Amantadine for the Treatment of Traumatic Brain Injury Irritability and Aggression: A Multi-site Study

Not Applicable

Completed

Conditions: Aggression
Brain Injury

Interventions: Drug: Placebo
Drug: Amantadine Hydrochloride

Registration Number: NCT00779324

Lead Sponsor: Wake Forest University Health Sciences

Brief Summary: The purpose of this study is to study the effect of amantadine on irritability and aggression caused by traumatic brain injury.

Detailed Description: PURPOSE OF PROJECT: To study the effect of amantadine 100 mg administered twice daily compared to placebo on irritability from baseline to treatment Day 28.

SUMMARY OF PROJECT: It is anticipated that 168 subjects with 168 corresponding subject informants will be recruited for the study. Carolinas Rehabilitation, the lead center, and 5 collaborating centers will enroll approximately 28 subjects each.

Subjects will be recruited primarily from the clinics. Also, letters will be sent to patients in our data base. If the first encounter with research personnel is by telephone, the research assistant will obtain verbal (telephone) consent from the subject's informant for the Neuropsychiatric Inventory (NPI) for subject irritability. The score on this questionnaire must be ≥ 6 for qualification. This allows pre-screening to take place and avoid an unnecessary clinic visit.

Subjects who consent and qualify will be randomized in a 1:1 ratio, amantadine to placebo. Stratification to randomization group will occur based on the presence of depression defined by a Beck's Depression Inventory-II (BDI-II) score ≥ 13. Randomized subjects will receive amantadine or placebo 100 mg twice daily every morning and 12 Noon. There will be 4 clinic visits. Visits will occur at baseline, for consenting and screening, day 28, day 60 and day 90. At all 4 clinic visits, both the subject and the informant will be given questionnaires regarding the subject's behavior and mood. Follow up phone calls will occur each week that the subject is not seen in the clinic until the end of the study. Follow up phone calls will assess for study medication compliance, adverse events and concomitant medication changes. Day 60 ends the period of the Randomized Clinical Trial phase of the study and the subjects will begin the 1 month continuation phase of the study when all participants receive active amantadine.

The following questionnaires will be used as measures of irritability for the subject and the informant: Neuropsychiatric Inventory (NPI), State Trait Anger Expression Inventory (STAXI-2), and Global Impression of Change.

The following questionnaires will be dispensed to the subject only: Short Form -12, Satisfaction With Life Scale, Patient Health Questionnaire, Beck Depression Inventory, Brief Symptom Inventory, Family Assessment Device, Fatigue Impact Scale, and tests of cognitive function. The Glasgow Outcome Score-Extended will be completed by the research assistant using information obtained primarily from the informant.

The Investigator will complete the Clinical Global Impression of change at Visits 1, 2, 3, and 4.

History and Physical Exam, creatinine level (kidney function) will be obtained for safety and tolerability. Serum pregnancy tests will be drawn at screening for females of childbearing potential.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 168

Inclusion Criteria

Closed head injury (defined as impaired brain function resulting from externally inflicted trauma without penetrating injury) at least 6 months prior to enrollment
Irritability that is either new or worse than the level of irritability before the traumatic brain injury, by report of the Observer or person with TBI
Age at time of enrollment: 16 to 75 years
Voluntary informed consent and authorization of participant and informant
Subject and informant willing to comply with the protocol
Informant-rated NPI Irritability Domain score 6 or greater (moderate-to-severe irritability)
Medically and neurologically stable during the month prior to enrollment
If taking antidepressant, anxiolytic, hypnotic, or stimulant medications, no change anticipated in these medications during the month prior to enrollment or during the 90-day participation
No change in therapies or medications planned during the 90-day participation
No surgeries planned during the 90-day participation
Vision, hearing, speech, motor function, and comprehension sufficient to complete interviews
Observer (e.g.: family member, close friend, employer) with whom subject interacts sufficiently to observe occurrences of irritability. The observer interacts with the participant for a period long enough and of a nature to be able to judge the participant's irritability. The interactions would need to be adequate to judge observer distress over the irritability, severity of irritability and frequency of irritability on the following scale: < once weekly; once per week; several times per week, but not every day; essentially continuous.

Exclusion Criteria

Previous participation in the Carolinas TBI Model System amantadine irritability study
Ingestion of amantadine hydrochloride during the month prior to enrollment
Potential subject without a reliable informant
Penetrating head injury as defined by head injury due to gunshot, projectile or foreign object
Injury < 6 months prior to enrollment
Inability to interact sufficiently for communication with caregiver
Clinical signs of active infection
Diagnosis of seizure in the month prior to enrollment
Creatinine clearance <60 mL/min
Pregnancy (Beta-HCG + females of child-bearing potential) and lactating females
Concurrent use of first generation neuroleptic agents or phenelzine
History of schizophrenia or psychosis
Active concern of schizophrenia or psychosis
Diagnosis of progressive or additional neurologic disease that affects brain function, except stroke that occurs at th same time as the TBI
Previous allergy or adverse reaction to amantadine hydrochloride

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo tablets
Amantadine	Amantadine Hydrochloride	Amantadine 100 mg every morning and Noon

Primary Outcome Measures

Name	Time	Method
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Observer Day 28	Day 28	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

Secondary Outcome Measures

Name	Time	Method
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 28	Day 28	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Participants Day 60	Day 60	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observer Day 28	Day 28	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 28	Day 28	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Clinical Global Impressions Day 60	60 days	Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.
Clinical Global Impressions Day 28	28 Days	Study physician's impression of change since study onset. Clinicians Global Impressions of Change (CGI) is a sensitive, standardized tool to assess psychopharmacologic treatment response completed by the study physician. The Global Improvement (GI) CGI subscale documented the clinician's impression of change. The GI uses a 7-point scale to assess beneficial and negative effects. Low GI values (1 -3) indicate improvement; higher values (4-7) represent worsening.
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory Irritability Domain Rated by Observers Day 60	60 days	As described above for the primary measure, assessed as a secondary measure at Day 60. The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Proportion of Participants With >2-point Increase on Neuropsychiatric Inventory - Irritability Domain Rated by Participant Day 60	Day 60	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).
Change in Neuropsychiatric Inventory - Irritability Domain Assessed by Observers Day 60	Day 60	The Neuropsychiatric Inventory (NPI) is a 40-item rating scale developed to assess 12 behavioral domains. Only the NPI-Irritability (NPI-I) domain was used for this study. NPI-I measures irritability with items including: bad temper, rapid mood changes, sudden anger, impatience, crankiness, argumentative. The rater selects the frequency (1-3) and severity (1-4) of the most problematic of these behavioral aspect(s) over the preceding month. The NPI score is the product of the frequency and severity for the NPI most problematic item score. The primary outcome measure was the proportion of participants with greater than two-point increase on the Neuropsychiatric Inventory Irritability domain. The total range is 1 (least irritability) - 12 (worst irritability).

Trial Locations

Locations (6): Indiana University and the Rehabilitation Hospital of Indiana
🇺🇸
Indianapolis, Indiana, United States
Carolinas Rehabilitation
🇺🇸
Charlotte, North Carolina, United States
The Ohio State University
🇺🇸
Columbus, Ohio, United States
Spaulding Rehabilitation
🇺🇸
Boston, Massachusetts, United States
TIRR Memorial Herman
🇺🇸
Houston, Texas, United States
University of Washington
🇺🇸
Seattle, Washington, United States

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