Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)
Condition: Traumatic Brain Injury
MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      This is a controlled trial of amantadine to improve level of function following severe
      traumatic brain injury.

      The purpose of this study is:

        1. To determine whether amantadine hydrochloride, given in a dose of 200-400 mg, improves
           functional recovery from the vegetative and minimally conscious states

        2. To determine whether amantadine-related gains in function persist following drug
           discontinuation

        3. To determine the safety profile of amantadine in patients with disorders of
           consciousness
    

Detailed description: 
      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 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.

      In the proposed study, 7 facilities (including two with TBI Model Systems designations) that
      participated in a multi-center research network called the Consciousness Consortium, join
      with four additional brain injury rehabilitation centers (two in the U.S. and two in Europe)
      and a Data Coordinating Center at Columbia University, to conduct a prospective double blind
      randomized controlled trial of amantadine hydrochloride. 184 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 and 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.
    

Intervention name(s): Amantadine Hydrochloride; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 184 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) 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.; Placebo administered twice daily.
Other intervention name(s): Symmetrel
Intervention MeSH terms: Amantadine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Traumatic Brain Injury; Rehabilitation; Disorders of Consciousness; Functional Outcome; Amantadine Hydrochloride