Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)

This study has been completed.
Sponsor:
Collaborator:
U.S. Department of Education
Information provided by (Responsible Party):
Joseph T Giacino, Spaulding Rehabilitation Hospital
ClinicalTrials.gov Identifier:
NCT00970944
First received: September 2, 2009
Last updated: September 11, 2012
Last verified: September 2012

September 2, 2009
September 11, 2012
February 2003
March 2010   (final data collection date for primary outcome measure)
Disability Rating Scale: Functional Status [ Time Frame: Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6. ] [ Designated as safety issue: No ]
Measure of function after traumatic brain injury (TBI) intended to measure function from "coma to community." Minimum score= 0; Maximum score= 29 (High scores are indicative of greater degree of disability).
Disability Rating Scale: Functional Status [ Time Frame: Randomization, weekly for 6 consecutive weeks. ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT00970944 on ClinicalTrials.gov Archive Site
JFK Coma Recovery Scale-Revised: Neurobehavioral Status [ Time Frame: Week 4 (primary endpoint); Week 6 (post-washout) ] [ Designated as safety issue: No ]

Measure of neurobehavioral function and clinical change for individuals with severe alterations of consciousness.

Minimum score= 0; Maximum score= 23 (Higher scores are indicative of a higher-level of neurobehavioral function).

JFK Coma Recovery Scale-Revised: Neurobehavioral Status [ Time Frame: Randomization, week 4, week 6. ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)
A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury

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

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.

Interventional
Phase 2
Phase 3
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Traumatic Brain Injury
  • Drug: 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) 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.
    Other Name: Symmetrel
  • Drug: Placebo
    Placebo administered twice daily.
  • Experimental: Amantadine HCL
    100mg BID administered for 2 weeks, then increased to 150mg BID in week 3 if change on primary outcome measure (ie Disability Rating Scale, DRS) was less than 2 points after week 2. If change in DRS score remained less than 2 points after week 3, dose was increased to 200mg BID in week 4.
    Intervention: Drug: Amantadine Hydrochloride
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo
Giacino JT, Whyte J, Bagiella E, Kalmar K, Childs N, Khademi A, Eifert B, Long D, Katz DI, Cho S, Yablon SA, Luther M, Hammond FM, Nordenbo A, Novak P, Mercer W, Maurer-Karattup P, Sherer M. Placebo-controlled trial of amantadine for severe traumatic brain injury. N Engl J Med. 2012 Mar 1;366(9):819-26. doi: 10.1056/NEJMoa1102609.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
184
March 2010
March 2010   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • Individuals between ages 16 and 65 with traumatic brain injury as defined by the TBI Model System syllabus (i.e., damage to brain tissue caused by an external mechanical force as evidenced by loss of consciousness or post-traumatic amnesia due to brain trauma, skull fracture, or objective neurological findings that can be reasonably attributed to TBI on physical or mental status examination).
  • Individuals are at least 4 weeks but less than 16 weeks post-injury and have a Disability Rating Scale (DRS) score at enrollment of 12 or greater, and no consistent command following or functional communication (as defined by the JFK.

Exclusion Criteria:

  • Women who are pregnant,
  • Individuals with missile-type penetrating brain injury,
  • Premorbid major CNS/developmental abnormality (e.g., mental retardation, prior significant brain damage, etc.),
  • History of more than 1 seizure (clinical or electrographic, but not including epileptiform or other irritative discharges) in the 4 weeks prior to enrollment (individuals with premorbid idiopathic epilepsy are eligible to enroll under two conditions: a) if their pre-injury seizure frequency was less than once/month and they have had no more than 1 seizure/month since injury and b) if a clear provocation was present that would otherwise disqualify a subject, the subject can be enrolled, since these events would not be considered idiopathic),
  • Prior exposure to AH post-TBI,
  • Unwillingness to discontinue or change confounding psychotropic drugs prior to enrollment, OR
  • Allergy or medical contraindication to AH and significant impairment of renal function (as evidenced by a calculated creatinine clearance of < 60 ml/min).
Both
16 Years to 65 Years
No
Contact information is only displayed when the study is recruiting subjects
United States,   Denmark,   Germany
 
NCT00970944
H133A031713
Yes
Joseph T Giacino, Spaulding Rehabilitation Hospital
JFK Medical Center
U.S. Department of Education
Principal Investigator: Joseph T. Giacino, Ph.D. Spaulding Rehabilitation Hospital
Principal Investigator: John Whyte, MD, Ph.D. Moss Rehabilitation Research Institute
JFK Medical Center
September 2012

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP