Traumatic Brain InjuryPhase 2/3NCT00970944
Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI)
A Phase 2/3 study testing Amantadine Hydrochloride in people with Traumatic Brain Injury, run by JFK Medical Center at 11 sites in 3 countries.
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. Read more about this study
- Who is it for?
- Ages 16 to 65 years
- Conditions the study is for
- Traumatic Brain Injury
- What is being tested?
- Amantadine Hydrochloride
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 184 participants
- Where
- 11 sitesin 3 countries
- Study dates
- Feb 2003to Mar 2010
- Phase
- Phase 2/3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 16 to 65 years
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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).
Trial locations and contacts
11 sites in 3 countries.
11 sites in 3 countries
United States8 sites
Texas NeuroRehabilitation Center
Austin, Texas, 78745
Braintree Rehabilitation Hospital
Braintree, Massachusetts, 02184
Charlotte Rehabilitation Center
Charlotte, North Carolina, 28203
Moss Rehabilitation Research Institute
Elkins Park, Pennsylvania, 19027
Methodist Rehabilitation Center
Jackson, Mississippi, 39216
Bryn Mawr Rehabilitation Hospital
Malvern, Pennsylvania, 19355
Columbia University
New York, New York, 10032
Sunnyview Rehabilitation Hospital
Schenectady, New York, 12308
Germany2 sites
Neurologische Klinik Bad Aibling
Bad Aibling, 83043
Fachkrankenhaus Neresheim
Neresheim, 73450
About this study
Official title: 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:
- To determine whether amantadine hydrochloride, given in a dose of 200-400 mg, improves functional recovery from the vegetative and minimally conscious states
- To determine whether amantadine-related gains in function persist following drug discontinuation
- To determine the safety profile of amantadine in patients with disorders of consciousness
Read the 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.
- Conditions
- Traumatic Brain Injury
- Being tested
- Amantadine Hydrochloride, Placebo
- Keywords
- Traumatic Brain Injury, Rehabilitation, Disorders of Consciousness, Functional Outcome, Amantadine Hydrochloride
- Medical subject headings
- Brain Injuries, Traumatic, Consciousness Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Amantadine HydrochlorideDrug
Also called Symmetrel
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.
PlaceboDrug
Placebo administered twice daily.
| Study group | Role | What they receive |
|---|---|---|
| Amantadine HCL | Experimental | 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. Receives: Drug: Amantadine Hydrochloride |
| Placebo | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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).
Measured: Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6.
Secondary outcomes (1)
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).
Measured: Week 4 (primary endpoint); Week 6 (post-washout)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted3 Sep 2009 (estimated)
- Study startFeb 2003
- Primary completionMar 2010
- Study completionMar 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Traumatic Brain InjuryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2/3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 184 participants (actual)
Sponsor and investigators
- Lead sponsor
- JFK Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- U.S. Department of Education
- Responsible party
- Principal investigator, Joseph T Giacino, Spaulding Rehabilitation Hospital
- Investigators
- Joseph T. Giacino, Ph.D., Principal investigator, Spaulding Rehabilitation HospitalJohn Whyte, MD, Ph.D., Principal investigator, Moss Rehabilitation Research Institute
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00970944
- Sponsor's protocol ID
- H133A031713
- Status last verified
- Sep 2012
- First submitted
- 2 Sep 2009
- Last updated
- 24 Sep 2012
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 22375973
Study at a glance
From the registry record, last updated by the sponsor on 24 Sep 2012. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multicenter Prospective Randomized Controlled Trial of the Effectiveness of Amantadine Hydrochloride in Promoting Recovery of Function Following Severe Traumatic Brain Injury
- ClinicalTrials.gov ID
- NCT00970944
- Acronym / sponsor ID
- H133A031713
- Conditions
- Traumatic Brain Injury
- Keywords
- Traumatic Brain Injury, Rehabilitation, Disorders of Consciousness, Functional Outcome, Amantadine Hydrochloride
- Phase
- Phase 2/3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 184 participants (actual)
- Lead sponsor
- JFK Medical CenterUniversity, hospital or other
- Collaborators
- U.S. Department of Education
- Study start
- Feb 2003
- Primary completion
- Mar 2010 (actual)
- Study completion
- Mar 2010 (actual)
- First posted
- 3 Sep 2009 (estimated)
- Results
- Posted 24 Sep 2012
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a controlled trial of amantadine to improve level of function following severe traumatic brain injury.
The purpose of this study is:
- To determine whether amantadine hydrochloride, given in a dose of 200-400 mg, improves functional recovery from the vegetative and minimally conscious states
- To determine whether amantadine-related gains in function persist following drug discontinuation
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Amantadine HCL | Experimental | Drug: Amantadine Hydrochloride100mg 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. |
| Placebo | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 16 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (2 listed)
- 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.
Key exclusion criteria (7 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Amantadine HydrochlorideAlso: Symmetrel184 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. | Drug | Amantadine HCL |
| PlaceboPlacebo administered twice daily. | Drug | Placebo |
Primary outcome
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.
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).
1 secondary outcome
JFK Coma Recovery Scale-Revised: Neurobehavioral Status
Time frame: Week 4 (primary endpoint); Week 6 (post-washout)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 24 Sep 2012.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 22375973Giacino 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Joseph T. Giacino, Ph.D. principal investigator
Spaulding Rehabilitation Hospital
John Whyte, MD, Ph.D. principal investigator
Moss Rehabilitation Research Institute
11 sites in 3 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2/3 study testing Amantadine Hydrochloride in people with Traumatic Brain Injury, run by JFK Medical Center at 11 sites in 3 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 24 Sep 2012. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in United States, Germany, Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 24 Sep 2012). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the 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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00970944, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 24 Sep 2012.