Modified Process Hepatitis B Vaccine in Japanese Young Adults (V232-062): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Modified Process Hepatitis B Vaccine in Japanese Young Adults (V232-062) (NCT01463683), a randomized phase 3 study. The primary outcome is Percentage of Participants Receiving Subcutaneous Vaccination Who Achieved Seroprotection.

2. Clinical Question

The comparison is between two vaccine formulations administered by the same route and on the same stated schedule. The record identifies the study as randomized, double-masked, and parallel-group. It also lists immunogenicity, safety, and tolerability as study aims. The available primary result is restricted to participants receiving subcutaneous vaccination, so it should not be read as a result for the intramuscular group. The registry record does not report the specific randomization procedure or the details of how masking was maintained.

3. Trial Design

This was a randomized, double-masked, parallel-group Phase 3 study in healthy Japanese young adults. The registry lists enrollment as 722 and the status as completed. The recorded study start was 2011-11-29, and primary completion was 2012-11-06. The sponsor was Merck Sharp & Dohme LLC. The stated purpose was to assess safety, tolerability, and immunogenicity of HEPTAVAX-II manufactured using a modified process.

Three intervention arms are described: 2XP HEPTAVAX-II by subcutaneous injection, 1XP HEPTAVAX-II by subcutaneous injection, and 2XP HEPTAVAX-II by intramuscular injection. Each arm description specifies 10 mcg in 0.5 mL, administered on Day 1, Month 1, and Month 6. The primary outcome presented compares only the two subcutaneous groups. It is measured at Month 7, after the stated schedule.

The primary analysis population was per protocol rather than all enrolled participants. It included randomized participants who met enrollment criteria, did not violate the protocol, were seronegative at Baseline, and had vaccination and blood collection. The record’s population description says that seroprotection was evaluated only among participants receiving vaccine subcutaneously. The reason for excluding participants from the per protocol population, and the number excluded for each reason, are not reported in the registry record.

The registry identifies the design features and arm schedules but does not report the original sample-size justification, the planned allocation ratio, or details of the random sequence generation and concealment. The trial’s original statistical analysis plan, including any prespecified interim analyses, is not reported in the registry record. Those omissions limit what can be inferred about the design decisions from the posted endpoint alone.

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: The per protocol population consisted of all randomized participants who met enrollment criteria, did not violate the protocol, were seronegative at Baseline, and had vaccination and blood collection. Seroprotection was evaluated only for participants receiving vaccine subcutaneously; intramuscular vaccination was evaluated for safety only.

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 Percentage of Participants Receiving Subcutaneous Vaccination Who Achieved Seroprotection, measured over Month 7.

The primary endpoint is the percentage of participants receiving subcutaneous vaccination who achieved seroprotection at Month 7. Seroprotection was defined as an anti-hepatitis B antibody concentration of ≥10 mIU/mL, measured from blood samples using anti-hepatitis B antibody assays. The endpoint therefore reduces an antibody measurement to a binary outcome: each eligible participant either met the stated threshold or did not.

This type of endpoint is useful for comparing the proportion of participants in each group who reach a prespecified antibody threshold. It provides a direct summary of how frequently the defined immune response occurred in the analysed population. It does not show the distribution of antibody concentrations above or below the threshold, and the registry result does not describe how far participants’ measurements were from that cutoff.

For this endpoint, the registry reports 90.1% in the 2XP SC group and 82.5% in the 1XP SC group, with the assessment at Month 7. These are percentages in the per protocol population described by the record, not percentages of everyone enrolled. The record does not give a clinical disease endpoint alongside this result. As a general statistical point, a threshold-based antibody endpoint answers a different question from whether participants later experienced hepatitis B disease or another clinical outcome; those outcomes should not be inferred from seroprotection alone.

7. Results Posted in the Registry

• V232-1XP SC: 82.5% (179/217) versus 90.3% (223/247) on control; risk difference -7.8 percentage points (95% CI -14.1 to -1.5), risk ratio 0.91 (0.85–0.98); unadjusted two-proportion z-test p = 0.014.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a binary percentage endpoint and two different statistical presentations of the comparison. The sponsor’s reported analysis uses the Miettinen & Nurminen method and presents a difference in percentage of participants with a 95% confidence interval. A simple unadjusted recalculation is also available from the posted group summaries. These approaches should be kept distinct: the sponsor’s reported method is the formal analysis identified in the record, while the recalculation is a basic comparison from the posted counts and is not an adjusted analysis.

What does a percentage endpoint count?

The endpoint classifies each participant according to whether the Month 7 antibody result met the seroprotection definition, ≥10 mIU/mL. A group percentage is the proportion of participants in the analysed group who met that definition, expressed as a percentage. It does not retain the full antibody measurement: participants just meeting the threshold and participants with a higher measurement both count as having achieved seroprotection for this endpoint.

The arm summaries report 90.1% for 2XP SC and 82.5% for 1XP SC. The comparison summary lists 223 participants meeting the endpoint among 247 in the 2XP SC group and 179 among 217 in the 1XP SC group. The outcome population is per protocol as defined by the registry, so these group denominators should not be treated as the total enrolled population.

What does a risk difference express?

A risk difference subtracts one group’s event proportion from the other group’s event proportion. Its sign depends on which group is placed first. The recalculation is stated as 1XP SC relative to 2XP SC and has an estimate of -0.078. In that orientation, a negative estimate corresponds to a lower observed seroprotection proportion in 1XP SC. The sponsor’s reported difference is 7.6 percentage points and is presented in the opposite direction, with the 2XP SC group first. These are different sign conventions for describing the same direction of the observed comparison; the reported sponsor result remains the analysis identified by the registry.

General: a risk difference is an absolute contrast between proportions, unlike a risk ratio, which expresses a relative contrast. Absolute and relative measures answer different questions. The risk difference is often easier to interpret as a change in the proportion meeting the endpoint, while a relative measure compares the proportions as a ratio. Neither measure by itself explains the clinical importance of the endpoint or establishes that a prespecified decision criterion has been met.

Why is a confidence interval reported?

A confidence interval describes the statistical uncertainty around an estimated contrast. The sponsor’s 95% interval for its reported difference is 1.9 to 13.6 percentage points. The recalculated interval for the opposite-direction contrast is -0.141 to -0.015. General: a confidence interval is generated by a method with a stated coverage level and reflects sampling uncertainty under that method and its assumptions. It is not a guarantee that the true value lies within a particular interval, and it does not address biases or limitations in the trial conduct or analysis population.

The sponsor’s interval and the recalculated interval are not interchangeable outputs: they arise from different presentations and methods. The sponsor’s analysis is identified as Miettinen & Nurminen, while the recalculation is a simple unadjusted calculation from the posted summary statistics. The registry does not report the sponsor’s p-value for this analysis. The recalculated unadjusted p-value is 0.014, but it should not be substituted for an unreported sponsor p-value or treated as a full account of the study’s analysis plan.

What does the named method contribute?

The registry identifies Miettinen & Nurminen for the sponsor’s difference-in-percentage analysis. This is a method for estimating and testing a difference between binomial proportions. The record does not provide additional implementation details, such as whether any particular continuity correction was used, nor does it include the full statistical analysis plan. Those details should not be inferred from the method name alone.

The analysis is labelled NON-INFERIORITY OR EQUIVALENCE. Such analyses compare an observed difference with a prespecified margin that defines how much difference is acceptable for the stated objective. General: the margin and the direction of the decision rule are essential to interpreting a non-inferiority or equivalence conclusion; a confidence interval cannot be judged against an undisclosed margin. The margin is not reported in the registry record, so the posted estimate and interval can be described, but the formal non-inferiority or equivalence decision cannot be independently assessed from this record alone.

The posted primary analysis is confined to the two subcutaneous groups. The record lists three outcome measures and seven analyses, but no secondary results are posted. It does not report whether multiplicity adjustments were planned or applied. General: when multiple outcomes, time points, or comparisons are tested, the chance of at least one apparently noteworthy result can increase unless the analysis plan accounts for those tests. The record does not allow that issue to be evaluated beyond noting the available primary comparison.

10. Confidence Intervals and Precision

The sponsor’s reported difference is 7.6 percentage points, with a 95% confidence interval from 1.9 to 13.6. This interval describes uncertainty around the estimated difference under the sponsor’s stated Miettinen & Nurminen analysis. The endpoints of the interval are both positive in the reported contrast, but the registry record does not report the non-inferiority or equivalence margin needed to interpret the result against that formal criterion.

The simple unadjusted recalculation reports a risk difference of -0.078 for 1XP SC relative to 2XP SC, with an interval from -0.141 to -0.015. This is the reverse contrast direction from the sponsor presentation. The recalculated interval is not the sponsor’s interval and should be read as an unadjusted estimate derived from the posted summary statistics. The recalculated p-value is 0.014; it is not a substitute for the sponsor analysis, whose p-value is not reported in the registry record.

General: precision concerns how narrowly an estimate is bounded by its confidence interval. A narrower interval indicates less sampling uncertainty under the analysis method, while a wider interval indicates more. The interval does not account for unreported design choices, deviations from the protocol, measurement limitations, or uncertainty about whether the per protocol population represents a broader population.

The record does not provide confidence intervals for each group’s individual percentage, and it does not report the antibody-value distribution. The available uncertainty estimate is for the between-group difference. Therefore, the group percentages alone should not be treated as a complete description of precision, and the reported interval should not be extended to outcomes or populations that were not analysed.

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 illustrations based on the observed comparison, not the trial’s original sample-size design. For this binary endpoint, the figures are participants per arm, not total events. The planning 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 set to a stated fraction of the observed effect. The original design assumptions and sample-size justification are not reported in the registry record.

For the full observed effect, the illustration gives 303 participants per arm for 80% power and 405 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 506 participants per arm for 80% power and 677 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 1,064 participants per arm for 80% power and 1,424 participants per arm for 90% power.

In plain terms, the 80% power column gives the illustrated participants per arm for a design with an 80% chance of detecting the specified effect under the stated assumptions. The 90% power column does the same for a 90% chance. These are planning probabilities conditional on the assumed effect and statistical setup; they do not describe what happened in this completed trial. This is not observed power.

The figures increase as the assumed effect becomes smaller: detecting a less pronounced difference generally requires more participants when other assumptions are held constant. The illustrations are based on the observed effect and equal allocation, so they should not be mistaken for proof that the original trial used those assumptions or was designed around those sample sizes.

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 = 0.903; treatment proportion p₁ = 0.825; average p̄ = 0.864.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.4850 = 0.9506.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.4818 = 0.4055.
4. n = (0.9506 + 0.4055)² / (-0.0779)² = 302.7, rounded up to 303 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 <- 0.902834008097166                          # control proportion
p1 <- 0.824884792626728                          # 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(1463683)
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 = 303 (80% power), 405 (90% power)
 75% of observed effect: n per arm = 506 (80% power), 677 (90% power)
 50% of observed effect: n per arm = 1,064 (80% power), 1,424 (90% power)
power.prop.test: 302.7 
Simulated power at n = 303 per arm: 0.805 (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. Analyses Reported by the Sponsor

The sponsor’s own reported analysis gives a difference in percentage of participants of 7.6 percentage points, with a 95% confidence interval from 1.9 to 13.6, using the Miettinen & Nurminen method. The registry identifies this as a non-inferiority or equivalence analysis. It does not report a p-value for the sponsor analysis or the margin used for that objective.

The simple recalculation is an unadjusted comparison of posted summary statistics. It reports a risk difference of -0.078 for 1XP SC relative to 2XP SC, with a confidence interval from -0.141 to -0.015 and an unadjusted p-value of 0.014. The group order is reversed from the sponsor’s reported contrast, which accounts for the opposite sign. The recalculation is useful as a transparent supplementary description, but it is not the sponsor’s analysis and does not replace it.

The registry does not flag a discrepancy between the sponsor result and the recalculation. Even so, the two estimates arise from differently specified presentations, and the sponsor’s named method should be treated as the reported trial analysis. A formal interpretation of the non-inferiority or equivalence result would require the margin and decision criteria, which are not reported in the registry record.

14. Multiplicity, Missing Data and Analysis Populations

The primary endpoint population is described as per protocol. Eligible participants had to be randomized, meet enrollment criteria, avoid protocol violations, be seronegative at Baseline, and have vaccination and blood collection. The endpoint was evaluated only among participants receiving vaccine subcutaneously. This definition is important because the reported percentages do not refer to every enrolled participant.

The registry record does not report how many participants were excluded from the per protocol population, the reasons for each exclusion, or how missing antibody measurements were handled. It does not state whether missing outcomes were imputed, treated as failures, or omitted from the analysis. The record also does not report a separate intention-to-treat analysis for this endpoint. Those omissions prevent a direct comparison of the posted per protocol result with an analysis retaining all randomized participants.

The registry lists three outcome measures and seven analyses, while no secondary results are posted. It does not describe whether the sponsor adjusted for multiple comparisons, whether a hierarchical testing strategy was used, or whether the posted primary comparison was protected from other tests by a prespecified plan. The multiplicity strategy is therefore not reported in the registry record.

General: multiplicity is the issue that arises when several statistical tests or outcomes are considered. Without an appropriate plan, the chance of obtaining at least one apparently positive result can rise as the number of tests grows. That general concern does not establish that an error occurred in this study; it identifies information needed to assess the interpretation of multiple analyses. The available record does not provide enough detail to evaluate the study’s full multiplicity strategy or missing-data sensitivity analyses.

The per protocol restrictions, absence of a reported missing-data approach, and lack of posted secondary results limit how completely the primary finding can be audited from the registry record. They do not change the stated endpoint definition or the reported percentages, but they constrain assessment of the robustness and scope of the analysis.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: ectopic pregnancy (0.3%), abortion induced (0.3%), abortion spontaneous (0.3%).

The registry reports serious adverse events separately for three groups. In the 2XP SC group, 1 serious adverse event was reported among 309 at risk; in the 1XP SC group, 2 were reported among 308 at risk. In the 2XP IM group, 0 were reported among 104 at risk. These are group-specific counts and denominators, and they should be read as safety summaries rather than as the primary immunogenicity analysis.

The registry also lists the serious adverse event terms ectopic pregnancy, abortion induced, and abortion spontaneous, each at 0.3%. The record does not give a further breakdown linking each listed term to a particular treatment group in the information available for this summary. Death counts are not reported in the registry record.

The counts should not be added across groups to create a participant total, and they do not establish comparative safety by themselves. General: rare-event counts can be difficult to compare precisely, especially when group sizes differ; a small count does not by itself show whether groups differ meaningfully. The registry does not report a statistical comparison for serious adverse events. Other adverse events are also listed: 239 among 309 at risk in 2XP SC, 225 among 308 at risk in 1XP SC, and 69 among 104 at risk in 2XP IM. The record does not provide further event-level detail in this summary.

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

The posted primary results show that the Month 7 seroprotection percentage was 90.1% in the 2XP SC group and 82.5% in the 1XP SC group, using the registry’s stated definition of ≥10 mIU/mL anti-hepatitis B antibody. The sponsor reports a difference of 7.6 percentage points with a 95% confidence interval from 1.9 to 13.6. These findings describe the observed antibody-threshold outcome in the per protocol population receiving subcutaneous vaccination.

The result does not establish what the difference would be in every setting or population. The study population is described as healthy Japanese young adults, and the primary endpoint excludes the intramuscular group. The registry record does not report a clinical disease endpoint for this comparison, so the antibody result should not be interpreted as a direct estimate of hepatitis B cases prevented, duration of protection, or protection in populations not described by the study.

The record identifies the sponsor analysis as a non-inferiority or equivalence analysis, but the margin and formal decision criteria are not reported. The estimated difference and confidence interval can be described, but they do not allow an independent determination of whether the prespecified non-inferiority or equivalence criterion was met. The sponsor’s analysis is distinct from the simple unadjusted recalculation, which uses the opposite contrast direction and a different method.

Safety information should also be kept within its limits. Serious adverse events were uncommon in the posted group counts, but the registry does not provide a statistical comparison or enough detail to draw a broad comparative safety conclusion. Overall, the record supports a precise description of the posted Month 7 seroprotection proportions and the sponsor’s estimated difference, while leaving important questions about the formal decision rule, missing data, and broader clinical interpretation unanswered.

17. Why This Trial Matters Statistically

This trial illustrates how the definition and population of an endpoint shape the statistical question. The primary outcome is not a continuous antibody measurement but the percentage crossing a specified seroprotection threshold. That makes the group result straightforward to state, while also discarding information about the spread and magnitude of antibody measurements within each category.

It also shows why the direction and scale of a comparison matter. The sponsor reports a difference in percentage points in one direction, while the unadjusted recalculation presents a risk difference with the groups reversed. The sign changes with group order; it does not imply a different underlying ordering of the observed results. Reading the contrast definition alongside its estimate is essential.

The reported analysis is labelled non-inferiority or equivalence, highlighting that statistical interpretation depends on more than the observed difference and its confidence interval. A prespecified margin is needed to evaluate that design objective, but the margin is not reported in the registry record. Without it, the posted estimate remains informative descriptively, while the formal decision cannot be independently checked.

Finally, the study provides a useful example of the boundary between immunogenicity and clinical outcomes. The antibody threshold is a defined laboratory endpoint; it is not a reported measure of hepatitis B disease. Statistical summaries should answer the question that was measured, rather than imply conclusions about outcomes absent from the record. The separate intramuscular arm and the safety summaries further demonstrate why results must be tied to the specific group, endpoint, and analysis population actually reported.

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 primary endpoint is limited to the per protocol population receiving subcutaneous vaccination. The record does not report the number or reasons for exclusions from that population, the handling of missing antibody measurements, or a parallel intention-to-treat result. This makes it difficult to assess how sensitive the result is to analysis-population choices or missing outcome data.

The sponsor’s analysis is identified as non-inferiority or equivalence, but the margin and detailed decision criteria are not reported in the registry record. The formal objective therefore cannot be independently evaluated from the posted estimate and confidence interval alone. The sponsor analysis has no reported p-value in the registry record; the recalculated unadjusted p-value should not be confused with it.

The primary result covers 2XP and 1XP vaccine given subcutaneously. Although a 2XP intramuscular arm is described, it is not included in the stated primary comparison. No result for that arm on the primary seroprotection endpoint is posted in this comparison. The registry also does not report antibody distributions, later follow-up for this endpoint, or a clinical hepatitis B outcome.

The record lists multiple outcomes and analyses, but does not report the multiplicity plan or the original sample-size assumptions. The planning illustrations based on the observed effect are not evidence of the original design rationale. Safety reporting includes group counts and selected serious-event terms, but death counts are not reported in the registry record, and no formal between-group safety analysis is presented in the available information.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Modified Process Hepatitis B Vaccine in Japanese Young Adults (V232-062) — NCT01463683.
• Registry record last updated 2018-07-18; status last verified 2018-06.
• Results first posted 2014-02-17.
• 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

NCT01463683 is a completed randomized, double-masked, parallel-group Phase 3 study in healthy Japanese young adults. The registry lists enrollment as 722 and describes subcutaneous 2XP and 1XP HEPTAVAX-II arms, as well as a 2XP intramuscular arm. The primary endpoint is Month 7 seroprotection, defined as ≥10 mIU/mL anti-hepatitis B antibody, in the per protocol subcutaneous population.

The posted percentages are 90.1% for 2XP SC and 82.5% for 1XP SC. The sponsor reports a 7.6 percentage-point difference with a 95% confidence interval from 1.9 to 13.6 using Miettinen & Nurminen. The non-inferiority or equivalence margin is not reported in the registry record. Serious adverse-event counts are reported by group, but the record does not provide a formal safety comparison. Missing-data handling, multiplicity procedures, and the original sample-size justification are not reported.