Hepatitis A Vaccine, Inactivated and Measles, Mumps, Rubella and Varicella Virus Vaccine Live Safety Study (V251-066)(COMPLETED): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Hepatitis A Vaccine, Inactivated and Measles, Mumps, Rubella and Varicella Virus Vaccine Live Safety Study (V251-066)(COMPLETED) (NCT00326183), a randomized phase 4 study. The primary outcome is Participants With 1 or More Serious Vaccine-Related Adverse Experiences.

2. Clinical Question

The study addresses a safety question about the reported occurrence of serious vaccine-related adverse experiences after vaccination. Its primary endpoint counts participants who experienced at least one such event, rather than counting every event or measuring symptom severity. The registry record describes a randomized, open, multicenter comparison, with VAQTA alone as the comparator and VAQTA plus ProQuad as the other arm.

The overall study description says that two doses of each vaccine would be given concomitantly or non-concomitantly, with safety data collected after each vaccination. The record does not give further detail about the timing or sequence for each arm. The primary question is therefore limited to the posted endpoint and its stated follow-up window; it does not establish a comparison of other safety outcomes, vaccination schedules, or longer-term outcomes.

3. Trial Design

The registry record identifies this as a completed phase 4, randomized, open-label, parallel-group study. It describes the study as multicenter, but the number of centers is not reported in the registry record. The study began on 2007-03-26, and primary completion was recorded as 2008-01-15. Enrollment was 1800.

The two posted arms were VAQTA alone and VAQTA plus ProQuad. The record describes two doses of each vaccine, given concomitantly or non-concomitantly, and says safety data would be collected following each vaccination. It does not report the detailed allocation procedure, arm-specific vaccination schedules, or whether the timing of the vaccines differed in a particular way between arms. Masking is listed as none, so the study was open-label.

For the primary outcome, the posted denominators are 1415.0 in the VAQTA arm and 334.0 in the VAQTA plus ProQuad arm. The endpoint population is described as subjects with safety follow-up data after any vaccine dose. Enrollment and these outcome denominators describe different record entries; the registry record does not explain the difference between them. The record lists one posted secondary outcome, participants with one or more systemic adverse experiences. It does not list statistical analyses for the outcomes.

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: Includes all subjects who provided safety follow-up data after any dose of vaccine out of the total number of subjects enrolled.

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 Participants With 1 or More Serious Vaccine-Related Adverse Experiences, measured over Days 1 to 14 after any vaccination.

The primary endpoint is the number of participants with one or more serious vaccine-related adverse experiences during Days 1 to 14 after any vaccination. This is a binary participant-level outcome: each participant is classified according to whether at least one qualifying experience occurred during the stated window. It does not count multiple events separately for a participant, and it does not describe the severity of experiences beyond the endpoint’s serious and vaccine-related criteria.

In general, a participant-level event indicator can make a safety outcome easier to compare between groups than a raw event count when one person could have multiple experiences. It answers how commonly participants experienced at least one event, rather than how many total events occurred. The follow-up window also defines which reported experiences contribute to this particular result; experiences outside Days 1 to 14 after vaccination are not represented by this endpoint.

The posted result records no participants with the endpoint in the VAQTA arm and one participant in the VAQTA plus ProQuad arm. These counts describe this narrowly defined outcome and window. Other listed safety outcomes are distinct from the primary endpoint and should not be treated as interchangeable with it.

7. Results Posted in the Registry

• Arm 2: VAQTA™ +ProQuad™: 0.3% (1/334) versus 0.0% (0/1415) on control; risk difference 0.3 percentage points (95% CI -0.3 to 0.9); unadjusted two-proportion z-test p = 0.040.

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary because it records whether each participant had at least one qualifying serious vaccine-related adverse experience. For a binary outcome, a common comparison is the difference between the observed proportions in two groups. The registry reports that comparison as a risk difference of 0.003, with the VAQTA arm as the reference and VAQTA plus ProQuad as the comparison arm. The direction is positive for the combination arm. The record does not give a more detailed account of the statistical procedure used to estimate the difference.

What does a risk difference represent?

In general, a risk difference expresses the contrast between two event proportions on the same absolute scale. It is distinct from a ratio measure, which compares relative rather than absolute event frequencies. An absolute contrast can be useful for a safety question because it describes the difference in observed event frequency between the groups. Here, however, the very small number of observed primary events means that the estimate is based on sparse information. The point estimate alone does not convey that uncertainty; the confidence interval is also important.

How should the confidence interval be read?

In general, a confidence interval gives a range of effect values compatible with the observed data under the assumptions of the method used to calculate it. It is not a guarantee that the true effect lies in the interval, and it is not a direct probability statement about a particular effect. The interval reported for this result spans zero. Thus, it includes the possibility of no difference and values on either side of no difference. Its width and position need to be considered alongside the estimate and the event counts, rather than treating the estimate as exact.

What does the p-value add?

The record reports an unadjusted p-value of 0.04. In general, a p-value is calculated relative to a null hypothesis and a statistical model. It describes the degree of incompatibility between observed data and that model, if the model assumptions hold. It does not measure the size or importance of an effect, and it does not provide the probability that an observed association is due to chance. The registry record does not state the test, its assumptions, or whether the reported value was based on a one-sided or two-sided procedure. It also does not report an adjusted p-value.

The confidence interval includes zero while the p-value is 0.04. Under familiar paired procedures, a two-sided test and its corresponding confidence interval generally lead to aligned conclusions at matching thresholds. The record does not identify the methods or confidence level sufficiently to determine why these summaries appear different. The p-value is explicitly unadjusted, and the record contains no analysis details that would allow independent reconstruction. The result should therefore be described as posted, while retaining this qualification rather than choosing one statistic over the other.

Why are sparse events important?

In general, estimates based on rare events can be imprecise and sensitive to a small change in the observed counts. Conventional approximations for binary outcomes may perform less well when event counts are very low, depending on the method and the data structure. Alternatives may be used in such settings, but the record does not report which approach was used. No alternative analysis should be assumed. The posted point estimate and interval should be considered in light of the fact that the primary endpoint occurred once across the two arms.

The registry lists no outcome analyses. This means the method, model adjustments, handling of any repeated vaccination observations, and any sensitivity analyses are not reported in the registry record. The endpoint is defined at the participant level, but follow-up occurs after any vaccination; the record does not provide enough detail to determine how observations across vaccination periods were handled statistically.

The record includes planning assumptions for sample-size illustrations based on the observed effect: a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. Such illustrations are planning exercises, not evidence of the trial’s achieved statistical power. The registry does not report the trial’s own sample-size justification or a power calculation, so those should not be inferred from the planning assumptions.

10. Confidence Intervals and Precision

The confidence interval for the risk difference extends across zero, including both negative and positive values. This indicates that the posted estimate is not precise enough to rule out no difference under the interval’s calculation method. The interval also allows for effects in either direction; the point estimate alone should not be treated as a definitive account of the contrast.

In general, precision depends on the amount of information available and on the variability of the outcome. For a rare binary endpoint, the number of observed events is particularly important. The primary outcome occurred once in the posted arm results, so the estimate is based on sparse event information even though the arm denominators are larger. A small event count can leave substantial uncertainty about the underlying event frequencies.

The registry does not report the confidence-interval method or its confidence level. It also does not report an adjusted analysis that might provide a different estimate. The reported unadjusted p-value is 0.04, but it does not remove the uncertainty reflected by the interval; the interval includes zero. These summaries should be read together, with their apparent disagreement noted rather than resolved by assumptions about methods not described in the record.

Precision is not the same as clinical importance. A narrow interval would indicate greater statistical precision, while the meaning of any possible effect depends on the endpoint, context, and broader evidence. The registry result concerns only serious vaccine-related adverse experiences during Days 1 to 14 after any vaccination. It cannot establish precision for other adverse events or for outcomes outside that period.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and one secondary outcome: participants with one or more systemic adverse experiences. It also reports 12 outcome measures, but the record details do not include results for the secondary outcome. The number of outcome measures does not by itself establish how many statistical tests were conducted or which tests were planned for inference.

In general, examining multiple outcomes or multiple comparisons can increase the chance of finding an apparently unusual result even when no underlying effect exists. Statistical plans may address this through prespecified testing sequences or multiplicity adjustments. The registry record does not report a multiplicity strategy, a testing hierarchy, or adjusted inference for the primary result. The reported p-value is unadjusted. It is therefore not possible to assess from the record whether or how multiplicity was considered.

The primary endpoint population is described as participants with safety follow-up data after any dose. The arm denominators are 1415.0 and 334.0, whereas enrollment is recorded as 1800. The registry does not explain the differences in these counts, specify the extent or reasons for missing safety follow-up, or describe an imputation or missing-data procedure. It also does not provide a participant flow account for the primary endpoint.

In general, missing outcome information can affect a comparison if the availability of follow-up differs between groups or is related to participants’ outcomes. The record does not give enough information to assess whether missingness could have influenced this result. It does not report sensitivity analyses for missing data.

The record describes the primary population using safety follow-up after vaccination, but does not report a fuller analysis-population definition or a separate intention-to-treat analysis. The criteria for inclusion in each posted arm denominator, and the handling of any participants who did not complete the intended vaccination schedule, are not reported in the registry record.

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

The posted result describes one participant with a serious vaccine-related adverse experience in the VAQTA plus ProQuad arm and none in the VAQTA arm, within Days 1 to 14 after any vaccination. The reported risk difference is 0.003. The confidence interval spans zero, and the unadjusted p-value is 0.04. Together, these results show a sparse-event comparison with uncertainty and inferential summaries that are not fully aligned under a conventional two-sided reading.

This finding does not establish that the combination regimen causes a higher rate of serious vaccine-related adverse experiences. It also does not establish that the groups have identical safety profiles. With one observed primary event, the data offer limited information for distinguishing small differences from no difference or effects in the opposite direction. The registry record does not provide methods or follow-up details sufficient to resolve those limits.

The result is restricted to the stated endpoint and observation window. It does not describe all adverse experiences, all possible safety outcomes, or outcomes beyond Days 1 to 14 after any vaccination. The record lists a systemic adverse-experience secondary outcome, but does not include its result in the details. No conclusion about that outcome follows from the primary result.

In general, a trial’s result is one contribution to evidence, and its interpretation depends on design, follow-up, outcome definitions, statistical methods, and the broader evidence base. This record supports a description of what was observed in the posted safety population; it does not support medical advice or a general conclusion about treatment effects.

13. Why This Trial Matters Statistically

This trial illustrates a recurring challenge in safety research: the outcome of interest may be serious but observed rarely. A low event count can make an estimated group contrast highly sensitive to a single participant’s outcome. As a result, the point estimate is not sufficient to convey what the data can establish; uncertainty and the event counts matter.

The record also illustrates why statistical summaries need to be read together. The reported risk difference is positive, the confidence interval includes zero, and the unadjusted p-value is 0.04. Since the record does not specify the methods behind these summaries, readers cannot determine whether differing procedures, definitions, or other details explain their apparent tension. Reporting the analysis method alongside the estimate and interval would make the result easier to assess.

Finally, enrollment and endpoint denominators are not interchangeable. The registry reports enrollment of 1800, while the primary outcome uses arm-specific safety follow-up denominators. The record does not explain the difference. Clear participant-flow reporting and a detailed account of analysis populations help readers understand which participants contribute to each result and how missing follow-up may affect interpretation.

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.

The record gives limited information about the statistical analysis. It lists no outcome analyses and does not identify the method used for the risk difference, confidence interval, or p-value. The confidence interval includes zero while the unadjusted p-value is 0.04; without the methods and confidence level, the reason for this apparent difference is not reported in the registry record.

The primary endpoint was observed once across the posted arm results. This sparse count limits the information available about the between-arm contrast. The record also does not report an adjusted analysis, sensitivity analyses, or the prespecified statistical plan. The trial’s own sample-size justification and interim analyses are not reported in the registry record.

The primary outcome denominators are 1415.0 and 334.0, compared with enrollment of 1800. A participant flow account, reasons for differences in the denominators, missing-follow-up details, and the handling of missing data are not reported in the registry record. The record does not provide enough detail to assess whether follow-up completeness differed between arms.

The study is open-label, and masking is listed as none. The record does not explain whether outcome assessment was independently adjudicated or how vaccine-relatedness and seriousness were determined. The stated endpoint window is limited to Days 1 to 14 after any vaccination; the record does not support conclusions about events outside that window. The number of study centers and detailed vaccination schedules are also not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Hepatitis A Vaccine, Inactivated and Measles, Mumps, Rubella and Varicella Virus Vaccine Live Safety Study (V251-066)(COMPLETED) — NCT00326183.
• Registry record last updated 2019-02-04; status last verified 2019-01.
• Results first posted 2008-11-20.
• 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

This completed phase 4 study was randomized, open-label, parallel-group, and described as multicenter. It enrolled 1800 healthy children 12 to 23 months of age and compared VAQTA alone with VAQTA plus ProQuad. The overall study description specified two doses of each vaccine, given concomitantly or non-concomitantly, with safety data collected after vaccination.

The primary outcome was participants with one or more serious vaccine-related adverse experiences during Days 1 to 14 after any vaccination. The posted counts were none in the VAQTA arm and one in the combination arm; the reported risk difference was 0.003, and the unadjusted p-value was 0.04. The confidence interval spans zero. The record does not report outcome-analysis methods, a multiplicity strategy, or details explaining the endpoint denominators.