A Study to Evaluate the Safety and Immunogenicity of the Hepatitis A Virus Vaccine HAVpur in Healthy Young Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Evaluate the Safety and Immunogenicity of the Hepatitis A Virus Vaccine HAVpur in Healthy Young Children (NCT01349829), a randomized phase 4 study. The primary outcome is Seroprotection at Month 1.

2. Clinical Question

3. Trial Design

The registry record describes a Phase IV, randomized, controlled, open, parallel-group study comparing HAVpur Junior with Havrix 720 Junior in healthy young children. The official title specifies children aged between and including 18 months to 47 months, a pediatric presentation of 0.25 ml, and a 0/6 month immunization schedule. The record lists 251 enrolled participants. The study status is completed; its recorded start was 2010-03 and its primary completion was 2011-04.

The two interventions were biological products. Random allocation was used, but masking was listed as none. The registry does not provide arm descriptions beyond the intervention names. The primary endpoint was seroprotection at Month 1, assessed in the ATP population described in the clinical question. That population required receipt of the first vaccination, negative anti-HAV antibody concentration at screening, no major protocol violations, and an available post-vaccination serum sample for immunogen measurement.

The primary result lists 122 participants for HAVpur and 117 for Havrix. These endpoint denominators should not be treated as the number randomized to each group: the record identifies a restricted analysis population for the primary outcome. Safety counts are presented separately by vaccine and vaccination occasion, with their own at-risk denominators.

The registry does not report the method used to generate the random sequence, allocation concealment, the original sample-size justification, or the detailed protocol for administration and follow-up. It also does not report the non-inferiority margin or the analysis plan used for the trial's original objective. Those omissions limit reconstruction of the trial design from the registry record 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: Results are for the ATP population included all randomized subjects who received the first vaccination and had negative anti-HAV antibody concentration at screening, and who had no major protocol violations and whose serum sample after the first vaccination was available for measurement of immunogenicity

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 Seroprotection at Month 1, measured over Month 1.

The primary endpoint measures the proportion of participants whose anti-HAV antibody concentration met the study's seroprotection threshold at Month 1. The threshold was at least 10 mIU/ml. The registry reports the outcome as a percentage of participants and gives a 95% confidence interval for each group.

Seroprotection is an immunogenicity measure: it summarizes the proportion meeting a specified antibody criterion after vaccination. It is not a direct count of hepatitis A cases, and the primary endpoint does not itself report clinical disease prevention. In vaccine studies, an antibody threshold can provide a standardized way to compare immune responses between groups. Whether that threshold is accepted as a correlate of clinical protection for a particular use is a separate scientific and regulatory question; the registry result alone does not settle that question.

The endpoint was measured at Month 1 after the first vaccination. The record also lists seroprotection at Month 6 and Month 7 and geometric mean concentrations among secondary outcomes, but the registry record does not report all of those results. The primary analysis population was restricted to participants meeting the ATP criteria, so the reported percentages describe that population rather than every enrolled participant.

7. Results Posted in the Registry

• Havrix: 96.6% (113/117) versus 95.9% (117/122) on control; risk difference 0.7 percentage points (95% CI -4.1 to 5.5), risk ratio 1.01 (0.96–1.06); unadjusted two-proportion z-test p = 0.783.

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.

Seroprotection at Month 6

• 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:
  • Havrix: 99.0% (104/105) versus 98.3% (113/115) on control; risk difference 0.8 percentage points (95% CI -2.2 to 3.8), risk ratio 1.01 (0.98–1.04); unadjusted two-proportion z-test p = 0.615.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Havrix and the control. The interval gives the range of effects that remain compatible with the data.

The secondary outcomes listed in the registry include seroprotection at Month 6 and Month 7 and geometric mean concentrations. The posted Month 6 result follows the broad pattern of high seroprotection percentages in both vaccine groups, resembling the high Month 1 percentages. This offers descriptive context about the antibody endpoint at another recorded time point, but it does not independently establish the primary non-inferiority objective.

The registry record does not report results for every listed secondary outcome. In particular, results for Month 7 seroprotection and the geometric mean concentration outcomes are not reported in the registry record. The record lists no reported analyses for the secondary outcomes, so there is no documented inferential analysis to interpret for those outcomes.

Secondary endpoints can help describe response over time and provide supporting information, but they usually carry less confirmatory weight than a prespecified primary endpoint. When many outcomes or time points are examined, the chance of finding an apparently notable result by chance can increase. Statistical methods that address multiplicity may be used to control that issue, but the registry record does not report whether an adjustment or hierarchy was planned or applied. Accordingly, secondary results should be treated as supportive or exploratory unless the original analysis plan establishes otherwise.

The secondary findings also cannot compensate for the missing non-inferiority margin or an unreported formal decision rule for the primary objective. They may describe whether the general pattern of antibody response is similar across the recorded time points, but they do not change what the primary confidence interval says or establish clinical protection. Interpretation remains bounded by the available registry results and the analysis populations used for each outcome.

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

• Seroprotection at Month 6
• Seroprotection at Month 7
• Geometric Mean Concentrations (GMCs)
• Geometric Mean Concentrations (GMCs)
• Geometric Mean Concentrations (GMCs)

9. Statistical Interpretation

10. Statistical Methods Explained

The main comparison is between two independent parallel groups. For a binary endpoint such as seroprotection, each participant either meets the stated antibody threshold or does not. The group percentage expresses the fraction meeting the criterion among those included in the relevant analysis population. The registry reports percentages and 95% confidence intervals for the primary endpoint.

What does the risk difference express?

The risk difference compares the two groups by subtracting one group's event proportion from the other's. In this setting, the event is seroprotection. Its direction depends on which group is taken first in the comparison; the posted comparison is for Havrix relative to HAVpur. A value near zero indicates similar observed proportions, while a positive or negative value indicates the direction of the observed difference under that ordering. The posted estimate is 0.007. Its confidence interval, -0.041 to 0.055, expresses the uncertainty around that estimate.

What does the confidence interval contribute?

A confidence interval is an uncertainty range calculated from the observed data under a statistical procedure. In general, it shows which values remain compatible with the data and the procedure's assumptions; it is not a guarantee that the true value falls inside the particular interval. For this comparison, the range includes zero and extends on either side. A conclusion of non-inferiority would require comparing the interval with the prespecified non-inferiority margin. That margin is not reported in the registry record.

How should the p-value be read?

The posted unadjusted p-value is 0.783. In general, a p-value measures how unusual data at least as discordant with a null hypothesis would be if that null hypothesis and the analysis assumptions were correct. It is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of a difference. A non-small p-value does not prove equivalence. Equivalence and non-inferiority require their own prespecified margins and decision procedures, which are not reported in the registry record.

Why distinguish the analysis populations?

The primary outcome is reported for the ATP population, defined by vaccination, screening antibody status, absence of major protocol violations, and availability of a post-vaccination serum sample. These rules determine who contributes to the primary percentage. The record also gives safety groups by vaccination occasion. Those denominators are not interchangeable with the primary endpoint denominators, because they refer to different outcomes and group definitions. The registry record does not report a full participant-flow account or an intention-to-treat primary analysis.

What does an unadjusted re-calculation mean?

The displayed comparison statistics are simple, unadjusted calculations from the posted summary statistics. They do not incorporate adjustment for baseline characteristics or other covariates. The registry lists no reported analyses for the secondary outcomes. The sponsor's own analysis takes precedence if a discrepancy is identified; the registry record does not identify a discrepancy for this result.

Why can percentages look similar while uncertainty remains?

Observed percentages summarize the participants with outcome data, while the confidence interval reflects the imprecision associated with the available information and the method used. Similar point estimates do not by themselves show that a sufficiently narrow range of differences has been ruled out. The interval is therefore central to interpreting the comparison. For a non-inferiority question, the relevant issue is not merely whether the observed percentages are close, but whether the uncertainty range satisfies the prespecified margin. That margin and the sponsor's formal statistical plan are not reported in the registry record.

In general, binary-outcome methods rely on assumptions about how participants contribute to the analysis and how the outcome is measured. The registry provides a population definition and summary values, but it does not report the detailed estimation method, handling of missing values, or any model specification. No more specific claim about those methods can be established from the registry record.

11. Confidence Intervals and Precision

The primary percentages are 95.9% for HAVpur and 96.6% for Havrix, with 95% confidence intervals of 90.7% to 98.7% and 91.5% to 99.1%. These intervals show that the group estimates are not exact measurements of the underlying proportions. The observed values are high, but the ranges remain relevant when comparing the groups.

For the risk difference, the estimate is 0.007 and its 95% confidence interval runs from -0.041 to 0.055. The interval includes zero, which is consistent with no difference under the comparison's direction, while also allowing values on either side. The interval should be considered in relation to the size of difference that would matter for the study's non-inferiority objective. That margin is not reported in the registry record, so the interval cannot be used to verify a non-inferiority criterion.

Confidence intervals are a measure of statistical precision, not a complete account of study quality. They do not address possible bias from open-label conduct, selection into the ATP population, or unreported aspects of outcome handling. Nor do they establish whether the antibody threshold is an adequate substitute for clinical disease outcomes. The registry record supplies no additional information that resolves those issues.

The posted unadjusted p-value, 0.783, does not replace the interval. The interval describes a range of plausible effect estimates under the analysis procedure, while the p-value addresses compatibility with a particular null hypothesis. Neither provides evidence of equivalence on its own. Precision for a non-inferiority question depends on the relationship between the interval and a prespecified margin, which is unavailable in the registry record.

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 sample-size figures are planning illustrations based on the observed effect, not the trial's original design calculations. They are expressed as participants per arm, not as a total across both arms or as total events. The assumptions listed for the illustration are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning row uses the stated fraction of the observed effect: 100%, 75%, or 50%.

The 80% power column gives the estimated participants per arm for a future study to have an 80% chance of detecting the specified effect under the stated assumptions, if that effect is the one that truly exists and the assumptions hold. The 90% power column gives the corresponding planning figure for a 90% chance. These are design probabilities, not probabilities that a treatment is effective and not summaries of the completed trial's results.

The figures are shown separately for the Month 1 and Month 6 comparisons. For Month 1, the planning estimates rise from 12,296 participants per arm when planning for 100% of the observed effect to 22,334 for 75% and 51,317 for 50% at 80% power. The corresponding figures at 90% power are 16,460, 29,898, and 68,698. For Month 6, the corresponding 80% power figures are 3,366, 6,416, and 15,405; the 90% power figures are 4,506, 8,589, and 20,622.

Smaller effects are harder to distinguish from random variation, so planning for a smaller effect requires more participants. The plotted planning curve reflects this relationship. These estimates are not observed power: observed power is not a useful replacement for reading the effect estimate and its confidence interval after a study has been completed. The original trial's sample-size assumptions and justification are not reported in the registry record.

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 = 0.959; treatment proportion p₁ = 0.966; average p̄ = 0.962.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2690 = 0.5272.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2689 = 0.2263.
4. n = (0.5272 + 0.2263)² / (0.0068)² = 12,295.0, rounded up to 12,296 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 <- 0.959016393442623                          # control proportion
p1 <- 0.965811965811966                          # 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(1349829)
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 = 12,296 (80% power), 16,460 (90% power)
 75% of observed effect: n per arm = 22,334 (80% power), 29,898 (90% power)
 50% of observed effect: n per arm = 51,317 (80% power), 68,698 (90% power)
power.prop.test: 12295 
Simulated power at n = 12,296 per arm: 0.804 (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 record lists several secondary outcomes in addition to the primary Month 1 seroprotection endpoint. Examining multiple endpoints and time points raises a multiplicity issue: when many statistical tests are considered, some may appear notable by chance even if no underlying difference exists. In general, a prespecified hierarchy or adjustment procedure can help control the interpretation of multiple comparisons. The registry record does not report whether such a procedure was planned or used.

The record lists five secondary outcomes and reports a Month 6 seroprotection comparison. It does not report analyses for the secondary outcomes, nor results for every listed outcome. A p-value from one outcome should therefore not be treated as if it were the result of a single, isolated confirmatory test unless the trial's analysis plan supports that interpretation. The original statistical analysis plan is not reported in the registry record.

The primary analysis population is the ATP population. It included randomized participants who received the first vaccination, had negative anti-HAV antibody concentration at screening, had no major protocol violations, and had an available post-first-vaccination serum sample. The registry provides this definition but does not report how many participants were excluded for each reason, how missing measurements were handled, or whether other populations were analyzed for the primary endpoint.

For studies intended to assess non-inferiority, analysis population choices can matter because exclusions may affect comparability between groups. Best practice often considers more than one analysis population, but whether such analyses were planned or performed is not reported in the registry record. The registry also does not report the non-inferiority margin, the method used to construct the confidence interval, an interim-analysis plan, or a detailed missing-data strategy. These omissions prevent a full assessment of multiplicity control, robustness across populations, and the formal non-inferiority decision.

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 0.5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: gastritis (0.8%), typhoid fever (0.8%).

The registry presents safety counts separately for first and second vaccinations and separately for HAVpur and Havrix. For serious adverse events, it lists 0 among 126 at risk for HAVpur at the first vaccination and 1 among 125 at risk for Havrix at the first vaccination. For the second vaccination, it lists 1 among 118 at risk for HAVpur and 0 among 108 at risk for Havrix. These are group- and occasion-specific counts; they should not be combined into an overall participant count because the record does not establish whether the same participants contributed at both occasions.

The record names gastritis and typhoid fever among the top serious adverse-event terms, each at 0.8%. It does not link those terms to a particular vaccine group in the listed summary. Death counts are not reported in the registry record; a missing count should not be interpreted as zero.

These summaries describe reported safety events in the registry. They do not by themselves establish whether an event was caused by vaccination, and the counts are too limited to characterize uncommon risks comprehensively. The record's safety counts are also distinct from the ATP population used for the primary immunogenicity analysis.

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

The posted results describe antibody seroprotection after vaccination in a defined analysis population. At Month 1, the reported percentages were high in both groups, and the risk-difference estimate was close to zero. The confidence interval nevertheless spans values on both sides of zero. The record therefore supports a descriptive statement that the observed Month 1 percentages were similar, while leaving uncertainty about the size and direction of the underlying difference.

The study's stated purpose was to test non-inferiority of HAVpur Junior relative to Havrix 720 Junior. A non-inferiority conclusion is not established simply because the observed percentages look close or because an unadjusted p-value is not small. The interpretation requires the prespecified non-inferiority margin and a rule for comparing the interval with that margin. Neither is reported in the registry record, so the formal objective cannot be assessed from these posted statistics alone.

The endpoint is an antibody measure, not a count of hepatitis A illness. The Month 1 result therefore does not directly report clinical disease outcomes. The registry lists additional antibody outcomes, but not all of their results. The available figures should be interpreted as immunogenicity findings rather than as a complete account of clinical protection.

The primary result applies to the ATP population, with exclusions defined by screening status, vaccination, protocol violations, and sample availability. It should not be generalized automatically to every enrolled participant or to populations outside the study's stated age range and health description. Open-label conduct, limited reporting of missing data, the absence of a reported analysis plan, and unreported details of the non-inferiority design further constrain interpretation.

In short, the record documents a randomized comparison and closely placed observed seroprotection percentages, alongside uncertainty that includes no difference. It does not provide enough information to confirm the study's non-inferiority criterion, establish equivalence, or infer clinical disease prevention.

17. Why This Trial Matters Statistically

This trial illustrates why a close pair of observed percentages is not, by itself, a complete statistical conclusion. The primary values are near one another, but the risk-difference interval spans zero and extends in both directions. Interpreting a non-inferiority study depends on how that interval relates to a margin chosen in advance. Without the margin, the central decision criterion is unavailable even when the endpoint percentages are clear.

It also highlights the distinction between immunogenicity and clinical outcomes. Seroprotection is defined using an antibody threshold, making it a measurable endpoint for comparing immune responses. The result does not directly count hepatitis A cases. Statistical interpretation must stay aligned with what was measured rather than extending the result to an outcome the registry does not report.

The primary analysis population is another important feature. The registry gives explicit ATP eligibility criteria, including sample availability and absence of major protocol violations. Those criteria clarify which participants contributed to the primary result, but the record does not provide a complete account of exclusions or alternative analyses. Such information matters when judging how robust a comparative estimate is.

Finally, the record distinguishes the primary endpoint from a set of secondary antibody outcomes and provides safety counts by vaccination occasion. Secondary findings can add context, but missing results and unreported multiplicity procedures limit their confirmatory value. The case demonstrates how effect estimates, intervals, analysis populations, endpoint meaning, and protocol details all contribute to interpretation; no single p-value or percentage answers the full research question.

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 registry record does not report the non-inferiority margin, the original sample-size justification, or the detailed statistical analysis plan. As a result, the formal decision rule for the stated non-inferiority objective cannot be evaluated. The registry also does not report the method used for random-sequence generation or allocation concealment, and masking was listed as none.

The primary result is restricted to the ATP population. Although its criteria are described, the record does not give a full participant-flow account, reasons for exclusion by group, or a detailed strategy for missing measurements. It does not report whether a separate intention-to-treat analysis was conducted. The endpoint denominators therefore require careful interpretation and should not be assumed to represent all randomized participants.

Seroprotection is an antibody endpoint defined by a threshold; the primary result does not report hepatitis A disease outcomes. The registry lists Month 7 seroprotection and geometric mean concentration outcomes, but results for those listed outcomes are not reported in the registry record. It also does not report a multiplicity strategy for the secondary outcomes.

Safety summaries are presented by vaccine and vaccination occasion, and the record does not provide participant-level linkage across occasions. The serious adverse-event terms are not assigned to specific groups in the listed summary, and deaths are not reported in the registry record. These limitations mean the safety figures should be read as a registry summary, not as a complete causal assessment. Additional protocol and analysis information would be needed to resolve these uncertainties.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: A Study to Evaluate the Safety and Immunogenicity of the Hepatitis A Virus Vaccine HAVpur in Healthy Young Children — NCT01349829.
• Registry record last updated 2013-12-17; status last verified 2013-08.
• Results first posted 2013-12-17.
• 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

The registry record describes a completed Phase IV, randomized, controlled, open, parallel-group comparison of HAVpur Junior and Havrix 720 Junior in healthy young children. It lists 251 enrolled participants and an immunization schedule of 0/6 months. The primary endpoint was Month 1 seroprotection, defined as anti-HAV antibody concentration of at least 10 mIU/ml, in the specified ATP population.

Month 1 seroprotection percentages were 95.9% for HAVpur and 96.6% for Havrix. The risk-difference estimate was 0.007, with a 95% confidence interval from -0.041 to 0.055 and an unadjusted p-value of 0.783. Because the non-inferiority margin and formal analysis plan are not reported in the registry record, these figures do not establish whether the stated non-inferiority criterion was met.

The record includes Month 6 seroprotection and safety summaries, but results for some listed secondary outcomes are not reported. Safety counts are separated by vaccination occasion, and death counts are not reported in the registry record.