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
  Purpose

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

Condition Intervention Phase
Traumatic Brain Injury
Drug: Amantadine Hydrochloride
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury

Resource links provided by NLM:


Further study details as provided by JFK Medical Center:

Primary Outcome Measures:
  • 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).


Secondary Outcome Measures:
  • 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).



Enrollment: 184
Study Start Date: February 2003
Study Completion Date: March 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
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
Placebo Comparator: Placebo Drug: Placebo
Placebo administered twice daily.

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.

  Eligibility

Ages Eligible for Study:   16 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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).
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00970944

Locations
United States, Massachusetts
Braintree Rehabilitation Hospital
Braintree, Massachusetts, United States, 02184
United States, Mississippi
Methodist Rehabilitation Center
Jackson, Mississippi, United States, 39216
United States, New York
Columbia University
New York, New York, United States, 10032
Sunnyview Rehabilitation Hospital
Schenectady, New York, United States, 12308
United States, North Carolina
Charlotte Rehabilitation Center
Charlotte, North Carolina, United States, 28203
United States, Pennsylvania
Moss Rehabilitation Research Institute
Elkins Park, Pennsylvania, United States, 19027
Bryn Mawr Rehabilitation Hospital
Malvern, Pennsylvania, United States, 19355
United States, Texas
Texas NeuroRehabilitation Center
Austin, Texas, United States, 78745
Denmark
Hvidovre University Hospital
Hvidovre, Denmark, DK 2650
Germany
Neurologische Klinik Bad Aibling
Bad Aibling, Germany, 83043
Fachkrankenhaus Neresheim
Neresheim, Germany, 73450
Sponsors and Collaborators
JFK Medical Center
U.S. Department of Education
Investigators
Principal Investigator: Joseph T. Giacino, Ph.D. Spaulding Rehabilitation Hospital
Principal Investigator: John Whyte, MD, Ph.D. Moss Rehabilitation Research Institute
  More Information

No publications provided by JFK Medical Center

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Joseph T Giacino, Director of Rehabilitation Neuropsychology, Spaulding Rehabilitation Hospital
ClinicalTrials.gov Identifier: NCT00970944     History of Changes
Other Study ID Numbers: H133A031713
Study First Received: September 2, 2009
Results First Received: December 12, 2011
Last Updated: September 11, 2012
Health Authority: United States: Institutional Review Board

Keywords provided by JFK Medical Center:
Traumatic Brain Injury
Rehabilitation
Disorders of Consciousness
Functional Outcome
Amantadine Hydrochloride

Additional relevant MeSH terms:
Brain Injuries
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Amantadine
Antiparkinson Agents
Anti-Dyskinesia Agents
Central Nervous System Agents
Therapeutic Uses
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents

ClinicalTrials.gov processed this record on August 19, 2014