A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink.: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink. (NCT04194645), a randomized phase 1 study. The primary outcome is Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events..

2. Clinical Question

The trial had two distinct aims. The SRD component examined safety, tolerability and pharmacokinetics across single rising doses and formulations. The BA component compared exposure-related outcomes for the 10.0 mg tablet and oral solution, including the tablet with and without food. The outcome information available for the primary safety question is the percentage with drug-related adverse events in the SRD groups. Pharmacokinetic outcomes are listed, but their numerical results are not reported in the registry record.

This distinction matters when interpreting the results. The primary endpoint is a safety measure from the SRD part, not a direct measure of whether tablet and solution exposures are equivalent. The BA comparisons address formulation and food conditions, but the posted primary endpoint does not itself answer those pharmacokinetic questions. The registry record does not report numerical estimates for those comparisons.

3. Trial Design

The registry describes NCT04194645 as a completed Phase 1 randomized trial sponsored by Boehringer Ingelheim, with 66 participants enrolled. The trial record lists single masking and a parallel model overall. Its official title describes two components: a single-rising-dose (SRD) safety, tolerability and pharmacokinetic component, and a bioavailability (BA) comparison.

In the SRD part, participants received a single oral dose of BI 474121 or matching placebo. The active doses were 0.25 mg and 1 mg as oral solution, and 2.5 mg, 5 mg, 10 mg, 20 mg or 40 mg as tablets. The arm descriptions state that active doses were taken after an overnight fast with water. Placebo participants were distributed across dose groups, with solution placebo in the lower dose groups and tablet placebo in the upper dose groups. The primary endpoint is reported for these SRD groups.

The BA part used a different structure. The registry describes it as a randomized, open-label, single-dose, three-way cross-over comparison. Participants received 10.0 mg in the oral solution fasted condition, the tablet fasted condition and the tablet fed condition, with the order varying by sequence. The fed condition followed a high-fat, high-caloric breakfast. This component's structure should not be conflated with the parallel SRD groups or with the single-blind label recorded for the trial overall.

The listed primary outcome is drug-related adverse events in the SRD part, with a stated follow-up period from drug administration until 7 days after administration. Secondary outcomes include plasma concentration measures for the SRD and a pharmacokinetic measure for the BA part. The registry record does not report a detailed allocation procedure, dose-escalation decision rules, sample-size justification, or full statistical analysis plan.

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. Participants attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Participants were not to be allocated to a treatment group if any of the entry criteria were violated.

Only the first 6 of 15 groups are shown.

Treatment Period 1 (SRD and BA Part)

Wash-out Period 1 (BA Part Only)

Treatment Period 2 (BA Part Only)

Wash-out Period 2 (BA Part Only)

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated set (TS) The TS included all participants who were randomized and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the participant received. The TS was used for safety analyses.

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 included all participants who were randomized and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the participant received. The TS was used for safety analyses.

Only the first 6 of 16 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Single Rising Dose (SRD): Percentage of Subjects With Drug-related Adverse Events., measured over From drug administration until 7 days after drug administration, 7 days..

The primary endpoint is the percentage of participants in the SRD part with drug-related adverse events. The registry states that it was used to assess safety and tolerability of BI 474121. The analysis population is the treated set: randomized participants who received at least 1 dose of trial drug. Treatment assignment was based on the first treatment received, and the treated set was used for safety analyses.

The registry describes the outcome window as from drug administration until 7 days after drug administration, and its endpoint description refers to adverse events occurring between first drug intake and 7 days after last drug intake. Since the SRD component involved single doses, the reported arm percentages describe the proportion with a drug-related event during the stated safety observation period. They are not counts of all events: each percentage concerns participants who experienced an event.

This endpoint is useful for describing the occurrence of short-term safety events across dose and placebo groups. It does not measure the severity, duration or clinical importance of every event in a single summary, and it is not a pharmacokinetic outcome. The registry reports the percentage by arm, but the posted primary results do not include confidence intervals or a formal comparative estimate. The endpoint therefore supports a descriptive reading of the observed group results, not a precise estimate of a treatment difference.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does a percentage endpoint communicate?

For a binary outcome such as whether a participant experienced a drug-related adverse event, a percentage expresses the share of participants in an arm who had at least one qualifying event. It is a participant-level summary rather than a count of every event. A participant with multiple events is still represented as a participant who experienced the outcome, according to the endpoint definition. The registry's primary outcome is expressed as a percentage, and the arm results are accompanied by the number of participants in each group.

Percentages are easy to compare descriptively, but their precision depends on how much information the group contains. In small groups, a change in the outcome status of one participant can alter the reported percentage appreciably. A percentage of 0.0% in a small group means no qualifying participants were recorded in that group; it does not establish that the underlying event probability is zero. Confidence intervals can communicate uncertainty around a percentage, but the registry record does not report them for this primary outcome.

Why distinguish description from a treatment contrast?

An arm-specific percentage answers how often the endpoint was recorded within that group. A treatment contrast answers how the outcome differs between specified groups, with an estimate of uncertainty. These are different statistical quantities. A descriptive percentage alone does not establish that one treatment caused a higher or lower event rate than another. A comparative analysis needs a defined contrast and a method appropriate to the data and design.

The record lists two placebo formulations and multiple active dose groups. A comparison of an active tablet dose with tablet placebo would be a different question from a comparison of an oral solution dose with solution placebo. Pooling arms would also require a rationale and an analysis plan. No such pooled comparison or formal primary-endpoint contrast is reported in the registry record. The posted results therefore should be read at the arm level, without inferring a statistically established difference.

What would a confidence interval add?

In general, a confidence interval describes the range of effect values compatible with the observed data under the analysis method. It helps readers distinguish a precise estimate from an imprecise one. For a small group and a binary endpoint, uncertainty can be substantial even when the observed percentage is at an extreme, such as 0.0%. A confidence interval would not remove the limitations of the design or prove that a treatment has no effect; it would quantify statistical uncertainty under stated assumptions. Such intervals for the primary endpoint are not reported in the registry record.

How should the design affect the analysis?

The SRD component has separate dose and placebo groups, while the BA component is described as a three-way cross-over comparison in which conditions are given in different sequences. In a parallel comparison, each participant contributes to one treatment group for that comparison. In a cross-over design, participants receive more than one condition, so within-participant comparisons can account for some stable differences between participants. The appropriate analysis must respect that structure, sequence and period. The registry record does not report the BA analysis model or details of how sequence and period were handled.

The overall record lists single masking, while the BA component is described as open-label. The SRD and BA components therefore should not be treated as identical in design or masking. The record does not report further details about who was masked in the SRD component. Those details matter when considering subjective safety-event reporting, but no conclusions about bias can be drawn from the labels alone.

What can the sample-size illustrations tell readers?

In general, sample-size planning depends on the effect size of interest, outcome variability, allocation, significance level and target power. The planning illustration associated with the posted results uses a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation; it considers effects stated as fractions of the observed effect. Such values are planning illustrations, not observed power and not evidence that a future study will attain a particular result. The trial's own sample-size justification is not reported in the registry record. No planning values need to be interpreted as part of the observed endpoint results.

For binary outcomes, planning based on an observed percentage difference can be especially sensitive to the small groups and the observed event pattern. The illustrative calculations do not resolve uncertainty in the trial results, provide a retrospective test of efficacy, or establish that the study was adequately sized for every safety or pharmacokinetic question. No new sample-size estimate or power calculation can be inferred from the arm percentages alone.

What is not available for statistical review?

The registry lists secondary plasma concentration outcomes, including AUC and maximum measured concentration measures, but numerical results are not reported in the registry record. It also does not report test statistics, p-values, confidence intervals, model specifications or covariate adjustments for the primary outcome. Without those items, statistical interpretation should remain descriptive. General statistical concepts explain how estimates might be analyzed, but they do not fill in analyses that the registry does not report.

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: Placebo Matching BI 474121 Oral Solution (OS)", "SRD: Placebo Matching BI 474121 Tablet (T)", "SRD: 0.25 Milligram (mg) BI 474121 - OS", "SRD: 1 mg BI 474121 - OS", "SRD: 2.5 mg BI 474121 - T", "SRD: 5 mg BI 474121 - T")
n      <- c(4, 9, 6, 6, 6, 6)
events <- c(0, 1, 0, 0, 1, 1)
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: Placebo Matching BI 474121 Oral Solution (OS)  4  0  0.0  0.0  60.2  0.0  49.0  0.5  52.2
ARM  SRD: Placebo Matching BI 474121 Tablet (T)  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  SRD: 0.25 Milligram (mg) BI 474121 - OS  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  SRD: 1 mg BI 474121 - OS  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  SRD: 2.5 mg BI 474121 - T  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SRD: 5 mg BI 474121 - T  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9

11. Multiplicity, Missing Data and Analysis Populations

The trial includes multiple dose groups, two formulations in the SRD component, and pharmacokinetic outcomes in both the SRD and BA components. Considering many outcomes or comparisons can increase the chance of observing an apparently notable result by chance if each is tested separately. Statistical approaches to multiplicity can control or describe that issue, but the registry record does not report a multiplicity adjustment, a hierarchy of hypotheses, or a prespecified strategy for choosing among comparisons. No inferential findings should therefore be treated as if a particular multiplicity method had been applied.

The record lists six outcome measures and six analyses, but details of the analysis methods for these outcomes are not reported in the registry record. The primary safety result is an arm-specific percentage. No confidence intervals or formal pairwise estimates are reported for it. Numerical results for the listed pharmacokinetic outcomes are also not reported in the registry record, limiting review of how those analyses were conducted or interpreted.

For missing data, the record defines the treated set used for safety: randomized participants who received at least 1 dose, assigned according to the first treatment received. It does not report how missing event information, withdrawals, incomplete follow-up or missing pharmacokinetic observations were handled. It would be inappropriate to assume that missing observations were absent, excluded, imputed or otherwise treated in a particular way.

The stated safety population is not automatically interchangeable with an intention-to-treat population or a pharmacokinetic analysis set. Definitions of those additional populations are not reported in the registry record. These omissions limit reproducibility and make it difficult to assess whether the analysis population and handling of incomplete data could affect 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 5% reporting threshold.

Most frequent non-serious adverse event terms

The serious-adverse-event figures are reported separately from the primary drug-related adverse-event percentage. Across the listed SRD groups, the registry reports 0 serious adverse events in each group. In the BA groups, it also reports 0 serious adverse events in each group. No deaths are reported in any of the listed groups.

These zero counts describe what was recorded during the trial; they do not demonstrate that serious events are impossible or that the risk is absent. The groups are small, and the registry record does not provide confidence intervals for these safety figures. The number of participants at risk varies across groups, so the zero counts should be read alongside each group's size rather than as evidence of identical safety across all conditions.

The record also lists other adverse events, which are not necessarily serious and are not necessarily drug-related. For example, the other-event counts vary across the SRD dose and placebo groups and across the BA conditions. Those counts should not be mistaken for the primary endpoint, which specifically reports the percentage of participants with drug-related adverse events in the SRD part. The registry record does not provide a detailed narrative of event types or severity in the information summarized for these results.

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

The posted primary results give a descriptive account of the percentage of participants with drug-related adverse events after single doses in the SRD part. Percentages range from 0.0% to 33.3% across the listed groups, with participant counts ranging from 4 to 9. The observed values differ among groups, but their small sizes and the absence of reported uncertainty estimates mean the precision of those percentages cannot be judged from the endpoint results alone.

These data do not establish that one dose, formulation or placebo condition has a higher or lower underlying event rate than another. The registry does not provide a formal comparative estimate for the primary endpoint, and a percentage difference between groups should not be treated as proof of a causal difference. Nor does a zero observed percentage establish the absence of risk. It means no qualifying drug-related event was recorded among the participants in that particular group.

The primary endpoint also does not answer the pharmacokinetic questions motivating the BA comparison. Although the registry lists outcomes for plasma exposure and concentration, numerical results for those outcomes are not reported in the registry record. Therefore, the posted primary safety percentages cannot establish whether oral solution and tablet exposures are similar or whether food changes exposure.

The trial is confined to healthy male participants and single-dose exposure as described in the record. Its results do not provide evidence about repeated dosing or other populations. The record also does not describe a sample-size justification or detailed statistical plan that would support broader claims about the ability to detect particular differences. The appropriate reading is limited: the registry reports the observed short-term event percentages and no serious adverse events in the listed groups, while uncertainty about comparisons and unreported pharmacokinetic results remains.

14. Why This Trial Matters Statistically

This trial illustrates why a clinical result should be interpreted in light of its outcome, design and analysis population. The primary endpoint is a participant-level safety percentage, while the trial's broader aims include pharmacokinetics and a formulation comparison. Those questions are related to the same investigational product but are not answered by the same statistic. A safety percentage cannot substitute for an exposure comparison, and a listed pharmacokinetic endpoint without numerical results cannot support a conclusion about bioavailability.

The design also demonstrates the importance of separating study components. The SRD part contains multiple single-dose groups with matching placebo formulations. The BA part is an open-label three-way cross-over comparison of oral solution and tablet conditions, including fed and fasted tablet administration. Analyses should reflect these differing structures rather than treating every arm as one interchangeable comparison. The registry's overall parallel-model label does not remove the need to recognize the separately described BA cross-over component.

Statistically, the small group sizes make uncertainty a central consideration. Arm percentages communicate the observed pattern, but without confidence intervals or formal contrasts they do not quantify how precisely differences are estimated. This matters especially for binary outcomes, where percentages from small groups can move noticeably with a small change in participant outcomes. A lack of serious events in the listed groups is informative as a record of what occurred, but it cannot establish a zero underlying risk.

The record is also a useful reminder that transparency about multiplicity, missing data, populations and analysis models affects reproducibility. Those details are not reported for the comparisons. This limits the scope of statistical conclusions, even when the descriptive results themselves are clear.

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 safety outcome applies to the SRD component, while the trial also includes a BA component with a different design and different aims. The primary endpoint therefore does not summarize every objective in the trial. Numerical results for the listed pharmacokinetic outcomes are not reported in the registry record, so the formulation and food comparisons cannot be assessed from those outcomes.

The SRD groups are small, ranging from 4 to 9 participants for the primary endpoint. The registry reports percentages but not confidence intervals or formal comparisons. As a result, the precision of the group estimates and the uncertainty around any apparent differences cannot be evaluated from the posted primary results. The record also does not report a dose-response analysis.

The registry does not report the sample-size justification, detailed statistical analysis plan, multiplicity strategy, missing-data procedures, or the analysis model for the BA cross-over component. It does not report additional analysis-population definitions beyond the treated set used for safety. These omissions limit assessment of how analyses were selected and whether incomplete observations could have affected results.

The study population was healthy male participants, and the reported active regimens were single doses. The results therefore describe that setting rather than repeated administration or other populations. The record identifies the SRD part as single-blind and the BA part as open-label, but details of masking for the SRD component are not reported. These design and reporting limits should remain in view when interpreting the descriptive safety findings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study in Healthy Men to Test How the Body Takes up and Tolerates Different Doses of BI 474121, and Whether it Makes a Difference if BI 474121 is Taken as a Tablet or a Drink. — NCT04194645.
• Registry record last updated 2024-03-26; status last verified 2024-03.
• Results first posted 2024-03-26.
• 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

NCT04194645 is a completed Phase 1 randomized trial sponsored by Boehringer Ingelheim, with 66 participants enrolled. It studied healthy men and included a single-rising-dose component and a bioavailability component. The SRD part examined single doses of BI 474121 as oral solution or tablet, alongside matching placebos. The BA part compared 10.0 mg oral solution and tablet conditions, including fed and fasted tablet administration.

The primary outcome was the percentage of SRD participants with drug-related adverse events during the stated safety follow-up. Reported percentages ranged from 0.0% to 33.3% across the listed groups. The registry reports no serious adverse events and no deaths in the listed SRD or BA groups. It does not report confidence intervals or a formal comparative estimate for the primary outcome, and numerical results for the listed pharmacokinetic outcomes are not reported in the registry record.