Placebo-controlled trial of amantadine for severe traumatic brain injury

Joseph T. Giacino, John Whyte, Emilia Bagiella, Kathleen Kalmar, Nancy Childs, Allen Khademi, Bernd Eifert, David Long, Douglas I. Katz, Sooja Cho, Stuart A. Yablon, Marianne Luther, Flora M. Hammond, Annette Nordenbo, Paul Novak, Walt Mercer, Petra Maurer-Karattup, Mark Sherer

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359 Scopus citations


BACKGROUND: Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery. METHODS: We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models. RESULTS: During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P = 0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P = 0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events. CONCLUSIONS: Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (Funded by the National Institute on Disability and Rehabilitation Research; number, NCT00970944.)

Original languageEnglish (US)
Pages (from-to)819-826
Number of pages8
JournalNew England Journal of Medicine
Issue number9
StatePublished - Mar 1 2012

ASJC Scopus subject areas

  • Medicine(all)

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    Giacino, J. T., Whyte, J., Bagiella, E., Kalmar, K., Childs, N., Khademi, A., Eifert, B., Long, D., Katz, D. I., Cho, S., Yablon, S. A., Luther, M., Hammond, F. M., Nordenbo, A., Novak, P., Mercer, W., Maurer-Karattup, P., & Sherer, M. (2012). Placebo-controlled trial of amantadine for severe traumatic brain injury. New England Journal of Medicine, 366(9), 819-826.