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

Traumatic Brain Injury Clinical Trial

Official title:

A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00970944
• Other study ID #: H133A031713
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: September 2, 2009
• Last updated: September 11, 2012
• Start date: February 2003
• Est. completion date: March 2010

Study information

• Verified date: September 2012
• Source: JFK Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 184
• Est. completion date: March 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 16 Years to 65 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Brain Injuries
• Traumatic Brain Injury

Intervention

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.
• Placebo
Placebo administered twice daily.

Locations

Country	Name	City	State
Denmark	Hvidovre University Hospital	Hvidovre
Germany	Neurologische Klinik Bad Aibling	Bad Aibling
Germany	Fachkrankenhaus Neresheim	Neresheim
United States	Texas NeuroRehabilitation Center	Austin	Texas
United States	Braintree Rehabilitation Hospital	Braintree	Massachusetts
United States	Charlotte Rehabilitation Center	Charlotte	North Carolina
United States	Moss Rehabilitation Research Institute	Elkins Park	Pennsylvania
United States	Methodist Rehabilitation Center	Jackson	Mississippi
United States	Bryn Mawr Rehabilitation Hospital	Malvern	Pennsylvania
United States	Columbia University	New York	New York
United States	Sunnyview Rehabilitation Hospital	Schenectady	New York

Sponsors (2)

Lead Sponsor	Collaborator
JFK Medical Center	U.S. Department of Education

Countries where clinical trial is conducted

United States,  Denmark,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disability Rating Scale: Functional Status	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).	Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6.	No
Secondary	JFK Coma Recovery Scale-Revised: Neurobehavioral Status	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).	Week 4 (primary endpoint); Week 6 (post-washout)	No