Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection (NCT01368497), a na phase 3 study. The primary outcome is Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss & Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels ≤1,000 International Units (IU) Per Milliliter (mL).

2. Clinical Question

The primary question is about the proportion meeting a combined endpoint, rather than a comparison between assigned treatments. The endpoint requires both hepatitis B e antigen (HBeAg) loss and the specified HBV DNA level; meeting only one component would not meet the stated combined definition.

The registry describes the study purpose as determining the safety and efficacy of the entecavir/peginterferon combination in children with immunotolerant chronic hepatitis B. With a single group, the study can describe outcomes observed during the treatment strategy, but it does not provide a concurrent untreated or alternative-treatment group for a direct comparison. The registry record does not report the observed primary endpoint proportion or its confidence interval, so the primary question cannot be answered from the endpoint information alone.

3. Trial Design

This completed phase 3 study is registered as a single-group trial of entecavir and peginterferon in children with chronic hepatitis B. The registry reports enrollment of 60 and lists the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) as sponsor. The recorded start is 2012-09, and primary completion is 2016-12-23.

The treatment schedule begins with entecavir for 8 weeks, followed by 40 weeks of entecavir and peginterferon together. The primary endpoint is assessed at the end of follow-up, defined as up to 96 weeks. These durations describe the registered schedule and assessment window; they do not establish the timing of an individual participant’s assessments or treatment completion.

Allocation is listed as not applicable, masking is none, and the model is single-group. Thus, there is no registry-described randomized allocation or blinded comparison. Outcomes observed during treatment can be described for the group, but a difference attributable to treatment cannot be isolated by comparing this group with a concurrent control in this design.

The registry lists secondary outcomes concerning loss and seroconversion of hepatitis B surface antigen (HBsAg) and HBeAg. The record identifies 24 outcome measures overall. Details such as the statistical analysis plan, participant flow, and the handling of protocol deviations are not reported in the registry record.

4. Participant Flow and Accounting

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

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.

6. Primary Endpoint

The registry lists the primary outcome as Proportion of Participants With Hepatitis B e Antigen (HBeAg) Loss & Hepatitis B Virus (HBV) Deoxyribonucleic Acid (DNA) Levels ≤1,000 International Units (IU) Per Milliliter (mL), measured over End of follow-up (up to 96 weeks).

The primary endpoint is the proportion of participants with HBeAg loss and HBV DNA levels ≤1,000 IU per mL at the end of follow-up, up to 96 weeks. It combines a marker-based outcome, HBeAg loss, with a threshold for the amount of viral DNA measured in blood. Both conditions are part of the registered endpoint definition.

A proportion expresses how common an outcome was in the group assessed: the numerator is the number meeting the endpoint, and the denominator is the number assessed under the analysis definition. The registry record does not report those primary endpoint counts, the observed proportion, or the population used for its calculation. Those quantities therefore cannot be described from the endpoint definition alone.

In general, a combined endpoint can represent more than one aspect of an outcome in a single measure. Its interpretation depends on the definition being applied consistently, including how missing assessments and participants who meet only one component are handled. Those analysis details are not reported in the registry record.

The registry lists a 95% confidence interval as the endpoint’s dispersion measure. In general, a confidence interval conveys uncertainty around an estimated proportion under the statistical method used. Without the estimate, interval limits, and method, the precision of the primary result cannot be assessed.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a proportion measure?

The primary outcome is binary at the participant level: each assessed participant either meets the combined endpoint definition or does not. A proportion summarizes the share meeting that definition. In general, it is calculated from an event count and a denominator defined by the analysis population and assessment rules. The registry record does not report the primary event count, denominator used in analysis, or resulting proportion, so those values cannot be interpreted.

The endpoint requires both HBeAg loss and HBV DNA at or below the stated threshold. This is not equivalent to reporting either component separately. If component results are presented elsewhere, they should be read according to their own definitions and denominators rather than substituted for the combined primary endpoint.

What does a confidence interval add?

The registry names a 95% confidence interval as the measure of dispersion for the primary proportion. In general, an estimate from a sample is subject to sampling variability. A confidence interval describes uncertainty around that estimate under a specified statistical procedure. It is not a guarantee that the true value lies within the particular interval, and it does not address systematic bias, missing outcomes, or limitations of the study design.

Interpreting an interval requires both its endpoints and the method used to construct it. The registry record does not report the observed primary estimate, interval limits, or interval method in the information available for this interpretation. It is therefore not possible to judge how precise the primary estimate was or whether alternative methods would have changed the interval.

Why does the single-group structure matter?

A single-group study estimates outcomes in the group treated under the registered schedule. A randomized comparison, by contrast, can estimate a between-group contrast when groups are assigned and analyzed appropriately. This record lists allocation as not applicable, masking as none, and the model as single-group. Accordingly, it does not describe a randomized control comparison.

Without a comparator, a treated-group proportion is descriptive. It cannot show what would have happened to the same participants under a different strategy. General influences over time, participant selection, measurement, and follow-up may affect observed outcomes. The registry record does not report methods that would address those sources of uncertainty, and no causal interpretation should be inferred from the design description alone.

What can the sample-size illustrations establish?

Any sample-size values associated with the record are planning illustrations, not observed power. The stated illustration assumptions use a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the effect to detect defined as a fraction of the observed effect. Those assumptions describe a planning exercise rather than the registered single-group design. They should not be read as the trial’s protocol or as evidence that the study had a particular probability of detecting an effect.

The registry record does not report the trial’s own sample-size justification. It also does not report whether interim analyses were planned or conducted, or a statistical analysis plan specifying model choices. The planning assumptions should not be used to fill those gaps. They do not provide an observed result, and they do not resolve the absence of a comparator in the trial design.

How should multiple outcomes be considered?

The registry lists 24 outcome measures, including secondary outcomes involving HBsAg loss, HBeAg loss, HBeAg seroconversion, and HBsAg seroconversion. When studies assess multiple outcomes, the chance of obtaining at least one apparently notable result can depend on how many tests are performed and how they are interpreted. This is a general statistical concern, not a claim that a particular result in this study is spurious.

The registry record does not report multiplicity adjustment, a hierarchy among outcomes, or an analysis plan identifying which tests were confirmatory. It lists no analysis entries. Therefore, the record does not establish whether or how the outcome family was handled statistically. The primary endpoint remains defined in the registry, but its status alone does not reveal the methods used to analyze it.

What does the safety summary represent?

Safety counts describe recorded events within the treatment group and are distinct from a comparative safety estimate. The record gives the numbers at risk and the numbers affected for serious and other adverse events, as well as deaths. In general, event counts should be interpreted with their denominators, event definitions, observation period, and rules for counting recurrent events. The registry fields do not establish from these figures alone whether counts represent unique participants or event instances.

Attribution is also separate from event occurrence. An adverse event recorded during a trial is not automatically caused by the intervention. A single-group design has no concurrent control group for estimating whether an event occurred more often under treatment than under another condition. The registry record does not report a comparative safety analysis or detailed adjudication methods.

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("Entecavir and Peginterferon")
n      <- c(60)
events <- c(0)
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  Entecavir and Peginterferon  60  0  0.0  0.0  6.0  0.0  6.0  0.0  5.9

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 24 outcome measures, including primary and secondary outcomes. It does not report a multiplicity strategy, such as a testing hierarchy or adjustment method. When several outcomes are examined, the interpretation of isolated statistical findings can be affected by the number of analyses and by whether outcomes were prespecified as primary, secondary, or exploratory. This is a general issue; the record does not establish which approach was used for this trial.

The registry record lists no analysis entries. The primary endpoint definition and its stated 95% confidence interval do not specify how results were analyzed, which participants were included in the analysis, or how departures from the treatment schedule were handled. Those details are not reported in the registry record.

Missing-data methods and the number of participants with an evaluable primary assessment are not reported in the registry record. In general, missing outcomes can affect both the estimated proportion and its uncertainty, particularly if participants with missing assessments differ in outcome from those observed. The record does not describe whether missing outcomes were excluded, imputed, or handled by another method. No assumption about the direction or size of any missing-data effect is warranted.

The analysis population is also not reported in the registry record. Enrollment of 60 does not by itself establish the denominator for the primary endpoint: the analyzed population may depend on follow-up and analysis definitions. The reported enrollment should therefore not be substituted for an unreported endpoint denominator.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: myasthenia gravis (1.7%).

The registry reports 1 serious adverse event among 60 at risk in the entecavir and peginterferon group. It lists myasthenia gravis among the serious adverse-event terms at 1.7%. The registry also reports 37 other adverse events among 60 at risk and 0 deaths.

These figures describe recorded events in the single treatment group. They are not a comparison with an untreated group or another treatment, and they do not by themselves establish that an event was caused by the intervention. The record does not report a comparative safety analysis or detailed rules for event attribution and counting.

In general, event counts are interpreted alongside the population at risk, the observation period, and the definitions used to classify events. The registry lists the at-risk figures, but does not report further details about event timing, recurrence, or how missing safety observations were handled. The counts should be read as descriptive registry results rather than as a standalone estimate of comparative risk.

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

The trial’s registered question is whether participants met a combined HBeAg-loss and HBV-DNA endpoint at the end of follow-up, up to 96 weeks, after the stated entecavir/peginterferon schedule. The registry record establishes the intended outcome and study design. It does not report the observed primary endpoint proportion or confidence interval in the endpoint information available for interpretation, so the result of that question is not reported in the registry record.

The single-group design allows outcomes in the treated group to be described. It does not provide a direct comparison against another treatment or no treatment. A proportion observed in this group would not, on its own, show how outcomes would have differed under an alternative strategy. This limitation concerns what the design can establish, not whether any particular individual outcome occurred.

The safety fields report serious and other adverse-event counts and deaths, including the serious-event term myasthenia gravis. Those figures give descriptive information for the treatment group, but do not establish causation or comparative safety. The registry record does not report details sufficient to assess all aspects of event ascertainment or attribution.

More broadly, the registry record does not report analysis populations, missing-data handling, multiplicity methods, or a statistical analysis plan. These omissions limit assessment of how results were calculated and how uncertainty should be interpreted. They do not justify filling in those methods by assumption. The posted record supports statements about the registered design and recorded safety counts, but not a treatment-effect estimate or a definitive interpretation of an unreported primary result.

14. Why This Trial Matters Statistically

This trial is statistically informative as an example of the distinction between a registered clinical question and the evidence needed to answer it. The primary outcome is carefully stated as a proportion meeting both HBeAg loss and an HBV DNA threshold. Yet a definition is not an estimate: without the observed count, denominator, proportion, and confidence interval, neither the frequency nor precision of the primary result can be assessed.

The single-group structure also shapes the kinds of conclusions available. A treated group can be described, but without a concurrent comparator the registry does not provide a between-group treatment contrast. This distinction helps prevent a descriptive outcome from being interpreted as proof of a causal effect.

The record also lists a range of secondary outcome measures, while reporting no analysis entries. That makes transparent reporting of analysis populations, missing-data handling, endpoint hierarchy, and multiplicity methods especially relevant to statistical interpretation. These details are not reported in the registry record.

Finally, the safety counts illustrate why denominators and context matter. Recorded events can be described, but occurrence during a study does not alone establish attribution to treatment. In combination, the design and reporting features show how statistical conclusions depend not only on the endpoint but also on the comparison structure, analysis details, and precision information.

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 primary endpoint information defines the outcome and identifies a 95% confidence interval as the dispersion measure, but does not report the observed proportion, interval limits, event count, or analysis denominator. The primary result and its precision therefore cannot be evaluated from the registry record.

The study is single-group, with allocation listed as not applicable and masking as none. There is no registry-described concurrent comparator. This limits interpretation to outcomes observed in the group and precludes a direct treatment comparison within this design.

The registry lists 24 outcome measures and no analysis entries. It does not report a statistical analysis plan, multiplicity method, analysis population, missing-data approach, or details on how protocol deviations were handled. These omissions prevent assessment of whether analysis decisions could affect the estimated outcomes.

Enrollment of 60 does not establish how many participants contributed to each outcome analysis. The record does not report the primary endpoint denominator or the number assessed at follow-up. Follow-up is defined as up to 96 weeks, but individual assessment timing and completeness are not reported in the registry record.

The safety figures are descriptive for the treatment group. Further details on event definitions, timing, recurrence, adjudication, and attribution are not reported in the registry record. The record therefore does not support a comparative safety estimate or a causal conclusion about the listed events.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Entecavir/Pegylated Interferon in Immune Tolerant Children With Chronic Hepatitis B Virus (HBV) Infection — NCT01368497.
• Registry record last updated 2022-05-26; status last verified 2022-05.
• Results first posted 2018-07-03.
• 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

NCT01368497 is a completed phase 3, single-group study of entecavir and peginterferon in children with immune-tolerant chronic hepatitis B. The registry reports enrollment of 60, identifies NIDDK as sponsor, and records a start of 2012-09 and primary completion of 2016-12-23. The schedule is entecavir for 8 weeks followed by 40 weeks of entecavir and peginterferon.

The primary endpoint is the proportion with HBeAg loss and HBV DNA levels ≤1,000 IU per mL at the end of follow-up, up to 96 weeks. The endpoint definition is reported, but the observed primary result and confidence interval are not reported in the registry record. The record lists 24 outcome measures and no analysis entries. Safety figures include 1 serious adverse event among 60 at risk, 37 other adverse events among 60 at risk, and 0 deaths. These are descriptive figures from a single treatment group.