A Long-term Follow-up Study (ZOE-LTFU) of Two Studies 110390 (ZOSTER-006) and 113077 (ZOSTER-022) to Assess the Efficacy, Safety, and Immunogenicity Persistence of GSK Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine and Assessment of 1 or 2 Additional Doses in Two Subgroups of Older Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Long-term Follow-up Study (ZOE-LTFU) of Two Studies 110390 (ZOSTER-006) and 113077 (ZOSTER-022) to Assess the Efficacy, Safety, and Immunogenicity Persistence of GSK Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine and Assessment of 1 or 2 Additional Doses in Two Subgroups of Older Adults (NCT02723773), a non-randomized phase 3 study. The primary outcome is Number of Participants Having at Least One Confirmed Herpes Zoster (HZ) Case During the Total Duration of ZOSTER-049:EXT 006-022 Study, Overall.

2. Clinical Question

The study followed participants from the ZOSTER-006/022 primary studies to assess long-term herpes zoster (HZ) outcomes, safety and immunogenicity after HZ/su vaccination. It also assessed one or two additional vaccine doses in subgroups of older adults who had received two doses in the primary studies.

This is a long-term follow-up and additional-dose assessment, not a randomized comparison of all groups in the current study. The registry record does not report the primary outcome count or an estimated comparative effect, so the clinical question cannot be answered from the posted primary result information.

3. Trial Design

NCT02723773 is a Phase III, open-label, non-randomized study with a factorial model designation. It enrolled 7539 participants and is listed as completed. The registry gives a start date of 2016-04-16 and a primary completion date of 2023-06-28. GlaxoSmithKline is the sponsor.

The study followed participants from two primary studies, ZOSTER-006 and ZOSTER-022, also identified as studies 110390 and 113077. The long-term follow-up group included participants who had received at least one HZ/su dose in the primary studies and received no additional doses in this follow-up. The one-additional-dose group received one dose at Month 0, while the revaccination group received two additional doses at Month 0 and Month 2. A control group also received no additional doses and served as a control for the additional-dose groups.

The registry describes the control group as a subset of the long-term follow-up group, treated similarly but used as a control for the groups receiving additional doses. The analysis description says that the long-term follow-up and control groups were combined for the primary efficacy assessment. This structure means the groups are not a like-for-like randomized comparison within the follow-up study. The registry specifically identifies the allocation as non-randomized and masking as none.

For the primary efficacy assessment, historic controls were used because placebo recipients in the primary studies were offered cross-vaccination. The registry describes estimation of historical control incidence rates using Poisson regression and placebo data from the primary studies, with coefficients obtained by age ranges. The primary endpoint covered Month 0 to Month 72. The registry lists 26 outcome measures and 79 analyses, but does not report a full protocol, sample-size justification, or detailed statistical analysis plan.

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: Out of the 7534 participants enrolled in the current ZOSTER-049 EXT:006-022 study, 5 participants originally enrolled in the Long-term follow-up (LTFU) group were eliminated due to data modification post-investigator signature, and hence 7529 participants were included in the Total Vaccinated Cohort and started the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The analysis was performed on the Modified Total Vaccinated cohort (mTVC) - LTFU+Control group, which included all participants in the LTFU and Control groups combined, with efficacy data available for the specified analysis during the specified period, minus those participants who were not administered with the second vaccination during the ZOSTER-006/022 studies, or who developed a confirmed case of HZ prior to 1 month after the second vaccination in the ZOSTER-006/022 studies.

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 Participants Having at Least One Confirmed Herpes Zoster (HZ) Case During the Total Duration of ZOSTER-049:EXT 006-022 Study, Overall, measured over During the total duration of ZOSTER-049:EXT 006-022 study (From Month 0 to Month 72).

The primary endpoint is the number of participants with at least one confirmed herpes zoster case during the total duration of the ZOSTER-049:EXT 006-022 study. The specified timeframe is Month 0 to Month 72. It is a count of participants with an event, rather than a measurement of symptom severity or the total number of episodes.

A suspected case was defined as a new unilateral rash accompanied by pain and no alternative diagnosis. Confirmation was by Polymerase Chain Reaction (PCR) and/or determination by the HZ Ascertainment Committee, according to an algorithm described as pre-specified in the protocol. The endpoint therefore uses a defined case-identification process rather than relying only on an unconfirmed suspected event.

Counting participants who experience at least one event is a direct way to describe how many people met the case definition during follow-up. It does not, by itself, express how quickly events occurred or account for differing time at risk. The registry describes a separate historical-control incidence-rate approach for the efficacy assessment, but the primary outcome count and comparative estimate are not reported in the registry record. The endpoint definition is available; the magnitude and precision of the primary result are not.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies the primary outcome as a count of participants with at least one confirmed HZ case. Its analysis description adds a historical-control incidence-rate method for efficacy assessment. The exact model specification and numerical estimates are not reported in the registry record.

What does a participant count describe?

A count of participants with at least one event records whether each person met the endpoint during the stated observation period. A participant is counted for this endpoint if there was at least one confirmed HZ case. This differs from counting every episode: repeated events in the same participant do not make that participant multiple people in this endpoint. The registry uses the count as the primary outcome, but the count alone does not incorporate how long each person was observed.

General statistical explanation: counts are easy to interpret as numbers of people meeting a definition, but they can be harder to compare when observation time differs. An incidence rate relates events to time at risk. The registry says the historical-control incidence rates were estimated using Poisson regression. General statistical explanation: Poisson regression is a model often used for event counts or rates, with an adjustment for time at risk when specified. Its validity depends on the model and data assumptions; the registry record does not report enough detail to assess those assumptions.

Why use a historical control?

The registry states that placebo recipients in ZOSTER-006/022 were offered cross-vaccination because of the high vaccine efficacy observed in those studies. Since this follow-up study had no placebo group, historic controls were used for efficacy assessment. The record says placebo data from the primary studies were used to obtain coefficients by age ranges.

General statistical explanation: historical controls allow an outcome in a later study to be interpreted against earlier data, but the comparison can be affected by differences in participants, time periods, measurement practices, or follow-up. A concurrent randomized control group helps balance known and unknown baseline differences on average; the registry does not describe such randomization for the groups in this follow-up study. This does not mean the historical-control approach is necessarily invalid, but it makes the assumptions and available details important to interpretation. The record does not give the historical rate estimates or their uncertainty.

What does the case definition contribute?

The endpoint definition begins with a suspected case: a new unilateral rash accompanied by pain and no alternative diagnosis. A confirmed case required PCR and/or HZ Ascertainment Committee determination, under an algorithm described as pre-specified in the protocol. General statistical explanation: specifying and applying case criteria can reduce ambiguity in outcome classification. The registry record does not provide the algorithm’s complete details, so the exact adjudication process cannot be evaluated from the posted information.

How should uncertainty be considered?

General statistical explanation: an estimate summarizes the observed data, while a confidence interval describes the range of values reasonably compatible with those data under the analysis assumptions. A p-value, when reported, assesses how compatible the data are with a stated null model; it does not measure clinical importance or the probability that a hypothesis is true. The primary endpoint’s numerical estimate, confidence interval and p-value are not reported in the registry record. Its precision therefore cannot be evaluated.

Poisson models can be affected by over-dispersion, which is general statistical terminology for variability greater than the model expects. If over-dispersion is present and not addressed, uncertainty estimates can be too narrow. The registry record does not report whether over-dispersion was assessed or how it was handled. This is a methodological question, not a claim that over-dispersion occurred in this study.

What do planning calculations mean?

The sample-size assumptions describe planning illustrations based on the observed effect, using a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation. The illustration uses the stated fraction of the observed effect; for time-to-event tables it gives total events using Schoenfeld, while other illustrations give participants per arm. These are planning illustrations, not observed power and not evidence that the trial was designed with those assumptions. The actual sample-size justification is not reported in the registry record. No numerical illustration values are available in the record information.

The registry reports 7539 enrolled participants, but enrollment alone does not establish how many contributed to any particular endpoint analysis. The primary analysis population is described as the Modified Total Vaccinated cohort, combining long-term follow-up and control participants with efficacy data available for the specified period. The remaining description of exclusions is incomplete in the registry record. Thus, the enrolled total should not be treated as the endpoint-specific denominator.

10. Exact Estimates for Each Arm

No two-arm comparison is shown for this trial, but each arm's result can still be summarized with exact interval estimates computed from the posted counts. The Clopper-Pearson interval is exact and conservative; the Wilson interval is a common closer-to-nominal alternative; the Bayesian credible interval uses a uniform Beta(1, 1) prior. For small groups the three can differ noticeably.

R code and output

arm    <- c("LTFU+Control >=50YOA Group", "Historical Control >=50 YOA Group")
n      <- c(7258, 7258)
events <- c(69, 341)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  LTFU+Control >=50YOA Group  7258  69  1.0  0.7  1.2  0.8  1.2  0.8  1.2
ARM  Historical Control >=50 YOA Group  7258  341  4.7  4.2  5.2  4.2  5.2  4.2  5.2

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 26 outcome measures and 79 analyses. The listed outcomes include HZ events overall and by age range or follow-up period, post-herpetic neuralgia, other HZ-related complications and antibody concentrations. Multiple outcomes and subgroup analyses create opportunities for findings to arise by chance when many statistical comparisons are made.

General statistical explanation: multiplicity procedures can control the chance of false-positive conclusions across a family of tests, while a pre-specified hierarchy can identify which comparisons are intended to support the main conclusion. The registry record does not report a multiplicity-adjustment method, a testing hierarchy, or which secondary analyses were confirmatory versus exploratory. It also does not report interim analyses or a full statistical analysis plan. No adjustment strategy should be assumed.

The primary analysis population is described as the Modified Total Vaccinated cohort combining the long-term follow-up and control groups, with efficacy data available for the specified analysis and period. The remainder of the population definition is truncated in the registry record, so the complete exclusion criteria are not reported. The record does not provide endpoint-specific denominators or describe how missing outcome data were handled.

General statistical explanation: missingness can affect an estimate if the chance of having an observed outcome is related to participant characteristics or outcomes. Complete-case analysis, imputation and other approaches rely on different assumptions. Because the registry record does not state the missing-data method, the consequences of missing follow-up cannot be assessed. The enrolled total of 7539 is not a substitute for the number analyzed for a particular outcome. The registry record also does not report the number of participants lost to follow-up or the reasons for missing data.

12. 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: syncope (1.7%), myocardial infarction (1.7%), cardiac failure chronic (1.7%), diverticulitis (1.7%), mantle cell lymphoma (1.7%).

The registry reports serious adverse event counts for four groups. In the long-term follow-up group, 7289 were listed at risk and 62 were reported as affected; in the one-additional-dose group, 61 were at risk and 4 affected; in the revaccination group, 60 were at risk and 4 affected; and in the control group, 119 were at risk and 11 affected. Deaths are listed as 56 in the long-term follow-up group and 0 in each of the other groups.

For other adverse events, the registry lists 61 at risk and 54 affected in the one-additional-dose group, and 60 at risk and 58 affected in the revaccination group. It lists 0 at risk and 0 affected for the long-term follow-up and control groups. These are the registry’s reported counts; the record information does not describe the event definition or observation window for these figures.

The most frequent serious-event terms listed are syncope, myocardial infarction, cardiac failure chronic, diverticulitis, mantle cell lymphoma and metastases to peritoneum, each at 1.7%. These terms and percentages are descriptive. The registry information does not establish that an event was caused by the vaccine, nor does it report a comparative causal analysis. Because the study was non-randomized and group sizes differ substantially, simple contrasts between groups should be interpreted cautiously.

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

The registry record documents a long-term follow-up study designed to assess HZ outcomes, safety and immunogenicity after vaccination, as well as one or two additional doses in subgroups of older adults. It specifies a primary endpoint based on confirmed HZ cases and describes a historical-control approach for efficacy assessment. Those details explain the study’s analytic question, but they do not give the result.

The primary outcome count, an effect estimate, and measures of statistical uncertainty are not reported in the registry record. Therefore, the posted information cannot establish the amount of HZ observed, the size of any efficacy estimate, or how precise an estimate might be. The same caution applies to the listed secondary outcomes: their names describe intended assessments, not findings.

The study’s non-randomized allocation and open-label masking status matter when interpreting group comparisons. Participants receiving additional doses and those receiving none were not assigned through randomization in this follow-up study. Historic placebo data were used for efficacy assessment because placebo recipients in the primary studies were offered cross-vaccination. General statistical explanation: comparisons involving non-concurrent or non-randomized groups may be influenced by differences unrelated to the intervention, so the analysis design and its assumptions are central to interpretation.

Safety counts provide a descriptive record of reported events in the listed groups. The counts do not, on their own, identify causes or establish that one group has a higher or lower risk. The registry information does not state a causal safety analysis or provide enough detail to assess comparability and follow-up across groups.

Accordingly, the appropriate statistical reading is limited: the record describes the intended questions, case definition, study structure and some safety counts, while the primary efficacy result and its precision are absent. Neither the study’s purpose nor its completed status supplies the missing outcome evidence.

14. Why This Trial Matters Statistically

This study raises several important statistical issues in long-term vaccine follow-up. First, the clinical question concerns outcomes over an extended observation period, while the primary endpoint is a count of participants with at least one confirmed HZ case. Counts are intuitive, but comparisons also depend on the time participants remain under observation and on how cases are identified.

Second, placebo recipients from the primary studies were offered cross-vaccination, so the follow-up study did not have a placebo group for its efficacy assessment. The registry describes using historical placebo data and Poisson regression to estimate historical incidence rates by age range. This approach makes the relationship between earlier control data and later follow-up participants a central interpretive issue. The registry’s description is useful, but the rate estimates, uncertainty and full model details are not reported.

Third, the extra-dose groups are not randomized comparisons in this study. The presence of a control group does not by itself make the comparison randomized or equivalent to a concurrent controlled trial. The registry’s designation of non-randomized allocation and its description of the control group’s relationship to the long-term follow-up group should guide interpretation.

Finally, a large enrolled total and numerous planned outcome analyses do not guarantee that a particular estimate is precise or that multiple comparisons have been addressed. The analysis population can differ from enrollment, and the record does not give the endpoint-specific denominator, missing-data method, or multiplicity plan. These gaps illustrate why statistical conclusions require both the study design and the actual estimates with their uncertainty, rather than the outcome list or study purpose alone.

15. Limitations

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

The registry record does not report the primary endpoint result, comparative efficacy estimate, confidence interval or p-value. This is the most direct limitation for interpreting the main question: neither the magnitude nor precision of the primary result can be assessed from the posted information.

The study is listed as non-randomized and open-label. The groups receiving additional doses therefore do not form a randomized, like-for-like comparison in this follow-up study. The control group is described as a subset of the long-term follow-up group, and the primary efficacy analysis combines those groups. Historical placebo data were used for efficacy assessment because placebo recipients from the primary studies were offered cross-vaccination. The record does not provide enough model output or detail to assess the comparability of historical and follow-up data.

The primary population description is incomplete: it identifies the Modified Total Vaccinated cohort, but the remainder of the exclusion description is truncated. The registry does not report endpoint-specific analysis denominators, missing-data handling, loss-to-follow-up counts, or reasons for missing information. Enrollment of 7539 should not be read as the number analyzed for every outcome.

The record lists many outcomes and analyses but does not report a multiplicity strategy, analysis hierarchy, interim-analysis plan, or complete statistical analysis plan. It also does not provide detailed specifications for the Poisson model, including how its assumptions were assessed. Finally, the safety figures are descriptive and do not establish causality. These limitations arise from the registry information available; they do not establish that the underlying study documents lacked further detail.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Long-term Follow-up Study (ZOE-LTFU) of Two Studies 110390 (ZOSTER-006) and 113077 (ZOSTER-022) to Assess the Efficacy, Safety, and Immunogenicity Persistence of GSK Biologicals' Herpes Zoster Subunit (HZ/su) Vaccine and Assessment of 1 or 2 Additional Doses in Two Subgroups of Older Adults — NCT02723773.
• Registry record last updated 2025-12-12; status last verified 2025-11.
• Results first posted 2024-09-19.
• 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.

19. Record Summary

NCT02723773 is a completed Phase III, open-label, non-randomized long-term follow-up study sponsored by GlaxoSmithKline, with 7539 participants enrolled. It followed participants from ZOSTER-006/022 and assessed HZ outcomes, safety and immunogenicity, including additional-dose groups.

The primary endpoint was the number of participants with at least one confirmed HZ case during Month 0 to Month 72. Confirmation was by PCR and/or HZ Ascertainment Committee determination. For efficacy assessment, the registry describes historical placebo controls and Poisson regression, with age-range coefficients.

The registry record does not report the primary endpoint result, its comparative estimate, or its precision. It also does not report the full sample-size justification, complete statistical plan, multiplicity strategy or missing-data method. The available safety counts are descriptive and do not establish causation.