H3N2 M2SR in Pediatric Population: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for H3N2 M2SR in Pediatric Population (NCT03553940), a randomized phase 1 study. The primary outcome is Number of Participants With Adverse Events of Special Interest (AESIs).

2. Clinical Question

This was a Phase I safety and immunogenicity study, not a trial of clinical influenza illness as its primary outcome. Its primary objective was to assess the safety and reactogenicity of the monovalent live attenuated H3N2 M2SR vaccine. The posted primary endpoint focuses on a particular set of safety events during the period from the first vaccination through the QIV boost date.

The randomized comparison is specifically about adding an M2SR prime rather than a placebo prime before QIV. It does not compare a complete M2SR-plus-QIV regimen with no vaccination: both groups were scheduled to receive QIV. Secondary outcomes concerned immune responses, but the primary result is the AESI participant count.

3. Trial Design

The registry describes a randomized, double-blind, parallel-group, placebo-controlled Phase I trial. Participants were assigned to receive either M2SR intranasally or placebo intranasally on Day 1. Both groups were scheduled to receive licensed QIV intramuscularly on Day 92. This structure permits a randomized comparison of the two priming approaches while holding the planned QIV boost common to both groups.

The brief summary describes an intended enrollment of 50 healthy children and adolescents 9-17 years old, with one-to-one assignment and 25 planned in each arm. The registry’s enrollment field reports 43. The posted safety group sizes are 22 for M2SR and 21 for placebo. These are the recorded group counts for the reported safety results; the registry record does not explain the difference between planned enrollment and recorded enrollment.

The study start date is 2018-08-15, and the primary completion date is 2020-08-27. The registry status is completed. The brief summary describes an overall study duration of approximately 28 months and participant participation of approximately 13 months. Those durations describe the study plan, while the primary AESI timeframe is Day 1 through Day 92.

The stated primary objective was safety and reactogenicity assessment. The registry also lists immune-response outcomes, including measures of spot-forming cells and nasal secretory IgA responses. The detailed protocol, randomization procedure, allocation concealment method, and blinding procedures are not reported in the registry record. The registry identifies the study as double-blind but does not specify which roles were blinded.

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 includes all participants who received at least one dose of study vaccine.

5. Baseline Characteristics

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

Population: The baseline analysis population includes all enrolled participants.

6. Primary Endpoint

The registry lists the primary outcome as Number of Participants With Adverse Events of Special Interest (AESIs), measured over Day 1 through Day 92.

The primary endpoint is the number of participants with adverse events of special interest (AESIs) from Day 1 through Day 92. The registry defines AESIs as including medically significant wheezing and otitis media. Collection began with receipt of the first study vaccination and continued through 3 months after the first vaccination. The endpoint is a participant count: it records whether participants experienced an AESI during the specified period, rather than counting repeated episodes as separate participants.

A safety endpoint of this kind is used to describe the occurrence of selected events after vaccination. Focusing on prespecified events can make safety monitoring more targeted than an undifferentiated count of every symptom or event. General statistical context: a participant-level count is easy to interpret, but the count alone does not describe event timing, severity beyond the endpoint definition, or how many episodes an affected participant experienced.

The registry identifies the analysis population as all participants who received at least one dose of study vaccine. The posted result is zero participants with an AESI in the M2SR group and zero in the placebo group. The endpoint is distinct from the separate adverse-event summaries, which also report serious adverse events, other adverse events, and deaths. Those categories should not be treated as interchangeable with AESIs.

7. Results Posted in the Registry

• M2SR: 0.0% (0/22) versus 0.0% (0/21) on control; risk difference 0.0 percentage points (95% CI 0.0 to 0.0); unadjusted two-proportion z-test p = n/a.

8. Statistical Interpretation

9. Statistical Methods Explained

Randomization is intended to create groups that are comparable on average, so that differences in outcomes can be interpreted in relation to assigned treatment rather than deliberate selection. In this trial, the randomized contrast was an M2SR intranasal prime versus an intranasal placebo prime. Both groups were scheduled for a QIV boost. The registry identifies the allocation as randomized and the model as parallel, but details of the sequence generation and concealment are not reported in the registry record.

What does a participant count represent?

The primary endpoint counts participants with at least one AESI during the specified period. This is a binary outcome at the participant level: a participant either meets the endpoint definition during follow-up or does not. The group count is the number meeting the definition, and the group size is the number in the analysis population. This form of result can be understood without assumptions about how many times an event occurred in a participant, but it also omits recurrence and event timing.

The reported primary population includes participants who received at least one dose of study vaccine. This is a safety-oriented population definition. It differs conceptually from analyzing only participants who completed every planned study procedure. Whether any additional analysis populations were used is not reported in the registry record.

How should the risk difference be read?

A risk difference compares the proportion of participants with the outcome in one group with the corresponding proportion in the other group. A value of 0.0 means that the posted group summaries show no difference in the observed AESI proportions. Here, neither group had an observed AESI, so the descriptive contrast is zero. The registry also posts an interval from 0.0 to 0.0. The interval-generation method is not reported in the registry record, so its statistical coverage and interpretation cannot be assessed from the record alone.

General statistical context: an interval estimate is intended to express uncertainty around an estimate under a specified method. Its width depends on the data and the method. With rare outcomes and no observed events, estimates can be especially sensitive to the chosen method; a zero observed count does not imply that the underlying event probability is exactly zero. A degenerate posted interval should therefore not be mistaken for proof of certainty.

What analysis details are available?

The registry gives the arm-level counts and a risk-difference comparison. It records zero analysis entries, and a p-value or detailed inferential procedure is not reported in the registry record. The approach used to handle missing outcome data, the confidence-interval method, and any covariate adjustment are not reported in the registry record. No additional analysis procedure should be inferred from the counts alone.

The record describes 58 outcome measures and 53 posted secondary outcomes. Multiple outcomes can create a multiplicity issue: when many hypotheses are tested, the chance of at least one apparently unusual result can increase. General statistical context: investigators may address multiplicity through prespecified primary outcomes, adjusted testing, or cautious interpretation of exploratory results. Whether any such adjustment or hierarchy was used is not reported in the registry record. The primary AESI result should not be conflated with the many immune-response outcomes.

What does the planning information mean?

The stated sample-size assumptions describe a planning illustration based on a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect defined as a stated fraction of the observed effect. The assumptions also specify that non-time-to-event planning quantities are expressed as participants per arm, while time-to-event quantities are total event counts. The actual calculated planning values are not reported in the registry record.

General statistical context: a sample-size calculation is a design illustration, not a measure of the probability that a completed study detected an effect. It depends on assumptions about the target effect, variability, significance level, and analysis method. In this trial the observed primary risk difference is zero, so a target defined as a fraction of that observed effect does not provide a positive observed magnitude to anchor planning for a nonzero difference. The planning assumptions should not be described as observed power.

The registry record does not report the trial’s own sample-size justification, an interim-analysis plan, or a detailed statistical analysis plan. Such information cannot be reconstructed from the posted counts or from the general planning assumptions.

10. Confidence Intervals and Precision

The observed AESI counts were zero in each group, with group sizes of 22 for M2SR and 21 for placebo. The posted risk difference is 0.0, and its reported interval runs from 0.0 to 0.0. This is the interval as recorded; the method used to calculate it is not reported in the registry record.

An interval is generally intended to show a range of values compatible with the observed data under a particular statistical procedure. General statistical context: narrower intervals are often read as greater precision, but that reading depends on the interval being calculated with an appropriate method and on the assumptions being met. An interval with identical endpoints suggests no displayed uncertainty, yet zero events in finite groups cannot rule out a nonzero underlying event risk. The posted interval should not be interpreted as establishing that the true difference is known exactly.

For rare outcomes, precision is especially important. When no events are observed, the data give a direct description of the study experience but limited information about how frequently an event could occur beyond the study. The modest group sizes also mean that the result addresses the enrolled trial population and follow-up period, not every possible participant or longer-term observation.

No alternative confidence interval, event-rate bound, or precision estimate is reported in the registry record. A different interval should not be substituted without the underlying method and a clearly stated analysis. The most defensible reading is therefore to report the observed counts, state the posted interval exactly, and keep the limitations of its interpretation explicit.

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 58 outcome measures and 53 posted secondary outcomes. The primary AESI endpoint is one part of a broader assessment that also includes immune-response measures. When many outcomes are assessed, multiplicity matters because repeated testing can make chance findings more likely. General statistical context: a prespecified primary endpoint can help distinguish the central question from secondary or exploratory questions, while adjustment methods can alter how evidence is evaluated across outcomes.

The registry record does not report a multiplicity adjustment, a formal hierarchy among the secondary outcomes, or how secondary analyses were intended to be interpreted. It is therefore not possible to determine from the record whether multiplicity was controlled. The AESI result should be interpreted on its own terms rather than combined with unreported or unspecified testing procedures.

The primary population is described as participants who received at least one dose of study vaccine. The posted group sizes are 22 and 21. The record does not describe missing-data handling, participant-level follow-up completeness, or whether all participants contributed observations through the end of the AESI period. These details are not reported in the registry record, so the effect of missing observations cannot be assessed.

The registry records zero analysis entries while also posting group counts and a risk-difference comparison. A detailed statistical analysis plan, p-value, and method for the reported interval are not reported in the registry record. This limits independent assessment of the inferential procedures. It does not change the direct descriptive observation that the posted AESI counts were zero in both groups.

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 serious adverse-event summary reports zero affected participants among 22 at risk in the M2SR group and zero among 21 at risk in the placebo group. The death count is also zero in each group. Separately, other adverse events were reported for 11 participants in the M2SR group and 17 participants in the placebo group.

These categories are not interchangeable. The primary AESI endpoint concerns medically significant wheezing and otitis media during Day 1 through Day 92. The serious adverse-event summary is a separate safety category, and “other adverse events” is another separate count. The registry record does not provide event-level details for the other adverse events in these results, so their types, timing, severity, and relationship to vaccination cannot be inferred from the counts.

These figures describe events recorded in this study and do not establish that a vaccine caused or prevented an event. A zero count means no participants in the reported group were recorded with an event in that category; it does not show that the possibility of such events is absent. The registry’s specific definitions and any adjudication procedures beyond those stated are not reported in the registry record.

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

The central descriptive finding is that the registry reports no participants with an AESI in either randomized group during Day 1 through Day 92. The reported risk difference is 0.0, with an interval from 0.0 to 0.0. This describes the observed study data; it is not proof that the underlying risks are identical or that such events cannot occur.

The comparison concerns an M2SR prime versus a placebo prime, with a planned QIV boost in both groups. It does not estimate the effect of receiving QIV versus not receiving QIV. It also does not directly answer whether the regimen prevents influenza illness, because the primary endpoint is a safety count rather than a clinical influenza outcome.

The study was Phase I and enrolled 43 participants according to the registry enrollment field, with posted safety groups of 22 and 21. Results from groups of this size have limited ability to characterize uncommon events. The follow-up window for the primary endpoint also matters: the AESI result applies to the stated period, not to later follow-up or other outcomes.

The study’s secondary outcomes address immune responses, but immune measurements are not the same as demonstrated clinical protection. The record lists these outcomes but the primary result does not establish a clinical benefit. No medical conclusion should be drawn from the absence of observed AESIs alone.

In short, the result is reassuring only in the narrow descriptive sense that no AESIs were recorded in these groups during the reported interval. It remains uncertain how precisely the trial estimates rare-event risk, and the record does not provide enough analysis detail to judge the posted interval method. Broader claims about safety, comparative risk, or effectiveness are not established by this endpoint result.

14. Why This Trial Matters Statistically

This trial illustrates how a randomized design can isolate a specific treatment contrast even when both groups receive a common component. Here, random assignment compared an M2SR intranasal prime with an intranasal placebo prime, while both groups were scheduled to receive QIV. That structure is important for interpreting the result: it concerns the prime within the planned prime-boost regimen, not QIV itself against no vaccination.

It also shows why safety results need both a clear endpoint definition and a clear observation window. The primary measure is a participant count for AESIs, defined to include medically significant wheezing and otitis media, over Day 1 through Day 92. That makes the reported zero counts straightforward to state, but it does not capture every possible safety outcome or establish what happened outside the defined period.

The record is a useful example of the distinction between an observed estimate and its precision. Both groups had zero observed AESIs, and the posted risk difference is zero. Yet the reported interval has identical endpoints, while the method behind it is not reported. Statistical interpretation should acknowledge both the simple observed result and the uncertainty that remains with rare outcomes and limited group sizes.

Finally, the registry includes a broad set of immune-response outcomes alongside the primary safety endpoint. This makes the separation between primary and secondary questions consequential. Without reported multiplicity procedures or detailed analysis methods, readers should avoid treating a collection of outcomes as if each had the same confirmatory status. The trial highlights the value of transparent analysis plans and interpretable uncertainty estimates in early-phase studies.

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 sample is small for evaluating uncommon safety events. The enrollment field reports 43, while the brief summary describes intended enrollment of 50 and arm descriptions specify 25 planned per group. The registry record does not explain the difference between planned and recorded enrollment. The posted safety group sizes are 22 and 21, and the AESI count is zero in each group. These observations provide limited information about the frequency of rare events.

The endpoint covers a specific set of events and a specific period. The registry identifies medically significant wheezing and otitis media as AESIs and gives Day 1 through Day 92 as the timeframe. The result does not encompass all adverse events, later events, or clinical influenza outcomes. Details on completeness of follow-up and missing outcomes are not reported in the registry record.

The reported risk-difference interval is 0.0 to 0.0, but the method used to calculate it is not reported in the registry record. This makes its interpretation difficult, particularly given the zero observed events. The record also does not report a p-value, detailed statistical analysis plan, multiplicity procedure, or sample-size justification for the trial.

The registry identifies the design as randomized and double-blind, but the specific randomization and blinding procedures are not reported. The other adverse-event counts lack event-level descriptions in the posted summary. Accordingly, the counts cannot establish cause, characterize event severity, or resolve whether group differences in those events are meaningful.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: H3N2 M2SR in Pediatric Population — NCT03553940.
• Registry record last updated 2021-10-21; status last verified 2021-03-01.
• Results first posted 2021-10-21.
• 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

NCT03553940 is a completed, randomized, double-blind, parallel-group Phase I trial in children and adolescents 9-17 years old. It compared an intranasal M2SR prime followed by QIV with an intranasal placebo prime followed by QIV. The primary outcome was the number of participants with AESIs, including medically significant wheezing and otitis media, from Day 1 through Day 92.

The registry reports zero AESIs among 22 participants in the M2SR group and zero among 21 in the placebo group. The posted risk difference is 0.0, with a reported interval from 0.0 to 0.0. Serious adverse events and deaths were also recorded as zero in both groups; other adverse events were reported for 11 and 17 participants, respectively.

The study’s primary focus was safety and reactogenicity, with additional immune-response outcomes. The record does not report the interval method, missing-data approach, multiplicity procedure, or detailed statistical analysis plan. The findings are descriptive of the enrolled groups and reported follow-up period.