Phase I Study of OPC-61815: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Phase I Study of OPC-61815 (NCT03510663), a randomized phase 1 study. The primary outcome is Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG).

2. Clinical Question

QTcF is the QT interval corrected for heart rate using Fridericia’s formula. The endpoint concerns a change from each treatment-period baseline and a comparison with placebo at matching times after dosing. The question is therefore about the pattern of QTcF changes over the assessment schedule, not simply a single overall average or a comparison of raw measurements.

The registry lists a baseline assessment and postdose assessments at 1h, 1.5h, 2h, 3h, 4h, 6h, 12h, and 24h. The stated criterion requires the confidence interval’s upper limit to be below 10 msec at all postdose time points for each dose. The record does not state whether that criterion was met.

3. Trial Design

This was a Phase I, randomized, double-blind, single-center, four-period crossover study. The stated purpose was to investigate the effects of intravenous OPC-61815 at 16 and 32 mg on QT/QTc intervals in healthy male subjects. The study also included placebo and moxifloxacin treatment conditions. It was sponsored by Otsuka Pharmaceutical Co., Ltd., and its status is completed.

The registry reports an enrollment of 48. In a crossover design, participants receive multiple treatment conditions in separate periods, so comparisons can account for measurements from the same person under different conditions. This differs from a parallel-group design, in which each participant is assigned to only one treatment group. The registry’s model designation is crossover, and the official title describes four periods.

The treatment descriptions state that OPC-61815 at 16 mg and 32 mg was administered intravenously once a week, placebo was administered intravenously once a week, and moxifloxacin was given as a 400mg tablet once a week. The record describes masking as triple and identifies random allocation. Further details of the masking roles, randomization procedure, treatment sequences, and period schedule are not reported in the registry record.

The study began on 2018-05-08, and primary completion was recorded as 2018-07-05. The primary outcome description specifies repeated QTcF measurements, baseline adjustment, and a model that includes treatment, sequence, treatment period, time point, and a treatment-by-time interaction. The registry record does not report a sample-size justification, the rationale for the enrollment target, or additional protocol details that would clarify those design decisions.

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.

Only the first 6 of 8 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Central tendency analysis for OPC-61815 was performed for subjects in the Pharmacodynamic Analysis Set who appropriately completed all IMP treatments and for whom predose and postdose QT data are available for all 4 treatment periods. One subject was excluded from the central tendency analysis due to lack of QT data following OPC-61815 16 mg, OPC-61815 32 mg, and placebo administration.

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.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Time-matched Difference Between the OPC-61815/Moxifloxacin and Placebo Data in Change From Baseline for QTcF in 12-lead Holter Electrocardiogram (ECG), measured over Baseline, 1h, 1.5h, 2h, 3h, 4h, 6h, 12h, 24h after dosing.

The primary endpoint is the time-matched difference between OPC-61815 or moxifloxacin and placebo in change from baseline QTcF measured by 12-lead Holter electrocardiogram. QTcF adjusts the measured QT interval for heart rate using Fridericia’s formula. Expressing the outcome as change from baseline focuses the comparison on how the measurement shifts after dosing relative to the treatment-period baseline.

The registry describes the reported quantity as a least-squares mean difference, with standard error as the dispersion measure. The analysis description also says point estimates and confidence intervals were calculated. It specifies a criterion for each OPC-61815 dose: the upper limit of the confidence interval for its time-matched difference from placebo was to be evaluated against 10 msec at every postdose time point.

Repeated assessments matter because a treatment-related change may vary over time. The listed schedule includes baseline and measurements at 1h, 1.5h, 2h, 3h, 4h, 6h, 12h, and 24h after dosing. Evaluating matched times preserves the intended comparison between treatment conditions at each point rather than combining measurements taken at different times.

In general, a confidence interval describes uncertainty around an estimated effect under the analysis assumptions. Its upper limit is relevant to the registry’s stated criterion because the question concerns whether that limit remains below the specified threshold. Numerical estimates, standard errors, and confidence intervals are not reported in the registry record, so the endpoint’s observed pattern cannot be described from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome description specifies a linear mixed effect model for the time-matched QTcF comparisons. In general, a mixed model is useful when observations are related, such as repeated measurements from the same participant or measurements collected under several treatment periods. It can represent that dependence while estimating treatment contrasts. The registry identifies subject as a random effect, consistent with modeling participant-level variation, and specifies fixed effects for treatment, sequence, treatment period, time point, and the interaction between treatment and time point.

In general, fixed effects represent the factors whose effects are explicitly estimated in the model. Treatment distinguishes the study conditions; sequence and treatment period account for aspects of the crossover schedule; time point represents the repeated assessment times; and a treatment-by-time interaction allows treatment differences to vary over time. The registry states that baseline QTcF in each treatment period was included as a covariate. Baseline adjustment relates the postdose outcome to the corresponding period’s starting measurement rather than treating all baseline values as interchangeable.

The reported measure is a least-squares mean. In general, a least-squares mean is a model-based mean adjusted for the other terms included in the model, rather than necessarily being the simple arithmetic average of the observations. The registry describes comparisons of changes from baseline, with standard error as the dispersion measure, and says point estimates and confidence intervals were calculated. Standard errors describe the model-based uncertainty in an estimate; confidence intervals express a range of values compatible with the estimate and its uncertainty under the model.

The endpoint is assessed at multiple time points, and the registry’s stated criterion applies at all postdose times. This makes the time-specific estimates important: the model allows the treatment contrast to change with time, while the decision criterion concerns each postdose contrast rather than one pooled summary. The actual estimates and confidence limits are not reported in the registry record, so the model’s numerical output cannot be evaluated.

General statistical interpretation also depends on model assumptions and data quality. Mixed models rely on an appropriate specification of the mean structure and the dependence among repeated measurements. The registry provides the listed model terms, but further diagnostic results, covariance structure, estimation details, and sensitivity analyses are not reported in the registry record. It would be inappropriate to infer those choices or to claim that assumptions were checked in a particular way.

The crossover structure permits within-participant comparisons in principle, but it does not eliminate the need to consider period and sequence effects. The registry includes both as fixed effects in the described model. Details about washout periods, possible carryover considerations, or the evidence used to assess them are not reported in the registry record. The single-center setting and the stated healthy male population also define the context to which findings would pertain; the record does not describe broader populations as part of this study.

The posted planning illustrations use assumptions described as a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect set as a stated fraction of the observed effect. For continuous outcomes, those illustrations are expressed as participants per arm. These are planning calculations, not observed power, and they do not establish the study’s original sample-size rationale. The numerical illustration values are not reported in the registry record. Because the primary outcome has several categories or time points, it was not reduced to one comparison for the planning display.

General concepts such as statistical significance and precision should not be conflated. A significance test addresses evidence against a specified null under a model; a confidence interval communicates an estimated range and its uncertainty. The registry’s described threshold approach centers on an upper confidence limit at every postdose time point. The record does not report a complete statistical analysis plan, a significance-testing hierarchy, interim analyses, or further rules for handling multiple comparisons. Those details cannot be inferred from the mixed-model description alone.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome involves multiple postdose assessment times and comparisons involving OPC-61815 doses, placebo, and moxifloxacin. The registry lists 24 analyses for one outcome measure, but does not report how the multiplicity of comparisons was addressed. No adjustment procedure, testing hierarchy, or prespecified rule for interpreting the family of estimates is reported in the registry record. The stated requirement that the upper confidence limit be below 10 msec at all postdose time points describes the endpoint criterion, but does not by itself establish how multiplicity was handled.

The outcome description identifies a pharmacodynamic analysis set for the central tendency analysis: subjects who appropriately completed all investigational medicinal product treatments and had predose and postdose QT data for all four treatment periods. It also notes that one subject was excluded from that analysis. The full reason is not reported in the registry record; the description ends before the reason is complete. The record does not provide further details about the number of participants contributing to each time-specific estimate or how incomplete measurements were handled.

Missing-data assumptions, imputation methods, and sensitivity analyses are not reported in the registry record. In general, missing repeated measurements can affect estimates if the participants or times with available data differ systematically from those with missing data. The registry’s analysis-population description establishes a completeness requirement for the central tendency analysis, but does not explain whether other analyses used different populations or how missingness was evaluated.

Interim analyses and any additional statistical-plan details are not reported in the registry record. The analysis description should therefore be read as the stated model and endpoint criterion, not as a complete account of all decisions affecting multiplicity, missing data, or analysis populations.

11. 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 event counts of 0 in each listed treatment condition: OPC-61815 16 mg, OPC-61815 32 mg, moxifloxacin, and placebo. It also reports deaths of 0 in each condition. The numbers at risk were 47 for OPC-61815 16 mg, 47 for OPC-61815 32 mg, 48 for moxifloxacin, and 47 for placebo.

For other adverse events, the registry reports 3 affected for OPC-61815 16 mg, 5 for OPC-61815 32 mg, 1 for moxifloxacin, and 2 for placebo. These are the counts recorded for the respective conditions. The record does not provide further detail about event terms, severity, timing, relatedness, or whether a participant experienced more than one event.

Because this is a crossover study, participants received treatment conditions in different periods. Counts across conditions should not automatically be interpreted as if they came from separate, independent groups of participants. Zero serious adverse events in the posted counts means no serious events were recorded in those groups; it does not establish that an event is impossible or characterize risk beyond the study record. The registry does not report additional safety detail in the registry record presented for this analysis.

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

The registry record establishes the study question, the planned comparison structure, and the model terms used for the primary QTcF analysis. It describes an evaluation of time-matched changes from baseline for two OPC-61815 doses against placebo, with moxifloxacin included as a positive control. It also states the criterion involving confidence-interval upper limits at every postdose time point.

However, the numerical primary-outcome findings are not reported in the registry record. Without point estimates and confidence intervals, it is not possible to say whether the differences were small or large, whether they were positive or negative, how precisely they were estimated, or whether the stated criterion was met. The study’s completed status does not answer those statistical questions.

In general, a confidence interval conveys uncertainty around an estimate, and an interval’s upper limit can be compared with a prespecified threshold when that is the stated question. The criterion described for this study is not equivalent to checking only whether a point estimate is below 10 msec: it concerns the upper confidence limit and applies at all postdose assessment times. Those distinctions matter when interpreting an endpoint designed around a threshold.

The record also does not establish effects in populations other than the healthy male subjects named in the study description. Nor does it report a sample-size rationale, detailed missing-data procedures, or all aspects of the statistical plan. The observed safety counts are descriptive registry counts and do not supply the missing efficacy or pharmacodynamic estimates.

Accordingly, the defensible conclusion is limited to what the record documents: the study was randomized, crossover, and designed to assess a specified QTcF comparison using a stated mixed model and confidence-interval criterion. Whether the observed results satisfied that criterion is not reported in the registry record. No broader clinical conclusion follows from the available numerical information.

13. Why This Trial Matters Statistically

This study illustrates why the design and the estimand need to be read together. A crossover trial makes treatment comparisons within a schedule of periods, while the primary outcome compares changes from period-specific baselines at matched postdose times. The registry’s model includes subject, sequence, treatment period, time point, and a treatment-by-time interaction, reflecting the repeated and time-varying structure of the question.

The endpoint also shows the importance of distinguishing an estimate from its uncertainty. The criterion is based on the upper confidence limit, not just the point estimate, and must be considered across the postdose assessment times. A single average could obscure time-specific variation, while a point estimate without its interval would not convey the precision relevant to the stated criterion.

The record highlights the value of reporting complete numerical results. It identifies the outcome, analysis population, model structure, dispersion measure, and threshold, but does not report the estimated contrasts or confidence limits. Without those results, readers cannot judge the magnitude or precision of the observed pattern or determine whether the stated criterion was satisfied.

It also illustrates limits of registry summaries. Enrollment, study status, and adverse-event counts provide useful context, but they do not substitute for endpoint estimates, details of missing-data handling, or a full account of multiplicity. In general, clear reporting of these elements helps readers distinguish the research question, the analysis, and the evidence available to answer it.

14. 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 most direct limitation for interpreting this trial from the registry record is the absence of numerical primary-outcome results. The least-squares mean differences, standard errors, confidence intervals, and time-specific values are not reported in the registry record. As a result, the effect’s direction, magnitude, precision, and relation to the stated threshold cannot be assessed.

The primary outcome description identifies the analysis model and its terms, but other implementation details are not reported in the registry record. These include the covariance structure, estimation details, diagnostic findings, and sensitivity analyses. The record also does not report a complete statistical analysis plan, a multiplicity adjustment method, or interim-analysis details.

The central tendency population description says that one subject was excluded because the required QT data were not available for all four treatment periods, but the full exclusion reason is not reported in the registry record. Further information about missing observations, participant flow into each analysis, and any missing-data sensitivity analyses is not reported. This limits assessment of how the analyzed set relates to all enrolled participants.

The study’s stated population was healthy male subjects, and the trial was single-center. These design features define the study context; the registry record does not establish whether results apply to other populations or settings. Finally, although enrollment and treatment conditions are described, the sample-size justification and the rationale for the planned enrollment are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Phase I Study of OPC-61815 — NCT03510663.
• Registry record last updated 2021-05-10; status last verified 2021-04.
• Results first posted 2021-05-10.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

The registry record describes a completed Phase I, randomized, triple-masked, single-center, four-period crossover study sponsored by Otsuka Pharmaceutical Co., Ltd. It reports enrollment of 48 and a study population of healthy male subjects. The interventions included intravenous OPC-61815 at 16 mg and 32 mg, intravenous placebo, and moxifloxacin.

The primary outcome was the time-matched difference from placebo in change from baseline QTcF measured by 12-lead Holter ECG. The described mixed model included treatment, sequence, treatment period, time point, a treatment-by-time interaction, baseline QTcF as a covariate, and subject as a random effect. The stated criterion concerned the upper confidence limit at all postdose times.

Numerical primary-outcome estimates and confidence intervals are not reported in the registry record. Serious adverse events and deaths were recorded as 0 in each listed condition; other adverse-event counts were 3, 5, 1, and 2, respectively. Further details about multiplicity, missing-data handling, and sample-size justification are not reported in the registry record.