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A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury

Abstract:
Severe traumatic brain injury may result in severe disorders of consciousness (DOC), including coma, the vegetative state (VS) and the minimally conscious state (MCS). The longer the duration of impaired consciousness, the worse the ultimate functional prognosis, with only about half of those individuals who remain unconscious for a month post-TBI regaining consciousness within a year. The severe functional disability associated with prolonged DOC places enormous emotional, financial, ethical, and logistical strains on caregivers and major resource demands on society. Numerous treatments have been recommended to hasten the return of consciousness or improve the ultimate level of recovery, including various psychotropic drugs, "coma stimulation" therapy, deep brain electrical stimulation, hyperbaric oxygen therapy, and others. However, none of these treatments has proven efficacy in well-controlled research. The main obstacles to Class I evidence in this area have been the small samples of individuals with serious DOC in individual facilities, the variability of recovery trajectories within this heterogeneous population, and the reluctance to undertake placebo controlled trials.

Over the past 5 years a group of 7 facilities in the United States and Europe that have specialized programs for persons in VS and MCS have assembled a multi-center research network called the Consciousness Consortium. Longitudinal observational research has demonstrated the feasibility of using this consortium to conduct controlled treatment trials. Specifically, we have demonstrated adequate enrollment rates, have identified variables that are predictive of recovery that can be used to stratify treatment assignment and increase statistical power, and have identified amantadine hydrochloride, a dopaminergic agent, as promising for further study.

In the proposed study, these 7 facilities (2 of which are also TBI Model Systems), join with the Mississippi Model System and a Data Coordinating Center at Columbia University, to conduct a prospective double blind randomized controlled trial of amantadine. More than 180 patients who remain in VS or MCS 4 – 16 weeks post-TBI will be randomized in a stratified fashion to 4 weeks of amantadine (200 – 400 mg/day) vs. placebo, followed by a 2-week washout period. The Disability Rating Scale (DRS) will be the primary dependent variable with the Coma Recovery Scale-Revised (CRS-R) serving as a supplementary measure. We hypothesize superior recovery in the amantadine group and maintenance of that advantage after washout. We will also explore whether treatment response differs by time post-injury and by diagnosis (i.e., VS or MCS) at treatment onset, and whether specific outcomes of importance to caregivers are achieved more often in the amantadine group. We have developed plans for intensive education of caregivers and clinicians about this study to address perceived barriers to enrollment and will also use the information gathered during these interactions to develop consumer-oriented dissemination activities. Project outputs and findings will be disseminated to appropriate consumer and professional audiences using a variety of formats. Project outcomes will include: (1) improved family member understanding of DOC which will facilitate improved adjustment and caregiving and (2) clear guidance to clinicians regarding the effectiveness of amantadine for persons with DOC.

Registry Project Number: 493
Lead Investigator: Giacino, J
Lead Center for Project: JFK Johnson Rehabilitation Institute
Collaborating Investigators: Whyte, J, Kalmar, K, Yablon, S, Sherer, M, Bagiella, E, Murathe, S, Singh, V, Long, D, Murphy, E, Merges, B, Eifert, B, Mauer, P, Katz, D, Edelstein, M, Novak, P, Wright, L, Van Wie, S, Childs, N, Mercer, W
Collaborating Institutions: Moss Rehabilitation Research Institute, Methodist Rehabilitation Center
Keywords: rehabilitation, outcome, traumatic brain injury
Expected Completion: 12/31/2008
Type: National
Status of Project: Latest Information Shown

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