A Study of V503, a 9-valent Human Papillomavirus (9vHPV) Vaccine in Females 12-26 Years of Age Who Have Previously Received GARDASIL™ (V503-006): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study of V503, a 9-valent Human Papillomavirus (9vHPV) Vaccine in Females 12-26 Years of Age Who Have Previously Received GARDASIL™ (V503-006) (NCT01047345), a randomized phase 3 study. The primary outcome is Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study.

2. Clinical Question

The registry describes a study of tolerability and immunogenicity in participants who had previously received GARDASIL™. The primary endpoint concerns reported injection-site events, including redness, swelling, and pain, tenderness, or soreness. An adverse event was defined broadly as an unfavorable and unintended change in the body temporally associated with use of the study vaccine, whether or not considered related to it. Worsening of a preexisting condition could also qualify when temporally associated with vaccination.

The primary comparison is between the randomized Base Study groups. It is not a comparison of all possible health outcomes, nor does the endpoint measure protection against HPV-related disease. The registry also lists seroconversion to vaccine HPV types as a secondary outcome, but the primary result is the percentage reporting an injection-site adverse event. The posted endpoint data describe observed events in participants with available follow-up, rather than a forecast for every person who might receive either injection.

3. Trial Design

This was a Phase III, randomized, international, placebo-controlled, double-blind, parallel-group clinical trial. The study enrolled 924 participants, and the registry lists the study status as completed. The recorded start date is 2010-02-24, and the primary completion date is 2011-06-10. The sponsor was Merck Sharp & Dohme LLC.

In the Base Study, participants were assigned to blinded 9vHPV vaccine or blinded saline placebo. Both were administered by intramuscular injection on Day 1, Month 2, and Month 6. Participants assigned to 9vHPV vaccine did not continue to the Extension Study. Participants assigned to placebo could receive open-label 9vHPV vaccine on the same schedule in the Extension Study after completing the Base Study. The primary endpoint concerns only the Base Study.

For the primary endpoint, the registry reports 608 participants in the 9vHPV Vaccine - Base Study group and 305 in the Placebo - Base Study group. The endpoint population is described as participants who received at least 1 vaccination and had available follow-up data. These endpoint group counts should be understood in the context of that stated analysis population; the registry record does not provide a further account of how the endpoint population relates to the total enrollment.

The study also included immunogenicity assessment. The listed secondary outcome concerns the percentage of participants who seroconverted to each HPV type contained in the vaccine. The record reports 8 outcome measures and 10 analyses overall, but a detailed account of each analysis is not reported in the registry record. The record does not describe the original sample-size justification, the intended statistical analysis plan, or whether interim analyses were planned.

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.

Base Study

Reasons for not completing this period:

Extension

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: All participants who received at least 1 vaccination and had available follow-up 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 Percentage of Participants Who Experience an Injection-site Adverse Event (AE) - Base Study, measured over up to 5 days after any vaccination - Base Study.

The primary endpoint is the percentage of participants who experienced an injection-site adverse event up to 5 days after any vaccination in the Base Study. The registry identifies examples of injection-site events as redness, swelling, and pain, tenderness, or soreness. Its adverse-event definition also includes other unfavorable and unintended changes temporally associated with study vaccination, whether or not judged related to the vaccine, and worsening of a preexisting condition when temporally associated.

This endpoint is used to describe local tolerability after vaccination. Reporting the percentage makes the event frequency interpretable in relation to the participants in each group, rather than presenting event counts alone. The comparison between the vaccine and placebo groups helps describe how often participants reported these events under the study conditions. It does not by itself establish the cause of an event for an individual participant, and the registry’s definition explicitly does not require that an event be considered related to vaccination.

The endpoint is limited to injection-site events during the specified follow-up window after Base Study vaccinations. It is not a measure of all adverse events, long-term safety, immunogenicity, or clinical protection. The registry lists seroconversion as a secondary outcome, but the primary endpoint result presented in the record is the injection-site event percentage. The analysis population was participants who received at least 1 vaccination and had available follow-up data.

7. Results Posted in the Registry

• 9vHPV Vaccine - Base Study: 91.1% (554/608) versus 43.9% (134/305) on control; risk difference 47.2 percentage points (95% CI 41.2 to 53.2), risk ratio 2.07 (1.82–2.36); unadjusted two-proportion z-test p = <0.001.

8. Statistical Interpretation

9. Statistical Methods Explained

The posted comparison is an unadjusted comparison of two participant-level proportions. For the primary endpoint, each participant is classified according to whether an injection-site adverse event was reported during the stated follow-up. The percentage for each arm describes the proportion of participants with an event, rather than the number of event episodes. The registry reports 91.1% for 9vHPV vaccine and 43.9% for placebo.

What does the risk difference describe?

The risk difference is the vaccine-group event proportion minus the placebo-group event proportion, expressed on a proportion scale in the registry’s comparison output. The estimate is 0.472, with a confidence interval from 0.412 to 0.532. It describes the absolute separation between the observed group proportions. A risk difference is useful because it stays on the original probability scale: it communicates how far apart the event frequencies were, rather than expressing the contrast only as a relative multiple.

The interval is a measure of statistical uncertainty around that estimated difference. It is not a range containing a fixed proportion of individual participant outcomes, nor a guarantee that the underlying value lies within the interval. Under the method’s assumptions, intervals constructed in this way would cover the underlying parameter at the stated confidence level over repeated studies. The assumptions and precise interval method are not reported in the registry record.

How should the p-value be read?

The registry reports an unadjusted p-value of <0.001 for the comparison. In general, a p-value assesses how compatible the observed data are with a specified null hypothesis under the statistical model and its assumptions. A small p-value indicates that data as different from the null as those observed would be uncommon if the null hypothesis and assumptions held. It does not provide the probability that the null is true, does not measure the size of the effect, and does not identify the cause of the events. The record does not describe a multiplicity adjustment for this result.

Why might relative measures differ from the risk difference?

The registry also reports a risk ratio of 2.074, with an interval from 1.823 to 2.36, and an odds ratio of 13.09, with an interval from 9.139 to 18.75. The risk ratio compares the event proportions as a ratio; the odds ratio compares the event odds. They are not interchangeable with the risk difference. When an event is common, an odds ratio can be farther from 1 than the corresponding risk ratio, so interpreting it as though it were a ratio of probabilities can mislead. These relative measures complement, rather than replace, the absolute difference in observed proportions.

What does over-dispersion mean in general?

Over-dispersion is a general statistical issue that arises when observed variability exceeds what a model assumes. It can make standard errors too small and confidence intervals too narrow if the model does not account for the extra variation. It is especially relevant for some count and clustered-data models. The primary endpoint is reported as a percentage of participants with an event, and the registry record does not state that an over-dispersion adjustment was used or was needed.

What can be said about analysis choices?

The result is identified as unadjusted. The registry record does not report a covariate-adjusted model, the detailed test used, handling of missing endpoint observations beyond the stated population definition, or whether other analysis populations were used. It also does not report whether there were interim analyses or how the primary analysis was prespecified. Those details should not be inferred from the p-value or the reported estimates. The interpretation should remain anchored to the endpoint definition, stated population, and reported Base Study comparison.

10. Confidence Intervals and Precision

The risk-difference estimate is 0.472, and its 95% confidence interval runs from 0.412 to 0.532. The interval indicates statistical uncertainty around the estimated difference in participant-level event proportions. Its endpoints are both positive, so the range of values compatible with this calculation does not include zero. This supports a difference in the observed proportions under the assumptions of the analysis, while leaving uncertainty about the exact size of that difference.

A confidence interval is not a statement that the true effect has a 95% probability of being inside this particular interval. In general, it is a procedure that would capture the underlying parameter at the stated rate over repeated samples when its assumptions hold. The interval’s width reflects both the information in the data and the method used. The specific interval procedure is not reported in the registry record.

Precision should be considered alongside the observed percentages and the population definition. The reported percentages are 91.1% for 9vHPV vaccine and 43.9% for placebo, among 608 and 305 participants, respectively. These figures describe the stated endpoint population and the follow-up window up to 5 days after any Base Study vaccination. They do not describe all possible events, later outcomes, or participants without available follow-up data.

The p-value of <0.001 addresses compatibility with a null hypothesis under test assumptions; it does not replace the interval as a way to understand effect-size uncertainty. Nor does statistical precision resolve limitations in how events were defined, observed, or reported. The registry record does not provide enough detail to assess all sources of measurement or analysis uncertainty. The confidence interval should therefore be read as precision for the reported unadjusted comparison, not as a complete measure of certainty about safety in every setting.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The planning figures are illustrations based on the observed effect, not the original trial design. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. Each planning scenario uses a stated fraction of the observed effect to detect. The figures are participants per arm for 80% power and participants per arm for 90% power; they are not total events.

For planning for 100% of the observed effect, the illustration gives 15 participants per arm for 80% power and 19 participants per arm for 90% power. For planning for 75% of the observed effect, it gives 29 participants per arm for 80% power and 38 participants per arm for 90% power. For planning for 50% of the observed effect, it gives 69 participants per arm for 80% power and 92 participants per arm for 90% power.

In plain terms, the 80% power column gives an illustrative group size intended to yield an 80% chance of detecting the stated effect under the planning assumptions, if that effect is real and the assumptions hold. The 90% column describes the corresponding target at 90% power. Smaller effects are harder to distinguish from random variation, so the illustrations require more participants per arm as the assumed effect becomes smaller. These are not observed power figures. The trial’s original design assumptions and sample-size justification are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.439; treatment proportion p₁ = 0.911; average p̄ = 0.675.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.6622 = 1.2980.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.5721 = 0.4815.
4. n = (1.2980 + 0.4815)² / (0.4718)² = 14.2, rounded up to 15 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.439344262295082                          # control proportion
p1 <- 0.911184210526316                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(1047345)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 15 (80% power), 19 (90% power)
 75% of observed effect: n per arm = 29 (80% power), 38 (90% power)
 50% of observed effect: n per arm = 69 (80% power), 92 (90% power)
power.prop.test: 14.2 
Simulated power at n = 15 per arm: 0.855 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary endpoint and a secondary outcome concerning seroconversion to each HPV type contained in the vaccine. It also reports 8 outcome measures and 10 analyses. Multiple outcomes or analyses can raise a multiplicity issue: when many statistical tests are considered, the chance of at least one apparently unusual result can increase if each is judged separately at the same threshold. Methods such as prespecifying a testing hierarchy or adjusting significance thresholds can address that general concern.

The registry record does not report whether a multiplicity adjustment was planned or applied, whether the listed secondary outcome was tested formally, or how the analyses were prioritized. The reported p-value for the primary comparison is unadjusted. It should not be represented as multiplicity-adjusted, and the absence of reported adjustment does not establish that no adjustment was used in other documents or analyses.

The primary endpoint population is stated as participants who received at least 1 vaccination and had available follow-up data. The record does not give a detailed missing-data strategy, the number lacking endpoint follow-up, or the assumptions used for any missing observations. It does not describe imputation or sensitivity analyses. The group counts for the endpoint are 608 and 305, while total enrollment was 924; those figures alone do not explain the reasons for any difference in counts, so attrition or exclusions should not be inferred.

The registry record does not report the full analysis population definitions, whether an intention-to-treat analysis was performed, or whether results were checked in other populations. It also does not state whether interim analyses took place. The endpoint comparison should therefore be interpreted using the population definition actually reported, without assuming additional methods or a particular approach to missing data and multiplicity.

14. 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: abdominal pain (1.0%), diarrhoea (1.0%), lumbar vertebral fracture (0.3%), thoracic vertebral fracture (0.3%), migraine (0.3%).

The Base Study serious adverse event figures are 3 among 608 participants in the 9vHPV Vaccine group and 3 among 305 participants in the Placebo group. In the Extension Study 9vHPV group, the registry reports 2 serious adverse events among 99 participants. These are participant counts in the serious-event fields; they are distinct from the primary endpoint, which concerns injection-site events.

The record also lists the most frequent serious adverse event terms and their reported percentages: Abdominal pain and Diarrhoea, each 1.0%; Lumbar vertebral fracture, Thoracic vertebral fracture, Migraine, and Abortion induced, each 0.3%. The registry does not specify the denominator or provide enough detail to determine whether participants could appear under more than one term. These entries should be read as reported event terms, not as a complete description of all safety outcomes.

Other adverse event counts are 566 among 608 in the Base Study vaccine group, 197 among 305 in the Base Study placebo group, and 0 among 99 in the Extension Study vaccine group. Death counts are not reported in the registry record. Counts do not by themselves establish causality or compare risk without considering the study’s definitions, follow-up, and analysis methods.

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

The primary result describes the proportion of participants reporting at least one injection-site adverse event up to 5 days after any Base Study vaccination. The reported proportions were 91.1% in the 9vHPV Vaccine group and 43.9% in the Placebo group. The unadjusted risk difference was 0.472, with a 95% confidence interval from 0.412 to 0.532 and a p-value of <0.001. The posted data therefore show a higher observed frequency of these events in the vaccine group than in the placebo group under the study conditions.

This result does not identify the cause of an event in any participant. The registry’s adverse-event definition includes events whether or not considered related to study vaccine, and the primary endpoint is based on participant reports within a specific follow-up window. The findings do not quantify events occurring outside that window, establish long-term safety, or describe every potential adverse outcome.

The result also does not answer whether the vaccine prevents HPV infection or HPV-related disease. Although the registry lists seroconversion as a secondary outcome and lists cervical cancers, vulvar cancers, vaginal cancers, and genital warts as conditions, the primary result is an injection-site event endpoint. It should not be treated as evidence for or against those clinical outcomes.

The comparison applies to females 12-26 years of age who had previously received GARDASIL™, within a randomized, double-blind, placebo-controlled Base Study. It should not automatically be generalized to people outside that population or to other schedules and settings. The registry record does not provide the original sample-size justification, detailed missing-data procedures, or a full statistical analysis plan, which limits assessment of some design and analysis choices.

16. Why This Trial Matters Statistically

This trial offers a useful example of how a binary safety endpoint can be described with more than a p-value. The endpoint is the percentage of participants experiencing an injection-site event, and the registry reports the group percentages, participant counts, an absolute risk-difference estimate, a confidence interval, and relative measures. Reading these together distinguishes the observed event frequency from the uncertainty around the comparison.

The result also illustrates why the endpoint definition matters. Events were counted when temporally associated with study vaccination, whether or not considered related to the vaccine, and the endpoint focused on injection-site reactions during a defined period after vaccination. A statistical comparison cannot correct for ambiguity in an endpoint definition; clear definitions are essential for understanding what a percentage represents.

The Base Study placebo comparison and the later Extension Study should not be conflated. Placebo participants could receive open-label vaccine in the Extension Study, while participants assigned vaccine did not continue to that extension. This matters when interpreting which groups belong in a randomized comparison and which safety counts describe a different study period.

Finally, the registry record offers a reminder that a small p-value is only one part of an interpretation. Effect size, interval precision, outcome definition, analysis population, multiplicity, missing data, and reporting detail all shape what can be concluded. In this record, several of those analysis details are not reported, so the statistical reading should remain specific to the posted Base Study endpoint and comparison.

17. 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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

The primary endpoint is limited to injection-site adverse events reported up to 5 days after any Base Study vaccination. It does not capture every possible safety outcome or establish the duration of events. The registry defines adverse events broadly and does not require that they be judged related to vaccination, so the endpoint should not be interpreted as a count of events confirmed to have been caused by the study vaccine.

The population was females 12-26 years of age who had previously received GARDASIL™. The result may not apply to populations with different ages or prior vaccination histories. The record reports the endpoint population as participants who received at least 1 vaccination and had available follow-up data, but does not give a detailed account of missing endpoint data, reasons for unavailable follow-up, or any sensitivity analysis.

The registry reports an unadjusted comparison, but the precise statistical test and confidence-interval method are not reported in the registry record. The original sample-size justification, analysis plan, covariate adjustments, interim analyses, and multiplicity approach are also not reported. These omissions limit the ability to evaluate prespecification and the full robustness of the analysis.

The record includes serious adverse event counts and selected terms, but it does not provide enough detail to determine the denominator for the listed term percentages or whether a participant could contribute to multiple terms. Death counts are not reported in the registry record. The primary endpoint and serious-event summaries also address different types of outcomes and should not be substituted for one another.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: A Study of V503, a 9-valent Human Papillomavirus (9vHPV) Vaccine in Females 12-26 Years of Age Who Have Previously Received GARDASIL™ (V503-006) — NCT01047345.
• Registry record last updated 2018-11-27; status last verified 2018-10.
• Results first posted 2014-12-22.
• 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.

21. Record Summary

NCT01047345 is a completed Phase III randomized, international, double-blind, placebo-controlled, parallel-group study of V503, a 9-valent HPV vaccine, in females 12-26 years of age who had previously received GARDASIL™. The registry records enrollment of 924 and identifies Merck Sharp & Dohme LLC as the sponsor. The recorded study start was 2010-02-24, and primary completion was 2011-06-10.

The primary endpoint was the percentage experiencing an injection-site adverse event up to 5 days after any Base Study vaccination. The reported percentages were 91.1% with 9vHPV vaccine and 43.9% with placebo. The unadjusted risk difference was 0.472, with a 95% confidence interval from 0.412 to 0.532 and p <0.001. The endpoint population consisted of participants who received at least 1 vaccination and had available follow-up data. The registry also lists seroconversion as a secondary outcome.