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”

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

Study Type: Interventional

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

Study Primary Completion Date: November 2012

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.

Intervention(s) in this Clinical Trial

• Drug: Carbamazepine
  • 800 mg daily
• Drug: Placebo
  • Placebo

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: A
  • Carbamazepine 800 mg daily
• Placebo Comparator: B
  • Placebo

Primary Measures

• Neuropsychiatric Inventory Irritability Domain (frequency and severity) completed by caregiver
  • Time Frame: 42 days
    Safety Issue?: No
• Clinicians Global Impression of Change
  • Time Frame: 42 days
    Safety Issue?: No

Secondary Measures

• Neuropsychiatric Inventory Aggression Domain (frequency, severity, and caregiver distress) completed by the caregiver
  • Time Frame: 42 days
    Safety Issue?: No
• Neuropsychiatric Inventory Irritability Domain (caregiver distress) completed by the caregiver
  • Time Frame: 42 days
    Safety Issue?: No
• Global Impression of Change
  • Time Frame: 42 days
    Safety Issue?: No
• STAXI-2 by caregiver
  • Time Frame: 42 days
    Safety Issue?: No
• STAXI-2 completed by person with brain injury
  • Time Frame: 42 days
    Safety Issue?: No

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

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 16 Years

Maximum Age for this Clinical Trial: 70 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Carolinas Healthcare System

Overall Clinical Trial Officials and Contacts

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

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00621751

Study ID Number: 12-07-02A

ClinicalTrials.gov Identifier: NCT00621751

Health Authority: United States: Institutional Review Board