A Study of OPC-41061 Orally Disintegrating (OD) Tablets Using 2 Different Formulations and 2 Dosing Regimens in Healthy Adult Male Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of OPC-41061 Orally Disintegrating (OD) Tablets Using 2 Different Formulations and 2 Dosing Regimens in Healthy Adult Male Subjects (NCT02994394), a randomized phase 1 study. The primary outcome is Maximum Plasma Concentration (Cmax) of Tolvaptan.

2. Clinical Question

The clinical question is pharmacokinetic rather than a question about a treatment effect on a health outcome. Maximum plasma concentration, or Cmax, is used to characterize the highest measured plasma concentration after a dose. Comparing this measure across formulations can inform an assessment of whether they produce similar concentration profiles. However, the posted numerical comparisons are unadjusted differences in group means; they are not, by themselves, a formal bioequivalence conclusion. The registry record does not report bioequivalence margins or the sponsor’s formal bioequivalence analysis results.

3. Trial Design

This was a Phase 1 randomized, unmasked crossover study sponsored by Otsuka Pharmaceutical Co., Ltd. The registry lists an enrollment of 84 and a healthy adult male population. The study started on 2017-01-06, reached primary completion on 2017-02-28, and is recorded as completed. The detailed protocol and the original design rationale are not reported in the registry record.

The interventions were OPC-41061 formulations. Cohort 1 received 15 mg conventional tablets with water, 15 mg orally disintegrating tablets without water, or 15 mg orally disintegrating tablets with water. Cohort 2 received the corresponding 30 mg conditions: conventional tablets with water, orally disintegrating tablets without water, or orally disintegrating tablets with water. The record identifies the study as crossover, but sequence allocation, washout details, and period-specific procedures beyond the stated sampling schedule are not reported in the registry record.

Because the study was unmasked, participants and study personnel were not blinded according to the registry classification. Random allocation is recorded, but the method used to generate or conceal allocation is not reported in the registry record. The posted primary endpoint summaries give arm-level means and standard deviations. The outcome analysis population is described as subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3. The registry record does not explain how the crossover structure was incorporated into the sponsor’s inferential model, nor does it give a period, sequence, or carryover analysis.

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: A total of 84 subjects were divided into 2 cohorts of 42 subjects each. The 42 subjects each in 2 cohorts were randomly assigned to the conventional tablet first group, OD tablet with water first group, or OD tablet without water first group according to the randomization code in a 1:1:1 ratio. Forty subjects in Cohort 1 and 41 subjects in Cohort 2 completed the trial.

Period 1 (Days 1 to 3)

Reasons for not completing this period:

Period 2 (Days 4 to 6)

Reasons for not completing this period:

Period 3 (Days 7 and 8)

Analysis population for the primary outcome, as defined in the registry: Bioequivalence analysis set: all subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3.

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: Safety analysis set: all subjects that received at least 1 dose of investigational medicinal product (IMP).

6. Primary Endpoint

The registry lists the primary outcome as Maximum Plasma Concentration (Cmax) of Tolvaptan, measured over Pre-dose and 1, 2, 3, 4, 5, 6, 8, 10, 12, 16 hours post-dose.

The primary endpoint is maximum plasma concentration of tolvaptan, abbreviated Cmax, measured in ng/mL. It is a continuous pharmacokinetic measure: the highest concentration observed in plasma after administration. Concentration sampling was scheduled pre-dose and at 1, 2, 3, 4, 5, 6, 8, 10, 12, and 16 hours post-dose in each period in Cohort 1 and Cohort 2. The registry describes these blood samples as being collected for pharmacokinetic evaluation.

Cmax is used in formulation comparisons because it describes the peak of the measured concentration profile. In general, pharmacokinetic measures can help characterize how drug exposure varies with formulation and administration conditions. Similar mean Cmax values may be relevant to bioequivalence assessment, but a mean comparison alone does not establish bioequivalence. That assessment ordinarily depends on the prespecified analysis and acceptance criteria; those criteria and the formal sponsor analysis are not reported in the registry record.

The posted summaries report the mean and standard deviation for each group. The endpoint population is described as the bioequivalence analysis set, consisting of subjects with both AUCt and Cmax values across the three stated periods. The registry record lists two outcome measures, but the other outcome’s detailed results are not reported in the registry record.

7. Results Posted in the Registry

• Cohort 1: 15 mg OD Tablet Without Water: mean 149.00 versus 131.00 on control; difference 18.00 (95% CI -13.87 to 49.87), standardized effect d = 0.25; z-test p = 0.268.
• Cohort 1: 15 mg OD Tablet With Water: mean 125.00 versus 131.00 on control; difference -6.00 (95% CI -35.81 to 23.81), standardized effect d = -0.09; z-test p = 0.693.
• Cohort 2: 30 mg Conventional Tablet: mean 203.00 versus 131.00 on control; difference 72.00 (95% CI 40.51 to 103.49), standardized effect d = 1.00; z-test p = <0.001.
• Cohort 2: 30 mg OD Tablet Without Water: mean 218.00 versus 131.00 on control; difference 87.00 (95% CI 58.89 to 115.11), standardized effect d = 1.36; z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted endpoint is continuous, and its summary statistic is the mean. The arm summaries pair each mean with a standard deviation. In general, the mean describes the central value of observations, while the standard deviation describes their spread around that mean. A larger standard deviation indicates more variability in individual measurements; it does not describe the uncertainty in the mean in the same way that a confidence interval does.

What the recalculated comparisons represent

The comparison estimates are simple, unadjusted differences between posted group means. For example, a positive difference means that the listed group’s mean Cmax is higher than the reference mean; a negative difference means it is lower. These are recalculations from the posted summary statistics, not a reported sponsor model. They do not incorporate a crossover-specific paired analysis, adjustment for period or sequence, or any other covariate adjustment. The registry record does not report enough detail to determine whether those features were included in the sponsor’s formal analysis.

The comparison estimates are presented in the same concentration units as the endpoint, ng/mL. Their associated confidence intervals quantify uncertainty in the estimated mean difference under the recalculation’s assumptions. A confidence interval that crosses zero is compatible with a range of differences in either direction, including no mean difference. A confidence interval that does not cross zero indicates evidence against a zero difference under the calculation, but it does not establish equivalence or identify the cause of the difference.

How to interpret the p-values

The p-values in the comparisons are unadjusted. In general, a p-value measures how incompatible the observed data are with a specified null hypothesis under a statistical model; it is not the probability that the null hypothesis is true. A small p-value does not measure clinical importance and is not proof of bioequivalence or its absence. Since the 30 mg groups are compared with the 15 mg conventional group, their low p-values reflect differences against that stated reference, not a clean test of the 30 mg formulations against each other.

Multiplicity refers to the increased chance of false-positive findings when many statistical tests are considered. The registry record does not report whether the sponsor adjusted for multiple comparisons, or how any endpoint hierarchy was handled. The recalculated p-values should therefore be read as unadjusted results, not as a family-wise confirmatory analysis. In general, a prespecified multiplicity strategy can help control the interpretation of several related tests.

Why the crossover design matters

In general, a crossover design allows participants to receive different conditions in different periods, so within-participant comparisons can remove some variability between people. That advantage depends on an analysis that respects the repeated measurements and on suitable handling of period and sequence effects. The registry identifies the study as crossover and defines an analysis population across Period 1, Period 2, and Period 3, but the posted summaries and recalculated comparisons do not show the sponsor’s crossover model. The recalculated results should thus be treated as unadjusted group-mean comparisons, not as a replacement for the study’s intended crossover analysis.

Over-dispersion is a general concern when observations vary more than a statistical model assumes. In general, underestimating variability can make standard errors too small and confidence intervals too narrow. The registry record reports standard deviations, but it does not report model diagnostics or whether over-dispersion was assessed. This is not evidence that over-dispersion occurred; it is a limitation on what can be concluded about the model’s adequacy from the record.

What the endpoint population means

The stated bioequivalence analysis set includes subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3. This definition indicates that endpoint availability across periods is relevant to inclusion in that set. The record does not report the number excluded from that analysis set, reasons for missing measurements, or methods for handling missing data. In general, complete-case analyses can be affected if missingness is related to treatment or observed outcomes. Whether that concern applies cannot be determined from the registry record.

These explanations describe general statistical principles. The registry record does not report the original sample-size justification, the formal analysis specification, or a complete set of model details. The posted results support descriptive interpretation and cautious reading of the unadjusted comparisons, rather than reconstruction of an unreported sponsor analysis.

10. Confidence Intervals and Precision

The confidence intervals around the 15 mg comparisons are relatively broad. For the 15 mg orally disintegrating tablet without water versus the 15 mg conventional tablet, the recalculated mean difference is 18.0 ng/mL and its 95% confidence interval extends from -13.87 to 49.87. For the orally disintegrating tablet with water, the estimated difference is -6.0 ng/mL and the interval extends from -35.81 to 23.81. Each interval includes zero and permits values on both sides of zero. The point estimates alone therefore give an incomplete picture of uncertainty.

The three posted comparisons of 30 mg groups against the 15 mg conventional reference have confidence intervals entirely above zero: 40.51 to 103.5 for the 30 mg conventional tablet, 58.89 to 115.1 for the 30 mg orally disintegrating tablet without water, and 39.13 to 94.87 for the 30 mg orally disintegrating tablet with water. These intervals describe uncertainty in unadjusted differences against the 15 mg reference. Because the doses differ, they do not isolate formulation differences at 30 mg.

In general, a confidence interval gives a range of estimates compatible with the data and the calculation’s assumptions. It is not a range containing a known proportion of individual participants’ measurements, and it is not a probability statement about the true value after the data have been observed. Here, the intervals are based on simple recalculations from posted summaries. The registry record does not report confidence intervals from the sponsor’s formal crossover bioequivalence analysis or equivalence bounds. Precision for a mean difference cannot substitute for those missing elements, and it does not determine whether the formulations meet a bioequivalence criterion.

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 sample-size illustrations express the number of participants per arm for 80% power and the number of participants per arm for 90% power. They are planning illustrations based on the observed recalculated effect, not the original trial design assumptions. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set to the stated fraction of the observed effect. These participant figures are per arm, not totals across arms; the record’s convention for time-to-event outcomes is total events, but that convention does not apply to this continuous endpoint.

The 80% power column describes the planned per-arm sample size that, under those assumptions and for the selected effect, would give an 80% chance of detecting an effect at the stated significance level if that effect were the true one. The 90% power column uses a higher target chance of detection and consequently calls for a different planning size. The figures do not describe the study’s achieved power. This is not observed power.

The rows that plan for 75% or 50% of the observed effect ask what sample size would be needed if the effect of interest were smaller than the observed estimate. Smaller effects are harder to distinguish from random variation, so the corresponding illustrations require more participants. The curve serves the same planning purpose by showing how the required sample changes with the effect assumption; it is not a record of enrollment or an outcome of the trial.

The original sample-size justification, the assumptions used when designing the trial, and any planned power calculation are not reported in the registry record. These illustrations should not be used to infer that the trial was designed around the observed results or that the posted comparisons had a particular power.

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, Δ is the difference in means to detect and σ is the common standard deviation.

Worked calculation for this trial

1. Observed difference Δ = 18.000; pooled standard deviation σ = 71.804.
2. n = 2 × (1.96 + 0.842)² × 71.804² / 18.000² = 249.8, rounded up to 250 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
delta <- 18                      # observed difference in means
sigma <- 71.8044566861974                     # pooled standard deviation
n_per_arm <- function(power, frac = 1) {
  ceiling(round(2 * (z_a + qnorm(power))^2 * sigma^2 / (delta * frac)^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 (t-based, so very slightly larger)
cat("power.t.test:", round(power.t.test(delta = delta, sd = sigma, power = 0.80)$n, 1), "\n")

# Simulation: exact two-sample t-test using simulated means and variances
set.seed(2994394)
n    <- n_per_arm(0.80)
reps <- 20000
m_diff <- rnorm(reps, delta, sigma * sqrt(2 / n))             # difference in sample means
s2     <- sigma^2 * rchisq(reps, 2 * (n - 1)) / (2 * (n - 1))   # pooled sample variance
tstat  <- m_diff / sqrt(s2 * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(tstat) > qt(0.975, 2 * (n - 1))), reps))

Output from running the code

100% of observed effect: n per arm = 250 (80% power), 335 (90% power)
 75% of observed effect: n per arm = 445 (80% power), 595 (90% power)
 50% of observed effect: n per arm = 1,000 (80% power), 1,338 (90% power)
power.t.test: 250.8 
Simulated power at n = 250 per arm: 0.802 (20000 replicates)

The simulation draws many sets of group means and variances at the planned sample size and counts how often the two-sample t-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 two outcome measures, but it posts detailed results for the primary endpoint only. The other outcome’s results are not reported in the registry record. The number of posted analyses is recorded as 0, while five unadjusted comparisons are listed for the primary endpoint. The record does not explain how these fields relate to the posted comparison results, so they do not establish a complete analysis inventory.

Multiplicity arises when several endpoints, treatment comparisons, or analysis choices are examined. In general, testing many hypotheses without a prespecified strategy increases the chance that at least one result appears statistically significant by chance. The posted comparison p-values are unadjusted, and the registry record does not report a multiplicity adjustment, hierarchy, or confirmatory testing strategy. This limits the interpretation of the results as a group: an isolated p-value should not be treated as though it came from a single prespecified test unless that analysis plan is documented.

The primary endpoint population is described as subjects with both AUCt and Cmax values across Period 1, Period 2, and Period 3. The record does not provide a flow of subjects into that analysis set, counts of missing endpoint values, reasons for missingness, or imputation procedures. It also does not state how the analysis handled subjects who did not contribute data for every period. Those details matter because a complete-case population can differ from the randomized population, and missingness can affect the interpretation of estimates.

The arm-level endpoint summaries report 39.0 participants for each Cohort 1 condition and 41.0 participants for each Cohort 2 condition. These counts should not be assumed to document the number analyzed under the sponsor’s formal method without a corresponding analysis report. The registry record does not report the formal model, crossover-specific adjustment, missing-data strategy, or sensitivity analyses. The posted results therefore leave important aspects of multiplicity and analysis-population handling unresolved.

14. 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 2% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse events separately for the listed treatment groups. The serious-event count is 0 in each reported group: Cohort 1’s 15 mg conventional tablet, 15 mg orally disintegrating tablet without water, and 15 mg orally disintegrating tablet with water; and Cohort 2’s corresponding 30 mg conditions. The serious-event at-risk counts are 41, 41, 41, 42, 42, and 41, respectively. No deaths are reported in any group.

These figures describe the registry’s serious adverse event summaries; they do not establish that no event of any kind occurred. The record separately reports other adverse events, with at least one affected participant in some groups, so serious and other adverse event categories should not be conflated. In general, a zero count in a study group is a description of the observed record, not proof that the risk is absent. The study population was healthy adult male subjects, and the registry record does not provide enough detail to generalize these safety summaries beyond the reported trial conditions.

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

The posted data show how mean tolvaptan Cmax varied across the described dose, formulation, and administration groups. In Cohort 1, the unadjusted mean differences for both orally disintegrating tablet conditions relative to the 15 mg conventional tablet have confidence intervals that include zero. In Cohort 2, all three reported 30 mg group comparisons are against the 15 mg conventional tablet reference, and each has a positive estimated difference with a confidence interval above zero. These comparisons describe observed concentrations; they do not isolate the effect of formulation when the dose and cohort also differ.

The study’s stated objective was to assess bioequivalence of orally disintegrating and conventional tablets at 15 mg and 30 mg. The registry record does not report bioequivalence acceptance margins or the sponsor’s formal analysis results. Mean differences and unadjusted p-values are not enough to determine whether a bioequivalence criterion was met. In particular, the posted comparisons do not directly compare the 30 mg orally disintegrating tablet with the 30 mg conventional tablet.

The posted results also do not answer whether any formulation changes a clinical outcome or is appropriate for a particular person. The endpoint is a pharmacokinetic concentration measure in healthy adult male subjects, not a measure of symptom benefit or long-term health outcomes. These results should be read as a limited description of the observed pharmacokinetic summaries and recalculated comparisons. The registry record does not report enough detail to extend the findings to other populations or to draw conclusions beyond the stated study conditions.

16. Why This Trial Matters Statistically

This trial illustrates why a stated study objective and the available numerical comparison are not always interchangeable. The objective concerns bioequivalence between formulations at each dose, but the posted comparisons are unadjusted mean differences and use the 15 mg conventional tablet as the reference for every listed comparison. The 30 mg results therefore combine dose and cohort differences with any formulation or administration differences. A statistically clear difference against that reference does not answer whether two 30 mg formulations are equivalent.

It also demonstrates the importance of design-aware analysis. A crossover study can use within-participant information, but simple comparisons of arm means do not show how repeated measurements were modeled. The record identifies a three-period analysis population, while the model details and formal sponsor analysis are not reported in the registry record. Readers need to distinguish the posted summary statistics from a crossover-specific inference.

Finally, the confidence intervals convey more information than point estimates alone, while still leaving key questions open. The 15 mg intervals include zero, and the intervals for the 30 mg groups against the 15 mg reference do not. Neither pattern supplies an unreported equivalence margin or adjustment for multiple comparisons. This is a useful statistical example of why endpoint meaning, comparator choice, design, uncertainty, and analysis plan must be considered together before interpreting a pharmacokinetic study.

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.

The main limitation for interpretation is the structure of the posted comparisons. Each comparison uses the 15 mg conventional tablet group as the reference, including the comparisons involving 30 mg conditions. This prevents those 30 mg estimates from isolating formulation or water-administration differences at the same dose. The registry record does not post a direct 30 mg orally disintegrating versus 30 mg conventional comparison.

The estimates described are unadjusted recalculations from group summary statistics. The study is identified as a crossover trial, but the registry record does not report the formal crossover model, period or sequence effects, or whether the sponsor used within-participant contrasts. The recalculated intervals and p-values may therefore not represent the sponsor’s intended inference. The registry record also does not report equivalence margins, a multiplicity strategy, or the original sample-size justification.

The population is restricted to healthy adult male subjects, and the primary endpoint is a pharmacokinetic measure. The record does not establish applicability to other populations or clinical outcomes. Although the endpoint population definition refers to measurements across Period 1, Period 2, and Period 3, missing-data counts, reasons, and handling methods are not reported in the registry record. The registry lists two outcome measures, but detailed results are posted for only the primary endpoint. These gaps limit assessment of analysis completeness, robustness, and the intended bioequivalence conclusion.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study of OPC-41061 Orally Disintegrating (OD) Tablets Using 2 Different Formulations and 2 Dosing Regimens in Healthy Adult Male Subjects — NCT02994394.
• Registry record last updated 2021-06-28; status last verified 2021-06.
• Results first posted 2021-06-28.
• 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

The registry record describes a completed Phase 1, randomized, unmasked crossover study of OPC-41061 in healthy adult male subjects. The study assessed 15 mg and 30 mg conventional tablets and orally disintegrating tablets administered with or without water. Its primary endpoint was mean maximum plasma concentration of tolvaptan, measured in ng/mL.

The posted means and standard deviations are accompanied by unadjusted recalculated comparisons. The 15 mg comparisons against the conventional tablet have confidence intervals that include zero. The 30 mg group comparisons use the 15 mg conventional tablet as reference, so they do not isolate formulation differences at 30 mg. The registry record does not report the formal bioequivalence analysis, acceptance margins, or multiplicity and missing-data methods.