Therapeutic Hepatitis B Vaccine (Mimogen-based) Joint Entecavir in Treating Chronic Hepatitis B Patients: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Therapeutic Hepatitis B Vaccine (Mimogen-based) Joint Entecavir in Treating Chronic Hepatitis B Patients (NCT01326546), a randomized phase 2 study. The primary outcome is Percentage of Participants With HBeAg Seroconversion at Week 48.

2. Clinical Question

3. Trial Design

The registry describes a randomized, double-blind, multicenter Phase II clinical trial with a parallel-group design and quadruple masking. Its listed purpose was to evaluate the efficacy and safety of therapeutic hepatitis B vaccine, described as mimogen-based, given jointly with entecavir in chronic hepatitis B patients. The official title specifies HBeAg-positive chronic hepatitis B. Enrollment is recorded as 378, and the trial status is completed. The start is listed as 2010-06, with primary completion in 2014-01.

The two posted arms differ in the injection component. Participants in the therapeutic HBV vaccine plus entecavir arm were assigned εPA-44 900μg by injection at week 0, 3, 6, 9, 12, 15, 18, 21, 24, 28, 32, 36, 40, 44, and 48, together with oral entecavir 0.5mg per day. The placebo plus entecavir arm had placebo injections of 900μg at the same listed weeks and the same oral entecavir dose. The number of participants assigned to each arm according to the primary endpoint counts is 189 and 188, respectively.

Randomization and masking are stated in the registry, but the method used to generate the allocation sequence, the allocation concealment procedures, and which specific parties were masked are not reported in the registry record. Further details about the participating centers, eligibility criteria, treatment adherence, or permitted concomitant care are also not reported in the registry record. The registry lists serological, virological, biochemical, and histological response among secondary outcomes, but numerical results for those outcomes 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:

Analysis population for the primary outcome, as defined in the registry: Intention-To-Treat Population

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: Population analysis based on intention to treat

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With HBeAg Seroconversion at Week 48, measured over 48 weeks.

The primary endpoint is the percentage of participants with HBeAg seroconversion at week 48. It is a binary outcome: each participant is counted according to whether the endpoint event was recorded. The registry reports counts of 21 participants in the therapeutic HBV vaccine plus entecavir arm and 23 in the placebo plus entecavir arm. The endpoint population is identified as intention-to-treat, and the primary endpoint data were summarized under End of Study using the last available post-baseline observation, described as Last Observation Carried Forward.

In general, a seroconversion endpoint captures a specified change in serological status and can serve as a marker of an immune-response outcome. The precise laboratory criteria used to define HBeAg seroconversion, including any confirmation requirements, are not reported in the registry record. The endpoint is assessed at week 48, but the registry’s description indicates that the analysis summary could use the last available post-baseline observation rather than requiring an observed result specifically at that week. The timing and handling of individual measurements between baseline and the endpoint are not reported in the registry record.

The endpoint was selected as the primary measure in the registry record, but the rationale for choosing it over other possible measures is not reported in the registry record. The listed secondary outcome domains include serological, virological, biochemical, and histological response. Those outcomes may describe different aspects of response, but their definitions and numerical results are not reported in the registry record.

7. Results Posted in the Registry

• Therapeutic HBV Vaccine+Entecavir: 11.1% (21/189) versus 12.2% (23/188) on control; risk difference -1.1 percentage points (95% CI -7.6 to 5.4), risk ratio 0.91 (0.52–1.58); unadjusted two-proportion z-test p = 0.734.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a binary participant-level measure: a participant either met the registry’s definition of HBeAg seroconversion or did not. The posted arm summaries give event counts and the number of participants in each arm. The comparison statistics include a risk difference, risk ratio, odds ratio, confidence intervals, and an unadjusted p-value. General explanations of these measures follow; the exact computational procedures and model specifications used for the registry’s comparison are not reported in the registry record.

What does a risk difference express?

In general, a risk difference subtracts the event proportion in one group from the event proportion in the other group. It is expressed on an absolute scale: values near zero indicate little separation in the proportions, while positive or negative values indicate the direction of the subtraction used. The posted risk difference is -0.011, and the posted comparison labels the vaccine-plus-entecavir arm against the placebo-plus-entecavir control. The arm-specific proportions are reported as 0.111 and 0.122, respectively. No conversion of these values is needed to interpret the posted estimate.

The risk difference is useful because it describes absolute separation between the groups rather than relative change. It can also be directly connected to the event counts and group sizes. Its interpretation depends on the event definition, population, and observation approach. Here, the endpoint is HBeAg seroconversion at week 48, summarized for the intention-to-treat population with the last available post-baseline observation carried forward. The registry does not report whether the risk difference was adjusted for any baseline characteristics or other variables; the posted p-value is explicitly unadjusted.

How do risk ratios and odds ratios differ?

In general, a risk ratio compares the event proportion in one group with the event proportion in another. A value of 1 represents equal proportions, with values on either side indicating a relative difference. The posted risk ratio is 0.908, with an interval from 0.521 to 1.584. An odds ratio compares event odds rather than event proportions. The posted odds ratio is 0.897, with an interval from 0.478 to 1.683. Because odds and proportions are distinct quantities, these measures are not interchangeable. Both posted intervals include 1, the value that represents no relative difference.

These relative measures can be useful alongside an absolute measure, but they do not replace examination of the actual event counts. The primary endpoint counts are 21 of 189 in the vaccine-plus-entecavir arm and 23 of 188 in the placebo-plus-entecavir arm. For a binary outcome, small changes in the number of recorded events can affect the comparison, particularly when event counts are limited. The registry does not report whether any alternative models, covariate-adjusted estimates, or subgroup comparisons were performed.

What does a confidence interval add?

In general, a confidence interval communicates uncertainty around an estimate. It gives a range of values compatible with the observed data under the procedure used to calculate it; it is not a guarantee that the true value lies in the interval, and it does not show the results of every possible analysis. The risk-difference interval runs from -0.076 to 0.054. It therefore includes zero, the value corresponding to no absolute difference. The relative-measure intervals include 1. The confidence level and calculation method for these intervals are not reported in the registry record, so those details should not be inferred.

Precision depends on the width of an interval as well as on the point estimate. A narrow interval would restrict the range of values compatible with the data more than a broad interval. The posted intervals extend across values representing different directions of association, which limits the precision with which the direction and magnitude of the group difference can be described. Statistical uncertainty is distinct from clinical importance: the registry does not report a threshold for a clinically important difference, so the posted estimates cannot be classified against such a threshold.

Why can over-dispersion matter?

General explanation: over-dispersion occurs when outcome variability is greater than a statistical model expects. It can make model-based uncertainty estimates too small if the model does not account for the extra variability. This issue can arise in some grouped or clustered data settings, but the registry record does not describe such a model or identify over-dispersion as a concern for this analysis. The trial is described as multicenter, but center-level modeling or adjustment is not reported in the registry record. It would therefore be inappropriate to assume that a particular over-dispersion correction was used or was needed.

How should the p-value be read?

General explanation: a p-value evaluates the compatibility of data with a stated null hypothesis under the assumptions of a statistical procedure. It is not an effect-size measure and does not convey precision by itself. The posted unadjusted p-value is 0.734. The test procedure, null formulation, and assumptions used to obtain that value are not reported in the registry record. It should be read together with the point estimate, confidence interval, event counts, and endpoint definition, rather than as a standalone verdict.

10. Confidence Intervals and Precision

The primary risk-difference estimate is -0.011, and its confidence interval extends from -0.076 to 0.054. Because the interval includes zero and spans both negative and positive values, the posted result leaves uncertainty about the direction of the absolute difference. The interval also covers a range of possible magnitudes, so the point estimate alone should not be treated as a precise description of the underlying difference. The confidence level and method used to calculate the interval are not reported in the registry record.

The relative comparisons are also uncertain. The risk ratio is 0.908, with an interval from 0.521 to 1.584. The odds ratio is 0.897, with an interval from 0.478 to 1.683. In general, 1 is the null value for these relative measures; both intervals include it. The point estimates are close to 1, but that fact alone does not establish that the groups are equivalent. Equivalence would require a prespecified margin and an analysis designed to assess it, neither of which is reported in the registry record.

The confidence intervals should be considered alongside the event counts: 21 participants in the vaccine-plus-entecavir arm and 23 in the placebo-plus-entecavir arm. The posted endpoint denominators are 189 and 188. The registry’s endpoint description also specifies last observation carried forward, while the extent of missing endpoint information and its effect on precision are not reported in the registry record. The posted summaries therefore describe both an estimated difference and substantial uncertainty about its magnitude; they do not establish that the groups have the same outcome or that a particular difference is present.

11. 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 figures are participants per arm, not total participants or total events. They are planning illustrations based on the observed effect, not the trial’s original design calculation. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, a normal approximation, and an effect to detect set to the stated fraction of the observed effect. The original trial’s sample-size assumptions and justification are not reported in the registry record.

For planning at 100% of the observed effect, the figures are 12,834 participants per arm for 80% power and 17,181 participants per arm for 90% power. At 75% of the observed effect, they are 23,055 per arm for 80% power and 30,863 per arm for 90% power. At 50% of the observed effect, they are 52,407 per arm for 80% power and 70,157 per arm for 90% power. The endpoint is binary, so these entries are participants per arm; they are not total-event counts.

In general, power is the probability that a study will detect an effect of a specified size under the assumptions used for planning. The 80% and 90% columns represent different target probabilities of detecting that specified effect; the higher target generally requires more participants under otherwise identical assumptions. The rows illustrate that smaller effects require more participants to detect. The displayed curve should be read as a visual representation of the planning relationship between the assumed effect and required sample size, not as an additional trial result. These figures are not observed power.

12. 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 = 0.122; treatment proportion p₁ = 0.111; average p̄ = 0.117.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4541 = 0.8900.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4540 = 0.3821.
4. n = (0.8900 + 0.3821)² / (-0.0112)² = 12,833.8, rounded up to 12,834 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 <- 0.122340425531915                          # control proportion
p1 <- 0.111111111111111                          # 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(1326546)
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 = 12,834 (80% power), 17,181 (90% power)
 75% of observed effect: n per arm = 23,055 (80% power), 30,863 (90% power)
 50% of observed effect: n per arm = 52,407 (80% power), 70,157 (90% power)
power.prop.test: 12833.8 
Simulated power at n = 12,834 per arm: 0.802 (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.

13. Multiplicity, Missing Data and Analysis Populations

The registry identifies one primary endpoint and lists four secondary outcome domains: serological response, virological response, biochemistry response, and histological response. It records five outcome measures in total. Numerical results for the secondary outcomes are not reported in the registry record. The posted primary comparison includes an unadjusted p-value of 0.734. Whether any multiplicity adjustment was planned or used for the primary and secondary outcomes is not reported in the registry record.

In general, testing multiple outcomes or multiple comparisons can increase the chance of obtaining at least one apparently unusual result by chance. A prespecified hierarchy, adjustment procedure, or other multiplicity strategy can address that issue, but the registry does not describe such a strategy. It also does not report whether there were interim analyses, stopping rules, subgroup analyses, or additional post hoc comparisons. Their presence or absence should not be assumed from the posted endpoint summary.

The primary endpoint population is identified as intention-to-treat. In general, this approach aims to analyze participants according to randomized assignment, regardless of treatment received, but the specific population rules and handling of participants without endpoint data are not fully described in the registry record. The primary endpoint summary used the last available post-baseline observation carried forward. The number of missing observations, timing of those observations, reasons for missingness, and any sensitivity analyses are not reported in the registry record.

It is also not reported whether the secondary outcomes used the same analysis population or missing-data approach as the primary endpoint. The registry does not provide a detailed statistical analysis plan, a description of adjustment covariates, or the methods used to calculate the confidence intervals and p-value. These omissions limit assessment of how outcome selection, missing data, and multiple testing may affect interpretation. They do not by themselves show that the analysis was inappropriate; they mean that the relevant procedures cannot be evaluated from the registry record.

14. 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 3% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: anaphylactic shock (0.5%).

The posted serious adverse event counts are 1 among 189 participants in the therapeutic HBV vaccine plus entecavir group and 0 among 189 participants in the placebo plus entecavir group. The registry lists anaphylactic shock as a top serious event term, at 0.5%. It records 0 deaths in each group. These are counts and a listed percentage; they do not by themselves establish whether an event was caused by a study intervention.

The registry separately reports other adverse event counts of 38 in the vaccine-plus-entecavir group and 54 in the placebo-plus-entecavir group, with 189 participants at risk in each group. The record distinguishes these from serious adverse events, so they should not be combined into one total. Definitions of serious adverse events, event coding procedures, severity grades, and the relationship assessment for individual events are not reported in the registry record. Follow-up time for safety events and whether participants could contribute more than one event are also not reported in the registry record.

Safety counts describe events recorded during the trial and are not a complete measure of comparative risk. The registry’s safety summary does not provide event-level narratives or uncertainty estimates. The small number of posted serious events limits what can be concluded about comparative safety from these counts alone.

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

The posted evidence describes a randomized comparison of therapeutic HBV vaccine plus entecavir against placebo plus entecavir for HBeAg seroconversion at week 48. The observed counts were 21 of 189 in the vaccine group and 23 of 188 in the placebo group. The unadjusted risk difference was -0.011, with an interval from -0.076 to 0.054, and the unadjusted p-value was 0.734. These statistics indicate that the registry’s estimate is uncertain and do not establish a clear direction or precise magnitude of difference.

The result does not show that the groups are identical. A non-small p-value is not proof of no effect, and intervals that include the null value do not demonstrate equivalence. A formal equivalence or non-inferiority conclusion would require a prespecified margin and analysis, neither of which is reported in the registry record. Conversely, the point estimate alone is not sufficient to claim a meaningful benefit or harm. The registry does not report a threshold for clinical importance.

The interpretation is specific to the stated endpoint, population, regimen, and follow-up. The vaccine regimen was combined with entecavir, and the comparator also received entecavir, so this comparison concerns the addition of the vaccine regimen relative to placebo injections in that treatment context. The primary endpoint used the intention-to-treat population and last observation carried forward. The missing-data extent and sensitivity analyses are not reported in the registry record, which restricts evaluation of how those choices affect the result.

The safety summary records 1 serious adverse event in the vaccine-plus-entecavir group and 0 in the placebo-plus-entecavir group, along with 0 deaths in each group. Those limited counts are descriptive and do not establish causation or fully characterize safety. The record’s secondary outcome domains are listed, but their numerical results are not reported in the registry record. Conclusions should therefore remain limited to the posted primary comparison and safety counts, without extending them to other endpoints, populations, treatment schedules, or follow-up periods.

16. Why This Trial Matters Statistically

This trial is statistically informative as an example of why a point estimate, uncertainty interval, event counts, and analysis population need to be read together. The primary result is based on 21 and 23 endpoint events in groups with 189 and 188 participants. The risk-difference estimate is -0.011, but its interval runs from -0.076 to 0.054. The estimate’s direction is therefore not enough to resolve what differences remain compatible with the posted data.

The endpoint handling also matters. The registry reports an intention-to-treat population and a last-observation-carried-forward summary for the primary endpoint. Those choices are important context for a week-48 measure, but the number and pattern of missing observations are not reported. Without those details or sensitivity analyses, readers cannot assess how robust the endpoint estimate is to alternative assumptions about missing outcomes.

The planning illustration highlights the distinction between an observed estimate and a future design target. Its participant counts are derived under stated assumptions and vary with the fraction of the observed effect that a future study aims to detect. They do not describe the probability that this completed trial detected an effect. The original design rationale is not reported in the registry record, so the planning illustration should not be mistaken for evidence about the trial’s intended sample size.

Finally, the registry identifies several secondary outcome domains but does not post their numerical results or a multiplicity strategy. This leaves uncertainty about the broader outcome picture and how the family of analyses was handled. The statistical value of the record lies in clearly describing the limits of the available estimates, rather than treating a single p-value as a complete account of efficacy or safety.

17. 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.

Several trial-specific details needed to assess the primary comparison are not reported in the registry record. The endpoint definition does not include the laboratory criteria for HBeAg seroconversion, and the number of participants with missing week-48 data or with an earlier observation carried forward is not given. The reasons for missingness and sensitivity analyses are not reported. Although enrollment is recorded as 378, the primary endpoint counts are listed for 189 and 188 participants; the reason for the difference between these figures is not reported in the registry record.

The registry identifies randomization, double blinding, and quadruple masking, but does not explain the random sequence generation, allocation concealment, or which parties were masked. It describes a multicenter trial but does not report center-specific results or whether the analysis accounted for center. The criteria for inclusion, participant characteristics, baseline balance, adherence, withdrawals, and treatment discontinuation are not reported in the registry record.

The primary comparison is presented with an unadjusted p-value, but the test method, confidence-interval method, confidence level, and any model adjustments are not reported. The registry does not describe a prespecified multiplicity plan, interim analyses, stopping rules, or subgroup analyses. It lists secondary outcomes, but numerical results are not reported in the registry record. The sample-size assumptions for the original trial are also not reported; the posted planning figures are an illustration based on the observed effect.

The safety summary provides event counts and a serious-event term but does not report detailed event definitions, severity grading, causality assessments, or the observation period for safety events. These limitations restrict interpretation of precision, missing-data sensitivity, outcome completeness, and safety. They do not establish that any unreported procedure was or was not carried out.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Therapeutic Hepatitis B Vaccine (Mimogen-based) Joint Entecavir in Treating Chronic Hepatitis B Patients — NCT01326546.
• Registry record last updated 2019-06-26; status last verified 2019-03.
• Results first posted 2019-06-26.
• 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.

21. Record Summary

The registry describes a completed, randomized, double-blind, multicenter Phase II parallel-group trial with quadruple masking, enrolling 378 participants with chronic hepatitis B. The primary question concerns HBeAg seroconversion at week 48 in HBeAg-positive patients assigned to therapeutic HBV vaccine plus entecavir or placebo plus entecavir. The posted primary endpoint uses the intention-to-treat population and last observation carried forward.

There were 21 endpoint events among 189 participants in the vaccine-plus-entecavir arm and 23 among 188 in the placebo-plus-entecavir arm. The posted unadjusted risk difference is -0.011, with an interval from -0.076 to 0.054 and an unadjusted p-value of 0.734. Serious adverse event counts are 1 and 0, respectively, with 0 deaths in each group. Numerical findings for the listed secondary outcome domains and further details of the statistical analysis are not reported in the registry record.