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

• ClinicalTrials.gov Identifier: NCT00621751
• Recruitment Status: Completed
• First Posted: February 22, 2008
• Last Update Posted: August 13, 2014
• Sponsor: Atrium Health
• Collaborator: U.S. Department of Education
• Information provided by (Responsible Party): Flora Hammond, Atrium Health

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Traumatic Brain Injury	Drug: Carbamazepine; Drug: Placebo	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 74 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• 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 Start Date: February 2008
• Actual Primary Completion Date: September 2013
• Actual Study Completion Date: October 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: A; Carbamazepine 800 mg daily	Drug: Carbamazepine; 800 mg daily; Other Name: Tegretol
Placebo Comparator: B; Placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures :

1. Neuropsychiatric Inventory Irritability Domain (frequency and severity) completed by observer [ Time Frame: 42 days ]

Secondary Outcome Measures :

1. Neuropsychiatric Inventory Aggression Domain (frequency, severity, and caregiver distress) completed by the observer and person with brain injury [ Time Frame: 42 days ]
2. Neuropsychiatric Inventory Irritability Domain (caregiver distress) completed by the observer and the Neuropsychiatric Inventory Irritability Domain (frequency, severity and distress) completed by person with brain injury [ Time Frame: 42 days ]
3. Global Impression of Change [ Time Frame: 42 days ]
4. STAXI-2 by observer [ Time Frame: 42 days ]
5. STAXI-2 completed by person with brain injury [ Time Frame: 42 days ]
6. Clinicians Global Impression of Change [ Time Frame: 42 days ]
   Study physician's impression of change since study onset

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 75 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 75 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); lactating females; sexually active females who do not agree to use birth control
• 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, ritonavir, 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
• Asian heritage

Contacts and Locations

Locations

United States, North Carolina

Carolinas Rehabilitation

Charlotte, North Carolina, United States, 28203

Sponsors and Collaborators

Atrium Health

U.S. Department of Education

Investigators

• Principal Investigator: Flora M Hammond, MD; Atrium Health

More Information

Additional Information:

Carolinas Rehabilitation 

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.

• Responsible Party: Flora Hammond, PI, Atrium Health
• ClinicalTrials.gov Identifier: NCT00621751 History of Changes
• Other Study ID Numbers: 12-07-02A; NIDRR H133A
• First Posted: February 22, 2008
• Last Update Posted: August 13, 2014
• Last Verified: August 2014

Keywords provided by Flora Hammond, Atrium Health:

Brain Injury; Irritability; Aggression

Additional relevant MeSH terms:

Carbamazepine; Psychotropic Drugs; Brain Injuries; Brain Injuries, Traumatic; Aggression; Wounds and Injuries; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Behavioral Symptoms; Anticonvulsants; Antimanic Agents; Tranquilizing Agents; Central Nervous System Depressants; Physiological Effects of Drugs; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Sodium Channel Blockers; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action; Cytochrome P-450 CYP3A Inducers; Cytochrome P-450 Enzyme Inducers