Evaluation of Safety and Immunogenicity of Co-administering Human Papillomavirus (HPV) Vaccine With Other Vaccines in Healthy Female Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Safety and Immunogenicity of Co-administering Human Papillomavirus (HPV) Vaccine With Other Vaccines in Healthy Female Subjects (NCT00426361), a randomized phase 3 study. The primary outcome is Number of Subjects Seroprotected Against Diphtheria and Tetanus.

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group Phase III study of co-administering an HPV vaccine with Boostrix Polio. The official title describes a multicentre study in healthy female subjects aged 10–18 years. The registry record lists enrollment of 751 and marks the study as completed. Its recorded start was 2007-02-13 and its primary completion was 2008-03-17.

The three described arms used different vaccination schedules. The Cervarix group received Cervarix at Month 0, 1 and 6. The Cervarix plus Boostrix Polio group received Cervarix at Month 0, 1 and 6, with Boostrix Polio co-administered at Month 0. In the Boostrix Polio then Cervarix group, Boostrix Polio was given at Month 0 and Cervarix at Month 1, 2 and 7. These schedules distinguish co-administration from sequential administration and from the Cervarix-only schedule.

Random allocation can, in general, reduce systematic differences between groups at the outset, while an open-label design means treatment assignment was not masked. The record does not describe the randomization procedure, concealment of allocation, or any steps to limit bias in outcome assessment. It lists a parallel model, meaning the groups followed their assigned schedules rather than crossing between interventions.

The stated study aims concerned safety and immunogenicity. The registry describes one primary endpoint, seroprotection against diphtheria and tetanus, and several secondary immunogenicity outcomes concerning HPV, diphtheria, tetanus, polio and pertussis antibodies or responses. The record does not provide a detailed protocol rationale for the schedules, recruitment, or enrollment target.

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: Analysis was performed on the Month 1 According-to-Protocol (ATP) cohort for analysis of immunogenicity and only on those subjects vaccinated with Boostrix Polio.

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 Seroprotected Against Diphtheria and Tetanus, measured over One month after vaccination with Boostrix Polio.

The primary endpoint is the number of subjects seroprotected against diphtheria and tetanus. The registry defines seroprotection as anti-diphtheria and anti-tetanus antibody titres of at least 0.1 IU/mL. The stated assessment time is one month after vaccination with Boostrix Polio.

This is an immunogenicity endpoint: it classifies antibody measurements against a prespecified threshold rather than measuring a clinical illness or a clinical complication. Such a threshold can make a laboratory response easier to summarize as a count of participants meeting the criterion. The count is meaningful only alongside the number assessed and the precise analysis population; the registry record identifies the Month 1 According-to-Protocol cohort for immunogenicity, limited to subjects vaccinated with Boostrix Polio.

The word “and” matters to interpretation. The endpoint title refers to protection against both diphtheria and tetanus, and the definition gives a threshold for each antibody. The registry record does not give a single numerical endpoint result, denominators for the primary analysis, or a comparison estimate. It also does not say how the primary result was handled across the endpoint’s categories or time points. Accordingly, the endpoint’s definition can be described, but its observed level and between-group difference cannot be inferred from this record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Several statistical ideas help distinguish what the design can address from what the registry record actually reports. The explanations below are general; they do not imply that a particular analysis was performed in this trial. The record identifies randomized allocation and a parallel-group design, but it does not provide a full statistical analysis plan or inferential results.

What does randomization contribute?

In general, randomization assigns participants to study groups using a chance-based process. Its purpose is to make group assignment independent of measured and unmeasured participant characteristics on average, rather than allowing clinicians or participants to choose a schedule based on those characteristics. Randomization does not guarantee identical groups, and it does not prevent bias caused by missing outcome data, deviations from assigned schedules, or differences in outcome measurement.

The record says the study was randomized, but does not report how the sequence was generated, whether allocation was concealed before assignment, or whether randomization was stratified. It also identifies the study as having no masking. In an open-label trial, participants and study personnel know the assigned schedule. Knowledge of assignment may affect some aspects of care or reporting, although laboratory antibody measurements can be more objective than subjective outcomes. The registry record does not describe blinding of laboratory staff or outcome assessors.

How should a binary endpoint be understood?

The primary endpoint turns antibody measurements into a classification: a subject either meets the stated seroprotection definition or does not. A count of participants meeting a criterion is therefore a binary-outcome summary. Counts should be interpreted with their denominators, because the same count can mean different things in groups of different sizes. The primary analysis denominators and the group-specific primary counts are not reported in the registry record, so the endpoint cannot be quantified or compared from the posted information.

In general, an analysis might compare the proportion meeting a binary criterion between groups, or estimate an effect with an uncertainty interval. These are general possibilities, not methods documented for this trial. A confidence interval, when reported, expresses the range of effect values reasonably compatible with the data and the statistical method. Its width conveys precision; it does not by itself establish clinical importance. No primary effect estimate, confidence interval, or p-value is reported in the registry record.

What does the analysis population mean?

The registry identifies the Month 1 According-to-Protocol cohort for immunogenicity and says that it includes only subjects vaccinated with Boostrix Polio. An according-to-protocol analysis generally focuses on participants who satisfy specified protocol requirements, but the criteria used in this study are not described in the registry record. This population is not necessarily the same as everyone randomized. Excluding participants after assignment can affect comparability if exclusion is related to prognosis, treatment, or outcome. The record does not report the number eligible for this analysis, exclusions, or reasons for exclusion.

The registry record’s primary endpoint has multiple categories or time points and is not reduced to one comparison. That makes the intended estimand—the particular group contrast and endpoint summary of interest—unclear from the posted record. Statistical interpretation depends on defining that target before examining results, especially when multiple schedules and outcomes are available.

What can the planning illustration tell a reader?

In general, a sample-size calculation asks how much information a study would need to detect an effect under stated assumptions. The registry’s planning illustration is described as based on an observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; it is not the trial’s own design justification. The assumed effect is a stated fraction of the observed effect. Such a calculation is a planning illustration, not observed power and not evidence that the study was originally designed around those assumptions. The record does not report the trial’s sample-size justification.

A planning result depends on the assumed effect, variability or event frequency, allocation, and analysis method. If the assumed effect is smaller, more information is generally required to distinguish it from random variation. Those are general statistical principles, not trial-specific findings. No planning values need to be treated as observed study outcomes.

Why are several outcomes and safety counts not a single test?

The listed secondary outcomes cover HPV seroconversion and titres, diphtheria and tetanus titres and responses, poliovirus antibody titres, and pertussis booster responses. Examining many outcomes creates a multiplicity issue: even when each test has a controlled false-positive chance, the chance of at least one chance-positive result across a collection of tests can increase. Common approaches include prespecifying a hierarchy or adjusting inference, but the registry record does not report a multiplicity strategy.

Safety counts are descriptive unless a comparative method and its assumptions are stated. For rare events, estimates can be imprecise, and a small difference in counts does not by itself establish a real difference in underlying risk. General statistical methods may use exact or approximate procedures depending on the data and analysis plan; the registry record does not say which, if any, were used. No inferential safety comparison is reported.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 15 outcome measures and several secondary outcomes spanning HPV antibody seroconversion and titres, diphtheria and tetanus antibodies, polio antibody titres, and booster responses to pertussis antigens. Testing multiple outcomes or comparing several schedules raises multiplicity concerns. In general, multiplicity can make chance-positive findings more likely across a set of tests. Researchers may address it through a prespecified testing hierarchy or other adjustment, but a strategy is not reported in the registry record.

The primary endpoint is described as having several categories or time points and is not reduced to one comparison in the posted analysis. The record therefore does not establish which contrast was intended to be primary for statistical inference. It also does not report a family of hypotheses, an adjustment method, or how any secondary results would be interpreted in relation to the primary endpoint.

The primary population is described as the Month 1 According-to-Protocol cohort for immunogenicity among subjects vaccinated with Boostrix Polio. The registry does not report the number included, the number excluded, reasons for exclusion, or a missing-data method. It also does not report whether any sensitivity analysis assessed the effect of missing observations or protocol deviations. These omissions matter because restricting an analysis to participants with available, protocol-compliant measurements can affect the interpretation of randomized comparisons.

The record does not report interim analyses, stopping rules, or a detailed statistical analysis plan. It lists zero analyses in its analysis field, while listing outcome measures. Thus, the registry contains endpoint descriptions and selected safety counts but not a reported inferential analysis for the immunogenicity outcomes.

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: gastroenteritis (0.4%), ovarian cyst (0.4%), suicide attempt (0.4%), tonsillitis streptococcal (0.4%), ovarian cyst ruptured (0.4%).

The registry reports serious adverse event counts with the numbers at risk for each group. The Cervarix group has 3 serious adverse events among 248 at risk; the Cervarix plus Boostrix Polio group has 4 among 255 at risk; and the Boostrix Polio then Cervarix group has 3 among 248 at risk. These counts describe what was posted for the groups and should not be treated as a formal comparison. The record does not provide confidence intervals, a comparative test, or details of follow-up that would support a conclusion about differences between schedules.

The registry also lists six serious-event terms, each with 0.4%: gastroenteritis, ovarian cyst, suicide attempt, streptococcal tonsillitis, ruptured ovarian cyst, and presyncope. A term’s appearance in a serious-event listing does not establish that a vaccine caused it. The record does not give event-level narratives or a causal assessment for each listed term.

Other adverse events are reported as counts: 232 among 248 in the Cervarix group, 245 among 255 in the Cervarix plus Boostrix Polio group, and 242 among 248 in the Boostrix Polio then Cervarix group. These are not serious-event counts. The registry record does not report deaths; the blank entries should not be read as confirmation of zero deaths.

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

This trial addresses a practical study question: whether an HPV vaccine can be co-administered with Boostrix Polio in a study of healthy female subjects aged 10–18 years, with safety and immunogenicity as the stated areas of evaluation. Its three schedules make it possible in principle to examine co-administration alongside sequential administration and Cervarix alone. The registry record supplies schedule descriptions and identifies the primary seroprotection measure.

The primary measure is a laboratory-based classification against a defined antibody threshold, not a clinical endpoint such as HPV infection or cervical disease. Antibody outcomes can inform whether participants mounted measurable immune responses, but they do not, by themselves, demonstrate prevention of disease. The record’s background rationale about HPV vaccination and cervical cancer should not be mistaken for a trial result on cancer prevention.

The key limitation for interpreting the trial’s stated primary question is that no primary outcome counts or comparison estimates are reported. The record therefore cannot show the observed degree of seroprotection, the precision of that estimate, or whether the schedules differed. It likewise does not report results for the secondary antibody outcomes. Without those results, no conclusion about comparative immunogenicity can be drawn from the registry entry.

Safety information is available as adverse event counts, but the listed counts alone do not establish a causal relationship or a between-group difference. The serious-event terms each carry the same registry-reported 0.4% entry, and the record does not provide a detailed causal assessment or comparative uncertainty. Absence of a reported death count is not equivalent to evidence that no deaths occurred.

In short, the record describes a randomized study design and its intended outcomes, and it posts selected adverse-event counts. It does not provide enough outcome and analysis information to determine what the study found about its primary immunogenicity question or the comparative safety of the schedules.

13. Why This Trial Matters Statistically

Statistically, this study is useful for illustrating the difference between a clearly defined endpoint and a reported result. The primary endpoint has a specified antibody threshold and an assessment time, and the analysis population is identified. Yet the registry record does not report the group-specific endpoint counts or a single comparison. A reader can understand what was intended to be measured without being able to assess the result.

The three schedules also make the definition of a comparison important. Co-administration, sequential vaccination, and Cervarix alone are distinct strategies. A conclusion depends on which of these is compared, in which analysis population, and at what endpoint time. The registry record supplies arm schedules but does not state a single primary contrast in the posted results. That distinction is important whenever a study has more than two arms or multiple outcomes.

The endpoint is a thresholded immunogenicity measure. Converting antibody titres into a count meeting a threshold aids interpretation, but it discards information about how far individual titres lie above or below that threshold. The secondary outcome list includes antibody titres as well as seroconversion and booster-response measures, emphasizing that different summaries answer different questions. No numerical results for those summaries are reported.

The record also illustrates why descriptive safety counts should not be over-interpreted. Counts provide information about reported events, but comparative inference requires attention to denominators, follow-up, event definitions, and uncertainty. The registry posts counts and serious-event terms without a comparative analysis. This makes clear the difference between documenting events and establishing a treatment-related safety difference.

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 trial-specific limitations arise from what the registry record does not report. It gives the primary endpoint definition and analysis population, but not the primary outcome counts, group denominators for that analysis, effect estimates, confidence intervals, or p-values. The posted record therefore does not permit assessment of the magnitude or precision of the primary result.

The primary endpoint is not reduced to one comparison because it has several categories or time points. The registry does not identify which group contrast should anchor interpretation or explain the treatment of multiple endpoint categories. With three schedules and multiple secondary outcomes, the absence of a reported multiplicity strategy further limits interpretation of any potential collection of findings.

The record identifies an according-to-protocol population but does not provide its eligibility criteria, participant flow, exclusions, or reasons for missing measurements. It does not state how missing data were handled or whether sensitivity analyses were conducted. These details are needed to judge how closely the analyzed participants reflect the randomized groups.

The design is listed as open-label, but the record does not describe whether laboratory assessors were masked or how outcome assessment was standardized. It also does not report the randomization procedure or allocation concealment. These are design details relevant to bias assessment, not evidence that bias necessarily occurred.

For safety, the registry gives adverse-event counts and a short list of serious-event terms, but not detailed event narratives, exposure duration, or comparative uncertainty. Death entries are blank, and the record does not report deaths. Finally, the trial’s sample-size justification, interim analyses, and full statistical plan are not reported in the registry record.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Evaluation of Safety and Immunogenicity of Co-administering Human Papillomavirus (HPV) Vaccine With Other Vaccines in Healthy Female Subjects — NCT00426361.
• Registry record last updated 2018-07-20; status last verified 2017-04.
• Results first posted 2010-08-23.
• 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 randomized, open-label, parallel-group Phase III study of Cervarix and Boostrix Polio schedules in healthy female subjects aged 10–18 years. Enrollment is recorded as 751. The three arms cover Cervarix alone, co-administration of Cervarix and Boostrix Polio, and Boostrix Polio followed by Cervarix.

The primary endpoint is the number of subjects seroprotected against diphtheria and tetanus one month after Boostrix Polio vaccination, using antibody titres of at least 0.1 IU/mL. Its analysis population is the Month 1 According-to-Protocol immunogenicity cohort among subjects vaccinated with Boostrix Polio. Primary and secondary immunogenicity results are not reported in the registry record.

Selected adverse-event counts and serious-event terms are posted, but no comparative safety analysis is reported. The record does not report a detailed statistical plan, missing-data methods, or a multiplicity strategy.