This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Citicoline for the Treatment of Traumatic Brain Injury (COBRIT) (NCT00545662), a randomized phase 3 study. The primary outcome is Functional and Cognitive Outcome.
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT00545662 |
| Phase | Phase 3 |
| Condition | Traumatic Brain Injury |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 1213 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
| Results posted | Yes |
2. Clinical Question
The central question is whether the trial’s global measure of functional and cognitive outcome at 90 days differed between participants assigned to citicoline and those assigned to placebo. The registry record describes a randomized comparison in people with complicated mild, moderate, or severe traumatic brain injury. It lists functional and cognitive outcome as the primary outcome and says that a global statistic based on the Network Core Battery was analyzed using logistic regression.
Population
Patients with complicated mild, moderate, or severe traumatic brain injury. The primary analysis included patients with complete outcome data and patients with at least one measure; patients who died were also included.
Intervention
Citicoline, administered orally or enterally depending on whether the participant could swallow, at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment.
Comparator
Placebo tablets formulated to resemble the citicoline treatment.
Primary question
How did the global functional and cognitive outcome at 90 days compare between the citicoline and placebo groups?
The registry record does not report the primary outcome estimate, the global odds ratio, a confidence interval, or a significance test. Therefore, the treatment-group comparison cannot be quantified from the registry record. The question can be described from the stated design and endpoint, but the posted information does not establish the direction or precision of the primary outcome result.
3. Trial Design
COBRIT is described as a randomized, parallel-group, placebo-controlled phase 3 trial sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). The registry record lists enrollment of 1213 and traumatic brain injury as the condition. It gives a start date of 2007-07 and primary completion of 2011-05, and lists the study status as terminated. The reason for termination is not reported in the registry record.
Participants were assigned to citicoline or placebo. The citicoline description specifies oral or enteral administration according to whether a participant could swallow, at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment. The placebo tablets were formulated to resemble the citicoline treatment. The registry record describes the study as randomized, double-blind, and placebo-controlled in its summary, while its masking classification is quadruple. The record does not explain the difference between those descriptions.
The primary outcome was assessed at 90 days. It used a global statistic drawing on scales of cognitive performance and functional status, rather than reporting a single scale as the primary outcome. The registry lists one primary outcome measure and one analysis, but a detailed statistical analysis plan is not reported in the registry record.
The record does not report the allocation sequence method, concealment procedures, the operational details of masking, or whether the planned enrollment changed during conduct of the trial. It also does not report why the study was terminated. These omissions limit what can be concluded about the trial’s conduct and planning from registry information alone; they do not, by themselves, establish a problem with the study.
4. Participant Flow and Accounting
The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.
Overall Study
| Stage | Control | Treatment |
|---|---|---|
| STARTED | 606 | 607 |
| COMPLETED | 521 | 528 |
| NOT COMPLETED | 85 | 79 |
Analysis population for the primary outcome, as defined in the registry: 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.
5. Baseline Characteristics
The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.
| Characteristic | Unit | Control | Treatment | Total |
|---|---|---|---|---|
| Participants analysed | 606 | 607 | 1213 | |
| Age, Categorical: <=18 years | Participants | 0 | 1 | 1 |
| Age, Categorical: Between 18 and 65 years | Participants | 568 | 563 | 1131 |
| Age, Categorical: >=65 years | Participants | 38 | 43 | 81 |
| Age Continuous | years | 41.1 (SD 15.5) | 39.7 (SD 16.2) | 40.4 (SD 15.9) |
| Sex: Female, Male: Female | Participants | 159 | 151 | 310 |
| Sex: Female, Male: Male | Participants | 447 | 456 | 903 |
| Region of Enrollment: United States | participants | 606 | 607 | 1213 |
6. Primary Endpoint
The registry lists the primary outcome as Functional and Cognitive Outcome, measured over 90 days.
| Element | Registry entry |
|---|---|
| Result type | Number |
| Measure of spread | not applicable |
| Unit | percentage of participants |
| Endpoint classification | Binary Endpoint |
The primary outcome is titled Functional and Cognitive Outcome and is expressed as a percentage of participants. It is based on a global statistic from the Network Core Battery. The record lists nine component scales: the California Verbal Learning Test II, Controlled Oral Word Association Test, Digit Span, Glasgow Outcome Scale Extended, Processing Speed Index, Stroop Test 1 and 2, and Trail Making Test parts A and B. Each scale was assigned a cutoff for a good outcome. The listed cutoffs are GOSE >7, CVLT >36, PSI >85, TMT part A <42, TMT part B <138.1, DS >7.15, ST1 <60.29, ST2 <151.47, and COWAT >32.5.
Using multiple measures can represent different aspects of recovery within a single broad outcome, rather than relying only on one test. A global statistic can provide an overall comparison across the components, while the cutoffs define what the record classifies as good performance on each scale. These choices also mean the overall result depends on how the components are combined and modeled. The registry record says logistic regression was used to estimate the global odds ratio, but does not report the estimate or explain the construction of the global statistic in further detail.
The endpoint is stated for 90 days. The registry record does not report separate outcome results for each component scale, so the contribution of any individual test to the overall comparison cannot be determined from the posted information.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record identifies the primary comparison and analysis approach, but does not report the primary outcome result. In particular, it does not give the global odds ratio, a confidence interval, a p-value, or the group-level percentages for good outcome. The direction, magnitude, and statistical precision of the primary comparison are therefore not reported in the registry record. No conclusion about the comparative primary outcome can be drawn from the endpoint description alone.
The primary measure combines cognitive and functional scales into a global statistic, with a good-outcome cutoff assigned to each scale. This makes the planned comparison broader than a comparison on a single test. It also means the estimate is specific to the chosen scales, thresholds, and statistical construction. The record does not provide enough detail to assess the relative influence of individual scales or whether separate component results differed from the global result.
The registry describes logistic regression as the method used to estimate a global odds ratio. In general, an odds ratio compares the odds of an outcome between groups under the model; it is not itself a percentage-point difference or a direct description of the proportion of participants with the outcome. Interpretation depends on knowing the modeled outcome and the estimated value, along with uncertainty. Those numerical results are not reported in the registry record, so a reader cannot assess whether the estimate was close to no difference or how precisely it was estimated.
Enrollment is listed as 1213, but enrollment alone does not show how many participants contributed to the primary analysis. The record says that the analysis included patients with complete outcome data and those with at least one measure, and that patients who died were included. It does not report the number with outcome data in each group, the extent or pattern of missing measurements, or the handling of partially observed outcomes. Consequently, the analysis population cannot be reconstructed from the posted information.
The study status is listed as terminated, while the reason is not reported in the registry record. Termination status alone does not establish whether the trial stopped early, why the status was assigned, or whether the primary comparison was affected. The registry also does not report an interim analysis plan or any interim results. Those details should not be inferred from the status label.
The record includes serious and other adverse-event counts, but these are separate from the primary functional and cognitive outcome. Their interpretation is limited by the available summaries, including the absence of death counts and of clear denominators for the listed serious-event categories. Safety counts do not fill the gap in the primary efficacy result.
9. Statistical Methods Explained
The following describes general statistical concepts and how they relate to the methods named in the registry record. The record’s brief methods information does not constitute a complete statistical analysis plan.
What does randomization contribute?
Random assignment is intended to make the treatment groups comparable, on average, with respect to factors known and unknown at the time of assignment. This helps support an interpretation of the group comparison as an estimate of the effect of assignment to the study treatments, provided the trial is conducted and analyzed appropriately. Randomization does not guarantee that every characteristic will be balanced in a particular trial. The registry record identifies the allocation as randomized, but does not describe the sequence-generation method, allocation concealment, or a detailed analysis population strategy.
The trial is also described as parallel-group: participants were assigned to one of the two listed treatment groups rather than receiving both treatments in sequence. The registry’s brief summary calls the study double-blind, and the masking classification is quadruple. The record does not specify which people were included in the latter classification or how masking was maintained and assessed.
What is the global endpoint?
The primary outcome uses a global statistic based on nine scales that cover functional and cognitive performance. Each scale has a cutoff for a good outcome. Combining multiple measures can create a single broad endpoint for an overall comparison, rather than requiring the primary question to depend on one measure alone. The cutoff approach also turns scale performance into a good-outcome classification for the global analysis described in the record.
A global endpoint can be useful when a study is concerned with several related dimensions of outcome. However, its meaning depends on the selected components, cutoffs, and method of combination. If different components show different patterns, an overall statistic may not reveal those patterns on its own. Component-level results and details of the global construction would help interpret the aggregate estimate, but component results and a fuller construction are not reported in the registry record.
Why logistic regression and an odds ratio?
Logistic regression is commonly used when the modeled outcome is binary, such as an outcome classified into two categories. It estimates how the odds of that outcome relate to group assignment, potentially allowing adjustment for specified variables. The registry record states that logistic regression was used to estimate the global odds ratio, but does not identify any adjustment variables or describe the full model. It is therefore not possible to determine from the record whether the estimate was adjusted or unadjusted, or which covariates may have been included.
An odds ratio is a relative measure of the odds between groups. It should be read together with its confidence interval and the definition of the modeled outcome. A confidence interval expresses the range of estimates compatible with the data and model under the method’s assumptions; a narrower interval generally indicates greater precision. The primary odds ratio and its confidence interval are not reported in the registry record. No inference about statistical significance or precision can therefore be made.
What do the planning assumptions mean?
The registry record describes sample-size planning illustrations based on the observed effect, rather than the trial’s original design. The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is specified as a stated fraction of the observed effect. For outcomes other than time-to-event outcomes, the illustrations are expressed as participants per arm; time-to-event illustrations are expressed as a total number of events.
These are planning illustrations, not observed power. A calculation using an observed effect is a retrospective planning exercise and does not show the probability that the completed trial detected an effect. It also does not establish the assumptions used when the trial was designed. The registry record does not report the original sample-size justification. Without the displayed planning results and the primary effect estimate, no numerical planning comparison can be interpreted from the registry record.
Why can over-dispersion matter?
Over-dispersion is a general issue in models for counts or proportions when the observed variability is greater than the model assumes. If ignored, uncertainty can be understated and confidence intervals may be too narrow. The registry record describes the primary endpoint as a percentage of participants and identifies logistic regression for the global odds ratio; it does not identify an over-dispersion adjustment. The record does not provide evidence that over-dispersion was relevant to this analysis, and no such adjustment should be assumed.
What can be inferred from one listed analysis?
The registry record lists one analysis for the primary outcome, but the endpoint itself includes multiple scales. A single global analysis does not reveal whether the investigators also examined component outcomes or other secondary comparisons. The multiplicity plan, including any adjustment for multiple testing, is not reported in the registry record. General statistical caution is warranted when interpreting several outcomes or comparisons, because repeated testing can increase the chance of finding an apparently unusual result. Whether and how that issue was addressed in this trial is not reported.
10. Multiplicity, Missing Data and Analysis Populations
The primary endpoint combines nine scales into a global statistic, and the registry record lists one primary outcome measure and one analysis. That does not establish how multiplicity was handled. The record does not report whether the component scales were also tested as separate outcomes, whether there were additional planned comparisons, or whether any adjustment for multiple testing was applied. It also does not report a hierarchy of outcomes or a statistical analysis plan. These details are not reported in the registry record.
For the primary analysis population, the record states that patients with complete outcome data and patients with at least one measure were included, and that patients who died were included. This indicates that the analysis was not described as limited only to participants with every outcome measure observed. However, the record does not explain how partially observed measurements were incorporated, how missing values were handled, or what outcome classification was assigned when some components were unavailable. The amount and pattern of missingness by group are also not reported.
Including patients who died is an important feature of the stated analysis population, but the record does not explain how death was represented in the global endpoint or how it affected each scale’s classification. The registry also does not describe sensitivity analyses for missing data or alternative analysis populations. Therefore, the robustness of the primary result to missing-data assumptions cannot be assessed from the posted information. The stated analysis population should be distinguished from a full account of the statistical methods used.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Control | 117 | 606 | 19.3% |
| Treatment | 117 | 607 | 19.3% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Control | 452 of 606 |
| Treatment | 449 of 607 |
Most frequent serious adverse event terms
| Event term | Organ system | Control | Treatment |
|---|---|---|---|
| CNS | Nervous system disorders | 62 of 606 | 63 of 607 |
| Respiratory | Respiratory, thoracic and mediastinal disorders | 31 of 606 | 24 of 607 |
| Cardiovascular | Vascular disorders | 14 of 606 | 14 of 607 |
| Digestive | Gastrointestinal disorders | 7 of 606 | 13 of 607 |
| Circulatory | Blood and lymphatic system disorders | 6 of 606 | 11 of 607 |
| Musculoskeletal | Musculoskeletal and connective tissue disorders | 5 of 606 | 5 of 607 |
| Immune | Immune system disorders | 5 of 606 | 4 of 607 |
| Excretory/Urinary | Renal and urinary disorders | 5 of 606 | 3 of 607 |
| Dermatology/Skin | Skin and subcutaneous tissue disorders | 3 of 606 | 1 of 607 |
| Endocrine | Endocrine disorders | 1 of 606 | 3 of 607 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Control | Treatment |
|---|---|---|---|
| Neurological | Nervous system disorders | 319 of 606 | 308 of 607 |
| Gastrointestinal | Gastrointestinal disorders | 184 of 606 | 193 of 607 |
| Abnormal Lab | Investigations | 143 of 606 | 175 of 607 |
| Musculoskeletal | Musculoskeletal and connective tissue disorders | 157 of 606 | 132 of 607 |
| Respiratory | Respiratory, thoracic and mediastinal disorders | 132 of 606 | 143 of 607 |
| Fever/Infection | Infections and infestations | 118 of 606 | 127 of 607 |
| Cardiovascular | Vascular disorders | 88 of 606 | 86 of 607 |
| Genitourinary | Renal and urinary disorders | 73 of 606 | 75 of 607 |
| Dermatologic/Skin | Skin and subcutaneous tissue disorders | 69 of 606 | 59 of 607 |
| Ophthalmologic | Eye disorders | 51 of 606 | 48 of 607 |
Serious events with the highest arm-level rate: cns (10.4%), respiratory (5.1%), cardiovascular (2.3%), digestive (2.1%), circulatory (1.8%).
The registry lists 606 participants at risk in the control group and 607 in the treatment group for serious adverse events. It reports 117 affected in each group. For other adverse events, it lists 606 at risk and 452 affected in the control group, and 607 at risk and 449 affected in the treatment group. These are the registry’s counts; no rates or comparative effect estimates are reported in the record, and no calculations are added.
The record also lists serious-event categories with percentages: CNS, 10.4%; Respiratory, 5.1%; Cardiovascular, 2.3%; Digestive, 2.1%; Circulatory, 1.8%; and Immune, 0.8%. The registry summary does not specify the denominator or provide an arm-specific breakdown for these category percentages. They should not be interpreted as direct comparisons between the treatment groups.
Death counts are not reported in the registry record. The adverse-event figures do not indicate timing, duration, severity beyond the serious classification, or whether an event was considered related to treatment. These summaries describe reported event counts, not a complete safety analysis.
12. What the Result Does, and Does Not, Mean
The posted information establishes that COBRIT was a randomized, placebo-controlled phase 3 trial of citicoline for traumatic brain injury, and that its primary question concerned a global functional and cognitive outcome at 90 days. It also identifies the broad endpoint construction and says logistic regression was used to estimate a global odds ratio. These details explain what comparison the trial set out to make.
They do not establish the primary result. The global odds ratio, group outcome percentages, confidence interval, and p-value are not reported in the registry record. Without those results, the direction and magnitude of the group comparison, and the precision of any estimate, cannot be determined. The endpoint description should not be treated as evidence for a particular treatment effect.
The safety summaries report counts of affected participants in the two groups and several serious-event categories. They do not provide the detail needed to assess timing, treatment attribution, or comparative uncertainty. Death counts are not reported. Those figures therefore should be read as limited registry summaries, not as a complete account of the trial’s benefit-risk profile.
The trial status is listed as terminated, but the reason for termination is not reported in the registry record. Status alone does not show when or why the study ended, whether the planned enrollment was reached as intended, or whether the primary analysis was affected. The record also does not provide an original sample-size justification, a complete statistical plan, or detailed handling of missing measurements.
In general, a trial result is interpreted by considering the estimated effect together with its uncertainty, the outcome definition, and the analysis population. Here, the registry record supplies important design and endpoint information but does not report the primary effect estimate. It is therefore not possible to use this record alone to quantify the primary comparison or assess its statistical precision.
13. Why This Trial Matters Statistically
This trial is statistically notable for using a broad global outcome rather than relying on a single functional or cognitive scale. The registry describes nine component measures, each with a cutoff for good outcome, and a global statistic analyzed with logistic regression. This approach makes the primary question encompass several dimensions, but it also makes the definition and construction of the global endpoint central to interpretation.
The registry’s wording about the analysis population is also relevant. It says that the analysis included participants with complete outcome data and those with at least one measure, and that patients who died were included. Those statements communicate that the primary analysis was not described as requiring every measure to be observed for every participant. The record does not, however, explain how incomplete profiles or death were incorporated into the global endpoint.
COBRIT also illustrates why registry design information and outcome reporting need to be considered separately. Randomization, masking descriptions, the intervention schedule, and the endpoint definition describe the planned or recorded framework. They do not substitute for an effect estimate and its uncertainty. Since the primary result is not reported in the registry record, the central statistical comparison cannot be evaluated from these details.
Finally, the sample-size assumptions are described as planning illustrations based on the observed effect, with specified significance level, allocation, and approximation assumptions. This distinction matters: such calculations are not observed power and do not establish the original design rationale. The original sample-size justification is not reported in the registry record.
14. Limitations
- The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
- Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.
The primary limitation for interpretation is that the registry record does not report the primary outcome estimate or its uncertainty. There are no group-level primary outcome percentages, global odds ratio, confidence interval, or p-value in the record. As a result, the primary comparison cannot be quantified or assessed for precision from the posted information.
The endpoint is described through its component scales and cutoffs, but the record does not give component-level results or a fuller account of how the global statistic was constructed. It does not report how partially observed outcome profiles were handled, how death was represented in the endpoint, or the amount and pattern of missing data by group. The analysis population is described, but the associated procedures are not.
The record lists one primary analysis, yet does not report a multiplicity strategy, a full statistical analysis plan, or whether component scales or additional outcomes were tested. It also does not identify model adjustment variables. The record’s short description therefore does not allow a detailed appraisal of model specification or robustness.
For safety, affected counts and serious-event category percentages are listed, but the category denominators and arm-specific category results are not reported. Death counts are not reported, and the summaries do not describe event timing or attribution. The study is marked terminated, but the reason for termination is not reported in the registry record. These omissions limit interpretation of both the primary outcome and the safety summaries without establishing why the information is absent.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Citicoline for the Treatment of Traumatic Brain Injury (COBRIT) — NCT00545662.
- Registry record last updated 2012-12-19; status last verified 2012-11.
- Results first posted 2012-12-19.
- Data retrieved from ClinicalTrials.gov on 2026-11-09.
- Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.
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18. Record Summary
The registry record identifies NCT00545662 as the Study of Citicoline for the Treatment of Traumatic Brain Injury (COBRIT), with the official title Citicoline Brain Injury Treatment Trial. It lists a phase 3 randomized, parallel-group study sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), with traumatic brain injury as the condition and enrollment of 1213.
The comparison was citicoline against placebo. Citicoline was described as oral or enteral treatment at 1,000 mg twice a day for 90 days or until the 90-day outcome assessment. The primary outcome was functional and cognitive outcome at 90 days, based on a global statistic using the Network Core Battery and analyzed with logistic regression.
The record lists a start date of 2007-07, primary completion of 2011-05, and status as terminated. The reason for termination and the primary outcome result are not reported in the registry record.