Study of VIR-2218 With or Without Pegylated Interferon Alpha-2a for Treatment of Chronic Hepatitis B Virus Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of VIR-2218 With or Without Pegylated Interferon Alpha-2a for Treatment of Chronic Hepatitis B Virus Infection (NCT04412863), a non-randomized phase 2 study. The primary outcome is Number of Subjects With Adverse Events as Assessed by CTCAE v5.0.

2. Clinical Question

3. Trial Design

This completed phase 2 study was designed to evaluate VIR-2218 alone or in combination with pegylated interferon alfa-2a in chronic hepatitis B virus infection. The registry record gives a start date of 2020-07-03 and a primary completion date of 2024-03-25. Its enrollment is 84. The study used a parallel model, with non-randomized allocation and no masking.

The cohort descriptions cover VIR-2218 alone and combinations with pegylated interferon alfa-2a. They specify different treatment schedules, including schedules with VIR-2218 given every four weeks and interferon given weekly. For example, one combination description starts interferon at Week 12; others specify longer or variable treatment durations. These are cohort descriptions, not evidence that treatment was randomly allocated or that the cohorts were otherwise comparable.

The posted adverse-event results give counts for Cohorts 1d, 2d, 3d, 1f, 2f, and 3f. Although the registry record also describes Cohorts 1e, 2e, and 3e, adverse-event counts for those cohorts are not reported in the registry record. The six sets of counts therefore should not be treated as a complete numerical account of every described cohort.

Non-randomized allocation matters when interpreting group differences: participant features, treatment schedules, or other factors could differ across cohorts. No adjusted comparison, randomization procedure, allocation rationale, or detailed protocol for assigning participants to cohorts is reported in the registry record. The posted numbers are descriptive cohort-level results, rather than a controlled estimate of a treatment effect.

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

Reasons for not completing this period:

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

Only the first 6 of 7 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Adverse Events as Assessed by CTCAE v5.0, measured over Up to 148 Weeks.

The primary endpoint is the number of participants with adverse events assessed by CTCAE v5.0, with a timeframe of up to 148 Weeks. A participant count is a direct way to describe how many people in a group experienced an event during the stated observation period. In the posted results, the record distinguishes serious adverse events from other adverse events, giving counts of participants affected and counts at risk for each reported cohort.

Safety endpoints are used to describe unwanted events recorded during a study and to help characterize the safety experience under the study conditions. Counts are understandable, but they do not by themselves describe event severity beyond the serious-event classification, duration, timing, recurrence, or whether an event was judged related to a treatment. The registry record does not report those details alongside the primary endpoint counts.

A count also depends on how many participants were observed and for how long. The registered timeframe is up to 148 Weeks, but cohort-specific follow-up completeness and exposure time are not reported in the registry record. Consequently, the posted counts should be read as descriptive participant counts, not as exposure-adjusted rates or as an estimate of comparative risk.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

For binary outcomes such as whether a participant had an adverse event, a basic summary reports the number affected and the number at risk. This is a descriptive presentation: it records the observed event experience in each group. The posted adverse-event data use this form, with separate counts for serious and other adverse events. No additional calculation is needed to understand the counts, and no recalculated comparative estimate is reported.

What does non-randomized allocation imply?

Random allocation is a method intended to make treatment groups comparable, on average, with respect to both measured and unmeasured factors. It is not used in this study: the registry record identifies allocation as non-randomized. That does not invalidate the descriptive counts, but it changes what can be inferred from comparisons between cohorts. Differences may reflect treatment, participant characteristics, cohort schedules, or other differences. Statistical adjustment can sometimes address measured differences, but an adjusted analysis is not reported in the registry record, and adjustment cannot guarantee removal of unmeasured confounding.

The study is parallel, which means the registry describes treatment groups as separate cohorts rather than a crossover comparison. Masking is absent. These design features are relevant context for interpreting the recorded outcomes; they do not determine the direction or size of any treatment effect. The cohort descriptions include varied dosing schedules, so a comparison of two cohorts would also compare the schedules and treatment combinations as recorded, not just the presence or absence of a single drug.

How should counts and uncertainty be read?

A participant count is not the same as an event count. A participant may experience more than one event, while the endpoint count concerns participants affected. Counts also do not convey event timing or exposure duration. The registry record provides the primary endpoint timeframe as up to 148 Weeks, but does not report cohort-specific follow-up or exposure-adjusted rates. That limits interpretation of between-cohort differences, particularly when observation time may not be the same.

In general, uncertainty around an estimated event frequency or contrast can be expressed using a confidence interval. An interval gives a range of values compatible with the data and statistical assumptions; a narrower interval indicates greater precision than a wider one. No confidence intervals or inferential test results for the adverse-event counts are reported in the registry record. The data therefore support a descriptive account, not a precise estimate of a difference between treatment groups.

What do the planning illustrations mean?

Any sample-size illustrations associated with these results are planning exercises based on an observed effect, not the original trial design and not observed power. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect considered is a stated fraction of the observed effect. In general, such an illustration estimates the number of participants per arm that might be needed under those assumptions to detect a target effect. It does not show that the completed study had that probability of detecting an effect, and it does not establish that the assumptions are appropriate for a future study.

For binary participant outcomes, the event frequency and the effect targeted are central to planning. A change in either can change a planning estimate. Such estimates also depend on the proposed allocation and statistical method. The posted assumptions should therefore be treated as conditional illustrations, not as a sample-size justification recorded for the trial. The registry record does not report the trial's own sample-size justification or detailed statistical plan.

What analyses are available?

The registry record lists outcome measures but reports no analysis results for inferential comparisons. It does not report a model, covariate adjustment, handling of repeated events, confidence intervals, or p-values for the primary safety outcome. Without those details, interpretation should remain close to the observed counts. General statistical methods can help explain what comparisons might require, but they cannot supply missing trial analyses or establish that a particular model was used.

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("Cohort 1d: VIR-2218 200 mg Q4W x 6 on NRTI", "Cohort 2d: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180 ", "Cohort 3d: VIR-2218 200 mg Q4W x 3 + PEG-IFNα 180 ", "Cohort 1f: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180 ", "Cohort 2f: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180 ", "Cohort 3f: VIR-2218 200 mg Q4W x ≤13 + PEG-IFNα 18")
n      <- c(15, 15, 5, 18, 18, 13)
events <- c(9, 13, 3, 16, 17, 13)
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  Cohort 1d: VIR-2218 200 mg Q4W x 6 on NRTI  15  9  60.0  32.3  83.7  35.7  80.2  35.4  80.2
ARM  Cohort 2d: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180   15  13  86.7  59.5  98.3  62.1  96.3  61.7  96.0
ARM  Cohort 3d: VIR-2218 200 mg Q4W x 3 + PEG-IFNα 180   5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2
ARM  Cohort 1f: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180   18  16  88.9  65.3  98.6  67.2  96.9  66.9  96.6
ARM  Cohort 2f: VIR-2218 200 mg Q4W x 6 + PEG-IFNα 180   18  17  94.4  72.7  99.9  74.2  99.0  74.0  98.7
ARM  Cohort 3f: VIR-2218 200 mg Q4W x ≤13 + PEG-IFNα 18  13  13  100.0  75.3  100.0  77.2  100.0  76.8  99.8

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists seven outcome measures, including the primary adverse-event outcome and secondary outcomes concerning serum HBsAg and HBeAg. The listed secondary outcomes include mean maximum reduction of serum HBsAg, HBsAg loss, sustained HBsAg loss for greater than 6 months, anti-HBs seroconversion, and HBeAg loss and/or anti-HBe seroconversion among HBeAg-positive participants. No numerical results for these outcomes are reported in the registry record.

When a study evaluates multiple outcomes or makes multiple comparisons, the chance of at least one apparently notable result can increase. A multiplicity strategy can specify how conclusions should account for that. The registry record does not report a multiplicity adjustment or a hierarchy for interpreting outcomes. It also does not report a detailed statistical analysis plan, so it is not possible to determine whether any such approach was specified elsewhere.

Missing-data methods and analysis populations are not reported in the registry record. The record does not explain how participants with incomplete follow-up, missing assessments, or treatment discontinuation were handled in the outcome summaries. It also does not identify whether the posted counts use an intention-to-treat, safety, or other analysis population. These omissions matter because the population included in a summary and the handling of missing observations can affect how its result should be interpreted.

The registry has no analysis results listed for formal comparisons. Thus, multiplicity, missing-data handling, and population definitions cannot be evaluated from the posted information, and no unreported statistical procedure should be assumed.

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: biliary colic (7.7%), ankle fracture (5.6%), mania (5.6%).

The serious adverse-event counts are participant counts by cohort. The registry reports none of 15 participants in Cohort 1d, none of 15 in Cohort 2d, and none of 5 in Cohort 3d as affected by a serious adverse event. It reports 1 of 18 in Cohort 1f, 1 of 18 in Cohort 2f, and 1 of 13 in Cohort 3f. The other-adverse-event counts are reported separately and should not be read as serious-event counts.

The record also lists biliary colic at 7.7%, ankle fracture at 5.6%, and mania at 5.6% among the serious adverse-event terms. These are registry-listed term percentages; the record does not report a detailed denominator or explain how they relate to the participant counts. A person-level count and an event-term percentage need not represent the same quantity, since one participant can have multiple events.

Serious-event classification does not, on its own, establish that an event was caused by study treatment. The reported figures do not include event-level descriptions, timing, attribution, recurrence, or a randomized comparator. They are useful as a descriptive safety record, but should not be treated as a comparative estimate of harm.

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

The posted results describe adverse-event experience in the reported cohorts of this phase 2 study. They show participant counts for serious and other adverse events, with different counts across cohorts. They also identify several serious adverse-event terms and their recorded percentages. These observations provide a snapshot of the safety information entered in the registry for the specified outcome and timeframe.

They do not establish that VIR-2218 alone or in combination with pegylated interferon alfa-2a caused, prevented, increased, or reduced any particular event. The study used non-randomized allocation, had no masking, and included different cohort schedules. As a result, simple differences in counts are not a like-for-like causal comparison. The registry record does not provide adjusted estimates or inferential results that could address these limitations.

The results also do not answer the registered antiviral activity questions. The secondary outcomes include HBsAg and HBeAg measures, but numerical results for those outcomes are not reported in the registry record. Likewise, participant counts do not provide a full account of event severity, duration, timing, or exposure-adjusted rates.

The most defensible interpretation is therefore narrow: the record reports the stated number of participants affected in each listed cohort. A broader judgment about comparative safety or antiviral activity would require results and analyses not reported in the registry record. The counts should be understood as descriptive findings, rather than as proof for or against any treatment effect.

14. Why This Trial Matters Statistically

This study is statistically notable for the way it combines multiple treatment schedules with non-randomized allocation. Those features make the distinction between description and causal comparison especially important. Cohort-level counts can document what was recorded, but they do not isolate the effect of a treatment when groups may differ for reasons other than treatment.

The endpoint also illustrates a basic reporting distinction: a count of participants with an event is not the same as a count of all events or an event rate adjusted for time at risk. The registry record gives a timeframe of up to 148 Weeks, but cohort-specific observation time and exposure-adjusted summaries are not reported. Keeping those quantities distinct prevents participant counts from being overstated as comparative risks.

The trial's listed objectives extend beyond adverse events to pharmacokinetics and antiviral activity, and its registered secondary outcomes include antigen and seroconversion measures. However, the safety counts alone cannot answer those questions. This makes the alignment between a study's broad objectives and the outcomes with numerical results particularly important when readers assess what can be concluded.

Finally, the registry record does not report inferential analyses, uncertainty intervals, detailed missing-data methods, or a multiplicity strategy. Those absences do not change the descriptive counts, but they constrain the strength and precision of statistical interpretation. This is a useful example of why a transparent account of design and analysis is essential alongside outcome numbers.

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 principal limitation for interpreting the adverse-event results is the non-randomized design. The registry itself cautions that the arms are not a like-for-like control comparison. Cohort differences may reflect treatment, participant characteristics, or the distinct schedules; the record does not report an adjusted analysis to address these potential differences.

Adverse-event results are reported for six cohorts, while the record describes nine cohorts. Numerical adverse-event results for Cohorts 1e, 2e, and 3e are not reported in the registry record. The reported group counts therefore do not cover every described cohort. In addition, the registry does not provide cohort-specific follow-up duration, exposure time, event timing, or details of treatment discontinuation.

The primary outcome is a participant count, but the available record does not report confidence intervals, p-values, or comparative effect estimates. It does not specify the analysis population or methods for missing data, nor does it explain whether events were judged related to study treatment. The serious-event term percentages are listed without a detailed explanation of their denominator or calculation.

Finally, the registry record does not provide numerical results for the listed antiviral secondary outcomes, a detailed statistical analysis plan, a multiplicity strategy, or a sample-size justification. These gaps limit assessment of precision, outcome selection, and the completeness of the posted findings. They should not be filled by assuming procedures that are not reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study of VIR-2218 With or Without Pegylated Interferon Alpha-2a for Treatment of Chronic Hepatitis B Virus Infection — NCT04412863.
• Registry record last updated 2026-04-16; status last verified 2026-03.
• Results first posted 2026-04-16.
• 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 2, parallel, non-randomized, unmasked study of VIR-2218 alone or with pegylated interferon alfa-2a in chronic hepatitis B virus infection. Enrollment is 84. The primary outcome is the number of participants with adverse events assessed by CTCAE v5.0, over a timeframe of up to 148 Weeks.

Adverse-event counts are reported for Cohorts 1d, 2d, 3d, 1f, 2f, and 3f. The record also lists secondary outcomes concerning HBsAg and HBeAg. The non-randomized design means cohort counts are descriptive and do not constitute a like-for-like treatment comparison. Numerical analyses of the secondary outcomes, confidence intervals, p-values, missing-data methods, analysis populations, and detailed statistical plan are not reported in the registry record.