Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI) (NCT00970944), a randomized phase 2, phase 3 study. The primary outcome is Disability Rating Scale: Functional Status.

2. Clinical Question

This was a prospective randomized controlled trial with a parallel-group design. Its stated objectives distinguish the immediate functional outcome from the question of whether any functional gains persisted after discontinuation. The registry record does not report results for either question, so the treatment-group difference in function and the course of scores after drug discontinuation cannot be described from this record.

3. Trial Design

The registry record describes a multicenter prospective randomized controlled trial with a parallel design. Allocation was randomized, and masking was recorded as quadruple. The trial is listed as Phase 2 and Phase 3, with a completed status. JFK Medical Center is named as the sponsor. The recorded study start is 2003-02, and primary completion is recorded as 2010-03.

Enrollment is listed as 184. The primary outcome population description states that analyses followed the intention-to-treat principle and that 184 randomized subjects were included for analysis. The record says missing data were infrequent and unrelated to the study outcome, and that imputation methods were not undertaken. It does not report how many outcome observations were missing, how missingness was assessed, or whether all scheduled assessments were available for every participant.

The intervention arm description gives a dose-adjustment schedule based on change in the primary outcome measure. Participants were to receive 100mg BID for 2 weeks, with an increase to 150mg BID in week 3 if the Disability Rating Scale change after week 2 was less than 2 points. If the change remained less than 2 points after week 3, the dose was to increase to 200mg BID in week 4. The registry record does not provide a corresponding placebo-arm description.

The primary endpoint was scheduled at week 4. Assessments were planned at randomization and weekly for 6 weeks, with drug washout at week 6. A secondary outcome listed in the record was the JFK Coma Recovery Scale-Revised: Neurobehavioral Status. The record does not provide the results for either outcome or enough detail to reconstruct the full analysis plan.

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

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analyses were conducted according to the intention-to-treat principle. 184 subjects were randomized and included for analysis. Since missing data were infrequent and unrelated to the study outcome, imputation methods were not undertaken.

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.

6. Primary Endpoint

The registry lists the primary outcome as Disability Rating Scale: Functional Status, measured over Randomization and weekly for 6 weeks. The primary study endpoint was week 4 and drug washout was week 6..

The primary endpoint was functional status measured by the Disability Rating Scale (DRS). The registry describes the measure as assessing function after traumatic brain injury across a range from “coma to community.” Its scale runs from a minimum score of 0 to a maximum score of 29, with higher scores indicating a greater degree of disability. Thus, the score is not a direct measure in which a larger value represents better function.

The DRS was used because the trial’s stated aim was to assess functional recovery following severe traumatic brain injury, including recovery from vegetative and minimally conscious states. A measure spanning levels of function can represent changes in disability across that clinical range. The registry record identifies the DRS as the primary outcome measure and also uses its change to guide the intervention’s possible dose increases.

Assessments were scheduled at randomization and weekly for 6 weeks. The primary study endpoint was week 4, and drug washout was at week 6. The registry record does not report the week 4 group means, standard deviations, between-group estimate, confidence interval, or p-value. It therefore does not establish the magnitude or precision of any treatment-group difference in DRS scores. It also does not report the week 6 outcome values needed to describe functional scores after washout.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry record identifies the outcome type as continuous and the summary parameter as a mean, with standard deviation as the measure of dispersion. A mean describes the average score in a group; a standard deviation describes how spread out individual scores are around that average. Reporting both can help readers understand the group’s central outcome and the variability among participants. The registry record does not report the primary outcome means or standard deviations.

What does a randomized comparison estimate?

Random allocation is intended to make the assigned groups comparable, on average, with respect to factors that could influence the outcome. A trial comparison then evaluates outcomes according to the assigned groups, subject to the analysis plan and the available data. Here, the record says analyses followed the intention-to-treat principle and that randomized subjects were included for analysis. It does not report a numerical treatment-group contrast for the primary endpoint.

In general, an unadjusted difference in group means compares the average outcome in one group with the average outcome in the other, without adjustment for additional covariates. A confidence interval around such a difference conveys statistical uncertainty; a narrow interval indicates greater precision than a wide one. These are general concepts, not reported analyses for this trial. The registry record does not state whether its primary comparison was adjusted or unadjusted, nor does it report a confidence interval.

How should the scale direction be read?

The DRS ranges from 0 to 29, and higher scores mean greater disability. This direction should be kept in view when interpreting a mean or a change in mean. The intervention’s dose schedule also refers to change in DRS score, using a less-than-2-point change as a condition for increasing the dose. The record does not provide the observed score changes, so this dosing rule does not reveal how many participants had a change meeting either condition.

What do repeated assessments add?

Measurements were planned at randomization and weekly for 6 weeks. Repeated measurements can describe how an outcome changes over time and can support comparisons at specified time points or across a trajectory, depending on the statistical method. Those approaches are not interchangeable: a comparison focused on week 4 answers a different question from a comparison of the overall pattern across visits. The record identifies week 4 as the primary study endpoint, but does not describe a longitudinal model, covariance structure, or other method for using repeated scores.

The week 6 assessment followed drug washout and was relevant to the objective of whether gains persisted after discontinuation. The record does not provide week 6 results or describe a specific persistence estimand. Consequently, it is not possible to distinguish a planned persistence question from a numerical finding about persistence.

What is the role of sample-size planning?

The registry record describes planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between arms, and a normal approximation. It also states that the effect to detect is expressed as a fraction of the observed effect. These are planning assumptions, not evidence that the trial was designed around those assumptions. The record does not report the trial’s own sample-size justification or design assumptions.

In general, a sample-size illustration estimates the number of participants needed under specified assumptions to detect a target effect with a chosen power. Such a calculation is not observed power and does not describe the strength of evidence from the completed trial. Where the target effect is based on an observed effect, the illustration is conditional on that estimate and should not be treated as an independent confirmation of it. The registry record does not report the numerical planning outputs in the information available for this analysis.

Why does variability matter?

For a continuous endpoint, the precision of a group comparison depends in part on the variability of scores and the amount of outcome information available. Greater dispersion can make a difference harder to estimate precisely when other factors are unchanged. Standard deviations are therefore useful alongside means. Since neither group means nor standard deviations are reported for the DRS, the variability and precision of the primary comparison cannot be evaluated from the registry record.

The record says missing data were infrequent and unrelated to the study outcome, and that no imputation methods were used. In general, imputation fills in missing values under specified assumptions; omitting imputation means the reported analysis would rely on the available observations as described by the analysis approach. The record does not give the amount or pattern of missing outcome data, the checks used to assess its relationship to the outcome, or sensitivity analyses. Those details would help readers assess the robustness of an analysis to missingness.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists two outcome measures and two analyses. It identifies the Disability Rating Scale: Functional Status as the primary outcome and lists the JFK Coma Recovery Scale-Revised: Neurobehavioral Status as a secondary outcome. It also identifies weekly DRS assessments and a primary endpoint at week 4, with drug washout at week 6. The record does not report how statistical testing across outcomes or time points was handled.

Multiplicity arises when several hypotheses are tested, for example across multiple outcomes, time points, or subgroups. In general, conducting many tests can increase the chance that at least one result appears statistically notable by chance. A prespecified hierarchy, adjustment procedure, or clear distinction between primary and exploratory comparisons can help readers interpret such results. The registry record does not report a multiplicity adjustment, testing hierarchy, or analysis plan specifying how the listed outcomes and repeated assessments were handled. Their absence from the record does not establish whether such methods were or were not used.

The primary outcome population description states that the analysis followed the intention-to-treat principle and included the 184 randomized subjects. It also says missing data were infrequent and unrelated to the study outcome, and that imputation was not undertaken. The number of missing observations, their distribution across groups and visits, and the method used to assess whether missingness was related to outcome are not reported in the registry record.

In general, intention-to-treat analysis retains participants in the groups to which they were randomized, supporting interpretation according to assignment. It does not, by itself, resolve how missing measurements are handled. Because the record does not provide a detailed missing-data analysis or sensitivity analyses, readers cannot assess how dependent the outcome findings would be on the assumptions used for incomplete observations. No primary outcome results are reported against which to evaluate these issues.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (6.9%), infection (5.2%), hydrocephalus (3.4%), other gastrointestinal problems (3.1%), epilepsy (2.1%).

The registry record lists serious adverse events and other adverse events separately for the amantadine and placebo arms. For serious adverse events, it reports 15 affected among 87 at risk in the amantadine arm and 19 among 97 at risk in the placebo arm. For other adverse events, it reports 54 among 87 at risk and 51 among 97 at risk, respectively. These are the posted group counts; the record does not provide a comparative estimate or confidence interval.

The listed serious adverse-event terms and percentages are Pneumonia, 6.9%; Infection, 5.2%; Hydrocephalus, 3.4%; Other Gastrointestinal Problems, 3.1%; Epilepsy, 2.1%; and General Medical Problems, 2.1%. The registry record does not specify in this listing how these terms are distributed by treatment arm. The percentages should therefore be read as the recorded frequencies for these terms, not as arm-specific comparisons.

In general, counts and percentages describe recorded events or affected participants, but do not alone show whether a difference between arms is statistically precise or attributable to treatment. Interpretation also depends on definitions, ascertainment, and the analysis method. Death counts are not reported in the registry record.

12. What the Result Does, and Does Not, Mean

The registry record establishes that a randomized, quadruple-masked, parallel-group trial evaluated amantadine hydrochloride and placebo in the context of severe traumatic brain injury. It identifies the DRS as the primary functional outcome, sets week 4 as the primary endpoint, and describes week 6 as the point of drug washout. It also states that the study aimed to consider persistence of gains after discontinuation and safety.

Those design details do not establish what the trial found. The registry record does not report primary DRS values, a between-group estimate, a confidence interval, or a p-value. It therefore does not show the magnitude, direction, or precision of any difference in functional status. Nor does it report the week 6 results needed to assess the stated persistence objective.

The adverse-event counts are descriptive information. Without a comparative analysis and its uncertainty, they should not be treated as proof that the arms had equivalent or different safety outcomes. The record also does not report death counts. The listed serious adverse-event terms provide context about reported event categories, but do not answer the primary functional question.

In general, the absence of a reported estimate is different from evidence of no effect. A conclusion about a treatment effect requires results and an assessment of their uncertainty; a conclusion about clinical importance also requires a suitable interpretive context. Neither can be drawn from the registry record’s design information alone. The appropriate reading is limited: the trial’s stated question, outcome, and analysis population are described, while the primary result needed to answer that question is not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for the distinction between a detailed design record and an interpretable treatment-effect estimate. Randomization, masking, a defined continuous primary outcome, and an identified primary endpoint describe how the study was structured. Yet those features do not reveal the observed treatment contrast. Without DRS results and measures of uncertainty, readers cannot judge either the estimated effect or its precision.

The outcome schedule also raises an important general issue in longitudinal trials. A sequence of weekly assessments can support different questions: a comparison at one prespecified visit, a comparison of change over time, or an assessment of whether a change persists after treatment ends. The registry identifies week 4 as the primary endpoint and week 6 as drug washout, but does not report results or the model used to analyze repeated observations. Clear alignment between the clinical question, estimand, time point, and analysis is important for interpretation.

Another statistical lesson is that sample-size planning and completed-trial evidence are separate. The record describes planning illustrations based on an observed effect under stated assumptions, but those illustrations are not observed power and do not replace the trial’s own design justification. The registry record does not report that justification. A planning calculation can describe hypothetical requirements under assumptions; it cannot supply missing outcome evidence.

Finally, the record states that analyses used the intention-to-treat principle and did not impute missing data, while giving limited detail about missingness. This underscores why analysis-population labels and missing-data methods should be accompanied by transparent information about available observations and sensitivity to assumptions. Without the primary results, these methodological details cannot be connected to the estimated treatment effect.

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 main trial-specific limitation of the registry record is that it does not report the primary endpoint results. No group-level DRS summaries, comparative effect estimate, confidence interval, or p-value are available. The study’s central functional question therefore cannot be answered from the record, and the direction, magnitude, and precision of a possible difference remain unknown.

The record also does not report outcome results at the other scheduled visits or at week 6 after drug washout. This prevents assessment of change over the planned follow-up and of the stated objective concerning persistence after discontinuation. Although the JFK Coma Recovery Scale-Revised: Neurobehavioral Status is listed as a secondary outcome, its results are not reported in the registry record.

Further analysis details are not reported in the registry record, including the statistical model for repeated assessments, any covariate adjustment, the approach to multiplicity, and the trial’s own sample-size justification. The record says missing data were infrequent and unrelated to outcome, with no imputation, but does not provide the number or pattern of missing observations or sensitivity analyses.

The placebo-arm description is blank, and the registry record does not explain the masking procedures. Adverse-event counts and selected serious adverse-event terms are listed, but no comparative safety estimates or uncertainty intervals are reported; death counts are not reported in the registry record. These limitations concern the available record and do not establish whether further analyses or details exist elsewhere.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effectiveness of Amantadine Hydrochloride for Treatment of Severe Traumatic Brain Injury (TBI) — NCT00970944.
• Registry record last updated 2012-09-24; status last verified 2012-09.
• Results first posted 2012-09-24.
• 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.

18. Record Summary

The registry record describes a completed multicenter randomized, quadruple-masked, parallel-group trial of amantadine hydrochloride versus placebo for severe traumatic brain injury. Enrollment was 184, and the primary outcome population description states that 184 randomized subjects were included in an intention-to-treat analysis.

The primary outcome was functional status on the Disability Rating Scale, where higher scores indicate greater disability. Assessments were scheduled at randomization and weekly for 6 weeks, with week 4 designated as the primary endpoint and drug washout at week 6. A secondary outcome was the JFK Coma Recovery Scale-Revised: Neurobehavioral Status.

The registry record describes dose adjustment in the amantadine arm and reports adverse-event counts by group. It does not report the primary outcome results, statistical uncertainty for a treatment-group comparison, or results for the stated persistence objective.