Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation (NCT01483183), a randomized phase 1 study. The primary outcome is Part 1: Maximum (Peak) Plasma Concentration (Cmax).

2. Clinical Question

The trial asked whether ascending doses of intravenous OPC-108459 could be administered safely and tolerably to participants with paroxysmal or persistent atrial fibrillation, and what plasma concentrations followed infusion. Its stated aims differed by part: Part 1 was intended to determine the maximally tolerated dose, while Part 2 was intended to assess potential efficacy of dose or doses of OPC-108459.

The posted primary endpoint is the mean maximum peak plasma concentration, measured in μg/mL over the 24-hour timeframe. It is reported across dose groups and separately for paroxysmal and persistent AF. No comparative estimate between OPC-108459 and placebo is reported for this endpoint. Nor are Part 2 results for time to normal sinus rhythm or duration of normal sinus rhythm included among the posted outcome values described in the registry record.

3. Trial Design

This was a phase 1, randomized, double-blind, placebo-controlled, parallel-group, ascending-dose trial sponsored by Otsuka Pharmaceutical Development & Commercialization, Inc. The registry lists enrollment of 40 and status as terminated. The study start is recorded as 2011-11 and primary completion as 2015-10. The reason for termination is not reported in the registry record.

The protocol description separates the study into two parts. Part 1 was intended to determine the maximally tolerated dose in participants with paroxysmal and persistent AF. Its arm description specifies nine target Cmax levels: 1.0, 1.6, 2.4, 3.6, 5.4, 7.0, 8.0, 9.0, and 10.0 µg/mL. Part 2 was intended to investigate potential efficacy. Its OPC-108459 description states that a second dose could be given if a participant did not convert to sinus rhythm within 10 minutes, to achieve a 25% increase compared with the first infusion.

The posted pharmacokinetic results are arranged by AF subtype and dose in mg/kg. Results are available for several dose groups, but the mean and standard deviation are not reported for the persistent AF 1.35 mg/kg group. The placebo groups appear in the safety information, while the primary pharmacokinetic results shown in the registry record are for OPC-108459 groups. The number of participants contributing to an endpoint can differ from the study enrollment: for example, the pharmacokinetic population was defined by concentration-time profiles consistent with proper infusion, and the safety figures have their own at-risk counts.

Randomization and masking describe how treatment allocation and knowledge of allocation were handled in the study. They do not, by themselves, establish that a reported estimate is a randomized comparison. For the primary endpoint, the registry reports group-specific means rather than a treatment contrast with uncertainty. Details of the sequence generation, allocation concealment, dose assignment procedures, and reasons for terminating the study are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: The trial consists of two parts (Part 1 and Part 2). Each part evaluates two populations of participants for cardioversion in a hospital setting; one diagnosed with paroxysmal atrial fibrillation (AF) and the second diagnosed with persistent AF. However, Part 2 was not conducted and therefore is not included in this document.

Only the first 6 of 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: PK analysis dataset included all participants who had concentration time profiles consistent with proper intravenous infusion.

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 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part 1: Maximum (Peak) Plasma Concentration (Cmax), measured over 24 hours.

The primary endpoint is Part 1 maximum, or peak, plasma concentration (Cmax), summarized as a mean with standard deviation in μg/mL. Cmax is the highest measured plasma concentration after a dose. As a pharmacokinetic measure, it describes systemic drug exposure and can help characterize how exposure varies across dose groups. It does not directly measure whether AF converted to normal sinus rhythm, how long sinus rhythm lasted, or whether participants experienced a clinical benefit.

OPC-108459 was administered as a constant-rate intravenous infusion over 10 minutes. Blood samples were scheduled before dosing, within 45 minutes of dosing, at the end of infusion, and at 0.5, 1, 2, 4, 8, and 24 hours after the infusion start. The stated endpoint timeframe is 24 hours. These repeated samples allow concentration over time to be observed and the peak value to be identified for the pharmacokinetic summary.

The endpoint is relevant to an ascending-dose study because measured exposure can be examined alongside the administered dose and can inform dose characterization. However, the posted mean Cmax values alone do not establish a dose-response relationship, a maximally tolerated dose, or efficacy. Interpretation also depends on the number of observations in each group, the spread of individual values, and whether the pharmacokinetic profiles were suitable for analysis. The registry defines the pharmacokinetic analysis population as participants with concentration-time profiles consistent with proper intravenous infusion; it does not describe other analysis-population definitions.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary endpoint is continuous: Cmax can take a range of measured values rather than being a simple event count. The registry summarizes it with a mean and standard deviation. The mean represents the average concentration in the analyzed group, while the standard deviation describes how dispersed individual concentrations are around that average. These summaries are useful for describing exposure, but they do not by themselves quantify uncertainty in the mean or establish a difference between groups.

What does the standard deviation tell the reader?

In general, a standard deviation describes the spread of observations within a group. It is not the same as a confidence interval, and it does not show how precisely the mean has been estimated. A small standard deviation can indicate that observations cluster relatively closely around the mean, while a larger one indicates more spread. The standard deviation should be interpreted alongside the group size and the shape of the observed data. When groups are small, a few observations can strongly influence both the mean and the estimated spread.

For this endpoint, the registry reports standard deviations for several groups but not for the paroxysmal AF 0.40 mg/kg group. That group has one participant, so a standard deviation is not reported. The persistent AF 1.35 mg/kg group has a listed group size but no reported mean or standard deviation. The registry record does not explain why those values are absent. They should not be imputed from other dose groups or inferred from the planned dose sequence.

Why is there no treatment comparison?

A treatment comparison ordinarily estimates a contrast between groups, such as a difference in mean concentration, and reports uncertainty around that contrast. Here, the registry presents dose-group means for OPC-108459 and does not provide a valid two-arm comparison for the continuous primary endpoint. The record marks values as missing or not estimable for such a comparison. Consequently, there is no reported treatment-effect estimate, confidence interval, or p-value for the primary endpoint to interpret. Comparisons of displayed group means made informally by a reader are not substitutes for a prespecified statistical analysis.

In general, a confidence interval expresses a range of values compatible with the data and the statistical method under its assumptions. Its width reflects precision: a wider interval indicates more uncertainty. Since no confidence interval is reported for these group means or their contrasts, the reader cannot use interval width to assess precision. A p-value, if reported, would address compatibility with a specified null model; it would not measure the size or clinical importance of an effect. No primary-endpoint p-value is reported in the registry record.

How should dose patterns be considered?

An ascending-dose design examines exposure across dose levels, but a sequence of group means is not, on its own, a statistical dose-response analysis. Differences may reflect dose, random variation, the participants in each group, or other factors. A formal analysis might model concentration in relation to dose and account for design features, but the statistical plan and any such model are not reported in the registry record. The available summaries also separate AF subtype, and the record does not report a model testing whether the exposure pattern differs by subtype.

Pharmacokinetic profiles are collected at multiple scheduled time points, but the posted primary summary is Cmax rather than a full concentration-time model. The record states that the pharmacokinetic analysis population included participants with concentration-time profiles consistent with proper intravenous infusion. General pharmacokinetic analysis may use the time course of concentrations to characterize exposure, but the specific estimation procedures beyond the Cmax summary are not reported in the registry record. No additional parameters should be inferred from the listed sampling schedule.

What do planning calculations represent?

In general, a sample-size calculation estimates how many participants would be needed under stated assumptions to detect a defined effect with a chosen level of statistical power. It is a planning exercise, not evidence that a trial had that power after enrollment, and not a measure of whether a result is true. The registry’s planning illustration is described as using a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and fractions of an observed effect. These assumptions do not substitute for the trial’s design rationale, which is not reported in the registry record.

The record also specifies that time-to-event planning illustrations use a total event count, while other illustrations use participants per arm. These are planning conventions, not observed findings. Because the primary continuous endpoint has no estimable two-arm comparison in the posted results, there is no observed treatment contrast on which to base a meaningful effect-detection illustration for this endpoint. Any planning figures should therefore be distinguished from results and should not be described as observed power.

Finally, analyses of continuous outcomes can depend on distributional assumptions. In general, methods based on means may be sensitive to skewed values or influential observations, especially in small groups. A transformed or robust analysis could be considered in some settings, but the registry record does not report whether such methods were used. No additional method, test, or model should be presumed from the descriptive summaries alone.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and four posted secondary-outcome entries. Those entries include the percentage of participants with normal sinus rhythm in Part 1, time to normal sinus rhythm in Part 2, and duration of normal sinus rhythm in Part 2, with duration appearing twice in the list. The primary endpoint is Cmax. When multiple outcomes or dose groups are examined, the chance of finding an apparently notable result by chance can increase. Statistical methods can address multiplicity through prespecified testing strategies or adjusted thresholds, but whether such methods were planned or used is not reported in the registry record.

The registry does not report a statistical analysis plan, a hierarchy for testing outcomes, or any multiplicity adjustment. It also does not provide comparative analyses for the primary endpoint. The record’s analysis count is zero, and the posted Cmax information is descriptive rather than a set of inferential treatment comparisons. The absence of a reported multiplicity method means the reader cannot determine how the study handled repeated comparisons across doses, AF subtypes, and outcomes.

Some primary endpoint values are absent: the mean and standard deviation are not reported for the persistent AF 1.35 mg/kg group, and a standard deviation is not reported for the paroxysmal AF 0.40 mg/kg group. The registry record does not explain whether these omissions reflect missing measurements, analysis exclusions, or another reason. General missing-data methods depend on why measurements are absent and how the missingness relates to observed or unobserved values; those assumptions cannot be evaluated without further information.

The pharmacokinetic analysis population is defined as participants with concentration-time profiles consistent with proper intravenous infusion. The registry does not report the full set of analysis populations, rules for exclusions, imputation procedures, or sensitivity analyses. It is also not reported in the registry record whether an intention-to-treat or per-protocol analysis was conducted. The participant counts displayed for pharmacokinetic and safety results differ in some groups, so each outcome’s denominator should be read from its own report rather than assumed to be identical across analyses.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: major depression (33.3%), atrial fibrillation (20.0%).

The safety entries report counts of participants at risk and participants affected by serious adverse events and other adverse events for each treatment group. Serious adverse events are recorded for 1 of 3 participants at risk in the paroxysmal AF placebo group and 1 of 5 participants at risk in the persistent AF placebo group. Each OPC-108459 group has zero serious adverse events recorded; the at-risk counts range across the listed groups from 1 to 5. These are small groups, so the counts are descriptive and do not establish comparative safety.

For other adverse events, the registry records affected participants in several groups: 1 of 4 at 0.26 mg/kg and 1 of 1 at 0.40 mg/kg in paroxysmal AF; 2 of 5 at 1.00 mg/kg in paroxysmal AF; 1 of 4 at 0.40 mg/kg, 1 of 4 at 1.35 mg/kg, and 1 of 4 at 1.55 mg/kg in persistent AF. No other adverse events are recorded as affecting participants in the other listed OPC-108459 groups. In persistent AF placebo, 2 of 5 are recorded as affected; in paroxysmal AF placebo, zero of 3 are recorded as affected.

The registry lists Major Depression at 33.3% and Atrial fibrillation at 20.0% among the top serious-event terms. The context and denominators for these percentages are not reported in the registry record. Death counts are not reported in the registry record. These entries should not be interpreted as estimates of event risk in a broader population or as proof of a difference between OPC-108459 and placebo.

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

The posted results support a limited descriptive account of plasma exposure after OPC-108459 infusion. Mean peak concentrations are reported for several dose groups, separately for paroxysmal and persistent AF, and standard deviations are available for most groups with a reported mean. They show the observed summaries in the analyzed pharmacokinetic groups; they do not provide a formal estimate of a dose effect or a randomized comparison with placebo.

The values do not establish the maximally tolerated dose. Although Part 1 had that stated purpose, the record does not report a dose-limiting toxicity analysis or a conclusion about a maximum tolerated dose. Nor do the Cmax values establish efficacy. Part 2 was intended to assess potential efficacy, and the listed secondary outcomes concern normal sinus rhythm, but numerical results for those outcomes are not reported in the registry record. Thus the pharmacokinetic endpoint cannot answer whether participants converted to sinus rhythm or how long conversion lasted.

The results also do not establish that exposure differs by AF subtype. Separate descriptive means are given, but there is no reported statistical comparison between paroxysmal and persistent AF. The small group sizes and missing summary values further limit how confidently patterns can be generalized. Without confidence intervals, a reported model, or a comparative test, the precision and statistical compatibility of apparent differences cannot be assessed from the record.

The safety counts offer a record of events in the trial groups, not a definitive comparison of adverse-event risk. Small denominators mean that an event count can change substantially in relative terms with only a small change in the number of affected participants. No comparative safety analysis is reported. The registry’s terminated status is clear, but the reason for termination is not reported in the registry record and should not be inferred from the results.

Overall, the record documents an early-phase, ascending-dose investigation and selected exposure and safety summaries. It does not provide enough reported analysis to draw conclusions about treatment efficacy, comparative safety, the appropriate dose, or how findings might apply beyond these trial groups.

13. Why This Trial Matters Statistically

This trial illustrates an important distinction in clinical research: a pharmacokinetic endpoint can describe exposure without answering an efficacy question. Cmax is useful for characterizing peak plasma concentration following infusion, and the ascending-dose context makes exposure summaries relevant. But a concentration result is not itself a measure of conversion to normal sinus rhythm, symptom change, or other clinical outcome. Keeping that distinction clear prevents a descriptive exposure pattern from being mistaken for proof of a treatment effect.

The record also shows why group size and uncertainty matter. Several dose groups contain few participants, and at least one group has only a single participant in the pharmacokinetic results. Means and standard deviations can be calculated and reported, but their stability and interpretability are limited when group sizes are small. The absence of confidence intervals and formal comparisons leaves uncertainty about how much of the variation between group means may be attributable to chance.

Another statistical lesson is that a randomized, double-blind design does not guarantee that every posted result is presented as a randomized comparison. The trial design includes placebo, yet the primary endpoint results are group-specific OPC-108459 summaries without a reported treatment contrast. Readers need to distinguish design features from the analysis actually reported for a particular endpoint.

Finally, the record emphasizes the value of transparent reporting about analysis populations, missing values, multiplicity, and termination. The pharmacokinetic population has a stated eligibility criterion, but explanations for absent summary values and details of the statistical plan are not reported. Those details help readers assess selection, precision, and the scope of conclusions. Without them, the appropriate statistical reading remains descriptive and cautious.

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 posted primary endpoint information is limited to group means and standard deviations, with no confidence intervals or inferential comparisons. The values are reported for small dose groups, and one dose group has a participant count but no mean or standard deviation. The reason these values are absent is not reported in the registry record. The standard deviation is also absent for the paroxysmal AF 0.40 mg/kg group.

The results describe the pharmacokinetic analysis population, defined by profiles consistent with proper intravenous infusion, rather than an explicitly stated intention-to-treat population. The registry does not give full participant flow, endpoint-specific exclusion rules, missing-data methods, or sensitivity analyses. Safety counts use their own at-risk denominators, which differ from some of the pharmacokinetic group sizes. The record does not explain these differences in detail.

Although the trial was randomized and placebo-controlled, the primary Cmax data do not include a reported placebo comparison or an adjusted analysis. The posted record does not report a statistical analysis plan, the approach to multiple comparisons, or a formal dose-response model. Consequently, the observed group means should not be treated as confirmatory evidence of dose effects or differences between AF subtypes.

The study status is terminated, but the reason is not reported in the registry record. The record also does not provide numerical results for the listed rhythm-related secondary outcomes. These limitations constrain interpretation to the available descriptive pharmacokinetic summaries and event counts, and prevent assessment of the intended efficacy questions from the posted results.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Ascending Dose Study of OPC-108459 Intravenous Infusions in Patients With Paroxysmal and Persistent Atrial Fibrillation — NCT01483183.
• Registry record last updated 2017-04-10; status last verified 2017-02.
• Results first posted 2017-04-10.
• 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

NCT01483183 is a phase 1 randomized, double-blind, placebo-controlled, parallel-group ascending-dose study of intravenous OPC-108459 in people with paroxysmal or persistent atrial fibrillation. Enrollment is listed as 40; the registry status is terminated. The recorded study start is 2011-11 and primary completion is 2015-10.

Part 1 aimed to determine the maximally tolerated dose, while Part 2 aimed to assess potential efficacy. The primary posted outcome is mean maximum peak plasma concentration over 24 hours, summarized with standard deviation. Group-specific pharmacokinetic results are reported for several OPC-108459 doses, with some summary values absent. The record lists rhythm-related secondary outcomes but does not report their numerical results in the posted outcomes.

The record includes serious and other adverse-event counts by group. It does not report a comparative primary-endpoint analysis, confidence intervals, the statistical analysis plan, multiplicity procedures, or the reason the trial was terminated. The findings therefore describe selected exposure and safety data rather than establishing efficacy or a comparative treatment effect.