Evaluation of Safety and Tolerability of BI 894416 in Patients With Mild Asthma: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Evaluation of Safety and Tolerability of BI 894416 in Patients With Mild Asthma (NCT03971539), a randomized phase 1 study. The primary outcome is Percentage of Patients With Treatment-emergent Adverse Events Related to BI 894416.

2. Clinical Question

The study was a phase 1 safety and tolerability trial. Its primary objective was to assess safety and tolerability at each dose, with the main comparison of interest being the percentage of participants with drug-related adverse events in each dose group versus placebo. The listed secondary objectives concerned pharmacokinetics after single and multiple administration; a secondary measure also concerned change from baseline in airway resistance after treatment in the multiple-dose part.

The registry reports enrollment of 68 participants overall. The primary endpoint population was the treated set: randomized participants who received at least one dose of trial medication, with treatment assignment based on the first treatment received. The registry does not report a separate primary question about symptom improvement, asthma control, or clinical benefit.

3. Trial Design

This was a randomized, single-blind, parallel-group phase 1 trial, recorded as completed. Enrollment was 68. The registry lists a start date of 2019-07-15 and primary completion on 2020-10-26. The sponsor was Boehringer Ingelheim.

The trial had a single rising dose part and a multiple rising dose part. In the single-dose part, the active groups received a single oral dose of 75 mg, 125 mg, or 170 mg BI 894416, and a separate group received placebo. The active tablets were taken once after an overnight fast of at least 10 hours, with 240 milliliter of water; the placebo description specifies the same administration conditions.

In the multiple-dose part, active groups received 10 mg, 25 mg, 50 mg, or 60 mg BI 894416 for 9 days, with a corresponding placebo group. The schedule was once daily in the morning on Day 1 and Day 9, and three times daily at 8-hour intervals on Day 2 through Day 8. The record describes oral administration with 240 milliliter of water. It does not provide further detail about whether the dose labels refer to each administration or another dosing convention.

The posted primary results give small group denominators: 6 to 8 participants in each listed dose or placebo group. The registry does not report the method used to generate the random sequence, allocation concealment, the identity of the blinded parties, or whether any procedures differed between the two parts. It also does not report a sample-size justification or a protocol-level statistical analysis plan. These omissions limit assessment of design details beyond the randomized, single-blind, parallel-group description.

4. Participant Flow and Accounting

The registry reports how participants moved through each stage of the study. All counts below are exactly as posted; missing counts are not inferred from other stages.

Before assignment: All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Only the first 6 of 9 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: Treated set (TS): the TS includes all patients who were randomised and treated with at least one dose of trial medication. The treatment assignment was determined based on the 1st treatment the patient received.

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: Treated set (TS): the TS includes all patients who were randomised and treated with at least one dose of trial medication. The treatment assignment was determined based on the 1st treatment the patient received.

Only the first 6 of 10 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Patients With Treatment-emergent Adverse Events Related to BI 894416, measured over From start of treatment till the end of trial, up to 30 days..

The primary endpoint is the percentage of participants with treatment-emergent adverse events related to BI 894416. The recorded timeframe runs from the start of treatment until the end of the trial, up to 30 days. The primary analysis population is the treated set, defined as randomized participants who received at least one dose of trial medication; assignment was based on the first treatment received.

This endpoint captures whether participants experienced at least one qualifying adverse event, expressed as a percentage of the group. It is a participant-level measure, not a count of every event or a measure of event duration or severity. The registry describes the events as treatment-emergent and related to BI 894416, making the attribution part of the endpoint definition.

In general, safety studies use such participant percentages to describe how commonly an event category occurred under each regimen. A placebo group provides a contemporaneous reference for events observed during the study period that were not attributed to the active drug. Such percentages are descriptive unless accompanied by an inferential comparison and its uncertainty. The registry record reports the percentages by group but does not report a two-arm estimate, confidence interval, or p-value for these comparisons.

The measure is relevant to the stated safety and tolerability objective, but it does not by itself characterize the type, timing, duration, or clinical seriousness of each event. Serious adverse events are recorded separately in the safety results. The registry record does not provide a breakdown of the primary endpoint by event term or a more detailed account of how relatedness was determined.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage represent?

The primary measure is a binary participant outcome: each participant is classified according to whether a treatment-emergent adverse event related to BI 894416 was recorded during the stated timeframe. The percentage describes the share of participants in a group who met that definition. It does not count repeated events as additional participants, and it does not indicate how many events each participant experienced.

In general, binary outcomes are summarized by the number of participants meeting a definition relative to the number assessed, then expressed as a percentage. The registry reports percentages and group sizes for the primary outcome. The treated set is defined in the record, but the registry does not give a separate account of missing endpoint observations or of any imputation procedure.

Why does group size matter?

In general, a percentage based on a small group can change noticeably when the outcome status of one participant differs. This makes the estimate less precise than a similar percentage based on a much larger group. The listed dose and placebo groups contain 6 to 8 participants each, so the posted percentages should be read as estimates from small groups. The registry does not report confidence intervals for these percentages, leaving their statistical precision unquantified in the posted results.

A zero percentage is also subject to this limitation. It records no qualifying events in the participants observed in that group; it is not proof that the event cannot occur. The same caution applies when comparing a group with a zero percentage against another group: without an inferential estimate and uncertainty interval, the size and precision of the underlying difference are not established.

What is and is not available for comparisons?

The trial objective identifies comparisons between each active dose and placebo within the single-dose and multiple-dose parts. However, the registry record does not post an analysis estimate for those two-arm comparisons. It notes that values were missing or not estimable for a two-arm comparison of this binary percentage endpoint. There are no reported p-values or confidence intervals for those contrasts. Therefore, the posted group percentages support descriptive reading, not a quantified inferential claim about a difference between treatment and placebo.

The record lists randomized allocation and single masking, but the operational details of randomization and masking are not reported in the registry record. It also does not report covariate adjustment, a model for the primary endpoint, or a prespecified method for handling multiple comparisons. In general, methods such as a test of proportions or a regression model can be used for binary outcomes, but the record does not identify such a method for this trial; no specific test should be inferred.

How should planning calculations be understood?

The sample-size assumptions describe planning illustrations based on the observed effect, not the trial's own design justification. The stated assumptions are a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is described as a stated fraction of the observed effect. Such calculations are hypothetical planning aids rather than an account of what the trial was powered to detect.

In general, a sample-size illustration asks how many participants might be needed under explicit assumptions about the target effect, variability or event rate, statistical threshold, and allocation. An illustration based on an observed effect is particularly dependent on that estimate, which may be unstable when groups are small. It should not be called observed power or treated as the trial's actual sample-size rationale. The registry record does not report the protocol's sample-size justification.

No trial-specific interim analysis, stopping boundary, or sequential testing method is reported in the registry record. The record also does not describe how the primary endpoint was adjudicated, how relatedness was assessed, or whether any sensitivity analyses were prespecified. These details matter because analytic choices can affect how a safety percentage and its comparisons are interpreted.

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("SRD Part: Placebo", "SRD Part: 75 mg BI 894416", "SRD Part: 125 mg BI 894416", "SRD Part: 170 mg BI 894416", "MRD Part: Placebo", "MRD Part: 10 mg BI 894416")
n      <- c(6, 7, 8, 8, 8, 7)
events <- c(0, 2, 3, 5, 0, 2)
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  SRD Part: Placebo  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  SRD Part: 75 mg BI 894416  7  2  28.6  3.7  71.0  8.2  64.1  8.5  65.1
ARM  SRD Part: 125 mg BI 894416  8  3  37.5  8.5  75.5  13.7  69.4  13.7  70.1
ARM  SRD Part: 170 mg BI 894416  8  5  62.5  24.5  91.5  30.6  86.3  29.9  86.3
ARM  MRD Part: Placebo  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  MRD Part: 10 mg BI 894416  7  2  28.6  3.7  71.0  8.2  64.1  8.5  65.1

11. Multiplicity, Missing Data and Analysis Populations

The trial includes multiple active doses in each of two parts, alongside placebo groups, and the registry states that the primary comparisons of interest were dose-specific comparisons with placebo. Several secondary measures are also listed, covering pharmacokinetics after single and multiple administration and airway resistance after treatment. This creates multiple outcomes and potential comparisons to consider when interpreting a collection of results.

The registry record does not report a method for controlling multiplicity, such as an adjustment to the significance threshold or a hierarchy for testing outcomes. It does not report whether the primary dose comparisons were considered confirmatory or exploratory. Since two-arm analysis results are not posted for the primary endpoint, the record does not provide a set of p-values on which to assess any multiplicity procedure.

Missing-data handling is not reported in the registry record. The treated-set definition includes participants randomized and treated with at least one dose, but this definition alone does not explain what happened if an endpoint value was unavailable, how participants who discontinued were handled, or whether any imputation was used. The registry does not report missingness by group or a sensitivity analysis for missing outcomes.

The record lists seven secondary outcome measures, including pharmacokinetic measures and difference from baseline in airway resistance. Numerical results for these measures are not reported in the registry record. The population definitions used for secondary analyses are also not reported. The available results therefore do not allow assessment of the completeness of secondary-outcome data or of how those analyses relate to the primary treated-set analysis.

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 record reports 0 serious adverse events among participants at risk in each listed group, and 0 deaths. Across the full trial, 68 participants were at risk for serious adverse events; none were recorded. This is a count from the observed trial population and period, not proof that serious events are impossible or that the risk is zero outside the study.

The registry separately reports other adverse events. In the overall group, 48 of 68 participants were recorded as affected by other adverse events. These are broader safety counts and are not the same as the primary endpoint, which is restricted to treatment-emergent events related to BI 894416. A participant could contribute to the broader adverse-event record without meeting the primary endpoint definition.

In general, serious-event counts and other-event counts answer different safety questions. Serious-event counts describe events categorized as serious under the study's safety reporting, while the primary endpoint concerns relatedness to BI 894416. The registry record does not provide a list of serious-event terms because no serious terms are listed, nor does it provide further detail on event duration, severity grading, or relatedness assessment.

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

The posted primary results describe the percentages of participants with treatment-emergent adverse events related to BI 894416 in small dose groups over the trial period. The single-dose groups show percentages of 28.6%, 37.5%, and 62.5% across the listed active doses, with 0.0% in placebo. In the multiple-dose part, the active-group percentages are 28.6%, 0.0%, 25.0%, and 25.0%, with 0.0% in placebo. These are descriptive observations from the participants enrolled.

The patterns do not establish a dose-response relationship. The groups are small, and no uncertainty intervals or formal comparisons are reported. In particular, the absence of a two-arm estimate means that the registry does not quantify the precision of an active-versus-placebo contrast. The percentages should not be treated as proof that a particular dose increases or decreases risk relative to placebo.

The serious adverse-event record reports no serious events and no deaths. That observation is reassuring only in the limited descriptive sense that none were recorded among the participants observed. A small trial and limited exposure cannot, by themselves, characterize uncommon risks or establish safety in populations and settings beyond those studied.

The study's stated focus is phase 1 safety, tolerability, and pharmacokinetics. It does not provide numerical secondary results for the listed pharmacokinetic measures or airway resistance outcome in the registry record. The posted primary results also do not answer questions about asthma symptom control, long-term outcomes, or comparative clinical benefit. No treatment recommendation follows from these registry data.

14. Why This Trial Matters Statistically

This trial illustrates how early-phase safety results can be presented as group-level percentages while still leaving substantial uncertainty about comparisons. A dose-specific percentage is easy to read, but its meaning depends on the group denominator, endpoint definition, follow-up period, and whether an inferential contrast is available. Here, each dose and placebo group is small, and the registry reports no comparison estimate or confidence interval for the primary binary outcome.

The two-part structure also matters. Single rising dose and multiple rising dose regimens represent different exposure schedules, so their summaries should be interpreted within their respective parts rather than treated as a single dose ladder. The regimen groups and placebo groups are reported separately, while pooled totals are also listed. Pooled values describe combined participants and do not replace dose-specific comparisons.

Another statistical distinction is the difference between adverse events attributed to BI 894416 for the primary endpoint and other safety events recorded in the adverse-event results. The primary percentage does not capture every adverse event, and the broader counts do not establish the primary endpoint. Keeping these measures separate avoids treating distinct safety definitions as interchangeable.

Finally, the record demonstrates the limits of registry results when analysis details are sparse. No multiplicity method, missing-data strategy, or detailed primary statistical method is reported. Those omissions do not alter the posted descriptive percentages, but they constrain how far readers can go in judging the precision and robustness of comparisons. The results are most informative when read as observations from this particular phase 1 trial, not as a definitive estimate for a broader population.

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 primary endpoint groups are small, with 6 to 8 participants in each listed dose or placebo group. The registry reports percentages but no confidence intervals, so the precision of each percentage is not quantified. It also reports no two-arm primary analysis estimates or p-values; the reason given is that values were missing or not estimable for a two-arm comparison of this binary outcome.

The registry does not report detailed participant characteristics or eligibility criteria beyond the description of male patients with asthma and the mild-asthma title. It does not provide the random-sequence method, allocation concealment, blinding procedures, or a detailed account of how adverse-event relatedness was determined. Missing-data handling, multiplicity control, and the protocol's sample-size justification are not reported in the registry record.

The two dosing parts have different schedules and should not be treated as a direct head-to-head comparison. Follow-up for the primary endpoint is described as from treatment start until the end of the trial, up to 30 days; the results do not establish longer-term safety. The registry lists secondary pharmacokinetic and airway-resistance measures, but their numerical results are not reported in the registry record. These limitations leave the results primarily descriptive and specific to the enrolled groups and study regimens.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Evaluation of Safety and Tolerability of BI 894416 in Patients With Mild Asthma — NCT03971539.
• Registry record last updated 2023-08-21; status last verified 2022-09.
• Results first posted 2023-08-21.
• 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

The registry record describes a completed, randomized, single-blind, parallel-group phase 1 trial sponsored by Boehringer Ingelheim, with 68 participants enrolled. It evaluated BI 894416 against placebo in male patients with asthma through a single rising dose part and a multiple rising dose part.

The primary endpoint was the percentage of participants with treatment-emergent adverse events related to BI 894416, assessed in the treated set from treatment start through the end of the trial, up to 30 days. Group percentages are posted, but two-arm comparison estimates are not reported. The safety record reports no serious adverse events and no deaths. Numerical results for the listed secondary outcomes are not reported in the registry record.