Study Evaluating Safety and Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine With Influenza Vaccine in Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Evaluating Safety and Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine With Influenza Vaccine in Adults (NCT00492557), a randomized phase 3 study. The primary outcome is TIV Comparisons: Percentage of Participants Achieving at Least a 4-fold Increase in the Titer of the Standard Hemagglutination Inhibition Assay (HAI).

2. Clinical Question

The clinical question is about the measured influenza immune response when TIV is administered alongside 13vPnC, rather than a direct comparison of rates of influenza illness. The registry describes the rationale as assessing whether giving the vaccines together affects immune response while evaluating safety and tolerability. The primary endpoint concerns three influenza virus subtypes: A/H1N1, A/H3N2, and B. A result for one subtype would not, by itself, describe the results for the other subtypes.

The registry record does not report a single summarized primary comparison result. It describes percentages and 95% confidence intervals as the intended outcome format, but the outcome has multiple subtype categories and is not reduced to one comparison in the available record. Therefore, the clinical question can be specified, but the posted record does not permit a numerical conclusion about the primary immune-response comparison.

3. Trial Design

This was a phase 3, randomized, double-blind, parallel trial with quadruple masking. The registry reports enrollment of 1185 and a completed status. Participants were healthy adults aged 65 years or older who were naive to 23-valent pneumococcal polysaccharide vaccine.

The study evaluated 13-valent pneumococcal conjugate vaccine, alone or administered concomitantly with trivalent inactivated influenza vaccine. The listed arm sequences include 13vPnC+TIV followed by placebo one month later, and placebo+TIV followed by 13vPnC one month later. The registry also lists placebo and 13vPnC groups in the adverse-event results. These descriptions identify the interventions and sequences but do not provide a detailed account of allocation procedures, treatment adherence, or the timing of every assessment.

Randomization is intended to make treatment groups comparable on average, while masking is intended to reduce the influence of treatment knowledge on participant experience, care, or outcome assessment. Those are general design purposes; the registry record does not describe how masking was implemented or assessed. The parallel model indicates that participants were assigned to study groups rather than all participants receiving every treatment in a crossover design.

The primary outcome was assessed at baseline and one month after TIV vaccination. Its stated analysis population was the evaluable immunogenicity population, defined by protocol adherence, valid and determinate assay results, and absence of major protocol violations. The record does not report the number included in that population, nor does it provide a full participant-flow account. Although enrollment is reported, enrollment should not be assumed to equal the number contributing to each endpoint or safety analysis.

The registry lists five outcome measures and 29 analyses. It does not report a detailed statistical analysis plan, sample-size justification, or interim-analysis plan. Those omissions limit what can be inferred about prespecified analysis choices or how the reported analyses relate to the original design.

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 1185 participants were enrolled, of which 1160 were randomized.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Evaluable immunogenicity population: had participants who adhered to protocol requirements, had valid and determinate assay results, and had no major protocol violations.

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 TIV Comparisons: Percentage of Participants Achieving at Least a 4-fold Increase in the Titer of the Standard Hemagglutination Inhibition Assay (HAI), measured over Baseline and 1 month after TIV vaccination.

The primary endpoint is the percentage of participants achieving at least a 4-fold increase in standard hemagglutination inhibition assay titer for each influenza virus subtype: A/H1N1, A/H3N2, and B. The comparison is based on baseline and one month after TIV vaccination. The registry describes the results as percentages with 95% confidence intervals.

The hemagglutination inhibition assay measures an antibody response to influenza virus. A 4-fold rise is a threshold-based way of describing change from an individual’s baseline titer. Reporting the percentage above a threshold makes the outcome interpretable as the proportion meeting that specified response criterion, while retaining a separate result for each subtype. The endpoint is therefore a laboratory immunogenicity measure, not a count of influenza infections or a direct measure of clinical protection.

Using a change from baseline helps frame the endpoint in relation to each participant’s starting titer. However, converting a continuous titer change into a threshold-based percentage means that participants just below the threshold and those with little change are grouped together, while those reaching the threshold are counted as responders. This is a general feature of dichotomizing a measurement; it does not establish that all responders have equivalent immune responses.

The registry record does not report the primary endpoint percentages or confidence limits as one summarized comparison. It also does not report an overall result combining the three subtype-specific outcomes. The endpoint definition is available, but the reported material does not establish the direction, magnitude, or precision of a primary treatment contrast.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage with a confidence interval describe?

The primary endpoint is a percentage: the share of participants who meet a specified response criterion. A 95% confidence interval communicates uncertainty around an estimated percentage. In general, the interval reflects the range of values reasonably compatible with the data and the calculation method. It is not a guarantee that the true value lies within a particular interval, and it is not a measure of the probability that a treatment is effective. The registry states that 95% confidence intervals were used, but the record does not present a single primary comparison with its estimate and interval.

For comparisons, the relevant question is not only whether each group’s percentage is estimated precisely, but also how the groups differ and how uncertain that difference is. Separate confidence intervals around group percentages do not automatically provide the confidence interval for a between-group contrast. A clear comparative interpretation requires the actual contrast and an account of its uncertainty. Those numerical primary results are not reported in the registry record as a single summarized comparison.

Why define a responder threshold?

The endpoint counts participants whose HAI titer increased by at least 4-fold from baseline. This threshold turns a measurement of antibody response into a responder/non-responder classification for analysis. It can make a result easier to express as a percentage, but it discards some detail about the size of changes within each category. A participant who narrowly misses the threshold and one whose titer does not rise may both fall outside the responder category, even though their measurements differ. This is a general consequence of using a cut point.

Results are specified separately for A/H1N1, A/H3N2, and B. Each subtype is a distinct outcome category, so a finding for one cannot automatically be generalized to the others. The registry record does not provide a single combined endpoint that would summarize performance across these subtypes.

What does the analysis population mean?

The evaluable immunogenicity population includes participants who adhered to protocol requirements, had valid and determinate assay results, and had no major protocol violations. This is a defined subset for immunogenicity assessment, rather than a statement that every enrolled participant contributed a valid result. Such criteria can help ensure that assay-based analyses use interpretable measurements, but excluding participants can also affect how representative the resulting estimate is of all randomized participants. The record does not report the size of this population, the number excluded, or the reasons for exclusions.

The safety summaries use their own at-risk denominators for each listed group. Those denominators should be read with the corresponding affected counts, rather than assumed to equal enrollment or the immunogenicity analysis population. The record does not give a detailed explanation of how participants were assigned to each safety reporting group over time.

Why does the design matter?

Randomization is a general method for balancing known and unknown participant characteristics across assigned groups on average. Double-blind and quadruple-masked labels indicate masking at more than one level, but the registry record does not explain which parties were masked or how masking was maintained. A parallel design compares assigned groups over the study rather than relying on each participant to serve as their own comparator.

These design features can strengthen a treatment comparison when implemented and analyzed appropriately, but they do not replace reporting the effect estimates, uncertainty, analysis population, and handling of missing results. The registry record does not report a detailed statistical analysis plan. It also does not report an interim-analysis plan or a sample-size justification. Consequently, the specific planned model, adjustment strategy, and decision rules cannot be established from the registry record.

How should planning calculations be read?

Sample-size planning illustrations are hypothetical calculations based on stated assumptions, not observed power and not a result of the trial. In general, a planning calculation asks how much information a future study would need under a specified assumed effect, variability, allocation, and significance threshold. The registry record does not state that such illustrations were the trial’s original design justification. A planning estimate should therefore not be interpreted as evidence that the completed trial had a particular probability of detecting an effect.

More generally, over-dispersion matters when observed variation is greater than a statistical model assumes: standard errors can then be underestimated and confidence intervals can be too narrow if the extra variation is ignored. That concept is not evidence that over-dispersion occurred in this trial. The registry record does not report a model-specific analysis or diagnostic information from which to assess it.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome covers three influenza virus subtypes: A/H1N1, A/H3N2, and B. Examining several outcome categories creates a multiplicity question: when many hypotheses or comparisons are assessed, the chance of at least one apparently unusual result can increase. This is a general statistical issue, not evidence that any particular result in this trial is false. The registry record does not report whether an adjustment for multiplicity was planned or used, how the subtype comparisons were prioritized, or whether a single subtype was designated as the basis for a primary conclusion.

The registry lists five outcome measures and 29 analyses. That count indicates multiple recorded analyses, but it does not by itself show which analyses were confirmatory, exploratory, or part of a prespecified testing sequence. The statistical analysis plan and the rules for interpreting multiple results are not reported in the registry record. No single primary comparison is presented to resolve that ambiguity.

Missing assay results and exclusions are relevant because the primary endpoint uses an evaluable immunogenicity population. The registry defines that population by protocol adherence, valid and determinate assay results, and no major protocol violations. It does not report the population size, the amount or pattern of missing assay data, or how missing measurements were handled. Without this information, readers cannot judge whether exclusions might have changed the estimated response percentages.

The record also does not provide a full participant-flow account or the numbers contributing to every outcome. Enrollment of 1185 should not be treated as the denominator for each analysis. The presence of a defined analysis population is useful, but it does not answer how many randomized participants were excluded or why. These reporting gaps limit assessment of multiplicity and missing-data risks.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: cardiac failure (0.4%), duodenal ulcer perforation (0.2%), gastrointestinal haemorrhage (0.2%), peritonitis (0.2%), sternal fracture (0.2%).

The registry reports serious adverse-event counts and at-risk denominators by listed group. The entries are 4 affected among 576 at risk for 13vPnC+TIV, 8 among 559 for Placebo, 0 among 575 for Placebo+TIV, and 5 among 558 for 13vPnC. These are the posted counts; they should be interpreted within their stated group denominators and not converted into a claim about causation. The record does not report a numeric death count in these group entries, so a null death field should not be read as a confirmed count of zero.

The registry also lists other adverse events: 307 affected among 576 at risk for 13vPnC+TIV, 194 among 559 for Placebo, 256 among 575 for Placebo+TIV, and 237 among 558 for 13vPnC. These are separate from the serious-event counts. The registry does not provide a detailed definition of the reporting window or further context for interpreting the group differences in this summary.

Among the serious-event terms listed, cardiac failure is reported at 0.4%. Duodenal ulcer perforation, gastrointestinal haemorrhage, peritonitis, sternal fracture, and basal cell carcinoma are each reported at 0.2%. These term percentages describe the registry entries; they do not establish that the events were caused by study treatment or that the groups differed reliably. Rare-event comparisons require careful attention to counts, denominators, follow-up, and uncertainty, details not fully reported in the registry record.

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

The trial addresses a focused statistical question about immune response: the percentage meeting a threshold for HAI titer increase after TIV, with results specified for three influenza virus subtypes. The registry record establishes the endpoint definition, assessment timing, study population, and randomized masked design. It does not report one summarized primary comparison with numerical estimates and confidence intervals. Therefore, the record does not establish the magnitude or precision of the primary contrast.

The endpoint concerns a laboratory measure of immunogenicity. A percentage meeting a threshold is not the same as a comparison of diagnosed influenza illness, severe disease, or other clinical outcomes. The registry’s rationale mentions prevention of pneumococcal disease and the importance of evaluating the vaccines when given together, but the listed primary endpoint is the influenza HAI response. The record does not report a clinical disease endpoint as the primary outcome.

The safety entries describe serious and other adverse-event counts for the listed groups. They are useful as recorded observations, but counts alone do not determine whether an event was caused by vaccination. Differences in counts should not be treated as proof of a treatment effect without a defined comparison, suitable uncertainty estimates, and consideration of follow-up and analysis methods. Those details are not fully reported in the registry record.

Nor does the trial’s randomized and masked design eliminate the need to examine analysis populations, missing data, and multiplicity. The immunogenicity endpoint is restricted to an evaluable population, and the record does not report its size or how missing assay results were handled. Multiple subtype outcomes and the listed analyses also make prespecification and interpretation relevant, but the analysis plan is not reported.

In short, the record supports an account of what the trial was designed to assess and what safety counts it lists. It does not support a numerical conclusion about the primary immune-response comparison or a conclusion about clinical protection. The absence of a reported primary contrast is a limitation of the available registry record, not evidence that the trial found no difference.

13. Why This Trial Matters Statistically

This trial illustrates why the outcome definition and the outcome estimate must be distinguished. A precisely specified responder threshold, assay, assessment window, and analysis population make clear what investigators intended to measure. Yet without the group-specific percentages and a comparative estimate with uncertainty, readers cannot determine the size or precision of the primary treatment contrast from the registry record.

It also illustrates the importance of endpoint structure. The primary question covers A/H1N1, A/H3N2, and B separately. Multiple outcome categories can complicate interpretation if there is no clearly reported hierarchy or multiplicity approach. The registry lists five outcome measures and 29 analyses, but does not report which comparisons were primary for decision-making or how multiple results were handled. Statistical transparency matters because readers need to distinguish a prespecified confirmatory claim from results among many analyses.

The evaluable immunogenicity population highlights another key issue: denominators depend on the analysis being conducted. Enrollment is reported as 1185, while adverse-event results have their own at-risk denominators and the immunogenicity population is defined by eligibility criteria. Without endpoint-specific population sizes and missing-data details, it is difficult to assess how complete or representative the immune-response estimates would be.

Finally, safety counts and laboratory immune responses answer different questions. Descriptive adverse-event summaries can document reported events, while the primary endpoint measures a threshold-based assay response. Neither should be treated as a substitute for the other. Clear reporting of effect estimates, confidence intervals, participant flow, and analysis choices would help readers understand both the statistical evidence and its limits.

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 primary endpoint is described but no single numerical comparison result is reported in the registry record. This prevents assessment of the estimated difference in responder percentages and its precision. The record states that 95% confidence intervals were used, but does not give one summarized primary contrast with an interval.

The primary outcome has separate categories for A/H1N1, A/H3N2, and B. The registry does not report a multiplicity strategy, a hierarchy among these categories, or which result would guide a primary conclusion. It lists five outcome measures and 29 analyses without identifying their confirmatory or exploratory roles in the available summary.

The immunogenicity population is defined, but its size and participant flow are not reported. The record does not describe the amount or pattern of missing assay data, reasons for exclusion, or the method used to handle missing measurements. These omissions make it difficult to assess whether the evaluable population differs from all randomized participants in ways that could affect interpretation.

The registry does not report a detailed statistical analysis plan, sample-size justification, or interim-analysis plan. It also does not provide enough detail in this summary to assess the implementation of masking, adherence, or the reporting windows underlying adverse events. The adverse-event counts are descriptive; deaths are not given as numeric counts in the listed group entries, and causal attribution is not established by those entries.

Finally, the primary endpoint is an assay-based immune-response measure rather than a clinical disease outcome. The registry record does not provide a primary comparison of influenza illness or pneumococcal disease. Accordingly, the available information is limited to the design, endpoint definition, and posted safety summaries rather than a complete assessment of clinical outcomes.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study Evaluating Safety and Immunogenicity of 13-Valent Pneumococcal Conjugate Vaccine With Influenza Vaccine in Adults — NCT00492557.
• Registry record last updated 2012-02-17; status last verified 2012-01.
• Results first posted 2012-02-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT00492557 is a completed phase 3 randomized, double-blind, parallel trial with quadruple masking in healthy adults aged 65 years or older who were naive to 23-valent pneumococcal polysaccharide vaccine. Enrollment was 1185. The study evaluated 13vPnC given with TIV and related comparator sequences, including placebo with TIV.

The primary endpoint was the percentage achieving at least a 4-fold increase in HAI titer for A/H1N1, A/H3N2, and B from baseline to one month after TIV vaccination. The stated analysis population was the evaluable immunogenicity population. The registry record does not report a single summarized primary comparison estimate. Safety summaries list serious and other adverse-event counts by group and several serious-event terms with percentages.

The record lists five outcome measures and 29 analyses. It does not report a detailed statistical analysis plan, multiplicity strategy, sample-size justification, interim-analysis plan, or full missing-data and participant-flow details.