Immunogenicity & Safety of Hepatitis A Vaccine Co-admin With a Measles/Mumps/Rubella & a Varicella Vaccine in Children: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Immunogenicity & Safety of Hepatitis A Vaccine Co-admin With a Measles/Mumps/Rubella & a Varicella Vaccine in Children (NCT00197015), a randomized phase 3 study. The primary outcome is Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups..

2. Clinical Question

3. Trial Design

This was a Phase 3 randomized, parallel-group trial with no masking recorded. The registry reports enrollment of 1474 and a completed study. The listed study start was 2003-10-06, and primary completion was 2009-06-09. The sponsor was GlaxoSmithKline. The registry title identifies children 15 months of age, and the brief summary describes evaluation of immune response and safety for a two-dose inactivated hepatitis A vaccine administered with measles-mumps-rubella and varicella vaccines.

Three groups are described. The HAV group received two doses of Havrix®, at Day 0 and between Month 6 and Month 9. The HAV+MMR+V group received Havrix® at Day 0 at the same time as M-M-R®II and VARIVAX®, then another Havrix® dose between Month 6 and Month 9. The MMR+V→HAV group received M-M-R®II and VARIVAX® at Day 0, followed by Havrix® at Day 42 and between Month 7.5 and Month 10.5. Thus, the primary endpoint compares the first two groups; the third group follows a different sequence.

Random allocation is recorded, but the method used to generate the allocation sequence, concealment procedures, and allocation ratio are not reported in the registry record. Masking is recorded as none. The total enrollment does not itself establish how many participants contributed to each outcome analysis: the primary immunogenicity analysis uses an According-To-Protocol cohort with available results, and its reported group sizes differ from the overall enrollment. Further details about recruitment, follow-up, and protocol deviations are not reported in the registry record.

4. Participant Flow and Accounting

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

Before assignment: While the total numbers of subjects enrolled in the study was 1474, the total number of subjects that entered the study was 1241. The remaining subjects received a subject number but no vaccine dose and were therefore excluded from the analysis and group assignment.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was performed on the According-To-Protocol (ATP) cohort for immunogenicity, on subjects with available results from HAV and HAV+MMR+V Groups.

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 Anti-hepatitis A Virus (HAV) Antibody Concentrations in HAV and HAV+MMR+V Groups., measured over 31 days following the second dose of Havrix®.

The primary endpoint is anti-hepatitis A virus antibody concentration, expressed in milli-international units per milliliter (mIU/mL), measured 31 days following the second dose of Havrix®. The registry reports geometric mean concentrations (GMCs) and 95% confidence intervals for the HAV and HAV+MMR+V groups. The analysis population is the According-To-Protocol cohort for immunogenicity, restricted to participants with available results in those groups.

A geometric mean is a way to summarize measurements that are analyzed on a multiplicative scale; it is often used for antibody concentrations because such values can span a wide range. A confidence interval describes uncertainty around an estimated group mean under the analysis assumptions. It is not a range expected to contain every participant’s antibody concentration, and it does not by itself establish whether groups differ statistically. A direct inferential comparison requires an appropriate contrast and its uncertainty or a reported test.

The registry lists the endpoint and the group estimates, but does not report a formal between-group estimate, confidence interval for the difference, or p-value for this primary comparison. The endpoint therefore describes antibody levels at a specified post-vaccination time point in the stated analysis cohort. It does not, on its own, summarize every secondary immune response, safety outcome, or longer-term outcome.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation depends on the type of outcome, the analysis population, and the way uncertainty is reported. The primary outcome is continuous antibody concentration summarized as a geometric mean, while some secondary outcomes are counts of participants meeting a criterion. These quantities answer different questions and are not directly interchangeable.

What does a geometric mean describe?

General statistical explanation: a geometric mean summarizes values after applying a logarithmic transformation and then returning the summary to the original scale. It is useful when the distribution is skewed or when relative, multiplicative differences are more natural to describe than absolute differences. It is not the same as an arithmetic average. The primary endpoint reports GMCs in mIU/mL, with separate 95% confidence intervals for the HAV and HAV+MMR+V groups.

A confidence interval communicates the precision of an estimate under the statistical model and assumptions used to construct it. A narrower interval indicates greater precision than a wider interval on the same scale, but a confidence interval is not a statement that a particular fraction of individual measurements lies inside it. Nor do separate group confidence intervals replace a confidence interval for a treatment contrast. For the primary endpoint, the registry reports each group’s interval but not a between-group contrast, its interval, or a p-value.

How should binary comparisons be read?

Some secondary endpoints count participants, including the endpoint defined by an antibody concentration at or above a cut-off and the endpoint defined as vaccine response to Havrix®. A risk difference expresses the difference between two group proportions on an absolute scale. A risk ratio compares those proportions as a ratio. An odds ratio compares odds rather than proportions. These measures have different interpretations, and their values should be read alongside the endpoint definition, group denominators, and uncertainty interval. The registry’s recalculated comparisons are unadjusted calculations from posted summary statistics. They do not represent a reported sponsor analysis; reported analyses are absent from the record.

A p-value is a measure of how compatible the observed data are with a specified null model, under the assumptions of the test. It is not the probability that the null hypothesis is true, and it does not measure clinical importance. The unadjusted p-values in secondary comparisons do not account for the fact that multiple outcomes and comparisons are considered. A p-value alone also does not describe the size or precision of an effect, so it should be read together with the estimate and its confidence interval.

Why do analysis populations matter?

The primary endpoint uses the According-To-Protocol cohort for immunogenicity and participants with available results from the two named groups. This defines who contributes to the primary estimates. The analysis is not described as including every randomized participant. In general, an analysis population based on protocol adherence and outcome availability may differ from the population initially randomized. Such differences can affect interpretation if inclusion is related to outcome or group assignment. Participant-flow details and reasons for missing results are not reported in the registry record, so their possible influence cannot be evaluated from the posted record alone.

The reported sample sizes vary by endpoint. This is expected to require attention because different assessments may have different eligibility, timing, or availability. Those reasons are not fully described in the registry record. Outcome-specific denominators should therefore be used when interpreting each result rather than assuming that the overall enrollment is the denominator for every endpoint.

What do the planning illustrations mean?

General statistical explanation: a sample-size calculation estimates how many participants would be needed under stated assumptions to detect a specified effect with a chosen power and significance level. The registry’s planning illustrations use a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and fractions of the observed effect. They are illustrative calculations based on the observed effect, not the trial’s own design justification. The row for planning for 100% of the observed effect uses 651 participants per arm for 80% power and 871 per arm for 90% power for the antibody cut-off comparison. The corresponding figures for planning for 75% of the observed effect are 1,209 and 1,617 participants per arm; for 50%, they are 2,833 and 3,792.

For the vaccine-response comparison between HAV and HAV+MMR+V, the illustration for planning for 100% of the observed effect is 20,951 participants per arm for 80% power and 28,047 per arm for 90% power. For 75% of the observed effect, the figures are 38,570 and 51,634; for 50%, they are 89,760 and 120,162. These values are planning illustrations, not observed power, and do not show that the trial was designed with those assumptions. The record does not report the trial’s sample-size justification. The large changes across assumed effect fractions illustrate how sensitive planning can be to the effect one chooses to detect.

Over-dispersion is a general issue for count or binary data when observed variability exceeds what a simple model assumes. In such settings, standard errors may be too small if the extra variability is ignored. The registry record does not report whether over-dispersion was assessed or whether any adjustment was used. The same caution applies to other model choices: the statistical plan, covariate adjustment, handling of clustering, and missing-data methods are not reported in the registry record. Interpretation should remain close to the quantities and populations that are actually described.

10. Multiplicity, Missing Data and Analysis Populations

Multiplicity arises when several outcomes, time points, or group comparisons are assessed. If each is tested separately without adjustment or a planned hierarchy, the chance of at least one apparently unusual result can be greater than for a single prespecified test. This is a general statistical concern, not a claim that a particular result in this trial is false. The registry lists 13 secondary outcomes and reports no sponsor analyses for the secondary comparisons represented in the record. A multiplicity adjustment, testing hierarchy, or designation of confirmatory versus exploratory outcomes is not reported in the registry record.

The primary endpoint is specified as antibody concentration in the HAV and HAV+MMR+V groups 31 days following the second Havrix® dose. The record gives group-level GMCs and confidence intervals but no formal between-group estimate or p-value. The registry does not report the full statistical analysis plan, including whether the primary analysis was prespecified in its posted form, how covariates were handled, or how multiple outcomes were considered. These missing details limit assessment of the intended inferential framework.

The primary population is the According-To-Protocol cohort for immunogenicity, with available results from the two groups. This is the population named in the registry, but the record does not give a full participant flow, reasons for unavailable measurements, or an analysis comparing participants with and without results. The missing-data method, if any, is not reported in the registry record. It is therefore not possible to determine from this record whether missingness was related to treatment group, participant characteristics, or antibody measurements.

Other analysis-population definitions, handling of protocol deviations, and methods for sensitivity analyses are not reported in the registry record. These omissions do not invalidate the posted numbers; they define the limits of what can be inferred from the registry entry. The stated cohort and available-result restriction should remain part of any interpretation, particularly when comparing the primary estimates with secondary outcomes that use different denominators.

11. 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: dehydratation (0.6%), autism (0.3%), gastroenteritis (0.3%), respiratory syncytial virus bronchiolitis (0.3%), convulsion (0.3%).

The registry reports serious adverse events for the three groups, with group-specific numbers at risk and affected counts. The HAV group had 7 affected among 324 at risk; the MMR+V→HAV group had 12 among 455; and the HAV+MMR+V group had 16 among 462. These are descriptive counts recorded for the safety groups. They are not, by themselves, estimates of a causal effect of one schedule compared with another. No formal comparative safety analysis is reported in the registry record.

The listed serious-event terms include Dehydratation at 0.6%, and Autism, Gastroenteritis, Respiratory syncytial virus bronchiolitis, Convulsion, and Groin abscess at 0.3% each. The record does not establish from these entries whether an event was caused by a vaccine. Serious-event reports and ordinary adverse-event counts are distinct: the registry also records other affected counts of 251 among 324, 366 among 455, and 363 among 462 for the three groups, respectively.

Deaths are not reported in the registry record. The record does not provide further detail about event timing, seriousness criteria, exposure time, or adjudication. These counts should therefore be interpreted as registry safety summaries, not as a complete account of each event or a standalone comparison of risk.

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

The posted primary result describes antibody concentrations among participants in the stated immunogenicity cohort, at a specified time after the second Havrix® dose. It provides a geometric mean and 95% confidence interval for each of the two groups included in that endpoint. This is useful as a summary of measured immunogenicity, but it is not a direct measure of clinical disease prevention, duration of protection, or outcomes beyond the assessment time.

The registry does not report a formal comparison for the primary endpoint. The group estimates alone cannot establish the size or precision of a between-group difference on the appropriate analysis scale. Nor does the presence of a confidence interval for each group answer every question about comparative evidence. The results should be read as group summaries rather than as a definitive statistical test of the schedules.

The trial included a third schedule, with M-M-R®II and VARIVAX® given at Day 0 and Havrix® doses given later. That group is not included in the primary endpoint comparison described in the registry. Results from it should not be treated as if they were part of the primary contrast. The trial’s randomized, parallel-group design is relevant context, but the registry record does not provide enough detail about allocation procedures or the full analysis plan to assess every aspect of conduct and inference.

Secondary outcomes add information about threshold-based antibody measures, vaccine response, antibodies to the other vaccines, and solicited symptoms. Their interpretation depends on their individual denominators and timeframes. Recalculated unadjusted results are exploratory descriptions of posted summary data, not sponsor-reported analyses. Because multiplicity handling is not reported, secondary p-values should not be treated as isolated confirmatory evidence.

The safety figures record serious events and other affected counts in each group, but do not establish causation or provide a formal comparative analysis. Overall, the registry supports a description of the measured immune-response estimates and recorded safety counts in the analyzed groups. It does not, on its own, provide a complete inferential account of between-group effects, clinical outcomes, longer-term antibody persistence, or the trial’s statistical plan.

13. Why This Trial Matters Statistically

This trial is statistically interesting because its primary outcome is a laboratory measurement summarized as a geometric mean, while several secondary outcomes are binary counts. These outcome types require different summaries and different interpretations. A GMC describes the scale of antibody concentrations in a group; a threshold-based count describes how many participants meet a defined criterion. Neither quantity can stand in for the other, and the conclusion from one should not be extended automatically to the other.

The design also includes three schedules, but the primary endpoint compares only the HAV and HAV+MMR+V groups. The third group follows a different sequence of vaccinations and contributes to other registered outcomes. Keeping the primary comparison distinct from the broader set of groups and endpoints helps prevent an overgeneralized reading of the results.

The record illustrates why analysis populations matter. The primary immunogenicity endpoint uses participants with available results in an According-To-Protocol cohort, and the reported group sizes are outcome-specific. Overall enrollment is not the denominator for every analysis. Without participant flow and reasons for missing measurements, the consequences of the available-result restriction cannot be assessed fully.

Finally, the record gives a useful example of the difference between reported trial analyses and recalculated planning illustrations. Secondary comparisons include unadjusted recalculations from summary data, while sponsor-reported analyses are not present. Sample-size illustrations show how assumed effect size affects planning, but they are not the trial’s design justification and not observed power. These distinctions are central to reading registry results responsibly: estimates, uncertainty, analysis populations, multiplicity, and planning assumptions each have a separate role.

14. 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 limits are specific to interpreting this registry record. First, the primary endpoint is reported as separate group GMCs and confidence intervals, without a formal between-group estimate, confidence interval for a contrast, or p-value. This prevents direct assessment of the uncertainty around the primary comparison from the posted primary results alone.

Second, the primary analysis is restricted to the According-To-Protocol immunogenicity cohort and participants with available results. The registry does not report a full participant flow, reasons for missing measurements, or sensitivity analyses. The extent to which missing outcomes or protocol deviations could affect the reported estimates therefore cannot be assessed from the record.

Third, the study has three groups and multiple immune and safety outcomes, but the record does not report a statistical analysis plan, a multiplicity strategy, or which secondary analyses were intended to be confirmatory. Unadjusted secondary calculations should consequently be treated as descriptive rather than as a complete confirmatory analysis.

Fourth, the registry records no masking. It does not report details about allocation generation or concealment, so those features cannot be evaluated. The reported safety data are counts and do not include a formal comparative analysis; the listed serious-event terms do not establish causation. Deaths are not reported in the registry record.

Finally, the primary endpoint is measured at one stated time after the second dose. Long-term antibody persistence and clinical outcomes are not represented by this endpoint. Eligibility details beyond the age described, follow-up procedures, and the trial’s sample-size justification are not reported in the registry record. These gaps limit interpretation to the outcomes, populations, and timeframes that the record actually describes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Immunogenicity & Safety of Hepatitis A Vaccine Co-admin With a Measles/Mumps/Rubella & a Varicella Vaccine in Children — NCT00197015.
• Registry record last updated 2018-07-31; status last verified 2016-10.
• Results first posted 2010-04-01.
• 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.

18. Record Summary

The registry identifies a completed Phase 3 randomized, parallel-group study sponsored by GlaxoSmithKline, with enrollment of 1474 and no masking recorded. It evaluated hepatitis A vaccination given alone or with measles-mumps-rubella and varicella vaccines in children described as 15 months of age. Three vaccination schedules are listed.

The primary endpoint was anti-hepatitis A antibody concentration 31 days following the second Havrix® dose, summarized as GMCs with 95% confidence intervals in the According-To-Protocol immunogenicity cohort. The record also lists secondary immune-response and safety outcomes. It reports group-level primary estimates, secondary counts and recalculated comparisons, and safety counts, but no sponsor-reported analyses for the secondary comparisons represented in the record. The statistical plan, multiplicity approach, sample-size justification, and missing-data methods are not reported in the registry record.