Study Assessing the Effect of Medications to Prevent Fever on Prevenar 13®: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study Assessing the Effect of Medications to Prevent Fever on Prevenar 13® (NCT01392378), a randomized phase 4 study. The primary outcome is Geometric Mean Concentration (GMC) for Serotype-specific Pneumococcal Immunoglobulin G (IgG) Antibody 1 Month After the Infant Series.

2. Clinical Question

The clinical question is about immune measurements following vaccination, not a direct comparison of illness outcomes. IgG concentrations are laboratory measures of antibodies directed against pneumococcal serotypes. The record also describes safety evaluation and secondary immune outcomes involving pneumococcal responses and antibodies to components of other routine vaccines. The information reported does not establish how any immune measurement relates to an individual infant’s later health.

3. Trial Design

This was a Phase 4, randomized, open-label, parallel-group trial. The registry records an enrollment of 908 and lists the study as completed. The study began in 2011-08, with primary completion in 2013-01. The sponsor was Pfizer. These registry entries describe the study record and do not, by themselves, indicate how many participants contributed data to each analysis.

Participants were assigned to groups receiving 13-valent pneumococcal conjugate vaccine and INFANRIX hexa at 2, 3, 4 and 12 months of age, with different antipyretic regimens. The record describes paracetamol twice daily, ibuprofen twice daily, paracetamol thrice daily, ibuprofen thrice daily, and a vaccine group without study antipyretic medication. The group descriptions specify medication on vaccination days. The record’s intervention descriptions name the vaccines and antipyretics, while its arm descriptions provide the regimen details.

Random allocation is intended to distribute measured and unmeasured participant characteristics across treatment groups on average. It does not guarantee identical groups, especially for any particular characteristic. Open-label means the trial was not masked; the record lists masking as none. Knowledge of assigned regimen can affect participant or caregiver reports and clinical assessments, although the primary endpoint is a laboratory antibody measurement. The registry does not report further details about assay blinding or laboratory procedures.

The primary endpoint was assessed 1 month after the infant series. The record also lists outcomes at other times, including after the toddler dose, and safety groups labelled for the infant series, after the infant series, and the toddler dose. Full details of visit conduct, treatment adherence, withdrawals, protocol deviations, and the statistical plan 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.

Infant Series

Reasons for not completing this period:

After Infant Series

Reasons for not completing this period:

Toddler Dose

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Modified intent-to-treat (mITT) infant immunogenicity set: all eligible participants who had \>=1 valid,determinate assay result, 56-98 days of age at Vaccination 1, received antipyretic regimen as per randomization,may have had received additional anti-pyretic medication,had blood drawn within specified time frames,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 Geometric Mean Concentration (GMC) for Serotype-specific Pneumococcal Immunoglobulin G (IgG) Antibody 1 Month After the Infant Series, measured over 1 month after the infant series.

The primary endpoint is the geometric mean concentration of serotype-specific pneumococcal immunoglobulin G (IgG) antibody, measured 1 month after the infant series. It is expressed in micrograms per milliliter. The endpoint covers 13 pneumococcal serotypes: 4, 6B, 9V, 14, 18C, 19F, 23F, 1, 3, 5, 6A, 7F and 19A.

A geometric mean summarizes measurements on a multiplicative scale. In general, this can be useful when laboratory concentrations are positive and vary proportionally rather than by a constant additive amount. It gives a concise description of the central antibody concentration while reducing the influence of very high values compared with an arithmetic mean. This general explanation does not establish that the underlying antibody measurements follow any particular distribution.

The registry describes geometric least squares mean concentrations and corresponding two-sided 95% confidence intervals. In general, a confidence interval communicates the uncertainty around an estimated group mean under the analysis used; it is not a range containing a fixed proportion of individual participants’ measurements. The numerical estimates and intervals for the primary endpoint are not reported in the registry record.

The record says that geometric means were calculated using participants with available data for the specified blood draw. It distinguishes participants evaluable for the measure from those with a determinate concentration for a given serotype. The complete endpoint calculation and handling of values that could not be determined are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary measure as a geometric mean concentration of serotype-specific pneumococcal IgG antibody. It also describes geometric least squares means and two-sided 95% confidence intervals. These labels identify a summary measure and an uncertainty measure, but they do not supply the actual estimates, the model used to obtain them, or the contrasts between groups. Those numerical results and full analysis details are not reported in the registry record.

What does a geometric mean summarize?

In general, a geometric mean is calculated by taking the mean on a logarithmic scale and then returning to the original measurement scale. It is useful for quantities that vary multiplicatively, such as concentrations that may differ by proportional amounts. A geometric mean is not the same as an arithmetic average. The choice of summary affects how a reader should understand the center of the measurements, and the registry’s chosen measure should be interpreted on that basis.

The primary endpoint includes 13 serotypes, with separate concentrations defined for each. A result for one serotype would not, by itself, summarize the results for all serotypes. In general, measurements across serotypes can differ in their distributions and levels, so each estimate and its uncertainty should be read in relation to the specific serotype. The numerical serotype-specific estimates are not reported in the registry record.

What does a confidence interval communicate?

In general, a confidence interval expresses the uncertainty associated with an estimate under the specified statistical method and its assumptions. A narrower interval indicates greater precision than a wider interval for the same kind of estimate. The interval does not show the range of individual participant values, and it does not guarantee that the true value lies within the interval. The registry describes 95% confidence intervals for the primary measure, but their numerical limits are not reported in the registry record.

A group mean and a comparison between groups answer different questions. The group mean describes an estimated concentration for a group. A contrast describes how groups differ on a chosen scale. A contrast might use an additive or multiplicative scale, and conclusions can depend on which scale was prespecified. The registry entries do not identify the primary comparison scale or report numerical contrasts. These details are not reported in the registry record.

Why do the analysis population and available samples matter?

The primary endpoint description refers to a modified intent-to-treat infant immunogenicity set. It defines eligibility in terms of at least one valid, determinate assay result, age at the first vaccination, receipt of the assigned antipyretic regimen, and blood-draw conditions. The population description is incomplete in the registry record, so the full criteria cannot be reconstructed. The record also says the geometric means used participants with available data for the specified blood draw.

In general, an analysis based on available measurements uses observations that can be evaluated for the endpoint. If measurements are unavailable for reasons related to assignment or antibody response, the analyzed participants may not represent all randomized participants in the same way. A comparison can then be affected by missing-data patterns. The number of missing measurements, reasons for missingness, and any imputation or sensitivity analyses are not reported in the registry record.

Why can many analyses complicate interpretation?

In general, conducting many statistical tests increases the chance that some results appear noteworthy by chance, even when there is no corresponding underlying effect. Multiplicity methods can control or describe this issue, but they depend on which outcomes and comparisons are considered part of a testing family. The registry lists 24 outcome measures and 236 analyses. It does not report whether multiplicity adjustment was used, what comparisons were grouped together, or which analyses formed the primary testing family.

The registry’s sample-size assumptions describe planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is stated as a fraction of the observed effect. Such illustrations are planning calculations, not observed power and not evidence that the trial had a particular probability of detecting an effect. Their numerical outputs are not reported in the registry record. The record does not report the trial’s own sample-size justification.

These general concepts help frame the endpoint, uncertainty, analysis population, and multiplicity. They cannot substitute for the missing numerical estimates or for a complete statistical analysis plan. In particular, no recalculated comparison can be made from the registry entries because group-level primary endpoint estimates and their uncertainty are not reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 24 outcome measures and 236 analyses. The primary outcome itself concerns 13 serotypes, and the record also describes secondary immunogenicity outcomes involving pneumococcal antibody responses, opsonophagocytic activity, and antibodies to components of other routine vaccines. Multiple outcomes and analyses create a multiplicity issue: in general, the more hypotheses examined, the greater the chance of obtaining an apparently unusual result by chance. How that issue should be handled depends on the planned comparisons and the inferential goals.

Whether the sponsor adjusted for multiple comparisons, which comparisons were included in any adjustment, and whether analyses were organized into confirmatory families are not reported in the registry record. The registry entries do not identify a hierarchy of outcomes or a prespecified testing procedure. Therefore, the presence or absence of multiplicity control cannot be inferred from the analysis count alone.

For the primary measure, the record describes a modified intent-to-treat infant immunogenicity set and says geometric means used participants with available data for a specified blood draw. The set description includes assay validity, age, assigned-regimen, and blood-draw conditions, but its complete wording is not reported in the registry record. The record distinguishes those evaluable for the measure from those with a determinate concentration for each serotype.

Counts and reasons for missing or indeterminate antibody measurements, group-specific exclusions, imputation methods, and sensitivity analyses are not reported in the registry record. The handling of participants who did not follow the assigned medication regimen is also not fully reported. These omissions limit assessment of whether the analyzed population differs from the randomized population or whether missing data could have influenced the estimates.

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: gastroenteritis (2.3%), pneumonia (1.7%), gastroenteritis rotavirus (1.7%), diarrhoea (1.4%), head injury (1.2%).

The safety record gives, for each listed group and study period, a number of participants at risk and a number affected by serious adverse events and other adverse events. These are counts, not comparative effect estimates. The record separates the infant series, the period after the infant series, and the toddler dose. A participant may be represented in more than one period, so entries from separate periods should not be combined or interpreted as unique-person totals.

The listed serious-event terms include Gastroenteritis at 2.3%, Pneumonia at 1.7%, Gastroenteritis rotavirus at 1.7%, Diarrhoea at 1.4%, Head injury at 1.2%, and Bronchopneumonia at 1.2%. The registry entries do not specify the denominator or the precise method used for these percentages. They should not be treated as group-specific risks unless the record establishes that interpretation.

Deaths are not reported in the registry record. The counts alone do not establish whether differences between groups are meaningful; that assessment would require the relevant time window, event definitions, denominators, and comparative uncertainty. In general, adverse-event counts describe what was recorded in the defined population and period, while a causal or comparative interpretation requires additional design and analysis information.

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

The trial addresses a specific statistical and clinical question: whether prophylactic antipyretic regimens given with routine vaccinations correspond to different pneumococcal IgG geometric mean concentrations after the infant series. It does so in a randomized, parallel-group design with an open-label allocation. The registry also describes safety outcomes and a range of secondary immune measures.

The posted record does not report numerical primary endpoint results. Consequently, it cannot support a description of which regimen had higher or lower antibody concentrations, how large any difference was, or how precisely a difference was estimated. The design and endpoint identify what was intended to be compared; they are not themselves evidence of a particular result.

Even when numerical antibody results are available, a laboratory concentration is not the same as a clinical outcome. The listed secondary outcomes include thresholds and antibody measures, but the registry entries do not establish how any particular immune measurement predicts protection for an individual infant. The registry record also does not report a clinical efficacy outcome that would permit conclusions about illness prevention.

The safety counts describe recorded events across specified groups and periods. They do not, on their own, show that one regimen caused more or fewer events than another. Such a conclusion would require appropriately defined comparisons and an assessment of uncertainty, neither of which is reported in the registry entries.

Accordingly, the record establishes the study question, design, endpoint definition, and selected safety summaries, but not the primary numerical findings needed to characterize an observed immunogenicity effect. It should not be read as evidence that any regimen does or does not alter immune response or safety. The unreported analysis and missing-data details also constrain assessment of precision and robustness.

13. Why This Trial Matters Statistically

This trial is statistically notable because it compares several prophylactic medication regimens within a randomized parallel-group study, while measuring a laboratory endpoint across multiple pneumococcal serotypes. That structure raises practical questions about how to summarize repeated, serotype-specific measurements and how to define the main comparison. The registry identifies the endpoint and its timing, but does not report the numerical estimates or the full comparison plan.

The use of geometric means is relevant because antibody concentrations can be interpreted on a multiplicative scale. In general, the selected summary can better represent proportional variation than an arithmetic mean when the data have that structure. A confidence interval is also important because an estimate without uncertainty gives limited information about precision. The record specifies a 95% confidence interval but does not report its limits.

The large number of listed outcomes and analyses makes multiplicity a key interpretive consideration. A reader needs to know which hypotheses were primary, whether adjustments were used, and how secondary findings were treated. Those elements are not reported in the registry record. Likewise, understanding the endpoint population requires the full eligibility and missing-data rules, which are not available in the record’s description.

Finally, the registry’s planning assumptions illustrate that sample-size calculations depend on a chosen effect, significance level, allocation, and approximation. General planning calculations do not establish observed power or reveal the precision of the trial’s actual estimates. The numerical planning outputs and the trial’s own sample-size justification are not reported in the registry record. These statistical details matter because they determine what can be concluded from estimates, not merely whether a trial was conducted.

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 main limitation for interpreting immunogenicity is that numerical primary endpoint estimates and comparisons are not reported in the registry record. Although the endpoint is defined by measure, serotypes, and timing, the record does not give the group-level concentrations, confidence interval limits, or inferential results needed to assess direction, magnitude, or precision.

The record does not report the complete statistical analysis plan, including the planned group contrasts, comparison scale, model, or multiplicity procedure. With 24 outcome measures and 236 analyses listed, the absence of a reported testing strategy makes it difficult to distinguish the role of individual analyses. The registry does not report a trial-specific sample-size justification or the numerical outputs of its planning illustrations.

The primary analysis-set description is incomplete. The record refers to a modified intent-to-treat infant immunogenicity set and available blood-draw data, but does not give the complete criteria, counts excluded from analysis, or reasons for missing and indeterminate results. Imputation and sensitivity-analysis details are not reported in the registry record. These gaps limit evaluation of how representative the analyzed measurements are of the randomized groups.

The open-label design means masking was absent. The primary endpoint is a laboratory measurement, but the record does not report whether laboratory staff were blinded to group assignment or provide sufficient assay-process detail to assess that possibility. The reported safety summaries do not include comparative estimates or uncertainty intervals, and the denominator for the listed serious-event percentages is not reported. These limitations constrain both efficacy interpretation and comparative safety assessment.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study Assessing the Effect of Medications to Prevent Fever on Prevenar 13® — NCT01392378.
• Registry record last updated 2014-02-26; status last verified 2014-01.
• Results first posted 2014-02-26.
• 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 describes a completed Phase 4, randomized, open-label, parallel-group trial of prophylactic antipyretic medication given with 13-valent pneumococcal conjugate vaccine and INFANRIX hexa in healthy infants. Enrollment was 908. The regimens included paracetamol or ibuprofen at different dose frequencies, as well as a group without study antipyretic medication.

The primary endpoint was serotype-specific pneumococcal IgG geometric mean concentration 1 month after the infant series, covering 13 serotypes. Secondary outcomes included additional pneumococcal and routine-vaccine antibody measures. The registry lists safety summaries for the infant series, the period after it, and the toddler dose.

Numerical primary endpoint findings, full statistical methods, multiplicity handling, and detailed missing-data information are not reported in the registry record. Safety counts and serious-event terms are listed, but comparative safety estimates are not reported.