Safety and Immunogenicity of GSK Biologicals' HPV-16/18 L1 VLP AS04 Vaccine (GSK-580299) in Healthy Female Children 4-6 Years Old: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of GSK Biologicals' HPV-16/18 L1 VLP AS04 Vaccine (GSK-580299) in Healthy Female Children 4-6 Years Old (NCT01627561), a randomized phase 3 study. The primary outcome is Number of Subjects With Any and Grade 3 Solicited Local Symptoms.

2. Clinical Question

The study also evaluated immunogenicity and safety. Its stated comparison was between the Cervarix schedule and the sequential Priorix-plus-Infanrix schedule in children of the same age range. The planned vaccine schedules differ in both the products administered and the sequence of vaccination. As a result, the study question concerns these regimens as assigned, rather than an isolated comparison of one vaccine component.

The registry lists secondary outcomes for HPV-16 and HPV-18 seroconversion and antibody concentrations, as well as measles, mumps and rubella seropositivity and antibody concentrations. Some HPV measurements were scheduled for both groups, while later follow-up measurements were listed only for the Cervarix group. The record therefore describes a broad set of safety and immune-response questions, not only the primary local-symptom question. It does not report a single summary result that answers all of those questions.

3. Trial Design

This was a randomized, single-masked, parallel-group Phase 3 study sponsored by GlaxoSmithKline. The registry lists enrollment of 148 and a completed study. The recorded study start was 2012-10-15, and primary completion was 2014-04-23. These dates describe the registry timeline; they do not establish when every participant was vaccinated or followed.

The experimental group received Cervarix at Day 0 and Month 6. The control group received Priorix at Day 0 and Infanrix at Month 6. Both group descriptions specify healthy female subjects aged between, and including, 4 and 6 years, and intramuscular administration in the left upper arm. The record identifies the allocation as randomized and the model as parallel. It describes masking as single, but does not report which people involved in the study were masked or how masking was maintained.

For the primary local-symptom outcome, follow-up covered the 7-day period beginning on the day of vaccination and extending through the subsequent 6 days after each dose, with symptoms also considered across doses. The Total vaccinated cohort was the stated analysis population for this outcome. This population included vaccinated subjects who received at least one dose, had their symptom sheet filled in, and had data available.

The listed secondary outcomes include HPV-16 and HPV-18 seroconversion and antibody concentrations. The record gives follow-up times of Month 7 and Month 12 for both groups, and Month 18, Month 24 and Month 36 for the Cervarix group only. Measles, mumps and rubella seropositivity and antibody concentrations are also listed. The record does not report further details of the randomization procedure, the masking arrangements, or the statistical plan.

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: All 148 subjects enrolled in the study, received the study vaccination and were included in the Total Vaccinated cohort (TVC).

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was based on the Total vaccinated cohort (TVC), which included all vaccinated subjects who received at least one dose of vaccine in this study, who had their symptom sheet filled in and for whom data 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 Any and Grade 3 Solicited Local Symptoms, measured over During the 7-day follow-up period (i.e. from the day of vaccination up to 6 subsequent days) after each vaccine dose and across doses.

The primary endpoint counts subjects with solicited local symptoms: pain, redness and swelling. It distinguishes any occurrence of a symptom, regardless of intensity, from symptoms classified as Grade 3. The registry defines Grade 3 pain as crying when the limb was moved or being spontaneously painful. Grade 3 redness or swelling means that the affected area extended beyond 20 millimeters from the injection site.

Counting affected subjects is a direct way to describe how often participants experienced these prespecified symptoms during the short follow-up after vaccination. The endpoint’s “any” category captures symptoms of any listed intensity, while the Grade 3 category focuses on the more severe definitions specified in the record. Considering symptoms after each dose and across doses gives the endpoint a vaccination-schedule context.

These counts describe solicited local symptoms, not every possible safety outcome. They also do not, by themselves, establish that a vaccine caused a symptom or indicate whether a difference between groups is statistically distinguishable from chance. The registry record does not report a single primary-outcome result or a single comparison for this endpoint. It lists several symptom categories and time points, and the record indicates that these were not reduced to one comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Statistical interpretation depends on matching each number to the question, population and time period it represents. This trial’s primary outcome is a count of subjects with solicited local symptoms, and the registry defines both “any” and Grade 3 categories. The listed safety figures are also counts of subjects. They should not be treated as continuous measurements or as immune-response estimates.

What does randomization contribute?

In general, randomization assigns participants to study groups by chance. When implemented as intended, it can reduce systematic differences between groups at the start of a trial, making a comparison more interpretable. Randomization does not guarantee that groups will be identical, and it does not remove uncertainty due to the number of observed events or missing outcome data. The registry identifies this study as randomized but does not report the allocation procedure, concealment process or baseline characteristics needed to assess those details.

What does the parallel design mean?

In general, a parallel-group design assigns participants to one study group and compares outcomes across groups. Here, the registry describes a Cervarix schedule in one group and a Priorix-then-Infanrix schedule in the other. Because the assigned schedules differ in their vaccine products and sequence, a between-group contrast would concern the regimens as a whole. It would not isolate the contribution of an individual product or dose.

How should symptom counts be understood?

A count of affected subjects communicates how many people in the stated analysis population met an outcome definition. The interpretation depends on the denominator, the definition of the event, and the observation period. For this endpoint, “any” includes symptoms regardless of intensity, whereas Grade 3 applies the definitions in the registry. Counts across different symptom categories should not be combined unless the analysis explicitly defines such a combined outcome. Likewise, the symptom follow-up after each vaccination and the across-dose summaries answer related but not identical questions.

The primary outcome is not reported as one comparison in the registry record. This matters because a reader cannot infer a group contrast from a list of endpoint definitions alone. A useful comparison would identify the outcome category and period, give the group-specific results, and report an effect estimate with its uncertainty. Those items are not reported for a single primary endpoint comparison in the record available for this interpretation.

What does a confidence interval communicate?

In general, a confidence interval expresses the statistical uncertainty around an estimated effect under the method used to construct it. A narrow interval indicates greater precision than a wide interval, but precision is not the same as clinical importance. An interval’s compatibility with a null value is also not, on its own, a complete interpretation: the outcome, effect scale, analysis plan and context matter. Confidence intervals for the primary comparison are not reported in the registry record, so its precision cannot be assessed from the listed primary endpoint information.

Why consider over-dispersion?

In general, over-dispersion arises when observed variability exceeds what a statistical model assumes. It can make standard errors too small if the model does not account for the extra variability, leading to overconfident uncertainty estimates. The primary endpoint is a participant count rather than a reported rate model, and the registry record does not specify an analysis model or report an over-dispersion assessment. It would therefore be inappropriate to assert that over-dispersion was present or that a particular method was used to address it.

What do the planning illustrations mean?

In general, a sample-size calculation describes a planning scenario under stated assumptions; it is not a measure of the evidence observed in a completed study. The planning illustrations associated with this record are described as using a fraction of the observed effect, equal allocation, a two-sided significance level of 0.05 and a normal approximation. They are not the trial’s own design justification. They should not be described as observed power, and they do not show what effect the trial was designed to detect unless that information is independently reported. The registry record does not report the trial’s sample-size justification.

For time-to-event settings, a sample-size method may be expressed in terms of total events; for other settings, a planning illustration may be expressed as participants per arm. That distinction is general. No new sample-size result or inference about achieved power follows from the descriptive enrollment and adverse-event counts. No interim analysis or formal statistical analysis plan is reported in the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists many outcomes rather than a single endpoint alone. The primary outcome includes symptom categories and timing after doses and across doses. Secondary outcomes cover HPV-16 and HPV-18 seroconversion and antibody concentrations, along with measles, mumps and rubella seropositivity and antibody concentrations. The record lists 30 outcome measures. Considering many outcomes can create a multiplicity issue: in general, the more statistical comparisons conducted, the greater the chance that some findings may appear unusual by chance alone. The registry record does not report a multiplicity adjustment or a testing hierarchy.

The record lists 0 analyses. It therefore does not provide a complete analysis-level account of which comparisons were conducted, how they were specified, or how uncertainty was calculated. The statistical plan is not reported in the registry record. Details about interim analyses are also not reported, so it is not possible to determine whether the results were examined before the stated completion of the study.

For the primary symptom outcome, the stated population is the Total vaccinated cohort, with inclusion dependent on vaccination, a completed symptom sheet and available data. This definition describes who was eligible for that analysis; it does not explain how missing symptom information was handled or whether participants with incomplete follow-up were excluded from particular summaries. The registry does not report the extent or pattern of missing data, imputation procedures, or sensitivity analyses.

The registry record does not report analysis-population definitions for all secondary outcomes. It also does not describe whether the analysis followed randomized assignment, how participants who did not receive all planned vaccinations were treated, or how deviations from the planned schedule were handled. These omissions limit assessment of bias and of how well the reported outcomes, where available, represent the randomized groups.

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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abscess limb (1.4%), gastroenteritis (1.4%), dehydration (1.4%).

The registry lists serious adverse event counts separately from other adverse event counts. In the Cervarix group, 1 subject is listed with a serious adverse event among 74 at risk; in the Priorix + Infanrix group, the corresponding figures are 2 among 74. For other adverse events, the listed counts are 70 among 74 and 65 among 74, respectively. These figures describe recorded subjects, not necessarily the number of event episodes: the registry summary does not provide an event-by-event accounting for these totals.

Abscess limb, Gastroenteritis and Dehydration are listed among the top serious adverse event terms, each at 1.4%. The record does not identify a group for each term in this listing. It also lists 0 deaths in each group. The percentages and counts should be read as registry summaries, not as evidence about causation or comparative risk. A serious event can be serious by regulatory criteria without being caused by a study vaccine.

The registry record does not report timing, duration, severity details beyond the serious-event classification, relatedness assessments, or a statistical test comparing groups. It also does not give enough context to interpret the top terms as a complete list of all serious events. These figures therefore support a limited descriptive reading, not a causal conclusion or a definitive comparison of safety between the vaccination schedules.

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

The record establishes that a randomized, single-masked, parallel-group Phase 3 study compared two vaccination schedules in healthy female children aged 4-6 years. It describes a primary outcome focused on solicited local symptoms and a wider set of immunogenicity and safety outcomes. It also provides selected adverse-event counts. These details clarify what the trial was intended to assess and what kinds of observations were recorded.

The record does not establish whether the schedules differed in the primary outcome. The symptom outcome is not presented as one group comparison, and the primary result is not reported in a form that supports a statement about the size or precision of a difference. The record also does not report the listed immune-response results in the information available for this interpretation. It is therefore not possible to draw conclusions about comparative immunogenicity from the outcome names alone.

The adverse-event counts are descriptive. They do not establish that any event was caused by a vaccine, and they do not provide a statistical test of the difference between groups. The terms listed as serious events are not assigned to groups in the record’s summary. The zero death counts are limited to the registry record and do not answer broader questions about the completeness or duration of safety follow-up.

More generally, absence of a reported result is not evidence that an outcome did not occur or that groups were equivalent. A claim of equivalence or non-inferiority would require an appropriate prespecified question, margin and analysis, none of which is reported in the registry record. Likewise, a failure to report a p-value cannot be interpreted as a statistically nonsignificant finding. The registry summary supports careful description of the design and recorded counts, while leaving key comparative questions unresolved.

The trial’s findings should therefore be interpreted in line with the endpoints and populations actually reported. The available record does not support medical advice, a treatment recommendation, or a broad conclusion about vaccine safety or effectiveness beyond the specific information recorded.

13. Why This Trial Matters Statistically

This trial is statistically informative as an example of the difference between a clearly defined endpoint and a reported endpoint result. The registry specifies local symptoms, severity definitions, follow-up timing and an analysis population. Those details are essential for interpreting an outcome consistently. Yet a well-defined measure does not by itself answer a comparative question: the group-specific results and a suitable contrast are also needed.

The study also illustrates how a trial can have several kinds of outcomes. Local symptoms, serious adverse events, other adverse events and antibody measures are not interchangeable. Each has a different scale and interpretation. A count of subjects with symptoms cannot answer an immunogenicity question, and an antibody outcome cannot substitute for a safety outcome. Keeping these outcome domains distinct helps prevent overstatement.

The trial’s two schedules differ in the products and sequence administered. A comparison between the randomized groups would therefore describe the schedules as assigned, rather than identify the effect of one product in isolation. This distinction matters when translating a statistical contrast into a scientific claim.

Finally, the record highlights the importance of transparent reporting. Information about the analysis plan, missing data, multiplicity, masking procedures and uncertainty around estimates helps readers judge how robust a result is. Those details are not reported. Recognizing that limitation is part of sound statistical interpretation: a registry record can establish what was planned and list selected observations without supplying enough evidence to resolve every comparative question.

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 details needed for a full statistical assessment are not reported in the registry record. Although the study is identified as single-masked, the record does not specify who was masked or describe how masking was maintained. It also does not give the randomization method or allocation concealment details. These omissions prevent assessment of how these safeguards were implemented.

The primary endpoint comprises symptom categories and time points, but the registry record does not report a single comparison or corresponding effect estimate and confidence interval. The reported adverse-event summaries are limited: the serious-event terms are not assigned to groups, and details on timing, duration and relatedness are not reported. The record does not report results for the listed immunogenicity outcomes in the information available for this interpretation.

The Total vaccinated cohort definition is given for the primary symptom analysis, but the record does not describe the extent of missing symptom data or how incomplete records were handled. It does not report analysis-population definitions for every outcome, a statistical analysis plan, multiplicity procedures, or interim analyses. These gaps limit evaluation of outcome selection, risk of bias and the precision of any treatment contrast.

The registry lists enrollment and adverse-event denominators, but does not provide the trial’s sample-size justification. Planning illustrations based on observed effects are not the original design rationale and cannot establish observed power. Finally, the available summary does not provide enough information to assess generalizability beyond the described population of healthy female children aged 4-6 years or to infer effects in other populations and settings.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of GSK Biologicals' HPV-16/18 L1 VLP AS04 Vaccine (GSK-580299) in Healthy Female Children 4-6 Years Old — NCT01627561.
• Registry record last updated 2020-04-10; status last verified 2020-03.
• Results first posted 2015-05-08.
• 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, single-masked, parallel-group Phase 3 study compared Cervarix given at Day 0 and Month 6 with Priorix at Day 0 followed by Infanrix at Month 6 in healthy female children aged 4-6 years. The registry lists enrollment of 148, with a study start of 2012-10-15 and primary completion on 2014-04-23.

The primary endpoint counted subjects with any and Grade 3 solicited local symptoms during the 7-day follow-up after each dose and across doses. The stated analysis population was the Total vaccinated cohort. The registry also lists HPV, measles, mumps and rubella immune-response outcomes.

Selected safety summaries report serious adverse events, other adverse events and deaths by group. The record does not provide a single primary-outcome comparison, complete immunogenicity results, or a reported analysis plan. The available information supports a description of the trial design and selected counts, but not a definitive comparative conclusion.