Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Participants ≥65 Years in the US: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Participants ≥65 Years in the US (NCT03282240), a randomized phase 3 study. The primary outcome is Geometric Mean Titers (GMTs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or High-Dose Trivalent Influenza Vaccine.

2. Clinical Question

The primary endpoint concerns antibody titers rather than a clinical illness outcome. Comparisons were not identical across all four strains: for each A strain, QIV-HD was compared with pooled TIV-HD groups; for each B strain, it was compared with the TIV-HD group containing the corresponding B strain. TIV-HD1 did not contain B2, and TIV-HD2 did not contain B1. The registry record does not report numerical primary endpoint estimates or confidence intervals, so the direction and precision of those comparisons cannot be described from the recorded information.

3. Trial Design

This was a phase 3, randomized, active-controlled, parallel-group trial described as modified double-blind and multi-center. It enrolled 2670 participants and is marked completed in the registry. The record gives a start date of 2017-09-08 and a primary completion date of 2017-11-02. Its stated focus was the safety and immunogenicity of QIV-HD compared with licensed or investigational high-dose trivalent influenza vaccine in adults.

Participants assigned to QIV-HD received a single 0.7 mL intramuscular injection at Day 0. Participants assigned to either TIV-HD1 or TIV-HD2 received a single 0.5 mL intramuscular injection at Day 0. The registry identifies TIV-HD1 as licensed and TIV-HD2 as investigational. The available record does not report the allocation ratio or the number randomized to each group as a complete set, so the total enrollment should not be treated as the analyzed number for every endpoint.

The primary immunogenicity outcome was measured at Day 28 post-vaccination in a per-protocol analysis set. That set included randomized participants who received at least one dose and had a post-vaccination HAI result for at least one strain, with no relevant protocol deviations. For each category, the number analyzed was the number of participants with available data. Thus, the outcome population was defined by both protocol adherence and available assay data, rather than simply by enrollment.

Fifteen outcome measures and twelve analyses are listed. Secondary outcomes include antibody titers and ratios, seroconversion and seroprotection measures, and neutralization assay outcomes. Numerical findings for those measures are not reported in the registry record. Details such as the precise allocation procedure, concealment, masking procedures, site count, and recruitment method are not reported in the registry record.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: A total of 2670 participants were randomized in the study.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Per-protocol analysis set (PPAS): all randomized participants who received at least 1 dose of trial vaccine \& had a post-vaccination blood sample HAI result for at least 1 strain, with no relevant protocol deviations. Here, 'number analyzed' = participants with available data for each category.

5. Baseline Characteristics

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

Population: Analysis was performed on all randomized participants for whom a vaccine group was allocated.

6. Primary Endpoint

The registry lists the primary outcome as Geometric Mean Titers (GMTs) of Influenza Antibodies Following Vaccination With Either a High-Dose Quadrivalent Influenza Vaccine or High-Dose Trivalent Influenza Vaccine, measured over Day 28 post-vaccination.

The primary endpoint is the geometric mean titer (GMT) of anti-influenza antibodies at Day 28 post-vaccination. The registry says titers were measured with a hemagglutination inhibition (HAI) assay for A/H1N1, A/H3N2, B Victoria lineage (B1), and B Yamagata lineage (B2). The reported unit is titers (1/dilution), with a 95% confidence interval as the stated dispersion measure.

In general, a GMT is used for measurements that are positive and often behave multiplicatively: it is obtained by taking the mean on a logarithmic scale and converting back to the original scale. This can be more suitable than an arithmetic mean when observations are unevenly distributed across a range of values. An HAI antibody titer is an assay-based measure, so the endpoint describes measured immune response rather than directly counting influenza illness or its complications.

The comparison structure matters to interpretation. For each A strain, QIV-HD was compared with pooled TIV-HD groups. For each B strain, the comparator was the TIV-HD group that contained that B strain. TIV-HD1 did not contain B2, while TIV-HD2 did not contain B1. Consequently, a single pooled comparison across all strains would not reflect the comparison specified in the registry. Numerical GMT estimates and their confidence intervals are not reported in the registry record, so the magnitude and precision of the primary outcome cannot be assessed from the recorded results.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a geometric mean describe?

In general, a geometric mean summarizes positive measurements on a multiplicative scale. The measurements are transformed to logarithms, averaged, and transformed back. This approach is commonly used when values can span a wide range and relative changes are more meaningful to the scale than equal absolute changes. The registry identifies GMT as the primary summary for the HAI titers; it does not report the individual titer distributions or numerical GMT results.

The endpoint’s 95% confidence interval is a measure of uncertainty around an estimate. In general, repeated use of the same procedure would yield intervals that cover the underlying parameter at the stated rate over repetitions, under the method’s assumptions. A confidence interval is not a probability statement about the one realized interval, and it is not a substitute for understanding the estimated difference and its scale. Here, confidence intervals for the GMT endpoint are not reported in the registry record, so their width and the precision of the estimates cannot be evaluated.

Why does the comparison structure matter?

The trial’s endpoint description specifies different reference groups by strain. For each A strain, the QIV-HD comparison used pooled TIV-HD groups. For each B strain, the comparison used the TIV-HD group containing that strain. Since TIV-HD1 did not contain B2 and TIV-HD2 did not contain B1, the B-strain comparisons use a strain-specific comparator. In general, estimates from distinct comparison populations should be interpreted according to their own reference groups; they should not be collapsed into one contrast without a prespecified rationale and the underlying results.

The registry lists GMT ratios among secondary outcomes. In general, a ratio compares two quantities by division and expresses relative rather than absolute difference. Its interpretation depends on which group is placed in the numerator and which in the denominator, and on the endpoint scale. The direction convention and numerical ratios are not reported in the registry record. No claim about the size or direction of a ratio can therefore be made.

What does the per-protocol analysis set mean?

The primary analysis population is described as the per-protocol analysis set. It includes randomized participants who received at least one dose, had a post-vaccination HAI result for at least one strain, and had no relevant protocol deviations. The record states that the number analyzed for each category is the number with available data. In general, a per-protocol analysis focuses on participants meeting specified treatment and protocol criteria, while an analysis based on all randomized participants preserves the original randomization more fully. The registry does not report an all-randomized primary analysis in the registry record.

Using available results can mean that the number analyzed differs across categories or strains. In general, missing measurements can reduce precision and can introduce bias if having a measurement is related to the outcome or group assignment. The registry does not report the number with missing HAI results by arm or strain, reasons for missingness, or a missing-data sensitivity analysis. It is therefore not possible to assess whether availability of post-vaccination samples could have affected the estimates.

How should multiple outcomes be considered?

The registry lists fifteen outcome measures and twelve analyses, including GMTs, GMT ratios, seroconversion, seroprotection, and neutralization assay measures. In general, testing many outcomes or making many comparisons increases the chance of at least one apparently unusual result if each is judged separately. Methods for controlling multiplicity may adjust significance thresholds or interpret findings within a prespecified hierarchy. The registry record does not report whether such a method was used, which analyses were confirmatory, or how the outcome families were ordered. No multiplicity adjustment should be assumed.

For planning, the record describes an illustration based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says the target effect is a stated fraction of the observed effect. In general, such values are planning illustrations conditional on the assumed effect and analysis conditions; they are not observed power and are not evidence that the trial was designed around those assumptions. The record does not report the trial’s own sample-size justification. Numerical planning outputs are not reported in the registry information.

The outcome descriptions also include seroconversion, seroprotection, and neutralization measures. In general, these are distinct summaries: a threshold-based status or a change category is not interchangeable with a continuous GMT. Their definitions, analysis details, and numerical results are not reported in the registry record. Interpretations should remain tied to the endpoint actually analyzed rather than treating all immunogenicity outcomes as equivalent.

10. Multiplicity, Missing Data and Analysis Populations

The primary outcome uses multiple strain categories and comparator structures, and the registry lists several secondary immunogenicity outcomes. The record identifies fifteen outcome measures and twelve analyses. It does not report a multiplicity adjustment, testing hierarchy, or which comparisons were designated confirmatory. Consequently, the recorded information does not establish how the chance of false-positive findings across multiple comparisons was addressed. Numerical results for the primary and secondary outcomes are not reported in the registry record, so no pattern of statistical findings can be evaluated in light of multiplicity.

The primary population is the per-protocol analysis set: randomized participants who received at least one dose, had a post-vaccination HAI result for at least one strain, and had no relevant protocol deviations. The number analyzed for a category is defined as those with available data. The record does not report the numbers missing by arm and strain, reasons for missing measurements, or an analysis of the effect of missingness. It also does not report a sensitivity analysis or an alternative missing-data approach.

In general, an analysis restricted to participants meeting per-protocol criteria can differ from an analysis retaining all randomized participants, particularly if exclusions or unavailable measurements are associated with outcomes. This is a general consideration, not evidence that bias occurred in this trial. The registry record does not report enough information to determine whether the analysis population or missing-data handling changed the primary estimates.

11. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

Deaths

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: osteoarthritis (0.9%), coronary artery disease (0.7%), pneumonia (0.5%), facial paralysis (0.4%), syncope (0.4%).

The registry lists serious adverse event figures by group. For QIV-HD, 80 of 1777 participants were recorded as affected; for licensed TIV-HD1, 29 of 443; and for investigational TIV-HD2, 19 of 450. Death counts are 3, 2, and 0, respectively. These counts describe what is recorded for the groups and should not be read as evidence that vaccination caused an event or death.

The registry also lists serious-event terms with percentages: osteoarthritis, 0.9%; coronary artery disease, 0.7%; pneumonia, 0.5%; facial paralysis, 0.4%; syncope, 0.4%; and cardiac failure congestive, 0.2%. The record information does not specify in these entries the group distribution, event timing, relationship to vaccination, or the precise calculation basis for each percentage. The percentages should therefore be read as listed descriptive figures, not as comparative risks.

In general, safety interpretation depends on definitions, observation periods, event collection, and assessment of whether events may be related to treatment. Those details are not reported in the registry record. The counts alone also do not indicate statistical uncertainty or establish whether group differences are meaningful.

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

The record describes a randomized phase 3 trial comparing QIV-HD with licensed and investigational high-dose trivalent influenza vaccines in adults aged 65 years and older. It identifies a Day 28 HAI antibody GMT endpoint across four strains and explains how the comparator groups were selected for those strains. It also records group-specific serious adverse event and death counts. These design and outcome descriptions establish what the trial set out to assess, but they do not supply the numerical primary immunogenicity findings.

Because GMT estimates and confidence intervals are not reported in the registry record, the measured antibody responses cannot be compared quantitatively from this information. The listed endpoint does not show the magnitude or precision of any difference. Likewise, the names of secondary outcomes do not establish their results. Neither an endpoint definition nor a count of participants enrolled can substitute for the outcome estimates.

The safety counts are descriptive, with no reported attribution or contextual details sufficient to infer cause. The listed serious-event percentages also lack group-specific interpretation in the information available. These figures cannot by themselves establish that one vaccine group had a better or worse safety profile.

In general, an immunogenicity measure and a clinical outcome answer different questions. Antibody titers summarize assay measurements; they do not directly report rates of influenza illness. The registry lists safety and immunogenicity as the trial focus, but the numerical results needed to characterize those outcomes are not reported in the registry record. Accordingly, the record supports a description of trial design and planned measurement, alongside limited descriptive safety counts, but not a conclusion about comparative clinical benefit or harm.

13. Why This Trial Matters Statistically

This trial is statistically notable for its strain-specific comparison structure. QIV-HD was compared with pooled TIV-HD groups for the A strains, but with the trivalent group containing the relevant B strain for each B endpoint. The distinction reflects the fact that TIV-HD1 did not contain B2 and TIV-HD2 did not contain B1. It illustrates why endpoint definitions and comparator selection need to be read together: the meaning of an estimate depends on the population and contrast from which it came.

The primary outcome is a geometric mean of assay titers, accompanied in the registry description by a 95% confidence interval. In general, this combination conveys both a summary of measured antibody levels and the uncertainty around that summary. Yet the numerical estimates are not reported in the registry record, underscoring that a detailed endpoint definition is not the same as a report of results.

The record also illustrates differences among immunogenicity outcomes. GMTs, ratios, seroconversion, seroprotection, and neutralization measurements are separate outcome types. They answer related but nonidentical statistical questions and may involve different scales or criteria. The registry lists these measures but does not report numerical results or the multiplicity strategy, limiting interpretation across the outcome family.

Finally, the described per-protocol population and available-data definition matter when interpreting an endpoint. In general, analysis populations and missing measurements can affect both precision and the scope of inference. The registry’s population criteria are explicit, while details about missing results and sensitivity analyses are not reported. These are useful distinctions for clinical researchers assessing what the record can establish and what remains uncertain.

14. Limitations

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

The main limitation for interpreting efficacy-related findings is that numerical primary endpoint estimates and confidence intervals are not reported in the registry record. Although the endpoint, assay, time point, strains, analysis population, and comparison structure are specified, the measured GMTs and comparative results are absent. Numerical results for the listed secondary outcomes are also not reported. This prevents assessment of effect magnitude, direction, and precision.

Several details needed to evaluate design and analysis are not reported in the registry record. These include the allocation ratio, group counts as a complete randomized set, sequence generation and allocation concealment, masking procedures, site count, and recruitment method. The trial is described as modified double-blind, but the operational meaning of that description is not detailed in the available information.

The primary population is per-protocol and requires available post-vaccination assay data with no relevant protocol deviations. Counts missing by arm and strain, reasons for missingness, and sensitivity analyses are not reported. The record also does not report whether a multiplicity method or a confirmatory testing hierarchy was used. The sample-size justification for the trial itself is not reported in the registry record; the listed planning assumptions are an illustration and should not be taken as the trial’s own design rationale.

Safety interpretation is constrained by the absence of event timing, attribution, observation-period details, and the percentage calculation basis for the listed serious-event terms. The reported counts and terms are descriptive and do not independently establish causality or comparative risk.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine in Participants ≥65 Years in the US — NCT03282240.
• Registry record last updated 2022-04-07; status last verified 2022-03.
• Results first posted 2019-12-17.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

18. Record Summary

NCT03282240 is a completed phase 3 randomized, active-controlled, parallel-group, modified double-blind, multi-center trial of influenza vaccines in adults aged 65 years and older in the US. Enrollment was 2670. The registry gives a start date of 2017-09-08 and a primary completion date of 2017-11-02.

The primary outcome was Day 28 HAI antibody GMT for four influenza strains, using a per-protocol analysis set. QIV-HD was compared with pooled TIV-HD groups for the A strains and with the trivalent group containing the corresponding B strain for the B strains. The registry lists fifteen outcome measures and twelve analyses. Numerical primary and secondary immunogenicity results, multiplicity procedures, missing-data details, and the trial’s sample-size justification are not reported in the registry record.

Serious adverse event counts were 80 of 1777 for QIV-HD, 29 of 443 for licensed TIV-HD1, and 19 of 450 for investigational TIV-HD2; deaths were 3, 2, and 0, respectively. The available record does not establish event attribution or comparative safety conclusions.