A Study of V503 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Preadolescents and Adolescents (V503-002): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of V503 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Preadolescents and Adolescents (V503-002) (NCT00943722), a randomized phase 3 study. The primary outcome is Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1]).

2. Clinical Question

3. Trial Design

This was a randomized, open-label, parallel-group Phase III trial of V503. The registry record lists enrollment of 3074 participants and a completed study. The recorded start date is 2009-08-27, and primary completion is dated 2011-04-30. The sponsor is Merck Sharp & Dohme LLC.

The base study included females aged 9 to 15 years assigned to vaccine from Lot 1, Lot 2, or Lot 3; males aged 9 to 15 years assigned to Lot 1; and females aged 16 to 26 years assigned to Lot 1. Each described group received the 9-valent vaccine by intramuscular injection at Day 1, Month 2, and Month 6. The registry record describes assessment of manufacturing consistency across three final manufacturing lots, but it does not report the detailed method used to compare them.

The main immune-response comparison uses younger females and young adult females, both receiving Lot 1. A separate stated hypothesis compares younger males with young adult females. These comparisons address immune responses across age and sex groups rather than the effect of vaccination against no vaccination. The record identifies random allocation but does not report allocation ratios, the sequence-generation method, or concealment procedures. It lists masking as none, so the study was open-label.

The registry record also includes extension-study outcomes concerning persistent HPV infection, HPV-related lesions and cancers, genital warts, and serious adverse events. The extension outcomes are distinct from the primary immune-response outcome. Details of extension follow-up duration and the relationship between the base-study and extension populations 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.

Before assignment: Extension study 1 (EXT1) collected data to Month 36. Extension study 2 (EXT2) collected long-term data through \~Month 126. No study vaccine was administered. Per protocol, participants enrolled in the 16- to 26-year-old arm in the base study were not included in the extension study. Per protocol, the extension study included data from 9- to 15-year-old females regardless of lot administered (arm: "Extension Study: 9- to 15- Year Old Females").

Only the first 6 of 7 groups are shown.

Base Study

Reasons for not completing this period:

First Extension Study: EXT 1

Reasons for not completing this period:

Second Extension Study: EXT 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: 9-15-year-old females and 16-26-year-old females who received 3 vaccinations from Lot 1 and met following criteria for at least 1 of the 9 HPV types: no general protocol violations, received all 3 vaccinations within acceptable day ranges, seronegative at Day 1 for HPV type(s), and had a Month 7 serum sample collected within an acceptable day range.

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.

Population: Per protocol, baseline characteristics were analyzed in all participants randomized in the base study.

6. Primary Endpoint

The registry lists the primary outcome as Base Study: Geometric Mean Titers (GMTs) for Each of the HPV Types Contained in the Vaccine (9- to 15-Year-Old Females [Lot 1] and 16- to 26-Year-Old Females [Lot 1]), measured over 4 weeks post-vaccination 3 (Month 7).

The primary endpoint is the geometric mean titer of serum antibodies to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. Titers are reported in milli Merck Units/mL and were measured with a competitive luminex immunoassay. The specified measurement time is 4 weeks after vaccination three, at Month 7.

A geometric mean summarizes antibody titers using their multiplicative scale. In general, this is useful when measurements are positive and vary across a wide range; analysis on a logarithmic scale can make relative differences easier to assess. The endpoint therefore describes the level of the measured antibody response, rather than counting clinical HPV infections or disease events at the primary time point.

The registry record frames the main immune-response question as non-inferiority: whether titers in younger females are not meaningfully lower than titers in young adult females. That conclusion requires an estimated comparison and a prespecified non-inferiority margin. Neither the primary geometric mean titer values, their confidence intervals, nor the margin are reported in the registry record. The endpoint definition alone therefore does not establish whether the stated hypothesis was met.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical questions in this trial include estimating antibody titers, comparing age groups, assessing manufacturing-lot consistency, and describing adverse events. These require different summaries and interpretations. The registry record identifies the primary endpoint and several hypotheses, but detailed statistical methods are not reported in the registry record.

What does a geometric mean represent?

In general, a geometric mean is calculated by averaging measurements after taking logarithms and then transforming the average back to the original measurement scale. It is suited to outcomes whose meaningful variation is multiplicative rather than additive. For antibody titers, it gives a central summary that is less dominated by a small number of very high values than an arithmetic mean may be. The primary endpoint is expressed in milli Merck Units/mL, but the group-specific titer estimates are not reported in the registry record.

A confidence interval describes uncertainty around an estimated quantity under the statistical model and assumptions used. A narrower interval indicates greater precision for that estimate; it does not, by itself, indicate that a comparison is clinically important or that the model is appropriate. The primary endpoint is described as having a 95% confidence interval, but the numerical intervals are not reported in the registry record. The method used to construct them is also not reported.

How should non-inferiority be assessed?

In general, a non-inferiority analysis asks whether a new treatment or group is not worse than a comparator by more than a prespecified margin. The margin must be set before interpreting the observed results, and the analysis must report a treatment contrast with uncertainty. For a ratio-scale endpoint such as a geometric mean titer, the comparison may be expressed as a ratio or through a difference on the log scale; the specific contrast and procedure used in this trial are not reported in the registry record. The record states non-inferiority hypotheses but does not report the margin, contrast estimate, confidence interval, or decision rule. The hypothesis cannot be evaluated from the endpoint description alone.

The registry record describes younger females and young adult females as the primary comparison and younger males and young adult females as another planned comparison. Because age and sex differ across those groups, the comparisons should be interpreted as the stated group comparisons, not as isolated estimates of an age effect or a sex effect. The record does not report an adjusted model or other method intended to separate those characteristics.

What does lot consistency require?

Manufacturing consistency is a comparison among vaccine lots. In general, this requires a defined measure of similarity or an acceptable range for differences, together with estimates and uncertainty. The trial included younger-female groups receiving Lots 1, 2, and 3 and listed a lot-consistency outcome. The statistical criteria, model, and results for the comparison are not reported in the registry record. Separate groups and similar treatment schedules are not enough to determine whether a formal consistency criterion was met.

How should event counts be read?

Adverse-event counts are summaries of events observed or recorded within the listed groups. In general, comparisons of event frequencies need clear definitions of the population at risk, follow-up period, event attribution, and analysis method. The registry record gives denominators and counts for serious and other adverse events, but a full comparative method and event-level details are not reported. The counts are therefore descriptive in this account, rather than estimates of an adjusted causal effect.

The record lists 16 outcome measures and 90 analyses. Multiple endpoints, HPV types, groups, or analyses can raise multiplicity concerns: when many hypotheses are tested, the chance of at least one apparently notable finding may increase. In general, investigators may address this through a prespecified hierarchy, adjustment procedures, or interpretation focused on estimates and uncertainty. The multiplicity strategy used for this trial is not reported in the registry record. The number of listed analyses alone does not reveal whether or how multiplicity was controlled.

The record also includes an illustrative sample-size approach based on a stated fraction of an observed effect, a two-sided significance level of 0.05, equal allocation, and a normal approximation. Such calculations are planning illustrations and do not describe observed power. The actual numerical illustrations are not reported in the registry record, and the record does not report the trial’s own sample-size justification or design assumptions.

10. Multiplicity, Missing Data and Analysis Populations

The registry record lists 16 outcome measures and 90 analyses, with outcomes spanning antibody responses, seroconversion, persistent infection, HPV-related lesions and cancers, genital warts, and adverse events. Multiple outcomes and subgroup comparisons create a multiplicity issue in general: the more hypotheses considered, the more important it is to know which analyses were primary, which were secondary, and whether any statistical adjustment or testing hierarchy was planned.

The primary outcome is identified as geometric mean titers for the vaccine’s HPV types in younger females compared with young adult females. The record also states other hypotheses, including a comparison involving younger males and an assessment of consistency across three manufacturing lots. The statistical plan for prioritizing or adjusting these comparisons is not reported in the registry record. It is therefore not possible to determine how the full set of analyses was handled or how individual findings should be interpreted relative to one another.

Missing-data methods and analysis populations are also not reported in the registry record. The primary outcome description refers to participants meeting criteria that include receipt of all three vaccinations, specified timing, and seronegativity at Day 1 for the relevant HPV type. It also refers to a Month 7 serology criterion, but the description is incomplete. The record does not report how missing measurements, missed vaccinations, protocol deviations, or incomplete follow-up were handled in the primary analysis.

For a non-inferiority question, the analysis population and handling of missing data can be particularly important in general, because exclusions or incomplete measurements may affect interpretation. The available record does not identify whether additional analysis populations were used or whether sensitivity analyses were conducted. These details are not reported in the registry record, so their influence on the primary comparison cannot be assessed.

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 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: abortion induced (1.1%), appendicitis (0.5%), abdominal pain (0.2%), biliary colic (0.2%), urinary tract infection (0.2%).

The serious-adverse-event counts are reported against denominators for each listed group. In the base study, the counts were 6 of 643 younger females in Lot 1, 2 of 639 in Lot 2, 8 of 641 in Lot 3, 11 of 662 younger males, and 15 of 466 young adult females. The extension-study groups are reported separately: 2 of 1604 younger females in EXT1, 0 of 568 younger males in EXT1, 3 of 971 younger females in EXT2, and 0 of 301 younger males in EXT2. The record lists 1 death in each of the two extension-study female groups and 0 deaths in the other listed groups.

These are event counts within the registry’s group definitions. They do not show whether events were judged related to the vaccine, and the registry record does not report a causal comparison for these groups. Extension groups should not be added to base-study groups without information establishing whether participants overlap and how their follow-up differs.

The listed serious-event terms include Abortion induced at 1.1%, Appendicitis at 0.5%, and Abdominal pain, Biliary colic, Urinary tract infection, and Concussion, each at 0.2%. These listed terms are descriptive entries; the record does not provide enough detail to infer causation or compare risks across groups. Other adverse events were also recorded in base-study groups, with counts ranging from 404 to 554 across those groups, while the extension groups report 0. The registry record does not provide a comparative statistical analysis of these counts.

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

The study addresses whether antibody responses after V503 vaccination in younger participants are non-inferior to responses in young adult females, and whether responses are consistent across manufacturing lots. It also records tolerability and extension outcomes involving HPV infection and HPV-related conditions. These are separate questions: the primary endpoint is an antibody measurement, while the extension outcomes concern clinical events over follow-up.

The registry record reports the primary endpoint definition and the intended non-inferiority comparisons, but not the primary geometric mean titers, confidence intervals, non-inferiority margin, or analysis results. Consequently, the record excerpt does not show whether younger participants’ titers met the stated criterion, how large any difference was, or how precisely the comparison was estimated. It also does not report the findings needed to assess whether the three manufacturing lots met a consistency criterion.

The study’s randomized design does not make the primary comparison a vaccine-versus-no-vaccine comparison: the described primary groups both received vaccine. It is an immune-response comparison across participant groups. The open-label design is recorded, but the implications for any particular outcome depend on how that outcome was measured and analyzed; those detailed methods are not reported in the registry record.

The adverse-event counts describe events recorded in specified groups, including extension groups. They do not establish that the vaccine caused an event, and the registry record does not report a formal comparative safety estimate in the information summarized. Similarly, the listed extension outcomes do not establish a result without their event counts, follow-up details, and analysis estimates.

Thus, the posted information supports a description of the trial’s design, endpoint, intended hypotheses, and recorded event counts. It does not support a conclusion about the primary non-inferiority result, lot consistency, or comparative treatment effects. Missing estimates and methods limit both the assessment of effect size and the assessment of statistical precision.

13. Why This Trial Matters Statistically

This trial illustrates a common distinction in clinical research: an immune-response endpoint can answer a different question from a clinical disease endpoint. The primary outcome measures antibody titers at Month 7, whereas listed extension outcomes concern persistent HPV infection and HPV-related conditions. Readers should interpret each outcome according to what it measures rather than treating an antibody summary as a direct count of clinical events.

The design also makes the comparison structure important. Younger females and young adult females both received Lot 1 in the primary comparison, while separate groups were included for younger males and for younger females receiving Lots 2 and 3. The study therefore combines age-group immune comparisons with a manufacturing-consistency objective. Those aims require different contrasts and decision criteria, which are not interchangeable.

Non-inferiority studies are especially dependent on reporting the margin, estimate, and confidence interval. Without these, readers cannot judge how much lower a response could be while still satisfying the intended criterion, or how precisely the observed comparison was estimated. The registry record states the hypotheses but does not report those primary numerical results.

The trial also demonstrates why event counts require context. Serious adverse events are listed by group and denominator, while extension cohorts are presented separately. Counts alone do not describe causality, adjusted differences, or the role of follow-up time. In general, those questions depend on definitions and analysis methods, which are not reported in the registry record.

Finally, the record lists numerous outcomes and analyses. This makes transparent reporting of the analysis hierarchy, multiplicity strategy, analysis populations, and missing-data handling important. Those details are not reported in the registry record. The value of the trial record is therefore clearest as an account of the planned questions and broad design, while the inferential results remain unavailable in the reported information.

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 statistical interpretation is that the primary outcome’s numerical results are not reported in the registry record. The geometric mean titers, confidence intervals, non-inferiority margin, and comparison estimate are absent, so the main stated hypothesis cannot be evaluated from the reported information. Numerical results for manufacturing-lot consistency are also not reported.

The primary population description is incomplete. It identifies criteria involving protocol violations, vaccination timing, Day 1 serostatus, and a Month 7 serology result, but the description ends before the full criterion is given. The registry record does not fully report the primary analysis population or explain how participants who did not satisfy criteria were handled.

Methods relevant to interpretation are not reported in the registry record, including the detailed statistical model, confidence-interval construction, non-inferiority margin, multiplicity strategy, missing-data approach, and analysis populations. The record also does not report the trial’s sample-size justification. A separate planning illustration is described as based on the observed effect, but its numerical output is not reported in the registry record and should not be mistaken for observed power.

The design compares vaccinated groups rather than including an untreated or placebo comparator in the primary immune-response question. The trial is open-label, and detailed procedures for outcome assessment are not reported. The available adverse-event summaries are group counts without a reported comparative analysis or event-attribution details. Extension outcomes are listed, but the information summarized does not give their event estimates or full follow-up context.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study of V503 (A Multivalent Human Papillomavirus [HPV] L1 Virus-Like Particle [VLP] Vaccine) in Preadolescents and Adolescents (V503-002) — NCT00943722.
• Registry record last updated 2022-10-03; status last verified 2022-09.
• Results first posted 2015-01-13.
• 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 record describes NCT00943722, a completed randomized, open-label, parallel-group Phase III study of V503. Enrollment was 3074. The study included females aged 9 to 15 years receiving vaccine from three manufacturing lots, males aged 9 to 15 years receiving Lot 1, and females aged 16 to 26 years receiving Lot 1. The recorded schedule was vaccination at Day 1, Month 2, and Month 6.

The primary outcome was antibody geometric mean titers to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58, measured by competitive luminex immunoassay at 4 weeks after vaccination three. The registry record states non-inferiority and lot-consistency hypotheses, but the primary numerical results, confidence intervals, and non-inferiority margin are not reported in the registry record.

Other listed outcomes include seroconversion, persistent infection, HPV-related conditions, and serious adverse events. The record lists 16 outcome measures and 90 analyses. Detailed methods for multiplicity, missing data, and the analysis populations are not reported in the registry record.