Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke (NCT03574038), a randomized na study. The primary outcome is Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm.

2. Clinical Question

3. Trial Design

The registry describes a prospective, single-center, randomized, triple-masked, sequential study of transcranial direct current stimulation in acute stroke. It is characterized as a dose-escalation study focused on safety, tolerability, feasibility and potential efficacy. The listed status is completed, with enrollment of 10 participants. The recorded start date is 2018-09-28 and the primary completion date is 2022-04-01. The registry lists the phase as NA.

Three groups appear in the primary outcome record: Active Stimulation-Tier 1, Active Stimulation-Tier 2 and Sham Stimulation. Their reported group sizes are 3, 4 and 3 participants, respectively. The title of the primary outcome frames the comparison as active treatment arms versus sham. These group sizes leave little information for estimating event rates precisely, particularly when the primary outcome is an uncommon safety event. The registry record does not provide the planned allocation ratio or explain how the sequential model governed enrollment or movement between tiers.

Randomization and triple masking are stated, but further implementation details are not reported in the registry record. The record does not say who was masked, how treatment assignment was concealed, or how the stimulation tiers differed. It also does not report a statistical analysis plan, a sample-size justification, or interim-analysis procedures. The description of the study’s aims should not be taken to mean that each aim has a posted result: the primary measure is safety, and the registry names secondary safety outcomes involving early neurologic deterioration, mortality and serious adverse events during 90 days of study participation.

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.

Before assignment: The first 4 patients (3 Active and 1 Sham) were assigned to Tier 1 (1mA of C-tDCS for 20 min) of the study, and the next 6 patients (4 Active and 2 Sham) were assigned to Tier 2 (2mA of C-tDCS for 20 min) of the study.

Overall Study

Analysis population for the primary outcome, as defined in the registry: One SICH occurred in a Tir 2 patient due to a rupture of mycotic aneurysm causing subarachnoid hemorrhage. This misenrollment was later deemed to be a protocol deviation due to not meeting the entry criteria.

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 Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm, measured over At 24-hour post-stimulation.

The primary endpoint is the count of participants with symptomatic intracranial hemorrhage at 24-hour post-stimulation. The registry definition requires a hemorrhage on the 24-hour scan—intracranial parenchymal hemorrhage, subarachnoid hemorrhage or intraventricular hemorrhage—along with an increase of 4 or more points on the National Institute of Health Stroke Scale within 24 hours of stimulation. The NIHSS is described as a quantitative assessment of stroke-related neurological deficits, ranging from 0, indicating no neurological deficits, to a maximum of 42, indicating very severe impairment.

This endpoint is used to assess a potential safety concern after stimulation in people with acute stroke. The registry’s stated safety criterion is lower or equivalent rates of symptomatic intracranial hemorrhage in the active treatment arms compared with sham. Because the endpoint is a count of participants with an event, the result is naturally described as event counts within groups. Counts can be informative for safety monitoring, but with very small groups they provide limited precision about the underlying event rates. The endpoint does not, by itself, measure all aspects of safety, tolerability, feasibility or efficacy.

The posted outcome records one symptomatic intracranial hemorrhage in a Tier 2 patient and zero in Tier 1 and sham. The event narrative says that it followed rupture of a mycotic aneurysm causing subarachnoid hemorrhage, and that the enrollment was later deemed a protocol deviation because entry criteria were not met. That context is relevant to interpreting the event, but it does not erase the event from the posted outcome count.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each person either meets the symptomatic intracranial hemorrhage definition at the specified assessment or does not. The registry reports counts of participants with an event rather than a continuous measurement. For this kind of outcome, the basic descriptive information is the number with the event and the number in the group. Here, the listed group sizes are 3 for Tier 1, 4 for Tier 2 and 3 for sham, with event counts of 0, 1 and 0. Those counts are the direct basis for interpretation; they should not be expanded into conclusions that the record does not support.

What does a count tell us?

A count describes what happened among the participants recorded in a group. It does not, by itself, reveal the true event probability for the broader population from which participants might be drawn. In general, uncertainty is especially important when event counts and group sizes are small. A group with no recorded events can still be compatible with a range of possible underlying risks. A group with one event also leaves substantial uncertainty about how often the event would occur in other participants. Confidence intervals can express this uncertainty, but the registry record does not post confidence intervals for the primary outcome.

The distinction between a descriptive result and an inferential comparison matters. A comparison may be framed as a difference in event rates, a relative measure, or a model-based estimate, each with its own assumptions and uncertainty. The registry record does not include an inferential estimate for active stimulation versus sham. Therefore, the counts can be stated and contextualized, but no precise comparative effect or statistical significance can be attributed to the posted primary result.

Why are the stimulation tiers important?

The outcome lists two active groups rather than one homogeneous active-treatment group. The study is described as dose-escalation, but the actual tier doses and the decision rules for escalation are not reported in the registry record. Pooling tiers would require an explicit rationale and an analysis plan, particularly if the tiers represent different exposures. The primary outcome title refers to active treatment arms compared with sham, but no posted analysis explains how the active groups were combined or compared. The single event in Tier 2 should not be treated as an estimate of a uniform active-treatment risk across both tiers.

The record labels the study model sequential. In general, a sequential design can involve decisions made as data accumulate, but the label alone does not specify the rules, timing or statistical consequences of those decisions. The registry does not report whether there were interim analyses, how escalation decisions were made, or whether any stopping boundaries were used. No such design details can be inferred from the model label alone.

What do the planning assumptions mean?

The registry describes sample-size calculations as planning illustrations computed from the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The effect to detect is described as a stated fraction of the observed effect. These assumptions describe a hypothetical planning exercise, not a prospective justification of the actual enrollment. The sample-size justification used to design the trial is not reported in the registry record.

In general, power is the probability that a planned test will detect a specified effect under assumed conditions when that effect is present. A retrospective planning illustration using an observed effect is not observed power and does not establish that a trial can reliably detect an effect. When observed data are sparse, the estimated effect used for such a calculation can be highly uncertain. Planning quantities should therefore be read as conditional illustrations, not as evidence that the clinical comparison was adequately powered.

The normal approximation is a method for approximating the distribution of a statistic. In general, approximations may be unreliable when data are sparse or event counts are small, and a binary outcome with few events calls for particular caution. The registry record does not state whether a different method was considered or whether any method was prespecified for the primary comparison. The posted record contains no analysis output by which to assess the operating characteristics of a particular test.

How should the event definition be read?

The endpoint requires both imaging evidence of a specified hemorrhage and neurological worsening, defined as an increase of 4 or more NIHSS points within 24 hours of stimulation. This composite definition is more specific than counting any hemorrhage on imaging. It ties the imaging finding to a change in neurological status within a stated period. The registry says the assessment is based on a 24-hour post-stimulation scan. Its narrative identifies the sole event as subarachnoid hemorrhage following rupture of a mycotic aneurysm, but does not separately report the NIHSS change for that participant.

The record’s event narrative also describes the participant as a misenrollment, later deemed a protocol deviation because entry criteria were not met. In general, protocol deviations may affect the interpretation of an analysis, but their treatment depends on prespecified rules and the analysis population. Those rules are not reported. The narrative should therefore be presented alongside the outcome count, without assuming that the participant was removed or retained in a particular analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Active Stimulation-Tier 1", "Active Stimulation-Tier 2", "Sham Stimulation")
n      <- c(3, 4, 3)
events <- c(0, 1, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Active Stimulation-Tier 1  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  Active Stimulation-Tier 2  4  1  25.0  0.6  80.6  4.6  69.9  5.3  71.6
ARM  Sham Stimulation  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 8 outcome measures and identifies 3 secondary safety outcomes: early neurologic deterioration among active patients compared with sham, mortality among active patients compared with sham, and serious adverse events during 90 days of study participation among active patients compared with sham. Considering multiple outcomes can raise a multiplicity issue: in general, testing many hypotheses can increase the chance of at least one apparently notable result by chance. Whether and how to address that issue depends on the planned analysis strategy. A multiplicity adjustment or hierarchy is not reported in the registry record, and no outcome analyses are posted.

The record does not describe missing outcome data, the number of participants with unavailable assessments, or methods for handling missingness. It also does not report the analysis populations, such as whether the primary outcome was analyzed according to randomized assignment or whether participants with protocol deviations were excluded. This is particularly relevant because the primary outcome narrative identifies a Tier 2 participant as a misenrollment and protocol deviation. The registry does not specify how that status affected the analysis.

Randomized allocation is stated, but the record does not report the statistical analysis plan, the prespecified treatment of protocol deviations, or rules for selecting among analysis populations. It also does not describe interim analyses or multiplicity control. Without these details and posted analyses, readers cannot determine from the registry record whether the reported counts correspond to an intention-to-treat, per-protocol or other analysis set, or whether the secondary outcomes were treated as confirmatory or exploratory.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anticipated serious adverse events (66.7%), unanticipated serious adverse event (0.0%).

The registry’s serious adverse event counts are 1 among 3 participants at risk in Active Stimulation-Tier 1, 2 among 4 in Active Stimulation-Tier 2 and 2 among 3 in Sham Stimulation. These are event counts in small groups, not precise comparative estimates. The record also reports other adverse event counts of 1 among 3 in Tier 1, 0 among 4 in Tier 2 and 0 among 3 in sham. The recorded deaths are 0, 2 and 1, respectively. These categories should be kept distinct: serious adverse events, other adverse events and deaths are separately reported fields, and the registry does not explain whether deaths overlap with serious adverse events.

The serious adverse event terms include Anticipated serious adverse events at 66.7% and Unanticipated serious adverse event at 0.0%. The record does not provide enough detail in these summary labels to interpret them as comparative risks or to infer the underlying denominator beyond the listed percentages. Small group counts, limited detail about event timing and the lack of posted comparative analyses all constrain interpretation. The figures describe what is recorded, not whether treatment caused an event or whether one group was safer.

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

The posted primary outcome shows one symptomatic intracranial hemorrhage in Active Stimulation-Tier 2, and none in Active Stimulation-Tier 1 or Sham Stimulation. The event is described as following rupture of a mycotic aneurysm causing subarachnoid hemorrhage. The registry says the enrollment was later deemed a protocol deviation because the patient did not meet the entry criteria. This context is important when assessing the relevance of the event to the intended study population, but the posted count remains part of the registry outcome record.

The result does not establish that tDCS caused the event, nor does the event narrative by itself establish that it was unrelated to stimulation. The registry record does not post an analysis that attributes causation. The count also does not establish that the active treatment met or failed the stated safety criterion of lower or equivalent SICH rates compared with sham. With only 10 participants enrolled and very few events, the observed counts cannot provide a precise estimate of comparative safety.

Absence of an event in the Tier 1 and sham groups is not proof that the event cannot occur in those groups. In general, rare outcomes can be missed in small studies even when the underlying risk is not zero. Conversely, an event in a single participant cannot establish the frequency of the event in a larger population. The registry does not provide confidence intervals or a statistical comparison to quantify the uncertainty.

The study’s stated aims include safety, tolerability, feasibility and potential efficacy, but the primary posted measure addresses SICH. Secondary outcome labels cover early neurologic deterioration, mortality and serious adverse events. The record’s adverse-event counts are descriptive; they do not support a causal conclusion or broad generalization. The record also does not provide enough protocol or analysis detail to determine how the misenrollment was handled analytically. The appropriate interpretation is therefore limited to the recorded outcomes and the uncertainty attached to them.

14. Why This Trial Matters Statistically

This trial raises statistical issues that commonly arise in early, small clinical studies. The randomized and triple-masked design is relevant to reducing some sources of bias, but it does not remove uncertainty created by sparse outcomes. The primary safety endpoint is a binary event, and the posted event count is one across the three groups. Such data can flag an event for careful review, yet they do not yield a precise estimate of how often it might occur.

The dose-escalation setting also matters. Tier 1 and Tier 2 are distinct active groups, but the registry record does not describe their stimulation doses or the rules for moving between tiers. An overall comparison of active treatment with sham may require choices about combining the active groups. Without a reported statistical plan, those choices and their implications cannot be assessed. The sequential model label likewise does not provide enough information to infer how decisions were made as enrollment proceeded.

The protocol deviation illustrates why analysis populations and prespecified handling rules matter. The sole primary outcome event is linked to a participant later deemed ineligible, yet the record does not say whether that participant was included in the primary analysis or how the deviation was treated. Transparent reporting of such decisions is important because including or excluding an event may change a sparse descriptive result.

Finally, planning illustrations based on the observed effect should not be confused with evidence that the trial had sufficient precision. The registry does not report its original sample-size justification, and no inferential analysis is posted. The statistical value of this record is in documenting the study design, outcome definition, observed counts and reporting gaps; it is not a definitive comparative estimate.

15. 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 limitation for interpreting the primary result is the small enrollment: 10 participants across three groups, with group sizes of 3, 4 and 3. The event count is sparse, and the record does not include confidence intervals or inferential comparisons. Consequently, uncertainty about comparative event rates is not quantified.

The sole SICH event occurred in a participant later deemed a protocol deviation for not meeting entry criteria. The event is described as resulting from rupture of a mycotic aneurysm causing subarachnoid hemorrhage. The registry does not report the prespecified handling of this deviation, whether the participant was included in an analysis population, or the NIHSS change associated with the event. This makes it difficult to determine how the event was treated in the formal outcome analysis.

The record does not give the tDCS doses, details distinguishing the tiers, randomization ratio, masking procedures or escalation rules. It identifies the design as sequential but does not report interim analyses or stopping rules. No statistical analysis plan or original sample-size justification is reported. Missing outcome data and analysis populations are also not described.

The registry states that the study had 8 outcome measures and names 3 secondary safety outcomes, but does not post analyses for them. It does not report multiplicity procedures or explain whether the secondary outcomes were confirmatory or exploratory. These omissions limit assessment of how fully outcomes were observed, analyzed and interpreted. The single-center setting and the narrow eligibility description further define the context to which the recorded findings apply; broad generalization is not supported by the posted counts alone.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke — NCT03574038.
• Registry record last updated 2023-06-27; status last verified 2023-06.
• Results first posted 2023-06-08.
• 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.

19. Record Summary

The registry record describes a completed, prospective, single-center, randomized, triple-masked, sequential dose-escalation study of transcranial direct current stimulation in acute stroke. Enrollment was 10. The primary outcome was symptomatic intracranial hemorrhage at 24-hour post-stimulation, reported as counts of 0 among 3 in Active Stimulation-Tier 1, 1 among 4 in Active Stimulation-Tier 2 and 0 among 3 in Sham Stimulation.

The Tier 2 event narrative describes subarachnoid hemorrhage after rupture of a mycotic aneurysm and says the participant was later deemed a protocol deviation for not meeting entry criteria. The registry also lists secondary safety outcomes concerning early neurologic deterioration, mortality and serious adverse events. No outcome analyses are posted. The statistical analysis plan, sample-size justification, missing-data handling, analysis populations and protocol-deviation handling are not reported in the registry record. The counts should therefore be read as descriptive observations with substantial uncertainty, not as a definitive comparative safety conclusion.