Traumatic Brain Injury
Conditions
Keywords
Brain Injury, Irritability, Aggression
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.
Interventions
DRUGCarbamazepine
800 mg daily
DRUGPlacebo
Placebo
Sponsors
U.S. Department of Education
Wake Forest University Health Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to 75 Years
Healthy volunteers
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 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure -- Observer | 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, 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
| Measure | Time frame | Description |
|---|---|---|
| Global Impression of Change -- Observer | 42 days | 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] | Day 42 | 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 -- Observer Rating | 42-day | 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. |
| Clinicians Global Impression of Change | 42 days | 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 | Day-42 | 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. |
| Proportion of Participants With Minimal Clinically Important Difference (MCID) -- Participant | Day-42 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Carbamazepine Carbamazepine 800 mg daily
Carbamazepine: 800 mg daily | 35 |
| Placebo Placebo
Placebo: Placebo | 35 |
| Total | 70 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Total | Carbamazepine |
|---|---|---|---|
| Age, Continuous | 40.5 years STANDARD_DEVIATION 13.7 | 40.4 years STANDARD_DEVIATION 13.2 | 40.2 years STANDARD_DEVIATION 12.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants | 68 Participants | 35 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 18 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 24 Participants | 52 Participants | 28 Participants |
| Sex: Female, Male Female | 28 Participants | 53 Participants | 25 Participants |
| Sex: Female, Male Male | 7 Participants | 17 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 29 / 35 | 19 / 35 |
| serious Total, serious adverse events | 6 / 35 | 1 / 35 |
Outcome results
Primary
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.
Time frame: 42 days
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbamazepine | Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure -- Observer | 37.7 score on a scale | Standard Error 1.4 |
| Placebo | Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure -- Observer | 36.7 score on a scale | Standard Error 1.5 |
Comparison: The primary outcome was a composite measure of observer-rated NPI-I \& NPI-A domains transformed to a Rasch logit scale ranging 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 the placebo vs. carbamazepine groups using ANCOVA with baseline score as covariate.p-value: 0.6ANCOVA
Secondary
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.
Time frame: 42 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carbamazepine | Clinicians Global Impression of Change | 3.1 units on a scale | Standard Deviation 1.3 |
| Placebo | Clinicians Global Impression of Change | 2.9 units on a scale | Standard Deviation 1.1 |
Secondary
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.
Time frame: 42 days
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carbamazepine | Global Impression of Change -- Observer | 3.3 units on a scale | Standard Deviation 1.4 |
| Placebo | Global Impression of Change -- Observer | 3.1 units on a scale | Standard Deviation 0.9 |
Secondary
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.
Time frame: Day-42
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Carbamazepine | Global Impression of Change -- Participant | 3.1 score on a scale | Standard Deviation 1.3 |
| Placebo | Global Impression of Change -- Participant | 3.1 score on a scale | Standard Deviation 0.9 |
Secondary
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.
Time frame: Day 42
Population: There were fewer participants scores than observers scores.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Carbamazepine | Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure Completed by Participant [Time Frame: 42 Days] | 37.5 score on a scale | Standard Error 1.4 |
| Placebo | Neuropsychiatric Inventory Irritability-Aggression Domains Composite Measure Completed by Participant [Time Frame: 42 Days] | 36.4 score on a scale | Standard Error 1.4 |
Secondary
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.
Time frame: Day-42
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carbamazepine | Proportion of Participants With Minimal Clinically Important Difference (MCID) -- Participant | 21 Participants |
| Placebo | Proportion of Participants With Minimal Clinically Important Difference (MCID) -- Participant | 16 Participants |
Secondary
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.
Time frame: 42-day
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Carbamazepine | Proportion of Participants With Minimal Clinically Important Difference -- Observer Rating | 20 Participants |
| Placebo | Proportion of Participants With Minimal Clinically Important Difference -- Observer Rating | 26 Participants |
p-value: <0.05ANCOVA