This page provides an independent statistical analysis and educational interpretation of publicly reported results. ClinicalTrials.gov provides the official trial registry record. Numerical trial results on this page are restricted to the results posted in the ClinicalTrials.gov record; calculations added by Clinical Biostats are labelled as such.
1. Trial at a Glance
This page covers the registry results for Study of Quadrivalent Influenza Vaccine Among Adults (NCT01218646), a randomized phase 3 study. The primary outcome is Geometric Mean Titers Against Influenza B Strains After Vaccination With Fluzone® Quadrivalent Influenza Vaccine or With Trivalent Influenza Vaccines With Corresponding B Strain in Participants Aged 65 Years and Older..
| Feature | Registry value |
|---|---|
| ClinicalTrials.gov identifier | NCT01218646 |
| Phase | Phase 3 |
| Condition | Influenza |
| Allocation | Randomized |
| Design model | Parallel |
| Masking | Quadruple |
| Enrollment | 739 |
| Arms in the primary outcome | n/a |
| Lead sponsor | Sanofi Pasteur, a Sanofi Company |
| Results posted | Yes |
2. Clinical Question
Population
The trial enrolled adults with influenza as the listed condition. Its primary immunogenicity objective concerned participants aged 65 years and older. The primary outcome description specifies randomized and vaccinated participants in the per-protocol population who had valid serology results for the B antigens.
Intervention
The intervention of primary interest was an investigational quadrivalent inactivated influenza vaccine. The registry describes a dose of this vaccine in Group 1. The primary objective was to assess antibody responses to its four virus strains separately.
Comparator
The comparison vaccines were an investigational trivalent vaccine containing the alternate B strain and the licensed 2010-2011 trivalent vaccine containing the primary B strain. The record also lists a second group receiving the licensed trivalent vaccine, without explaining the distinction between the two licensed-vaccine groups.
Primary question
Among participants aged 65 years and older, were geometric mean titer responses to the quadrivalent vaccine non-inferior to responses to the trivalent vaccines for their corresponding B strains? The objective describes comparisons using geometric mean titer ratios for each of the four virus strains separately. The non-inferiority margin and the numerical results needed to assess that question are not reported in the registry record.
3. Trial Design
This was a randomized, quadruple-masked, parallel-group Phase 3 trial. The registry lists an enrollment of 739 and describes four groups: investigational quadrivalent vaccine, investigational trivalent vaccine, and two groups receiving licensed 2010-2011 trivalent vaccine. The record does not explain why the licensed vaccine appears in two separate groups or how participants were allocated among groups. It does not report the allocation ratio.
The study started in 2010-10, reached primary completion in 2011-03, and is listed as completed. The sponsor was Sanofi Pasteur, a Sanofi Company. The summary describes the trial as evaluating antibody responses to the quadrivalent vaccine against the licensed trivalent vaccine containing the primary B strain and an investigational trivalent vaccine containing the alternate B strain.
The primary immunogenicity objective concerned participants aged 65 years and older. Safety objectives were broader in age: the summary describes safety profiles of trivalent vaccine in participants aged 18 years and older and quadrivalent vaccine in participants aged 65 years and older. The safety collection windows included solicited injection-site and systemic events collected for 7 days post-vaccination, unsolicited events collected from 21 days post-vaccination, and adverse events of special interest and serious adverse events collected from Visit 1 to Visit 2.
The masking roles, detailed allocation procedures, eligibility criteria, and any stratification factors are not reported in the registry record. The record labels the study Phase 3 but does not state how its design features were implemented in practice.
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 739 participants who met all the inclusion criteria and none of the exclusion criteria were enrolled, randomized and vaccinated in the study.
Overall Study
| Stage | Group 1 (Investigational Quadrivalent Influenza Vaccine) | Group 2 (Investigational Trivalent Influenza Vaccine) | Group 3 (Licensed Trivalent Influenza Vaccine) | Group 4 (Licensed Trivalent Influenza Vaccine) |
|---|---|---|---|---|
| STARTED | 225 | 225 | 225 | 64 |
| COMPLETED | 224 | 225 | 223 | 63 |
| NOT COMPLETED | 1 | 0 | 2 | 1 |
Reasons for not completing this period:
| Reason | Group 1 (Investigational Quadrivalent Influenza Vaccine) | Group 2 (Investigational Trivalent Influenza Vaccine) | Group 3 (Licensed Trivalent Influenza Vaccine) | Group 4 (Licensed Trivalent Influenza Vaccine) |
|---|---|---|---|---|
| Adverse Event | 0 | 0 | 1 | 0 |
| Lost to Follow-up | 1 | 0 | 0 | 0 |
| Protocol Violation | 0 | 0 | 1 | 1 |
Analysis population for the primary outcome, as defined in the registry: Geometric mean titers to the influenza vaccine B antigens were determined in randomized and vaccinated participants, per-protocol population. Data presented for participants with valid serology results for the B antigens, including results reported as less or greater than lower limit of quantitation (\<LLOQ or \>ULOQ).
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.
| Characteristic | Unit | Group 1 (Investigational Quadrivalent Influenza Vaccine) | Group 2 (Investigational Trivalent Influenza Vaccine) | Group 3 (Licensed Trivalent Influenza Vaccine) | Group 4 (Licensed Trivalent Influenza Vaccine) | Total |
|---|---|---|---|---|---|---|
| Participants analysed | 225 | 225 | 225 | 64 | 739 | |
| Age, Categorical: <=18 years | Participants | 0 | 0 | 0 | 0 | 0 |
| Age, Categorical: Between 18 and 65 years | Participants | 0 | 0 | 0 | 64 | 64 |
| Age, Categorical: >=65 years | Participants | 225 | 225 | 225 | 0 | 675 |
| Age Continuous | Years | 72.4 (SD 5.7) | 72.8 (SD 5.6) | 72.8 (SD 5.3) | 46.0 (SD 11.6) | 70.4 (SD 9.8) |
| Sex: Female, Male: Female | Participants | 129 | 121 | 126 | 27 | 403 |
| Sex: Female, Male: Male | Participants | 96 | 104 | 99 | 37 | 336 |
| Region of Enrollment: United States | Participants | 225 | 225 | 225 | 64 | 739 |
6. Primary Endpoint
The registry lists the primary outcome as Geometric Mean Titers Against Influenza B Strains After Vaccination With Fluzone® Quadrivalent Influenza Vaccine or With Trivalent Influenza Vaccines With Corresponding B Strain in Participants Aged 65 Years and Older., measured over Day 21 post-vaccination.
| Element | Registry entry |
|---|---|
| Result type | Geometric Mean |
| Measure of spread | 95% Confidence Interval |
| Unit | Titers |
| Endpoint classification | not reduced to a single comparison |
The primary outcome is geometric mean titers against influenza B strains after vaccination, assessed at Day 21 post-vaccination. Titers were measured in serum using a hemagglutination inhibition assay. The endpoint is an antibody-response measure: it summarizes the concentration of antibodies capable of inhibiting the assay’s hemagglutination reaction. The record describes the primary objective as comparing geometric mean titer ratios for each of the four virus strains separately among participants aged 65 years and older.
A geometric mean is a measure of a group’s typical response that is suited to values spread multiplicatively across a range. In general, it is calculated using logarithms and then transformed back to the original measurement scale. Comparing geometric means through a ratio expresses the relative antibody response between vaccine groups. For a non-inferiority question, the ratio and its confidence interval are interpreted against a prespecified margin; that margin is not reported in the registry record.
The assay’s lower limit of quantitation was 1/10, the lowest dilution used. Titers below that level were reported as <10. The outcome population was randomized and vaccinated participants in the per-protocol population with valid B-antigen serology results, including results reported as less than or greater than the lower limit of quantitation.
7. Why No Re-analysis Is Shown
8. Statistical Interpretation
The registry record describes the intended immunogenicity comparison but does not report numerical geometric mean titers, geometric mean titer ratios, confidence intervals, or a conclusion about non-inferiority. The primary outcome is therefore defined, but the posted information does not permit an assessment of the size or precision of the antibody responses or whether the stated objective was met. The non-inferiority margin is also not reported, so even a ratio estimate alone would not establish how the study’s decision rule was applied.
The stated objective compares the quadrivalent vaccine with two trivalent vaccine formulations for corresponding B strains and assesses four virus strains separately. These are multiple related comparisons, not one single overall contrast. The registry record does not describe how the comparisons were combined, whether any were designated as more important than others, or whether multiplicity was addressed in the statistical plan. A result for one strain would not, by itself, establish the result for the others.
Confidence intervals are important because they show the range of estimates compatible with the data under the statistical model. For a non-inferiority assessment, the interval is interpreted relative to the prespecified margin, not merely by asking whether it includes a null ratio. The registry record does not give the intervals or the margin, so the precision and decision cannot be reconstructed from the posted results.
The safety information lists serious adverse-event counts for the groups, but these counts do not establish whether an event was caused by vaccination. Nor do the reported counts, on their own, provide a complete comparison of event types, timing, or clinical context. The record also lists other adverse-event counts, but does not provide a detailed statistical comparison for those outcomes.
Overall, the record supports a description of the trial’s design, outcome definition, and selected safety counts. It does not provide the numerical primary outcome results or the statistical plan needed to evaluate the planned non-inferiority comparisons. Any conclusion about the comparative antibody response would go beyond what the registry record reports.
9. Statistical Methods Explained
The statistical methods can be understood through the endpoint definition and the trial’s stated comparison. The registry record describes a randomized, quadruple-masked, parallel-group study and an immunogenicity objective based on geometric mean titer ratios. It does not report the detailed statistical analysis plan, so general explanations of these methods should not be mistaken for confirmation of the exact procedures used.
What does a geometric mean titer represent?
Antibody titers can vary over a wide range, and changes are often interpreted multiplicatively rather than as equal additive steps. In general, a geometric mean is calculated by taking logarithms of the observations, averaging on that scale, and transforming the average back to the titer scale. The resulting summary describes a central response while accommodating a skewed distribution. It is not the same as an arithmetic average, and it does not show how widely individual responses vary.
The registry states that titers were measured by hemagglutination inhibition assay. The assay’s lower limit of quantitation was the lowest dilution used, 1/10; results below that level were reported as <10. This convention identifies observations below the assay’s quantifiable range. It does not mean that the underlying antibody level is known exactly. The way such observations were handled in calculating the endpoint is not reported in the registry record.
How should a ratio be read?
A geometric mean titer ratio compares the geometric mean response in one vaccine group with that in another. In general, a ratio expresses relative response rather than an absolute difference in titer units. Its interpretation depends on which group is in the numerator, the comparison group in the denominator, and the prespecified criterion. The registry describes comparisons of the quadrivalent vaccine with trivalent vaccines containing corresponding B strains, but does not report the numerical ratios or specify the ratio orientation in a results presentation.
What does non-inferiority mean?
In a non-inferiority design, the question is whether the new or investigational treatment’s response is not worse than the comparator by more than a defined amount. That amount is the non-inferiority margin. The margin must be specified in advance and the confidence interval assessed against it. A general statistical explanation cannot determine the study’s conclusion without both the margin and the estimate with its uncertainty. Neither the margin nor the numerical primary results is reported in the registry record.
Confidence intervals communicate uncertainty around an estimate. A narrower interval generally indicates greater precision under the model and data used; a wider interval indicates less precision. For non-inferiority, the relationship between the full interval and the margin matters. A point estimate alone is not enough to judge the criterion, and a confidence interval is not a guarantee that the true value lies within its limits.
Why do randomization and masking matter?
Random allocation is intended, in general, to make comparison groups more similar in measured and unmeasured characteristics at the start of a trial. Masking is intended to reduce the potential for expectations to influence trial conduct or outcome assessment. The registry labels this study randomized and quadruple-masked, but does not detail the allocation procedure or identify which roles were masked. Those labels describe design features; they do not establish that all potential sources of bias were eliminated.
The primary outcome population is described as randomized and vaccinated participants in the per-protocol population with valid serology results. Per-protocol analyses generally focus on participants who meet specified study requirements, whereas analyses that include all randomized participants can preserve the balance created by randomization. The registry record does not describe the full eligibility rules for the per-protocol population, give the numbers with valid results for each strain, or report a complementary analysis population.
Finally, the registry lists no reported statistical analyses for the primary outcome. The detailed model, confidence level used for the non-inferiority decision, handling of missing or invalid samples, multiplicity procedures, and sensitivity analyses are not reported in the registry record. Those omissions limit independent reconstruction of the trial’s inferential methods.
10. Multiplicity, Missing Data and Analysis Populations
The primary objective involves comparisons of the quadrivalent vaccine with trivalent vaccines containing corresponding B strains, with geometric mean titer ratios assessed separately for each of the four virus strains. Multiple related comparisons raise a multiplicity question: when several hypotheses are assessed, the chance of at least one apparently favorable result can differ from the chance associated with a single prespecified test. This general issue does not establish that an adjustment was required or used in this trial. The registry record does not report a multiplicity procedure, a hierarchy among strain-specific comparisons, or a rule for interpreting the set of results.
The endpoint description identifies the per-protocol population of randomized and vaccinated participants with valid serology results for the B antigens. It does not report how many participants had valid results for each strain, how missing blood samples or invalid assay results were handled, or whether participants with incomplete data were included in another analysis. The record mentions results below or above the assay’s lower limit of quantitation, but does not explain the statistical treatment of those values. The assay threshold was 1/10, and titers below it were reported as <10.
The registry summary describes safety observations over specified collection windows, but the approach to missing safety follow-up is not reported. It also does not describe a statistical plan for comparing safety outcomes. Without these details, the available registry information cannot establish how missingness or multiple outcomes affected inference.
11. Safety Results
The registry reports serious adverse events as affected participants divided by participants at risk.
| Arm | Participants with serious adverse events | Participants at risk | Percentage |
|---|---|---|---|
| Group 1 (Investigational Quadrivalent Influenza Vaccine) | 0 | 225 | 0.0% |
| Group 2 (Investigational Trivalent Influenza Vaccine) | 1 | 225 | 0.4% |
| Group 3 (Licensed Trivalent Influenza Vaccine) | 2 | 225 | 0.9% |
| Group 4 (Licensed Trivalent Influenza Vaccine) | 0 | 64 | 0.0% |
Other (non-serious) adverse events
Participants with at least one non-serious event at or above the registry's 5.00% reporting threshold.
| Arm | Participants affected of at risk |
|---|---|
| Group 1 (Investigational Quadrivalent Influenza Vaccine) | 73 of 225 |
| Group 2 (Investigational Trivalent Influenza Vaccine) | 52 of 225 |
| Group 3 (Licensed Trivalent Influenza Vaccine) | 64 of 225 |
| Group 4 (Licensed Trivalent Influenza Vaccine) | 31 of 64 |
Most frequent serious adverse event terms
| Event term | Organ system | Group 1 (Investigational Quadrivalent Influenza Vaccine) | Group 2 (Investigational Trivalent Influenza Vaccine) | Group 3 (Licensed Trivalent Influenza Vaccine) | Group 4 (Licensed Trivalent Influenza Vaccine) |
|---|---|---|---|---|---|
| Retina detachment | Eye disorders | 0 of 225 | 0 of 225 | 1 of 225 | 0 of 64 |
| Cellulitis | Infections and infestations | 0 of 225 | 0 of 225 | 1 of 225 | 0 of 64 |
| Malignant melanoma | Neoplasms benign, malignant and unspecified (incl cysts and polyps) | 0 of 225 | 1 of 225 | 0 of 225 | 0 of 64 |
Most frequent non-serious adverse event terms
| Event term | Organ system | Group 1 (Investigational Quadrivalent Influenza Vaccine) | Group 2 (Investigational Trivalent Influenza Vaccine) | Group 3 (Licensed Trivalent Influenza Vaccine) | Group 4 (Licensed Trivalent Influenza Vaccine) |
|---|---|---|---|---|---|
| Injection site pain | General disorders | 73 of 224 | 52 of 225 | 64 of 224 | 31 of 63 |
| Myalgia | Musculoskeletal and connective tissue disorders | 41 of 224 | 32 of 225 | 41 of 224 | 22 of 63 |
| Headache | Nervous system disorders | 30 of 224 | 26 of 224 | 26 of 225 | 16 of 63 |
| Malaise | General disorders | 24 of 224 | 14 of 224 | 26 of 225 | 16 of 63 |
| Injection site Swelling | General disorders | 4 of 224 | 0 of 224 | 3 of 224 | 5 of 63 |
Serious events with the highest arm-level rate: retina detachment (0.4%), cellulitis (0.4%), malignant melanoma (0.4%).
The registry reports serious adverse-event counts and the number of participants at risk in each group. Group 1 had 0 serious adverse events among 225 participants at risk; Group 2 had 1 among 225; Group 3 had 2 among 225; and Group 4 had 0 among 64. These are descriptive counts in the registry record, not evidence by themselves that a vaccine caused or prevented an event. The record does not provide a statistical comparison of serious adverse events between groups.
The listed serious-event terms are retina detachment, cellulitis, and malignant melanoma, each reported as 0.4%. The registry information does not assign these listed terms to a particular group in the details, so they should not be interpreted as group-specific rates. Death counts are not reported in the registry record.
The summary describes collection of solicited injection-site and systemic adverse events for 7 days post-vaccination, unsolicited adverse events collected from 21 days post-vaccination, and adverse events of special interest and serious adverse events from Visit 1 to Visit 2. Counts for other adverse events are also listed by group, but the detailed event definitions, severity grading, and statistical comparisons are not reported in the registry record.
12. What the Result Does, and Does Not, Mean
The registry record establishes that the study was designed to assess antibody responses to a quadrivalent influenza vaccine against trivalent comparators, with the primary immunogenicity objective focused on participants aged 65 years and older. It specifies the assay, the Day 21 post-vaccination assessment, the per-protocol population, and the broad structure of the planned non-inferiority comparisons. Those details clarify what the trial set out to measure.
However, the numerical primary outcome results are not reported in the registry record. There are no posted geometric mean titers, ratios, or confidence intervals in the information available for this analysis. The non-inferiority margin is also not reported. Consequently, the record does not establish whether antibody responses met the planned non-inferiority objective, how large any differences were, or how precisely they were estimated.
The listed serious adverse-event counts describe events recorded in each group, but they do not establish a causal relationship to vaccination. The registry’s selected counts and event terms also cannot represent every aspect of safety, such as the full clinical details, timing, severity, or completeness of follow-up. The safety collection windows are described, but a full safety analysis and its statistical methods are not reported.
In general, trial design and outcome definitions tell readers how evidence was intended to be generated; numerical results and a prespecified decision framework are needed to interpret the evidence. The posted record permits a limited descriptive reading of the trial and its safety counts, but not a conclusion about the comparative immunogenicity of the vaccines. It also cannot support medical advice or a claim about what an individual should receive.
13. Why This Trial Matters Statistically
This study illustrates why an immunogenicity question must be read together with its endpoint, assay, comparison, and decision rule. A geometric mean titer ratio is a relative measure of antibody response, while the non-inferiority objective asks whether the response is sufficiently close to a comparator under a prespecified margin. The margin and the numerical estimates are essential to interpreting that question; neither is reported in the registry information.
The trial also highlights the complexity of multiple strain-specific comparisons. The primary objective addresses four virus strains separately and includes comparisons with trivalent vaccines containing corresponding B strains. A reader needs to know how the investigators planned to interpret these related tests, including whether one result could be considered independently or whether a joint rule applied. The registry record does not report such a rule.
At the same time, the record shows the value of defining the analysis population and measurement process. It identifies a per-protocol population with valid serology, the Day 21 assessment, and the assay’s lower quantitation limit. These details matter because measurement thresholds and participant inclusion can affect the interpretation of group summaries. The record does not provide enough detail to assess how observations outside the assay’s quantifiable range or missing results were handled.
Finally, the descriptive serious adverse-event counts show why event counts should not be treated as causal comparisons. They are useful context, but require careful interpretation alongside follow-up, event definitions, group assignment, and analysis methods. The registry record offers a structured account of intended objectives and selected observations, while leaving important results and methods unreported.
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 this trial from the registry record is that numerical primary immunogenicity results are not reported. Geometric mean titers, ratios, and confidence intervals are unavailable, as is the non-inferiority margin. The central comparative question therefore cannot be evaluated from the posted information.
The record describes four groups but does not explain why there are two licensed trivalent-vaccine groups or what distinguishes them. It reports an enrollment of 739, but does not give group-specific enrollment for the primary immunogenicity analysis or clarify the allocation ratio. The primary outcome description narrows the population to participants aged 65 years and older with valid serology in a per-protocol population, but detailed population counts are not reported.
Several statistical details are also absent: the multiplicity approach for strain-specific comparisons, handling of missing or invalid samples, handling of measurements below the assay limit, the complete analysis model, and any sensitivity analyses. The record does not report an interim-analysis plan, sample-size justification, or detailed statistical plan. These gaps limit reproducibility and independent assessment.
Safety interpretation is limited by the selected event counts and terms. The record does not provide detailed event-level descriptions, group assignment for the listed serious-event terms, or a statistical comparison. Death counts are not reported in the registry record. The safety counts should therefore be read as descriptive registry information rather than as a complete assessment of comparative safety.
15. Related Tutorials
16. Related Statistical Calculators
17. Sources
- ClinicalTrials.gov: Study of Quadrivalent Influenza Vaccine Among Adults — NCT01218646.
- Registry record last updated 2013-10-23; status last verified 2013-09.
- Results first posted 2013-09-12.
- 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.
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18. Record Summary
The registry record describes a completed, randomized, quadruple-masked, parallel-group Phase 3 trial of quadrivalent and trivalent influenza vaccines, with an enrollment of 739. The primary immunogenicity objective was to compare geometric mean titer ratios for four virus strains in participants aged 65 years and older, using a Day 21 post-vaccination hemagglutination inhibition assay. The outcome population was per-protocol participants with valid serology results.
The record also describes safety monitoring across specified post-vaccination periods and reports serious adverse-event counts by group. Numerical primary immunogenicity results, the non-inferiority margin, and detailed statistical methods are not reported in the registry record. As a result, the design and outcome definitions can be described, but the primary non-inferiority conclusion cannot be assessed from the posted information.