A Study Evaluating the of OPC-34712 in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study Evaluating the of OPC-34712 in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects (NCT01299454), a non-randomized phase 1 study. The primary outcome is Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u).

2. Clinical Question

The study addressed a pharmacokinetic question: whether the amount of unbound brexpiprazole measured in plasma over the observed sampling period differed across participants grouped by hepatic function. It was not designed, as described in the registry record, to compare clinical benefit between treatments. The record states that the broader purpose was to evaluate how much investigational product enters the bloodstream and how long the body takes to eliminate it in people with varying liver impairment relative to people with normal liver function.

The primary endpoint was unbound AUCt, the area under the concentration-time curve through the last observable concentration. The record also lists measures of total exposure, peak concentration, timing of the peak, apparent clearance, unbound fraction, unbound clearance, and terminal elimination half-life. These outcomes characterize different aspects of drug concentration and disposition. However, their numerical results, the contrasts among hepatic-function groups, and any estimates of uncertainty are not reported in the registry record. The question can therefore be described from the design and endpoint definitions, but the magnitude and precision of any observed group differences cannot be assessed from the record information available.

3. Trial Design

This was a Phase 1, single-dose, open-label, non-randomized, parallel-group study of OPC-34712. The official title describes the product as an oral tablet and the groups as matched. The registry record identifies groups with normal hepatic function and mild, moderate, or severe hepatic impairment. It does not report the matching factors, how matching was carried out, or whether the groups were comparable on other characteristics.

The study was completed. Its recorded start was 2010-12, and its primary completion was 2011-06. Enrollment was 45. The registry record does not provide group-level enrollment in the registry record for this description. Although the record names schizophrenia as a condition, it does not explain how that condition related to eligibility or participant selection.

Because allocation was non-randomized and masking was absent, group membership was not assigned through a blinded random allocation process. The groups represent different hepatic-function categories rather than randomized arms receiving alternative treatments. This distinction matters: any contrast in pharmacokinetic measurements is an observational comparison across those groups, and could reflect differences beyond hepatic function. The record does not describe adjustment for such differences.

Blood sampling for the primary pharmacokinetic assessment was scheduled from pre-dose through 168 hours postdose or early termination. The primary endpoint timeframe is Day 1 to Day 8. The record defines a pharmacokinetics set consisting of enrolled participants with evaluable brexpiprazole plasma concentrations and evaluable PK parameters. It does not report how many participants met that definition in each group, how many observations were missing, or the methods used to handle incomplete profiles.

The registry record describes a planning illustration based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that the effect to detect is a stated fraction of the observed effect. The observed effect and the resulting participant-count illustrations are not reported in the registry record, and these planning calculations are not the trial's own design justification.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetics (PK) set consisting of all evaluable brexpiprazole PK parameters from enrolled particpants who had evaluable plasma concentrations.

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.

6. Primary Endpoint

The registry lists the primary outcome as Unbound Brexpiprazole Area Under the Concentration Time Curve (AUC) Calculated to the Last Observable Concentration at Time t (AUCt,u), measured over Day 1 to Day 8.

The primary endpoint is unbound brexpiprazole AUCt,u, reported in nanograms.hours/mL (ng*h/mL). AUC is the area under a concentration-time curve: it summarizes measured drug concentration across time rather than describing only one blood sample. The suffix t indicates that the calculation extends to the last observable concentration, while u indicates that the measure concerns the unbound fraction of brexpiprazole in plasma.

As a general pharmacokinetic concept, unbound drug is the portion not bound to plasma proteins. Measuring unbound exposure can complement total-concentration measures because the unbound fraction may provide a different view of drug present in plasma. AUCt,u therefore combines information about concentration and duration over the observed sampling interval. It does not, by itself, describe clinical benefit or harm.

The record gives the primary endpoint timeframe as Day 1 to Day 8 and describes blood samples from pre-dose through 168 hours postdose or early termination, at specified sampling times. Using an area-under-the-curve measure is useful when the research question concerns overall exposure across a period, rather than peak concentration alone. The record does not report the group means, standard deviations, or comparisons for this endpoint, so the amount of exposure and its precision cannot be assessed from the information recorded.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The study used continuous pharmacokinetic measurements to describe brexpiprazole in groups defined by hepatic function. The primary outcome is the mean unbound AUCt,u, with standard deviation as its stated measure of dispersion. The registry record also lists other pharmacokinetic outcomes, including measures of exposure, peak concentration, clearance, unbound fraction, and elimination half-life.

What does an area under the curve measure?

As a general statistical and pharmacokinetic explanation, a concentration-time curve plots measured concentration against time. Its area summarizes concentration across the observation period. AUC can reflect both the concentration reached and how long concentrations remain measurable. It differs from a single-timepoint measure such as maximum plasma concentration, which focuses on the peak. AUCt uses the last observable concentration as its endpoint; an AUC extrapolated to infinity is a distinct measure and is separately listed among the secondary outcomes.

The primary endpoint is unbound AUCt,u. The record describes sampling at pre-dose, 0.5, 1, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48, 72, 96, 120, 144, and 168 hours postdose or early termination. Those measurements provide the concentration-time observations used to characterize exposure. The record does not describe the specific calculation method used to derive each participant's AUC, nor does it report how early termination or missing samples affected the calculation.

What do the mean and standard deviation convey?

As a general explanation, a mean is an average that summarizes the level of a continuous measure in a group. A standard deviation describes the spread of individual measurements around that mean. A larger standard deviation indicates more variability among observed values, but it is not itself a confidence interval and does not quantify the precision of a group comparison. Precision for a mean or contrast depends on the data and the analysis method.

The primary outcome is defined as a mean with standard deviation. However, the numerical mean and standard deviation for each group are not reported in the registry record. No primary contrast or confidence interval is reported either. Therefore, readers cannot assess from the record whether the group estimates were close together or far apart, or how uncertain a comparison might be.

Why does the study design matter?

The study is non-randomized, open-label, and parallel-group. In a parallel-group design, each participant belongs to a group rather than being described as crossing between study conditions. Here, the groups correspond to hepatic-function categories. As a general principle, randomization can help balance measured and unmeasured characteristics between assigned treatment groups. Because allocation was non-randomized, differences among groups may also reflect other group characteristics. The record does not report adjustment methods that would address such differences.

The official title describes the study as matched, but the matching criteria, matching process, and any paired or matched analysis are not reported in the registry record. It would therefore be inappropriate to infer how matching affected the statistical analysis. The record also does not identify a randomized active comparator; the normal hepatic function group serves as the reference for the study's stated pharmacokinetic question, not as a separately assigned treatment arm.

How should uncertainty and planning calculations be read?

As a general explanation, a confidence interval gives a range of values compatible with the data under a statistical model and conveys uncertainty around an estimate. A narrow interval indicates greater precision than a wide interval, all else being equal. The registry record does not report confidence intervals for the primary endpoint or the group contrasts, so comparative precision cannot be evaluated.

The record describes planning illustrations based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It also describes planning for a stated fraction of the observed effect. Such calculations are prospective illustrations of sample sizes under specified assumptions, not observed power and not evidence about the study's results. The observed effect and the numerical sample-size illustrations are not reported in the registry record. The record does not state that these assumptions were the protocol's original design basis.

What about dispersion and multiple outcomes?

As a general concept, over-dispersion occurs when data vary more than a model assumes. It can make standard errors and confidence intervals too small if the model does not account for the extra variability. This study's primary outcome is continuous and is described using a mean and standard deviation, but the registry record does not provide enough detail to determine whether over-dispersion was assessed or relevant to the analysis. No distributional checks or alternative modeling methods are reported.

The record lists 27 outcome measures and 27 analyses. When many outcomes or comparisons are examined, the chance of at least one apparently notable result can increase if each is assessed separately without accounting for multiplicity. That is a general statistical concern, not a claim about the study's findings. The registry record does not report whether analyses were adjusted for multiple testing, how the 27 analyses map to the outcomes, or which results were designated primary beyond naming unbound AUCt,u as the primary outcome.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("Mild Hepatic Impairment", "Normal Hepatic Function Matched to Mild Hepatic Fu", "Moderate Hepatic Impairment", "Normal Hepatic Function Matched to Moderate Hepati", "Severe Hepatic Impairment", "Normal Hepatic Function Matched to Severe Hepatic ")
n   <- c(8, 8, 8, 8, 6, 6)
m   <- c(5.95, 4.87, 5.41, 4.28, 3.27, 3.63)
sp  <- c(2.58, 1.78, 1.37, 1.95, 0.93, 1.54)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  Mild Hepatic Impairment  8  5.950  2.580  3.793  8.107
CARM  Normal Hepatic Function Matched to Mild Hepatic Fu  8  4.870  1.780  3.382  6.358
CARM  Moderate Hepatic Impairment  8  5.410  1.370  4.265  6.555
CARM  Normal Hepatic Function Matched to Moderate Hepati  8  4.280  1.950  2.650  5.910
CARM  Severe Hepatic Impairment  6  3.270  0.930  2.294  4.246
CARM  Normal Hepatic Function Matched to Severe Hepatic   6  3.630  1.540  2.014  5.246

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 27 outcome measures and 27 analyses. The primary endpoint is identified as unbound brexpiprazole AUCt,u, while the secondary outcomes include additional measures of exposure, peak concentration, timing of peak concentration, clearance, unbound fraction, and elimination half-life. The number of outcomes and analyses does not by itself reveal which comparisons were planned, whether every outcome was analyzed in every group, or whether the analyses were confirmatory or exploratory.

As a general statistical principle, examining multiple outcomes or comparisons can increase the likelihood of finding an apparently notable result by chance if no multiplicity strategy is used. Common approaches include prioritizing a prespecified primary outcome, controlling an overall error rate, or treating secondary findings as exploratory. The registry record does not report a multiplicity adjustment, a hierarchy among secondary outcomes, or the statistical analysis plan needed to determine how these issues were handled. It also does not report interim analyses.

The primary pharmacokinetics population is described as enrolled participants with evaluable brexpiprazole PK parameters and evaluable plasma concentrations. This definition indicates that the primary analysis is not necessarily based on every enrolled participant. Group-specific numbers included in the PK analysis, reasons for exclusion, missing concentration data, and missing-data handling methods are not reported in the registry record. It is also not reported whether any sensitivity analyses assessed the impact of incomplete data.

The registry record does not report a trial-specific sample-size justification. It describes a separate planning illustration based on the observed effect, but the effect estimate and calculated participant counts are not reported. That description should not be treated as evidence about the original design rationale or as observed power.

12. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 0% reporting threshold.

Most frequent non-serious adverse event terms

The safety record lists serious adverse event counts separately from other adverse event counts for each hepatic-function group. For mild hepatic impairment, serious adverse events affected 0 of 8 at risk, and other adverse events affected 3 of 8. For moderate hepatic impairment, serious adverse events affected 0 of 8 at risk, and other adverse events affected 3 of 8. For severe hepatic impairment, serious adverse events affected 0 of 6 at risk, and other adverse events affected 1 of 6. For normal hepatic function, serious adverse events affected 0 of 23 at risk, and other adverse events affected 6 of 23.

These figures describe the number of participants affected, as recorded by group; they do not provide event-level detail, severity beyond the serious-versus-other distinction, timing, or attribution to treatment. The registry record lists no serious adverse event terms. It does not establish that reported events were caused by OPC-34712, and the counts alone do not support a comparative safety conclusion.

Death values are not reported in the registry record. A missing death count should not be read as a confirmed zero. Safety counts are descriptive and should be interpreted in light of the study's non-randomized design and the group-specific numbers at risk.

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

The study's stated purpose was to evaluate brexpiprazole pharmacokinetics across groups with normal hepatic function and hepatic impairment. Its primary measure, unbound AUCt,u, is designed to summarize unbound drug exposure over the observed sampling interval. The registry record also identifies a range of secondary pharmacokinetic measures and provides the scheduled sampling window.

What the registry information does not establish is the magnitude or direction of any difference in exposure across groups. Numerical group results for the primary endpoint are not reported in the registry record. Nor are comparison estimates, confidence intervals, or statistical test results reported. The design and endpoint definitions alone cannot show whether exposure differed, how precisely it was estimated, or whether any difference was clinically important.

The study is non-randomized and open-label. Group membership reflects hepatic-function categories, so a between-group contrast is not equivalent to a randomized treatment effect. The record calls the study matched but does not describe matching criteria or the corresponding analysis. Other group differences and the extent to which analysis accounted for them are not reported.

The record does not establish clinical efficacy, and the primary endpoint is a pharmacokinetic measure rather than a clinical outcome. It also does not establish the presence or absence of treatment-related harm. The listed adverse-event counts are descriptive, and the record does not provide causal attribution or detailed event information. Death values are not reported and should not be interpreted as zero.

Accordingly, the defensible interpretation is limited to the study's purpose, design, outcome definitions, and reported safety counts. A conclusion about the effect of hepatic impairment on brexpiprazole exposure would require the missing group estimates and their uncertainty. The absence of those results in the registry record does not imply that exposure was the same across groups; it means the result cannot be evaluated from the information reported.

14. Why This Trial Matters Statistically

This study is statistically relevant because it frames a pharmacokinetic question around distinct hepatic-function groups and a continuous exposure measure. Unbound AUCt,u integrates concentration over time, while the additional listed outcomes address other parts of drug disposition, including peak concentration, apparent clearance, and terminal elimination half-life. Considering several measures can provide complementary descriptions of a concentration profile, although the registry record does not report their numerical results.

The design also illustrates why the distinction between randomized and non-randomized comparisons matters. The groups are defined by hepatic function, not by random allocation to alternative treatments. As a general principle, measured differences among such groups may reflect characteristics besides the classification used to form them. The record's description of matching signals an intended design feature, but matching criteria and analysis details are not reported, so its statistical implications cannot be assessed.

Another important issue is the difference between an endpoint definition and an endpoint result. The registry record specifies the primary measure, units, timeframe, and sampling schedule, but does not report group estimates or uncertainty. A well-defined outcome makes the research question understandable; it does not by itself answer that question. Without numerical results, the magnitude and precision of any group contrast remain unknown.

Finally, the record lists 27 outcome measures and 27 analyses. This makes the unreported multiplicity strategy relevant to interpretation: as a general matter, multiple analyses can complicate the assessment of chance findings. The record does not report whether or how multiplicity was addressed. Taken together, these features make the study a useful example of how design, outcome selection, missing statistical detail, and incomplete results constrain what can be concluded from a registry record.

15. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

The main limitation for interpretation is that the registry record does not report numerical results for the primary endpoint. Group means, standard deviations, comparison estimates, confidence intervals, and test results are not reported. The listed secondary pharmacokinetic outcomes likewise lack numerical results in the registry record for this description. Thus, the study question and measurement plan can be described, but the observed pharmacokinetic findings cannot be evaluated.

The comparison is non-randomized and open-label. The record calls the groups matched but does not report the matching criteria, how matching was implemented, or whether analyses accounted for it. It also does not report adjustment for other possible group differences. These omissions prevent assessment of how comparable the hepatic-function groups were for purposes of the pharmacokinetic contrast.

The record defines the primary PK set using evaluable parameters and plasma concentrations, but does not report how many participants contributed to each group analysis or how incomplete measurements were handled. The sampling schedule is described, yet the calculation method for the AUC and the handling of early termination are not reported. The statistical analysis plan, multiplicity approach, interim analyses, and trial-specific sample-size justification are also not reported.

Safety information is limited to group-level counts for serious and other adverse events. Event terms and causal attribution are not reported, and death values are not reported. These limitations mean the counts cannot characterize event details or support a causal comparison. The registry record also does not provide participant characteristics beyond the stated condition and hepatic-function categories, limiting assessment of how broadly the results might apply even if outcome estimates were available.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study Evaluating the of OPC-34712 in Subjects With Normal Hepatic Function and Hepatically Impaired Subjects — NCT01299454.
• Registry record last updated 2015-10-20; status last verified 2015-09.
• Results first posted 2015-09-03.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

The registry record describes a completed Phase 1, single-dose, open-label, non-randomized, parallel-group study of OPC-34712, identified as an oral tablet. The study compared pharmacokinetic measurements among groups with normal hepatic function and mild, moderate, or severe hepatic impairment. Enrollment was 45; the recorded start was 2010-12, and primary completion was 2011-06.

The primary endpoint was mean unbound brexpiprazole AUCt,u in nanograms.hours/mL (ng*h/mL), measured over Day 1 to Day 8. The record lists 27 outcome measures and 27 analyses. It defines the PK set using evaluable parameters and plasma concentrations, but does not report group-level primary results or their uncertainty.

Serious adverse events affected 0 participants in each listed group. Other adverse events affected 3 participants in the mild group, 3 in the moderate group, 1 in the severe group, and 6 in the normal hepatic function group. Death values are not reported. The registry information supports description of the study design and outcome definitions, but does not provide the numerical pharmacokinetic findings needed to assess the primary question.