Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI) (NCT00453921), a randomized na study. The primary outcome is Neuropsychological Assessment, CVLT-II.

2. Clinical Question

The registry describes a two-by-two arrangement: medication (methylphenidate or placebo) and cognitive therapy (MAAT or an attention-control intervention). This structure allows the study to consider each component alone as well as their combination. However, the posted primary analysis is an overall comparison among four arms, not a reported factorial estimate that isolates the medication effect, the therapy effect, or their interaction. Those component-specific estimates are not reported in the registry record.

The primary measure is a test score rather than a direct measure of everyday functioning. Its stated scale range is 0-80, and higher scores are described as better. The endpoint therefore addresses performance on a verbal learning and memory assessment, while the study description also mentions attention, symptom distress, and functional MRI. The results discussed in the primary endpoint concern the memory score, not every study aim.

3. Trial Design

The registry identifies the study as randomized, quadruple-masked, and factorial. Its brief description calls the study randomized, placebo-controlled, and double-blind. The record does not explain how those masking labels relate to one another. The four posted arms combine the two medication conditions with the two therapy conditions: placebo for both, active drug with active therapy, active drug with placebo therapy, and placebo drug with active therapy.

The brief description says that participants were to receive a six week trial and gives the methylphenidate dose as 0.3 mg/kg BID. It also describes a planned group of 200 people with persistent cognitive deficits 6-12 months after mild traumatic brain injury. Registry enrollment is 76. The registry record lists the study as completed, with a start in 2007-02 and primary completion in 2013-05. These record entries do not explain the difference between the described planned group and recorded enrollment.

The primary endpoint was a mean score on the CVLT-II, total trials 1-5, assessed post-intervention at least 7 weeks later. The registry lists 7 outcome measures and 5 analyses, although details of all measures and analyses are not included in the available results. The posted secondary outcome is the Self Report Questionnaire - MASQ, also measured post-intervention at least 7 weeks later.

The primary outcome arm summaries list 18 participants in the placebo-both-conditions group, 17 in the active-drug/active-therapy group, 19 in the active-drug/placebo-therapy group, and 17 in the placebo-drug/active-therapy group. For the secondary outcome, the corresponding listed group sizes are 19, 18, 20, and 18. The record does not explain why the listed group sizes differ by outcome, or how missing measurements were handled. The protocol’s original statistical plan and sample-size justification are not reported in the registry record.

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:

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.

Population: Individuals age 18-65 with a traumatic brain injury of at least mild severity at least 4 months prior to study entry, with self-report of cognitive deficits as a result of the injury of sufficient severity to interfere with social and/or occupational functioning.

6. Primary Endpoint

The registry lists the primary outcome as Neuropsychological Assessment, CVLT-II, measured over post-intervention (at least 7 weeks).

The primary endpoint is the California Verbal Learning Test, 2nd edition (CVLT-II), total score across trials 1-5. It is a continuous measure of verbal learning and memory performance. The registry describes a score range of 0-80 and states that higher scores are better. The result is reported as a mean with a standard deviation for each arm, at post-intervention assessment at least 7 weeks later.

A standardized neuropsychological assessment gives researchers a defined way to compare memory performance across randomized groups. In this trial, the endpoint speaks to one aspect of the cognitive difficulties named in the study description. It does not, by itself, measure all attention, daily functioning, symptom distress, or neural activation outcomes. The trial description mentions functional MRI as an additional objective, but the primary result is the CVLT-II score.

Interpreting the mean requires attention to both the direction of the scale and the precision of the estimates. Since higher scores are described as better, a higher group mean indicates higher average test performance on this measure. It does not automatically establish that every participant improved, nor does a mean difference establish the importance of that difference in daily life. The registry record does not report a threshold for a clinically meaningful CVLT-II difference, or a primary endpoint analysis adjusted for baseline score.

7. Results Posted in the Registry

• Active Drug/Active Therapy: mean 51.80 versus 51.30 on control; difference 0.50 (95% CI -0.83 to 1.83), standardized effect d = 0.25; z-test p = 0.461.
• Active Drug/Placebo Therapy: mean 51.90 versus 51.30 on control; difference 0.60 (95% CI -0.62 to 1.82), standardized effect d = 0.32; z-test p = 0.337.
• Placebo Drug/Active Therapy: mean 57.20 versus 51.30 on control; difference 5.90 (95% CI 4.61 to 7.19), standardized effect d = 3.03; z-test p = <0.001.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Self Report Questionnaire - MASQ

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Active Drug/Active Therapy: mean 120.50 versus 116.40 on control; difference 4.10 (95% CI 1.10 to 7.10), standardized effect d = 0.88; z-test p = 0.007.
  • Active Drug/Placebo Therapy: mean 114.10 versus 116.40 on control; difference -2.30 (95% CI -5.13 to 0.53), standardized effect d = -0.51; z-test p = 0.111.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the mean is statistically higher for Active Drug/Active Therapy than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Active Drug/Placebo Therapy and the control. The interval gives the range of effects that remain compatible with the data.

The posted secondary measure is the Self Report Questionnaire - MASQ, assessed post-intervention at least 7 weeks later. Its four arm means range from 114.1 to 120.5. The registry reports two ANCOVA analyses across the groups, one with p < 0.01 and one labeled superiority with p < 0.05. The record does not give adjusted group estimates, confidence intervals, or the covariates used in these models, so the direction and size of the sponsor’s adjusted comparisons cannot be reconstructed from those p-values alone.

The unadjusted recalculations against the placebo-both-conditions group produce different patterns across the two active-drug arms. The active-drug/active-therapy comparison has a mean difference of 4.1, with an unadjusted p-value of 0.007; the active-drug/placebo-therapy comparison has a mean difference of -2.3, with an unadjusted p-value of 0.111. These recalculated contrasts are not the same as the reported ANCOVA results and should not be used to infer what the sponsor’s adjusted model found for each pair.

In relation to the primary outcome, the secondary findings do not provide a simple confirmation of a uniform treatment pattern. The primary reported test is an overall Kruskal-Wallis result, while the secondary reported analyses are ANCOVA results. They concern different measures and use different methods. The registry record does not report a joint analysis linking change in MASQ scores with CVLT-II performance, nor does it explain how the secondary outcome should support or qualify the primary finding.

Unadjusted secondary results carry less weight because multiple outcomes and comparisons create more opportunities for chance findings, and the pairwise calculations do not account for that multiplicity. In addition, the registry’s missing model details prevent a full assessment of the adjusted analyses. The secondary endpoint can contribute context about self-reported symptoms, but its p-values alone do not establish the magnitude, direction, or practical relevance of an effect. The original hierarchy of secondary outcomes and any multiplicity strategy are not reported in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Self Report Questionnaire - MASQ

9. Statistical Interpretation

10. Statistical Methods Explained

What does the overall Kruskal-Wallis test address?

The reported primary analysis is a Kruskal-Wallis test across the four randomized groups, with p < 0.04. In general, this rank-based method compares the distributions of an outcome across independent groups. It is often used when an analysis is framed around ranks rather than assuming that the outcome follows a normal distribution in each group. A significant overall result indicates evidence that the groups do not all share the same distributional pattern under the test. It does not specify which groups differ, estimate a mean difference, or test a particular medication-by-therapy interaction by itself.

The arm summaries are means and standard deviations, but the reported primary test is not a test of those means. Reading the group means alongside the Kruskal-Wallis p-value can describe the observed pattern, but it does not turn the test into a pairwise mean comparison. Follow-up comparisons and the way they account for multiple testing would be needed to make specific claims based on the overall test. Such follow-up results are not reported in the registry record.

What do the recalculated mean differences represent?

The recalculated estimates are unadjusted differences between each named arm and the placebo-both-conditions reference group. They use the posted group means and standard deviations and do not account for baseline values or other covariates. For the primary outcome, the comparisons are 0.5 for active drug with active therapy, 0.6 for active drug with placebo therapy, and 5.9 for placebo drug with active therapy. Their confidence intervals and unadjusted p-values are recalculations rather than sponsor-reported results. Because the registry marks a discrepancy, the sponsor’s own analysis takes precedence.

General explanation: a mean difference expresses the gap between two group averages on the outcome’s scale. A confidence interval expresses a range of values compatible with the data and the calculation’s assumptions. When an interval includes zero, the data are compatible with no difference as well as with differences in either direction at the interval’s stated confidence level. These recalculations are unadjusted; they should not be read as a substitute for the reported four-group test or an adjusted model.

Why do the analysis methods matter?

Different methods answer different questions and rely on different assumptions. A rank-based overall test compares group distributions, while an unadjusted difference in means summarizes the distance between averages for a selected pair. ANCOVA, used for the secondary outcome, models an outcome while adjusting for covariates. The registry does not report which covariates were included in the secondary ANCOVA or provide its adjusted estimates. The exact specifications of the sponsor’s primary analysis are not reported in the registry record beyond the named test.

General explanation: adjustment can improve precision when relevant baseline information is included appropriately, and it can account for differences in measured covariates. It does not remove uncertainty about unmeasured factors, make an analysis immune to missing data, or guarantee that a result is unbiased. A model’s interpretation depends on its specification and the assumptions it uses. Those details are necessary to reproduce or fully assess an adjusted result.

How should p-values be read?

A p-value measures how surprising data at least as incompatible with a specified null model would be if that model and the analysis assumptions held. The reported primary p < 0.04 is an overall test result, not the probability that the null hypothesis is true and not a measure of the size or clinical importance of the differences. The recalculated pairwise p-values are unadjusted, so they do not account for the fact that several comparisons are being considered. The secondary ANCOVA p-values also concern the reported group analyses and do not provide effect sizes or precision by themselves.

General explanation: statistical significance is not the same as clinical importance. A small p-value can occur with an estimate that is not important to patients, while a less compelling p-value can reflect limited precision in a small study. Effect estimates and confidence intervals provide complementary information about magnitude and uncertainty. For this trial, the registry does not report a clinical-importance threshold for the primary scale.

What does factorial design add?

A factorial design organizes treatment assignments around more than one intervention component. Here, the components are medication and cognitive therapy, each with active and comparison conditions. Such a design can support separate estimates of each component and an assessment of whether the combined effect differs from what would be expected from the components considered separately. The posted primary analysis, however, is an overall four-group Kruskal-Wallis test, and the reported pairwise recalculations compare individual arms with the placebo-both-conditions arm. No component-specific or interaction estimate is reported in the registry record.

General explanation: an interaction means that the effect associated with one component varies depending on the level of another component. Comparing four group means by eye is not a formal interaction test. Without reported factorial model results, it is not possible to determine from the registry analyses whether the effects of medication and therapy were additive or whether one modified the other.

What information is missing for a full statistical assessment?

The registry record does not report the original sample-size justification, a detailed primary analysis plan, handling of missing outcomes, the analysis population definition, or details of interim analyses. It also does not provide adjusted primary effect estimates or follow-up pairwise tests after the overall primary result. These omissions limit assessment of how closely the posted analyses follow the original design and whether the reported inferences account for all planned comparisons.

General explanation: over-dispersion refers to variability greater than a model assumes. When it occurs, standard errors can be too small and confidence intervals too narrow unless the model accounts for that extra variation. The posted primary test is rank-based, and the registry record does not report a model-based variance estimate or an over-dispersion assessment. This general concept does not establish that over-dispersion occurred in this trial.

11. Confidence Intervals and Precision

Precision is best considered alongside the estimated differences, not from a p-value alone. In the recalculated primary comparisons, the confidence intervals for active drug with active therapy and active drug with placebo therapy include zero. Their corresponding unadjusted mean differences are 0.5 and 0.6. This means the posted summaries do not pin down the direction of the difference from the placebo-both-conditions group with the same clarity as a confidence interval that excludes zero would. The registry does not report sponsor-derived confidence intervals for these primary contrasts.

The recalculated interval for placebo drug with active therapy runs from 4.606 to 7.194, around a mean difference of 5.9. This interval lies above zero under the unadjusted calculation. It is not an adjusted estimate from the sponsor’s primary analysis, and the registry’s discrepancy flag means the sponsor’s analysis takes precedence. The interval also does not establish the practical importance of the difference; the registry does not state a minimum clinically meaningful score difference.

General explanation: a confidence interval is a measure of statistical uncertainty around an estimate under the method’s assumptions. A narrower interval indicates more precision, while a wider interval indicates that a broader range of effects remains compatible with the data. An interval does not assign a probability to a fixed true value, and it does not account for sources of uncertainty omitted by the analysis, such as unreported missing-data procedures or multiplicity adjustments.

The listed primary group sizes are small, and the registry provides no sponsor-reported adjusted estimate with a confidence interval for the overall primary result. The Kruskal-Wallis p-value indicates an overall statistical finding but does not quantify the size or precision of specific group contrasts. As a result, the posted evidence is more informative about the broad presence of group variation than about the precise contribution of each intervention component.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are participants per arm for the two-arm comparisons, not total events. They use a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set as a stated fraction of the observed effect: 100%, 75%, or 50%. These are planning illustrations based on the observed effect, not the trial’s original design assumptions; the original sample-size justification is not reported in the registry record.

The 80% power column gives the estimated number of participants per arm under the listed assumptions for an analysis with an 80% chance of detecting the chosen effect if that effect is the true one and the assumptions hold. The 90% power column gives the corresponding per-arm estimate for a higher chance of detecting that same effect. These are prospective planning quantities, not a statement about what the completed trial achieved.

Smaller effects require more participants for the same target power, because a smaller separation between group outcomes is harder to distinguish from random variation. For example, the primary comparison of active drug with active therapy uses 252 participants per arm for 80% power at 100% of the observed effect, compared with 447 when planning for 75% of the observed effect and 1,005 when planning for 50% of the observed effect. These estimates are tied to the recalculated observed effect and should not be mistaken for a protocol requirement.

The listed planning estimates are not observed power. They do not describe the probability that the completed study’s results are correct, and they do not change the observed confidence intervals or p-values. Very small estimates can arise when the observed effect used as the planning target is large relative to the variation in the posted summaries. They should be interpreted as mathematical illustrations under the stated assumptions, not as evidence that a small future study would reliably reproduce the estimate.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 0.500; pooled standard deviation σ = 1.999.
2. n = 2 × (1.96 + 0.842)² × 1.999² / 0.500² = 251.0, rounded up to 252 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
delta <- 0.5                      # observed difference in means
sigma <- 1.99946962664572                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(453921)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 252 (80% power), 337 (90% power)
 75% of observed effect: n per arm = 447 (80% power), 598 (90% power)
 50% of observed effect: n per arm = 1,005 (80% power), 1,345 (90% power)
power.t.test: 252 
Simulated power at n = 252 per arm: 0.795 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Analyses Reported by the Sponsor

The registry’s reported primary analysis is a Kruskal-Wallis test across all four arms, with p < 0.04. It does not report a sponsor-derived primary mean difference, confidence interval, or arm-specific follow-up comparison. The pairwise mean differences and their confidence intervals are unadjusted recalculations from the posted summaries. They address selected comparisons with the placebo-both-conditions arm, rather than reproducing the sponsor’s overall analysis.

The registry marks a discrepancy between the posted summaries and the recalculated analysis. Under that circumstance, the sponsor’s own analysis takes precedence. The recalculated results can still help describe the arm means and the uncertainty implied by those summaries, but they should not be presented as if they were the registered analysis or as a correction to it.

For the secondary MASQ outcome, the registry lists ANCOVA analyses with p < 0.01 and p < 0.05, including an analysis labeled superiority. It does not provide the adjusted estimates, model details, or confidence intervals. Recalculated pairwise summaries therefore do not replace or fully explain those sponsor analyses. The registry record does not report enough detail to reconcile the models with the arm-level calculations.

15. Multiplicity, Missing Data and Analysis Populations

Several analysis questions are relevant to the interpretation of this record: the primary outcome is compared across four groups, recalculations compare multiple arms with a reference group, and a secondary outcome has two reported analyses. Considering multiple outcomes and comparisons increases the opportunity for at least one result to appear statistically notable by chance. Whether and how a study accounts for that issue affects the interpretation of nominal p-values.

The registry reports the primary Kruskal-Wallis result and the secondary ANCOVA results, but it does not report a multiplicity adjustment, a prespecified testing hierarchy, or a plan for follow-up comparisons. The recalculated pairwise p-values are explicitly unadjusted. Consequently, those pairwise values should not be treated as if they controlled the error rate across all contrasts. The record does not establish whether the sponsor used any additional procedure that is not included in the posted results.

Missing-data handling is also not reported in the registry record. The primary outcome group sizes differ from the secondary outcome group sizes, but the record does not explain the difference or identify whether all randomized participants were included in each analysis. It does not state how missing assessments were handled, whether any values were imputed, or how exclusions were determined. The analysis population definition is not reported in the registry record.

These omissions matter because complete-case results can differ from analyses that use other missing-data approaches, particularly if the likelihood of an observed assessment is related to participants’ outcomes. General explanation: missing-data methods rely on assumptions about why values are absent. Without the method and its assumptions, readers cannot assess whether the estimates represent all randomized participants or only those with observed measurements.

The original statistical plan, including whether interim analyses were planned or conducted, is not reported in the registry record. No interim-analysis schedule should be inferred from the completion dates or the posted p-values. These unreported details limit the ability to assess prespecification, the full set of analyses considered, and the degree to which the reported findings may reflect selective analysis or selective reporting.

16. Safety Results

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

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse event summaries list zero affected participants in each of the four groups, and zero deaths in each group. The corresponding numbers at risk for serious adverse events are 19 for placebo in both conditions, 18 for active medication with active therapy, 20 for active medication with placebo therapy, and 18 for placebo medication with active therapy. The registry lists no top serious-event terms.

These counts describe the serious adverse event entries recorded for the listed groups. They do not by themselves show that no other safety events occurred, because the record separately reports other adverse events and lists affected participants for those entries. The other-event counts are 8, 12, 11, and 9, respectively, in the four groups; those are not serious adverse event counts.

The serious-event group sizes differ from some of the outcome group sizes, and the registry does not explain why. The record also does not provide event-level descriptions or follow-up details for serious events. These summaries should therefore be read as registry counts, not as a complete assessment of comparative safety or of the risks for an individual.

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

The primary registry analysis reports an overall difference among the four randomized groups on the CVLT-II outcome, with p < 0.04. The arm means show the highest listed mean in the placebo-drug/active-therapy group. The overall test does not establish which individual groups differ, and it does not isolate a medication effect, a therapy effect, or an interaction between the two components. The recalculated pairwise estimates add descriptive contrasts, but they are unadjusted and the registry flags a discrepancy, so the sponsor’s own analysis takes precedence.

The endpoint is a verbal learning and memory test score, with higher scores described as better. It is not a direct measure of all cognitive symptoms or daily functioning. The registry does not provide a minimum clinically meaningful difference for this scale, so a statistically notable result cannot be translated from these data alone into a judgment about practical importance. The posted secondary results address self-reported symptoms but do not resolve the limitations in the primary analysis.

The trial description proposes a factorial comparison of methylphenidate and cognitive training, but the results available in the registry do not report separate factorial effect estimates. No conclusion about how the two components work independently or in combination can be drawn from the overall test alone. Nor do the results establish that every participant’s score changed in the same direction as a group mean.

The record’s enrollment is 76, while the brief description describes a planned 200 participants. The listed outcome group sizes are modest and differ by endpoint; the registry does not explain these differences or describe missing-data handling. Together with the absence of a detailed primary model, adjusted primary estimates, and multiplicity plan, these limitations call for caution in interpreting precision and scope.

These results describe what was posted for this trial and the uncertainty attached to those results. They do not establish outcomes beyond the measured assessments or provide an individual treatment recommendation. The registry record does not report enough information to determine whether the observed score patterns reflect the effects of each intervention component, a combination of components, or other features of the analysis and data.

18. Why This Trial Matters Statistically

This study is statistically informative because it combines two intervention components in a factorial randomized design. That structure can, in principle, address more than a simple active-versus-control question: it can distinguish the contribution of medication, the contribution of cognitive therapy, and whether their combination behaves differently from the components separately. The posted primary result, however, is an overall comparison among four groups. The gap between what a factorial design can estimate and what the registry results report is important for interpreting the evidence.

The contrast between the overall Kruskal-Wallis result and the recalculated pairwise comparisons also illustrates why a single p-value is not a complete account of a trial. The overall test indicates group-level variation, while the recalculations describe specific unadjusted differences relative to the placebo-both-conditions group. They are not interchangeable, and the registry’s discrepancy flag gives priority to the sponsor’s reported primary analysis.

The record also makes visible the importance of complete reporting. Adjusted estimates, confidence intervals from the sponsor’s primary analysis, factorial component estimates, missing-data procedures, and multiplicity methods would help readers understand the magnitude and reliability of the findings. Without those details, readers can identify the broad reported result but cannot fully evaluate the planned inferential pathway.

Finally, the planning illustrations show how sample-size requirements depend on the effect chosen for planning. They are not observed power and cannot repair limited precision in a completed study. Distinguishing planning assumptions from observed results, and distinguishing registry analyses from recalculations, is central to a careful statistical reading.

19. 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.

Several limitations are specific to the information posted for this trial. The registry’s primary result is an overall Kruskal-Wallis p-value, without a sponsor-reported primary effect estimate or confidence interval. The recalculated arm contrasts are unadjusted and are not a replacement for that analysis; the record flags a discrepancy, giving precedence to the sponsor’s own result. The overall test does not identify the particular arms responsible for the group pattern.

Although the study is described as factorial, no reported estimates separate the medication effect, the cognitive-therapy effect, or their interaction. The posted comparisons against the placebo-both-conditions group do not answer all those component questions. The registry record does not report adjusted primary pairwise analyses or the covariates used in the secondary ANCOVA.

The enrollment listed is 76, while the brief description states that 200 participants were to be randomized. The record does not explain this difference. Outcome group sizes vary between the primary and secondary results, and the registry does not report whether the difference reflects missing measurements, analysis exclusions, or another reason. Missing-data procedures and analysis populations are not reported.

The registry does not report the original sample-size justification, a clinical-importance threshold for the CVLT-II, the detailed analysis plan, multiplicity procedures, or interim-analysis details. The secondary result also lacks adjusted effect estimates and confidence intervals. These gaps limit assessment of the precision, clinical relevance, and robustness of the posted findings. The brief describes a persistent-deficit population after mild traumatic brain injury, while the condition field says brain injury; the record does not provide further detail about the enrolled population’s characteristics.

20. Related Tutorials

21. Related Statistical Calculators

22. Sources

• ClinicalTrials.gov: Methylphenidate (Ritalin) and Memory/Attention in Traumatic Brain Injury (TBI) — NCT00453921.
• Registry record last updated 2018-06-13; status last verified 2018-06.
• Results first posted 2018-06-07.
• 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.

23. Record Summary

The registry record identifies NCT00453921 as a completed randomized, quadruple-masked factorial study of methylphenidate and Memory and Attention Training after traumatic brain injury. It lists enrollment of 76 and describes a planned study of 200 people with persistent cognitive deficits 6-12 months after mild traumatic brain injury.

The primary endpoint was the CVLT-II total score across trials 1-5, assessed post-intervention at least 7 weeks later. The reported overall Kruskal-Wallis analysis across four groups has p < 0.04. Recalculated pairwise mean differences are unadjusted, and the registry flags a discrepancy; the sponsor’s own analysis takes precedence.

The posted secondary outcome is the Self Report Questionnaire - MASQ, with ANCOVA results of p < 0.01 and p < 0.05. The record does not provide adjusted estimates or full analysis details. Serious adverse event summaries list zero affected participants and zero deaths in each group.