Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain (NCT04978454), a randomized phase 1 study. The primary outcome is Number and Percentage of Participants With Symptomatic Influenza Virus Infection After Challenge..

2. Clinical Question

This is a controlled human challenge question, not a comparison of routine influenza prevention or treatment strategies. The outcome combines laboratory evidence of viral shedding with a symptom threshold, so it captures participants who met both criteria rather than participants with either laboratory detection or symptoms alone. The groups are dose levels within a challenge design, not clinical treatment regimens. The study’s stated goal was to characterize infection, symptoms, viral recovery, immune responses, and safety by dose. The registry record does not report a formal statistical comparison of the groups.

3. Trial Design

The registry record identifies NCT04978454 as a completed phase 1, randomized, sequential, dose-ranging influenza challenge study. Enrollment is recorded as 60. Its official title describes a multicenter, blinded, randomized, placebo-controlled study, and the record lists triple masking. However, the brief summary calls the study open-label. These descriptions conflict, and the registry record does not resolve the discrepancy. The actual masking practices should therefore not be inferred from the title or summary alone.

The study evaluated recombinant H3N2 challenge virus at three listed doses: 10^4, 10^5, and 10^6 TCID50. The dose-group descriptions specify intranasal administration. A sham inoculum served as the comparator. The design is described as sequential and adaptive, with cohort progression depending on infection and safety observations. The available cohort descriptions are truncated, so their complete escalation and stopping rules are not reported in the registry record.

The posted primary outcome counts are 4 participants among 12 in the 10^4 TCID50 group, 5 among 10 in the 10^5 TCID50 group, 28 among 36 in the 10^6 TCID50 group, and 0 among 2 in the sham group. These are descriptive counts of participants meeting the composite endpoint. They do not, on their own, establish the precision of a dose comparison or a causal difference between groups.

The brief summary says the study aimed to find a minimum dose that would elicit a high symptomatic attack rate without meeting safety-stopping criteria. It also describes a planned enrollment of up to 106 challenge participants plus 8 shams, whereas the enrollment field records 60 and the posted outcome groups contain 60 participants. The record does not explain this difference. The study dates recorded are 2021-08-19 for start and 2022-09-22 for primary completion; status is completed.

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: The Safety population consists of all participants who received study influenza challenge or sham inoculum.

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 and Percentage of Participants With Symptomatic Influenza Virus Infection After Challenge., measured over Day 2 through Day 8.

The primary endpoint is the number and percentage of participants with symptomatic influenza virus infection after challenge, assessed from Day 2 through Day 8. The registry defines a case using two components that must both be met. First, viral shedding must be demonstrated by a positive qualitative RT-PCR result or detectable quantitative RT-PCR result on at least two days, beginning 24 hours after challenge and continuing through Study Day 8. Second, the cumulative symptom score must be 6 across a consecutive five-day window through Day 8, with the window beginning on Day 2 post-challenge. Symptoms are scored using the Modified Jackson Score, which ranges from 0 to 36; higher scores correspond to worse outcomes.

This composite outcome is intended to distinguish symptomatic infection from viral detection alone or symptoms alone. Requiring both components makes the endpoint clinically and biologically more specific to the study’s stated question about symptomatic challenge infection. It also means that a participant who meets only one component does not meet the stated case definition.

As a general statistical point, composite endpoints can capture several related features in one outcome, but their interpretation depends on every component and threshold in the definition. Here, the endpoint is a binary participant-level classification, reported as counts and percentages. The registry record does not report an estimate of uncertainty around the posted counts or a formal statistical comparison among dose groups. It also does not explain how incomplete symptom or viral-testing data were handled. Thus, the observed case counts describe the registered outcome definition, while the precision and sensitivity of those classifications cannot be fully assessed from the record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary: each participant either met the registry’s symptomatic infection definition or did not. The reported count is the number meeting that definition within each group. A percentage is a way to express that count relative to the group size, but the registry record does not include an inferential analysis or uncertainty interval for these group results. The counts should therefore be read as descriptive observations in the enrolled groups.

What does a confidence interval add?

As a general statistical explanation, a confidence interval expresses uncertainty around an estimated quantity. For a participant-level event outcome, it can show a range of values compatible with the observed data under the assumptions of the method used. It does not guarantee that the underlying value lies in that particular interval, and it does not remove limitations such as small group sizes or selection into a study. No confidence intervals for the primary outcome are reported in the registry record, so the precision of the group event rates cannot be assessed from posted intervals.

Why are the group counts not a formal dose comparison?

As a general matter, comparing proportions can involve an estimate of the difference or another contrast, together with an uncertainty measure and a test or model. The choice depends on the design, group sizes, and planned estimand. This registry record has no posted analysis entries and says a two-arm binary comparison was not estimable from the available information. There is consequently no reported p-value, adjusted comparison, or model-based dose trend to interpret. The observed counts should not be turned into a claim of statistical significance.

The sequential dose-ranging structure is relevant to interpretation. As a general concept, when cohorts proceed in sequence and later enrollment may depend on earlier observations, the data-generating process can differ from a simple fixed parallel-group design. The full cohort rules, enrollment decisions, and safety-stopping criteria are not reported in the registry record. Without those details, it is not possible to assess how the adaptive process was incorporated into any analysis or how it might affect uncertainty in a dose comparison.

What does the sample-size illustration represent?

The record describes a planning illustration based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. It says that the effect to detect is expressed as a stated fraction of the observed effect; for non-time-to-event outcomes, the illustration is expressed as participants per arm for a selected power target. These are planning assumptions, not evidence about the trial’s actual design justification. They are not observed power, and they do not show that the study had a particular probability of detecting an effect. The protocol’s sample-size justification and any prespecified target power are not reported in the registry record. No resulting planning values are stated in the record information available for this analysis.

As a general explanation, power is a design-stage probability defined relative to a particular effect, variability or event-rate assumption, analysis method, and significance threshold. Retrospective calculations using the observed effect are especially sensitive to the observed data and are not a substitute for a prospective design rationale. A planning illustration can help describe the scale of a future study under its assumptions, but it does not strengthen or weaken the evidence from the current trial.

Why can over-dispersion matter?

As a general statistical concept, over-dispersion means that observed variation is greater than a model assumes. It is often discussed for count outcomes, where a simple model may underestimate uncertainty if counts vary more than expected. The primary endpoint is a binary participant-level outcome, not a count of repeated events for each participant, and no dispersion estimate is reported. The registry record does not describe a model that accounts for over-dispersion. The concept therefore does not supply an additional interpretation of the posted primary counts.

The outcome definition itself also has methodological consequences. A participant must satisfy both the virologic and symptom criteria, so the endpoint depends on measurement and availability of both types of information. As a general point, any composite outcome can be affected by how its components are measured, how thresholds are chosen, and how missing component data are classified. The registry record gives the criteria, including the PCR evidence, symptom score, time window, and score range, but does not report adjudication procedures, missing-data rules, or sensitivity analyses.

Finally, the safety population is defined as all participants who received study influenza challenge or sham inoculum. That definition identifies the stated population for safety assessment, but the registry record does not provide detailed analysis-population rules for every outcome, nor does it report a separate per-protocol or intention-to-treat analysis. The posted group denominators are the ones associated with the primary counts; further population definitions are not reported in the registry record.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("10^4 TCID50 Challenge Virus", "10^5 TCID50 Challenge Virus", "10^6 TCID50 Challenge Virus", "Sham Inoculum")
n      <- c(12, 10, 36, 2)
events <- c(4, 5, 28, 0)
for (i in seq_along(n)) {
  ci <- binom.test(events[i], n[i])$conf.int          # Clopper-Pearson exact interval
  cr <- qbeta(c(0.025, 0.975), 1 + events[i], 1 + n[i] - events[i])   # Bayesian, uniform Beta(1,1) prior
  wi <- (function(x, n) { p <- x / n; z <- qnorm(0.975); d <- 1 + z^2 / n
    c((p + z^2 / (2 * n) - z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d, (p + z^2 / (2 * n) + z * sqrt(p * (1 - p) / n + z^2 / (4 * n^2))) / d) })(events[i], n[i])
  cat(sprintf("ARM|%s|%d|%d|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f|%.1f\n", arm[i], n[i], events[i], 100 * events[i] / n[i],
              100 * ci[1], 100 * ci[2], 100 * wi[1], 100 * wi[2], 100 * cr[1], 100 * cr[2]))
}

ARM  10^4 TCID50 Challenge Virus  12  4  33.3  9.9  65.1  13.8  60.9  13.9  61.4
ARM  10^5 TCID50 Challenge Virus  10  5  50.0  18.7  81.3  23.7  76.3  23.4  76.6
ARM  10^6 TCID50 Challenge Virus  36  28  77.8  60.8  89.9  61.9  88.3  61.8  88.2
ARM  Sham Inoculum  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8

11. Multiplicity, Missing Data and Analysis Populations

The registry record lists 16 outcome measures and 10 posted secondary outcomes, including adverse-event counts, serological conversion, and geometric mean antibody titers. It reports no analysis entries for the outcome results. A multiplicity strategy—such as a hierarchy of confirmatory outcomes, adjustment across tests, or designation of outcomes as exploratory—is not reported in the registry record. Without that information and without posted inferential results, the secondary outcomes cannot be interpreted as a family of confirmatory hypothesis tests.

The record does not report a missing-data plan for the primary endpoint. It does not state how participants with incomplete viral testing, symptom diaries, or follow-up were classified, whether any imputation was used, or whether sensitivity analyses were conducted. This matters because the primary case definition requires both viral and symptom information over specified post-challenge periods. The registered safety population includes participants who received challenge or sham inoculum, but that definition alone does not specify how missing observations were handled.

The protocol’s planned analysis population beyond the stated safety population, details of randomization implementation, and analysis methods for the primary or secondary endpoints are not reported in the registry record. The record also does not report interim analyses or whether results were reviewed at cohort transitions under formal statistical monitoring rules. The sequential design description indicates that cohort progression was adaptive, but the detailed decision process is not available in the record information. These omissions limit assessment of multiplicity, missingness, and the relationship between the planned design and the posted descriptive counts.

12. Safety Results

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

Deaths

Other (non-serious) adverse events

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

Most frequent non-serious adverse event terms

The posted serious adverse event counts are zero in the 10^4 TCID50 group, zero in the 10^5 TCID50 group, zero in the 10^6 TCID50 group, and zero in the sham group. The corresponding numbers at risk are 12, 10, 36, and 2. The registry also lists no serious adverse event terms. These are observed results for the participants represented in the safety groups; a zero count does not establish that serious events are impossible or that the risk is zero in a broader population.

The registry lists other adverse events for 6 participants in the 10^4 group, 8 in the 10^5 group, 17 in the 10^6 group, and 2 in the sham group. The record does not give event terms in the information available for this analysis, so the nature, timing, severity, and relationship to inoculation cannot be described from these counts. Counts across groups should not be interpreted as a causal comparison, particularly without a prespecified safety analysis and uncertainty estimates.

The study’s stated purpose included evaluating safety and using safety-stopping criteria during dose escalation. The detailed stopping rules and whether any threshold was approached are not reported in the registry record. The absence of posted serious events should therefore be distinguished from a complete evaluation of safety across all possible event types and follow-up periods.

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

The results describe a controlled influenza challenge study in healthy adults, with observed symptomatic infection counts reported separately for three challenge doses and sham inoculum. The endpoint combines viral shedding and a symptom score within a defined period. The counts show that participants in each group did not all have the same observed outcome, and the largest posted case count is in the 10^6 TCID50 group. No participant in the sham group met the endpoint definition. These observations address the study’s descriptive dose-ranging question.

They do not, by themselves, establish a precise difference between doses. No confidence intervals, p-values, or formal primary-outcome comparisons are posted. The sham group is small, and the record does not explain how missing outcome information was handled. The counts also do not separate the virologic and symptom components, so they cannot show which component most often determined whether a participant met the composite endpoint.

The study’s stated aim was to identify a challenge dose for future research, taking account of symptomatic attack rate and safety criteria. The posted counts alone do not document which dose was selected as optimal or whether a prespecified stopping boundary was met. The complete cohort decision rules and a formal sponsor conclusion are not reported in the registry record. It would therefore be inappropriate to treat the observed ordering of counts as a definitive dose-selection result.

These findings also do not answer whether a vaccine or intervention prevents influenza. The study was a challenge-dose and safety study, and the posted primary outcome is symptomatic infection following challenge. The record does not report a vaccine efficacy comparison. The findings should not be generalized beyond the study population and setting without supporting evidence. They are best understood as descriptive data from the enrolled challenge groups, with substantial limitations in the inferential detail available in the registry record.

14. Why This Trial Matters Statistically

Challenge studies require careful definition of what constitutes infection. This study’s primary endpoint requires both evidence of viral shedding and a symptom score threshold, rather than relying on either component alone. That makes the endpoint definition central to interpretation: the result reflects a particular combination of laboratory and symptom criteria over a specific follow-up window.

The dose-ranging objective also illustrates why design context matters. The registry describes sequential cohorts and adaptive progression, so dose groups arise within a design intended to inform later cohort decisions. Understanding those decisions requires the full escalation rules, stopping boundaries, and analysis plan. Those details are not reported in the registry record, limiting the ability to evaluate the design’s statistical operating characteristics from the posted results.

The contrast between the descriptive counts and the absence of formal analyses is important for clinical researchers. Counts can reveal the pattern observed in the enrolled groups, but they do not quantify uncertainty or determine whether an apparent dose pattern is distinguishable from random variation. A planning illustration based on an observed effect may help frame future study size under stated assumptions, but it cannot serve as evidence of power in the completed study.

Finally, this record highlights the importance of consistency in trial descriptions. The official title and masking field describe a blinded study, while the brief summary calls it open-label. Enrollment in the record also differs from the larger projected enrollment described in the summary. These inconsistencies do not change the posted primary counts, but they limit certainty about the intended and implemented design unless clarified elsewhere. For statistical interpretation, transparent reporting of protocol decisions, analysis populations, missing-data rules, and uncertainty estimates is essential.

15. Limitations

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

The registry record contains several limitations specific to interpreting this trial. First, the description of masking is inconsistent: the official title calls the study blinded and the masking field says triple, while the brief summary calls it open-label. The record does not clarify which description reflects the conduct of the study. Second, enrollment is recorded as 60, while the brief summary describes plans to enroll up to 106 challenge participants plus 8 shams. The reason for this difference is not reported in the registry record.

The complete cohort descriptions and dose-escalation rules are not available in this discussion presented in the record. The study is characterized as sequential and adaptive, but the full stopping criteria and rules for moving between cohorts are not reported. That prevents a detailed assessment of how the dose groups were formed and how safety or attack-rate observations affected enrollment.

For the primary outcome, the registry provides counts but no reported confidence intervals or formal statistical comparisons. It does not describe missing-data handling, sensitivity analyses, or detailed analysis populations beyond the stated safety population. The registry also lists secondary outcomes but does not provide their detailed results in the analysis information. Thus, antibody response patterns and adverse-event types cannot be evaluated from the posted summaries.

Finally, the study concerns healthy adult volunteers receiving a defined challenge strain. Its findings are not a direct evaluation of prevention or treatment effectiveness, and the registry record does not establish how well the observed results apply beyond this study population and controlled challenge setting.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Influenza Challenge Study to Determine the Optimal Infection Dose and Safety of a Recombinant H3N2 (A/Texas/71/2017 (H3N2, Clade 3C3a) Influenza Strain — NCT04978454.
• Registry record last updated 2025-08-28; status last verified 2023-07-25.
• Results first posted 2023-11-30.
• Data retrieved from ClinicalTrials.gov on 2026-11-09.
• Group sizes, means, event counts and sponsor-reported p-values are reproduced as posted. Effect estimates, confidence intervals and p-values not attributed to the sponsor are independently calculated from the posted summary statistics.

19. Record Summary

NCT04978454 is a completed phase 1 randomized, sequential influenza challenge study with recorded enrollment of 60. The registry describes challenge with recombinant H3N2 A/Texas/71/2017, clade 3C3a, at 10^4, 10^5, and 10^6 TCID50, with sham inoculum as comparator. The primary endpoint was symptomatic influenza virus infection from Day 2 through Day 8, requiring both viral shedding and a symptom-score criterion.

Posted counts meeting the endpoint are 4 of 12, 5 of 10, 28 of 36, and 0 of 2 in the three dose groups and sham group, respectively. No serious adverse events are listed in the posted groups. Formal primary-outcome analyses, uncertainty intervals, multiplicity procedures, and missing-data methods are not reported in the registry record. The record also contains inconsistent descriptions of masking and planned enrollment, which limit interpretation of the design details.