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

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.

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