Clinical trial NCT00970944: Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)
Official title: A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
PHASE3
Conditions: Traumatic Brain Injury
Keywords: Traumatic Brain Injury
Rehabilitation
Disorders of Consciousness
Functional Outcome
Amantadine Hydrochloride
Lead sponsor: JFK Medical Center
Sponsor class: OTHER
Collaborators: name: U.S. Department of Education
First posted: 2009-09-03
Enrollment: 184
Sex: ALL
Minimum age (years): 16
Maximum age (years): 65
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility 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).

Primary outcomes:
measure: Disability Rating Scale: Functional Status
timeFrame: Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6.
Secondary outcomes:
measure: JFK Coma Recovery Scale-Revised: Neurobehavioral Status
timeFrame: Week 4 (primary endpoint); Week 6 (post-washout)
Other outcomes:
Locations:
city: Braintree
country: United States
facility: Braintree Rehabilitation Hospital
state: Massachusetts
city: Jackson
country: United States
facility: Methodist Rehabilitation Center
state: Mississippi
city: New York
country: United States
facility: Columbia University
state: New York
city: Schenectady
country: United States
facility: Sunnyview Rehabilitation Hospital
state: New York
city: Charlotte
country: United States
facility: Charlotte Rehabilitation Center
state: North Carolina
city: Elkins Park
country: United States
facility: Moss Rehabilitation Research Institute
state: Pennsylvania
city: Malvern
country: United States
facility: Bryn Mawr Rehabilitation Hospital
state: Pennsylvania
city: Austin
country: United States
facility: Texas NeuroRehabilitation Center
state: Texas
city: Hvidovre
country: Denmark
facility: Hvidovre University Hospital
city: Bad Aibling
country: Germany
facility: Neurologische Klinik Bad Aibling
city: Neresheim
country: Germany
facility: Fachkrankenhaus Neresheim
Study officials:
affiliation: Spaulding Rehabilitation Hospital
name: Joseph T. Giacino, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Moss Rehabilitation Research Institute
name: John Whyte, MD, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.