Safety Study of Herpes Simplex Vaccine in HSV Seronegative and Seropositive Females Between 10 and 17 Years Old: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety Study of Herpes Simplex Vaccine in HSV Seronegative and Seropositive Females Between 10 and 17 Years Old (NCT00224484), a randomized phase 3 study. The primary outcome is Number of Subjects With Serious Adverse Events (SAEs).

2. Clinical Question

The registry describes a safety and immunogenicity study, but the primary outcome addressed safety: the number of participants with SAEs during the period through Month 12. The registry definition includes medical occurrences resulting in death, being life threatening, requiring hospitalization or prolonging hospitalization, or resulting in disability or incapacity. The comparison therefore concerns observed participants with at least one qualifying event, rather than the total number of events or their duration.

The two comparator groups offer distinct reference points. Saline is the listed control for the primary safety objective, while Havrix is another study group. The registry record does not report the rationale for including each comparator or the planned statistical contrasts in detail. These results describe the recorded groups and the stated analysis population; they do not establish that the groups were equivalent on all characteristics or that any observed difference was caused by the intervention.

3. Trial Design

NCT00224484 is recorded as a completed phase 3, randomized, double-masked, parallel-group study sponsored by GlaxoSmithKline. The registry records enrollment of 5960. The study included female subjects aged 10-17 years who were HSV seronegative or seropositive. The recorded start date is 2004-04-07, and the primary completion date is 2007-07-24.

Three groups received three intramuscular doses in the deltoid region of the non-dominant arm on a 0, 1, 6 months schedule. The groups were gD2-AS04, Havrix (an investigational formulation), and saline. The registry record identifies randomization and double masking, but does not report the allocation ratio, the specific masking procedures, or how assignments were generated. Further details of these design features are not reported in the registry record.

The primary safety timeframe was Month 0 to Month 12. Its analysis population was the Total Vaccinated cohort, defined as subjects who received at least one dose and for whom data were available. The posted group denominators for this outcome are 2977.0 for gD2-AS04, 1491.0 for Havrix, and 1487.0 for saline. These are the denominators attached to the posted primary results; the registry record does not explain their relationship to the overall enrollment in further detail.

The registry also describes an extended safety follow-up period from Month 12 to Month 18 and reports a medically significant conditions outcome for that period. Its posted groups are gD2-AS04 and pooled. Other secondary outcomes concern solicited symptoms, unsolicited adverse events, medically attended visits, new onset chronic diseases, and laboratory abnormalities. The registry record does not provide the original protocol's sample-size justification, planned interim analyses, detailed statistical analysis plan, or fuller methods for follow-up and outcome ascertainment.

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.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analyses were performed on the Total Vaccinated cohort, which included all subjects who received at least one dose of the study vaccine and for whom data were available.

5. Baseline Characteristics

The table reproduces the baseline characteristics posted in the registry, which describe the participants analysed at baseline and help show whether the randomized groups were comparable.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Serious Adverse Events (SAEs), measured over From Month 0 to Month 12.

The primary endpoint is the number of participants with serious adverse events from Month 0 to Month 12. The registry defines an SAE as a medical occurrence that results in death, is life threatening, requires hospitalization or prolongation of hospitalization, or results in disability or incapacity. The outcome is a participant count: each group result records how many participants met the SAE definition, with the group denominator representing the participants in the analysis population.

SAEs are used in safety assessment because the definition focuses on serious clinical consequences, rather than every symptom or event reported during follow-up. This endpoint provides a broad summary across different medical events. It does not, by itself, indicate whether events were related to study treatment, how severe events were beyond meeting the SAE definition, when they occurred, or whether a participant experienced more than one event. Those details require separate reporting.

The analysis population included subjects who received at least one dose and for whom data were available. The primary timeframe ended at Month 12, so the outcome does not represent all follow-up described in the registry; an extended safety follow-up period ran from Month 12 to Month 18. The registry record does not report a more detailed primary endpoint analysis plan or a definition of how recurrent events were handled. The count should therefore be read as the posted number of participants with SAEs, not as a comparison of event rates per unit of time or a complete characterization of safety.

7. Results Posted in the Registry

• Havrix Group: 2.8% (42/1491) versus 2.4% (71/2977) on control; risk difference 0.4 percentage points (95% CI -0.6 to 1.4), risk ratio 1.18 (0.81–1.72); unadjusted two-proportion z-test p = 0.386.
• Saline Group: 2.5% (37/1487) versus 2.4% (71/2977) on control; risk difference 0.1 percentage points (95% CI -0.9 to 1.1), risk ratio 1.04 (0.70–1.54); unadjusted two-proportion z-test p = 0.832.

8. Secondary Efficacy Endpoints

The registry also posts results for secondary outcomes. For each outcome below, the endpoint type, the test applied to the posted summary statistics, the result and its interpretation are given in turn. Secondary endpoints are usually not adjusted for multiple testing, so they support rather than confirm the primary finding.

Number of Subjects With New Onset Chronic Diseases (NOCD)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Havrix Group: 0.7% (10/1491) versus 0.8% (23/2977) on control; risk difference -0.1 percentage points (95% CI -0.6 to 0.4), risk ratio 0.87 (0.41–1.82); unadjusted two-proportion z-test p = 0.708.
  • Saline Group: 0.7% (11/1487) versus 0.8% (23/2977) on control; risk difference -0.0 percentage points (95% CI -0.6 to 0.5), risk ratio 0.96 (0.47–1.96); unadjusted two-proportion z-test p = 0.905.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Havrix Group and the control. The interval gives the range of effects that remain compatible with the data.
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Saline Group and the control. The interval gives the range of effects that remain compatible with the data.

Number of Subjects With Medically Significant Conditions (MSC)

• Endpoint type: Binary: the number of participants with the event, compared as proportions.
• Test: Unadjusted two-proportion z-test, with a Wald 95% confidence interval for the risk difference.
• Result:
  • Pooled Group: 2.5% (73/2978) versus 2.3% (69/2977) on control; risk difference 0.1 percentage points (95% CI -0.6 to 0.9), risk ratio 1.06 (0.76–1.46); unadjusted two-proportion z-test p = 0.736.
• Interpretation:
  • The 95% confidence interval includes no difference, so these data do not show a statistically significant difference between Pooled Group and the control. The interval gives the range of effects that remain compatible with the data.

The registry lists 18 secondary outcomes spanning solicited local and general symptoms, unsolicited adverse events, medically attended visits, new onset chronic diseases, laboratory abnormalities, and safety follow-up. The posted results include comparisons for new onset chronic diseases during the active phase through Month 12 and medically significant conditions during extended safety follow-up from Month 12 to Month 18. Across these additional comparisons, the reported risk-difference intervals include zero, and the unadjusted p-values do not provide a clear signal of a difference. They add context to the safety record but do not resolve the uncertainty in the primary SAE comparison.

Secondary outcomes answer related but distinct questions. Symptom reports, medically attended events, chronic diseases, laboratory abnormalities, and medically significant conditions are not interchangeable with SAEs. Each outcome has its own definition, timeframe, and analysis population. The secondary findings should therefore be interpreted on their own terms, rather than treated as direct replications of the primary endpoint.

The registry record lists no reported analysis entries, and it does not report a multiplicity adjustment plan. General statistical explanation: when many outcomes and comparisons are considered, unadjusted results have a greater chance of producing an apparently notable finding by chance. This makes isolated secondary results less persuasive than a clearly prespecified primary analysis, particularly when the analysis plan and the status of each comparison are not documented. The broad consistency of estimates that remain uncertain may be reassuring as descriptive context, but it does not prove equivalence or exclude meaningful differences.

The secondary outcomes should be viewed as a set of additional safety observations rather than as a series of independent confirmatory tests. The registry record does not provide enough information about prespecification, missing data, or analysis methods to assess how much weight each finding should carry.

Secondary outcomes registered for this trial, for reference (only those above were recalculated):

• Number of Subjects With Any and Grade 3 Solicited Local Symptoms
• Number of Subjects With Any, Grade 3 and Related Solicited General Symptoms
• Number of Subjects With Any, Grade 3 and Related Unsolicited Adverse Events (AEs)
• Number of Subjects With Unsolicited Adverse Events (AEs) With Medically Attended Visits
• Number of Subjects With New Onset Chronic Diseases (NOCD)
• Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed
• Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed
• Number of Subjects Reporting Clinically Relevant Abnormalities in Biochemical and Haematological Laboratory Parameters Assessed

9. Statistical Interpretation

10. Statistical Methods Explained

The outcome is binary at the participant level: a subject either was or was not reported as having an SAE during the stated period. The posted counts and denominators describe the observed frequency in each group. For example, the primary outcome lists 71 participants with SAEs among 2977.0 in the gD2-AS04 group. The registry record does not provide the individual participant data, so a reader cannot independently examine event timing, repeated events, or patterns of missing follow-up.

What does a risk difference express?

General statistical explanation: a risk difference compares the proportion of participants with an event in one group with the proportion in another. A value of zero corresponds to equal observed proportions. The posted primary comparison with Havrix has a risk difference of 0.004; the comparison with saline has a risk difference of 0.001. The direction depends on the ordering of the groups used in the comparison. In both posted comparisons, the confidence interval extends across zero, so the range of values compatible with the estimate includes no difference.

The registry also posts risk ratios and odds ratios for these contrasts. General statistical explanation: a risk ratio compares the event proportions as a ratio, while an odds ratio compares the odds of an event. Ratios are interpreted relative to one, which represents no difference on the ratio scale. These measures can express the same group contrast on different scales; they do not change the underlying participant counts. The primary interpretation emphasizes the risk differences and their confidence intervals.

What do the p-values tell the reader?

General statistical explanation: a p-value describes how incompatible the observed data are with a specified null model, under the assumptions of the statistical test. It is not the probability that the null hypothesis is true, nor a measure of the size or clinical importance of a difference. The posted unadjusted p-values are 0.386 for gD2-AS04 versus Havrix and 0.832 for gD2-AS04 versus saline. The registry record does not report the exact test or all assumptions used to obtain these p-values. Because the values are unadjusted, they do not account for a reported correction across multiple outcomes or comparisons.

A confidence interval gives a range of estimates compatible with the observed data under the method used to construct it. General statistical explanation: the interval reflects sampling uncertainty and depends on the analysis assumptions; it is not a range that guarantees the true value lies within it. For the primary contrasts, the reported intervals include zero. Their width also matters: an interval spanning values on both sides of zero leaves uncertainty about whether the underlying difference is positive, negative, or negligible. The registry record does not specify the confidence-interval method.

Why distinguish counts from event totals?

The primary result counts participants with at least one SAE. It is not a count of every SAE occurrence. A participant with more than one qualifying event would still contribute to the number of participants with an event, according to the outcome's stated unit. The registry record does not describe recurrent-event analyses or the rules for grouping multiple events. As a result, these statistics do not characterize the total burden of events or compare event frequency over person-time.

The posted analysis population is the Total Vaccinated cohort, comprising subjects who received at least one dose and for whom data were available. This is different from simply describing everyone enrolled. General statistical explanation: defining a population for analysis determines which participants contribute to an estimate, and exclusions or unavailable outcome data can affect how representative that estimate is. The record does not report the number of participants with missing primary outcome data, how missing data were handled, or whether any sensitivity analyses were conducted.

What can be concluded about the analysis plan?

The registry records a randomized, double-masked, parallel-group design and posts unadjusted comparisons. It does not report the original sample-size justification or a detailed statistical analysis plan. It also records no reported analysis entries. The comparison statistics can therefore be described as posted results, but the exact inferential procedures, covariate adjustment, assumptions, and prespecified status of each contrast are not reported in the registry record.

General statistical explanation: randomization can help balance prognostic characteristics on average, while masking can reduce some opportunities for biased care or assessment. These design labels do not establish that masking was maintained or that all imbalances were eliminated. The registry record does not provide enough detail to assess these processes. Likewise, a parallel-group design means participants are assigned to groups that are followed as separate groups; it does not by itself specify allocation proportions, analysis methods, or adherence to assigned doses.

The report includes comparisons for two control groups and several secondary outcomes. General statistical explanation: when many outcomes or contrasts are examined, the chance of observing apparently unusual results can increase unless the analysis accounts for multiplicity or clearly distinguishes primary from exploratory questions. The registry record does not report a multiplicity plan. Consequently, the unadjusted secondary statistics should be regarded as exploratory evidence rather than as independent confirmation of the primary result.

11. Confidence Intervals and Precision

The two primary confidence intervals include zero: -0.006 to 0.014 for gD2-AS04 versus Havrix and -0.009 to 0.011 for gD2-AS04 versus saline. Their point estimates are 0.004 and 0.001, respectively. Because the intervals extend to both negative and positive values, the posted data do not pin down the direction of the underlying risk difference. A value of zero remains among the estimates compatible with each interval.

The intervals also include values that are not identical to the point estimates. This is the practical meaning of precision: the point estimate is a single summary of the observed groups, while the interval communicates uncertainty around it under the analysis method. The width of an interval should be considered alongside the estimate and the outcome definition. A confidence interval is not a guarantee that the true effect is inside its limits, and it does not state the probability that any particular effect is true.

The registry record does not report the method used to calculate these intervals, whether the comparisons were adjusted, or whether missing outcomes affected the estimates. Those omissions limit independent assessment of the precision calculations. The groups include 2977.0 participants in gD2-AS04, 1491.0 in Havrix, and 1487.0 in saline; the endpoint counts are 71, 42, and 37, respectively. Precision depends on the event information as well as the denominators, so the group sizes alone do not determine how conclusive the comparisons are.

Neither interval demonstrates equivalence or non-inferiority. Such conclusions require a prespecified margin and a suitable analysis, neither of which is reported in the registry record. The confidence intervals are best read as evidence of uncertainty around the estimated risk differences, not as proof of sameness or a formal safety threshold.

12. 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 sample-size table and curve are planning illustrations based on the observed effect, not the original design calculation. For the primary binary outcomes, the figures are participants per arm, not total events. The listed assumptions are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is the stated fraction of the observed effect. The registry record does not report the trial's own original sample-size assumptions or justification.

The 80% power column gives the illustrative number of participants per arm for a design with an 80% chance of detecting the specified effect under those assumptions, if the effect and model assumptions are correct. The 90% power column gives the corresponding planning number for a 90% chance. Power is a property of a planned study under assumed conditions; it is not the probability that a result is true or that a treatment is beneficial.

The rows for 100%, 75%, and 50% of the observed effect consider progressively smaller target effects. Smaller effects require more participants to distinguish them from random variation at the stated significance level and power. The figures can therefore become very large when the observed difference is small. This is not observed power: it is a planning exercise that uses the observed effect as an input, and it does not report the probability that the completed study detected a true effect.

The registry record does not report whether the trial was originally planned around this endpoint, another outcome, or a different statistical objective. These illustrations should not be read as evidence that the trial was adequately or inadequately sized under its original protocol.

13. 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 = 0.024; treatment proportion p₁ = 0.028; average p̄ = 0.026.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.2251 = 0.4412.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.2251 = 0.1894.
4. n = (0.4412 + 0.1894)² / (0.0043)² = 21,312.3, rounded up to 21,313 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 <- 0.0238495129324824                          # control proportion
p1 <- 0.028169014084507                          # 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(224484)
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 = 21,313 (80% power), 28,531 (90% power)
 75% of observed effect: n per arm = 37,124 (80% power), 49,698 (90% power)
 50% of observed effect: n per arm = 81,804 (80% power), 109,512 (90% power)
power.prop.test: 21312.3 
Simulated power at n = 21,313 per arm: 0.798 (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.

14. Multiplicity, Missing Data and Analysis Populations

The registry record identifies a primary safety outcome and lists 18 secondary outcomes, but does not report a detailed statistical analysis plan. It does not state whether the secondary outcomes were prespecified in the same form as posted, whether all comparisons were intended to be confirmatory, or whether any hierarchy of testing was used. A multiplicity adjustment plan is not reported. The posted comparison p-values are unadjusted.

General statistical explanation: multiplicity arises when multiple hypotheses are tested. Without an adjustment or a prespecified strategy, the chance of at least one small p-value across a collection of tests can be greater than for a single test. This does not mean that every unadjusted result is false; it means that the evidential weight of an isolated secondary result is harder to judge. A distinction between a primary endpoint and exploratory secondary outcomes helps organize interpretation, but it cannot replace information about the planned testing procedure.

The registry record does not report the extent of missing primary or secondary outcome data, reasons for missingness, or the method used to handle unavailable outcomes. The primary analysis population is described as subjects who received at least one dose and for whom data were available. That definition identifies the cohort but does not explain how data availability was established or how participants without available data were treated. No missing-data sensitivity analysis is reported in the record.

The record also does not describe interim analyses, stopping rules, covariate adjustment, or detailed statistical methods for the posted comparisons. These omissions prevent a full audit of whether the reported tests and intervals correspond to the original plans. They do not invalidate the posted counts; they limit what can be concluded about confirmatory inference.

The primary cohort is not described as an intention-to-treat population. It is specifically the Total Vaccinated cohort. The registry record does not provide enough detail to compare estimates across alternative populations or to assess the effects of exclusions from this analysis set. Accordingly, the results should be understood as applying to the reported cohort and available data, not automatically to every enrolled subject.

15. 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: appendicitis (0.4%), abortion spontaneous (0.3%), depression (0.3%), suicide attempt (0.2%), migraine (0.1%).

The primary safety result counts participants with at least one serious adverse event during Month 0 to Month 12. The posted counts are 71 among 2977.0 in the gD2-AS04 group, 42 among 1491.0 in the Havrix group, and 37 among 1487.0 in the saline group. The comparison estimates and confidence intervals indicate uncertainty in the differences between groups; neither primary interval excludes zero.

The serious-event definition includes death, life-threatening events, hospitalization or prolonged hospitalization, and disability or incapacity. The registry's adverse-event listing reports zero deaths in each listed group. The most frequently listed serious-event terms include appendicitis, abortion spontaneous, depression, suicide attempt, migraine, and pharyngotonsillitis, with the corresponding posted percentages of 0.4%, 0.3%, 0.3%, 0.2%, 0.1%, and 0.1%. These terms describe reported event categories and do not establish treatment relationship.

Counts of participants with serious events are not the same as counts of all events, and they do not convey event timing, recurrence, or attribution. The registry record does not report a causal assessment for individual events in the primary comparison. These figures describe the posted safety observations and their uncertainty; they do not by themselves settle whether the groups had the same safety profile.

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

The results establish what was recorded for the analyzed groups during the specified timeframe: 71 participants in the gD2-AS04 group, 42 in the Havrix group, and 37 in the saline group were reported with SAEs. The posted risk-difference estimates are small and their confidence intervals include zero. The data therefore leave uncertainty about the direction and size of the underlying difference between gD2-AS04 and either comparator.

A p-value above a conventional threshold is not proof that groups are identical. Likewise, an interval including zero does not show that there is no possible difference. It means that, under the analysis method used, the data are compatible with a range of risk differences that includes zero. The registry record does not report an equivalence or non-inferiority margin, so these results cannot support a formal claim of equivalence or non-inferiority.

The findings also do not establish that an observed event was caused by a study intervention. The primary endpoint includes serious events across medical categories, and the registry record does not report individual-level causal assessments in the comparison. Counts do not describe event severity beyond the qualifying SAE definition, time to occurrence, repeated events, or total event burden.

The results apply to the reported Total Vaccinated cohort and the Month 0 to Month 12 primary period. They should not automatically be generalized to all enrolled participants, other populations, other timeframes, or outcomes not measured in this comparison. The registry record does not report enough detail about missing data, the exact inferential methods, or the original statistical plan to make a more complete assessment of robustness.

The secondary safety outcomes provide related observations, but they are distinct outcomes and are reported without a documented multiplicity strategy. They can inform description of the study's recorded safety experience, not independently confirm the primary comparison. No medical advice or treatment recommendation follows from these statistics alone.

17. Why This Trial Matters Statistically

This study illustrates why safety comparisons require more than a glance at event counts. The group denominators differ, and the principal comparison is expressed through risk differences with confidence intervals. The point estimates alone do not show how uncertain the comparisons are; the intervals indicate that the observed data are compatible with more than one direction of difference.

It also highlights the importance of distinguishing a serious-event participant count from an event total. A broad endpoint can capture clinically consequential events, but it combines different medical categories and does not show frequency per person-time, recurrence, timing, or attribution. Those questions need distinct reporting and analyses.

The record makes several design features clear—randomization, double masking, parallel groups, and the three-dose schedule—while leaving other essential statistical details unreported. The absence of a reported original sample-size justification, detailed analysis plan, multiplicity approach, and missing-data methods limits how confidently the posted inferential statistics can be connected to prespecified objectives. This is a useful reminder that registry transparency is part of statistical interpretability.

Finally, the planning illustrations demonstrate the sensitivity of sample-size requirements to the target effect. Planning for a smaller effect requires more participants under the stated assumptions. Those calculations are not a measure of the completed study's observed power and do not substitute for the trial's original design rationale, which is not reported in the registry record.

18. Limitations

• The posted summary statistics are the only data these results rest on; patient-level data, full protocols and statistical analysis plans are not available.
• Recalculated results are simple, unadjusted calculations from posted summaries. They do not replace the sponsor's prespecified analysis.

Several trial-specific limitations follow from the information recorded. The primary endpoint is a broad participant-level SAE count, which does not describe event timing, recurrent events, event duration, or causal attribution. Although the registry lists serious-event terms, the posted primary comparison does not provide a detailed breakdown of outcomes by group or a case-level assessment.

The primary analysis uses the Total Vaccinated cohort, rather than a population explicitly identified as all randomized participants. The cohort is defined as subjects who received at least one dose and for whom data were available. The registry record does not report how many randomized subjects were excluded from this cohort, whether primary outcome data were missing, or how missing data were handled.

The registry record does not report the original sample-size calculation, the statistical analysis plan, interim analyses, the exact methods used for the confidence intervals and p-values, or a multiplicity procedure. Although the design is described as randomized and double-masked, allocation details and masking procedures are not reported. These gaps limit assessment of prespecification and robustness.

There are multiple secondary outcomes and more than one comparator, while the posted p-values are unadjusted. The registry does not explain the intended inferential role of every comparison. Secondary findings should therefore be interpreted cautiously, especially as evidence from a collection of outcomes rather than as independent confirmatory results.

Finally, the posted results concern specified groups and follow-up periods. The primary comparison ends at Month 12, while the registry separately identifies an extended safety follow-up through Month 18. These periods and their analysis groups should not be combined without an analysis plan. The registry record does not provide enough information to evaluate longer-term outcomes beyond the stated follow-up or generalize to populations outside the enrolled age and sex group.

19. Related Tutorials

20. Related Statistical Calculators

21. Sources

• ClinicalTrials.gov: Safety Study of Herpes Simplex Vaccine in HSV Seronegative and Seropositive Females Between 10 and 17 Years Old — NCT00224484.
• Registry record last updated 2019-01-07; status last verified 2019-01.
• Results first posted 2017-04-10.
• 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.

22. Record Summary

NCT00224484 is a completed phase 3, randomized, double-masked, parallel-group study of gD2-AS04 in healthy HSV seronegative and seropositive female subjects aged 10-17 years. The registry records enrollment of 5960 and a three-dose schedule at 0, 1, 6 months for gD2-AS04, Havrix, and saline groups.

The primary outcome was the number of participants with SAEs from Month 0 to Month 12 in the Total Vaccinated cohort. Posted counts were 71 of 2977.0 for gD2-AS04, 42 of 1491.0 for Havrix, and 37 of 1487.0 for saline. Both primary risk-difference confidence intervals include zero. The registry record does not report the original sample-size justification, a detailed statistical analysis plan, missing-data handling, or a multiplicity strategy.