A TAK-831-1001, Single and Multiple Rising Dose Study in Healthy Participants: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A TAK-831-1001, Single and Multiple Rising Dose Study in Healthy Participants (NCT02566759), 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

The primary question is descriptive and safety-focused: it counts participants with at least one treatment-emergent adverse event (TEAE), rather than counting the total number of events each participant experienced. The registry record defines the safety set as participants who received at least one dose of study drug. The outcome’s timeframe runs from baseline to 30 days after the last dose, with the stated end day varying by study part.

The posted results present the TEAE percentage separately for dose cohorts, pooled placebo groups, and the Part 4 formulation and food-condition groups. These comparisons describe the observed event proportions in the groups. They do not, on their own, establish whether any difference was caused by dose, formulation, food condition, or another factor.

Pharmacokinetic outcomes address a different question: how TAK-831 concentrations change after dosing. The registry record lists outcomes such as maximum observed concentration, time to maximum concentration, and areas under the concentration-time curve. Those measures characterize exposure and timing; they are not clinical benefit outcomes. The posted primary result is about the occurrence of at least one TEAE, not efficacy in schizophrenia or cerebellar ataxia.

3. Trial Design

This was a Phase 1, randomized, double-blind, placebo-controlled study of escalating single and multiple doses of TAK-831 in healthy participants. The registry record lists a parallel model and an enrollment of 110. It lists the study as terminated. The start date was 2015-09-23, and the primary completion date was 2016-06-09.

The study was organized into four parts. Part 1 included six single-dose TAK-831 cohorts, ranging from 10 mg to 750 mg, with placebo pooled across the part. Part 2 included four cohorts receiving a dose on Day 1 and once daily from Days 4 to 16, alongside pooled placebo. Part 3 included a 400 mg TAK-831 group dosed once daily from Days 1 to 14 and a placebo group. The posted group sizes in Part 3 were small, including a single participant in the placebo group.

Part 4 evaluated 100 mg TAK-831 as a tablet or suspension under fed or fasted conditions. Its arm descriptions list dosing sequences across periods, with washout intervals described for the sequences. The posted TEAE results give separate groups for tablet fasted, tablet fed, and suspension fasted. The registry record does not report a placebo group for Part 4 in these outcome results.

Across all parts, the registry describes oral TAK-831 suspension, placebo-matching suspension, and TAK-831 tablet. The study’s stated purpose was to determine safety, tolerability and pharmacokinetics. The primary outcome was the percentage of participants experiencing at least one TEAE. The posted secondary outcomes are pharmacokinetic measures, including maximum concentration, time to maximum concentration, and areas under the concentration-time curve. The registry record does not report further detail about the randomization procedure, sequence generation, concealment, or the statistical plan used for the original trial.

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 participants were enrolled in 4 part study to receive TAK-831: single rising dose (SRD) in Part 1; SRD/multiple rising dose (MRD) in Part 2; MRD in Part 3; relative bioavailability(rBA) in 3-sequence crossover in Part 4. Part 3 was terminated due to discomfort observed in participants from the cerebrospinal fluid (CSF) collection procedure.

Only the first 6 of 17 groups are shown.

All Parts

Reasons for not completing this period:

Washout Crossover Period (Part 4:5 Days)

Crossover Treatment (Part 4: 1 Day)

Reasons for not completing this period:

Washout Crossover Period (Part 4:5 Days)

Analysis population for the primary outcome, as defined in the registry: The safety set 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: The safety set included all participants who received at least 1 dose of study drug.

Only the first 6 of 18 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 Baseline up to 30 days after the last dose of study drug (Part 1 Day 31, Part 2 Day 46, Part 3 Day 44 and Part 4 Day 43).

The primary endpoint is the percentage of participants who experienced at least one treatment-emergent adverse event. A TEAE is counted at the participant level for this outcome: a participant with one or more qualifying events is counted as having experienced an event. The outcome does not show the total number of events, their duration, severity, or clinical importance.

The registry record specifies that the safety set includes all participants who received at least one dose of study drug. The follow-up begins at baseline and continues to 30 days after the last dose. The stated endpoint day differs by part: Part 1 Day 31, Part 2 Day 46, Part 3 Day 44 and Part 4 Day 43. These part-specific periods matter when interpreting the percentages, because the opportunity to observe an event is tied to the defined follow-up.

In general, a participant-level TEAE percentage is used to summarize how many participants in each group experienced at least one event during the defined period. It is useful for describing the incidence of participants with events, but it compresses varied experiences into a single yes-or-no outcome. It cannot distinguish one event from multiple events in the same person, and a percentage alone does not indicate seriousness or causality.

The posted results list the percentage for each group, alongside the number of participants in that group. These are descriptive group results. The endpoint is not a measure of treatment benefit, and the registry record does not identify the TEAEs as necessarily caused by TAK-831.

7. Results Posted in the Registry

• Part 4: TAK-831 100 mg Tablet Fasted: 21.7% (5/23) versus 50.0% (6/12) on control; risk difference -28.3 percentage points (95% CI -61.2 to 4.7), risk ratio 0.43 (0.17–1.14); unadjusted two-proportion z-test p = 0.087.
• Part 4: TAK-831 100 mg Tablet Fed: 13.0% (3/23) versus 50.0% (6/12) on control; risk difference -37.0 percentage points (95% CI -68.4 to -5.5), risk ratio 0.26 (0.08–0.86); unadjusted two-proportion z-test p = 0.018.
• Part 4: TAK-831 100 mg Suspension Fasted: 16.7% (4/24) versus 50.0% (6/12) on control; risk difference -33.3 percentage points (95% CI -65.3 to -1.4), risk ratio 0.33 (0.12–0.96); unadjusted two-proportion z-test p = 0.035.

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical methods help distinguish a group’s observed event proportion from the uncertainty around that proportion and from a formal comparison between groups. The registry record posts percentages and group sizes for the primary safety outcome, along with recalculated unadjusted comparisons for selected groups. It does not report the original trial’s full statistical analysis plan, including whether these comparisons were specified in advance.

What does the TEAE percentage describe?

The primary outcome records whether each participant experienced at least one TEAE during the defined follow-up. A percentage is a participant-level summary: participants are classified as having at least one event or not having one. This is different from a rate of events per person or an event count. If one participant experiences several events, the primary outcome still counts that participant once.

Each percentage should be read with its group size. With few participants, a change in the outcome for one person can noticeably alter the reported percentage. This makes estimates from the smaller cohorts less precise. It also means that a percentage at an extreme, such as 100.0%, does not by itself show that the underlying event probability is exactly 100.0% in a wider population.

What does a risk difference mean?

A risk difference compares the event proportions in two groups by subtracting one group’s proportion from the other’s. The posted recalculations express this as the Part 4 group relative to the Part 1 pooled placebo group. A negative value indicates that the observed proportion in the named Part 4 group was lower than in that placebo group. This is a description of the groups being compared; it is not automatically a causal effect, especially when the groups come from different study parts.

The recalculations also include confidence intervals and unadjusted p-values. A confidence interval gives a range of values compatible with the observed data under the statistical method used. If it spans values on both sides of no difference, the estimate is compatible with both a lower and a higher event proportion in the named group. A p-value measures how unusual the observed data, or more extreme data, would be under a stated no-difference model. It does not give the probability that the no-difference model is true, and it does not measure clinical importance.

The three posted p-values are unadjusted. In general, when several comparisons are considered, testing each separately can increase the chance of at least one small p-value even if no true differences exist. A multiplicity adjustment or a prespecified testing hierarchy can address that issue, but the registry record does not report whether the original analysis used either approach. These comparisons should therefore be interpreted as exploratory recalculations rather than as a declared set of confirmatory tests.

What is the role of pharmacokinetic measures?

The secondary outcomes concern concentration and exposure. Maximum observed plasma concentration describes the highest measured concentration after dosing; time to maximum concentration describes when it occurred. Area-under-the-curve outcomes summarize concentration over a defined time interval or, for one measure, to infinity. At steady state, the concentration measure reflects repeated dosing after concentrations have reached a stable pattern. These are general descriptions of pharmacokinetic quantities; the registry’s posted primary result does not report their numerical results.

Pharmacokinetic outcomes and TEAEs answer different questions. Concentration measures characterize drug exposure, whereas the primary endpoint describes the proportion of participants experiencing at least one event. A higher or lower exposure measure cannot be inferred from the TEAE percentages, and the primary outcome does not summarize pharmacokinetic findings.

What can be inferred from the posted comparisons?

The recalculated comparisons use the posted summary counts and are simple, unadjusted comparisons. They do not account for factors that might differ between study parts or for any unreported design features. No discrepancy is flagged between these calculations and the sponsor’s analysis, but the registry record does not provide a full statistical plan or detailed inferential results for the primary outcome. The trial’s original approach to modeling, covariate adjustment, interim analyses and sample-size justification is not reported in the registry record.

In general, randomization can help balance measured and unmeasured factors between groups when groups are randomized directly against one another under the same protocol. However, the posted Part 4 comparisons use the Part 1 pooled placebo group, so the posted summary alone does not establish that these cross-part contrasts preserve a randomized comparison. The differences may be affected by the distinct parts, regimens, follow-up or participant composition. This is why the descriptive event percentages and recalculated tests should be kept separate from causal claims.

10. Confidence Intervals and Precision

Precision concerns how narrowly the data estimate an underlying event proportion or group difference. The posted TEAE percentages come from groups that range from 1 participant in the Part 3 placebo group to 24 participants in the Part 4 suspension fasted group. The Part 1 and Part 2 active-dose cohorts each include 6 participants. Such group sizes leave substantial uncertainty around the percentages, particularly in the smallest cohorts.

The confidence intervals for the recalculated risk differences also communicate uncertainty. For the Part 4 tablet fasted comparison, the interval extends from -0.612 to 0.047; for tablet fed, it extends from -0.684 to -0.055; and for suspension fasted, it extends from -0.653 to -0.013. These intervals are wide, indicating that the estimated differences are not tightly pinned down. The tablet fasted interval includes no difference, while the fed tablet and fasted suspension intervals do not, under these recalculations. These interval results do not resolve the limitations of unadjusted comparisons between different study parts.

A confidence interval is not a guarantee that the true value lies within its particular endpoints. In general, it is a range produced by a method that, over repeated samples under its assumptions, would capture the target value at the stated confidence level. The confidence level used for these comparisons is not reported in the registry record, so no level should be inferred from the intervals alone.

The estimates are also limited by the endpoint’s binary form and the short, part-specific follow-up. The percentage does not show event timing, recurrence, severity or attribution. Group percentages and intervals should therefore be interpreted as imprecise descriptions of the observed safety data, not as exact estimates for a larger population.

11. Planning a Similar Trial: Sample Size

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

The planning figures are illustrations based on the observed effects in the recalculated comparisons, not the original trial’s sample-size plan. They use a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect equal to the stated fraction of the observed effect. The figures are participants per arm, not total participants across both arms and not total events.

The 80% power column gives the number of participants per arm the planning calculation estimates would be needed to have an 80% chance of detecting the selected effect under those assumptions, if that effect were real. The 90% power column gives the corresponding number per arm for a 90% chance. Higher target power generally requires more participants under the same assumptions. For the tablet fed comparison, for example, the calculation gives 24 participants per arm for 80% power and 32 participants per arm for 90% power when planning for 100% of the observed effect.

Each comparison also shows planning scenarios for 75% and 50% of its observed effect. These represent progressively smaller effects to detect; smaller effects need more participants. The calculated requirements are not observed enrollment targets from the trial. They are illustrations of how planning requirements change with the effect size and target power.

This is not observed power. Observed group sizes and outcomes do not establish the probability that the trial detected an effect, and a post hoc power calculation does not replace interpretation of the estimate and its uncertainty. The original trial’s sample-size justification and design assumptions are not reported in the registry record. The figures also should not be treated as a definitive design recommendation, particularly because the comparisons are unadjusted and use groups from different study parts.

12. How the Sample Size Is Derived

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

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.500; treatment proportion p₁ = 0.217; average p̄ = 0.359.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6783 = 1.3294.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.6482 = 0.5455.
4. n = (1.3294 + 0.5455)² / (-0.2826)² = 44.0, rounded up to 45 participants per arm for 80% power.

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

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.5                          # control proportion
p1 <- 0.217391304347826                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(2566759)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 45 (80% power), 59 (90% power)
 75% of observed effect: n per arm = 83 (80% power), 110 (90% power)
 50% of observed effect: n per arm = 192 (80% power), 256 (90% power)
power.prop.test: 44 
Simulated power at n = 45 per arm: 0.815 (20000 replicates)

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

13. Multiplicity, Missing Data and Analysis Populations

The registry record lists a primary TEAE endpoint and multiple secondary pharmacokinetic outcomes. It also posts several treatment groups and three unadjusted recalculations comparing Part 4 groups with the Part 1 pooled placebo group. The record does not report a multiplicity strategy, such as an adjustment across comparisons or a prespecified hierarchy controlling which tests are interpreted as confirmatory.

In general, considering multiple tests makes it more likely that at least one result will appear statistically notable by chance. The unadjusted p-values should therefore be read as individual, exploratory comparisons rather than as a family of results with a known overall error rate. The registry record does not report whether the sponsor conducted additional analyses or applied a multiplicity procedure outside the posted results.

The posted percentages are based on the safety set: participants who received at least one dose of study drug. The registry record does not report details about how missing TEAE information was handled, whether any participant was excluded from the safety analysis, or whether sensitivity analyses were conducted. It also does not report an intention-to-treat analysis population for this endpoint. These omissions matter because outcome completeness and analysis-population definitions can affect interpretation, especially in a small study.

Although the study is listed as randomized and double-blind, details of randomization implementation and blinding assessment are not reported in the registry record. Nor are the original statistical analysis plan, covariate adjustments, interim analyses, or rules for selecting comparisons reported. The absence of these details in the registry record does not establish what procedures were or were not used; it means their role cannot be assessed from the posted record.

14. 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 summary reports zero participants affected in every listed group. The groups include the Part 1 and Part 2 placebo and TAK-831 cohorts, the Part 3 groups, and all three Part 4 formulation and food-condition groups. No serious adverse event terms are listed in the registry record. Death counts are not reported in the registry record.

This serious-event summary is distinct from the primary TEAE outcome. A TEAE may be counted in the primary endpoint without being classified as serious. The reported TEAE percentages therefore should not be interpreted as serious adverse event percentages, and a group with a nonzero TEAE percentage can still have zero participants reported as affected by serious events.

Zero serious events in the posted groups is a description of the observed data, not proof that serious events cannot occur. The groups are small, and the registry record does not provide event-term details or a separate estimate of risk with uncertainty for serious events. The result also concerns healthy participants in this study and does not establish what would occur in another population or under a different regimen.

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

The posted results show that participants in each study group had varying observed percentages of at least one TEAE during the defined follow-up. The percentages differ across dose cohorts and study parts. In Part 4, the reported percentages were lower in the fed tablet group and the fasted suspension group than in the Part 1 pooled placebo group, while the tablet fasted comparison had a less clear unadjusted result. The recalculated p-values and confidence intervals describe these particular summary-data comparisons; they do not establish a causal effect.

The results do not show that TAK-831 works or does not work for schizophrenia or cerebellar ataxia. The study purpose and population were healthy participants, and the primary outcome was a safety measure. The posted data do not establish clinical benefit, treatment effectiveness, or the balance of benefits and harms in patients.

Likewise, the percentages cannot identify which events occurred, how severe they were, how long they lasted, or whether investigators considered them related to study drug. The separate serious-event summary reports no affected participants in the listed groups, but the registry record does not report deaths, and absence of reported serious events does not prove that a risk is absent.

The study’s small groups limit how precisely event proportions and between-group differences can be estimated. The cross-part comparisons also require caution because the recalculations compare Part 4 groups with a pooled placebo group from Part 1. The registry record does not establish that these comparisons were planned or adjusted for differences between parts. The most defensible interpretation is descriptive: the registry lists the observed TEAE percentages, group sizes and serious-event counts for the participating healthy volunteers. Broader conclusions require evidence beyond these posted results.

16. Why This Trial Matters Statistically

This study illustrates why early-phase safety results need to be read together with their group sizes, endpoint definition and study structure. A percentage can look substantial or small while being based on only a few participants. In the Part 3 placebo group, a single participant contributes to the entire group’s observed percentage. Such results are informative as descriptions of the participants enrolled but are imprecise for estimating event frequency beyond the study.

The study also illustrates that an endpoint is defined by what it counts. The primary outcome counts participants with at least one TEAE; it does not describe event burden, seriousness, timing or causality. The serious adverse event summary is a separate measure, and it reports no affected participants in the listed groups. Keeping these outcomes distinct prevents a general event percentage from being mistaken for a serious-event rate.

Finally, the design has several parts, differing regimens and formulation or food-condition groups. The recalculated comparisons use a placebo group from Part 1 as the reference for Part 4 arms. Statistical tests can summarize the observed contrast, but they cannot by themselves remove possible differences between parts or make an unreported comparison prespecified. This is a useful example of how numerical results, study design and missing analysis details jointly determine what can be concluded.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The registry record identifies this as a Phase 1 study in healthy participants and lists an enrollment of 110, but the posted outcome groups are small. Cohorts range from 1 participant to 24 participants. Consequently, observed percentages can be sensitive to individual outcomes, and the precision of group-specific estimates is limited.

The primary endpoint records whether each participant experienced at least one TEAE. It does not provide the number of events per participant, event severity, timing, duration or attribution. The registry record’s serious-event summary reports zero affected participants in every group but gives no serious-event terms; deaths are not reported in the registry record. These omissions constrain the detail available for safety interpretation.

The three recalculated comparisons use Part 1 pooled placebo as the reference for Part 4 groups. Since these groups belong to different study parts, the contrasts may reflect differences beyond the treatment condition. The registry record does not report that these comparisons were prespecified, nor does it provide an original analysis plan or multiplicity approach. The displayed p-values are unadjusted and should be treated as exploratory.

The record also does not report how missing outcome data were handled, whether sensitivity analyses were conducted, or the original sample-size justification. Numerical pharmacokinetic results are not included in the posted outcome information described for this analysis, although secondary pharmacokinetic outcomes are listed. The study’s termination status is recorded, but the reason for termination is not reported in the registry record. These limitations mean the results support a narrow description of the posted safety data rather than broad conclusions about efficacy or risk in other populations.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A TAK-831-1001, Single and Multiple Rising Dose Study in Healthy Participants — NCT02566759.
• Registry record last updated 2021-06-14; status last verified 2021-06.
• Results first posted 2018-02-06.
• 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.

21. Record Summary

NCT02566759 is a Phase 1 randomized, double-blind, placebo-controlled study of single and multiple rising doses of TAK-831 in healthy participants. It is listed as terminated, with an enrollment of 110, a start date of 2015-09-23 and a primary completion date of 2016-06-09.

The primary outcome was the percentage of participants with at least one TEAE during follow-up to 30 days after the last dose, with endpoint days specified by study part. The posted results give group-specific percentages and participant counts. The serious adverse event summary reports zero participants affected in each group; deaths are not reported in the registry record.

Three unadjusted recalculations compare Part 4 groups with Part 1 pooled placebo. Their interpretation is limited by small groups, cross-part comparisons, and the absence of reported details about the original statistical plan, multiplicity handling and missing data.