Comparative Study of Influenza Vaccines in Adults, FLUVACS-year 4: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Comparative Study of Influenza Vaccines in Adults, FLUVACS-year 4 (NCT00538512), a randomized phase 4 study. The primary outcome is Laboratory-confirmed (Culture and/or PCR) Symptomatic Influenza.

2. Clinical Question

3. Trial Design

The registry record describes NCT00538512, Comparative Study of Influenza Vaccines in Adults, FLUVACS-year 4. It lists the study as Phase 4, randomized and double-masked, with a single-group model designation. The record lists University of Michigan as sponsor, status as completed, and enrollment as 1952. The listed study dates are 2007-09 for start and 2008-05 for primary completion.

Three arms appear in the posted outcome results: Fluzone, Flumist and placebo. The arm descriptions identify Fluzone as trivalent inactivated influenza vaccine and Flumist as live-attenuated influenza vaccine. Placebo was physiologic saline administered as a nasal spray or intramuscular injection. The record does not explain how the route of placebo administration corresponded to the active vaccine routes, so no further detail about matching procedures can be inferred.

The primary outcome was laboratory-confirmed symptomatic influenza, with culture and/or PCR listed as confirmation methods. Its timeframe was one influenza season, 2007-2008, and the outcome population was labeled ITT. The arm counts posted for this endpoint are 814 for Fluzone, 813 for Flumist and 325 for placebo. These are the outcome denominators reported by arm; the record does not explain any difference between these denominators and overall enrollment.

Randomization and double masking are recorded, but the method used to generate the allocation sequence, concealment procedures, masking assessment, and details of the trial's own planned statistical analysis are not reported in the registry record. Although the study summary describes goals that include comparing the vaccines with each other, the posted contrasts are each vaccine versus placebo.

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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: ITT

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 Laboratory-confirmed (Culture and/or PCR) Symptomatic Influenza, measured over one influenza season - 2007-2008.

The primary endpoint counts participants with laboratory-confirmed symptomatic influenza. The registry specifies culture and/or PCR as confirmation methods, identifies the outcome unit as participants, and gives the timeframe as one influenza season, 2007-2008. The primary population is labeled ITT. The posted result is therefore a count of participants meeting the endpoint in each arm, rather than a count of all influenza episodes.

Laboratory confirmation provides a defined basis for classifying symptomatic illness as an endpoint event. In general, a prespecified clinical endpoint helps make comparisons interpretable by clarifying what qualifies as an event and when it is assessed. Combining symptom criteria with laboratory confirmation distinguishes this endpoint from a report of symptoms alone. The registry's brief summary states that the study aimed to evaluate outcomes caused by circulating strains, whether similar or dissimilar to strains included in the vaccines.

The posted arm counts are 28 participants in the Fluzone arm, 56 in the Flumist arm and 35 in the placebo arm. Those counts need to be read alongside each arm's denominator and the estimated comparisons: counts alone do not account for differences in the number of participants represented in each arm. The endpoint does not, by itself, describe the severity or duration of influenza illness, and those features are not reported as part of this primary measure.

7. Results Posted in the Registry

• Fluzone - Trivalent Inactivated Influenza Vaccine: 3.4% (28/814) versus 10.8% (35/325) on control; risk difference -7.3 percentage points (95% CI -10.9 to -3.7), risk ratio 0.32 (0.20–0.52); unadjusted two-proportion z-test p = <0.001.
• Flumist - Live-attenuated Influenza Vaccine: 6.9% (56/813) versus 10.8% (35/325) on control; risk difference -3.9 percentage points (95% CI -7.7 to -0.1), risk ratio 0.64 (0.43–0.96); unadjusted two-proportion z-test p = 0.029.

8. Statistical Interpretation

9. Statistical Methods Explained

In general, a binary endpoint records whether each participant experienced the event or did not. Here the posted endpoint is the number of participants with laboratory-confirmed symptomatic influenza. A risk is the proportion of participants in an arm who experienced the event during the stated timeframe. The registry provides the arm counts and denominators, as well as proportions used in its comparisons.

What does the risk difference describe?

A risk difference subtracts the comparator-arm risk from the intervention-arm risk. It is expressed on the absolute probability scale, so its sign gives the direction of the contrast under that ordering. The registry reports risk differences of -0.073 for Fluzone versus placebo and -0.039 for Flumist versus placebo. A negative value means the posted event proportion was lower in the vaccine arm than in placebo for that comparison. This description is about the observed contrast and does not by itself establish a causal effect or settle questions about bias or missing data.

How should the other effect measures be understood?

For each comparison, the record also lists a relative risk and an odds ratio with confidence limits. In general, a relative risk compares the event risk between two arms, while an odds ratio compares event odds. These measures use different scales from the risk difference. They are alternate descriptions of the same binary outcome contrast, not additional independent outcomes. Their values are not needed to interpret the risk-difference estimates, and the record does not describe an adjusted model behind them.

What does a confidence interval convey?

In general, a confidence interval describes the range of estimates reasonably compatible with the observed data under the method's assumptions. A narrower interval indicates greater statistical precision on the measure's scale; a wider interval indicates more uncertainty. It is not a range that contains the true effect with a stated probability after the data have been observed. For Fluzone, the reported risk-difference interval is -0.109 to -0.037. For Flumist, it is -0.077 to -0.001. These ranges describe uncertainty in the estimated risk differences; they do not incorporate every potential source of uncertainty, such as selection or measurement bias.

What do the p-values mean?

In general, a p-value measures how incompatible the observed data, or more extreme data, are with a specified null hypothesis, assuming the analysis model and other assumptions hold. The posted unadjusted p-values are p < 0.001 for Fluzone versus placebo and p = 0.029 for Flumist versus placebo. A p-value is not the probability that the null hypothesis is true, and it does not measure the size or clinical importance of an effect. Neither p-value is reported as adjusted for the presence of multiple comparisons.

What is the role of the intention-to-treat label?

The registry labels the primary outcome population ITT. In general, an intention-to-treat approach aims to analyze participants according to their randomized assignment, regardless of subsequent adherence. The label alone does not establish exactly how participants with missing outcome information, protocol deviations or other post-randomization events were handled. Those details are not reported in the registry record. The posted denominators are 814, 813 and 325 for the Fluzone, Flumist and placebo outcome groups, respectively; the record does not explain the relationship between those denominators and the overall enrollment count.

Why does randomization matter, and what does it not resolve?

In general, random assignment is intended to make comparison groups similar on average with respect to measured and unmeasured baseline factors. Double masking can reduce some differences in care or outcome assessment when it is successfully implemented. These design features do not guarantee that every source of bias is absent. They also do not replace reporting of allocation methods, masking procedures, adherence, missingness and analysis choices. The record identifies the study as randomized and double-masked but does not report those operational details.

The record gives no outcome dispersion measure because the primary outcome is a binary participant count. It also does not report model diagnostics or an analysis plan explaining the choice of each effect measure. General statistical caution is therefore appropriate: estimates and p-values should be read as the posted unadjusted summaries, while broader claims require details and analyses not reported in the registry record.

10. Confidence Intervals and Precision

The Fluzone-versus-placebo risk difference is -0.073, with a 95% confidence interval from -0.109 to -0.037. The interval stays below zero and spans a range of absolute differences, reflecting uncertainty around the point estimate. Its width should be interpreted on the risk-difference scale, not as a relative percentage or a measure of clinical importance.

The Flumist-versus-placebo estimate is -0.039, with a 95% confidence interval from -0.077 to -0.001. The upper limit is close to zero, so the reported interval includes estimates close to no difference, as well as more negative values. This interval is less separated from zero than the Fluzone interval, but both intervals' widths and locations are part of interpreting precision; a point estimate alone would conceal that uncertainty.

In general, confidence intervals summarize sampling uncertainty under the method used. They do not account automatically for possible outcome misclassification, missing data, departures from the analysis population or unreported design features. The registry does not report methods for handling missing endpoint data or adjustments for multiplicity. The intervals should therefore be understood as precision summaries for the posted comparisons, not as comprehensive measures of every uncertainty in the evidence.

The placebo arm has a smaller reported outcome denominator than either vaccine arm. In general, the amount of information available in each arm affects precision, along with the event frequency and analysis method. The posted intervals provide the most direct account of the uncertainty in these two risk-difference estimates. They do not establish how precise a future study would be, and the registry record does not report a direct interval for the contrast between the two vaccines.

11. Planning a Similar Trial: Sample Size

This is a planning illustration, not a re-evaluation of the original trial. It asks: if a new study wanted to detect a difference like the one observed, or a smaller one, how large would it need to be? It is deliberately not “observed power” of the finished trial, which is not a meaningful quantity.

The sample-size figures are planning illustrations for a two-arm comparison, reported as participants per arm. They are not total event counts. The assumptions listed for these illustrations are a two-sided significance level of 0.05, equal allocation between the two arms, and a normal approximation. The effect to detect is set at the stated fraction of the observed effect. These are planning assumptions, not the original trial's design assumptions; the trial's own sample-size justification is not reported in the registry record.

The 80% power column gives the number of participants per arm in a hypothetical design intended to have an 80% chance of detecting the specified effect under the listed assumptions, if that effect and those assumptions were correct. The 90% power column gives the corresponding planning number for a higher target chance of detection. These are design calculations, not a guarantee that a study of that size will detect an effect.

Rows for 100% of the observed effect use the observed estimate as the target effect in the illustration. Rows for 75% and 50% of the observed effect use smaller target effects. Smaller effects are harder to distinguish from no difference under otherwise unchanged assumptions, so they require more participants per arm in the planning calculations. The values differ by comparison because the observed effects differ.

The accompanying curve should be read as part of these planning scenarios, not as a depiction of the trial's achieved statistical power. The figures are not observed power. They do not show what the trial's original investigators planned, because the original design assumptions are not reported in the registry record.

12. How the Sample Size Is Derived

Power is the probability that a study of a given size rejects the null hypothesis when a specific true effect exists. It depends on four things: the effect to detect, the variability of the outcome, the significance level (here a two-sided α of 0.05, so z_1−α/2 = 1.960) and the desired power (z_1−β = 0.842 for 80% and 1.282 for 90%).

Formula

n is the number of participants in each arm, p₀ and p₁ are the control and treatment proportions, and p̄ is their average.

Worked calculation for this trial

1. Control proportion p₀ = 0.108; treatment proportion p₁ = 0.034; average p̄ = 0.071.
2. First term: z_1−α/2 × √[2p̄(1−p̄)] = 1.96 × 0.3633 = 0.7121.
3. Second term: z_1−β × √[p₀(1−p₀) + p₁(1−p₁)] = 0.842 × 0.3596 = 0.3026.
4. n = (0.7121 + 0.3026)² / (-0.0733)² = 191.7, rounded up to 192 participants per arm for 80% power.

The smaller-effect rows in the table above repeat the same calculation with the effect multiplied by 0.75 and 0.5 (for ratios, applied to the logarithm of the ratio).

R code

alpha <- 0.05
z_a   <- qnorm(1 - alpha / 2)          # two-sided
p0 <- 0.107692307692308                          # control proportion
p1 <- 0.0343980343980344                          # treatment proportion
n_per_arm <- function(power, frac = 1) {
  q1 <- p0 + (p1 - p0) * frac               # smaller effect = fraction of the observed difference
  pbar <- (p0 + q1) / 2
  z_b <- qnorm(power)
  ceiling(round((z_a * sqrt(2 * pbar * (1 - pbar)) + z_b * sqrt(p0 * (1 - p0) + q1 * (1 - q1)))^2 / (q1 - p0)^2, 6))
}
for (f in c(1, 0.75, 0.5))
  cat(sprintf("%3.0f%% of observed effect: n per arm = %s (80%% power), %s (90%% power)\n", 100 * f,
              format(n_per_arm(0.80, f), big.mark = ","), format(n_per_arm(0.90, f), big.mark = ",")))

# Check against R's built-in function (unrounded n per arm)
cat("power.prop.test:", round(power.prop.test(p1 = p0, p2 = p1, power = 0.80)$n, 1), "\n")

# Simulation: how often does the z-test reject at the 80%-power sample size?
set.seed(538512)
n    <- n_per_arm(0.80)
reps <- 20000
x0 <- rbinom(reps, n, p0); x1 <- rbinom(reps, n, p1)
ph <- (x0 + x1) / (2 * n)
z  <- ((x1 - x0) / n) / sqrt(ph * (1 - ph) * 2 / n)
cat(sprintf("Simulated power at n = %s per arm: %.3f (%d replicates)\n", format(n, big.mark = ","), mean(abs(z) > z_a, na.rm = TRUE), reps))

Output from running the code

100% of observed effect: n per arm = 192 (80% power), 257 (90% power)
 75% of observed effect: n per arm = 383 (80% power), 511 (90% power)
 50% of observed effect: n per arm = 951 (80% power), 1,272 (90% power)
power.prop.test: 191.7 
Simulated power at n = 192 per arm: 0.825 (20000 replicates)

The simulation draws many pairs of event counts at the planned sample size and counts how often the two-proportion z-test rejects the null. It should land close to the target power; at very small required sample sizes it can fall below it, because the normal approximation is rough there.

13. Multiplicity, Missing Data and Analysis Populations

The record lists one primary endpoint and also names secondary outcomes concerning vaccine-induced immune response, immune response to vaccination and infection, serologic correlates of protection, and postvaccination seroconversion. The registry lists four outcome measures and reports three secondary outcomes. The two posted primary-outcome contrasts each compare a vaccine arm with placebo. A direct contrast between Fluzone and Flumist is not posted.

When several hypotheses or endpoints are tested, the chance of at least one false-positive result can increase. In general, multiplicity procedures can control or otherwise address this issue, depending on the analysis plan. The registry record does not report a multiplicity strategy, a testing hierarchy, or adjusted p-values. The posted p-values should therefore be read as unadjusted, as identified in the comparison results, rather than as evidence that a multiplicity adjustment was applied.

The primary population is labeled ITT. The registry does not report how missing outcome data were handled, whether any participants were excluded from the primary analysis, or whether imputation or sensitivity analyses were used. The reported arm denominators are 814 for Fluzone, 813 for Flumist and 325 for placebo, while total enrollment is listed as 1952. The record does not explain the relationship between the enrollment figure and the outcome denominators; no assumptions about missingness or exclusions can be made from the counts alone.

Randomization and double masking are recorded, but allocation concealment, adherence assessment, protocol deviations, analysis-set definitions beyond the ITT label, and prespecified statistical procedures are not reported in the registry record. These omissions limit assessment of how the posted comparisons were selected and implemented. They do not change the numerical results, but they constrain how confidently the results can be interpreted beyond the reported unadjusted contrasts.

14. 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 0% reporting threshold.

Most frequent serious adverse event terms

Serious events with the highest arm-level rate: cholecystitis, cholecystectomy, cholelithiasis (0.6%), depression/anxiety (0.3%), breast cancer/mastectomy (0.1%), cellulitis left leg (0.1%), surgury - remove tumor in left ovary/fallopian tube (0.1%).

The serious adverse event results list 8 affected participants in the Fluzone group, 4 in the Flumist group and 3 in the placebo group. The corresponding groups at risk are reported as 814, 813 and 325. The record also lists zero participants with other adverse events for each group. Death counts are not reported in the registry record; a missing value should not be interpreted as a count of zero.

The listed serious-event terms include Cholecystitis, cholecystectomy, cholelithiasis at 0.6%, Depression/anxiety at 0.3%, Breast Cancer/Mastectomy at 0.1%, Cellulitis left leg at 0.1%, surgury - remove tumor in left ovary/fallopian tube at 0.1%, and Appendectomy at 0.1%. These terms and percentages are reported as serious-event information; the record does not specify a treatment-related attribution for them. They should not be read as a complete account of all safety outcomes or as a comparison adjusted for the different group denominators.

In general, adverse-event counts describe events recorded under the study's reporting procedures. The registry does not report detailed event definitions, follow-up duration for safety, causal assessments, or statistical comparisons of these safety results. The posted figures support a descriptive reading only.

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

The posted results describe laboratory-confirmed symptomatic influenza during one influenza season, 2007-2008, among participants assigned to Fluzone, Flumist or placebo. For each vaccine-versus-placebo comparison, the registry reports a negative unadjusted risk difference, with the corresponding confidence interval and p-value. The numerical estimates and their uncertainty are the central findings available for the primary endpoint.

These results do not establish a direct difference between Fluzone and Flumist. Although the study summary mentions relative efficacy of one vaccine compared with the other, the posted comparisons are each against placebo. A difference between two separate comparisons against a shared comparator cannot be treated as a reported direct comparison. No direct estimate or confidence interval for Fluzone versus Flumist appears in the registry record.

The results also do not show whether observed differences were consistent across particular circulating strains, because no strain-specific primary-outcome analysis is reported. The study summary describes interest in strains similar or dissimilar to those included in the vaccines, but the posted primary outcome is an overall participant count for the season. Nor does the endpoint describe illness severity, duration or other clinical outcomes beyond laboratory-confirmed symptomatic influenza.

In general, randomized, double-masked designs can strengthen comparisons by reducing some sources of systematic difference, but the record does not report enough procedural detail to assess all potential biases. Missing-data handling and multiplicity adjustment are not reported. The confidence intervals describe statistical precision for the posted contrasts under their analytical assumptions, not uncertainty from every possible source.

The results apply to the recorded study population, interventions, comparator and season. The registry record does not establish that the estimates will generalize to other populations or influenza seasons. The posted findings should therefore be understood as the observed evidence for this trial endpoint and not as a standalone recommendation or a guarantee of outcomes in another setting.

16. Why This Trial Matters Statistically

This trial presents a useful setting for distinguishing event counts from comparative effects. The posted counts are not directly comparable in isolation because the arm denominators differ, including a smaller placebo denominator. Risk differences place the contrasts on an absolute scale and make the direction and estimated magnitude of each vaccine-versus-placebo comparison explicit. Confidence intervals add information about how precisely each contrast is estimated.

The results also illustrate why a study's stated scientific aim and its posted contrasts need to be distinguished. The study summary describes both absolute and relative vaccine efficacy, but the registry posts two vaccine-versus-placebo comparisons rather than a direct comparison between the vaccines. Statistical interpretation should follow the estimates actually reported rather than infer an unreported contrast from separate results.

The two confidence intervals differ in their relationship to zero, with the Flumist interval extending close to zero. That highlights why estimates, intervals and p-values are best read together. A p-value alone does not convey the range of plausible effect sizes, and statistical evidence against a null value does not by itself resolve clinical importance, bias or reproducibility.

Finally, the record offers a basis for discussing the difference between trial results and planning illustrations. The planning figures use stated hypothetical assumptions and fractions of observed effects; they are not a report of the trial's original design rationale or its achieved power. In this way, the case underscores the importance of separating observed data, inferential summaries and prospective design calculations.

17. 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 primary results cover one influenza season, identified as 2007-2008. Findings from that season may not describe outcomes in another season, and the record does not post a strain-specific analysis despite the study summary's interest in circulating strains similar or dissimilar to vaccine strains.

The registry provides unadjusted vaccine-versus-placebo comparisons, but no direct Fluzone-versus-Flumist estimate. This limits interpretation of the relative comparison described in the study summary. The record does not report adjusted analyses, a detailed statistical plan, multiplicity procedures, missing-data methods, or sensitivity analyses. It also does not report the method of randomization, allocation concealment or details of how double masking was implemented.

The primary population is labeled ITT, but that label does not explain how the analysis treated participants whose outcome status may have been unavailable. The outcome denominators differ by arm, and the record does not explain their relationship to overall enrollment. Therefore, the posted counts alone cannot establish whether denominator differences reflect missing outcomes, exclusions or another reason.

The primary endpoint captures participants with laboratory-confirmed symptomatic influenza, not the number of episodes or their severity. Other outcomes such as symptom duration are not included in the posted primary result. The registry lists secondary immune-response outcomes, but does not provide corresponding results in the information summarized by the primary endpoint. These limitations restrict what can be concluded from the posted outcome comparisons without negating their descriptive value.

18. Related Tutorials

19. Related Statistical Calculators

20. Sources

• ClinicalTrials.gov: Comparative Study of Influenza Vaccines in Adults, FLUVACS-year 4 — NCT00538512.
• Registry record last updated 2017-12-06; status last verified 2017-11.
• Results first posted 2011-09-12.
• 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.

21. Record Summary

NCT00538512 is listed as a completed Phase 4 randomized, double-masked study sponsored by University of Michigan. The record gives the title Comparative Study of Influenza Vaccines in Adults, FLUVACS-year 4, enrollment of 1952, a start date of 2007-09 and primary completion in 2008-05.

The study compared trivalent inactivated influenza vaccine Fluzone and live-attenuated influenza vaccine Flumist with physiologic saline placebo. The primary endpoint was the number of participants with laboratory-confirmed symptomatic influenza during one influenza season, 2007-2008, in the ITT population. Posted unadjusted risk-difference comparisons are available for each vaccine versus placebo. A direct vaccine-versus-vaccine contrast, detailed missing-data procedures, multiplicity adjustment and the trial's own sample-size assumptions are not reported in the registry record.