A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of HPV and Tdap When Administered With MenACWY in Adolescents: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of HPV and Tdap When Administered With MenACWY in Adolescents (NCT01424644), a randomized phase 4 study. The primary outcome is Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 0.1 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo.

2. Clinical Question

The registry states that the main objective was to determine whether immune responses to Tdap and HPV vaccine given concomitantly with MenACWY were comparable to responses when those vaccines were given alone. The listed comparison uses placebo alongside Tdap and HPV vaccine, so the direct contrast concerns adding MenACWY-CRM to the concomitant Tdap and HPV regimen. The primary endpoint focuses on antibody threshold attainment for diphtheria and tetanus. The registry also lists hSBA titers against meningococcal serogroups A, C, W, and Y, along with solicited local and systemic adverse events and unsolicited adverse events, as secondary outcomes. The primary outcome results are not reported in the registry record, so the record does not establish how the groups compared on the antibody measures.

3. Trial Design

This was a randomized, double-masked, parallel-group, placebo-controlled Phase 4 study. The registry lists an enrollment of 801 and describes the trial as completed. The study start was 2011-09, and primary completion was 2012-12. Novartis is listed as the sponsor. These registry entries describe the study structure and administrative status; they do not provide evidence about the outcome of the comparison.

The two groups differed in whether MenACWY-CRM or placebo was given alongside Tdap and quadrivalent HPV vaccine. The arm descriptions state that the first vaccination included the assigned MenACWY-CRM or placebo with Tdap and HPV vaccine. The descriptions also state that the second and third HPV vaccine doses were given at 2 and 6 months after the first dose. The registry mentions serum collection at baseline and at Visit 2 (31 days); the visit descriptions are incomplete in the record, so the full schedule of sample collection cannot be reconstructed from it.

The primary outcome timeframe is 1 month post Tdap vaccination. The primary analysis population is described as the Tdap per-protocol population, rather than simply everyone enrolled or randomized. The registry does not report the number included in that analysis or give participant flow details. It also does not report the randomization procedure, allocation concealment method, or the identities of those masked. Those details should not be inferred from the labels randomized and double-masked. The design establishes a comparative framework, but interpreting its results would also require the outcome estimates, uncertainty, analysis details, and completeness of follow-up.

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 enrolled subjects were included in the trial.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Analysis was done on the Tdap per-protocol population, i.e., all subjects who received all the relevant doses of vaccine correctly, and provided serology results at one month postvaccination, and had no major protocol violation as defined prior to unblinding.

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 Percentages of Subjects With Anti-diphtheria and Anti-tetanus Antibody Concentrations ≥ 0.1 IU/mL When Tdap is Administered Concomitantly With HPV and MenACWY-CRM Vaccine Compared to Tdap Given Concomitantly With HPV and Placebo, measured over 1 month post Tdap vaccination..

The primary endpoint measures the percentages of participants whose anti-diphtheria and anti-tetanus antibody concentrations reached the stated threshold of ≥ 0.1 IU/mL. Concentrations were measured by ELISA, and the assessment timeframe was 1 month post Tdap vaccination. The endpoint therefore treats each antibody measure as threshold attainment rather than reporting a continuous concentration for each participant.

A threshold-based percentage is useful for describing how many participants in each group met a prespecified antibody concentration criterion. It can make a group comparison easier to interpret than a set of individual laboratory values, but it also discards information about how far above or below the threshold individual concentrations lie. The registry specifies a 95% confidence interval as the dispersion measure. In general, a confidence interval conveys uncertainty around an estimate; its width depends on the data and analysis, and it does not by itself establish that two groups are comparable.

The endpoint includes both anti-diphtheria and anti-tetanus antibody outcomes. The registry record does not provide the percentages, confidence intervals, or a single summarized contrast for these categories. It also does not report a margin or decision rule for defining comparability. Consequently, the endpoint description identifies what was intended to be measured, but the record does not permit a conclusion about the observed antibody responses.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a threshold-based endpoint represent?

The primary outcome is expressed as percentages of participants meeting an antibody concentration threshold for anti-diphtheria and anti-tetanus antibodies. Each participant’s measurement is classified according to whether it reaches ≥ 0.1 IU/mL. This is a binary outcome at the participant level, even though the antibody concentration itself is measured on a continuous scale. Reporting a percentage summarizes how frequently the threshold was reached within a group. It does not show the distribution of concentrations among participants who met the threshold, nor how close measurements below the threshold were to it.

The registry states that concentrations were measured by ELISA and that the primary outcome was assessed 1 month after Tdap vaccination. It identifies a 95% confidence interval as the dispersion measure. In general, a confidence interval expresses uncertainty around an estimate under the assumptions of the analysis. Its interpretation depends on the sampling process and statistical method. The registry record does not provide the estimates or intervals, nor does it state the detailed method used to calculate them.

Why does the analysis population matter?

The stated primary analysis population is the Tdap per-protocol population. It includes participants who received all relevant vaccine doses correctly, provided serology results at 1 month postvaccination, and had no major protocol violation as defined before unblinding. This definition makes the endpoint analysis dependent on both treatment adherence and availability of a postvaccination serology result. It is not necessarily the same population as everyone randomized.

In general, analysis populations answer different questions. A per-protocol analysis focuses on participants who followed specified treatment requirements, while an analysis based on all randomized participants preserves the original randomized comparison but requires appropriate handling of missing outcomes and deviations. Neither approach can be evaluated from a population label alone. The registry record does not report the number analyzed, participant flow by group, or a separate analysis of all randomized participants. It also does not state how deviations from protocol or missing serology results were handled.

What can randomization and masking contribute?

Random allocation is intended, in general, to reduce systematic differences between treatment groups at the start of a study. Masking can reduce the risk that knowledge of assignment influences participant behavior, care, assessment, or reporting. The registry labels this study randomized and double-masked and describes a parallel-group design. Those labels do not disclose the randomization sequence, concealment process, or who was masked. Such implementation details are not reported in the registry record.

The comparison is between MenACWY-CRM plus Tdap and HPV vaccine and placebo plus Tdap and HPV vaccine. If the groups were followed and assessed consistently, the contrast would address the addition of MenACWY-CRM within the concomitant vaccination setting. The record states the objective as assessing whether immune responses were comparable, but it does not supply the primary estimates or a formal criterion for comparability. A study design and objective alone cannot determine the result.

Why are multiple outcomes and contrasts relevant?

The primary outcome includes anti-diphtheria and anti-tetanus antibody categories, and the registry indicates that it has several categories or time points rather than reducing it to a single comparison. The listed secondary outcomes include geometric mean hSBA titers against N. meningitidis serogroups A, C, W, and Y, solicited local and systemic adverse events, and unsolicited adverse events. When multiple outcomes or comparisons are considered, the chance of observing a nominally notable result can increase. General methods for addressing multiplicity include prespecifying a hierarchy or adjusting inference across comparisons. The registry record does not report whether any multiplicity procedure was planned or used, so none should be assumed.

The registry’s outcome listing is not a substitute for a statistical analysis plan. Specific model choices, covariate adjustment, confidence interval construction, and testing procedures are not reported in the registry record. Where a result is absent, no reanalysis can recover it from the endpoint description alone.

What does over-dispersion mean in general?

For count outcomes, a statistical model may assume a particular relationship between the average count and its variability. Over-dispersion occurs when observed variability exceeds what a model assumes. If ignored, uncertainty can be understated and statistical tests can appear more decisive than the data justify. This is a general consideration for count data, not a reported feature of this trial. The posted safety information consists of participant counts and does not identify a count model or report an over-dispersion assessment.

How should planning illustrations be read?

Any sample-size figures associated with the posted results are planning illustrations computed from the observed effect, not the trial’s original design justification. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation, with the effect to detect expressed as a fraction of the observed effect. For outcomes other than time-to-event outcomes, the illustrations are participants per arm for the stated power; time-to-event illustrations use total events. These assumptions do not show that the trial had a particular probability of detecting an effect, and the illustrations are not observed power. The registry record does not report the trial’s own sample-size justification or design assumptions.

10. Multiplicity, Missing Data and Analysis Populations

The primary endpoint involves anti-diphtheria and anti-tetanus antibody categories, and the record indicates that the primary outcome has several categories or time points rather than a single reduced comparison. Additional outcomes include meningococcal hSBA titers for serogroups A, C, W, and Y, solicited adverse events, and unsolicited adverse events. Examining multiple outcomes can create multiplicity concerns because repeated statistical comparisons can increase the chance of a result appearing notable by chance. In general, a prespecified testing hierarchy or another multiplicity strategy can clarify how evidence across outcomes is interpreted. The registry record does not report such a procedure, so its presence or absence in the full study conduct cannot be determined from this record.

The primary analysis population is defined as the Tdap per-protocol population, requiring correct receipt of relevant doses, available serology at 1 month postvaccination, and no major protocol violation. The record does not report how many participants met that definition, the extent or reasons for missing serology, or how missing outcomes were handled. It does not describe imputation, sensitivity analyses, or a separate analysis population based on all randomized participants. Missing-data methods and analysis populations are therefore not fully characterized.

The registry also does not report detailed statistical methods, covariate adjustments, or the analysis plan used for each endpoint. The 95% confidence interval is identified for the primary outcome, but the interval construction is not described. These omissions limit independent assessment of how the primary and secondary results were analyzed. They should be treated as unreported details, not as evidence that a particular method was or was not used.

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: hypothyroidism (0.3%), abdominal adhesions (0.3%), small intestinal obstruction (0.3%), type 1 diabetes mellitus (0.3%), aggression (0.3%).

The registry lists serious adverse events for 4 participants among 396 at risk in the MenACWY-CRM plus Tdap plus HPV group, and for 3 participants among 397 at risk in the placebo plus Tdap plus HPV group. The listed serious adverse event terms are hypothyroidism, abdominal adhesions, small intestinal obstruction, type 1 diabetes mellitus, aggression, and haematuria, each reported as 0.3%. The record does not state that each term occurred in every group, nor does it provide a comparative analysis for individual terms.

Other adverse events are listed for 288 participants among 396 at risk in the MenACWY-CRM group and 248 among 397 at risk in the placebo group. These are posted counts, not adjusted effect estimates. The registry does not provide an analysis of causality, severity breakdown, or comparative uncertainty for these figures. A count difference alone cannot establish that an event was caused by an intervention, and these summaries do not provide the clinical context needed to characterize individual events.

Death counts are not reported in the registry record. A missing death count should not be interpreted as a reported count of zero. The at-risk denominators apply to the posted safety summaries and should not be taken as the number in the primary per-protocol analysis.

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

The trial was designed to compare immune responses and safety when MenACWY-CRM was administered with Tdap and HPV vaccine against placebo administered with Tdap and HPV vaccine. The primary endpoint was the percentage reaching the stated anti-diphtheria and anti-tetanus antibody threshold at 1 month post Tdap vaccination. The registry record gives the endpoint definition and the per-protocol population criteria, but it does not report the primary outcome percentages or their confidence intervals. Thus, it does not show the observed magnitude or precision of the primary comparison.

The stated objective of assessing whether responses were comparable should not be confused with a demonstrated finding of comparability. The record does not report a margin for comparability, an inferential decision rule, or the primary results. Without those details, the statistical meaning of any claim that responses were similar cannot be evaluated from the registry record. Likewise, the absence of reported primary results is not evidence that there was no difference.

The safety information gives descriptive event counts and a list of serious adverse event terms. Those summaries can describe what the registry posted, but they do not determine whether an event was caused by a vaccine, whether groups differed statistically, or whether the groups had comparable safety profiles. The registry does not report a causal assessment or a comparative analysis of the serious event terms. Its death fields are not populated with counts, so deaths cannot be described as absent.

General statistical interpretation depends on estimates, uncertainty, prespecified analysis methods, the analysis population, and the completeness of outcome data. Several of these elements are not reported in the registry record. The design and endpoint description clarify the intended question; the posted record is insufficient to answer it. Any sample-size illustrations based on observed effects are planning calculations rather than observed power or evidence that the original study was designed around those assumptions.

13. Why This Trial Matters Statistically

This trial raises a statistical question about interpreting immune responses when vaccines are administered concomitantly. Its randomized, double-masked, parallel-group design provides a comparative framework, and the placebo group received Tdap and HPV vaccine alongside placebo. That design makes the stated contrast relevant to the addition of MenACWY-CRM within the listed vaccination regimen. The registry’s objective is framed around comparability, which requires careful attention to what endpoint was measured and what evidence would support such a conclusion.

The primary outcome is threshold-based and includes anti-diphtheria and anti-tetanus antibody categories. Those percentages would need to be interpreted alongside their confidence intervals and the population actually analyzed. The registry defines a per-protocol population that depends on correct vaccine receipt, available serology, and absence of major protocol violations. That definition highlights why analysis-population counts and missing-data handling matter: the randomized study structure does not by itself explain who contributed to each endpoint estimate.

The record also illustrates the distinction between a trial’s objective and its posted findings. It describes the endpoint and supplies safety summaries, yet the primary antibody results are not reported. A well-specified question does not substitute for estimates and uncertainty. Similarly, descriptive safety counts do not replace a comparative analysis or establish causation. The multiplicity of antibody categories and secondary outcomes makes prespecified interpretation important, but the registry does not report the relevant multiplicity procedures.

For statistical readers, the central lesson is to separate design information, endpoint definitions, descriptive event counts, and inferential results. Here, the first three are partly available, while the primary estimates and several analysis details are not reported in the registry record. That distinction prevents the objective or the study status from being mistaken for evidence about the result.

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 trial-specific limitation of the available record is that it does not report the primary outcome estimates. The endpoint description names anti-diphtheria and anti-tetanus antibody threshold attainment and specifies a 95% confidence interval, but neither the percentages nor the intervals are included. The primary outcome is not reduced to a single comparison because it has several categories or time points. This prevents assessment of the direction, size, and precision of the primary result.

The record does not report a comparability margin, the statistical decision rule, or a detailed analysis plan. It also does not report whether multiplicity was addressed across the antibody categories and secondary outcomes. The primary analysis population is defined, but its size and participant flow are not given. Missing serology, protocol deviations, and the handling of missing outcomes are not described. These omissions limit assessment of whether the analyzed participants represent the randomized groups and how robust the results might be to missing data.

Some arm-description text is incomplete, including the description of serum collection visits. The record therefore does not allow the full assessment schedule to be reconstructed. It lists safety denominators and event counts but does not provide comparative statistical analyses, attribution, or detailed event context. Death counts are not reported in the registry record. The enrollment figure should not be treated as the size of either primary analysis population, and the safety denominators should not be assumed to describe that population.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Phase 4, Placebo-Controlled, Randomized Study to Evaluate the Immunogenicity and Safety of HPV and Tdap When Administered With MenACWY in Adolescents — NCT01424644.
• Registry record last updated 2014-02-14; status last verified 2014-01.
• Results first posted 2014-02-14.
• 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

NCT01424644 is a completed, randomized, double-masked, parallel-group, placebo-controlled Phase 4 study sponsored by Novartis. The registry lists enrollment of 801, a start date of 2011-09, and primary completion in 2012-12. It compares MenACWY-CRM plus Tdap and HPV vaccine with placebo plus Tdap and HPV vaccine in healthy adolescents.

The primary endpoint is the percentage reaching anti-diphtheria and anti-tetanus antibody concentrations ≥ 0.1 IU/mL at 1 month post Tdap vaccination, assessed in a defined Tdap per-protocol population. The registry describes secondary immunogenicity and safety outcomes. It lists serious and other adverse event counts by group, but does not report the primary outcome estimates, detailed analysis methods, missing-data handling, or multiplicity procedures. The primary comparison therefore cannot be interpreted from the registry record alone.