Effect of Risk Factors Likely to Influence Immuno of Combined Hepatitis A & B Vacc vs Monovalent Hepatitis A & B Vacc: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Effect of Risk Factors Likely to Influence Immuno of Combined Hepatitis A & B Vacc vs Monovalent Hepatitis A & B Vacc (NCT00289731), a randomized phase 4 study. The primary outcome is Number of Subjects With Anti-HAV and Anti-HBs Antibody Concentrations Above the Cut-off Value.

2. Clinical Question

3. Trial Design

This was a randomized, parallel-group Phase 4 study sponsored by GlaxoSmithKline. The registry lists the masking as none, so the study was open-label rather than masked. It reports 596 participants enrolled and a completed status. The listed study dates are 2003-11-24 for the start and 2004-12-21 for primary completion.

Three groups are described. Participants in the Twinrix Group received the combined vaccine. The other groups received separate hepatitis A and hepatitis B vaccines: Engerix-B+Havrix and HB VAX PRO+Vaqta. The arm descriptions identify healthy and non-healthy male or female subjects aged 41 years or older. The Twinrix schedule is described as intramuscular administration at 0, 1 and 6 months. The separate-vaccine arm descriptions also state a 0, 1 and 6 month schedule, but the record truncates details of their administration. Further details of the randomization procedure, including sequence generation and allocation concealment, are not reported in the registry record.

The study focused on immunogenicity and the possible influence of participant characteristics, including age, gender, body mass index, smoking, alcohol consumption, concomitant medication and medical condition. The record lists 30 outcome measures and 4 analyses, including secondary outcomes describing antibody concentrations and seropositivity across characteristic-based categories. The specific statistical plan, including how those analyses were to be conducted, is not reported in the registry record. This design can describe immune-response outcomes in the studied groups, but the registry information alone does not establish how potential imbalances or multiple comparisons were handled.

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: A total of 596 subjects (199 in Twinrix Group, 200 in Engerix-B+Havrix Group and 197 in HB VAX PRO+Vaqta Group) were enrolled and vaccinated in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the According-to-Protocol (ATP) cohort for immunogenicity, which included all subjects who met all eligibility criteria and for whom data concerning immunogenicity endpoint measures were available.

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 Number of Subjects With Anti-HAV and Anti-HBs Antibody Concentrations Above the Cut-off Value, measured over At Month 7.

The primary endpoint is the number of subjects with anti-HAV and anti-HBs antibody concentrations above the specified cutoff at Month 7. The record defines anti-HAV seropositivity as an antibody concentration of at least 15mIU/mL and anti-HBs seropositivity as at least 3.3 mIU/mL. In plain terms, the endpoint counts participants whose measured antibody concentration met the relevant threshold for each antigen.

Seropositivity is a binary outcome: each participant is classified as meeting or not meeting a cutoff. Counts can be useful for comparing how often participants in different groups crossed a prespecified antibody threshold. They are easier to interpret than a concentration alone when the question is whether participants reached a defined level. However, converting concentrations into a yes-or-no classification discards information about how far a participant's measurement was above or below the cutoff. The registry also lists antibody concentrations as secondary outcomes, which retain more of that measurement detail.

The endpoint was assessed in the ATP cohort for immunogenicity, comprising eligible subjects with available immunogenicity data. The numerical Month 7 endpoint results by group are not reported in the registry record. Therefore, the endpoint definition identifies what was to be counted, but does not establish the observed seropositivity counts or the precision of comparisons.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a measurement either meets the seropositivity cutoff or it does not. The endpoint reports counts of participants in those categories, rather than a continuous antibody value. The registry defines the anti-HAV cutoff as at least 15mIU/mL and the anti-HBs cutoff as at least 3.3 mIU/mL, with assessment at Month 7. The separate anti-HAV and anti-HBs measures should be interpreted in relation to their own thresholds.

Why use a cutoff?

General statistical explanation: a cutoff converts a continuous measurement into a classification that can be summarized as a count or proportion. This can make a result easier to connect to a defined threshold. The tradeoff is information loss: participants with measurements just above the cutoff and far above it are both counted as seropositive, while small measurement differences around the cutoff can change classification. Reporting antibody concentrations as well as cutoff-based counts can help retain context. The registry lists concentrations as secondary outcomes, but does not report their numerical results.

What does randomization contribute?

Random assignment is intended to make treatment groups comparable, on average, with respect to factors that could affect outcomes. It supports interpreting group contrasts as comparisons of assigned regimens, subject to the conduct of the study and the analysis. The record identifies the allocation as randomized and the model as parallel. It does not report the sequence-generation method, allocation concealment, randomization stratification or group-specific endpoint denominators. Those details would help readers assess how assignment was implemented and how the analysis relates to the enrolled participants.

What does the analysis population mean?

The primary analysis used the ATP cohort for immunogenicity. The record defines this as subjects who met all eligibility criteria and had available data concerning immunogenicity endpoint measures. This definition means that the endpoint analysis was not simply described as including every enrolled participant. General statistical explanation: analysis populations define which participants contribute to an estimate and can affect how directly it represents the randomized groups. The handling of participants excluded from this cohort, and the number excluded from each group, are not reported in the registry record.

How should subgroup outcomes be read?

The listed secondary outcomes examine antibody concentrations or cutoff status by gender, age, body mass index, smoking status, alcohol consumption, concomitant medication and medical condition. General statistical explanation: subgroup estimates usually use fewer participants than an overall estimate, and their uncertainty can be greater. A difference within one subgroup does not by itself show that the subgroup responds differently from another subgroup. Assessing whether an effect varies across groups requires an explicit comparison of effects, commonly an interaction analysis. Whether such analyses were planned or performed is not reported in the registry record.

What is multiplicity?

General statistical explanation: when many outcomes, groups or subgroup comparisons are examined, the chance of observing an apparently notable result by chance can increase. Statistical plans may address this by identifying a primary comparison, using an adjustment, or treating secondary analyses as exploratory. The record lists 30 outcome measures and 4 analyses, but the multiplicity strategy and the full prespecified analysis plan are not reported in the registry record. The count of outcomes alone does not show whether or how results were adjusted.

What can a planning illustration tell us?

The planning assumptions described for the sample-size illustrations use a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The illustrated effect is a stated fraction of the observed effect. These are planning illustrations, not observed power and not evidence that the original trial was designed around those assumptions. Their role is to indicate how a hypothetical future study might be sized under the stated assumptions. They do not replace an estimate and confidence interval for the trial's observed outcome. The registry record does not report the trial's own sample-size justification or statistical design plan.

General statistical explanation: confidence intervals communicate the range of values reasonably compatible with an estimate under a statistical model. A p-value, when reported, measures how unusual data at least as incompatible with a specified null model would be under that model; it is not the probability that the null hypothesis is true. Neither p-values nor confidence intervals for the primary endpoint are reported in the registry record. Without the endpoint counts, denominators and comparative estimates, statistical significance, precision and practical importance cannot be evaluated.

10. Multiplicity, Missing Data and Analysis Populations

The record defines the primary endpoint and the ATP cohort for immunogenicity, but does not report the numerical primary results, group-specific analysis denominators or missing-data counts. It says the analysis cohort included subjects who met all eligibility criteria and had immunogenicity endpoint data. The reasons participants might not have contributed data, and the method used to handle missing measurements, are not reported in the registry record. This matters because the analysis population and missing-data approach affect which participants inform the reported outcome.

The registry lists 30 outcome measures and 4 analyses. Several secondary outcomes examine antibody concentrations or cutoff status across participant characteristics, including gender, age, body mass index, smoking status, alcohol consumption, concomitant medication and medical condition. Considering multiple outcomes and subgroups can create many opportunities for comparisons. General statistical explanation: multiplicity can increase the chance of chance findings across a set of tests, while adjustment methods or a clear hierarchy of planned outcomes can help frame interpretation. The registry record does not report whether comparisons were adjusted, whether subgroup analyses were prespecified, or how the outcomes were prioritized beyond identifying the primary outcome.

The detailed statistical analysis plan, including any interim analyses or rules for stopping or changing analyses, is not reported in the registry record. No such procedures should be inferred from the Phase 4 designation or from the listed outcomes. Without the plan and numerical estimates, readers cannot determine whether the posted analyses followed prespecified methods or how multiplicity and missing data might have affected conclusions.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: pneumonia (1.0%), angina pectoris (0.5%), angle closure glaucoma (0.5%), blepharochalasis (0.5%), breast cancer female (0.5%).

The registry lists serious adverse event counts for the three groups. In the Twinrix Group, 199 participants were at risk and 11 were affected; 1 death is listed. In the Engerix-B+Havrix Group, 200 participants were at risk and 14 were affected; 2 deaths are listed. In the HB VAX PRO+Vaqta Group, 197 participants were at risk and 16 were affected; 2 deaths are listed. These are reported as counts, and the at-risk group sizes are not the same measure as the number affected.

The serious-event terms listed include pneumonia (1.0%), angina pectoris (0.5%), angle closure glaucoma (0.5%), blepharochalasis (0.5%), breast cancer female (0.5%) and carotid artery stenosis (0.5%). The registry information presented does not establish that a serious event was caused by vaccination. It also does not provide event timing, individual-level descriptions or a comparative safety analysis in the details available for interpretation. Death counts should be read as reported counts, not as evidence of a treatment effect. A fuller assessment would require context about event definitions, follow-up, attribution and the populations included in each safety summary; those details are not reported in the registry record.

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

The record identifies a randomized comparison of one combined vaccine regimen with two separate-vaccine regimens and defines a Month 7 antibody seropositivity endpoint. It also identifies participant characteristics that were relevant to the study's immunogenicity question. These details clarify what the trial set out to assess and how the primary outcome was classified.

They do not establish which regimen had more participants meeting the antibody cutoffs. The numerical primary endpoint counts, comparative estimates, confidence intervals and p-values are not reported in the registry record. The listed secondary outcomes likewise do not reveal whether antibody concentrations or seropositivity varied by age, gender, body mass index, smoking, alcohol consumption, concomitant medication or medical condition. No conclusion about the magnitude, direction or precision of those findings can be drawn from outcome titles alone.

General statistical explanation: a statistically detectable difference, if reported, would not by itself establish that the difference is important in practice. Conversely, an imprecise estimate may remain compatible with a range of effects. Interpreting a trial requires estimates, uncertainty, relevant clinical context and an understanding of the analysis population. The registry entries do not provide enough information to make those assessments for the primary endpoint.

The safety counts describe serious events and deaths recorded by group, but they do not establish causation. The open-label design, the absence of detailed analysis methods, and the lack of numerical immunogenicity results further limit interpretation. The appropriate reading is therefore narrow: the registry documents the trial design, endpoint definition and selected safety counts, while the comparative immune-response results and many details needed to judge their robustness are not reported in the registry record.

13. Why This Trial Matters Statistically

This trial is statistically notable for asking about both regimen-level immunogenicity and the possible influence of participant characteristics. The primary endpoint is a threshold-based count at Month 7, while the listed secondary outcomes include antibody concentrations and cutoff status across several participant categories. Together, those questions illustrate how a trial can include an overall comparison as well as analyses of whether responses may vary across characteristics.

The structure also highlights why outcome definitions matter. A binary seropositivity measure is straightforward to summarize, but it does not retain the full variation in antibody concentrations. Reporting both threshold-based counts and concentration outcomes can provide complementary views of response. In this record, those outcomes are named, but their numerical estimates are not reported, limiting the statistical interpretation.

The study also illustrates the importance of knowing the analysis population. The primary analysis was conducted in an ATP cohort defined by eligibility and available immunogenicity data. Without group-specific cohort sizes and missing-data details, readers cannot assess how closely the endpoint analysis reflects all randomized participants. Similarly, multiple outcomes and characteristic-based analyses make the prespecified analysis strategy important; the registry does not report how multiplicity was addressed.

These design features make the record useful for understanding the questions and methods categories involved, but not for quantifying comparative response. The absence of numerical endpoint results is a central interpretive limit: no estimate or uncertainty measure is available for evaluating how the groups differed. The record therefore demonstrates why an endpoint definition and a trial design are not substitutes for results and transparent analysis details.

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 most direct limitation for interpretation is that numerical Month 7 primary endpoint results are not reported in the registry record. The arm-specific seropositivity counts, denominators, between-group estimates and measures of uncertainty are therefore unavailable. The registry identifies 596 enrolled participants, but that total does not show how many contributed to each immunogenicity analysis.

The primary analysis population was the ATP cohort for immunogenicity, defined by eligibility and availability of immunogenicity endpoint data. The number excluded from that cohort, reasons for exclusion, group-specific missingness and missing-data handling are not reported in the registry record. These omissions prevent assessment of how participant availability may have shaped the analyzed groups.

The study was randomized and parallel, but the randomization method and allocation concealment are not reported. The registry lists no masking. Details about laboratory methods, assay characteristics and outcome-assessment procedures are also not reported in the registry record. The arm descriptions for the separate-vaccine groups are truncated, so full administration details cannot be established from those descriptions.

The study considered multiple outcomes and participant characteristics, but the analysis plan and multiplicity approach are not reported. The record does not establish whether subgroup comparisons were prespecified or how they were analyzed. Finally, the registry lists serious adverse event counts and selected terms, but the event-level context and attribution needed for causal interpretation are not reported. These limits mean that neither comparative immunogenicity nor comparative safety can be fully evaluated from the registry entries alone.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Effect of Risk Factors Likely to Influence Immuno of Combined Hepatitis A & B Vacc vs Monovalent Hepatitis A & B Vacc — NCT00289731.
• Registry record last updated 2019-11-15; status last verified 2019-10.
• Results first posted 2018-10-03.
• 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, randomized, open-label, parallel-group Phase 4 study enrolled 596 participants and was sponsored by GlaxoSmithKline. It compared combined Twinrix™ vaccination with separate Engerix-B+Havrix or HB VAX PRO+Vaqta vaccination. The described groups included healthy and non-healthy male or female subjects aged 41 years or older.

The primary outcome was the number of participants whose anti-HAV and anti-HBs concentrations met the respective seropositivity cutoffs at Month 7. The analysis used the ATP cohort for immunogenicity. Secondary outcomes addressed antibody concentrations and cutoff status across participant characteristics. The registry lists serious adverse event counts and deaths by group.

Numerical primary endpoint results, comparative estimates and detailed statistical methods are not reported in the registry record, so the relative immunogenicity and precision of group differences cannot be assessed from this record.