Safety, Tolerability, and Pharmacokinetics of Escalating Single Doses of TAK-935: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, and Pharmacokinetics of Escalating Single Doses of TAK-935 (NCT02201056), a randomized phase 1 study. The primary outcome is Percentage of Participants Who Experience at Least One Treatment-emergent Adverse Event (TEAE).

2. Clinical Question

This is a dose-escalation safety and tolerability question, not a test of clinical benefit. The study also posted pharmacokinetic outcomes: maximum observed plasma concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast), and area under the plasma concentration-time curve from time 0 to infinity (AUC∞). These outcomes describe drug exposure rather than clinical effectiveness.

The comparison is between each dose cohort and the shared placebo cohort. The posted primary outcome gives a percentage for each group, with group sizes also reported. The registry record does not report a formal inferential comparison for these groups, so the percentages should be read as descriptive results. Because the study enrolled healthy volunteers and evaluated single doses, its findings address the specified short-term exposure and observation period in that study population; they do not directly establish outcomes in other populations or with other dosing patterns.

3. Trial Design

The registry identifies this as a randomized, quadruple-masked, parallel-group Phase 1 study. It is titled “Safety, Tolerability, and Pharmacokinetics of Escalating Single Doses of TAK-935” and is sponsored by Takeda. The study status is completed. The recorded study start is 2014-07, and the primary completion is 2015-07.

Participants were assigned to one of six TAK-935 dose cohorts or to placebo. Each TAK-935 intervention is described as a single oral solution dose on Day 1. The placebo intervention was a placebo-matching solution given once orally on Day 1, and the placebo group is described as covering Cohorts 1-6. Group sizes reported for the primary outcome are 6 participants for each TAK-935 dose cohort and 12 for placebo. The registry record reports overall enrollment of 48; it does not describe the number screened, the number who discontinued, or the details of participant flow.

Randomization and masking are recorded, but the method used to generate the random sequence, conceal allocation, or maintain masking is not reported in the registry record. The details of how dose escalation was organized, including any criteria for moving between doses, are also not reported in the registry record. These details should not be inferred from the dose sequence alone.

The design places the emphasis on safety, tolerability, and pharmacokinetic characterization after a single administration. The registry record identifies the primary safety outcome as the percentage with at least one treatment-emergent adverse event during Day 1 to Day 30. It also lists three pharmacokinetic secondary outcomes. Specific sampling schedules, pharmacokinetic analysis methods, and other protocol details 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.

Before assignment: Healthy Volunteers were enrolled in 1 of 7 treatment groups, once a day placebo, TAK 935 15 mg, 50 mg, 200 mg, 600 mg, 900 mg or 1350 mg.

Only the first 6 of 7 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Safety set included all participants who were enrolled and received 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: Analysis was performed on safety set which included all participants who were enrolled and received study drug.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Who Experience at Least One Treatment-emergent Adverse Event (TEAE), measured over Day 1 to Day 30.

The primary endpoint is the percentage of participants who experienced at least one treatment-emergent adverse event (TEAE) during Day 1 to Day 30. An adverse event is an untoward medical occurrence after administration of a drug; the event does not have to be judged caused by the drug. A TEAE is an adverse event whose onset occurs after study drug is received and within 30 days after the last dose.

This endpoint is used to describe the frequency of participants with an event during the defined observation period. Counting participants with at least one event gives a participant-level summary: a person with multiple events remains represented as a participant who experienced an event. It does not, by itself, describe the number of events per participant, the duration or severity of events, or whether investigators considered an event related to treatment.

For a Phase 1 single-dose study, this safety summary offers a structured way to report events following study drug exposure across dose cohorts and placebo. It is descriptive: the registry record does not report a statistical test or confidence interval for the primary endpoint. Interpretation should therefore focus on the posted group percentages and the small group sizes, rather than treating differences between percentages as established effects. The registry record does not provide further detail on event severity or treatment relatedness for the primary outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either experienced at least one TEAE in the stated period or did not. A percentage is a natural descriptive summary for this type of endpoint because it expresses how common the event status was within a group. The posted percentages are accompanied by the group sizes, which are important context when judging how stable a percentage may be. A percentage based on a small group can change noticeably when the status of one participant changes.

What does a confidence interval add?

General statistical explanation: A confidence interval describes the uncertainty around an estimated quantity under a specified statistical procedure. For a group percentage, it can show a range of values compatible with the observed data and method. An interval is not a guarantee that the underlying value lies within its limits, and it does not by itself establish whether groups differ. The registry record does not report confidence intervals for the primary percentages, so the precision of these estimates cannot be assessed from intervals in the posted results.

How should the cohort percentages be compared?

The values describe each cohort separately. Although a reader may notice that some percentages are numerically higher or lower than others, a numerical contrast is not, on its own, evidence of a reliable treatment difference. Statistical comparison requires an analysis method and an account of uncertainty. The registry record does not report a statistical test, an adjusted estimate, or a confidence interval for a comparison of each TAK-935 cohort with placebo. No formal conclusion about differences among doses or between a dose and placebo can therefore be drawn from the percentages alone.

The placebo cohort is shared across Cohorts 1-6, while each dose is reported as its own cohort. This means that the reported layout presents several dose-specific descriptive comparisons with the same placebo group. Any inferential procedure for such comparisons would need to consider the analysis plan and potentially the fact that multiple comparisons are being considered. The registry record does not report a statistical plan for these comparisons, so it is not appropriate to assume that a particular test or adjustment was used.

What does “over-dispersion” mean in general?

General statistical explanation: For binary outcomes, a simple model may assume that variability is explained by the event probability and the number of participants. Over-dispersion means that the observed variability is greater than that model expects. It can arise when participants differ in important ways or when outcomes are more clustered than the model allows. Methods that account for extra variability can help avoid overstating precision. The registry record does not report an over-dispersion assessment or a model-based analysis for this endpoint; no such method should be inferred from the posted percentages.

What can planning illustrations say?

General statistical explanation: Sample-size calculations can illustrate how many participants per arm might be needed to detect a chosen effect under stated assumptions. Such calculations depend on the assumed effect, significance level, allocation, and statistical approximation. A planning illustration based on an observed effect is not the trial's original design justification and is not observed power. The registry record does not report a sample-size justification. Any planning figures associated with this study should therefore be understood as illustrations under their stated assumptions, rather than as evidence about what the study was designed to establish.

The record describes a randomized, quadruple-masked parallel design, but it does not report the randomization procedure, the precise masking arrangements, or the statistical analysis plan. Those omissions matter because design and analysis details influence how comparisons are interpreted. The primary percentages remain useful as a compact description of the observed safety results, but they do not answer inferential questions that require additional methods or uncertainty estimates.

The three listed secondary pharmacokinetic measures address different summaries of plasma exposure: Cmax is the maximum observed concentration; AUClast covers the area under the concentration-time curve through the last quantifiable concentration; and AUC∞ covers the curve from time 0 to infinity. These are distinct measures, and their estimates require concentration data and analysis procedures. Numerical estimates and the relevant analysis details are not reported in the registry record addressed by these results.

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("Cohorts 1-6: Placebo", "Cohort 1: TAK-935 15 mg", "Cohort 2: TAK-935 50 mg", "Cohort 3: TAK-935 200 mg", "Cohort 4: TAK-935 600 mg", "Cohort 5: TAK-935 900 mg")
n      <- c(12, 6, 6, 6, 6, 6)
events <- c(5, 2, 1, 2, 5, 2)
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  Cohorts 1-6: Placebo  12  5  41.7  15.2  72.3  19.3  68.0  19.2  68.4
ARM  Cohort 1: TAK-935 15 mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Cohort 2: TAK-935 50 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Cohort 3: TAK-935 200 mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Cohort 4: TAK-935 600 mg  6  5  83.3  35.9  99.6  43.6  97.0  42.1  96.3
ARM  Cohort 5: TAK-935 900 mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three secondary pharmacokinetic outcomes: Cmax, AUClast, and AUC∞. It also reports seven outcome measures and no posted analyses. The record does not report whether any formal comparisons were planned across the six dose cohorts, whether the primary outcome was tested against placebo, or whether multiplicity adjustments were specified. When several outcomes or group comparisons are considered, the chance of at least one apparently unusual finding can increase; this is a general statistical concern, not evidence that a particular adjustment was or was not performed in this study.

The analysis population for the primary safety outcome is described as the safety set, including participants who were enrolled and received study drug. The registry record does not describe an intention-to-treat analysis population or explain how participants who did not receive study drug would have been handled. The reported group sizes for the primary outcome are 12 for placebo and 6 for each TAK-935 cohort.

Missing outcome data, withdrawals, and the handling of unavailable observations are not reported in the registry record. It is therefore not possible to determine from these registry entries whether the reported percentages include every participant in the stated safety set, whether any participants had incomplete follow-up, or how missing event information was addressed. The follow-up window is stated as Day 1 to Day 30, but the record does not report completeness of observation for each participant.

Because no analysis methods or multiplicity plan are reported, the primary percentages are best treated as descriptive. This does not imply that no statistical work occurred; it means the registry record does not report the details needed to evaluate formal testing, adjustments, or missing-data assumptions.

12. 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 non-serious adverse event terms

The serious adverse-event results report 0 affected participants in the placebo group, with 12 at risk. Each TAK-935 cohort also reports 0 affected participants, with 6 at risk in each cohort. These figures describe the serious-event counts recorded in the registry. They do not establish that the risk of a serious event is absent; events not observed in these groups remain compatible with uncertainty, particularly when group sizes are small.

The serious-event figures are distinct from the primary TEAE endpoint. The primary outcome includes any qualifying treatment-emergent adverse event, whether or not it was considered related to treatment, whereas the serious-event summary concerns events classified as serious. Other adverse events were also recorded: the registry reports 5 in placebo, 2 at 15 mg, 1 at 50 mg, 2 at 200 mg, 5 at 600 mg, 2 at 900 mg, and 2 at 1350 mg. These are counts of affected participants in the other-event summary, not additional serious-event counts.

Deaths are not reported in the registry record. The absence of a reported death figure should not be interpreted as a reported count of zero. The registry record does not give further serious-event descriptions or event-level details in the posted serious-event summary.

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

The posted results describe the percentage of participants with at least one TEAE during Day 1 to Day 30 for each TAK-935 dose cohort and for placebo. The values vary across cohorts, with the highest reported percentage in the 600 mg cohort. The serious adverse-event summary reports 0 affected participants in each group. Together, these are descriptive observations from a randomized, masked, parallel Phase 1 study in healthy volunteers after a single oral dose.

These results do not establish that TAK-935 caused or prevented the reported events. The TEAE definition does not require a causal relationship to study drug, and the record does not provide a treatment-relatedness breakdown for the primary endpoint. The percentages also do not establish that one dose is safer or less safe than another: no formal comparison, confidence interval, or analysis plan is reported in the registry record. A visible difference between percentages may reflect chance variation as well as any underlying difference.

The findings do not describe safety with repeated administration, longer-term exposure, or use in people with a medical condition. The study population is identified as healthy volunteers, and the intervention is a single dose on Day 1. The results also do not answer a question about clinical efficacy. The primary endpoint is an adverse-event measure, while the listed secondary outcomes concern pharmacokinetics.

Accordingly, the registry results are most informative as a descriptive record of events observed during the specified period and as an indication of the study's scope. They should not be read as proof of no risk, proof of a dose-response pattern, or evidence of clinical benefit. Further details on event severity, relatedness, missing observations, and inferential analyses are not reported in the registry record.

14. Why This Trial Matters Statistically

This trial illustrates how early clinical studies can organize safety observations across escalating dose cohorts while including a placebo group. Its randomized, quadruple-masked, parallel design provides the structure for comparing the reported groups, and the single-dose approach focuses the question on events and drug exposure following one administration. The registry also identifies pharmacokinetic outcomes that describe different aspects of plasma concentration over time.

Statistically, the study highlights the distinction between a descriptive percentage and an inferential conclusion. The percentages communicate how common a TEAE was in each cohort, but the group sizes are small and the registry record does not report confidence intervals or formal tests. That combination makes it especially important not to interpret numerical differences as established contrasts. Reporting the group sizes alongside the percentages helps readers understand the scale of the observations, while still leaving uncertainty unquantified.

The common placebo group and multiple dose cohorts also show why a statistical analysis plan matters. A complete plan would clarify which comparisons were intended, how uncertainty was to be estimated, and whether adjustment for multiple comparisons was considered. Those details are not reported in the registry record. This is a limitation of the information available for interpreting the results, not a basis for assuming that a particular procedure was used.

The endpoint definition provides another important statistical distinction: the primary summary concerns participants with at least one TEAE, not the total number of events or their severity. The separate serious-event summary answers a narrower question. Keeping these summaries distinct prevents a low serious-event count from being mistaken for an absence of all adverse events.

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 primary results are reported as percentages for small cohorts, without confidence intervals or formal comparisons in the registry record. Their precision is therefore difficult to judge, and the descriptive differences should not be treated as established effects. The record also does not report a statistical analysis plan, multiplicity procedures, or a sample-size justification. It is not possible to assess whether the study was designed to detect a particular safety difference.

The safety findings apply to healthy volunteers receiving one oral dose and to the stated Day 1 to Day 30 endpoint window. They do not provide evidence about repeated dosing or other populations. The registry record does not report detailed participant flow, withdrawals, completeness of follow-up, or how missing outcome information was handled. Event severity and treatment relatedness for the primary outcome are not reported in the registry record.

The record lists three pharmacokinetic secondary outcomes but does not include their numerical results in the registry record considered for this interpretation. It also reports no posted analyses. As a result, neither the pharmacokinetic findings nor formal statistical comparisons can be assessed from the recorded details addressed. Serious-event counts are reported, but deaths are not reported in the registry record, and the serious-event summary does not supply event-level descriptions.

Finally, the registry record names the design features but does not describe how randomization or masking was implemented, how dose escalation was governed, or which inferential methods were planned. These omissions limit assessment of the analysis and conduct beyond the basic study structure.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, and Pharmacokinetics of Escalating Single Doses of TAK-935 — NCT02201056.
• Registry record last updated 2026-09-15; status last verified 2026-08.
• Results first posted 2016-07-12.
• 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

NCT02201056 is a completed Phase 1 randomized, quadruple-masked, parallel study sponsored by Takeda. It enrolled healthy volunteers and evaluated single oral solution doses of TAK-935 at 15 mg, 50 mg, 200 mg, 600 mg, 900 mg, and 1350 mg, with placebo as the comparator. The recorded study start is 2014-07, and primary completion is 2015-07.

The primary outcome was the percentage of participants with at least one TEAE from Day 1 to Day 30. The registry reports percentages of 41.7% for placebo and 33.3%, 16.7%, 33.3%, 83.3%, 33.3%, and 33.3% across the TAK-935 dose cohorts in dose order. No serious adverse events were reported in any group; death figures are not reported in the registry record. Three secondary pharmacokinetic outcomes are listed. Formal analysis details, confidence intervals, missing-data handling, and a sample-size justification are not reported in the registry record.