outcome measures were the difference in slope between the groups over the course of treatment on two scales, the Disability Rating Scale (DRS) and the Coma Recovery Scale-Revised (CRS-R). The DRS assesses function on eight activities, including eye-opening, communication, and motor response, with the highest score of 29 indicating the worst function. The CRS-R also assesses function in multiple domains, with higher scores indicating better function.

“Patients who received amantadine had significantly better functional recovery on the DRS compared to those who received placebo over the four weeks of treatment,” according to lead investigator Douglas Katz, MD, associate professor of neurology at Boston University School of Medicine, and medical director of the Acquired Brain Injury Program at Braintree Rehabilitation Hospital.

The mean score on the DRS improved from approximately 22 to about 17 for those on amantadine, and from 22 to just under 19 for those on placebo. The relative gains, while modest, were nonetheless significant for this short time period. Amantadine was also associated with superior improvement on the CRS-R, with those on active treatment more commonly displaying behaviors indicative of a higher level of consciousness, Dr. Katz said, including consistent command-following, reliable yes/no communication, verbalization, and functional object use.

DR. JOSEPH GIACINO: “I think this trial gives new hope for patients in this population, who in many ways have been marginalized. There is a very nihilistic attitude, and this maybe chips away at that. This trial suggests we can move the needle.”

Amantadine was also safe in this population, with no significant difference between groups in terms of gastrointestinal symptoms, agitation, restlessness, or seizures, he said.

“Even if the only impact of the drug is to accelerate rather than magnify gains, I think that's an important benefit,” Dr. Katz said. “Time is so short in the current reimbursement environment. If the patients manage to get into rehab in the first place, which a lot with disorders of consciousness don't, they [facility administrators] will try to get them out as soon as possible if they aren't making any gains.”

Amantadine's ability to improve consciousness may facilitate other aspects of rehabilitation therapy during that short stay, he suggested.

Now that the consortium of research centers is in place, the next study should take much less time to get going, according to co-leader Joseph Giacino, PhD, director of Rehabilitation Neuropsychology at the Spaulding Rehabilitation Hospital in Boston. “It is absolutely our intent to use this network,” he said, “and we are looking for additional centers to join us. We now have the infrastructure to carry out more work with these patients.”

“There are lot of other questions to ask,” including whether there are factors that predict which patients will have the best response, Dr. Giacino said. “We also don't really know whether the time period we used is a critical window.”

“I think this trial gives new hope for patients in this population, who in many ways have been marginalized. There is a very nihilistic attitude,” he added, “and this maybe chips away at that. This trial suggests we can move the needle.”

EXPERT COMMENTARY

“This was a good, well-conducted study,” according to G. Bryan Young, MD, professor of neurology and critical care medicine at the University of Western Ontario in London, Ontario. “The fact that they did a controlled study is very impressive. What I would like to see next is a study in patients further downstream, who have stabilized.”

Dr. Young also suggested that a study to determine whether amantadine is having a specific effect at the corticothalamic level could be done through neuroimaging.

Amantadine appears safe, he said: “I can't see much downside to using it at standard doses. I don't know that it is going to lead to carte blanche treatment without a larger study. But I am encouraged by it.”

REFERENCE:

Whyte J, Katz D, Eifert B, et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of astudy. Arch Phys Med Rehabil 2005;86(3):453–462.