Study of Citicoline for the Treatment of Traumatic Brain Injury (COBRIT)

• Sponsor: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00545662
• Collaborator: (none)
• Enrollment: 1,213
• Locations: 8
• Arms: 2
• Duration (Months): 46
• Patients Per Site: 151.6
• Patients Per Site Per Month: 3.3

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Traumatic Brain Injury	Drug: Placebo; Drug: citicoline	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1213 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Citicoline Brain Injury Treatment Trial
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: May 1, 2011
• Actual Study Completion Date: May 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo Placebo tablets formulated to resemble the citicoline treatment.	Drug: Placebo; 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.
Experimental: Citicoline Experimental treatment administered orally or enterally depending upon whether the participant can swallow at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment.	Drug: citicoline; 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.; Other Names: CDP-Choline, Cytidine 5-diphosphocholine, Somazina

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294-3295
2	University of Maryland, Baltimore	Baltimore	Maryland	United States	21201
3	Temple University	Philadelphia	Pennsylvania	United States	19141-3099
4	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213-3221
5	University of Tennessee Health Sciences Center	Memphis	Tennessee	United States	38163
6	University of Texas, Southwestern Medical Center	Dallas	Texas	United States	75390
7	Virginia Commonwealth University	Richmond	Virginia	United States	23298-0677
8	University of Washington	Seattle	Washington	United States	23298-0631

Sponsors and Collaborators

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Sherry Melton, MD, University of Alabama at Birmingham
• Principal Investigator: Howard Eisenberg, MD, University of Maryland, Baltimore
• Principal Investigator: Jack Jallo, MD, PhD, Temple University
• Principal Investigator: Joseph Ricker, PhD, University of Pittsburgh
• Principal Investigator: Shelly Timmons, MD, PhD, University of Tennessee Health Sciences Center
• Principal Investigator: Ramon Diaz-Arrastia, MD, PhD, University of Texas Southwestern Medical Center
• Principal Investigator: John Ward, MD, Virginia Commonwealth University
• Principal Investigator: Nancy Temkin, PhD, University of Washington
• Study Director: Beth Ansel, PhD, National Institute of Child Health and Human Development, National Center for Medical Rehabilitation Research
• Principal Investigator: William Friedewald, MD, Columbia University Department of Biostatistics

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: William Friedewald, Professor, Columbia University
• ClinicalTrials.gov Identifier: NCT00545662
• Other Study ID Numbers: BA-HD042; HD042687-04; HD042738-05; HD042678-03; HD042653-05; HD042689-05; HD042736-04; HD 042686-01A1; HD042652-04; HD042823-05
• First Posted: Oct 17, 2007
• Last Update Posted: Dec 19, 2012
• Last Verified: Nov 1, 2012

• Keywords provided by William Friedewald, Professor, Columbia University: traumatic brain injury; cognition; behavioral outcome; functional outcome; treatment; early intervention; citicoline
• Additional relevant MeSH terms: Brain Injuries; Brain Injuries, Traumatic; Wounds and Injuries; Choline; Cytidine Diphosphate Choline

Study Results

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.

Arm/Group Title	Control	Treatment
Arm/Group Description	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.	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.
Period Title: Overall Study
STARTED	606	607
COMPLETED	521	528
NOT COMPLETED	85	79

Baseline Characteristics

Arm/Group Title	Control	Treatment	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	606	607	1213
Age (Count of Participants)
<=18 years	0 0%	1 0.2%	1 0.1%
Between 18 and 65 years	568 93.7%	563 92.8%	1131 93.2%
>=65 years	38 6.3%	43 7.1%	81 6.7%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.1 (15.5)	39.7 (16.2)	40.4 (15.9)
Sex: Female, Male (Count of Participants)
Female	159 26.2%	151 24.9%	310 25.6%
Male	447 73.8%	456 75.1%	903 74.4%
Region of Enrollment (participants) [Number]
United States	606 100%	607 100%	1213 100%

Outcome Measures

1. Primary Outcome

Title	Functional and Cognitive Outcome
Description	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

Outcome Measure Data

Analysis Population Description

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/Group Title	Control	Treatment
Arm/Group Description	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.	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.
Measure Participants	509	508
Glasgow Outcome Scale - Extended	35.56 5.9%	35.43 5.8%
California Verbal Learning Test	60.48 10%	57.71 9.5%
Processing Speed Index	53.28 8.8%	52.68 8.7%
Trail Making A	61.96 10.2%	64.96 10.7%
Trail Making B	71.05 11.7%	74.44 12.3%
Digit Span	84.02 13.9%	86.50 14.3%
Stroop Task 1	67.95 11.2%	65.31 10.8%
Stroop Task 2	66.59 11%	68.29 11.3%
Controlled Oral Word Association Test	42.68 7%	37.32 6.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Control, Treatment
	Comments	Null hypothesis: The placebo and citicoline groups do not differ at 90-days on the Core Battery Power: Two sided type I error of 0.05 85% power Expected OR=1.40 for the global statistic Response rate in the control group 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.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.76
	Comments	a priori threshold for statistical significance is 0.05
	Method	Regression, Logistic
	Comments	Logistic regression estimated global OR. GEE accounted for correlations of the scales. Models adjusted for site & injury severity.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.83 to 1.14
	Parameter Dispersion	Type: Value:
	Estimation Comments	The odds in the citicoline group were compared to the odds in the placebo group.

Adverse Events

Arm/Group Title	Control		Treatment
Arm/Group Description	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.		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.
All Cause Mortality
	Control		Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Control		Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	117/606 (19.3%)		117/607 (19.3%)
Blood and lymphatic system disorders
Circulatory	6/606 (1%)		11/607 (1.8%)
Endocrine disorders
Endocrine	1/606 (0.2%)		3/607 (0.5%)
Gastrointestinal disorders
Digestive	7/606 (1.2%)		13/607 (2.1%)
Immune system disorders
Immune	5/606 (0.8%)		4/607 (0.7%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	5/606 (0.8%)		5/607 (0.8%)
Nervous system disorders
CNS	62/606 (10.2%)		63/607 (10.4%)
Renal and urinary disorders
Excretory/Urinary	5/606 (0.8%)		3/607 (0.5%)
Respiratory, thoracic and mediastinal disorders
Respiratory	31/606 (5.1%)		24/607 (4%)
Skin and subcutaneous tissue disorders
Dermatology/Skin	3/606 (0.5%)		1/607 (0.2%)
Vascular disorders
Cardiovascular	14/606 (2.3%)		14/607 (2.3%)
Other (Not Including Serious) Adverse Events
	Control		Treatment
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	452/606 (74.6%)		449/607 (74%)
Eye disorders
Ophthalmologic	51/606 (8.4%)		48/607 (7.9%)
Gastrointestinal disorders
Gastrointestinal	184/606 (30.4%)		193/607 (31.8%)
General disorders
Diaphoresis	36/606 (5.9%)		28/607 (4.6%)
Infections and infestations
Fever/Infection	118/606 (19.5%)		127/607 (20.9%)
Investigations
Abnormal Lab	143/606 (23.6%)		175/607 (28.8%)
Musculoskeletal and connective tissue disorders
Musculoskeletal	157/606 (25.9%)		132/607 (21.7%)
Nervous system disorders
Neurological	319/606 (52.6%)		308/607 (50.7%)
Renal and urinary disorders
Genitourinary	73/606 (12%)		75/607 (12.4%)
Respiratory, thoracic and mediastinal disorders
Respiratory	132/606 (21.8%)		143/607 (23.6%)
Skin and subcutaneous tissue disorders
Dermatologic/Skin	69/606 (11.4%)		59/607 (9.7%)
Vascular disorders
Cardiovascular	88/606 (14.5%)		86/607 (14.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.