Study to Investigate the Safety and Efficacy of BRII-835 and BRII-179 Combination Therapy Treating Chronic Hepatitis B Virus (HBV) Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Investigate the Safety and Efficacy of BRII-835 and BRII-179 Combination Therapy Treating Chronic Hepatitis B Virus (HBV) Infection (NCT04749368), a randomized phase 2 study. The primary outcome is Percentage of Participants With Sustained HBsAg Loss During the 48-week Follow-up Period After NRTI Withdrawal.

2. Clinical Question

The study was a Phase 2, randomized, parallel-group, open-label study. Its main statistical question concerns whether sustained HBsAg loss was observed in the three cohorts during follow-up after NRTI withdrawal. The posted primary summaries record 0.0 events in each cohort. They therefore do not show observed primary endpoint events in any cohort, and the reported risk differences are 0.0 for both comparisons against Cohort A.

A separate posted endpoint describes mean change from baseline in serum HBsAg at Week 72. That measure captures a continuous change in a laboratory marker; it is not the same outcome as sustained loss. The endpoint summaries should therefore be read as addressing related but distinct questions. The registry record does not report a sponsor analysis for the primary comparisons or a statistical analysis plan explaining how confirmatory conclusions were intended to be drawn.

3. Trial Design

This was a Phase 2, multicenter, randomized, open-label study with a parallel-group design. The registry record gives enrollment as 91 and lists three cohorts. Cohort A received BRII-835 (VIR-2218) for 32 weeks. Cohort B received BRII-835 and BRII-179 (VBI-2601) with IFN-α up to Week 40. Cohort C received BRII-835 and BRII-179 up to Week 40. The record does not describe masking; it identifies the study as open-label.

The posted primary outcome summaries list 10 participants for Cohort A, 39 for Cohort B, and 41 for Cohort C. These cohort counts are the denominators attached to the displayed primary summaries. The enrollment figure and the outcome-summary denominators describe different record fields; the registry record does not explain their relationship, and no total should be inferred from the cohort summaries.

The primary endpoint concerns sustained HBsAg loss during the 48-week follow-up period after NRTI withdrawal, with the stated timeframe extending up to Week 96. The primary population is described as the full analysis set: randomized participants who had received at least 1 dose of study treatment and had evaluable antiviral activity and immunological marker measurements. The record also lists secondary outcomes concerning NRTI withdrawal criteria, HBsAg loss, HBsAg seroconversion, serum HBsAg change, HBeAg outcomes among participants positive at screening, and anti-HBs appearance or titer.

The study status is completed. The record lists a start date of 2021-04-12 and a primary completion date of 2023-07-04. The sponsor is Brii Biosciences Limited. The registry record does not report the randomization procedure, allocation concealment, a sample-size justification, or detailed protocol procedures beyond the cohort descriptions.

4. Participant Flow and Accounting

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

Overall Study

Analysis population for the primary outcome, as defined in the registry: Full analysis set included all participants who were randomized and had received at least 1 dose of study treatment with evaluable measurements of antiviral activity and immunological markers

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: All randomized set included all randomized participants, irrespective of whether they received any study treatment

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Sustained HBsAg Loss During the 48-week Follow-up Period After NRTI Withdrawal, measured over Up to Week 96.

The primary endpoint is the number and percentage of participants with sustained HBsAg loss during the 48-week follow-up period after NRTI withdrawal. The registry definition requires undetectable HBsAg below 0.05 IU/mL for at least 24 weeks during that follow-up. The stated timeframe extends up to Week 96.

This endpoint uses a sustained, threshold-based definition rather than a single measurement at one visit. Requiring the marker to remain undetectable for the specified period makes the outcome a measure of persistent loss during follow-up, as defined in the record. It is distinct from a reduction in the measured concentration: a participant can have a change in serum HBsAg without meeting the endpoint's threshold and duration requirements.

The record describes the primary outcome as a percentage but reports participant counts in the posted arm summaries. Those summaries list 0.0 participants with the endpoint in each cohort. No event was recorded in the displayed cohort summaries. The record defines the primary population as randomized participants who received at least 1 dose and had evaluable antiviral activity and immunological marker measurements. It does not provide a detailed account of how unavailable measurements, discontinuations, or other deviations from follow-up were handled in the endpoint analysis.

In general, a sustained endpoint can be clinically and statistically different from an intermediate laboratory change. It should be interpreted according to its precise definition and observation period, without treating a change in the secondary serum measure as equivalent to sustained HBsAg loss.

7. Results Posted in the Registry

• Cohort B: 0.0% (0/39) versus 0.0% (0/10) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Cohort C: 0.0% (0/41) versus 0.0% (0/10) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Change From Baseline in Serum HBsAg at Week 72

• Endpoint type: Continuous: a mean value per participant, compared as a difference in means.
• Test: Unadjusted two-sample z-test for the difference in means, using the posted standard deviations.
• Result:
  • Cohort B: mean -0.91 versus -1.15 on control; difference 0.24 (95% CI -0.16 to 0.63), standardized effect d = 0.48; z-test p = 0.242.
  • Cohort C: mean -1.02 versus -1.15 on control; difference 0.13 (95% CI -0.26 to 0.53), standardized effect d = 0.28; z-test p = 0.511.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort B and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Cohort C and the control. The interval gives the range of effects that remain compatible with the data.

The registry record lists secondary outcomes spanning withdrawal criteria, HBsAg loss and seroconversion, serum HBsAg change, HBeAg outcomes among participants positive at screening, and anti-HBs appearance or titer. These outcomes cover related but non-identical aspects of virologic and immunologic response. The posted quantitative summary available for interpretation describes mean change from baseline in serum HBsAg at Week 72. The record lists 7 secondary outcomes, but does not provide a sponsor-reported analysis for them.

The displayed Week 72 comparisons have confidence intervals that include 0 and unadjusted p-values of 0.242 and 0.511. These summaries indicate uncertainty in the estimated mean differences. They do not answer the primary question, which is whether participants had sustained HBsAg loss after NRTI withdrawal. A continuous shift in a marker and a sustained threshold-based endpoint are not interchangeable; one cannot use the former to infer how many participants met the latter.

Unadjusted secondary findings generally carry less weight when multiple outcomes and comparisons are examined, because the chance of at least one apparently notable result can increase across repeated tests. This is a general statistical consideration, not evidence that a particular result is spurious. The registry record does not report whether outcomes were ranked in a testing hierarchy, whether multiplicity adjustments were planned, or whether the secondary comparisons were prespecified for formal inference. The p-values should therefore be treated as unadjusted descriptive evidence, not as a set of confirmatory claims.

Read together, the posted summaries show no observed primary endpoint events and provide a separate, uncertain estimate for mean serum HBsAg change. The secondary summaries do not reverse or explain the primary result. They add context about a different measure, while leaving questions about the other listed secondary outcomes and the planned inferential framework unresolved in the registry record.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Percentage of Participants Meeting the NRTI Withdrawal Criteria at Week 44
• Percentage of Participants With HBsAg Loss With or Without Antibodies to Hepatitis B Surface Antigen (Anti-HBs) at Week 72
• Percentage of Participants With HBsAg Loss at Any Timepoint
• Percentage of Participants With HBsAg Seroconversion at Any Timepoint
• Change From Baseline in Serum HBsAg at Week 72
• Percentage of Participants With HBeAg Loss and/or Anti-HBe Seroconversion at Week 44 in Those Who Were HBeAg Positive at Screening
• Change From Baseline in Serum Appearance and/or Titer of Anti-HBs at Any Timepoint

9. Statistical Interpretation

10. Statistical Methods Explained

The primary outcome is binary at the participant level: each participant either meets the sustained HBsAg loss definition during the specified follow-up or does not. The posted summaries give counts and denominators for each cohort, followed by pairwise risk differences comparing Cohort B and Cohort C with Cohort A. A risk difference expresses the difference between two event proportions. Here, the displayed differences are 0.0 because no primary events are recorded in any cohort summary. The registry record does not report the method used to calculate the primary confidence intervals.

What does a confidence interval describe?

In general, a confidence interval is a range of values compatible with an estimate under a specified statistical procedure. It reflects sampling uncertainty under that procedure; it does not describe the range of individual participant outcomes, and it is not the probability that a particular hypothesis is true. The primary comparisons have displayed limits of 0.0 to 0.0. Because the record does not identify the interval method, those limits should be read as the posted output rather than as proof that the true risk difference is known without uncertainty.

The secondary Week 72 outcome is continuous: change from baseline in serum HBsAg, measured in log10 IU/mL. The cohort summaries give a mean and standard deviation. The displayed pairwise mean differences compare the Cohort B or Cohort C mean with the Cohort A mean. A positive difference means the comparison cohort's reported mean change is numerically higher than the Cohort A mean; it should be interpreted on the stated change scale, not as a count of participants reaching HBsAg loss. The posted intervals for both mean differences cross 0, so the summaries do not rule out no difference under the calculation used.

The displayed p-values for the continuous comparisons are unadjusted: p = 0.242 for Cohort B versus Cohort A and p = 0.511 for Cohort C versus Cohort A. A p-value is a measure of how compatible the observed data are with a specified null model, given the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not by itself measure the size or clinical importance of a difference. The record lists no reported analyses, so these summary-statistic comparisons should not be mistaken for an analysis attributed to the sponsor.

Why are sample-size figures only planning illustrations?

The sample-size illustrations use the observed mean differences and pooled standard deviations, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The effect to detect is a stated fraction of the observed effect. For the Cohort B comparison, the illustrations give 68 participants per arm for 80% power and 90 participants per arm for 90% power when planning for 100% of the observed effect; the corresponding values for 75% are 120 and 160, and for 50% are 269 and 359. For the Cohort C comparison, the values are 202 and 270 for 100%, 358 and 479 for 75%, and 805 and 1,078 for 50%.

These are planning illustrations based on observed summaries, not the trial's design justification and not observed power. They concern the continuous mean-change endpoint and should not be used to reinterpret the primary binary endpoint. The registry record does not report the original sample-size assumptions or justification. In general, a planning calculation depends on the assumed effect, variability, allocation, significance level, and model; changing assumptions changes the planning result.

What can be inferred from the summaries?

The arm-level estimates and the unadjusted comparisons describe the posted data on their respective scales. They do not establish that the cohorts were equivalent, and a non-significant p-value is not proof of no effect. Conversely, a numerical difference alone does not establish a treatment effect. General statistical interpretation depends on the prespecified analysis, missing-data handling, and assumptions of the model. Those details are not reported in the registry record.

Over-dispersion is a general issue for count outcomes when the observed variability exceeds what a simple count model assumes; it can make standard errors too small if ignored. The primary endpoint is reported as participant counts with a binary event definition, and no dispersion estimate or model for over-dispersion is reported. There is therefore no basis to say whether an over-dispersion adjustment was considered or needed. More generally, the choice of statistical method should match the outcome type, study design, and analysis population, and should be interpreted alongside the outcome definition and missing-data strategy.

11. Confidence Intervals and Precision

Precision concerns how tightly an estimate is determined by the observed data and its statistical method. For the primary outcome, the posted summaries contain no observed events in any cohort and show risk differences of 0.0 for both comparisons. Their displayed confidence limits are 0.0 to 0.0. The registry record does not identify the interval method or explain how uncertainty for these zero-event comparisons was handled. The displayed limits should therefore not be read as evidence that the underlying event probabilities or treatment contrasts are known exactly.

For the Week 72 mean-change outcome, the Cohort B versus Cohort A mean difference is 0.237, with a 95% interval from -0.160 to 0.634. The Cohort C versus Cohort A mean difference is 0.132, with a 95% interval from -0.261 to 0.525. Both intervals include 0, so the displayed ranges include no mean difference as well as values on either side of 0. Their breadth signals uncertainty about the magnitude and direction of the contrast under the calculation used. The registry record does not report a sponsor analysis for these comparisons.

In general, an interval is more informative than a point estimate alone because it conveys a range of values compatible with the data and method. It does not guarantee that the true value lies within the displayed limits, and it cannot repair limitations in the underlying data or analysis. The cohort sizes differ, and the comparison with Cohort A uses the smaller listed cohort denominator. The record does not provide enough methodological detail to assess all assumptions behind the calculated intervals. The posted results therefore support cautious description of the observed estimates, rather than a precise conclusion about a treatment contrast.

12. Multiplicity, Missing Data and Analysis Populations

The registry record lists 11 outcome measures, including the primary endpoint and multiple secondary measures, and reports 0 analyses. It does not report a multiplicity plan, such as a prespecified sequence of tests or an adjustment for examining multiple outcomes and comparisons. In general, multiplicity matters because repeated statistical testing can increase the likelihood of at least one result appearing notable by chance. Without a stated plan, the displayed unadjusted secondary p-values should not be treated as confirmatory evidence.

The primary analysis population is defined as the full analysis set, including randomized participants who received at least 1 dose of treatment and had evaluable measurements of antiviral activity and immunological markers. The registry record does not report how many randomized participants lacked evaluable measurements, how missing endpoint measurements were treated, or whether any participants were excluded from individual analyses. It does not describe imputation, censoring, sensitivity analyses, or rules for handling treatment discontinuation.

These omissions matter because the interpretation of a participant-level endpoint depends on whether outcome status is observed and how unavailable measurements are addressed. A complete-case summary, an imputed analysis, and an analysis that treats missing outcomes in another way can answer different statistical questions. The record does not identify which approach, if any, was used beyond defining the full analysis set.

The registry record also does not report interim analyses, stopping rules, an analysis population for each secondary outcome, or a statistical analysis plan. No conclusions should be drawn about whether such procedures existed outside the registry record. The absence of these details limits assessment of prespecification and the robustness of the posted summaries, particularly for the several secondary outcomes and pairwise comparisons.

13. 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: non-cardiac chest pain (2.6%), appendicitis (2.6%), oesophageal cyst (2.6%), subarachnoid hemorrhage (2.6%), duodenal ulcer (2.4%).

The safety summaries list serious adverse events affecting 0 participants in Cohort A, 3 in Cohort B, and 6 in Cohort C. They also list other adverse events affecting 10, 37, and 37 participants, respectively. No deaths are listed in any cohort. These are participant counts in the registry summaries; they should not be read as causal evidence about a treatment or as a comparison adjusted for exposure or follow-up.

The registry record lists serious adverse event terms with percentages, including Non-cardiac chest pain, Appendicitis, Oesophageal cyst, and Subarachnoid hemorrhage at 2.6%, and Duodenal ulcer and Small intestinal obstruction at 2.4%. The record does not provide enough context in these summaries to determine the relationship of each term to treatment, the duration of exposure, or whether events were considered related by investigators.

In general, safety counts describe reported events under the registry's definitions and observation period. Differences in counts across cohorts are descriptive; without details on event ascertainment, exposure time, and analysis methods, they should not be interpreted as causal contrasts. No medical conclusion follows from these summaries alone.

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

The primary result means that the posted cohort summaries record 0.0 participants meeting the defined sustained HBsAg loss endpoint in each cohort. The two displayed risk differences versus Cohort A are 0.0. This is a description of the observed summaries, not proof that the event is impossible, that the cohorts have identical underlying risks, or that the treatments have no effect.

The endpoint requires undetectable HBsAg below 0.05 IU/mL for at least 24 weeks during the 48-week follow-up after NRTI withdrawal. A participant's change in serum HBsAg at Week 72 is a different measure. The posted mean-change comparisons do not show whether an individual met the sustained-loss definition, and cannot be used as a substitute for primary endpoint events.

The record does not report sponsor analyses, a detailed statistical plan, or a multiplicity strategy. The continuous secondary comparisons are unadjusted, and their displayed confidence intervals include 0. The sample-size illustrations are planning exercises based on observed mean effects, not evidence that the trial had a particular level of observed power. Together, these points mean that the displayed summaries are best treated as descriptive evidence with important limits to inferential interpretation.

They do not establish efficacy or lack of efficacy, demonstrate equivalence, or determine what would happen in another population or setting. They also do not provide individual-level outcome patterns or explain the impact of missing measurements. A valid interpretation should remain tied to the registered population, the endpoint definition, the follow-up period, and the statistical details actually reported. Unreported methods and outcomes cannot be filled in from the displayed summary statistics.

15. Why This Trial Matters Statistically

This trial is statistically informative as an example of why endpoint definition matters. The primary endpoint is a sustained, threshold-based participant outcome after NRTI withdrawal, while the posted secondary quantitative result is a mean change in a serum marker at Week 72. Those measures are related in topic but answer different questions. Treating them as interchangeable would lead to an unsupported interpretation.

The primary summaries also illustrate a limitation of zero-event comparisons. When no events are observed, a point estimate of zero does not by itself establish a zero underlying risk or a precise treatment contrast. The displayed primary intervals are 0.0 to 0.0, but the registry record does not report their calculation method. Without that methodological detail, the intervals require particular caution rather than a literal reading as certainty.

The study's three randomized cohorts allow the posted summaries to describe BRII-835 alone and two combination regimens, including a cohort with IFN-α. Yet the registry record does not provide sponsor-reported analyses or a detailed inferential plan. The unadjusted secondary comparisons and planning illustrations can aid statistical orientation, but they do not replace prespecified analyses or establish confirmatory conclusions.

Finally, the record makes clear that safety counts, continuous marker summaries, and the sustained primary outcome each need their own interpretation. Missing-data handling and multiplicity are not described, which constrains how confidently the posted findings can be generalized or compared. The statistical importance lies in reading each estimate on its own scale, distinguishing observed data from uncertainty, and keeping conclusions within what the registry record documents.

16. 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 method used to calculate the primary confidence intervals, the original sample-size justification, or the detailed statistical analysis plan. It also lists 0 reported analyses. As a result, the posted primary and secondary summaries do not provide the same documentation as a full prespecified analysis with methods and assumptions clearly attributed.

The primary endpoint has no observed events in the displayed cohort summaries. This makes the observed risk differences uninformative about distinctions among possible low event probabilities, and the displayed zero-to-zero intervals cannot be evaluated fully without their method. The registry record does not explain how missing outcome measurements or incomplete follow-up were handled, despite defining the full analysis set in terms of evaluable measurements.

The continuous Week 72 comparison is unadjusted, and the record does not state a multiplicity strategy across the listed outcomes. Its estimates and intervals therefore require cautious interpretation alongside the unreported analysis plan. The sample-size illustrations use observed effects and do not document the trial's design assumptions; they should not be mistaken for an original power calculation.

The safety summaries provide counts and selected event terms, but do not describe exposure-adjusted rates, event relatedness, or detailed ascertainment in the information recorded. The open-label design is stated, but the registry record does not provide further information about assessment procedures. These limitations constrain conclusions about statistical precision, comparative safety, and generalizability without negating the descriptive value of the recorded outcomes.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: Study to Investigate the Safety and Efficacy of BRII-835 and BRII-179 Combination Therapy Treating Chronic Hepatitis B Virus (HBV) Infection — NCT04749368.
• Registry record last updated 2026-07-23; status last verified 2026-06.
• Results first posted 2026-07-23.
• 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.

20. Record Summary

NCT04749368 is a completed Phase 2, randomized, open-label, parallel-group study of BRII-835 alone or in combination with BRII-179, with or without IFN-α, in adults with chronic HBV infection. The registry record lists enrollment as 91 and describes Cohort A, Cohort B, and Cohort C.

The primary endpoint was sustained HBsAg loss during the 48-week follow-up after NRTI withdrawal, defined by an undetectable measurement below 0.05 IU/mL for at least 24 weeks. The posted summaries list 0.0 participants meeting the endpoint in each cohort and risk differences of 0.0 versus Cohort A. A secondary Week 72 serum HBsAg change outcome has unadjusted comparisons with confidence intervals that include 0.

The registry record lists 11 outcome measures and 0 reported analyses. It does not report a detailed statistical plan, multiplicity approach, or missing-data methods. The results support descriptive reading of the posted summaries, with substantial limits on inferential interpretation.