Transcript Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain

Placebo-Controlled Trial of Amantadine
for Severe Traumatic Brain Injury
Topic Discussion
By Ben Selph
Mercer COPHS
April 2, 2012
SEGA Geriatrics
Background Information
 Traumatic brain injury—most common cause of death and
disability in persons between 15 and 30 years of age.
 Severe injuries can result in prolonged disorders of
consciousness.
 Vegetative state for at least 4 weeks: approximately 50% will
regain consciousness by 1 year.
 Outcomes generally more favorable for minimally conscious
state, but approx. 50% remain severely disabled at 1 year.
 No intervention has been shown in rigorous studies to alter
the pace of recovery or improve functional outcomes.
Amantadine hydrochloride
 Mechanism of action: precise mechanism is unknown, but
believed to inhibit NMDA receptors, block reuptake of
dopamine into presynaptic neurons, and increasing dopamine
release from presynaptic nerves.
 Uses: parkinsonism, drug-induced EPS
 Also used to treat influenza: blocks M2 ion channel to prevent viral
uncoating.
 Dosage: generally 100 mg BID, can increase to 300-400 mg/day
in divided doses.
 Common side effects: confusion, dizziness, dry mouth, and
hallucinations, orthostatic hypotension, edema, abnormal dreams.
Study
 Multicenter, prospective, double-blind, randomized, placebo-
controlled trial
 Purpose: determine the effectiveness of amantadine in
promoting recovery from a post-traumatic vegetative or
minimally conscious state.
 Hypothesis: 4 weeks of treatment with amantadine
administered between 4 and 16 weeks after injury in patients
with traumatic disorders of consciousness would improve the
rate of functional recovery during the treatment interval, that
improvement would be maintained 2 weeks after washout, and
that amantadine would be well-tolerated.
Methods
 Eligible patients:
 Age 16-65, had sustained a nonpenetrating traumatic brain injury 4 to
16 weeks before enrollment, and were receiving inpatient rehab at
each site.
 Additionally, either in a vegetative or minimally conscious state
indicated by DRS score greater than 11, and an inability to both
follow commands consistently and to engage in functional
communication assessed by CRS-R
 Exclusion criteria:
 Any disability to CNS that predated the injury, medical instability,
pregnancy, serious renal disease (<60 ml/min), more than one
seizure in previous month, prior treatment with amantadine, and
allergy to amantadine.
Methods cont’d
 Patients randomized to receive either amantadine or visually
identical placebo.
 Procedure: started on 100 mg twice a day for 2 weeks, then
increased to 150 mg twice a day at week 3 and to 200 mg
twice a day at week 4 if no improvement in DRS score by at
least 2 pts.
 List was made of confounding medications, from least to
highest, and physicians requested to follow the order.
 Primary outcome: rate of improvement in the DRS during
the 4 weeks of treatment
 Effects of amantadine assessed by scores on the CRS-R
Results
 Primary outcome: both groups had significant improvement
in the DRS score over the 4-week treatment interval, but the
amantadine group had significantly faster recovery
(difference in slope, -0.24 points per week, P=0.007)
 In both study groups, patients enrolled earlier (28-70 days)
vs. later (71-112 days) after injury and those who were in a
minimally conscious state rather than vegetative at
enrollment had faster recovery rates. But the treatment
effect was consistent across subgroups.
 Advantage of amantadine was most pronounced in patients
who enrolled later as compared with those who enrolled
earlier.
Results
New England Journal of Medicine, 2012; 366:819-826. Supplementary Index.
Results
New England Journal of Medicine, 2012; 366:819-826. Supplementary Index.
Results cont’d
 More patients in the amantadine group than placebo group had
favorable outcomes on the DRS, fewer remained in a vegetative
state after 4 weeks (A-18.6%; P-31.6%), and a greater percentage
had recovery of key behavioral benchmarks on CRS-R.
 Moderately severe to severe (after 4 weeks): A-55.8%; P-51.6%
 During the 2-week washout period, only placebo group had
significant improvement in the DRS score (slope, -0.44 points per
week; p<0.001)
 Behavioral improvements maintained, but pace was slower in the
amantadine group.
 Adverse events—no significant difference in the incidence
between groups.
Discussion
 What does the study show?
 Amantadine, given between 4 and 16 weeks after injury, improved the
rate of functional recovery over the 4-week period of treatment
compared to placebo.
 Both groups saw an improvement in function, but the amantadine
group had a faster rate of recovery.
 Amantadine effect on function was consistent regardless of interval
since injury or whether patient in vegetative state or minimally
conscious.
 Gains in functioning were maintained through washout, but rate
dropped significantly. Scores on DRS largely indistinguishable
between groups after 6 weeks.
 Results match observational reports.
Discussion
 Is the study valid?
 Prospective, double-blind, placebo-controlled
 Multicenter (11 clinical sites in 3 countries)
 *however, predominantly white patients in both groups (84% and 90%)
 Enough patients enrolled (184) to give 80% power to detect
difference in rate of change of DRS score of 0.3 points per
week.
 *Duration was long enough to see a causal relationship, but not
long enough to get a long-term outcome results.
 Patients treated similarly, and results matched objectives.
Discussion
 Limitations
 Selection bias?—patients were admitted to inpatient rehab
centers (influenced by probable further development?)
 Also majority of patients were white, limiting ability to generalize results.
 Findings do not address effects of prolonged treatment on long-
term outcomes. (practical and ethical constraints)
 Hard to determine degree of benefits seen from amantadine
due to other medications used, if amantadine effects were
independent or synergistic with standard treatments.
Conclusion
 While the study shows that amantadine increases the rate of
functional recovery of patients with TBI, it doesn’t show
long-term effects of using amantadine.
 Majority of patients at end of 4 weeks were still in the 14-up
range of DRS (severe-vegetative).
 Unknown whether amantadine improves long-term health
outcomes or just speeds up recovery to the same level.
 Future studies should be done to investigate the appropriate
dose, effective duration to see if it improves long-term
outcomes, and appropriate timing of administration.
Level of Evidence: Class IIa, Level B
References
 Giacino JT, et al. “Placebo-controlled Trial of Amantadine for
Severe Traumatic Brain Injury.” N Engl J Med Mar 1, 2012;
366:819-826.