A Study of Combination or Sequential Treatment With PEGASYS (Peginterferon Alfa-2a) and Entecavir in Patients With HBeAg Positive Chronic Hepatitis B: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of Combination or Sequential Treatment With PEGASYS (Peginterferon Alfa-2a) and Entecavir in Patients With HBeAg Positive Chronic Hepatitis B (NCT00940485), a randomized phase 4 study. The primary outcome is Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48.

2. Clinical Question

The registry describes a randomized, parallel-group study with no masking. Its question is about a laboratory-defined serologic outcome among people already selected for having responded to entecavir; it is not a comparison in an unselected chronic hepatitis B population. The reported primary comparison is an unadjusted comparison of the two groups at the stated time point. The record does not report the randomization procedure or additional details about how the comparison was specified in the original statistical plan.

3. Trial Design

This was a phase 4 randomized, parallel-group study of two treatment strategies for patients with HBeAg-positive chronic hepatitis B. The registry lists an enrollment of 200 and a completed status. The study began in 2009-04, and primary completion was 2011-12. It was sponsored by Hoffmann-La Roche. Masking is listed as none, so the study was open-label.

Participants had been treated with entecavir before enrollment and had responded to that treatment. The registry describes prior entecavir treatment for 9 to 36 months. Following randomization, one group received PEGASYS (peginterferon alfa-2a) 180 micrograms subcutaneously once weekly for 48 weeks, with entecavir 0.5 mg orally once daily for 8 weeks. The other group received entecavir 0.5 mg orally once daily for 48 weeks. Thus the groups differed both in the addition of peginterferon and in the duration of entecavir treatment. The trial compares the assigned strategies as a whole; it cannot isolate the effect of adding peginterferon while holding the entecavir schedule constant.

The primary endpoint was assessed at Week 48. The full analysis set was defined as randomized patients who received at least one dose of study drug. Its primary-outcome denominators were 94 in the combination group and 98 in the entecavir group. Safety denominators were 97 and 100, respectively. Those denominators describe the posted outcome populations and should not be treated as interchangeable. Details of allocation concealment, the randomization method, adherence, and handling of treatment discontinuation 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.

Before assignment: Of 332 participants, 200 were randomized, out of which 97 participants were assigned to Peginterferon alfa-2a + entecavir and 100 were assigned to entecavir, and three participants did not take any study drug.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Full analysis set included all patients who were randomized and received at least one dose of the 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: Full analysis set (FAS) included all randomized subjects who had baseline evaluations and at least one efficacy evaluation.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Hepatitis B Envelope Antigen Seroconversion at Week 48, measured over At Week 48.

The primary endpoint was the percentage of participants with hepatitis B envelope antigen (HBeAg) seroconversion at Week 48. Seroconversion was defined as absence of HBeAg together with presence of antibody to hepatitis B envelope antigen (anti-HBe). It is therefore a binary outcome: each participant either met the stated definition at the assessment or did not.

This endpoint is used to describe a change in hepatitis B serologic status, rather than a continuous change in a laboratory measurement. Reporting the percentage makes the result interpretable as the proportion meeting the definition in each group. The posted results give 14.89% in the peginterferon alfa-2a plus entecavir group, with a 95% confidence interval from 8.39% to 23.72%, and 6.12% in the entecavir group, with a 95% confidence interval from 2.28% to 12.85%.

The outcome is specific to the stated Week 48 assessment and definition. It does not by itself describe other measures such as hepatitis B surface antigen loss, viral DNA level, liver outcomes, or safety. Those are separate outcomes in the registry. The registry record does not report additional details about endpoint adjudication, the timing window around the Week 48 assessment, or how an unavailable test result was classified.

7. Results Posted in the Registry

• Entecavir: 6.1% (6/98) versus 14.9% (14/94) on control; risk difference -8.8 percentage points (95% CI -17.4 to -0.1), risk ratio 0.41 (0.16–1.02); unadjusted two-proportion z-test p = 0.047.

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.

Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Entecavir: 60.2% (59/98) versus 62.8% (59/94) on control; risk difference -2.6 percentage points (95% CI -16.3 to 11.2), risk ratio 0.96 (0.77–1.20); unadjusted two-proportion z-test p = 0.715.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Entecavir and the control. The interval gives the range of effects that remain compatible with the data.

Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Entecavir: 91.8% (90/98) versus 62.8% (59/94) on control; risk difference 29.1 percentage points (95% CI 17.9 to 40.2), risk ratio 1.46 (1.24–1.73); unadjusted two-proportion z-test p = <0.001.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically higher for Entecavir than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48

• Endpoint type: Binary: the percentage of participants with the event (counts rebuilt from the posted percentages and group sizes).
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Entecavir: 0.0% (0/98) versus 8.5% (8/94) on control; risk difference -8.5 percentage points (95% CI -14.2 to -2.9); unadjusted two-proportion z-test p = 0.003.
• Interpretation:
  • The 95% confidence interval excludes no difference, so the proportion with the event is statistically lower for Entecavir than for the control. This is an unadjusted, secondary comparison, so it is suggestive rather than confirmatory.

The secondary outcomes broaden the clinical and laboratory picture beyond the primary seroconversion definition. They include HBeAg loss, a viral DNA threshold, hepatitis B surface antigen loss and seroconversion, alanine aminotransferase normalization, changes in mean antigen measures over time, and adverse events. These endpoints are related to the same disease and treatment strategies, but they measure different features and should not be treated as interchangeable with the primary outcome.

Across the reported secondary results, the pattern is not uniformly in one direction. HBeAg loss was reported at similar percentages between groups, while the viral DNA threshold outcome favored the entecavir group in the posted comparison. Surface antigen loss was reported in the combination group and not in the entecavir group. These outcomes offer context for the primary result, but each has its own definition and uncertainty. A difference in one endpoint does not prove a corresponding difference in another, and the secondary pattern does not replace the primary endpoint assessment.

The registry lists nine secondary outcomes, but detailed numerical results are not present for every listed outcome in the record. The results available for some endpoints include unadjusted comparisons. Since no multiplicity adjustment or prespecified hierarchy among secondary outcomes is reported, isolated secondary findings carry less evidential weight than a primary finding defined in advance. General: when many outcomes are examined, some may appear different by chance even if there is no underlying effect for those measures. Confirmation would require a study with a clearly reported outcome hierarchy and analysis plan.

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

• Percentage of Participants With Loss of Hepatitis B Envelope Antigen at Week 48
• Percentage of Participants With Hepatitis B Virus - Deoxyribonucleic Acid <1000 Copies/ Millilitre at Week 48
• Percentage of Participants With Hepatitis B Surface Antigen Loss at Week 48
• Percentage of Participants With Hepatitis B Surface Antigen Seroconversion at Week 48
• Percentage of Participants With Normalized Alanine Aminotransferase at Week 48
• Quantitative Change in Mean Hepatitis B Envelope Antigen Over Time
• Quantitative Change in Mean Hepatitis B Surface Antigen Change Over Time
• Number of Participants With Incidence of Adverse Events and Serious Adverse Events

9. Statistical Interpretation

10. Statistical Methods Explained

Outcome type. The primary result is a binary percentage: participants are counted according to whether they meet the seroconversion definition at Week 48. For this kind of outcome, the percentage is the number meeting the definition divided by the number in the analysis population for that outcome. The posted group results use denominators of 94 and 98. General: binary outcomes are often summarized as proportions because the event status is categorical, rather than measured on a continuous scale.

Risk difference. The registry reports a risk difference comparing entecavir with the combination group. The sign depends on that comparison order: a negative value means the observed event proportion in the entecavir group is lower than in the combination group. For the primary endpoint, the posted interval for the risk difference is entirely on the negative side of zero. This agrees with the direction of the group percentages. General: a risk difference expresses an absolute contrast between two proportions; zero represents equal proportions under that measure.

Confidence intervals. The results include 95% confidence intervals for each group percentage and for the comparison. General: a confidence interval describes the range of estimates compatible with the data under the method used, while also reflecting sampling uncertainty. It is not a guarantee that the true value lies within the interval, nor does it show the probability that a particular treatment effect is true. For comparisons, whether the interval includes zero is relevant to whether the data distinguish the estimated difference from no difference under that interval procedure. The registry does not identify the interval method in the information reported for these results.

Unadjusted p value. The primary comparison has an unadjusted p value of 0.047. General: a p value measures how incompatible the observed data, or data more extreme, would be with a specified null model. It is not the probability that the null hypothesis is true and does not measure the size or clinical importance of an effect. “Unadjusted” means the posted value is not described as corrected for multiple comparisons; it also does not indicate adjustment for baseline characteristics. The registry record does not report a more detailed inferential model or adjustment strategy.

Randomization and masking. Random assignment is intended to make groups comparable, on average, with respect to both measured and unmeasured baseline features. The registry lists the allocation as randomized and the design as parallel, but does not report the allocation sequence method or concealment details. Masking is listed as none. General: lack of masking can affect behavior, care, reporting, or assessment, although the degree to which it matters depends on the outcome and procedures. The primary outcome is defined using laboratory markers, but the registry does not describe who assessed results or whether laboratory assessment was masked.

Analysis population and denominators. The primary population included randomized patients who received at least one dose of study drug. This definition is not the same as a statement that every randomized participant contributed a Week 48 measurement. The primary denominators are 94 and 98, while the safety denominators are 97 and 100. The registry does not report how many endpoint measurements were missing, why any participants were absent from a particular analysis, or whether missing results were imputed. General: changes in the analysis population or missing-outcome handling can affect the interpretation of a percentage, particularly when missingness is related to participant outcomes or treatment.

Multiple outcomes. The registry lists a primary endpoint and secondary outcomes, including HBeAg loss, viral DNA below the stated threshold, surface antigen outcomes, alanine aminotransferase normalization, changes in mean antigen measures over time, and adverse events. General: examining multiple outcomes creates more opportunities for apparently notable results to occur by chance. A prespecified testing hierarchy or multiplicity adjustment can help define how evidence is assessed across outcomes. Such a hierarchy or adjustment is not reported in the registry record. The reported secondary comparisons therefore warrant more caution than the primary outcome.

Planning calculations. Separate planning illustrations use the observed effect and stated assumptions to show how sample-size requirements would change under different effect sizes and power targets. General: power is the probability that a planned study would detect an effect of a specified size under the assumptions of the calculation, if that effect were present. A planning calculation based on an observed effect is not evidence that the completed study had a particular power, and it is not a substitute for the original sample-size justification. The trial's own original design assumptions and sample-size justification are not reported in the registry record.

Limits of the posted analysis. The registry reports no analyses in its analysis listing and no reported secondary analyses. This does not establish that no analyses were conducted; it means that detailed model results, covariate-adjusted estimates, sensitivity analyses, and subgroup analyses are not reported in the registry record. General: summary percentages and unadjusted comparisons are useful for describing the observed results, but they cannot answer questions that require individual-level data or a specified adjusted model.

11. Confidence Intervals and Precision

For the primary endpoint, the estimated percentage was 14.89% in the combination group, with a 95% confidence interval from 8.39% to 23.72%. In the entecavir group, it was 6.12%, with a 95% confidence interval from 2.28% to 12.85%. The intervals express uncertainty around each group's estimated percentage. Their width indicates that the underlying proportions are not pinned down to a narrow range by these data.

The risk-difference interval for the primary comparison excludes zero, but its endpoint is close to zero. This means that the posted analysis distinguishes the observed contrast from no difference under its reported interval, while still leaving uncertainty about the size of the contrast. The unadjusted p value of 0.047 is consistent with that interval result. Neither the p value nor the interval establishes the clinical importance of the difference, and the registry does not report a threshold for judging clinical importance.

Precision depends in part on the number of participants contributing to the endpoint. The primary outcome denominators were 94 and 98. Those numbers are distinct from the safety denominators of 97 and 100. The registry does not report the extent or handling of missing Week 48 assessments, so the effect of missing data on precision cannot be evaluated from the record.

General: a confidence interval is not a prediction interval for individual participants and does not show the spread of individual responses. It describes uncertainty in an estimated group-level quantity under the analysis method. The registry does not report the interval-construction method, so the precision should be read from the posted bounds without assuming a particular statistical procedure.

12. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning illustrations report participants per arm for this binary outcome; they are not totals of events. They use the observed effect as a reference and show scenarios for planning for 100%, 75%, and 50% of that observed effect. For planning for 100% of the observed effect, the illustration gives 191 participants per arm for 80% power and 255 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 371 participants per arm for 80% power and 497 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 904 participants per arm for 80% power and 1,210 participants per arm for 90% power.

The stated assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. Under these assumptions, the 80% power column represents a planning target with an 80% chance of detecting the specified effect if it were present; the 90% column represents a higher chance under the same assumptions. Smaller effects require more participants because they are harder to distinguish from random variation.

These figures are planning illustrations, not observed power. They are based on the observed trial effect rather than on the trial's original design assumptions. The original sample-size justification and planning assumptions for the trial are not reported in the registry record. The figures should therefore be read as conditional illustrations, not as a reconstruction of the study's original design or a statement about what the completed study could detect.

13. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.149; treatment proportion p₁ = 0.061; average p̄ = 0.105.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4337 = 0.8500.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4292 = 0.3612.
4. n = (0.8500 + 0.3612)² / (-0.0877)² = 190.7, rounded up to 191 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.148936170212766                          # control proportion
p1 <- 0.0612244897959184                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(940485)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 191 (80% power), 255 (90% power)
 75% of observed effect: n per arm = 371 (80% power), 497 (90% power)
 50% of observed effect: n per arm = 904 (80% power), 1,210 (90% power)
power.prop.test: 190.7 
Simulated power at n = 191 per arm: 0.811 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

14. Multiplicity, Missing Data and Analysis Populations

The registry identifies HBeAg seroconversion at Week 48 as the primary outcome and lists several secondary outcomes. These include other serologic outcomes, a viral DNA threshold, liver enzyme normalization, quantitative changes over time, and adverse events. The record does not report a statistical testing hierarchy, a familywise error procedure, or another multiplicity adjustment. It is therefore not possible to determine from the registry whether the secondary comparisons were intended as confirmatory tests or as exploratory descriptions.

Multiplicity matters because evaluating several outcomes creates more opportunities for a low p value to occur by chance. A nominal p value for an individual secondary comparison does not account for the full set of outcomes unless an adjustment is specified. The primary endpoint has a reported unadjusted p value; the record does not state a multiplicity-adjusted primary analysis. Secondary p values should consequently be interpreted cautiously and in the context of the full outcome set rather than as stand-alone confirmation.

The primary analysis population is defined as all randomized patients who received at least one dose of study drug. The posted primary denominators are 94 and 98. Safety denominators are 97 and 100. The registry does not explain the difference between these analysis denominators, report the number of missing Week 48 outcome measurements, or describe exclusions after randomization. It also does not report imputation methods, a missing-data sensitivity analysis, or whether participants were analyzed according to assigned group regardless of treatment received.

The record's analysis listing contains no reported analyses. Accordingly, detailed model specifications, covariate adjustment, interim analyses, protocol deviations, subgroup analyses, and sensitivity analyses are not reported in the registry record. Their absence from the record should not be read as evidence that they were not conducted; it limits what can be assessed from the posted information.

15. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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: hyperthyroidism (2.1%), hypothyroidism (1.0%), viral myocarditis (1.0%), lung infection (1.0%), myocardial ischaemia (1.0%).

The registry reports serious adverse events for safety populations of 97 in the peginterferon alfa-2a plus entecavir group and 100 in the entecavir group. Six participants in the combination group were reported as affected by serious adverse events; zero were reported as affected in the entecavir group. These are participant counts, not event rates adjusted for follow-up time. The registry lists no death counts; deaths are not reported in the registry record.

The serious adverse event terms listed include hyperthyroidism at 2.1%, and hypothyroidism, viral myocarditis, lung infection, myocardial ischaemia, and haemorrhoids at 1.0% each. The record does not provide enough detail to determine from these terms alone the event duration, severity beyond the serious classification, relatedness to treatment, or whether an individual could have had more than one event.

Other adverse events were reported for 65 participants in the combination group and 5 in the entecavir group, using the stated safety denominators. The open-label design and differences between the treatment regimens are relevant context when reading adverse event counts. The registry summary does not supply a detailed exposure-adjusted safety analysis or the methods used to collect and attribute events.

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

The primary result describes the percentage of participants meeting a specific serologic definition at Week 48. In the posted results, the percentage was higher in the peginterferon alfa-2a plus entecavir group than in the entecavir group. The reported unadjusted comparison interval excludes zero, while the group-level confidence intervals and comparison still express uncertainty about the underlying percentages and the size of the contrast.

This finding does not by itself establish that the difference is clinically important, durable beyond the stated assessment, or applicable to people outside the study population. Participants had previously responded to entecavir, and the registry does not report follow-up beyond the described outcome timing in the results presented. The result should not be generalized automatically to people without that treatment history.

The treatment comparison is between complete regimens: peginterferon alfa-2a plus entecavir for a specified schedule versus entecavir alone for a different schedule. Because entecavir treatment duration differed between groups, the result cannot be attributed solely to the addition of peginterferon. The registry describes a randomized design, but does not report detailed allocation procedures, masking, or adjusted analyses. The study was not masked.

HBeAg seroconversion is only one of the outcomes measured. Other laboratory and safety outcomes have separate definitions, denominators, and uncertainty. No multiplicity adjustment or formal ordering of secondary hypotheses is reported, so the other posted results should be considered alongside the primary result without treating them as independent proof. The registry record also does not report how missing Week 48 assessments were handled. Overall, the findings describe the posted outcomes for this selected trial population and these assigned treatment strategies; they do not settle broader questions about comparative benefit, long-term outcomes, or the effects of treatment in other groups.

17. Why This Trial Matters Statistically

This trial illustrates why a treatment contrast needs to be read together with its population, endpoint, and regimen details. The primary outcome is a defined binary serologic event at a fixed assessment time. The result is reported as a percentage in each group, with confidence intervals that show uncertainty rather than a single definitive value. The unadjusted comparison gives a compact contrast, but does not replace consideration of the interval, endpoint definition, and analysis population.

It also highlights that randomization does not make treatment strategies identical except for one component. The combination group received peginterferon alfa-2a and entecavir, while the comparator received entecavir for a different duration. The observed contrast therefore pertains to the assigned regimens. It cannot be interpreted as an isolated estimate of adding peginterferon while holding all other treatment features constant.

The study's selection of patients who had already responded to entecavir is another important statistical feature. It defines the population to which the observed proportions most directly apply. Furthermore, the registry reports multiple secondary measures and does not report a multiplicity plan. That makes the distinction between a primary result and secondary exploratory patterns especially important.

Finally, the record illustrates the limits of registry-level summaries. Group percentages and confidence intervals communicate the main result, but missing-data handling, detailed analysis methods, and protocol-level design assumptions are not reported. A careful interpretation separates the observed estimates from what cannot be established from the record.

18. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The population was restricted to patients with HBeAg-positive chronic hepatitis B who had been pretreated with and responded to entecavir for 9 to 36 months. This selection limits direct applicability to patients with different treatment histories or responses. The posted results do not provide subgroup estimates that would show whether outcomes varied across features of this selected population.

The regimens differed in more than the presence or absence of peginterferon: entecavir was scheduled for 8 weeks with the combination and for 48 weeks in the comparator group. The randomized comparison therefore estimates the contrast between those treatment strategies, not the separate contribution of each regimen component. The open-label design is another consideration; the registry does not describe masked laboratory assessment or other procedures that could limit awareness of assignment.

The primary outcome denominators and safety denominators differ. The record does not explain the differences, report missing outcome counts, or describe imputation and sensitivity analyses. It also does not report the randomization method, allocation concealment, detailed analysis model, original sample-size justification, or protocol-defined multiplicity strategy. Secondary results are not reported for every listed outcome, and no multiplicity adjustment is described.

These limitations do not negate the posted estimates, but they constrain how specifically the result can be interpreted. In particular, the registry summary cannot resolve how missing assessments might affect the endpoint estimate, whether the unadjusted comparison was supplemented by other analyses, or how the trial was originally designed to address uncertainty.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study of Combination or Sequential Treatment With PEGASYS (Peginterferon Alfa-2a) and Entecavir in Patients With HBeAg Positive Chronic Hepatitis B — NCT00940485.
• Registry record last updated 2016-03-25; status last verified 2016-02.
• Results first posted 2016-02-22.
• 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.

22. Record Summary

NCT00940485 is a completed phase 4 randomized, open-label, parallel-group study sponsored by Hoffmann-La Roche. It enrolled patients with HBeAg-positive chronic hepatitis B who had responded to prior entecavir treatment. The study compared peginterferon alfa-2a plus entecavir with entecavir alone, with different entecavir schedules in the two groups.

The primary endpoint was HBeAg seroconversion at Week 48, defined as absence of HBeAg and presence of anti-HBe. The posted percentages were 14.89% for the combination group and 6.12% for the entecavir group. The unadjusted comparison interval excluded zero, with a p value of 0.047. Interpretation is limited by the selected population, the regimen differences, open-label design, and details of missing-data handling and statistical planning that are not reported in the registry record.