Traumatic Brain Injury
Conditions
Keywords
traumatic brain injury, cognition, behavioral outcome, functional outcome, treatment, early intervention, citicoline
Brief summary
The Citicoline Brain Injury Treatment (COBRIT) is a randomized, double-blind, placebo controlled, multi-center trial of the effects of 90 days of citicoline on functional outcome in patients with complicated mild, moderate and severe traumatic brain injury.
Detailed description
Traumatic brain injury (TBI) is a major cause of death and disability. In the United States alone approximately 1.4 million sustain a TBI each year, of which 50,000 people die, and over 200,000 are hospitalized. Despite numerous prior clinical trials no standard pharmacotherapy for the treatment of TBI has been established in either the acute or post acute setting. Citicoline is a naturally occurring endogenous compound. This compound offers the potential of employing neuroprotection, neuro-recovery and neurofacilitation to enhance recovery after TBI. The primary goal of this study is to assess the efficacy of citicoline compared to placebo on functional and cognitive outcome in participants with traumatic brain injury.
Interventions
DRUGPlacebo
Drug Placebo Inactive twice a day given orally or enterally. The first dose is given within 24 hours of injury and treatment continues until 90 days or until the 90-day outcome assessment.
DRUGciticoline
1000 mg twice a day orally or enterally. The first dose is within 24 hours of injury and treatment continues for 90-days or until the 90-day outcome assessment.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Non-penetrating traumatic brain injury. 2. Age 18 (19 in Alabama) - 70 years. 3. GCS criteria on/off paralytics as specified in protocol 4. Reasonable expectation of completion of outcomes measures at a network center at six months post-injury. 5. Able to swallow oral medication or, if unable to swallow, a gastric tube or peg are placed by 23 hours after injury. 6. Reasonable expectation of enrollment within 24-hour time window. 7. English-speaking
Exclusion criteria
1. Intubated patients with GCS motor score = 6 and not meeting CT criteria. 2. Bilaterally fixed and dilated pupils 3. Positive pregnancy test, known pregnancy, or currently breast feeding 4. Evidence of diseases that interfere with outcome assessment 5. Current acetylcholinesterase inhibitor use (Appendix 1) 6. Imminent death or current life-threatening disease 7. Currently enrolled in another study 8. Prisoners
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Functional and Cognitive Outcome | 90 days | The primary outcome of this study was analyzed using a global statistic of the Network Core Battery. There were 9 scales: California Verbal Learning Test II (CVLT-II); Controlled Oral Word Association Test (COWAT); Digit Span (DS); Glasgow Outcome Scale Extended (GOSE); Processing Speed Index (PSI); Stroop Test 1 and 2 (ST1&2); and Trail Making Test part A and B (TMT parts A and B). Each scale was assigned cut-off for good outcome: GOSE\>7, CVLT\>36, PSI\>85, TMT part A \<42, TMT part B\<138.1, DS\>7.15, ST1\<60.29, ST2\<151.47, COWAT\>32.5. Logistic regression was used to estimate the global OR. |
Countries
United States
Participant flow
Recruitment details
Participant were recruited from eight level I trauma centers: Virginia Commonwealth University; University of Maryland; Temple University; University of Tennessee; University of Alabama (Birmingham); University of Texas Southwestern (Dallas); University of Pittsburgh; University of Washington. Recruitment began on 7/23/2007 and ended on 2/4/2011.
Participants by arm
| Arm | Count |
|---|---|
| Control The first dose of placebo was administered within 24 hours of traumatic brain injury. Placebo was administered orally or enterally depending upon whether the participant could swallow at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment. | 606 |
| Treatment Treatment with citicoline begun within 24 hours of traumatic brain injury. Treatment was administered orally or enterally depending upon whether the participant could swallow at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment. | 607 |
| Total | 1,213 |
Baseline characteristics
| Characteristic | Treatment | Control | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 43 Participants | 38 Participants | 81 Participants |
| Age, Categorical Between 18 and 65 years | 563 Participants | 568 Participants | 1131 Participants |
| Age Continuous | 39.7 years STANDARD_DEVIATION 16.2 | 41.1 years STANDARD_DEVIATION 15.5 | 40.4 years STANDARD_DEVIATION 15.9 |
| Region of Enrollment United States | 607 participants | 606 participants | 1213 participants |
| Sex: Female, Male Female | 151 Participants | 159 Participants | 310 Participants |
| Sex: Female, Male Male | 456 Participants | 447 Participants | 903 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 452 / 606 | 449 / 607 |
| serious Total, serious adverse events | 117 / 606 | 117 / 607 |
Outcome results
Primary
Functional and Cognitive Outcome
The primary outcome of this study was analyzed using a global statistic of the Network Core Battery. There were 9 scales: California Verbal Learning Test II (CVLT-II); Controlled Oral Word Association Test (COWAT); Digit Span (DS); Glasgow Outcome Scale Extended (GOSE); Processing Speed Index (PSI); Stroop Test 1 and 2 (ST1&2); and Trail Making Test part A and B (TMT parts A and B). Each scale was assigned cut-off for good outcome: GOSE\>7, CVLT\>36, PSI\>85, TMT part A \<42, TMT part B\<138.1, DS\>7.15, ST1\<60.29, ST2\<151.47, COWAT\>32.5. Logistic regression was used to estimate the global OR.
Time frame: 90 days
Population: The analysis included both the patients with complete outcome data and those with at least one measure. Patients who died were also included in the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Control | Functional and Cognitive Outcome | California Verbal Learning Test | 60.48 percentage of participants |
| Control | Functional and Cognitive Outcome | Digit Span | 84.02 percentage of participants |
| Control | Functional and Cognitive Outcome | Trail Making A | 61.96 percentage of participants |
| Control | Functional and Cognitive Outcome | Stroop Task 1 | 67.95 percentage of participants |
| Control | Functional and Cognitive Outcome | Processing Speed Index | 53.28 percentage of participants |
| Control | Functional and Cognitive Outcome | Stroop Task 2 | 66.59 percentage of participants |
| Control | Functional and Cognitive Outcome | Trail Making B | 71.05 percentage of participants |
| Control | Functional and Cognitive Outcome | Controlled Oral Word Association Test | 42.68 percentage of participants |
| Control | Functional and Cognitive Outcome | Glasgow Outcome Scale - Extended | 35.56 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Controlled Oral Word Association Test | 37.32 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Glasgow Outcome Scale - Extended | 35.43 percentage of participants |
| Treatment | Functional and Cognitive Outcome | California Verbal Learning Test | 57.71 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Processing Speed Index | 52.68 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Trail Making A | 64.96 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Trail Making B | 74.44 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Digit Span | 86.50 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Stroop Task 1 | 65.31 percentage of participants |
| Treatment | Functional and Cognitive Outcome | Stroop Task 2 | 68.29 percentage of participants |
Comparison: Null hypothesis: The placebo and citicoline groups do not differ at 90-days on the Core Battery~Power:~1. Two sided type I error of 0.05~2. 85% power~3. Expected OR=1.40 for the global statistic~4. Response rate in the control group~5. Correlations among the nine measures were accounted for. Response rates for the whole sample were a weighted average of the rates provided by TBI severity.~1240 participants were required to detect an OR \>= 1.4 for the global statistic.p-value: 0.7695% CI: [0.83, 1.14]Regression, Logistic