Pharmacokinetics of Voxilaprevir in Adults With Normal Hepatic Function and Moderate or Severe Hepatic Impairment: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Pharmacokinetics of Voxilaprevir in Adults With Normal Hepatic Function and Moderate or Severe Hepatic Impairment (NCT02397707), a non-randomized phase 1 study. The primary outcome is Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast.

2. Clinical Question

The study’s main focus was drug exposure rather than a clinical outcome such as improvement in HCV infection. AUClast measures the area under the plasma concentration-versus-time curve from time zero to the last quantifiable concentration. Comparing this measure across hepatic-function groups can describe differences in observed exposure under the study conditions. It does not, by itself, establish why any difference might occur or what it would mean for repeated dosing or clinical outcomes.

3. Trial Design

This was a phase 1, open-label, parallel-group, single-dose study. It was completed, with enrollment of 33. The registry record gives a study start date of 2015-03-24 and a primary completion date of 2016-03-04. The sponsor was Gilead Sciences.

Participants were classified by hepatic function rather than assigned at random to treatment groups. Participants with moderate hepatic impairment and matched healthy controls received a single dose of voxilaprevir on Day 1. The corresponding description for severe hepatic impairment also states that participants with severe impairment and matched healthy controls received a single dose on Day 1. The normal-function participants were matched to those with impairment on gender, age (± 10 years), and body mass index (± 15%). Matching can make selected characteristics more comparable, but it does not make group assignment random or ensure that groups are comparable on characteristics not used for matching.

Open-label means the registry record does not describe masking. The parallel-group structure means the hepatic-function groups are compared as separate groups, rather than as a crossover in which each participant receives multiple conditions. The design therefore supports a descriptive comparison of pharmacokinetic summaries following a single dose. It does not establish effects of repeated administration, and the registry record does not report an allocation process that would support a randomized causal comparison.

The primary outcome was AUClast, with a specified sampling schedule from pre-dose through 120 hours post-dose. The registry record also lists 3 outcome measures and 6 analyses, but it does not report a full statistical analysis plan or the results for the primary endpoint. Details of eligibility criteria, the rationale for the enrollment target, and any interim analyses 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: 54 participants were screened. 33 participants were enrolled, 14 participants with normal hepatic function, 10 with Moderate Hepatic Impairment (MHI), and 9 with Severe Hepatic Impairment (SHI). Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.

Overall Study

Analysis population for the primary outcome, as defined in the registry: PK Analysis Set included all enrolled participants who took at least 1 dose of study drug and had at least 1 nonmissing postdose concentration value reported by the PK laboratory for the corresponding analyte. Five of the same participants with normal hepatic function served as matched controls for the MHI and SHI Arms/Groups.

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 included all participants who took at least 1 dose of study drug.

6. Primary Endpoint

The registry lists the primary outcome as Pharmacokinetic (PK) Parameter of Voxilaprevir: AUClast, measured over 0 (pre-dose ≤ 5 minutes), 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 16, 24, 48, 72, 96, and 120 hours post-dose.

The primary endpoint is the pharmacokinetic parameter AUClast, measured in h*ng/mL. It is defined as the area under the plasma concentration-versus-time curve from time zero to the last quantifiable concentration. Concentration measurements were scheduled from pre-dose through 120 hours post-dose. The registry record says the intended summaries are unadjusted geometric means with confidence intervals.

As a general statistical concept, an area-under-the-curve measure compresses a series of concentration readings over time into a summary of exposure across the measured period. It can help describe the amount of drug measured in plasma after dosing while accounting for concentrations at different sampling times. AUClast is bounded by the final quantifiable measurement, so it describes exposure over the observed sampling window rather than necessarily representing total exposure over an unlimited period.

Geometric means are commonly used for positive measurements whose values may be right-skewed. A confidence interval communicates uncertainty around an estimated summary; it does not guarantee that the true value lies within the interval. Here, the registry record does not report the actual geometric means or confidence intervals. Consequently, the direction and precision of the primary pharmacokinetic comparison cannot be assessed from the available registry information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical information in the registry record is enough to describe the endpoint and several design features, but not enough to reconstruct the full analysis. The explanations below distinguish the general meaning of the methods from what is specifically reported for this study.

What does AUClast summarize?

As a general concept, pharmacokinetic measurements track drug concentration in plasma over time after dosing. AUClast combines those measurements into an area under the concentration-versus-time curve, from time zero to the last concentration that can be quantified. It gives a summary of measured exposure across that observed interval. Because the endpoint ends at the last quantifiable concentration, it is not automatically a measure of exposure beyond the final usable observation.

The registry record lists sampling at pre-dose and at multiple post-dose times through 120 hours. The planned schedule establishes when samples were to be collected; it does not establish that every participant contributed every scheduled measurement. The record does not report the number of measurements available at each time or how any missing concentration values were handled.

Why use a geometric mean?

As general statistical background, positive pharmacokinetic measures can have asymmetric distributions, with some values substantially higher than others. A geometric mean is a summary that is often useful for positive, skewed measurements. It is calculated on a logarithmic scale and then expressed back on the original scale. This can make a central summary less dominated by very large values than an arithmetic mean. The registry record specifically describes the AUClast summaries as unadjusted geometric means.

“Unadjusted” indicates that the reported summary is not described as adjusted for other variables. The record does not provide a model, covariate list, or adjusted comparison for the endpoint. A geometric mean is a summary of a group’s values; it does not itself quantify a contrast between groups. To evaluate a contrast, readers would need the group estimates and a clearly specified comparison, neither of which is numerically available in the registry record.

How should confidence intervals be read?

In general, a confidence interval expresses uncertainty associated with an estimate under the assumptions of the method used to calculate it. A narrower interval indicates greater precision than a wider interval for the same type of estimate, but precision is not the same as clinical importance. An interval around each group’s geometric mean is also not necessarily the same as an interval for a ratio or difference between groups. The registry record says confidence intervals are reported but does not specify the interval method or provide the numerical intervals for AUClast.

Without the point estimates and intervals, the size of any group separation cannot be evaluated. It is not possible to infer a result from the endpoint name, the sampling schedule, or the presence of a confidence-interval field. The record also does not report a p-value for the primary endpoint, so no significance conclusion can be drawn from the available information.

What does matching contribute?

Matching is a design approach that pairs or aligns participants across groups on selected characteristics. Here, the registry record says healthy controls were matched by gender, age (± 10 years), and body mass index (± 15%). As a general concept, matching can reduce imbalance in those measured characteristics. It does not guarantee balance in unmeasured characteristics, and it does not turn a non-randomized study into a randomized trial.

The registry record describes a parallel-group study with non-randomized allocation and no masking. The resulting group comparisons should therefore be interpreted as comparisons among groups defined by hepatic function, not as randomized comparisons of assigned treatments. The record does not report whether the analysis accounted for the matching in its uncertainty calculations or how the matched structure was handled statistically.

What can the planning illustrations establish?

Sample-size planning illustrations use assumptions to show how many participants per arm might be needed under a hypothetical design and effect size. The stated assumptions for the illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation; the effect to detect is expressed as a stated fraction of the observed effect. These are planning assumptions, not a report of the study’s design rationale. The record does not report a sample-size justification for the trial itself.

Such illustrations are not observed power. Observed power is not a substitute for examining an estimated effect and its uncertainty. The planning assumptions also do not establish that the actual study used equal allocation, a normal approximation, or a two-arm analysis. In this non-randomized study with more than one hepatic-function group, an illustrative two-arm planning framework cannot be taken as a complete description of the clinical study’s analysis.

What analysis details remain unclear?

The PK analysis set includes enrolled participants who took at least 1 dose and had at least 1 nonmissing postdose concentration value reported by the PK laboratory for the corresponding analyte. This definition identifies conditions for inclusion in that set. It does not state how the primary endpoint was calculated for each participant, how values below quantification limits were handled, how missing samples affected the area calculation, or how participants with incomplete profiles were treated. Those details are not reported in the registry record.

The registry record lists 3 outcome measures and 6 analyses, but it does not explain the full mapping between analyses, endpoints, groups, and comparisons. It also does not report the complete statistical analysis plan, the handling of multiplicity, or the method used to calculate confidence intervals. These omissions limit independent assessment of the intended inferential procedure. The posted information supports a description of the design and endpoint, but not a detailed reanalysis of the primary pharmacokinetic comparison.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 3 outcome measures and 6 analyses. Those counts indicate that more than the primary endpoint was considered, but they do not identify all analysis questions, how outcomes were grouped, or which comparisons were treated as confirmatory. A multiplicity strategy—such as a hierarchy of endpoints or an adjustment to control error across tests—is not reported in the registry record. Without those details, the risk of chance findings across multiple analyses cannot be evaluated from the record.

Missing-data handling is also not reported in sufficient detail to reconstruct the analysis. The PK analysis set includes enrolled participants who took at least 1 dose and had at least 1 nonmissing postdose concentration value reported by the PK laboratory for the corresponding analyte. This definition does not explain how incomplete concentration profiles were used in calculating AUClast, whether any values were imputed, or how measurements not quantifiable by the laboratory were handled. These details are not reported in the registry record.

The record does not give group-specific PK analysis-set counts with the primary numerical estimates. Safety group counts are available, but they should not be assumed to equal the PK analysis population. The registry record also does not describe an interim-analysis plan or a complete statistical analysis plan. These gaps make it difficult to assess the degree to which analysis choices could affect the reported endpoint or its uncertainty.

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 5% reporting threshold.

Most frequent non-serious adverse event terms

The safety record lists serious adverse events, other adverse events, and deaths by hepatic-function group. For normal hepatic function, 14 were at risk for serious adverse events and 0 were affected; 14 were at risk for other adverse events and 2 were affected; deaths were 0. For moderate hepatic impairment, 10 were at risk for serious adverse events and 0 were affected; 10 were at risk for other adverse events and 3 were affected; deaths were 0. For severe hepatic impairment, 9 were at risk for serious adverse events and 0 were affected; 9 were at risk for other adverse events and 1 was affected; deaths were 0.

These are descriptive counts. No serious adverse events or deaths are recorded in the listed groups. The record lists no serious adverse-event terms. The other-adverse-event counts indicate that events were recorded in each group, but the registry record does not provide event-term details in the registry record for this summary. The counts alone do not establish whether groups differ meaningfully in safety, and the non-randomized design does not support attributing a group difference to hepatic function or treatment. Follow-up duration for safety outcomes is not reported in the registry record.

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

This study is designed to characterize pharmacokinetics after a single dose of voxilaprevir across groups defined by hepatic function. Its primary endpoint, AUClast, is a measure of plasma exposure over the observed concentration-sampling interval. That focus is different from testing whether a treatment improves HCV infection or from evaluating the effects of a course of repeated dosing.

The registry record describes unadjusted geometric means and confidence intervals as the endpoint summaries, but the numerical AUClast results are not reported in the registry record. As a result, the available information does not establish the magnitude or direction of any exposure difference between groups, or how precisely such a difference was estimated. A conclusion about the primary pharmacokinetic result cannot be drawn from the endpoint definition alone.

The study also records safety outcomes. The listed groups have 0 serious adverse events and 0 deaths, while other adverse events are recorded in each group. These are observations in the recorded groups, not proof that risk is absent or that the groups have equivalent safety. The registry record does not provide a randomized comparison or uncertainty estimates for these outcomes.

More generally, a phase 1, open-label, non-randomized, single-dose study can describe measurements under its study conditions. Matching on gender, age, and body mass index may improve comparability on those characteristics, but unmeasured differences can remain. The registry record does not report enough information to extend findings to repeated administration, other populations, or clinical outcomes. Those questions are not answered by the record’s endpoint definition and safety counts.

13. Why This Trial Matters Statistically

Pharmacokinetic studies ask how drug concentrations behave in the body, and hepatic function can be an important dimension for describing exposure. This trial’s statistical focus is a measurable exposure summary, AUClast, after a single dose. Comparing that summary across hepatic-function groups is a way to characterize the data by group, provided the estimates and their uncertainty are available.

The study also illustrates why design details matter when interpreting a group comparison. Participants were not randomized, and matching was based on gender, age, and body mass index. Those features can support a more structured descriptive comparison, but they do not remove all possible differences between groups. Statistical interpretation must account for the distinction between matching and random allocation.

The registry record’s missing numerical primary endpoint results are consequential. An endpoint definition and a plan to report confidence intervals do not show how large or precise the observed estimates were. Readers need the actual estimates and intervals to evaluate the strength of the evidence about exposure. Without those values, the statistical question is identifiable, but its answer is not available in the registry record.

Finally, the record separates pharmacokinetic assessment from safety reporting. The group-specific safety counts can be described, but small event counts do not by themselves establish comparative risks. This trial is statistically informative as an example of why a defined endpoint, an appropriate understanding of the design, and transparent reporting of estimates and uncertainty are all needed for interpretation.

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 main limitation for interpreting the primary endpoint is that numerical AUClast estimates and confidence intervals are not reported in the registry record. This prevents assessment of the direction, magnitude, and precision of the pharmacokinetic findings. The record also does not report a numerical comparison between hepatic-function groups or a p-value for the primary endpoint.

The non-randomized design limits causal interpretation. Participants were grouped by hepatic-function status, and matching addressed gender, age (± 10 years), and body mass index (± 15%). The record does not describe adjustment for other characteristics or explain whether the statistical analysis accounted for matching. Open-label status and the parallel-group structure are additional features to consider when interpreting the design.

The study evaluated a single dose, so the record does not describe exposure after repeated dosing. The PK analysis-set definition requires at least 1 dose and at least 1 nonmissing postdose concentration value, but group-specific analysis counts and detailed handling of incomplete profiles are not reported in the registry record. The sampling schedule is specified, yet the completeness of collected measurements is not stated.

Safety information is limited to group-level counts in the record. Event terms for other adverse events, safety follow-up duration, and comparative uncertainty estimates are not reported in the registry record. The record also does not report a complete analysis plan, multiplicity strategy, or the rationale for the enrollment target. These limitations constrain evaluation of both the primary estimate and the broader applicability of the findings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Pharmacokinetics of Voxilaprevir in Adults With Normal Hepatic Function and Moderate or Severe Hepatic Impairment — NCT02397707.
• Registry record last updated 2020-04-09; status last verified 2020-04.
• Results first posted 2020-03-20.
• 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

NCT02397707 is a completed phase 1, open-label, parallel-group, non-randomized study sponsored by Gilead Sciences. It enrolled 33 and evaluated a single dose of voxilaprevir in adults with normal hepatic function, moderate hepatic impairment, or severe hepatic impairment. Healthy controls were matched to participants with impairment by gender, age (± 10 years), and body mass index (± 15%).

The primary endpoint was AUClast, defined as the area under the plasma concentration-versus-time curve from time zero to the last quantifiable concentration. The registry record describes unadjusted geometric means and confidence intervals, but numerical primary endpoint results are not reported in the registry record. Safety counts show no serious adverse events or deaths in the listed groups, with other adverse events recorded in each group. The record does not report a complete statistical analysis plan or detailed handling of missing PK measurements.