Carbamazepine for the Treatment of Chronic Post-Traumatic Brain Injury Irritability and Aggression

Condition(s) targeted: Traumatic Brain Injury

Intervention: Carbamazepine (Drug); Placebo (Drug)

Phase: N/A

Status: Recruiting

Sponsored by: Carolinas Healthcare System

Overall contact:
Marybeth Whiney, R.N., Phone: 704-355-1409, Email: marybeth.whitney@carolinashealthcare.org

The purpose of this study is to determine if carbamazepine reduces irritability and aggression among individuals with traumatic brain injury

Official title: Carbamazepine for the Treatment of Chronic Post-Traumatic Brain Injury Irritability and Aggression: A 42-Day, Single-Site, Forced-Titration, Parallel Group, Randomized, Double-Blind, Placebo Controlled Trial

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Efficacy Study

Primary outcome:

Neuropsychiatric Inventory Irritability Domain (frequency and severity) completed by caregiver

Clinicians Global Impression of Change

Secondary outcome:

Neuropsychiatric Inventory Aggression Domain (frequency, severity, and caregiver distress) completed by the caregiver

Neuropsychiatric Inventory Irritability Domain (caregiver distress) completed by the caregiver

Global Impression of Change

STAXI-2 by caregiver

STAXI-2 completed by person with brain injury

Detailed description: It is anticipated that 74 subjects with 74 corresponding subject informants will be recruited at Carolinas Rehabilitation. Subjects will be recruited from the clinic at Carolinas Rehabilitation. Subjects will also be referred by psychiatrists at North Carolina Neuropsychiatry.

Subjects who consent and qualify will be randomized in a 1: 1 ratio to Tegretol® or placebo. Stratification to randomization group will occur based on the presence of depression defined by a BDI-II score ≥ 13. Subjects randomized to active drug will be titrated up in dose, as tolerated, over a period of 3 weeks. Starting dose is 200mg twice daily to 200mg three times daily to 200mg, 2 tabs, twice daily. There will be 3 clinic visits. Visits will occur at baseline for consenting and screening, day 28, and day 42. 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 42 ends the period of the Randomized Clinical Trial phase of the study and the subjects will begin the 1 week of taper of Tegretol® at 400mg daily and then stop drug. A safety phone call will be made at day 49.

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 3 questionnaires will be dispensed to the subject only: Beck Depression Inventory, Brief Symptom Inventory, and Fatigue Impact Scale. The Investigator will complete the Clinical Global Impression of change at Visits 2 and 3.

History and Physical Exam, hematology, chemistry, including renal and liver function studies will be obtained for safety and tolerability. Serum pregnancy tests will be drawn at screening for females of childbearing potential. Carbamazepine levels will be drawn at visits 2 and 3.

Minimum age: 16 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

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

- Age at time of enrollment: 16 to 70 years

- Voluntary informed consent of patient and informant

- Subject and informant willing to comply with the protocol

- Informant-rated NPI Irritability Domain score 6 or greater to include only

moderate-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 No change in therapies or medications planned during the 42-day participation No surgeries planned during the 42-day participation Vision, hearing, speech, motor function, and comprehension sufficient for compliance with all testing procedures and assessments

- Informant (e. g. family member or close friend) with daily interaction in order to

observe occurrences of irritability

Exclusion Criteria:

- Potential subject without a reliable informant

- Penetrating head injury

- Injury < 6 months prior to enrollment

- Ingestion of CBZ during the month prior to enrollment

- Inability to interact sufficiently for communication with caregiver

- Acute and rehabilitation records unavailable or incomplete

- DSM-IV diagnosis of schizophrenia or psychosis

- Diagnosis of progressive or additional neurologic disease

- Clinical signs of active infection

- Creatinine clearance <60 mL/min

- Liver function tests > 2x normal values

- Pregnancy (Beta-HCG + females of child-bearing potential) and lactating females

- Hormonal birth control as only means of birth control if sexually active and of child

bearing age potential due to CBZ effect of lowering hormone levels, and potentially effectiveness

- Concurrent use of the following medicines due to potential for drug interaction:

macrolides, rifabutin, doxycycline, nicoumalone, warfarin, fluoxetine, fluvoxamine, viloxazine, nefazodone, tricyclic and tetracyclic antidepressants, clobazam, clonazepam, lamotrigine, phenytoin, sodium valproate, tigabine and topiramate, phenobarbitone, primidone, chloroquine and mefloquine, antipsychotics, indinavir, nelfinavir, saquinavir, ritonivir, diltiazem, verapamil, felodipine, isradipine, nicardipine, nifedipine, cimetidine, cyclosporins, corticosteroids, gestrinone and toremifene, danazol, tibolone

- Suicidal ideation

- Concurrent use of Monoamine Oxidase Inhibitors (MAOIs) or ingestion of MOAI within 2

weeks before starting study

- Hypersensitivity/allergy to CBZ, any of the ingredients in CBZ, or any structurally

related drugs (e. g. the tricyclic antidepressants)

- History of liver failure or hepatitis

- History of renal failure

- History atrio-ventricular (AV) conduction abnormalities unless paced

- History of bone marrow depression

- History of porphyria

Marybeth Whiney, R.N., Phone: 704-355-1409, Email: marybeth.whitney@carolinashealthcare.org

Carolinas Rehabilitation, Charlotte, North Carolina 28203, United States; Recruiting
Marybeth Whitney, R.N., Phone: 704-355-1409, Email: marybeth.whitney@carolinashealthcare.org
Flora Hammond, M.D., Phone: 704-355-9330, Email: flora.hammond@carolinashealthcare.org
Flora M Hammond, M.D, Principal Investigator
Timothy P Young, M.D., Sub-Investigator
Lori M Grafton, M.D., Sub-Investigator

Related publications:

Azouvi P, Jokic C, Attal N, Denys P, Markabi S, Bussel B. Carbamazepine in agitation and aggressive behaviour following severe closed-head injury: results of an open trial. Brain Inj. 1999 Oct;13(10):797-804.

Chatham-Showalter PE. Carbamazepine for combativeness in acute traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1996 Winter;8(1):96-9.

Lewin J, Sumners D. Successful treatment of episodic dyscontrol with carbamazepine. Br J Psychiatry. 1992 Aug;161:261-2.

Wroblewski BA, Joseph AB, Kupfer J, Kalliel K. Effectiveness of valproic acid on destructive and aggressive behaviours in patients with acquired brain injury. Brain Inj. 1997 Jan;11(1):37-47.

Starting date: February 2008
Ending date: November 2012
Last updated: October 23, 2008