Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Voxilaprevir in Adults With Chronic Hepatitis C Virus Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Voxilaprevir in Adults With Chronic Hepatitis C Virus Infection (NCT02185794), a randomized phase 1 study. The primary outcome is Percentage of Participants Experiencing Treatment Emergent Adverse Events.

2. Clinical Question

The study addressed safety and tolerability of voxilaprevir in adults with chronic hepatitis C virus infection, while also examining its antiviral activity. The primary endpoint was the percentage of participants experiencing treatment-emergent adverse events during the stated safety follow-up period. The posted primary results describe several voxilaprevir dose groups, a placebo group, a fed-dose group, and a group receiving voxilaprevir with SOF/VEL.

3. Trial Design

This was a Phase 1b, randomized, double-blind, parallel-group, multiple-dose-ranging study of voxilaprevir in adults with chronic hepatitis C virus infection. The registry lists enrollment as 101. The study start date was 2014-06-13, the primary completion date was 2014-12-22, and the status is completed.

The intervention program included placebo and voxilaprevir dose groups, with doses and food conditions varying across cohorts. Most described regimens involved once-daily treatment for 3 days under fasted conditions; the registry also describes a fed voxilaprevir group and cohorts receiving doses up to 600 mg under fasted or fed conditions. Another cohort received voxilaprevir with SOF/VEL 400/100 mg, with meal conditions varying by group and study day. These differences mean that the primary results should be read as summaries of the reported regimens, not as a single uniform exposure comparison.

The study description identifies safety and tolerability as primary objectives and antiviral activity as an objective. Participants were to be monitored for up to 48 weeks after the last dose. The posted primary endpoint, however, concerns treatment-emergent adverse events from the first dose through Day 3 plus 30 days. The registry lists three secondary outcome measures concerning HCV RNA levels and reductions, but does not provide posted numerical results for those outcomes in the record summarized by these results.

Randomization and double blinding are stated design features. The method of sequence generation, allocation concealment, and the exact masking arrangements are not reported in the registry record. The record also does not report a sample-size justification or explain how the multiple cohorts were assigned to particular dose comparisons.

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: Participants were enrolled in Cohorts 1, 2, 3, 4, 5, 6 and 10. Cohorts 7, 8, and 9 were not conducted.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug (voxilaprevir or placebo). Data were summarized by dose.

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: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug (voxilaprevir or placebo).

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants Experiencing Treatment Emergent Adverse Events, measured over First dose date up to Day 3 plus 30 days.

The primary endpoint is the percentage of participants experiencing treatment-emergent adverse events, with the timeframe defined as the first dose date up to Day 3 plus 30 days. A treatment-emergent event is an event arising during the specified treatment and follow-up period; the endpoint therefore describes the proportion of the safety analysis set with at least one such event as represented in the registry result.

Reporting a percentage makes it possible to describe event frequency in groups of different sizes. The corresponding group size matters when interpreting each percentage: the posted groups range from 6.0 to 30.0 participants. In small groups, each participant’s event status can have a visible effect on the percentage, so a point estimate should not be treated as precise evidence of a stable underlying rate. No confidence intervals are posted for these percentages.

Safety endpoints are used to characterize events observed during exposure and follow-up. They do not establish the cause of an event, and they do not by themselves establish comparative safety. The registry states that data were summarized by dose, but does not report a formal statistical test, adjusted estimate, or prespecified decision threshold for the primary endpoint. The endpoint is distinct from serious adverse events, which are reported separately in the safety information.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports percentages by dose for the primary safety endpoint. No inferential analyses are posted for this endpoint, so the results are best read as descriptive summaries rather than as estimates accompanied by a formal comparison. The registry record does not report the statistical analysis plan, the method used to calculate the percentages, or the handling of missing endpoint data.

What does a percentage describe?

General statistical explanation: a percentage for a binary endpoint expresses the share of an analysis group classified as having the event. It is useful for communicating event frequency, but it is not a complete account of uncertainty. The group size affects how much information supports the percentage. With small groups, the observed proportion may be sensitive to the outcome of a single participant. A percentage should therefore be considered alongside its denominator, the endpoint definition, and any interval estimate or comparative analysis that is available.

For these results, the group sizes and event percentages are posted, but interval estimates are not. The absence of a confidence interval does not imply that the rate is known precisely; it means the record does not give an interval to quantify its uncertainty. The record also does not report a statistical test comparing each dose group with placebo. Consequently, ranking the percentages from lowest to highest cannot establish that the groups have different underlying event rates.

What would a confidence interval add?

General statistical explanation: a confidence interval gives a range of values compatible with the observed data under a stated method. It communicates estimation uncertainty, which is particularly relevant when a group is small or events are uncommon. An interval is not a guarantee that the true value lies within its bounds, nor does overlap or non-overlap alone replace a prespecified comparison. The registry record does not post confidence intervals for the primary endpoint.

How should comparisons be assessed?

General statistical explanation: a comparative analysis should define the groups being contrasted, the effect measure, the analysis population, and the method for uncertainty estimation. A test or interval is needed to distinguish a descriptive difference between observed percentages from evidence about a broader treatment-group contrast. Adjustment may also be necessary when analyses involve multiple groups or outcomes, depending on the inferential goals and analysis plan. The record does not report these choices for the primary endpoint. The posted analysis count is 0, and values are marked as missing or not estimable for a two-arm comparison of the binary-percentage endpoint.

The record includes a planning illustration based on the observed effect, with two-sided significance level 0.05, equal allocation between two arms, and a normal approximation; it considers detecting a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the trial was designed with those assumptions. The record does not report the trial’s own sample-size justification. The stated planning assumptions should not be mistaken for a trial analysis plan or for a formal analysis of the posted group percentages.

Why can event variation matter?

General statistical explanation: event counts can vary more than a simple probability model assumes, a phenomenon often called over-dispersion. When present, it can make standard errors too small and confidence intervals too narrow if the analysis fails to account for the extra variation. Whether over-dispersion is relevant depends on the endpoint and data structure. The registry record does not describe an over-dispersion assessment or a model for these binary safety results, so no such feature can be attributed to this analysis.

The reported primary endpoint is binary at the participant level: a participant either experienced a treatment-emergent adverse event during the stated timeframe or did not, according to the registry summary. Event counts and person-time are not separately presented for this endpoint. The serious adverse event summary is a different safety measure and should not be substituted for the primary endpoint. The record also does not report whether recurrent events were counted, how multiple events in one participant were handled, or whether severity or relatedness affected inclusion in the primary endpoint.

Because the trial included varied doses, meal conditions, and combination treatment, a pooled estimate across all groups would need a clear rationale and a stated method. The registry reports results by dose instead. Without a reported model, adjusted estimates, or planned contrasts, combining the group results or treating them as a dose trend would go beyond the posted analysis.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("Placebo", "Voxilaprevir 50 mg", "Voxilaprevir 100 mg", "Voxilaprevir 300 mg", "Voxilaprevir 100 mg Fed", "Voxilaprevir 100 mg + SOF/VEL 400/100 mg")
n      <- c(8, 14, 30, 15, 6, 16)
events <- c(2, 2, 5, 2, 2, 2)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  Placebo  8  2  25.0  3.2  65.1  7.1  59.1  7.5  60.0
ARM  Voxilaprevir 50 mg  14  2  14.3  1.8  42.8  4.0  39.9  4.3  40.5
ARM  Voxilaprevir 100 mg  30  5  16.7  5.6  34.7  7.3  33.6  7.5  33.7
ARM  Voxilaprevir 300 mg  15  2  13.3  1.7  40.5  3.7  37.9  4.0  38.3
ARM  Voxilaprevir 100 mg Fed  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  Voxilaprevir 100 mg + SOF/VEL 400/100 mg  16  2  12.5  1.6  38.3  3.5  36.0  3.8  36.4

11. Multiplicity, Missing Data and Analysis Populations

The registry lists three secondary outcome measures: absolute HCV RNA level through Week 48, participant counts achieving reductions from baseline in HCV RNA, and percentages with HCV RNA below the lower limit of quantitation under the stated detected or target-not-detected categories. The record does not provide numerical results for these measures in the posted results. It also does not report how many comparisons or time points were planned for those outcomes, or whether any multiplicity adjustment was used.

Multiplicity arises when several hypotheses or outcomes are examined: even if each test uses a conventional threshold, the chance of at least one false-positive finding can increase across a set of tests. General statistical explanation: a prespecified testing strategy can define which outcomes are confirmatory, how tests are ordered, and whether error rates are controlled. The analysis plan and any such strategy are not reported in the registry record. Since no primary-endpoint comparison is posted, there is no reported inferential result for which multiplicity adjustment can be evaluated.

The primary endpoint population is described as participants who were randomized and received at least 1 dose of study drug. The registry does not report how missing endpoint observations were handled, whether every participant had complete follow-up, or whether any imputation or sensitivity analysis was used. It also does not report the number of participants excluded from the safety analysis set or reasons for exclusion. These omissions limit assessment of how missing or incomplete safety information might affect the percentages.

Other analysis populations, including populations used for antiviral activity outcomes, are not reported in the registry record. The endpoint description says that the safety data were summarized by dose, but the record does not provide a detailed analysis plan specifying dose-specific contrasts, covariate adjustment, or handling of participants who received combination treatment. These missing details should be treated as unreported methods, not inferred from the randomized and double-blind design.

12. 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 serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: atrial fibrillation (16.7%).

The serious adverse event summary reports 0 serious events in the placebo group, 0 in the voxilaprevir 50 mg group, 0 in the voxilaprevir 100 mg group, 0 in the voxilaprevir 300 mg group, 1 in the voxilaprevir 100 mg Fed group, and 0 in the voxilaprevir 100 mg + SOF/VEL 400/100 mg group. Deaths are reported as 0 in each listed group. The registry lists atrial fibrillation at 16.7% among the top serious terms.

These serious-event figures are separate from the primary treatment-emergent adverse event percentages. A serious event is not interchangeable with any treatment-emergent event, and the fact that an event is recorded does not establish that study treatment caused it. The record does not specify which group the listed atrial fibrillation term belongs to, nor does it provide a narrative connecting that term to the serious-event count in a particular group.

Group sizes are small, so these counts are descriptive and do not support a precise comparison of serious-event risk. The registry does not report confidence intervals or a formal between-group test for serious events. A zero count in a group means that no serious event was recorded in that group in this summary; it does not demonstrate that the underlying risk is zero.

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

The posted results describe treatment-emergent adverse event percentages across the reported placebo, voxilaprevir dose, fed-dose, and combination groups. They also separately report serious adverse events and deaths. The study’s randomized, double-blind design is a strength for organizing treatment-group comparisons, but the primary safety results available in the registry are descriptive and do not include inferential comparisons.

The results do not establish that a difference between percentages is statistically reliable, clinically important, or caused by treatment. They also do not show that a group with a lower observed percentage has a lower underlying event rate. Small group sizes and the absence of confidence intervals leave uncertainty around each percentage. The different doses, meal conditions, and combination regimen further mean that not every group is a direct, isolated comparison of one treatment component.

The figures do not establish a dose-response relationship. Although the study is described as multiple-dose ranging, the registry does not report a trend analysis or model for the primary endpoint. Nor do the posted safety findings answer the antiviral activity questions, for which the record lists secondary outcomes but does not include numerical results in this set of posted findings.

The serious-event summary records 1 serious adverse event in the voxilaprevir 100 mg Fed group and 0 in the other listed groups, with 0 deaths across the groups. These are observations within the study record, not proof of causation or a reliable ranking of group safety. The record does not report the statistical precision of these counts or a comparative analysis.

In short, the posted data support a descriptive account of adverse events during the stated safety period. They do not support a definitive comparative conclusion about safety or antiviral activity. The missing inferential methods, intervals, missing-data details, and secondary outcome results constrain what can be concluded from this registry record.

14. Why This Trial Matters Statistically

This trial illustrates why descriptive safety percentages need to be interpreted alongside their denominators and design context. The posted groups vary in size, dose, food condition, and treatment regimen. A percentage in a small group can be unstable, and differences between percentages do not automatically represent meaningful treatment effects. The absence of confidence intervals and formal comparisons makes that distinction especially important.

The record also makes clear that several safety concepts answer different questions. The primary endpoint concerns treatment-emergent adverse events over a defined period; serious adverse events are reported separately, as are deaths. Those measures should not be collapsed into one label or used interchangeably. The primary percentages characterize event frequency, while the serious-event counts describe a narrower category of safety outcomes.

Statistically, the study is a reminder that randomization and blinding do not replace transparent reporting of the analysis plan. Readers also need to know how comparisons were defined, how uncertainty was quantified, what was done with missing data, and how multiple endpoints were handled. Those details are not reported for the primary endpoint in the registry record, limiting the strength of any comparative interpretation.

Finally, multiple-dose-ranging studies can involve several cohorts and exposure conditions. A collection of group-specific percentages is not itself a dose-response analysis. The results are most informative when read within the limits of each group and endpoint, without converting descriptive patterns into claims of statistical significance, causation, or efficacy.

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 registry record does not provide confidence intervals, p-values, adjusted comparisons, or a statistical model for the primary endpoint. The values are percentages summarized by dose, and the stated analysis count is 0. This prevents assessment of the uncertainty around the group estimates or the statistical evidence for between-group differences.

Group sizes are limited, including 6.0 participants in the voxilaprevir 100 mg Fed group. Results from small groups can be imprecise, but the registry does not post interval estimates. It also does not give detailed participant flow, the number excluded from the safety analysis set, or reasons for any exclusion.

The study includes differing doses, meal conditions, genotype cohorts, and a combination regimen. The primary results do not provide a full set of cohort-specific outcomes, and the record does not explain how the displayed dose groups map to every cohort described in the study. These features make simple cross-group comparisons difficult to interpret. The registry does not report a dose-trend analysis or state whether any groups were intended for direct comparison.

Methods for missing data, recurrent events, event severity, relatedness, and endpoint classification are not reported in the registry record. The record also does not report a sample-size justification, interim analyses, or the statistical analysis plan. Numerical results for the listed antiviral secondary outcomes are not included in the posted findings addressed. These limitations restrict interpretation to the reported descriptive safety results and do not establish conclusions about comparative safety or antiviral activity.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Antiviral Activity of Voxilaprevir in Adults With Chronic Hepatitis C Virus Infection — NCT02185794.
• Registry record last updated 2020-09-17; status last verified 2020-08.
• Results first posted 2020-08-21.
• 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

This completed Phase 1b randomized, double-blind, parallel-group study enrolled 101 adults with chronic hepatitis C virus infection. It examined voxilaprevir across dose groups and conditions, including a regimen with SOF/VEL 400/100 mg. The primary endpoint was the percentage experiencing treatment-emergent adverse events from the first dose through Day 3 plus 30 days.

Posted percentages range from 12.5% to 33.3% across the listed groups. The serious adverse event summary reports 1 event in the voxilaprevir 100 mg Fed group and 0 in the other listed groups; deaths are reported as 0 in every group. The registry does not post comparative analyses or confidence intervals for the primary endpoint, and numerical results for the listed antiviral secondary outcomes are not reported in the record.