Study of Fluzone® Quadrivalent, Fluzone® Intradermal Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines in Adults: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study of Fluzone® Quadrivalent, Fluzone® Intradermal Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines in Adults (NCT02563093), a randomized phase 4 study. The primary outcome is Number of Participants With Solicited Injection-Site or Systemic Reactions After Receipt of the 2015-2016 Formulation of Fluzone Quadrivalent, Fluzone Intradermal Quadrivalent, or Fluzone High-Dose Vaccine.

2. Clinical Question

The study also had observational objectives concerning antibody responses and compliance with historical requirements for immunogenicity. These included geometric mean titers, seroprotection, seroconversion, and post-vaccination geometric mean titer ratios. Their presence in the objectives describes what the study aimed to assess; it does not, by itself, establish what the results were. Those numerical findings are not reported in the registry record.

3. Trial Design

This was a randomized, open-label, parallel-group Phase 4 study of the 2015-2016 formulations of Fluzone Quadrivalent, Fluzone Intradermal Quadrivalent, and Fluzone High-Dose. The registry lists enrollment of 208 participants and a completed study. The recorded start was 2015-09, and primary completion was 2015-12. Influenza is the listed condition.

Randomization allocated participants within two distinct age groups. Adults 18 to < 65 years of age were assigned to Fluzone Quadrivalent by intramuscular injection or Fluzone Intradermal Quadrivalent by intradermal injection. Adults ≥ 65 years of age were assigned to Fluzone Quadrivalent or Fluzone High-Dose, both by intramuscular injection. These are age-specific comparisons; the registry does not define a direct comparison between the younger and older participants.

Open-label means the registry lists no masking. In general, lack of masking can matter when outcomes involve participant-reported symptoms, since participants know which intervention they received. Random allocation is intended to reduce systematic differences between assigned groups, but it does not ensure that every group characteristic is identical. The registry record does not report details of sequence generation, concealment of allocation, or other randomization procedures.

The primary outcome was a count of participants with solicited injection-site or systemic reactions during the period from Day 0 up to Day 7 post-vaccination. Safety was assessed in the Safety Analysis Set. The record also refers to Full Analysis and Per-protocol analysis sets in describing a participant whose received vaccine differed from the assigned vaccine. Definitions of the sets beyond those details are not reported in the registry record.

The registry record does not report a sample-size justification, a prespecified statistical analysis plan, or any inferential analysis for the primary outcome. It lists no analyses. Consequently, the design information supports describing the groups and intended outcomes, but not reconstructing how the investigators planned to estimate or compare outcome rates.

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 208 participants who met all of the inclusion criteria and no exclusion criteria were enrolled and vaccinated.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The vaccine safety outcomes were assessed in the Safety Analysis Set. A participant (18 to \< 65 Years) who was assigned to receive Fluzone Intradermal Quadrivalent vaccine received Fluzone Quadrivalent vaccine instead; this participant was included in the Fluzone Quadrivalent vaccine (18 to \< 65 Years) group in the Safety Analysis Set.

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 With Solicited Injection-Site or Systemic Reactions After Receipt of the 2015-2016 Formulation of Fluzone Quadrivalent, Fluzone Intradermal Quadrivalent, or Fluzone High-Dose Vaccine, measured over Day 0 up to Day 7 post-vaccination.

The primary endpoint counts participants who experienced at least one of the specified solicited injection-site or systemic reactions after vaccination. The assessment period was Day 0 up to Day 7 post-vaccination. Listed injection-site reactions were pain, erythema, swelling, induration, and ecchymosis. Listed systemic reactions were fever, headache, malaise, myalgia, and shivering.

The registry also defines Grade 3 severity thresholds. Grade 3 pain was described as significant and preventing daily activity; erythema, swelling, induration, and ecchymosis were Grade 3 when >100 mm. Grade 3 fever was ≥ 39.0°C or ≥ 102.1°F. Grade 3 headache, malaise, myalgia, and shivering were described as significant and preventing daily activity. The primary outcome title refers to participants with reactions; the registry description does not report reaction counts by symptom or severity.

A participant count is an interpretable safety summary: it indicates how many people experienced a specified event, rather than how many episodes occurred. In general, this kind of endpoint is useful for describing the frequency of solicited symptoms over a defined observation period. It does not, without a comparison estimate and its uncertainty, establish how the groups differ. The endpoint’s participant counts, group-specific results, and uncertainty measures are not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a randomized, open-label, parallel-group design. Randomization is a method for assigning participants to study groups by chance. In general, this helps limit systematic differences in baseline characteristics, though chance imbalances can remain. Parallel-group means participants are assigned to a group and the groups are compared, rather than each participant receiving every intervention in sequence. The registry does not report how the random sequence was generated or concealed.

What does the primary outcome count?

The primary measure is the number of participants with solicited injection-site or systemic reactions from Day 0 up to Day 7 post-vaccination. For a binary participant-level outcome, each participant is classified according to whether the specified event occurred. In general, the event count and the number assessed are needed to describe the observed proportion. A comparison can then estimate how outcome frequency differs between groups, with an interval conveying uncertainty. The primary group counts and such comparison estimates are not reported in the registry record.

Why does the analysis population matter?

The registry says that vaccine safety outcomes were assessed in the Safety Analysis Set. It also describes a participant 18 to < 65 years of age who was assigned to Fluzone Intradermal Quadrivalent but received Fluzone Quadrivalent instead. That participant was excluded from the Per-protocol analysis Set and included in the Fluzone Quadrivalent group in the Safety Analysis Set and in the assigned group in the Full Analysis Set. This illustrates, in general, that a participant can be classified differently depending on whether an analysis follows treatment received or treatment assigned. The registry does not report full definitions for these analysis populations or the primary outcome results under each one.

What can be inferred from a confidence interval?

In general, a confidence interval describes the uncertainty around an estimate under the assumptions of the statistical method. A narrow interval indicates greater precision than a wide interval, while neither width nor statistical significance alone determines clinical importance. No confidence interval for the primary outcome is reported in the registry record. Accordingly, precision of a primary safety comparison cannot be assessed from this record.

What is the role of a p-value?

In general, a p-value measures how compatible data are with a specified statistical model in which a null hypothesis holds. It is not the probability that the null hypothesis is true, and it does not measure the size or importance of an effect. The registry lists no analyses and does not report a primary outcome p-value. No conclusion about statistical significance can be drawn for that outcome from the registry record.

How should the sample-size illustration be understood?

A planning illustration based on an observed effect is not the same as the study’s original design justification, and it is not observed power. The stated illustration assumptions are a two-sided significance level of 0.05, equal allocation between two arms, a normal approximation, and an effect to detect set as a stated fraction of the observed effect. In general, such an illustration asks how many participants per arm might be needed under those assumptions for a selected power target. It does not establish that the trial was designed that way or that its observed results provide that power. The study’s own sample-size justification is not reported in the registry record.

The registry record does not report the statistical model, adjustment strategy, handling of missing outcome data, or multiplicity procedure. It also does not report interim analyses. General statistical considerations cannot fill in those trial-specific omissions. In particular, no method should be attributed to the investigators unless it is documented in the registry record.

The trial includes multiple outcomes and vaccine comparisons. In general, making many statistical comparisons can increase the chance of observing an apparently notable result by chance, so a prespecified multiplicity strategy can be important. But whether and how multiplicity was addressed is not reported in the registry record. Because numerical primary and immunogenicity results are also absent, the statistical evidence for those objectives cannot be evaluated.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists a primary safety outcome and several immunogenicity outcomes, including geometric mean titers, seroprotection, seroconversion, and geometric mean titer ratios. The trial also has two age-specific vaccine comparisons. The registry record does not report a multiplicity plan describing how inference across these outcomes or comparisons was handled. It does not report whether any outcome hierarchy or adjustment procedure was used.

Missing-data methods are not reported in the registry record. The record does not state how participants with incomplete symptom diaries, unavailable measurements, or other missing observations were handled. It also does not give primary endpoint results from which the number or impact of missing observations could be assessed. An absence of reported results should not be interpreted as evidence that there were no missing observations.

The Safety Analysis Set is identified as the population for vaccine safety outcomes. The record further describes one participant assigned to Fluzone Intradermal Quadrivalent who received Fluzone Quadrivalent instead: this participant was excluded from the Per-protocol analysis Set, counted in the Fluzone Quadrivalent group for the Safety Analysis Set, and kept in the assigned group for the Full Analysis Set. Beyond that specific account, definitions and participant flow for the analysis populations are not reported in the registry record.

The registry lists no analyses. It therefore does not provide a basis for assessing whether results were adjusted for multiple comparisons, how missing data were handled, or whether analysis populations were applied consistently across all endpoints. These are uncertainties about reporting, not evidence that a particular method was or was not used in the full study.

11. Safety Results

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

Other (non-serious) adverse events

Participants with at least one non-serious event at or above the registry's 5.00% reporting threshold.

Most frequent serious adverse event terms

Most frequent non-serious adverse event terms

Serious events with the highest arm-level rate: atrial fibrillation (2.0%), cardiac failure acute (2.0%), transient ischaemic attack (2.0%).

The adverse-event figures list serious adverse events separately from other adverse events. Serious adverse-event counts were 0 of 53 for Fluzone Quadrivalent Vaccine (18 to < 65 Years), 0 of 51 for Fluzone Quadrivalent Intradermal Vaccine (18 to < 65 Years), 0 of 53 for Fluzone Quadrivalent Vaccine (≥ 65 Years), and 1 of 51 for Fluzone High-Dose Vaccine (≥ 65 Years). The corresponding counts for other adverse events were 29 of 53, 29 of 51, 15 of 53, and 22 of 51.

These figures are counts of participants, not event rates adjusted for differences between groups. In general, a count should be read with its denominator and the event definition. The registry record does not report a comparative estimate or interval for these adverse-event counts, and it does not specify a timeframe for the serious adverse-event figures in the registry record recorded. The one serious adverse event is recorded in the Fluzone High-Dose Vaccine (≥ 65 Years) group; this descriptive observation alone does not establish that the vaccine caused the event or that the groups differ.

Atrial fibrillation, cardiac failure acute, and transient ischaemic attack are each listed with 2.0%. The record does not identify the group for each term. Deaths are not reported as a numerical count in the registry record; the null entries do not establish that no deaths occurred.

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

The registry record establishes that this was a randomized, open-label Phase 4 study of three 2015-2016 influenza vaccine formulations in adults, with separate age-specific comparisons. It specifies a primary safety outcome based on solicited injection-site and systemic reactions, along with observational immunogenicity objectives. It also records adverse-event counts and describes one participant who received a vaccine different from the assigned formulation.

Those design and outcome details do not substitute for outcome results. The primary solicited-reaction counts and comparative estimates are not reported in the registry record. The immunogenicity results are also not reported in the registry entries used for this analysis. As a result, the available record cannot show the magnitude or precision of a difference in those outcomes, or establish whether any group met a historical immunogenicity requirement.

The reported serious and other adverse-event counts are descriptive. In general, an observed count is not itself a causal estimate: assignment, exposure, event definition, follow-up, and uncertainty all matter when interpreting safety comparisons. The registry provides no inferential comparison for these counts. Likewise, listed serious adverse-event terms should not be attributed to a specific vaccine group unless the record makes that connection.

The study’s randomized design is relevant to how a comparison may be interpreted, but randomization does not resolve the absence of reported results or analysis details. Open-label conduct is also relevant in general because solicited symptoms can depend on participant reporting. The record does not provide enough information to evaluate the impact of these features on the observed primary outcome.

Accordingly, the defensible reading is limited: the registry documents the trial’s intended comparisons and some adverse-event counts, but it does not report the main reaction outcome results or the immunogenicity findings. No conclusion about comparative efficacy, clinical benefit, or whether a formulation is preferable follows from the information recorded.

13. Why This Trial Matters Statistically

This trial is statistically interesting because it places randomized comparisons within two separate age groups while examining different formulations. That structure makes the comparator important: the younger adults were assigned to Fluzone Quadrivalent or Fluzone Intradermal Quadrivalent, while the older adults were assigned to Fluzone Quadrivalent or Fluzone High-Dose. These are not one common comparison across all participants.

The primary endpoint also illustrates the distinction between an outcome definition and an outcome result. The registry defines which solicited symptoms count and the period in which they are assessed, and it specifies severity thresholds for Grade 3 reactions. Yet it does not report the participant counts or statistical comparisons for that endpoint. A precise definition helps readers understand what was intended to be measured, but cannot establish the frequency or comparative uncertainty without the results.

Another statistical issue is the separation between assigned treatment and treatment received. The record describes a participant who received Fluzone Quadrivalent after assignment to Fluzone Intradermal Quadrivalent, and notes different placement in the Safety Analysis Set, Full Analysis Set, and Per-protocol analysis Set. In general, analysis-population choices can affect the question a result answers. The record’s limited details make the participant’s classification clear, but do not provide complete definitions or analyses.

Finally, multiple safety and immunogenicity outcomes are listed, while multiplicity methods and analysis details are not reported. This makes it important to distinguish study objectives from demonstrated findings. The available adverse-event counts can be described, but should not be treated as a complete comparative assessment. The trial therefore highlights how design, endpoint specification, analysis populations, and transparent results all contribute to statistical interpretation.

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 principal limitation of the registry record for interpreting the trial is that it does not report numerical results for the primary solicited-reaction endpoint. No group counts, effect estimates, confidence intervals, or p-values for that outcome are reported. Numerical findings for the listed immunogenicity outcomes are also not reported in the registry record recorded for this analysis. This prevents assessment of both the size and precision of those findings.

The record lists 208 participants overall but does not give a complete account of participant flow or endpoint-specific denominators. It describes one participant who received a vaccine different from the assigned formulation, with different handling across analysis populations, but does not provide the full definitions of those populations. The consequences of the classification for outcome estimates cannot be assessed without the corresponding results.

Methods that would affect interpretation are not reported in the registry record, including the sample-size justification, statistical analysis plan, handling of missing data, multiplicity strategy, and any interim analyses. The record lists no analyses. These omissions mean that the planned inferential approach and the robustness of any results cannot be evaluated from the registry information.

The study was open-label, and the primary endpoint includes solicited symptoms. In general, awareness of assigned treatment can influence reporting or assessment of subjective symptoms; the record does not quantify whether this affected the study. The stated primary follow-up period is Day 0 up to Day 7 post-vaccination, so it does not describe longer-term reaction assessment for this endpoint.

Finally, adverse-event counts are descriptive, and the record does not provide comparative uncertainty estimates. The serious adverse-event timeframe is not reported in the registry entries, and the listed serious-event terms are not linked to specific groups. Death counts are not reported. These reporting limits constrain conclusions about comparative safety.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Study of Fluzone® Quadrivalent, Fluzone® Intradermal Quadrivalent, and Fluzone® High-Dose, Influenza Vaccines in Adults — NCT02563093.
• Registry record last updated 2016-12-12; status last verified 2016-10.
• Results first posted 2016-12-12.
• 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

The registry describes a completed, randomized, open-label, parallel-group Phase 4 study with enrollment of 208 adults. It compared Fluzone Quadrivalent with Fluzone Intradermal Quadrivalent in adults 18 to < 65 years of age and Fluzone Quadrivalent with Fluzone High-Dose in adults ≥ 65 years of age. The recorded study start was 2015-09, and primary completion was 2015-12.

The primary outcome was the number of participants with solicited injection-site or systemic reactions from Day 0 up to Day 7 post-vaccination. The registry record does not report the primary outcome counts or a statistical analysis. It also lists immunogenicity objectives, without numerical findings in the registry record recorded for this analysis. Adverse-event counts are reported, including 1 serious adverse event among 51 participants in the Fluzone High-Dose Vaccine (≥ 65 Years) group and 0 in each of the other listed groups. The record does not report a sample-size justification, missing-data methods, multiplicity plan, or statistical analysis plan.