A Study to Test the Safety and Antibody Response of V212 in Healthy Adults (V212-004)(COMPLETED): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Test the Safety and Antibody Response of V212 in Healthy Adults (V212-004)(COMPLETED) (NCT00696709), a randomized phase 1 study. The primary outcome is Percentage of Participants With a Serious Adverse Event.

2. Clinical Question

The primary endpoint is a safety measure, not a direct measure of prevention of herpes zoster or other clinical disease. The study’s stated hypotheses concerned whether the vaccine formulations would elicit an acceptable VZV-specific immune response; the primary posted result discussed in this analysis is the percentage with a serious adverse event. A secondary outcome concerning geometric mean fold rise in heat-treated VZV-specific immune responses measured by gpELISA is listed, but its numerical result is not reported in the registry record.

The formulation groups represent distinct study regimens and should not be treated as if they were one pooled intervention. Part 1 separates heat-treated vaccine A, gamma-irradiated vaccine A, and placebo. Part 2 examines gamma-irradiated vaccines B and C. The available placebo comparisons are for the two Part 1 formulations with posted sponsor analyses and for the corresponding Part 1 groups in the recalculations.

3. Trial Design

This was a randomized, double-blind, placebo-controlled Phase I clinical trial with a parallel-group design. The registry record identifies 290 participants as enrolled and lists the study as completed. It describes two study parts and five groups: heat-treated VZV vaccine A, gamma-irradiated VZV vaccine A, placebo, gamma-irradiated VZV vaccine B, and gamma-irradiated VZV vaccine C.

In Part 1, participants received one of the two vaccine A regimens or placebo. In Part 2, the two listed groups received gamma-irradiated vaccine B or vaccine C. Vaccine groups were described as receiving an 0.65 mL subcutaneous injection in a four-dose regimen administered approximately 30 days apart. The placebo group also followed a four-dose regimen administered approximately 30 days apart. The registry record does not describe a Part 2 placebo group.

Randomization and double masking help structure comparisons by assigning participants to groups and limiting awareness of assigned treatment. Those design features do not, by themselves, resolve the uncertainty created by the small number of serious events. The primary safety population was defined by actual vaccination received: participants had to have received at least one dose and have safety follow-up, and those who received an incorrect vaccination were excluded.

The primary endpoint was the percentage of participants with one or more serious adverse events during follow-up up to approximately 28 days after dose 4, or up to approximately 118 days. The registry record defines a serious adverse event as one resulting in death, being life threatening, causing persistent or significant disability or incapacity, resulting in or prolonging hospitalization, or involving a congenital anomaly or birth defect. The purpose also included assessment of tolerability and immunogenicity, with VZV-specific antibody response measured by gpELISA.

The registry record does not report the randomization method, allocation ratio, stratification factors, or the details of the masking procedures. A sample-size justification and a complete statistical analysis plan are not reported in the registry record. These omissions limit how specifically the planned design and analysis can be reconstructed from the posted information.

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: In Part 1, all participants received heat-treated varicella zoster virus (VZV) vaccine, gamma-irradiated VZV vaccine A or placebo administered as a 4-dose regimen approximately every 30 days. In Part 2, all participants received either gamma-irradiated VZV vaccine B or C administered as a 4-dose regimen approximately every 30 days.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis population included all gamma-irradiated VZV vaccine A participants who received all 4 vaccinations with no protocol deviations; heat-treated VZV vaccine, vaccine B, vaccine C and placebo participants were not assessed for this outcome.

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 With a Serious Adverse Event, measured over Up to ~28 days Postdose 4 (Up to ~118 days).

The primary endpoint is the percentage of participants with at least one serious adverse event. It is a binary participant-level outcome: each participant either met the serious-adverse-event definition during the stated follow-up or did not. Counting participants with one or more events avoids treating repeated events in the same person as separate participants for this endpoint.

The registry definition covers events with major consequences, including death, life-threatening events, persistent or significant disability or incapacity, hospitalization or prolonged hospitalization, and congenital anomalies or birth defects. The endpoint is therefore intended to capture serious safety outcomes rather than every symptom or adverse event. The registry separately reports other adverse events, but those are not the primary endpoint.

For a safety study, reporting the proportion of participants with a serious event makes the observed burden visible within each study group. Comparisons with placebo can describe how the observed proportions differ, but interpretation depends on the number of participants and events as well as the uncertainty around each estimate. When events are rare, a group with no observed events can still have uncertainty about the underlying event risk. A zero count is an observation in this trial, not proof that the underlying risk is zero.

The endpoint is not a measure of vaccine-induced antibody response or clinical protection. The registry describes gpELISA antibody responses and a secondary outcome based on geometric mean fold rise, but those address immunogenicity rather than serious adverse events. The numerical result for that secondary outcome is not reported in the registry record.

7. Results Posted in the Registry

• Part 1: Heat-treated Varicella-Zoster Virus (VZV) Vaccine: 0.0% (0/64) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.
• Part 1: Gamma-Irradiated VZV Vaccine A: 1.6% (1/61) versus 0.0% (0/32) on control; risk difference 1.6 percentage points (95% CI -1.5 to 4.8); unadjusted two-proportion z-test p = 0.466.
• Part 2: Gamma-Irradiated VZV Vaccine B: 1.6% (1/63) versus 0.0% (0/32) on control; risk difference 1.6 percentage points (95% CI -1.5 to 4.7); unadjusted two-proportion z-test p = 0.474.
• Part 2: Gamma-Irradiated VZV Vaccine C: 0.0% (0/65) versus 0.0% (0/32) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

General: binary outcomes. A binary outcome records whether each participant experienced the event of interest. For this endpoint, the event is at least one serious adverse event during the defined follow-up. A percentage describes the proportion of participants with the event in a group. The registry reports the event percentage and group size for each arm; interpreting a percentage requires attention to how many participants contributed and how many events occurred.

General: risk differences. A risk difference subtracts the event proportion in one group from the event proportion in another. It is expressed on the same underlying proportion scale as the outcome. A value of zero represents no observed difference between the two proportions. A positive estimate means the event proportion is higher in the comparison group named in the calculation; a negative estimate means it is lower. This direction is descriptive and does not by itself establish a causal effect or clinical importance.

The recalculated comparisons use the placebo group as the reference and are simple, unadjusted calculations from the posted summary statistics. They are not a substitute for the sponsor’s own analysis. For gamma-irradiated vaccine A, the recalculated risk difference is 0.016 and its 95% confidence interval is -0.015 to 0.048. For gamma-irradiated vaccine B, the recalculated estimate is 0.016 and its interval is -0.015 to 0.047. The corresponding unadjusted p-values are 0.466 and 0.474. These results do not establish a difference from placebo, and no adjustment for testing multiple comparisons is reflected in those p-values.

General: confidence intervals. A confidence interval communicates the uncertainty around an estimated effect under the assumptions of the method used. It gives a range of values reasonably compatible with the data and analysis procedure. It is not a guarantee that the true value lies within the interval, nor does it assign a probability to each value inside it. When an interval includes zero for a difference, the data are compatible with no difference, while also allowing effects in either direction across the interval.

Rare outcomes require particular care. With few events, estimates can change substantially when only a small number of observations differ. If neither group has an observed event, a simple calculation based only on the observed event proportions yields a difference of zero. That observed equality does not imply that the underlying event rates are known without uncertainty. The zero-width recalculated intervals for comparisons involving the heat-treated vaccine A or vaccine C groups arise from zero observed events in both groups under this simple calculation. They should not be read as evidence of perfect precision.

General: p-values. A p-value describes how unusual data at least as discrepant as those observed would be under a specified null model and analysis. It is not the probability that the null hypothesis is true, nor a measure of the size or importance of an effect. The recalculated values, p = 0.466 and p = 0.474, are unadjusted. A p-value above a conventional threshold does not prove equality; it indicates that these data do not provide strong evidence against the null under the calculation used.

The sponsor’s posted comparisons use the label Difference in Percentage and report 95% confidence intervals. For heat-treated vaccine A versus placebo, the reported estimate is 0.0 with an interval from -10.8 to 5.7. For gamma-irradiated vaccine A versus placebo, the estimate is 1.6 with an interval from -9.2 to 8.8. The method is not reported in the registry record. These estimates and intervals are presented in percentage units, while the recalculated risk differences are expressed on a proportion scale. The numerical formats should not be compared without accounting for their units, and the record does not provide enough method detail to reproduce the sponsor’s interval procedure.

General: over-dispersion. Over-dispersion occurs when observed variation is greater than a statistical model expects. It can matter for count or rate outcomes when events are more variable across participants or groups than the model assumes, because standard errors may then be too small if that extra variation is ignored. The primary endpoint is a participant-level binary outcome, and the registry record does not report an over-dispersion adjustment. There is no basis in the record to infer that one was used.

The sample-size assumptions describe planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation; the target effect is a stated fraction of the observed effect. These are planning illustrations, not the trial’s original design justification and not observed power. The sample-size justification for this trial is not reported in the registry record. The precise planning values are not restated in this explanatory text.

The registry record reports 9 outcome measures and 14 analyses. Multiple outcomes and comparisons can create multiplicity: as the number of statistical tests increases, the chance of at least one apparently unusual result can increase if each is judged separately. The record does not report whether the analyses were prespecified in a complete plan, whether any multiplicity procedure was used, or whether there were interim analyses. No details should be inferred from the number of posted analyses alone.

10. Confidence Intervals and Precision

Precision is limited by the small number of serious events. One event was observed in each of the gamma-irradiated vaccine A and vaccine B groups, while no events were observed in the other listed groups. Group sizes ranged from 32.0 to 65.0. When events are this sparse, the point estimate can be sensitive to a single participant, and a zero count does not rule out an underlying event risk.

The recalculated 95% confidence intervals for gamma-irradiated vaccine A and vaccine B both include zero. For vaccine A, the interval is -0.015 to 0.048; for vaccine B, it is -0.015 to 0.047. Those intervals span values consistent with no difference and values in either direction. They do not provide a narrow estimate of the size of any difference.

The sponsor-reported 95% intervals for the two posted Part 1 comparisons also include zero: -10.8 to 5.7 for heat-treated vaccine A versus placebo, and -9.2 to 8.8 for gamma-irradiated vaccine A versus placebo. The registry record does not report the method behind those intervals. They are expressed in percentage units and should be interpreted as reported rather than assumed to arise from the same calculation as the unadjusted recalculations.

For comparisons where both groups had zero observed events, the simple recalculation produces an estimate of 0.0 and an interval from 0.0 to 0.0. This apparent exactness is a limitation of the calculation with zero counts, not evidence that the true group risks are known exactly. The sponsor-reported interval for heat-treated vaccine A versus placebo is wider and includes values on both sides of zero, illustrating that the method used can matter, particularly with sparse events.

Confidence intervals describe statistical uncertainty under their analysis assumptions; they do not cover all limitations, such as restricted population, short stated follow-up, or unreported analysis details. The available results support cautious description of observed events, not a precise estimate of rare-event risk.

11. Analyses Reported by the Sponsor

The registry record reports sponsor analyses for two Part 1 comparisons. For heat-treated vaccine A versus placebo, the reported difference in percentage is 0.0, with a 95% confidence interval from -10.8 to 5.7. For gamma-irradiated vaccine A versus placebo, the reported difference is 1.6, with a 95% confidence interval from -9.2 to 8.8. No sponsor-reported p-values are listed for these comparisons, and the method used for the intervals is not reported in the registry record.

The unadjusted recalculation for gamma-irradiated vaccine A gives a risk difference of 0.016, with a 95% confidence interval from -0.015 to 0.048 and p = 0.466. The sponsor estimate of 1.6 is expressed in percentage units, while the recalculated estimate is expressed on a proportion scale. Both estimates indicate a small observed difference, but the interval widths and limits are not the same. The available information does not identify the reason for that difference, so it cannot be resolved by assuming that the methods were identical.

For heat-treated vaccine A, the recalculation is zero because there were no observed serious adverse events in either that group or placebo. The sponsor reports a 0.0 difference but gives an interval from -10.8 to 5.7. The recalculated zero-width interval is not an equivalent account of uncertainty. The sponsor’s interval communicates uncertainty that the simple recalculation does not capture in this zero-event comparison.

The sponsor analyses and the recalculations answer closely related descriptive questions but are not interchangeable. The registry record does not report enough methodological detail to reproduce the sponsor’s intervals or determine precisely why they differ. The posted sponsor results should therefore be read as the sponsor’s reported analysis, while the recalculations remain simple, unadjusted analyses of the posted summary statistics.

12. Multiplicity, Missing Data and Analysis Populations

The record lists 9 outcome measures and 14 analyses. It identifies a primary serious-adverse-event endpoint and lists one secondary outcome concerning geometric mean fold rise in heat-treated VZV-specific immune responses measured by gpELISA. The numerical result for that secondary outcome is not reported in the registry record. The record does not provide a complete account of which analyses were prespecified, how the outcome hierarchy was handled, or whether any multiplicity adjustment was planned or applied.

Multiplicity matters because conducting several tests can increase the chance of at least one apparently notable result when each test is assessed separately. The two unadjusted p-values reported in the recalculations should be interpreted as individual comparison results, not as results adjusted for the full set of outcomes and analyses. The registry record does not report a multiplicity correction, so none should be assumed. Interim analyses are not reported in the registry record.

The primary safety population included participants who received at least one dose and had safety follow-up, using the vaccination actually received. Participants who received an incorrect vaccination were excluded. This defines the population for the posted primary endpoint, but the record does not report the number excluded for incorrect vaccination, the amount of missing safety follow-up, or how missing observations were handled. It also does not report whether the number analyzed differed from the number randomized in each group.

The listed arm sizes for the primary endpoint are the numbers contributing to the reported outcome. These group sizes do not, by themselves, reveal whether any participants lacked follow-up or whether exclusions occurred before analysis. Details of missing-data assumptions, imputation, sensitivity analyses, and handling of protocol deviations are not reported in the registry record.

These gaps limit assessment of the analysis’s robustness and the extent to which the posted comparisons reflect a prespecified testing strategy. The available material supports interpretation of the reported endpoint and comparisons, but not reconstruction of an undocumented statistical plan.

13. 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 0% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: chest pain (1.6%), breast cancer stage i (1.6%).

The serious-adverse-event percentages were 0.0% for heat-treated vaccine A, 1.6% for gamma-irradiated vaccine A, 0.0% for placebo, 1.6% for gamma-irradiated vaccine B, and 0.0% for gamma-irradiated vaccine C. The corresponding event counts were 0, 1, 0, 1, and 0. There were no deaths reported in the listed groups.

The serious-event terms listed in the registry include Chest pain at 1.6% and Breast cancer stage I at 1.6%. The record does not establish from these terms alone whether an event was caused by a study intervention. A serious adverse event is classified by its outcome or consequences under the registry definition; seriousness is not the same as an assessment that the intervention caused it.

Zero observed events means no participant in that group was recorded as having the endpoint during the stated follow-up. It does not establish zero underlying risk. Conversely, one event in a group should not be treated as a stable estimate of the rate outside this trial. The follow-up period was up to approximately 28 days after dose 4, or up to approximately 118 days, so the result describes that observation window rather than longer-term experience.

Other adverse events were also reported, but they are distinct from this primary serious-event endpoint. These brief counts and percentages describe what was recorded in this study; they are not a complete characterization of safety beyond the stated population and follow-up.

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

The posted results describe few serious adverse events during the trial’s stated follow-up. One event was observed in each of the gamma-irradiated vaccine A and vaccine B groups, and none was observed in the heat-treated vaccine A, placebo, or gamma-irradiated vaccine C groups. The recalculated comparisons of vaccine A and vaccine B with placebo have confidence intervals that include zero, and their unadjusted p-values do not provide strong evidence of a difference under the calculations used.

These findings do not establish that the groups have equal underlying risks. Sparse events and the size of the study leave substantial uncertainty about uncommon outcomes. A group with no observed events may still have a nonzero underlying risk, and a single event can have a noticeable effect on a group’s observed proportion. The confidence intervals and group sizes are therefore central to interpretation.

The record does not report clinical efficacy against herpes zoster. Although the study’s purpose included immunogenicity and the registry describes antibody responses measured by gpELISA, the numerical result for the listed secondary geometric mean fold-rise outcome is not reported in the registry record. The serious-adverse-event endpoint cannot substitute for an antibody-response result, and neither endpoint alone answers every question about a vaccine formulation.

The study involved healthy adults and was a Phase I trial. Its findings should be understood within that study population, the listed regimens, and the stated follow-up period. The results do not determine what event rates might be in other populations or with different regimens. The registry record also does not report enough detail to reconstruct every aspect of the statistical plan.

In statistical terms, the data provide descriptive safety observations and imprecise comparisons for rare events. They do not establish a difference between groups, and they do not establish the absence of a difference. No treatment recommendation follows from these results.

15. Why This Trial Matters Statistically

This trial illustrates a basic challenge in early clinical research: serious safety outcomes are important, but they may be rare enough that a study with modest group sizes observes very few events. Here, one event or no events in a group drives the reported percentages. That makes it especially important to show the event counts, the denominators, and the uncertainty rather than relying on a percentage alone.

It also illustrates why zero-event comparisons require care. When both groups have zero observed events, a simple risk-difference calculation returns zero. That arithmetic describes the observed data, but it does not make the underlying risks known exactly. A calculation can be mechanically correct while still giving an incomplete impression of precision if its limitations are not explained.

The record includes sponsor-reported intervals and simple recalculations, and the results are not numerically identical. The sponsor-reported method is not described, so the difference cannot be fully diagnosed from the registry information. This is a useful reminder that estimates depend on the method used, particularly when event counts are sparse. Clear reporting of the statistical procedure would make comparisons easier to reproduce and interpret.

Finally, the study had multiple formulations, study parts, outcomes, and analyses. Without a reported complete analysis plan, readers cannot determine how comparisons were prioritized or whether multiplicity was addressed. These issues are not reasons to dismiss the observed results; they define the limits of what can be concluded from the posted record.

16. 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 based on rare outcomes, with only one serious adverse event in each of two groups and none in the other listed groups. Such sparse data provide limited precision. The group sizes, ranging from 32.0 to 65.0, also constrain how much can be learned about uncommon events from these comparisons.

The study enrolled healthy adults and was a Phase I trial. The registry record does not establish how well these observations apply to populations outside the enrolled group. The regimen involved four doses administered approximately 30 days apart, and the primary safety follow-up extended up to approximately 28 days after dose 4, or up to approximately 118 days. The record therefore does not provide longer-term safety observations through this endpoint.

Several formulations were studied in two parts, but a placebo group is listed only for Part 1. The posted placebo comparisons do not provide a direct placebo comparison for the Part 2 vaccine B and C groups. The Part 2 group results can be described, but the registry record does not establish that they should be compared indirectly with the Part 1 placebo group.

The sponsor’s method for its reported confidence intervals is not reported in the registry record, and the record does not give a full statistical analysis plan, sample-size justification, interim-analysis details, or multiplicity strategy. Missing-data handling and the number of participants excluded for incorrect vaccination are also not reported in the registry record. These omissions limit reproducibility and assessment of potential analysis choices.

Finally, although an antibody-response outcome is listed, its numerical result is not reported in the registry record. The primary safety results therefore do not provide a complete account of the study’s stated immunogenicity objective.

17. Related Tutorials

18. Related Statistical Calculators

19. Sources

• ClinicalTrials.gov: A Study to Test the Safety and Antibody Response of V212 in Healthy Adults (V212-004)(COMPLETED) — NCT00696709.
• Registry record last updated 2019-11-08; status last verified 2019-10.
• Results first posted 2019-11-08.
• 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.

20. Record Summary

NCT00696709 is a completed, randomized, double-blind, placebo-controlled Phase I trial in healthy adults, with 290 participants enrolled. It evaluated heat-treated and gamma-irradiated VZV vaccine formulations in two parts, with a placebo group listed in Part 1. The listed regimens involved four doses administered approximately 30 days apart.

The primary endpoint was the percentage of participants with one or more serious adverse events during follow-up up to approximately 28 days after dose 4, or up to approximately 118 days. One serious event was reported in each of the gamma-irradiated vaccine A and vaccine B groups; no serious events were reported in the other listed groups. The unadjusted recalculations for the two groups with events have confidence intervals that include zero.

The registry also lists a secondary gpELISA antibody-response outcome, but its numerical result is not reported in the registry record. Details of the statistical plan, missing-data handling, and sponsor interval methods are not reported in the registry record.