TAK-114 Single- and Multiple-Dose Phase 1 Study: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for TAK-114 Single- and Multiple-Dose Phase 1 Study (NCT02286518), a randomized phase 1 study. The primary outcome is Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE).

2. Clinical Question

This is a Phase 1 safety and pharmacokinetic study, not a trial designed in the registry record as a test of clinical benefit. Its results therefore address observed adverse-event counts in the listed cohorts and do not establish how TAK-114 compares with a standard treatment or affects a disease. Randomization and masking are recorded, but the detailed allocation procedures and the exact masking arrangements are not reported in the registry record.

3. Trial Design

The registry record describes a randomized, quadruple-masked, parallel-model, single-center Phase 1 study. Enrollment was 82, and the study is recorded as completed. The stated purpose was to evaluate safety and tolerability after single and multiple ascending oral doses, alongside pharmacokinetic assessment. The registry record does not report the detailed randomization process, the identities of the masked parties, or the rationale for the enrollment target.

The study included several parts and cohorts rather than one simple comparison. Part 1 included single-dose cohorts receiving 10 mg, 20 mg or 50 mg, with placebo listed for selected cohorts. Part 2 included 20 mg fasted and fed conditions. The cohort descriptions specify a period in a fasting state and a period 30 minutes after breakfast, with the order differing between the listed sequences. Part 3 included placebo and multiple-dose cohorts receiving 20 mg or 50 mg twice daily for 10 days. These differences matter: a single-dose cohort, a food-effect sequence and a multiple-dose cohort answer different descriptive questions and should not be treated as interchangeable arms of one comparison.

The reported primary safety population is the safety analysis set, defined as participants who received study drug. The primary endpoint timeframe varies by part: it extends from baseline to 3 days after the last dose in Part 1 and Part 2, and to 7 days after the last dose in Part 3. The record gives the corresponding endpoint days as Day 3, Day 20 and Day 17, respectively. The exact cohort-level assignment process, participant flow, and reasons for any exclusions are not reported in the registry record.

Pharmacokinetic outcomes listed include maximum observed plasma concentration, area under the concentration-time curve, terminal elimination half-life, accumulation measures and urinary excretion. Numerical results for these outcomes are not reported in the registry record. The record does not give a detailed analysis plan or a sample-size justification.

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 Japanese, Caucasian participants enrolled in study with 3 parts to receive TAK-114 single rising dose (SRD) (10 milligram \[mg\], 20 mg and 50 mg, once daily) in Part 1, TAK-114 20 mg in fasted and fed conditions, cross-over in Period 1 and 2 of food effect Part 2 and TAK-114 multiple rising dose (MRD) (20 mg, 50 mg twice daily) in Part 3.

Only the first 6 of 14 groups are shown.

All Parts (16 Days)

Washout Crossover Period(Part 2:14 Days)

Crossover Treatment (Part 2: 3 Days)

Analysis population for the primary outcome, as defined in the registry: The safety analysis set includes all participants who received the 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: The safety analysis set was defined as all participants who were enrolled and completed the study.

Only the first 6 of 15 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAE), measured over Baseline up to 3 days after the last dose of study drug (Day 3 in Part 1), (Day 20 in Part 2) and 7 days after the last dose of study drug (Day 17 in Part 3).

The primary endpoint is the number of participants reporting one or more treatment-emergent adverse events (TEAEs). A participant is counted for this endpoint if at least one event meeting the endpoint definition was reported during the stated observation period. The endpoint is therefore a participant count, not a count of all events: a participant with multiple events still contributes as a participant reporting an event.

TEAEs are used in early-phase studies to describe the safety experience after study drug exposure. They provide a structured way to report how many participants experienced an event during the specified timeframe. They do not, on their own, establish that the study drug caused an event, nor do they summarize its severity, duration or clinical importance. Those details require additional event-level information, which is not reported in the registry record.

The timeframe differs by study part. For Part 1 and Part 2, the stated period is baseline up to 3 days after the last dose; for Part 3, it is baseline up to 7 days after the last dose. This difference affects how the counts should be read: the observation windows are not identical across parts. The registry record defines the analysis population as participants who received study drug. It does not report further details about missing safety observations or how participants with incomplete follow-up were handled.

The study also lists pharmacokinetic outcomes, but these are distinct from the primary safety endpoint. Numerical results for the listed pharmacokinetic measures are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a participant count represent?

The primary outcome is binary at the participant level: a participant either reported one or more TEAEs during the observation window or did not. The registry presents the number meeting that definition and the number in the cohort. This is not the same as counting every event, because multiple events in one person do not create multiple participants for the endpoint. General statistical explanation: binary outcomes are often summarized by event counts and denominators because those quantities make the observed cohort experience transparent without implying more precision than the data support.

Why are these results descriptive?

The posted results contain cohort-level counts, while the record reports no analyses. No inferential comparison, p-value or confidence interval is reported for the primary endpoint. A count such as 3 of 6 describes the observed participants in that cohort; it does not by itself determine whether the difference from another cohort is larger than could plausibly arise from sampling variation. General statistical explanation: inferential methods use a model and assumptions to quantify uncertainty about an underlying population quantity. With small groups and sparse events, estimates can be imprecise, and a result with no observed events does not establish that the true event risk is absent.

The record includes multiple dose levels, parts and conditions. The parallel-model label describes the overall design, while the Part 2 cohort descriptions also list fasting and fed periods in different orders. A comparison across distinct groups is not equivalent to a within-participant comparison unless the analysis accounts for the sequence and repeated observations. The registry record does not report the analysis details for Part 2, so no such method should be assumed.

How should the safety summaries be distinguished?

The primary endpoint counts participants with at least one TEAE. The adverse-event summary separately reports participants affected by serious events and other events. Serious events are a subset of safety concerns defined by seriousness criteria; they are not interchangeable with all TEAEs. General statistical explanation: reporting both broad treatment-emergent events and serious events can describe different aspects of a safety profile, but counts alone do not convey event severity, relatedness, duration or clinical course. Those details are not reported in the registry record.

What can confidence intervals and tests add?

General statistical explanation: a confidence interval describes a range of values compatible with the observed data under a specified statistical method and its assumptions. It is useful because it communicates uncertainty around an estimate, not just the estimate itself. A hypothesis test evaluates compatibility with a specified null hypothesis under a model; its p-value is not the probability that a treatment works or that a result occurred by chance. The registry record does not post confidence intervals or tests for these cohort counts. Their absence means the reader cannot use the registry record to assess a formal uncertainty interval or tested between-group difference.

For sparse binary data, conventional approximations can be unreliable, especially when groups have few participants or a count is zero. General statistical explanation: exact methods or carefully selected model-based methods may be considered in such settings, but the method must match the question and design. No particular method, adjustment strategy or model is reported in the registry record, so none can be attributed to this analysis.

What do the planning illustrations mean?

The planning assumptions describe an illustrative calculation based on an observed effect, equal allocation, a two-sided significance level of 0.05 and a normal approximation. Such an illustration is not the study's original sample-size justification and is not observed power. General statistical explanation: planning calculations ask how much information a hypothetical future study might need under chosen assumptions; they do not change the interpretation of the current trial. The assumed effect is especially uncertain when it is based on sparse pilot observations. The registry record does not report the original sample-size rationale, the target effect used in the study's planning, or a prospective power calculation.

The record indicates that some two-arm binary comparisons have missing or non-estimable values. That is a limitation of the comparison output, not evidence of no difference. In a multi-cohort Phase 1 design, an appropriate comparison depends on which groups are genuinely comparable and on the planned analysis. The registry record does not explain the omitted comparisons, so they should not be reconstructed from the cohort counts.

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 SRD-Cohort 1A - 3A: Placebo", "Part 1 SRD-Cohort 1A: TAK-114 10 mg", "Part 1 SRD-Cohort 2A: TAK-114 20 mg", "Part 1 SRD-Cohort 3A: TAK-114 50 mg", "Part 1 SRD - Cohort 1B : TAK-114 10 mg", "Part 1 SRD-Cohort 2B: TAK-114 20 mg")
n      <- c(6, 6, 6, 6, 6, 6)
events <- c(0, 0, 1, 1, 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  Part 1 SRD-Cohort 1A - 3A: Placebo  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part 1 SRD-Cohort 1A: TAK-114 10 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part 1 SRD-Cohort 2A: TAK-114 20 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1 SRD-Cohort 3A: TAK-114 50 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1 SRD - Cohort 1B : TAK-114 10 mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part 1 SRD-Cohort 2B: TAK-114 20 mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The registry lists several dose cohorts, study parts, food conditions and seven secondary outcomes. Considering many outcomes or comparisons raises a multiplicity issue: the more questions examined, the greater the chance that at least one apparently unusual result arises by chance when formal tests are used. General statistical explanation: multiplicity can be addressed through prespecified testing hierarchies, adjustments or a clearly exploratory interpretation. The registry record does not report a multiplicity strategy, a hierarchy of hypotheses or an analysis plan for controlling error across comparisons. Because the primary results are presented as counts and the record reports no analyses, no adjusted or unadjusted significance claims can be made from these data.

Missing-data handling is also not reported in the registry record. The safety population is defined as all participants who received study drug, but the record does not describe whether all such participants completed the full observation period, how incomplete event reporting was treated, or how missing pharmacokinetic observations were handled. The reported cohort denominators provide the number included in the posted results; they do not explain participant flow or any missing observations.

For the primary endpoint, the registry specifies follow-up through 3 days after the last dose in Parts 1 and 2 and through 7 days after the last dose in Part 3. Different follow-up windows can affect the opportunity to observe events, so event counts across parts are not directly interchangeable. The outcome summaries do not provide event timing or duration.

The primary population is the safety analysis set, comprising participants who received study drug. No additional analysis populations are described. Whether analyses were planned for all randomized participants, pharmacokinetics, or other populations is not reported in the registry record.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The serious adverse-event counts are 0 affected participants in every listed group. The corresponding numbers at risk range across the listed cohorts: the registry reports 6 for each Part 1 group, 12 for each Part 2 group, 4 for the Part 3 placebo group and 6 for each Part 3 active-treatment group. These are the reported group counts, not evidence that serious-event risk is zero in the wider population. With small groups, an event that was not observed may still be possible outside the observed participants.

The serious-event summary should not be confused with the primary TEAE endpoint. The primary endpoint includes participants reporting one or more treatment-emergent events, whereas the serious-event figures address events classified as serious. The posted results include participants with other, non-serious adverse events in several cohorts. The record does not provide event terms, severity grading, relationship to study drug, duration, or clinical outcomes for those events. Death counts are not reported in the registry record; a missing death count should not be read as a reported zero.

These summaries are useful for describing the safety observations recorded during the specified follow-up periods. They do not establish whether an event was caused by treatment or allow a precise estimate of uncommon harms.

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

The results establish what was recorded in the listed study cohorts: a count of participants with at least one TEAE, alongside separate serious-event counts. The Part 1 and Part 2 counts were generally low in these small cohorts, while the Part 3 multiple-dose cohorts included several participants with TEAEs. Those observations describe this study's participants and follow-up periods. They do not establish a dose-response relationship, because the parts differ in dosing schedule, cohort composition, sample size and observation window.

The counts do not show whether TAK-114 caused the reported events. Treatment-emergent means that an event occurred after treatment began within the defined period; it does not by itself establish a causal relationship. Nor do the counts describe the type, severity, duration or consequences of each event. The registry record does not report those details.

The serious-event counts are zero in the posted groups, but zero observed events is not proof that serious events cannot occur. The group sizes are small, and the record does not provide uncertainty intervals. The absence of a formal analysis also means the posted results do not establish statistically supported differences between active treatment and placebo or among dose levels.

The study's stated purpose includes pharmacokinetics, and the registry lists concentration and exposure outcomes. Their numerical results are not reported in the registry record, so the safety counts cannot answer questions about drug concentration, absorption, accumulation or elimination. The registry record also does not report enough detail to reconstruct the protocol's analysis plan, the enrollment justification, or handling of missing data.

Overall, these results are an early-phase descriptive account of observed tolerability in healthy male participants. They are not a demonstration of clinical benefit, a definitive comparison among regimens, or a guarantee about safety in populations not represented by the study description.

14. Why This Trial Matters Statistically

This trial illustrates why early-phase safety results require careful attention to design and scale. The study is divided into single-dose, food-effect and multiple-dose parts, with placebo included only in selected cohorts. The resulting counts answer different descriptive questions. A value from a single-dose group should not be treated as directly comparable to a value from a multiple-dose group without considering differences in exposure schedule and follow-up.

Small cohorts make the raw counts essential to interpretation. A count of affected participants is easy to read, but it is also sensitive to individual observations when only a few participants are included. General statistical explanation: this is one reason early-phase studies are often more informative about feasibility, exposure and observed tolerability than about precise population event rates. The registry record does not report confidence intervals or inferential comparisons that would quantify uncertainty.

The record also makes clear that a trial can list pharmacokinetic outcomes without presenting numerical results for them in its registered results. Separating outcomes that are listed from outcomes with reported numerical findings prevents readers from assuming that all study aims can be evaluated from the available record.

Finally, the distinct timeframes and cohort arrangements matter. Part 1 and Part 2 use a shorter stated post-dose window than Part 3, and the Part 2 descriptions include fed and fasted periods in different orders. A sound statistical reading starts with those structural details rather than treating all participant counts as if they arose from one uniform comparison. The record is therefore a useful example of the limits of interpreting multi-part Phase 1 safety counts without a reported analysis plan.

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.

Several limitations are specific to the registry record. The official title refers to healthy adult Japanese and Caucasian male subjects, whereas the brief summary refers to healthy Japanese male participants. The record does not clarify whether both populations were enrolled or explain the difference. Further eligibility and baseline characteristics are not reported in the registry record.

The study includes cohorts with different dose schedules, parts, group sizes and observation windows. Placebo is listed for selected cohorts rather than every active-treatment cohort. These differences limit straightforward comparisons across the posted counts. The food-effect descriptions specify fed and fasted periods in different orders, but the analysis handling of those periods is not reported in the registry record.

Although the registry lists pharmacokinetic outcomes, numerical results for them are not reported in the registry record. The primary safety results provide counts but not event terms, severity, relatedness, timing or duration. Serious adverse-event counts are reported as zero across groups, but death counts are not reported in the registry record.

The record reports no analyses and does not provide inferential estimates or uncertainty intervals for the binary endpoint. It also does not report the original sample-size justification, an analysis plan, multiplicity handling, missing-data procedures, detailed participant flow or reasons for exclusions. These omissions prevent a fuller assessment of the precision and robustness of the findings. The displayed cohort counts remain descriptive and should not be interpreted as a formal comparison of treatment effects.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: TAK-114 Single- and Multiple-Dose Phase 1 Study — NCT02286518.
• Registry record last updated 2016-07-25; status last verified 2016-06.
• Results first posted 2016-07-25.
• 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

NCT02286518 is a completed, randomized, quadruple-masked, parallel-model, single-center Phase 1 study of TAK-114 in healthy male participants. Enrollment was 82. The study included single-dose cohorts, fed and fasted 20 mg conditions, and multiple-dose cohorts receiving TAK-114 20 mg or 50 mg twice daily for 10 days, with placebo in selected cohorts.

The primary endpoint counted participants with one or more TEAEs during part-specific follow-up. The posted counts vary across cohorts; serious adverse-event counts are 0 in each group. The registry lists seven secondary outcomes, including pharmacokinetic measures, but their numerical results are not reported in the registry record. No inferential analyses are reported, and details on the analysis plan, missing data and sample-size justification are not reported in the registry record.