Study of TAK-935 as an Adjunctive Therapy in Participants With Developmental and/or Epileptic Encephalopathies: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of TAK-935 as an Adjunctive Therapy in Participants With Developmental and/or Epileptic Encephalopathies (NCT03166215), a randomized phase 1, phase 2 study. The primary outcome is Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment.

2. Clinical Question

3. Trial Design

The registry record describes a Phase 1b/2a, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-escalation study with an open-label part. The listed phase categories are Phase 1 and Phase 2. Allocation was randomized, masking was quadruple, and the model was parallel group. Takeda is listed as the sponsor. The study is marked completed.

The stated purpose was to characterize the multiple-dose safety and tolerability profile of TAK-935 in adults with developmental and/or epileptic encephalopathies. The official title also names pharmacokinetics and pharmacodynamics as study objectives. Enrollment is listed as 18. The registry record gives a start date of 2017-08-17 and primary completion date of 2018-09-19.

In Part 1, the active group received increasing TAK-935 doses during a titration period, while the comparator group received matching placebo. The posted descriptions specify oral or feeding-tube administration and twice-daily dosing. Part 2 is described as a TAK-935 maintenance period with dose selection at investigator discretion. The Part 2 arm description ends mid-sentence in the registry record, so its full treatment description is not reported in the registry record.

The primary safety endpoint draws on participants in Parts 1 and 2 who received at least one dose. The listed endpoint groups are Part 1 placebo, Part 1 TAK-935, and Part 2 TAK-935. The registry record does not list a Part 2 placebo result in these posted primary results. Because the parts have distinct group entries and the record does not explain participant overlap across them, their participant counts should not be added or treated as separate unique-person totals.

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: Participants with a diagnosis of developmental and/or epileptic encephalopathies were enrolled to receive TAK-935 or placebo in Part 1 \[Double Blind Treatment Period (TP)\] and Part 2 (Open Label TP).

Part 1 (Double-blind TP: Days 1 - 30)

Reasons for not completing this period:

Part 2 (Open-Label TP: Days 31 - 85)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Safety Analysis Set for Parts 1 and 2 included all participants who received at least 1 dose of study drug.

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: Randomized set included all participants who were randomly assigned to treatment through the interactive voice response system/ interactive web response system (IVRS/IWRS).

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With at Least One Treatment-Emergent Adverse Event (TEAE), as Reported by the Participants or Participant's Caregivers or Observed by the Investigator, After TAK-935 Treatment, measured over From first dose up to 30 days post last dose (approximately up to 120 days).

The primary endpoint is the percentage of participants with at least one treatment-emergent adverse event (TEAE), as reported by participants or their caregivers or observed by the investigator. The registry record defines an adverse event broadly as an untoward medical occurrence during a clinical investigation. It need not be considered caused by the study drug. A TEAE is an adverse event whose onset occurs after receiving study drug. The stated timeframe runs from first dose up to 30 days after the last dose, described as approximately up to 120 days.

This endpoint is used to describe the frequency of participants experiencing an event during the specified safety observation period. Counting whether a participant had at least one event gives a participant-level summary: it does not convey how many events each participant experienced, how long events lasted, or their severity. Those questions require other outcome definitions and results.

The endpoint is relevant to a study whose stated purpose includes characterizing safety and tolerability. Its percentage is descriptive, however. It does not establish whether an event was caused by TAK-935, and it is not itself a test of efficacy. The registry record lists the Safety Analysis Set as the population: participants in Parts 1 and 2 who received at least one dose of study drug. The posted percentages should therefore be read in the context of that treated safety population and the specific study parts, rather than as results from a single, common randomized comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: a participant either had at least one TEAE in the specified period or did not. Reporting a percentage makes the outcome easy to describe, but a percentage does not by itself show precision. Its interpretation depends on the number of participants assessed and on the completeness and consistency of event collection. The registry record gives group sizes alongside the percentages, but does not provide confidence intervals for this primary endpoint.

What the primary percentages summarize

The numerator for this kind of measure is the number of participants with one or more qualifying events, and the denominator is the number of participants in the relevant safety group. The posted percentages are 100.0%, 71.4%, and 68.8% for the three listed groups. The record describes the primary population as participants in Parts 1 and 2 who received at least one dose. The posted numbers do not tell whether participants had one event or several, and they do not distinguish events by duration or seriousness. Those details need separate summaries.

The outcome definition also makes an important distinction between temporal occurrence and causation. A TEAE begins after study-drug exposure, but an adverse event need not be caused by the drug. Thus, the endpoint records occurrence during a treatment-related period, not an adjudication that TAK-935 caused each event. This is a general distinction in adverse-event reporting.

What the continuous-outcome comparisons mean

The secondary pharmacokinetic outcomes are reported as means with standard deviations. A mean describes the central value in a group; a standard deviation describes the spread of individual measurements around that mean. A larger standard deviation indicates more variability in the measurements, but does not, on its own, describe the shape of their distribution or the precision of the mean.

The posted recalculated comparisons estimate an unadjusted mean difference between a dose group and the 100 mg BID group. The confidence interval expresses uncertainty around that estimated difference under the calculation assumptions. If an interval spans values on either side of no difference, that would be compatible with a range of possible directions under the method; when it lies on one side, the calculation’s range is consistent with a difference in that direction. These are general principles of confidence intervals. The posted registry record does not report these as sponsor analyses, and the recalculated values should be distinguished from analyses specified by the study team.

The listed p-values for these comparisons are unadjusted. An unadjusted p-value evaluates a single comparison under its statistical assumptions without accounting for the fact that many outcomes or comparisons may be examined. When many tests are considered, the chance of at least one apparently unusual result can increase. The registry record does not report a multiplicity procedure or a confirmatory testing hierarchy, so the posted unadjusted results warrant cautious interpretation.

How to read the planning illustrations

The sample-size illustrations use the observed effect as a reference and consider planning for 100%, 75%, and 50% of that observed effect. They assume a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The resulting entries describe participants per arm for 80% power and participants per arm for 90% power under those assumptions. They are planning illustrations only, not observed power and not evidence that the trial was designed with those assumptions. The registry record does not report the original sample-size justification.

Using an observed effect as the basis for future planning has a limitation: estimates from small samples can be unstable, and an unusually large observed difference can yield optimistic planning figures. Considering smaller fractions of the observed effect is one way to illustrate how required enrollment changes if the effect to detect is more modest. These values still depend on the assumptions and do not substitute for a prespecified design based on a clinically meaningful target.

Over-dispersion is a general concern when an outcome varies more than an assumed statistical model allows. It can make standard errors too small and intervals too narrow if not accounted for. The primary binary endpoint has no dispersion parameter posted, and the registry record does not report a model for that endpoint. For the continuous pharmacokinetic measures, the posted standard deviations show variability, but the record does not state that a model was fitted to account for additional distributional features. Therefore, readers should not infer a specific adjustment or model from the summary statistics alone.

Finally, the primary endpoint and pharmacokinetic summaries answer different questions. A proportion with a TEAE describes participant-level safety occurrence. Concentration and exposure summaries describe drug levels over specified sampling times. A pattern across pharmacokinetic dose groups cannot be interpreted as a clinical effect, nor does a safety percentage establish a pharmacokinetic mechanism. Each result should be read according to its outcome definition, analysis population, and stated limitations.

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("Part 1: Placebo", "Part 1: TAK-935", "Part 2: TAK-935")
n      <- c(4, 14, 16)
events <- c(4, 10, 11)
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  Part 1: Placebo  4  4  100.0  39.8  100.0  51.0  100.0  47.8  99.5
ARM  Part 1: TAK-935  14  10  71.4  41.9  91.6  45.4  88.3  44.9  88.2
ARM  Part 2: TAK-935  16  11  68.8  41.3  89.0  44.4  85.8  44.0  85.8

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 11 outcome measures, while the posted secondary outcomes include measures of pharmacokinetics and laboratory safety. It does not report a multiplicity adjustment, a hierarchy of hypotheses, or which outcomes were intended to be confirmatory. No analyses are listed as reported analyses for the recalculated secondary comparisons, and the primary binary endpoint has no posted comparative p-value or confidence interval. A formal multiplicity strategy is therefore not reported in the registry record.

Multiplicity matters because repeated testing can increase the likelihood of at least one result appearing statistically unusual by chance. An unadjusted p-value addresses a comparison in isolation, not the wider set of outcomes and comparisons. This general issue does not mean that any particular posted result is false; it means that the strength of evidence is harder to assess without knowing which analyses were planned and how testing across outcomes was handled.

Missing-data handling is not reported in the registry record. The primary population is described as participants who received at least one dose, but the record does not state how missing event information, withdrawals, or incomplete follow-up were handled in the endpoint calculation. The registry record also does not describe imputation, exclusions beyond the stated safety-set definition, or sensitivity analyses. These details can matter because the primary timeframe extends from first dose to 30 days after the last dose, approximately up to 120 days.

The analysis populations for each secondary outcome and the handling of missing pharmacokinetic samples are not reported in the registry record. Although group-specific sample sizes are posted for the outcomes with numerical summaries, those values do not explain why records might be unavailable for a particular measurement or whether the same participants contributed to each measure.

Sample-size justification, interim analyses, and a full statistical analysis plan are not reported in the registry record. The posted planning illustrations are recalculations from observed effects and stated assumptions, not the study’s original design rationale. Without a prespecified plan and fuller account of missingness and multiplicity, results should be interpreted as descriptive or exploratory where appropriate, rather than assuming a confirmatory framework.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: seizure cluster (12.5%), seizure (6.2%).

The serious adverse-event figures list 0 among 4 participants in Part 1: Placebo, 1 among 14 in Part 1: TAK-935, and 3 among 16 in Part 2: TAK-935. The listed death count is 0 in each of these groups. These are group-specific counts, and the Part 2 TAK-935 group should not be treated as a randomized placebo comparison because a corresponding Part 2 placebo result is not posted.

The registry record lists Seizure Cluster at 12.5% and Seizure at 6.2% among the top serious-event terms. The record does not specify the denominators for these term percentages in the registry record, so they should not be converted into counts or directly compared with the group-level serious-event counts. Event-term percentages also do not establish treatment causation.

Serious-event counts are not the same as the primary TEAE percentages. A participant may have an event that is not classified as serious, and the primary endpoint includes any qualifying TEAE rather than serious events alone. These summaries describe reported safety occurrence; the small group sizes and absence of a formal comparative analysis limit conclusions about differences between groups.

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

The primary result describes the percentage of participants with at least one TEAE in each posted study group. It does not establish that TAK-935 caused the reported events, because the registry definition does not require a causal relationship. It also does not show how many events occurred per participant, whether events were persistent, or how participants’ health changed apart from the occurrence indicator.

The randomized Part 1 design includes a placebo comparator, but the registry record does not post a formal primary-endpoint comparison or uncertainty interval. The percentages are therefore not enough to establish a statistically reliable difference between placebo and TAK-935. The Part 2 results are also not a placebo-controlled comparison in the posted primary results. They should be read as a separate study-part description, not merged with Part 1 to create a single treatment contrast.

The secondary results describe pharmacokinetic measures across dose groups. Their increasing means across the listed doses and the recalculated unadjusted comparisons describe exposure patterns under the posted summaries. They do not show whether participants experienced clinical benefit, and they do not establish that higher exposure caused or prevented adverse events. The registry record does not provide numerical results for every listed secondary outcome.

The planning illustrations do not indicate the trial’s observed power or demonstrate that its enrollment was adequate for a particular clinical question. They use observed effects and stated assumptions to illustrate future planning values. The original sample-size justification is not reported in the registry record.

More broadly, the record does not report missing-data methods, interim analyses, a full statistical plan, or a multiplicity procedure. Those omissions limit assessment of how completely the analyses followed a prespecified approach and how uncertainty should be judged across outcomes. The posted evidence is consequently best understood as a description of the safety percentages and pharmacokinetic summaries, not a definitive demonstration of treatment effectiveness or a complete comparative safety assessment.

14. Why This Trial Matters Statistically

This study illustrates why the design label and the posted analysis must be considered together. Randomization and placebo control are important design features in Part 1, but the primary endpoint results are presented as group percentages without a formal comparative estimate or its uncertainty. The presence of a randomized design does not itself supply a statistical comparison that the registry record does not report.

It also shows the importance of separating study parts and analysis populations. The posted primary results include Part 1 placebo, Part 1 TAK-935, and Part 2 TAK-935. The groups are not interchangeable, and the registry record does not support treating Part 2 as a parallel placebo-controlled comparison. The Part 2 description and results should not be used to create a contrast that is not posted.

The study’s stated aims include safety, tolerability, pharmacokinetics, and pharmacodynamics. The primary TEAE measure and the secondary concentration and exposure measures address different aspects of those aims. A pharmacokinetic gradient across dose groups is informative about exposure, but it is not a clinical outcome. Keeping these outcome types distinct helps prevent a plausible biological pattern from being overstated as evidence of clinical effect.

Finally, the record makes visible the difference between registry-reported analyses and recalculated exploratory comparisons. The latter can help readers understand the posted summary statistics, but they do not replace sponsor analyses or a prespecified statistical plan. With no reported multiplicity procedure, missing-data approach, or sample-size justification, the most defensible reading emphasizes descriptive results and uncertainty rather than confirmatory claims.

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 posted primary endpoint results are percentages for groups with listed sizes of 4, 14, and 16. These group sizes are small, so a participant’s outcome can have a substantial effect on the reported percentage; this is a general limitation of small-group proportions. The record does not provide confidence intervals for the primary endpoint, making its precision difficult to assess from the posted results alone.

The primary result includes a placebo group only in Part 1. The Part 2 results list TAK-935 without a corresponding placebo arm in the posted results, and the registry record’s Part 2 treatment description is truncated. Comparisons across study parts could be affected by differences between parts or treatment periods, but details needed to assess such differences are not reported in the registry record. Participant overlap between the parts is also not described, so the group counts should not be added.

The TEAE endpoint records whether a participant experienced at least one event, rather than event frequency or severity. Event onset after study-drug exposure does not establish causality. The registry record does not report adjudication procedures, relatedness summaries, or primary-endpoint uncertainty intervals in the registry record for this analysis.

For the secondary pharmacokinetic results, the posted means and standard deviations support descriptive comparisons, but the recalculated contrasts are unadjusted and not listed as sponsor-reported analyses. No multiplicity procedure is reported. Numerical findings for several other listed secondary measures are not reported in the registry record. The sample-size justification, interim analyses, statistical analysis plan, and missing-data methods are also not reported. These limitations constrain both the completeness of the evidence and the strength of conclusions that can be drawn.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of TAK-935 as an Adjunctive Therapy in Participants With Developmental and/or Epileptic Encephalopathies — NCT03166215.
• Registry record last updated 2026-09-14; status last verified 2026-08.
• Results first posted 2020-01-10.
• 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 completed study is listed as a randomized, quadruple-masked, parallel-group Phase 1/2 study with a dose-escalation design and an open-label part. Its stated purpose was to characterize multiple-dose safety and tolerability of TAK-935 in adults with developmental and/or epileptic encephalopathies. The primary endpoint was the percentage of participants with at least one TEAE during the specified observation period.

The posted primary percentages are 100.0% for Part 1 placebo, 71.4% for Part 1 TAK-935, and 68.8% for Part 2 TAK-935. The record does not report a formal primary comparison. Secondary pharmacokinetic summaries show increasing means across the posted dose groups for the outcomes with numerical results, while other listed secondary outcomes are not reported in the registry record. Recalculated secondary comparisons are unadjusted and exploratory. Important details—including the original sample-size justification, multiplicity approach, missing-data methods, and full statistical analysis plan—are not reported in the registry record.