Placebo-controlled trial of amantadine for severe TBI

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Clinical Question

In patients with disorders of consciousness after traumatic brain injury, does amantadine pharmacotherapy facilitate functional recovery during acute inpatient rehabilitation?


https://www.ncbi.nlm.nih.gov/pubmed/22375973

Bottom Line

Amantadine accelerates functional recovery during acute inpatient rehabilitation for traumatic brain injury patients with disorders of consciousness.

Major Points

Traumatic brain injury (TBI) is a common cause of death and disability. Severe TBI may result in disorders of consciousness including vegetative state, in which patients have a sleep wake cycle but no awareness or purposeful activity, and minimally conscious state, in which patients show definite but minimal evidence of conscious awareness. Several medications are used off label to improve arousal in these patients, but none have been extensively studied for their ability to improve functional outcome in these patients. Amantadine hydrochloride is one of the most commonly used neurostimulants for these patients while undergoing inpatient rehabilitation. Two preliminary randomized trials supported the effectiveness of amantadine [1][2]. A 1998 observational pilot study investigated the effect of multiple psychotropic medications on the rate of recovery in patients in vegetative and minimally conscious states using the Disability Rating Scale (DRS) [3]. The DRS measures functional outcomes specific to traumatic brain injury and is scored on a scale of 0 to 29, with lower scores indicating higher level of function. The pilot study showed patients who received amantadine compared to those who did not had better DRS scores at 16 weeks after injury. The results established the basis for this larger scale multicenter, prospective, double-blind, randomized, placebo-controlled trial.

This study recruited 184 TBI patients with disorders of consciousness to receive four weeks of amantadine therapy or placebo during acute inpatient rehabilitation. The primary outcome was rate of improvement in DRS score during the four weeks of treatment. Secondary outcome assessed the durability of the treatment by comparing the slope of change in DRS score during the washout period from week four to week six. DRS scores were taken at baseline and weekly through week six.

Baseline characteristics were similar for the 87 patients randomized to amantadine and 97 patients randomized to placebo: percent male sex (74% vs. 71%); median time from injury to randomization (48 vs. 47 days); DRS score (21.8 vs. 22.2); and percent in minimally conscious state vs percent in vegetative state (64/36 vs. 66/34). Results showed that patients on amantadine had a significantly higher rate of improvement in DRS scores during the four-week treatment interval (difference in slope of -0.24 points per week, P=0.007). However, during the wash-out period, the amantadine group lacked significant improvement while the placebo group continued to improve their DRS scores (between-group difference in slope of 0.30 points, P=0.02). At the end of the 6 weeks, both groups had similar improvements in DRS scores.

Guidelines

No guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, prospective, double-blind, randomized, placebo-controlled
  • N=184
    • Amantadine arm (n=87)
    • Placebo arm (n=97)
  • Setting: 11 inpatient rehabilitation centers in the United States, Canada, and Denmark
  • Enrollment: not stated
  • Mean follow-up: 6 weeks
  • Analysis: Intention-to-treat
  • Primary outcome: rate of improvement in the DRS score during the 4 weeks of treatment

Population

Inclusion Criteria

  • 16 to 65 years of age with nonpenetrating traumatic brain injury
  • Injury occurred 4 to 16 weeks before enrollment
  • Currently undergoing usual inpatient rehabilitation
  • Vegetative state or minimally conscious state (indicated by DRS score >11)
  • Inability to follow commands consistently
  • Inability to engage in functional communication

Exclusion Criteria

  • Any premorbid central nervous system disability
  • Medical instability
  • Pregnancy
  • Serious renal disease
  • More than one seizure in previous month
  • Prior treatment with amantadine
  • Allergy to amantadine

Baseline Characteristics

Comparisons are amantadine vs. placebo groups

  • Mean age (years): 35.5 vs. 37.2
  • Male sex (%): 74 vs. 71
  • White Race (%): 84 vs. 90
  • Score on DRS: 21.8 vs. 22.2
  • Score on CRS-R: 9.6 vs. 9.2
  • Minimally conscious state (%): 64 vs. 66
  • Vegetative state (%): 36 vs. 34

Interventions

  • Patients were stratified for diagnosis (vegetative state vs. minimally conscious state) and interval between injury and enrollment (28 to 70 days vs. 71 to 112 days) then randomly assigned to amantadine or placebo group
  • Amantadine group received amantadine 100mg twice daily starting the day after randomization for 14 days; dose increased to 150mg twice daily at week 3 and to 200mg twice daily at week 4 if DRS score had not improved by at least 2 points from baseline
  • Placebo group received a visually identical placebo with the same tapering schedule
  • Amantadine and placebo were discontinued on a 2-3 day taper
  • Follow-up continued through week 6

Outcomes

Comparisons are amantadine therapy vs. placebo.

Primary Outcomes

Difference in slope (rate of improvement in DRS score) during the 4 weeks of treatment
-0.24 points per week (P=0.007)

Secondary Outcomes

Difference in slope during the last 2 weeks of the study (post-treatment)
0.30 points per week (P=0.02)

Subgroup Analysis

Effect size for patients enrolled earlier vs. those enrolled later
-0.19 vs. -0.40
Effect size for patients in vegetative state vs patients in minimally conscious state
-0.25 vs. -0.24

Adverse Events

Adverse events included: seizure, changes on electroencephalography, nausea, vomiting, constipation, diarrhea, other gastrointestinal event, elevated liver-function tests, restlessness, agitation, insomnia, involuntary muscle contractions, hypertonia or spasticity, other motor problems, rash, congestive heart failure.

There were no significant differences in adverse events between the study groups.

Criticisms

  • Patients were recruited from inpatient rehabilitation, meaning they were thought to have potential for functional improvement
  • Predominantly white patient population which could limit generalizability
  • Treatment duration was limited to 4 weeks and follow-up was limited to 6 weeks

Funding

All financial support for this study was provided by The National Institute on Disability and Rehabilitation Research.

Further Reading

  1. ↑ Meythaler JM et al. Amantadine to improve neurorecovery in traumatic brain injury-associated diffuse axonal injury: a pilot double-blind randomized trial. J Head Trauma Rehabil 2002. 17:300-13.
  2. ↑ Schneider WN et al. Cognitive and behavioural efficacy of amantadine in acute traumatic brain injury: an initial double-blind placebo-controlled study. Brain Inj 1999. 13:863-72.
  3. ↑ Whyte J et al. Predictors of outcome in prolonged posttraumatic disorders of consciousness and assessment of medication effects: A multicenter study. Arch Phys Med Rehabil 2005. 86:453-62.
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