Concomitant Use of Gardasil (V501, Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine) With Combined Diptheria, Tetanus, Pertussis and Poliomyelitis Vaccine in Adolescents (V501-024)(COMPLETED): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Concomitant Use of Gardasil (V501, Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine) With Combined Diptheria, Tetanus, Pertussis and Poliomyelitis Vaccine in Adolescents (V501-024)(COMPLETED) (NCT00337428), a randomized phase 3 study. The primary outcome is Geometric Mean Titers (GMTs) for Anti-HPV 6 at Month 7 (4 Weeks Postdose 3).

2. Clinical Question

The clinical question concerns the immune response to HPV Type 6 when qHPV vaccine and REPEVAX™ are given together or at separate visits. The primary outcome is the geometric mean titer (GMT) of anti-HPV 6 antibodies at Month 7, four weeks after the third dose. The registry describes the comparison as an assessment of non-inferiority, but does not report the non-inferiority margin or the estimated between-group contrast.

3. Trial Design

This was a completed, randomized, open-label, multicenter, parallel-group Phase 3 study sponsored by Merck Sharp & Dohme LLC. The registry lists an enrollment of 843 and a study start of 2006-05, with primary completion in 2007-05. Participants were healthy adolescents 11–17 years of age. Masking was listed as none.

The study had four groups: concomitant administration with qHPV vaccine from the current manufacturing facility, non-concomitant administration with that vaccine, concomitant administration with qHPV vaccine from the future manufacturing facility, and non-concomitant administration with that vaccine. The primary outcome description focuses on the comparison between concomitant and non-concomitant administration. It describes the concomitant schedule as both vaccines at Day 1, and the non-concomitant schedule as qHPV vaccine at Day 1 followed by REPEVAX™ one month later.

The registry’s general study summary states an expectation that concomitant administration would remain immunogenic and well-tolerated without impairing the immune responses to the concomitant vaccines. That statement describes the study’s expectation, not a result. The posted primary endpoint is specifically an anti-HPV 6 antibody measure; the registry record does not establish that this endpoint captures every vaccine immune response or every aspect of tolerability.

The registry describes randomization but does not report the allocation ratio, the randomization procedure, or the number assigned to each of the four groups. It also does not report the sample-size justification or whether interim analyses were planned or conducted. These details cannot be inferred from the overall enrollment or the endpoint analysis counts.

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: The study enrolled healthy participants, 11-17 years old, with 0 lifetime sexual partners, vaccinated against diphtheria, tetanus, pertussis and polio but had not received the vaccine in the past 5 years or any prior human papillomavirus (HPV) vaccine. Additional inclusion and exclusion criteria applied.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol population: participants must have no major protocol violations, must be seronegative at baseline to the relevant HPV type, and must have post-vaccination data.

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 Titers (GMTs) for Anti-HPV 6 at Month 7 (4 Weeks Postdose 3), measured over Up to 7 Months (4 Weeks Postdose 3).

The primary endpoint is the geometric mean titer of serum antibodies to HPV Type 6 at Month 7, four weeks after the third dose. Titers were measured using a Competitive Luminex Immunoassay and reported in milliMerck units/mL. The endpoint description specifies a per-protocol population: participants had no major protocol violations, were seronegative at baseline to the relevant HPV type, and had post-vaccination data.

A GMT is a summary of a set of measurements that is commonly used when values are analyzed on a logarithmic scale. In general, titers can be strongly right-skewed, and taking logarithms can make statistical modeling more suitable; transforming the model-based summary back to the original scale yields a geometric mean. This makes the GMT a useful description of the typical antibody level in a group, while retaining the original measurement units.

The registry reports a 95% confidence interval for each group’s GMT. In general, a confidence interval describes the uncertainty around an estimated quantity under the assumptions of its statistical method. It is not itself a test of the clinical non-inferiority question. That question depends on a between-group comparison and a prespecified margin. The registry does not report the margin or the confidence interval for the comparison, so the group-level intervals alone do not show whether the non-inferiority criterion was met.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Why analyze titers on a logarithmic scale?

The registry states that the ANOVA used log individual titers as its response. In general, antibody titer measurements can have a multiplicative pattern: variation is often more naturally described by relative rather than fixed additive changes, and high values can create a long right tail. A logarithmic transformation compresses high values and can make the distribution more suitable for a model based on means and residual variation. These are general reasons for log-scale analysis, not additional claims about the distribution observed in this study.

On the log scale, a model estimates average log titers. Exponentiating such an average produces a geometric mean on the original scale. The registry reports GMTs in milliMerck units/mL, but does not report the model coefficients, residual diagnostics, or the exact method used to derive the displayed group estimates and confidence intervals.

What does the ANOVA model describe?

The endpoint description identifies an ANOVA model with log individual titers as the response and fixed effects for treatment group, manufacturing facility, study site, and the treatment-by-site interaction. In general, a fixed-effects model estimates associations for the specific categories included in the model, while accounting for the other modeled terms. Including manufacturing facility in the model recognizes the facility grouping in the study. Including site and a treatment-by-site interaction allows the treatment contrast to vary across sites in the fitted model rather than requiring a single identical site-specific pattern.

The registry does not report the number of sites, the fitted interaction estimates, or how the treatment contrast was summarized across sites. It also does not describe whether any model simplification, alternative model, or sensitivity analysis was used. The listed model components should therefore be treated as the reported analysis description, not as a complete account of every modeling choice.

In general, model adjustment can make an estimate differ from a comparison of unadjusted group summaries. The registry’s GMTs and confidence intervals do not include enough information to reproduce the model or determine whether the estimates are adjusted in precisely the same way as the reported hypothesis test. No recalculated comparison estimate or confidence interval is available for this continuous endpoint.

How should the confidence intervals and p-value be read?

A confidence interval conveys uncertainty about an estimated quantity under the assumptions of the statistical procedure. The endpoint record gives a 95% confidence interval for each group GMT, but does not give the 95% confidence interval for the difference or ratio between groups. The group intervals answer a different descriptive question from a confidence interval for the treatment contrast. In general, a non-inferiority conclusion is assessed by comparing the uncertainty around a treatment contrast with a prespecified margin. The margin and the contrast interval are not reported in the registry record.

The reported p-value is p < 0.001, and the analysis is labeled non-inferiority or equivalence. In general, a p-value is calculated under a stated null hypothesis and summarizes how incompatible the observed data are with that hypothesis under the model. It does not measure the probability that the null hypothesis is true, and it does not describe the magnitude of an effect. Because the registry does not report the precise null hypothesis or margin, the p-value cannot independently be translated into a fully specified non-inferiority decision from this record alone.

Non-inferiority and equivalence are related but distinct questions in general. Non-inferiority asks whether the result rules out an unacceptable loss relative to a comparator; equivalence asks whether the contrast falls within a margin in either direction. The registry classifies the analysis as non-inferiority or equivalence without identifying which formulation or decision rule applies. The margin, sidedness, and detailed testing procedure are not reported in the registry record.

What can the analysis counts and planning information establish?

The endpoint analysis includes 367 participants in the concomitant group and 376 in the non-concomitant group. These are endpoint-specific counts in the per-protocol population, not the total randomized enrollment. In general, an analysis population can differ from the enrolled population because eligibility for a particular analysis may depend on protocol adherence, baseline status, or availability of follow-up measurements. The registry states those per-protocol requirements, but does not report a full account of exclusions or missing endpoint data.

Planning illustrations, when based on an observed effect, are not observed power and are not evidence that the study had a particular probability of detecting an effect before it was conducted. The record does not report the trial’s own sample-size justification or design assumptions. It also does not report a complete statistical analysis plan. Specific sample-size assumptions, interim analyses, missing-data methods, and multiplicity procedures beyond the posted analysis description are not reported in the registry record.

10. Analyses Reported by the Sponsor

The registry reports the sponsor-associated primary analysis as an ANOVA non-inferiority or equivalence analysis, with p < 0.001. It also reports the two group GMTs and their 95% confidence intervals. However, the comparison estimate, its confidence interval, the non-inferiority or equivalence margin, and the exact hypothesis tested are not reported in the registry record.

A recalculated between-group comparison is not available for this continuous endpoint: the registry record indicates that values are missing or not estimable for a two-arm comparison. There is therefore no recalculated contrast to compare numerically with the reported ANOVA result. The listed group GMTs should not be treated as a replacement for that contrast, since the reported model includes treatment group, manufacturing facility, study site, and a treatment-by-site interaction.

The posted p-value is best described as the result reported for the sponsor’s labeled analysis, with its interpretation limited by the missing test details. The registry record does not identify a discrepancy between the reported and recalculated analyses. Without the analysis margin and contrast uncertainty, the statistical decision cannot be independently reconstructed from the posted information.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 17 outcome measures and 17 analyses, while the number of additional posted secondary results is 0. The primary result is anti-HPV 6 GMT at Month 7. The record does not describe how the analysis relates to the other listed outcomes, whether these outcomes were considered confirmatory or exploratory, or whether any multiplicity adjustment was planned or used.

In general, when several hypotheses are tested, the chance of at least one false-positive result can increase if each is assessed without accounting for the others. Methods for addressing multiplicity depend on the family of questions and the intended interpretation. Since the registry record does not report a multiplicity strategy, the p-value should not be assumed to have been adjusted for other outcomes, nor should it be assumed to be unadjusted as a documented protocol choice.

The endpoint uses a per-protocol population defined by the absence of major protocol violations, baseline seronegativity to the relevant HPV type, and availability of post-vaccination data. The counts reported for this endpoint are 367 and 376, compared with overall enrollment of 843. The registry does not report a participant flow accounting for the difference, the number excluded for each reason, or the amount and pattern of missing endpoint data.

In general, missingness can affect an estimate if the likelihood of an unavailable measurement is related to participant characteristics or outcomes. The record does not report the method used to handle missing data, any imputation procedure, or sensitivity analyses. It also does not report whether analyses in other populations were conducted. Randomization is listed, but the primary endpoint population is per-protocol; the record does not provide a corresponding intention-to-treat estimate for this endpoint.

The protocol’s statistical analysis plan, sample-size justification, interim analyses, and detailed rules for analysis populations are not reported in the registry record. These omissions limit assessment of prespecification, multiplicity control, and the robustness of the primary result.

12. 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: ligament rupture (0.2%), meniscus lesion (0.2%), ligament disorder (0.2%), constipation (0.2%), upper limb fracture (0.2%).

The registry reports serious adverse events among 1 of 420 participants in the concomitant group and 3 of 423 participants in the non-concomitant group. For other adverse events, the reported counts are 405 of 420 and 406 of 423, respectively. These are counts with the listed denominators; they do not by themselves describe event severity, duration, relatedness, or the number of events per participant.

The registry lists six serious-event terms, each reported as 0.2%: ligament rupture, meniscus lesion, ligament disorder, constipation, upper limb fracture, and hyperventilation. The record does not provide a group-specific breakdown for these terms in the information posted for this endpoint, so the terms should not be assigned to either schedule based on these figures. Deaths are not reported in the registry record.

In general, adverse-event counts are descriptive safety information. A comparison of counts does not establish that schedules have the same safety profile or that an event was caused by a vaccine. Interpretation also depends on event definitions, follow-up duration, ascertainment, and the handling of multiple events in one participant. Those details are not reported in the registry record. The reported figures should be read as the posted counts and terms, not as a complete assessment of safety.

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

The posted result describes anti-HPV 6 antibody GMTs at Month 7 among participants meeting the per-protocol criteria. The concomitant group estimate was 1151.0 mMU/mL, and the non-concomitant group estimate was 1245.0 mMU/mL. Their 95% confidence intervals describe uncertainty around each group estimate. The registry also reports an ANOVA analysis labeled non-inferiority or equivalence, with p < 0.001.

These results do not fully specify the treatment contrast. The registry does not report the contrast estimate, the confidence interval for that contrast, or the margin used for the non-inferiority or equivalence assessment. Thus, the posted group summaries and p-value do not allow a reader to independently reconstruct the decision criterion or judge how close the estimated contrast was to a margin.

The endpoint is an antibody measurement, not a direct clinical outcome. In general, an immune-response measure can answer a biological question about antibody levels, but it should not be treated as interchangeable with evidence about disease prevention or long-term protection unless the relevant relationship is established. The registry record does not report those outcomes for this result.

The finding is also limited to HPV Type 6, the specified timepoint, and the per-protocol population. It does not establish the result for every HPV type, for participants excluded from that population, or for other schedules and settings. The registry’s stated expectation that concomitant use would remain immunogenic and well-tolerated is an aim expressed in the study summary, not a conclusion that can be adopted without qualification from the incomplete contrast reporting.

In general, statistical evidence should be interpreted alongside effect size, uncertainty, design, and the question being tested. Here, the record supports a description of the group GMTs and the reported ANOVA p-value. It does not supply enough detail for a complete independent appraisal of the non-inferiority or equivalence conclusion.

14. Why This Trial Matters Statistically

This study illustrates an important distinction in clinical trial reporting: group summaries and a hypothesis-test result do not necessarily provide all the information needed to evaluate a non-inferiority question. A reader can see the GMT and confidence interval for each schedule, as well as the ANOVA p-value, but needs the treatment contrast and its uncertainty to assess how the comparison relates to the decision margin.

The design also highlights why analysis populations matter. The trial enrolled 843 participants, while the primary endpoint analysis includes 367 and 376 participants in the two reported groups. The endpoint is explicitly per-protocol, with eligibility depending on protocol adherence, baseline serostatus, and post-vaccination data. Distinguishing the randomized enrollment from the endpoint population helps avoid treating the observed analysis counts as if they represented every randomized participant.

The model description is relevant to interpretation because it includes treatment group, manufacturing facility, study site, and a treatment-by-site interaction. Such details indicate that the analysis considered features of the study structure beyond a simple comparison of two raw group averages. At the same time, the absence of the fitted contrast, margin, and model details limits independent reproduction.

Finally, immune-response endpoints, safety counts, multiplicity, and missing data answer different statistical questions. Keeping those distinctions clear helps readers describe what the registry record supports without turning an antibody summary into a broader claim about clinical outcomes or an incomplete safety profile.

15. 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 registry reports the analysis as non-inferiority or equivalence but does not identify the exact hypothesis, the margin, or the decision rule. It also omits the estimated treatment contrast and its confidence interval. These are central details for evaluating a non-inferiority or equivalence result, so the reported p-value cannot fully resolve the comparison on its own.

The endpoint population is per-protocol and requires no major protocol violations, baseline seronegativity to the relevant HPV type, and post-vaccination data. The record gives endpoint counts but not a flow of participants through randomization, follow-up, exclusions, and analysis. Missing-data methods and sensitivity analyses are not reported in the registry record.

The ANOVA description identifies several fixed effects, including a treatment-by-site interaction, but does not give the model coefficients, the number of sites, diagnostic checks, or the method used to produce the displayed GMTs and confidence intervals. Consequently, the analysis cannot be independently reproduced from the registry description.

The registry does not report the trial’s own sample-size justification, interim analyses, or multiplicity strategy. It lists 17 outcomes and 17 analyses, but reports 0 additional secondary results. The relationship between the primary result and the broader outcome set is therefore unclear from the record.

Finally, the primary outcome is one antibody measure at a specified follow-up point. The record does not report a clinical efficacy result for this comparison, and its safety figures do not include all details needed to assess event timing, relatedness, or participant-level event patterns. These limitations restrict the scope of conclusions that can be drawn from the posted statistics.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Concomitant Use of Gardasil (V501, Human Papillomavirus [Types 6, 11, 16, 18] Recombinant Vaccine) With Combined Diptheria, Tetanus, Pertussis and Poliomyelitis Vaccine in Adolescents (V501-024)(COMPLETED) — NCT00337428.
• Registry record last updated 2016-11-16; status last verified 2016-09.
• Results first posted 2010-02-11.
• 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.

19. Record Summary

NCT00337428 was a completed, randomized, open-label, multicenter, parallel-group Phase 3 study sponsored by Merck Sharp & Dohme LLC. It enrolled 843 healthy adolescents 11–17 years of age and compared concomitant with non-concomitant administration of qHPV vaccine and REPEVAX™, with groups using qHPV vaccine from two manufacturing facilities.

The primary endpoint was anti-HPV 6 GMT at Month 7 in a per-protocol population. The registry reports GMTs of 1151.0 mMU/mL for the concomitant group and 1245.0 mMU/mL for the non-concomitant group, with a 95% confidence interval for each, and an ANOVA non-inferiority or equivalence analysis with p < 0.001. The contrast estimate, its confidence interval, and the decision margin are not reported in the registry record. The record also does not report the sample-size justification, multiplicity plan, or missing-data methods.