Safety & Pharmacokinetics Study of Inhaled Laninamivir Octanoate TwinCaps® Dry Powder Inhaler in Children With Influenza: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety & Pharmacokinetics Study of Inhaled Laninamivir Octanoate TwinCaps® Dry Powder Inhaler in Children With Influenza (NCT02014649), a randomized phase 1, phase 2 study. The primary outcome is To Evaluate Time to First Alleviation of a Composite of Influenza Symptoms and Absence of Fever..

2. Clinical Question

3. Trial Design

The registry describes a randomized, parallel-dose Phase 1/2 study of inhaled laninamivir octanoate in children with naturally acquired influenza A or B. Masking is recorded as triple. The study was sponsored by Biota Scientific Management Pty Ltd. The registry lists its start as 2013-11 and primary completion as 2014-04, and its current status as terminated.

The intervention list names 20 mg laninamivir octanoate, 40 mg laninamivir octanoate, and placebo. The posted arm descriptions identify a 20 mg laninamivir octanoate arm receiving dry powder plus placebo and a 40 mg arm receiving dry powder. The primary outcome results likewise give values for those two dose arms. Although placebo appears in the intervention list, the posted primary outcome results do not include a placebo-only arm.

The recorded enrollment is 15. For the primary endpoint, the posted results report n=6 in the 20 mg arm and n=8 in the 40 mg arm. Safety groups at risk are recorded separately as 7 and 8, respectively. The registry record does not explain the difference between the enrollment entry and the group sizes in the outcome and safety results, or describe whether the groups reflect different analysis populations.

The stated purpose was to collect safety, tolerability, and pharmacokinetic data for two doses in children and adolescents. The protocol was also intended to explore virology and efficacy endpoints. A secondary outcome describes assessment of concentration profiles for laninamivir octanoate and its active metabolite, laninamivir, following a single dose. The registry record does not report posted pharmacokinetic results or a detailed account of the study's termination.

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

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 To Evaluate Time to First Alleviation of a Composite of Influenza Symptoms and Absence of Fever., measured over Subjects are assessed at clinic visits and followed up to 28-days post dose..

The primary endpoint is time to first alleviation of a composite of influenza symptoms and absence of fever, expressed in hours. It combines symptom improvement with a temperature condition: the endpoint is not simply a symptom score or a temperature reading in isolation. A shorter reported time would describe earlier attainment of the specified composite event, while a longer time would describe later attainment. This is a description of the endpoint's meaning, not a conclusion about treatment benefit.

For subjects aged 5 through 12 years, the subject or parent/legal guardian completed the Canadian Acute Respiratory Illness and Flu Scale symptom diary. Subjects aged 13 through 17 years completed the Influenza Symptom Questionnaire themselves. Both age groups measured otic body temperature twice a day, in the morning and evening, until the Day 10 visit. The registry says subjects were assessed at clinic visits and followed up to 28-days post dose.

Time to first alleviation is useful as a way to describe when a clinically recognizable combination of symptom and fever criteria is first reached. It retains a time dimension that a single symptom score would not express. However, the posted result reports a mean and standard deviation, not a survival curve, median, or other time-to-event summary. The registry record does not further define the composite's exact threshold or the rule for confirming that the first alleviation was sustained.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports the primary endpoint as a continuous measure summarized by a mean and standard deviation. A mean describes the arithmetic average of recorded times in a group. A standard deviation describes how dispersed those times are around that average. Neither summary alone conveys the full distribution, and neither is a measure of uncertainty around the mean in the way a confidence interval is.

What does a confidence interval add?

In general, a confidence interval gives a range of values compatible with the data and the assumptions of the analysis. For a treatment comparison, an interval around the estimated difference can convey both direction and precision. A narrow interval indicates more precision than a wide interval; an interval spanning values in opposing directions may leave substantial uncertainty about the comparison. The registry record does not report confidence intervals for the primary endpoint or a confidence interval for a between-arm effect.

Why is a formal comparison important?

In general, observing different group means is not enough to conclude that the underlying groups differ. Random variation can produce unequal sample means even when the population means are the same. A formal comparison uses the variability and group sizes, as well as the chosen analysis assumptions, to quantify evidence about the contrast. The registry record does not post a test or model for the primary endpoint. The reported means and standard deviations therefore remain descriptive results rather than a documented inferential test.

How does the endpoint's time dimension matter?

Time to first alleviation is naturally a time-to-event outcome: each subject's event time is the time at which the specified symptom and fever condition is first met. In general, time-to-event methods can account for participants whose event time is not observed during follow-up, using censoring information. Such methods may describe the event-time distribution without requiring the same assumptions as an analysis of means. The registry record does not report a time-to-event model, a median event time, a survival curve, or how censoring was handled. Its posted summary is a mean with standard deviation in hours, so interpretation should remain tied to that reported summary.

The diary and temperature procedures differ by age group in who completes the symptom questionnaire: a subject or parent/legal guardian for the younger group, and the subject for the older group. Both groups measured otic temperature twice daily until the Day 10 visit. In general, differences in measurement or reporting can affect the consistency of an endpoint, especially when a composite relies on more than one measure. The record describes the procedures but does not report an assessment of measurement reliability or how diary completion was handled when observations were missing.

What can the posted sample sizes say?

The primary endpoint results give n=6 for the 20 mg group and n=8 for the 40 mg group. Those values identify the reported group sizes for that result, but do not by themselves establish how many participants were randomized, treated, or included in every analysis. The registry's enrollment entry is 15, while its safety groups at risk have different recorded values from the primary outcome groups. The record does not explain these distinctions or name an analysis population such as all randomized participants or all treated participants.

The registry describes planning illustrations based on a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect to detect defined as a stated fraction of the observed effect. These are planning assumptions, not results from the trial's own design calculations. Any associated sample-size illustration is not observed power and should not be treated as evidence that the trial had a specified probability of detecting an effect. The registry record does not report the trial's own sample-size justification.

The primary endpoint results are not accompanied by recalculated comparisons. The registry record does not provide the information needed to present a documented inferential analysis, including a specified test, an effect estimate with uncertainty, and details about the observations included. With no posted formal comparison, interpreting the numerical separation between means as evidence of a dose effect would go beyond the reported analysis.

Why can over-dispersion matter?

In general, over-dispersion means the observed variability is greater than a model assumes. When a model underestimates variability, uncertainty intervals can be too narrow and tests can appear more conclusive than warranted. The posted endpoint summaries include standard deviations, but the registry record does not report a model that would allow assessment of over-dispersion. This general concern is relevant to model-based analyses, not a claim that over-dispersion occurred in this study.

The registry lists two outcome measures and one posted secondary outcome concerning pharmacokinetic concentration profiles. It reports zero posted analyses. The available information does not give a statistical analysis plan, multiplicity adjustment, model specification, handling of protocol deviations, or methods for missing data. These are not details that can be reconstructed from the arm summaries. Consequently, statistical interpretation should be confined to what the record reports: group means and standard deviations for the primary outcome, and descriptive safety counts.

10. Confidence Intervals for Each Arm

No two-arm comparison is shown for this trial, but each arm's mean can be given with a t-based 95% confidence interval computed from the posted mean, spread and number of participants.

R code and output

arm <- c("20mg Laninamivir Octanoate", "40mg Laninamivir Octanoate")
n   <- c(6, 8)
m   <- c(85.1, 79.7)
sp  <- c(34.2, 29.8)
sd  <- sp      # posted standard deviations
for (i in seq_along(n)) {
  se <- sd[i] / sqrt(n[i]); h <- qt(0.975, n[i] - 1) * se
  cat(sprintf("CARM|%s|%d|%.3f|%.3f|%.3f|%.3f\n", arm[i], n[i], m[i], sd[i], m[i] - h, m[i] + h))
}

CARM  20mg Laninamivir Octanoate  6  85.100  34.200  49.209  120.991
CARM  40mg Laninamivir Octanoate  8  79.700  29.800  54.787  104.613

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary endpoint and a secondary pharmacokinetic outcome, and says the protocol also explored virology and efficacy endpoints. It records two outcome measures and one posted secondary outcome, but reports zero posted analyses. The registry record does not describe a prespecified testing hierarchy, an adjustment for multiple comparisons, or which outcomes were designated for formal hypothesis testing. It is therefore not possible to determine how multiplicity was addressed or whether any statistical testing was planned for the several endpoint areas.

Missing-data procedures are not reported in the registry record. The primary outcome summary does not state how many observations were available for each assessment, how a participant without an observed alleviation event was handled, or whether any imputation was used. The record also does not explain whether missing diary entries, temperature readings, or clinic assessments affected inclusion in the analysis.

Analysis populations are not reported in the registry record. The recorded enrollment is 15, while the primary outcome groups are reported as n=6 and n=8 and safety groups at risk are 7 and 8. No explanation is given for these entries or for any differences between the groups used for outcome and safety summaries. The registry also does not state whether the results include all randomized participants, all participants who received an intervention, or another defined population.

These omissions matter because missingness and population definitions can change both the estimated average and its uncertainty. Without an accounting of participants and observations at each stage, the reported summaries cannot establish whether missing data were balanced between dose groups or whether the available observations represent the randomized groups. No assumptions about those issues should be inferred from the posted results.

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 0% reporting threshold.

Most frequent non-serious adverse event terms

The registry reports serious adverse event counts and deaths for the two listed dose groups. In the 20 mg group, 0 serious adverse events are recorded among 7 at risk, and deaths are recorded as 0. In the 40 mg group, 0 serious adverse events are recorded among 8 at risk, and deaths are recorded as 0. No serious adverse event terms are listed.

Other adverse events are recorded as 2 among 7 at risk in the 20 mg group and 5 among 8 at risk in the 40 mg group. These are counts from the registry's safety summaries. They are not estimates of causal risk, and the record does not report a statistical comparison of safety between groups. The safety group sizes are not the same as the primary endpoint group sizes in the registry results, and the registry record does not explain the difference.

A zero serious-event count means that no such event is recorded for the listed group in this result; it does not prove that the true possibility of a serious event is zero. Small group sizes provide limited information about uncommon outcomes. The registry record does not give event narratives, exposure-adjusted rates, or a detailed account of how events were assessed for relationship to treatment. These figures should therefore be read as descriptive safety counts, not as proof of absence of risk or proof that one dose is safer.

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

The results document mean times to the first alleviation of a composite of influenza symptoms and absence of fever in the two posted dose arms. The reported mean is 85.1 hours for 20 mg and 79.7 hours for 40 mg, with standard deviations of 34.2 and 29.8 hours, respectively. The values describe what was observed in the reported groups. The registry record does not provide a formal comparison or uncertainty interval, so the summaries do not establish the precision of a between-dose difference.

The study was designed to collect safety, tolerability, and pharmacokinetic data, while also exploring virology and efficacy endpoints. The record includes a secondary outcome about pharmacokinetic concentrations, but does not report its results. It also does not post a primary outcome result for a placebo-only group. As a result, the available primary endpoint summaries do not answer how either dose compares with a reported placebo-only group.

The numbers do not establish that either dose caused earlier symptom relief, nor do they show that the doses are equivalent. They also do not establish whether the observed separation in means is meaningful, whether it is compatible with chance, or whether the result would generalize beyond the reported groups. Those judgments would require design and analysis details not reported in the registry record, including an inferential comparison and information about missing observations.

The safety counts have similarly limited scope. The record lists no serious adverse events or deaths in the safety groups, and reports other adverse event counts for each dose group. These counts describe the registry entries but cannot establish a causal safety profile or rule out uncommon events. The study's termination status and limited posted outcome information further constrain interpretation; the reason for termination is not reported in the registry record.

The appropriate reading is therefore descriptive: the record gives means, standard deviations, and adverse event counts for the listed groups. It does not offer a complete basis for conclusions about comparative efficacy, pharmacokinetic findings, or the relative safety of the doses.

14. Why This Trial Matters Statistically

This trial illustrates a common statistical distinction between a numerical result and an inferential conclusion. The registry reports group means and standard deviations for a clinically interpretable time endpoint, but does not report a formal comparison, uncertainty interval, or test. Readers can describe the observed summaries, but cannot use them alone to determine how precisely the dose groups differ or whether the observed separation is compatible with random variation.

It also highlights the importance of matching the analysis to the endpoint. Time to first alleviation is an event-time question, while the posted results are summarized as a mean and standard deviation. Those summaries are informative about the reported observations but do not show the distribution of event times, how participants without an observed event were handled, or how censoring was addressed. Knowing the analysis method is therefore important when interpreting a time endpoint.

The record also shows why sample sizes and analysis populations need clear reporting. Enrollment, primary outcome group sizes, and safety group sizes appear in separate entries, without an explanation of their relationship. Without participant-flow details and explicit population definitions, readers cannot determine why the denominators differ or how complete the outcome summaries are.

Finally, the distinction between interventions listed in a registry and arms with posted results matters. Placebo appears in the intervention list, but the primary endpoint results list the two dose arms and not a placebo-only group. That distinction sets a clear boundary on what comparisons can be described from the posted results. Together, these features make the record useful for understanding the scope and limits of the available evidence, while underscoring that descriptive values are not a substitute for a reported statistical analysis.

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 status is terminated, but the reason for termination is not reported in the registry record. The record does not describe whether the study stopped early, how termination affected planned recruitment or follow-up, or whether the posted results represent all planned outcomes. These details should not be inferred from status alone.

There is limited information about participant flow. Enrollment is recorded as 15, while the primary outcome and safety entries give different group sizes. The registry record does not explain these values, identify withdrawals, or report how many participants completed outcome assessments. It also does not describe the analysis populations or the handling of missing endpoint data.

The primary endpoint combines symptom alleviation with absence of fever, but its exact operational threshold and the confirmation rules are not reported in the registry record. Diary procedures are described by age group, yet the record does not provide compliance information or explain how differences in questionnaire respondents were considered in analysis. The outcome is summarized as a mean and standard deviation even though it is defined as time to an event; details about censoring and event-time methods are not reported.

The primary endpoint results include only the two dose arms. Although placebo appears in the intervention list, the record does not post a placebo-only result for this outcome. No formal between-dose estimate, confidence interval, p-value, or adjustment strategy is reported. The registry record also does not provide posted pharmacokinetic results, despite listing a pharmacokinetic secondary outcome.

Safety information is limited to event counts and group sizes at risk. Event descriptions, seriousness criteria, relationship assessments, and exposure-adjusted summaries are not reported in the registry record. The small reported groups and limited detail make it important to treat all these findings as descriptive rather than definitive evidence about comparative effects or safety.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety & Pharmacokinetics Study of Inhaled Laninamivir Octanoate TwinCaps® Dry Powder Inhaler in Children With Influenza — NCT02014649.
• Registry record last updated 2025-01-13; status last verified 2025-01.
• Results first posted 2025-01-13.
• 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

NCT02014649 is a randomized, parallel-dose Phase 1/2 study of inhaled laninamivir octanoate in children and adolescents with naturally acquired influenza A or B. The record identifies triple masking and lists 20 mg and 40 mg dose arms; the 20 mg arm is described as dry powder plus placebo, and the 40 mg arm as dry powder. Placebo is listed as an intervention, but no placebo-only primary endpoint result is posted.

The primary endpoint is time to first alleviation of a composite of influenza symptoms and absence of fever. Mean times are reported as 85.1 hours for the 20 mg arm and 79.7 hours for the 40 mg arm, with standard deviations of 34.2 and 29.8 hours. The registry record does not report a formal comparison or confidence intervals. Safety results record no serious adverse events or deaths in either listed group, alongside other adverse event counts of 2 and 5.

The study is recorded as terminated. Its recorded enrollment is 15, and the registry lists a secondary pharmacokinetic outcome, but does not post pharmacokinetic results. Reasons for termination, missing-data methods, and analysis populations are not reported in the registry record.