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

Primary Purpose

Traumatic Brain Injury

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Carbamazepine
Placebo
Sponsored by
Wake Forest University Health Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Traumatic Brain Injury focused on measuring Brain Injury, Irritability, Aggression

Eligibility Criteria

16 Years - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 carbamazepine during the month prior to enrollment
  • Inability to interact sufficiently for communication with caregiver
  • Acute and rehabilitation records unavailable or incomplete
  • Diagnostic and Statistical Manual of Mental Disorders-IV (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; 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 carbamazepine 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 or ingestion of within 2 weeks before starting study
  • Hypersensitivity/allergy to carbamazepine, any of the ingredients in carbamazepine, or any structurally related drugs (e.g. the tricyclic antidepressants)
  • History of liver failure or hepatitis
  • History of renal failure
  • History atrio-ventricular conduction abnormalities unless paced
  • History of bone marrow depression
  • History of porphyria
  • Asian heritage

Sites / Locations

  • Carolinas Rehabilitation

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Carbamazepine

Placebo

Arm Description

Carbamazepine 800 mg daily

Placebo

Outcomes

Primary Outcome Measures

Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure -- Observer
Neuropsychiatry Inventory-Irritability (NPI-I) & Aggression domains (NPI-A): NPI is a 40-item assessment of 12 behavioral domains (NPI-I & NPI-A domains used in this study). The most problematic aspect of each domain is graded for severity (1=mild, to 3=severe) and frequency (1-4 with 4 representing highest frequency); the domain scores (0-12) are the product of severity and frequency. To best reflect treatment target intent and meet parametric statistical method criteria, the primary outcome was a composite measure of observer-rated NPI-I & -A domains transformed to a Rasch logit scale running from 0 (best) to 100 (worse) units (i.e., observer-rated NPI-I/A Rasch construct scores). Mean day-42 observer-rated NPI-I/A Rasch construct scores were compared between placebo vs. carbamazepine using ANCOVA with baseline score as covariate.

Secondary Outcome Measures

Proportion of Participants With Minimal Clinically Important Difference -- Observer Rating
Proportion of participants with Minimal Clinically Important Difference (MCID) on Neuropsychiatric Inventory Irritability-Aggression Composite Measure completed by Observer. Specifically, the proportion of participants that experienced a decrease of > 1 (MCID) in the NPI-I/A Rasch construct score (i.e., participants that are considered to have meaningful reduction in irritability/aggression) from baseline to day-42 between the groups using a chi-square test. MCID was defined as 0.5 times the standard deviation of baseline scores.
Global Impression of Change -- Observer
Global Impression of Change (GIC) is a 5-item Likert Scale rated participants and observer impression of change in the person with TBI. Responses range 1 = much improved to 5 = much worse.
Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure Completed by Participant [Time Frame: 42 Days]
Neuropsychiatry Inventory-Irritability (NPI-I) & Aggression domains (NPI-A): NPI is a 40-item assessment of 12 behavioral domains (NPI-I & NPI-A domains used in this study). The most problematic aspect of each domain is graded for severity (1=mild, to 3=severe) and frequency (1-4 with 4 representing highest frequency); the domain scores (0-12) are the product of severity and frequency. To best reflect treatment target intent and meet parametric statistical method criteria, a composite measure of participant-rated NPI-I & -A domains transformed to a Rasch logit scale running from 0 (best) to 100 (worse) units (i.e., participant-rated NPI-I/A Rasch construct scores). Mean day-42 participant-rated NPI-I/A Rasch construct scores were compared between placebo vs. CBZ using ANCOVA with baseline score as covariate.
Proportion of Participants With Minimal Clinically Important Difference (MCID) -- Participant
Proportion of participants with Minimal Clinically Important Difference (MCID) on Neuropsychiatric Inventory Irritability-Aggression Composite Measure completed by Participant. Specifically, the proportion of participants that experienced a decrease of > 1 (MCID) in the NPI-I/A Rasch construct score (i.e., participants that are considered to have meaningful reduction in irritability/aggression) from baseline to day-42 between the groups using a chi-square test. MCID was defined as 0.5 times the standard deviation of baseline scores.
Clinicians Global Impression of Change
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.
Global Impression of Change -- Participant
Global Impression of Change (GIC) is a 5-item Likert Scale rated participants and observer impression of change in the person with TBI. Responses range 1 = much improved to 5 = much worse.

Full Information

First Posted
February 13, 2008
Last Updated
April 20, 2022
Sponsor
Wake Forest University Health Sciences
Collaborators
U.S. Department of Education
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1. Study Identification

Unique Protocol Identification Number
NCT00621751
Brief Title
Carbamazepine for the Treatment of Chronic Post-Traumatic Brain Injury Irritability and Aggression
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 Type
Interventional

2. Study Status

Record Verification Date
August 2021
Overall Recruitment Status
Completed
Study Start Date
February 2008 (undefined)
Primary Completion Date
September 2013 (Actual)
Study Completion Date
October 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Wake Forest University Health Sciences
Collaborators
U.S. Department of Education

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to determine if carbamazepine reduces irritability and aggression among individuals with traumatic brain injury
Detailed Description
To achieve the enrollment of 66 needed, over enrollment of 70 subjects with 70 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 Beck Depression Inventory-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), and Global Impression of Change. The Beck Depression Inventory will be administered to the participant only at baseline for purposes of stratification of the randomization on depression. The Clinician Investigator will complete the Clinician Global Impressions scale 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Traumatic Brain Injury
Keywords
Brain Injury, Irritability, Aggression

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
70 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Carbamazepine
Arm Type
Experimental
Arm Description
Carbamazepine 800 mg daily
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo
Intervention Type
Drug
Intervention Name(s)
Carbamazepine
Other Intervention Name(s)
Tegretol
Intervention Description
800 mg daily
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Primary Outcome Measure Information:
Title
Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure -- Observer
Description
Neuropsychiatry Inventory-Irritability (NPI-I) & Aggression domains (NPI-A): NPI is a 40-item assessment of 12 behavioral domains (NPI-I & NPI-A domains used in this study). The most problematic aspect of each domain is graded for severity (1=mild, to 3=severe) and frequency (1-4 with 4 representing highest frequency); the domain scores (0-12) are the product of severity and frequency. To best reflect treatment target intent and meet parametric statistical method criteria, the primary outcome was a composite measure of observer-rated NPI-I & -A domains transformed to a Rasch logit scale running from 0 (best) to 100 (worse) units (i.e., observer-rated NPI-I/A Rasch construct scores). Mean day-42 observer-rated NPI-I/A Rasch construct scores were compared between placebo vs. carbamazepine using ANCOVA with baseline score as covariate.
Time Frame
42 days
Secondary Outcome Measure Information:
Title
Proportion of Participants With Minimal Clinically Important Difference -- Observer Rating
Description
Proportion of participants with Minimal Clinically Important Difference (MCID) on Neuropsychiatric Inventory Irritability-Aggression Composite Measure completed by Observer. Specifically, the proportion of participants that experienced a decrease of > 1 (MCID) in the NPI-I/A Rasch construct score (i.e., participants that are considered to have meaningful reduction in irritability/aggression) from baseline to day-42 between the groups using a chi-square test. MCID was defined as 0.5 times the standard deviation of baseline scores.
Time Frame
42-day
Title
Global Impression of Change -- Observer
Description
Global Impression of Change (GIC) is a 5-item Likert Scale rated participants and observer impression of change in the person with TBI. Responses range 1 = much improved to 5 = much worse.
Time Frame
42 days
Title
Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure Completed by Participant [Time Frame: 42 Days]
Description
Neuropsychiatry Inventory-Irritability (NPI-I) & Aggression domains (NPI-A): NPI is a 40-item assessment of 12 behavioral domains (NPI-I & NPI-A domains used in this study). The most problematic aspect of each domain is graded for severity (1=mild, to 3=severe) and frequency (1-4 with 4 representing highest frequency); the domain scores (0-12) are the product of severity and frequency. To best reflect treatment target intent and meet parametric statistical method criteria, a composite measure of participant-rated NPI-I & -A domains transformed to a Rasch logit scale running from 0 (best) to 100 (worse) units (i.e., participant-rated NPI-I/A Rasch construct scores). Mean day-42 participant-rated NPI-I/A Rasch construct scores were compared between placebo vs. CBZ using ANCOVA with baseline score as covariate.
Time Frame
Day 42
Title
Proportion of Participants With Minimal Clinically Important Difference (MCID) -- Participant
Description
Proportion of participants with Minimal Clinically Important Difference (MCID) on Neuropsychiatric Inventory Irritability-Aggression Composite Measure completed by Participant. Specifically, the proportion of participants that experienced a decrease of > 1 (MCID) in the NPI-I/A Rasch construct score (i.e., participants that are considered to have meaningful reduction in irritability/aggression) from baseline to day-42 between the groups using a chi-square test. MCID was defined as 0.5 times the standard deviation of baseline scores.
Time Frame
Day-42
Title
Clinicians Global Impression of Change
Description
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.
Time Frame
42 days
Title
Global Impression of Change -- Participant
Description
Global Impression of Change (GIC) is a 5-item Likert Scale rated participants and observer impression of change in the person with TBI. Responses range 1 = much improved to 5 = much worse.
Time Frame
Day-42

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility 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 carbamazepine during the month prior to enrollment Inability to interact sufficiently for communication with caregiver Acute and rehabilitation records unavailable or incomplete Diagnostic and Statistical Manual of Mental Disorders-IV (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; 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 carbamazepine 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 or ingestion of within 2 weeks before starting study Hypersensitivity/allergy to carbamazepine, any of the ingredients in carbamazepine, or any structurally related drugs (e.g. the tricyclic antidepressants) History of liver failure or hepatitis History of renal failure History atrio-ventricular conduction abnormalities unless paced History of bone marrow depression History of porphyria Asian heritage
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Flora M Hammond, MD
Organizational Affiliation
Wake Forest University Health Sciences
Official's Role
Principal Investigator
Facility Information:
Facility Name
Carolinas Rehabilitation
City
Charlotte
State/Province
North Carolina
ZIP/Postal Code
28203
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
10576463
Citation
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. doi: 10.1080/026990599121188.
Results Reference
background
PubMed Identifier
8845710
Citation
Chatham-Showalter PE. Carbamazepine for combativeness in acute traumatic brain injury. J Neuropsychiatry Clin Neurosci. 1996 Winter;8(1):96-9. doi: 10.1176/jnp.8.1.96.
Results Reference
background
PubMed Identifier
1521112
Citation
Lewin J, Sumners D. Successful treatment of episodic dyscontrol with carbamazepine. Br J Psychiatry. 1992 Aug;161:261-2. doi: 10.1192/bjp.161.2.261.
Results Reference
background
PubMed Identifier
9012550
Citation
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. doi: 10.1080/026990597123791.
Results Reference
background
Links:
URL
http://www.carolinasrehabilitation.org/
Description
Carolinas Rehabilitation

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

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