Study to Evaluate the Safety, Tolerability, and Efficacy of Vesatolimod in Combination With Tenofovir Disoproxil Fumarate (TDF) in Adults With Chronic Hepatitis B (CHB) Infection Who Are Currently Not Being Treated: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Safety, Tolerability, and Efficacy of Vesatolimod in Combination With Tenofovir Disoproxil Fumarate (TDF) in Adults With Chronic Hepatitis B (CHB) Infection Who Are Currently Not Being Treated (NCT02579382), a randomized phase 2 study. The primary outcome is Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24.

2. Clinical Question

The primary outcome is a laboratory measure of HBsAg change, not a direct measure of symptoms or clinical events. A more negative change indicates a larger decrease from baseline on this scale. Because the study had three vesatolimod dose groups and one placebo combination group, each reported primary comparison contrasts one dose group with the TDF-plus-placebo group.

Other registry outcomes include HBeAg and HBsAg loss and seroconversion, and further measures of HBsAg change. Those outcomes provide context on biomarker patterns at different visits; they do not replace the prespecified primary question. The registry record does not report a protocol-based sample-size justification or a hierarchy for interpreting secondary outcomes.

3. Trial Design

This was a Phase 2 randomized, double-blind, placebo-controlled, parallel-group study conducted at multiple centers. The registry record lists 192 participants enrolled and describes four main-study groups: TDF with placebo, or TDF with vesatolimod at 1 mg, 2 mg, or 4 mg. All groups received TDF, which helps make the primary contrast one of adding vesatolimod at different doses versus adding placebo to TDF.

In the main study phase, TDF was given orally once daily for up to 48 weeks. Vesatolimod or placebo was given orally once weekly for 12 doses. Participants had the option at Week 48 to continue into an extension phase. The extension descriptions specify continued TDF treatment, but the TDF-plus-placebo description is truncated in the registry record; further details for that group are not reported in the registry record.

Randomization assigns participants to groups by chance, while double masking is intended to keep participants and relevant study personnel unaware of assignment. A placebo comparator supports a like-for-like comparison of the added study drug, although the registry record does not report the detailed procedures used to maintain masking or the randomization method.

The primary analysis population was the Full Analysis Set: randomized participants who took at least 1 dose of study drug. The arm counts for the primary endpoint were 28 for TDF with placebo, 53 for TDF with vesatolimod 1 mg, 54 for the 2 mg group, and 54 for the 4 mg group. The analysis counts do not sum to the enrollment figure because enrollment and endpoint analysis populations describe different stages and records; reasons for the difference are not reported in the registry record.

The study is listed as completed. Its start and primary completion dates are 2015-11-10 and 2017-01-16. The record does not report the full recruitment flow, reasons for discontinuation, or the number of participants who entered or completed the optional extension.

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: 260 participants were screened

Main Study Phase

Reasons for not completing this period:

Optional Treatment Extension Phase(OTEP)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The Full Analysis Set included all participants who were randomized and took at least 1 dose of study drug.

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

6. Primary Endpoint

The registry lists the primary outcome as Mean Change (Measured in log10 IU/mL) in Hepatitis B Surface Antigen (HBsAg) From Baseline at Week 24, measured over Baseline; Week 24.

The primary endpoint is mean change from baseline in HBsAg, measured in log10 IU/mL, at Week 24. HBsAg is a marker of hepatitis B infection. Measuring its change provides a continuous laboratory outcome that can capture degrees of movement rather than only classifying participants as having or not having a particular event. A negative mean change represents a reduction from baseline on the stated scale.

The registry record reports adjusted least-squares means for each arm and adjusted differences between each vesatolimod dose group and TDF with placebo. The model accounts for listed baseline characteristics and repeated measurements over visits. This is intended to estimate the treatment-group contrast while incorporating the model terms specified in the registry description, rather than comparing raw arm means alone.

Interpretation depends on both the estimated contrast and its uncertainty. A confidence interval describes a range of values compatible with the data and model under the method used; it is not a guarantee that the true value lies within the interval. For this endpoint, the reported 95% confidence intervals for the three contrasts all include zero. Thus, the registry estimates do not establish a clear difference in mean Week 24 change between any vesatolimod group and the comparator under the reported analysis.

HBsAg change is a biomarker outcome. The registry record does not establish that a particular amount of change corresponds to a clinical benefit, nor does the primary endpoint measure clinical events or long-term outcomes.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome was analyzed with a mixed model for repeated measures (MMRM). General explanation: repeated-measures models are used when an outcome is collected at multiple visits from the same participant. Measurements within one participant are usually related, so a model that accounts for this structure can use the pattern across visits rather than treating each measurement as an unrelated observation.

The registry description lists treatment, baseline HBsAg, baseline HBeAg status, baseline ALT relative to the upper limit of normal, visit, and treatment-by-visit interaction as fixed effects. It also says visit was treated as a repeated measure. General explanation: fixed effects represent the model terms used to estimate systematic differences or relationships. The treatment-by-visit term allows estimated treatment contrasts to vary across visits rather than forcing one common difference at every visit.

The baseline ALT categories are specified as greater than 19 versus less than or equal to 19 IU/L for females, and greater than 30 versus less than or equal to 30 IU/L for males. Those thresholds are included in the registry model description. The registry record does not report other model details, including the covariance structure, estimation method, or how missing repeated measurements were handled.

The reported primary arm estimates are least-squares means, also called adjusted means. General explanation: these are model-based estimates for each group after accounting for the terms in the model; they are not necessarily identical to simple arithmetic averages of the observed values. The sponsor-reported contrasts compare each vesatolimod dose group with the TDF-plus-placebo group and include 95% confidence intervals and p-values.

A confidence interval communicates the precision of an estimate under the model and its assumptions. A narrower interval indicates greater precision than a wider interval. If a confidence interval for a difference includes zero, the data are compatible with no difference at that confidence level; they may also be compatible with positive or negative differences inside the interval. A p-value assesses how unusual data at least as incompatible with a null hypothesis would be under the statistical model if that null hypothesis were true. It is not the probability that the null hypothesis is true, nor does it measure clinical importance.

The reported adjusted analyses are the principal inferential results for the primary endpoint. For some secondary continuous outcomes, posted group means and standard deviations also permit simple unadjusted recalculations. These compare summary values and do not reproduce the sponsor's repeated-measures model or any unreported adjustment. They are descriptive checks, not a replacement for the sponsor-reported analysis. The registry record does not report sponsor-adjusted comparisons for those secondary outcomes.

General explanation: a standard deviation describes variation among individual observations, while a confidence interval describes uncertainty about an estimate. They answer different questions. When observed values vary substantially, estimates can be imprecise, especially when group sizes are limited. For continuous secondary outcomes, the recalculated contrasts use the posted means and standard deviations and are therefore sensitive to the variability in those summaries. They should not be treated as if they were randomized-trial model estimates with the same adjustment as the primary analysis.

For the Week 48 HBeAg outcome, some unadjusted comparisons are also posted as risk differences with confidence intervals and p-values. General explanation: a risk difference expresses the difference in proportions between groups. With few observed events, estimates can be imprecise and intervals can be wide. These secondary comparisons are not substitutes for the primary continuous endpoint, and the registry record does not report adjusted analyses for them.

Separate planning illustrations are based on observed secondary effects, a two-sided significance level of 0.05, equal allocation, and a normal approximation. General explanation: such calculations estimate how many participants per arm would be needed under the stated assumptions to detect a chosen effect size with a specified power. Since the illustration uses an effect observed in this trial, it is not the trial's original sample-size justification and is not observed power. Smaller assumed effects produce larger planning requirements. The registry record does not report the study's own sample-size justification or design assumptions.

Over-dispersion is a general issue for count or binary data when the observed variability exceeds what a simple model assumes. It can lead to confidence intervals that are too narrow if the model fails to account for the extra variability. The primary endpoint is continuous, and the record does not state that an over-dispersion adjustment was used. Its MMRM specification is the method reported for the primary analysis.

Multiplicity arises when many outcomes or comparisons are tested. General explanation: the more analyses conducted, the greater the chance that at least one result will appear statistically unusual by chance alone. Adjustments or a prespecified testing order can address this issue, but neither a multiplicity procedure nor an outcome hierarchy is reported in the registry record. Consequently, secondary p-values and unadjusted recalculations warrant more caution than the primary comparison.

10. Analyses Reported by the Sponsor

The registry record reports sponsor analyses for all three primary comparisons using MMRM, with least-squares mean differences, 95% confidence intervals, and p-values. These are the central inferential results for the primary endpoint because they use the model described in the record and directly compare each vesatolimod dose with TDF plus placebo.

The sponsor estimates are 0.107 for 1 mg, 0.018 for 2 mg, and 0.127 for 4 mg. The corresponding confidence intervals each include zero, and the reported p-values are 0.227, 0.840, and 0.151. The conclusions should be drawn from these adjusted results rather than from a subtraction of displayed arm means, since the adjusted contrasts arise from the specified repeated-measures model.

Simple recalculations from posted summary statistics are available for selected secondary outcomes. Those are unadjusted comparisons and cannot reproduce the sponsor's MMRM, its covariate adjustment, or its repeated-measures handling. No discrepancy between recalculated and sponsor-reported primary results is flagged in the record. The recalculations are therefore best treated as supplementary descriptions, not competing estimates or evidence that supersedes the sponsor's primary analysis.

The registry record does not report the complete statistical analysis plan, so it is not possible to assess whether every analysis detail or decision rule was prespecified. That limitation does not change the distinction between the reported adjusted primary analysis and the simpler secondary recalculations.

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 23 outcome measures and reports analyses for the primary endpoint, along with selected secondary outcome summaries. It does not report a multiplicity adjustment, a prespecified sequence for testing outcomes, or a rule for deciding which secondary comparisons should be considered confirmatory. General explanation: when many outcomes or contrasts are examined, isolated results can look persuasive by chance. A testing hierarchy or multiplicity correction can limit that risk, but the record does not state that either was used.

The primary endpoint has three dose-versus-placebo comparisons. The record reports each comparison with its own confidence interval and p-value, but does not report an adjustment across the three comparisons. The values should therefore be read as the estimates and p-values reported for those comparisons, without assuming control of the overall false-positive rate across them.

The primary analysis population is defined as randomized participants who took at least 1 dose of study drug. The endpoint arm counts are 28, 53, 54, and 54. The record does not report the number of randomized participants excluded from this analysis or the reasons for exclusion. It also does not describe a missing-data method, the amount or pattern of missing outcome data, or sensitivity analyses for missingness. Although MMRM is the stated primary method, its detailed assumptions and missing-data handling are not reported in the registry record.

The secondary Week 48 HBeAg event analysis has smaller arm counts than the primary analysis. The reasons for the difference are not reported in the registry record. The record also does not state whether participants with missing secondary measurements were counted as nonresponders, excluded, or handled by another rule. These omissions limit assessment of how missing data and selective availability may affect the secondary estimates.

These reporting gaps do not establish that the analysis was improperly conducted. They mean that readers cannot verify from the registry record which multiplicity, missing-data, or population rules governed all analyses. The primary estimates can be interpreted as reported, while conclusions from multiple secondary results should remain cautious.

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: hepatocellular carcinoma (3.9%), leiomyoma (3.7%), uterine haemorrhage (3.7%), pyrexia (2.0%), breast cancer (2.0%).

The registry record reports serious adverse events for the main-study groups and for the extension groups separately. In the main study, serious events were recorded for 0 of 28 participants receiving TDF with placebo, 1 of 53 receiving TDF with vesatolimod 1 mg, 1 of 56 in the 2 mg group, and 1 of 55 in the 4 mg group. The extension groups are reported separately, with serious events recorded for 1 of 27, 4 of 51, 5 of 54, and 1 of 49 participants, respectively.

No deaths were recorded in any of the listed groups. The record lists hepatocellular carcinoma at 3.9%, leiomyoma at 3.7%, uterine haemorrhage at 3.7%, pyrexia at 2.0%, breast cancer at 2.0%, and adenomyosis at 2.0% among the top serious terms. The registry record does not provide a causal assessment for these terms, so they should not be attributed to a study treatment based on these counts alone.

Serious adverse event counts are descriptive. They do not show whether events were judged treatment-related, and differences in group counts do not by themselves establish a difference in risk. The extension groups represent a separate treatment period, so their counts should not be combined with main-study counts as if they came from the same follow-up conditions. The registry record does not report further details needed to assess event timing, duration, severity grading, or causality.

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

The primary result describes a model-based comparison of mean HBsAg change at Week 24 among randomized participants who took at least 1 dose of study drug. The reported adjusted differences are close to zero relative to their confidence intervals, and all three 95% confidence intervals include zero. The posted analysis therefore does not show a clear adjusted difference between TDF with placebo and any of the vesatolimod dose groups for this endpoint.

This does not establish that the groups are equivalent. Equivalence requires a prespecified margin and an analysis designed to test whether differences lie within that margin; such a margin is not reported in the registry record. Nor does the result prove that no difference exists. The confidence intervals retain a range of plausible differences, and the registry record does not specify what size of HBsAg change would be clinically important.

The endpoint is a biomarker measured at a particular visit. It is not, by itself, a direct demonstration of effects on symptoms, complications, transmission, or long-term clinical outcomes. The registry record does not report those outcomes as the primary measure. Secondary biomarker results can add context, but they do not make the primary estimate more precise or remove uncertainty about how multiple outcomes should be interpreted.

The safety counts also need careful interpretation. Serious events occurred in the listed groups, but counts alone cannot determine whether treatment caused an event. No deaths were recorded in the groups listed in the registry record. These observations describe what was recorded during the reported study periods; they do not settle safety questions outside those groups, durations, or outcomes.

In practical statistical terms, the most defensible statement is narrow: under the reported MMRM, the data do not provide clear evidence of a Week 24 HBsAg mean-change difference for any of the three dose comparisons. The result remains uncertain, and the registry record lacks enough information to make broader claims about clinical value, equivalence, or longer-term outcomes.

14. Why This Trial Matters Statistically

This trial is statistically informative because it compares three vesatolimod dose groups with a shared TDF-plus-placebo comparator while measuring a continuous biomarker repeatedly. That design makes the primary question more specific than a simple before-and-after comparison: it asks whether the average change differs between randomized treatment groups at the specified follow-up, using a model that accounts for repeated visits and listed baseline characteristics.

The results also illustrate why estimates should be read with their uncertainty. The primary point estimates alone might suggest differences of varying sizes, but the confidence intervals include zero and the p-values do not provide strong evidence against no adjusted difference. A single point estimate is not a complete result; its precision and the analysis producing it matter.

The dose comparisons do not show a clear ordered pattern in the primary estimates. That is relevant when considering whether more exposure is associated with a progressively stronger biomarker response, but this study's estimates are too uncertain to establish such a pattern. The secondary summaries vary across visit and outcome type, reinforcing the importance of distinguishing supportive description from a confirmatory finding.

The statistical record also highlights the role of transparent reporting. The primary model is described at a useful level, but details about missing data, multiplicity, and the trial's own sample-size rationale are not reported in the registry record. Those omissions affect how fully readers can evaluate precision, analysis choices, and the weight of secondary results.

Finally, planning illustrations based on observed effects can help show how sample size requirements depend on the effect one wants to detect. They are not evidence that a study was adequately or inadequately powered, and they do not reveal the design rationale used for this trial. Separating planning assumptions, observed estimates, and formal trial analyses is essential to a sound statistical reading.

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 report the trial's original sample-size justification, target effect, or assumptions used to choose enrollment. The planning illustrations associated with selected secondary outcomes are based on effects observed in this trial and therefore cannot establish what the original design could reliably detect.

Although the primary MMRM terms are described, important implementation details are not reported in the registry record. These include the repeated-measures covariance structure, estimation approach, detailed missing-data handling, and sensitivity analyses. The record also does not report the extent of missing primary outcome data or participant flow from randomization through the primary analysis population.

Multiplicity is another limitation. Three primary dose comparisons are reported, along with numerous secondary outcomes, but no adjustment or testing hierarchy is stated. The secondary results should not be treated as independent confirmatory evidence without knowing how the analyses were planned and interpreted.

The study includes an optional extension, and separate extension safety counts are posted. The registry record does not give complete extension participation, follow-up, or outcome details. The TDF-plus-placebo extension description is truncated, limiting the ability to understand all treatment arrangements in that group. Main-study and extension counts should therefore be considered in their separate contexts.

Finally, the primary endpoint is a biomarker outcome at Week 24. The registry record does not establish the clinical importance of a particular change, nor does it provide a primary clinical-event endpoint. These limitations restrict conclusions to the posted outcomes and follow-up, and do not support broad claims about clinical effects beyond the trial measures.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Safety, Tolerability, and Efficacy of Vesatolimod in Combination With Tenofovir Disoproxil Fumarate (TDF) in Adults With Chronic Hepatitis B (CHB) Infection Who Are Currently Not Being Treated — NCT02579382.
• Registry record last updated 2020-05-18; status last verified 2020-05.
• Results first posted 2020-05-18.
• 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 randomized, double-blind Phase 2 parallel-group study in adults with chronic hepatitis B who were not being treated. It enrolled 192 participants and compared TDF with placebo against TDF combined with vesatolimod at 1 mg, 2 mg, or 4 mg.

The primary outcome was adjusted mean change in HBsAg from baseline at Week 24, analyzed with MMRM. The reported dose-versus-placebo differences were 0.107, 0.018, and 0.127; all corresponding 95% confidence intervals included zero. The posted primary analysis does not establish a clear difference for any dose comparison.

Secondary biomarker outcomes and serious adverse event counts provide additional descriptive context, but missing-data methods, multiplicity procedures, and the trial's original sample-size justification are not reported in the registry record. The findings should be interpreted within the limits of the stated outcome, model, and follow-up.