Safety, Tolerability, and Pharmacokinetics of Multiple Rising Doses of BI 425809 Tablets for 12 Days to Young and Elderly Healthy Male and Female Volunteers and Comparison of Pharmacokinetics of a Single Oral Dose of BI 425809 (Morning Versus Evening): Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, and Pharmacokinetics of Multiple Rising Doses of BI 425809 Tablets for 12 Days to Young and Elderly Healthy Male and Female Volunteers and Comparison of Pharmacokinetics of a Single Oral Dose of BI 425809 (Morning Versus Evening) (NCT02337283), a randomized phase 1 study. The primary outcome is Percentage of Subjects With Drug Related Adverse Events (AEs) in Part I.

2. Clinical Question

The study was registered as a Phase I investigation in healthy volunteers. Its aims covered both safety and pharmacokinetics: multiple rising doses over 12 days in Part I, and morning-versus-evening pharmacokinetics after a single dose in Part II. The primary outcome selected for the results was the percentage of participants with drug-related adverse events in Part I. It is a descriptive safety measure, rather than a pharmacokinetic measure or a direct estimate of a treatment effect from a prespecified between-group contrast.

The registry reports multiple age and dose groups, so the percentages describe particular groups rather than a single pooled population. The trial’s broad question about safety and tolerability should therefore be distinguished from the narrower primary endpoint: whether an adverse event was recorded as drug-related during the stated observation period. The record does not report the criteria used to attribute an event to study drug.

3. Trial Design

This was a randomized Phase I study with an overall registry enrollment of 96 and a completed status. The official title describes two parts. Part I was a randomized, double-blind, placebo-controlled study within dose groups of multiple rising doses of BI 425809. Part II was an open, randomized, two-sequence, two-period, two-way crossover comparison of a single oral dose in the morning versus the evening. The registry lists the study’s overall masking as double, while its Part II description explicitly identifies that part as open.

Part I included placebo groups for young and elderly healthy subjects and active-treatment groups with several dose regimens. The registry results distinguish young healthy subjects (YH) from elderly healthy subjects (EH). Part II involved young healthy subjects and the morning and evening single-dose conditions. The primary endpoint applies only to Part I; the Part II objectives concerned pharmacokinetics and a secondary safety outcome.

The title and brief summary describe multiple dosing once daily for 12 days, whereas several Part I arm descriptions say oral administration over 14 days. The registry record does not reconcile these descriptions. It gives the primary endpoint observation window as beginning with the first dose and continuing until 11 days after the last dose, up to 25 days.

The record lists an allocation of randomized and a single-group model, alongside the detailed multi-arm descriptions. It does not explain this classification or report the allocation procedure, concealment method, stratification factors, or the numbers assigned to each group before treatment. The group sizes in the outcome results are reported separately. The registry does not report a sample-size justification or a detailed 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. 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 11 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: The treated set (TS) included all subjects from the randomised set (RS) who were documented to have received at least 1 dose of trial drug.

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 treated set (TS) included all subjects from the randomised set (RS) who were documented to have received at least 1 dose of trial drug.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Drug Related Adverse Events (AEs) in Part I, measured over From first dose of study medication until 11 days after the last dose of study medication, up to 25 days.

The primary endpoint is the percentage of participants with drug-related adverse events in Part I. It covers events from the first dose of study medication until 11 days after the last dose, with an observation period of up to 25 days. The registry defines the treated set as randomized participants documented to have received at least one dose of trial drug.

This endpoint summarizes how often an event was recorded as related to study medication in each reported group. It is used in safety assessment because adverse events can occur during exposure and may be relevant to tolerability. The endpoint is not a measure of event severity alone: serious and non-serious events are distinct classifications, and the primary endpoint encompasses drug-related adverse events as a whole. The registry does not report the criteria used to decide whether an event was drug-related, how events were collected, or how repeat events in one participant were handled.

A percentage is an estimate of the proportion of participants in a group who experienced the event definition. It does not describe how many events each participant experienced, the duration of an event, or the distribution of event types. The group percentages are presented without confidence intervals, so their statistical precision cannot be read directly from the reported values. In particular, a percentage from a small group can be quite uncertain even when it is stated with a decimal place.

The registry reports adverse-event percentages separately for the Part I placebo and dose groups. It does not post a formal estimate of the difference between treatment and placebo for this primary endpoint. Thus, the endpoint supports a descriptive reading of the recorded event proportions, not an adjusted or causal comparison.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either had at least one drug-related adverse event during the defined observation period or did not. A group percentage expresses the number of participants meeting that definition relative to the participants evaluated in that group. This is different from counting all adverse-event episodes, since one participant may have experienced more than one event. The registry does not explain whether its percentage uses the treated-set size as the denominator in every group, although it defines the treated set as randomized participants documented to have received at least one dose.

What does a percentage estimate?

A percentage is an estimate of an underlying event proportion for the population represented by the study group. It is subject to sampling variation: another sample from the same population could yield a different proportion. Statistical uncertainty is often expressed with a confidence interval. In general, a confidence interval describes a range of values compatible with the observed data under the method’s assumptions; it is not a guarantee that the true value falls in the interval. No confidence intervals are reported for this primary endpoint, so readers cannot use the registry values alone to assess the precision of each group estimate.

Group sizes matter to that precision. The reported Part I group sizes are 6.0, 9.0, and 15.0. When denominators are limited, a change in the status of a small number of participants can move the percentage appreciably. Decimal reporting is a presentation convention, not evidence of narrow uncertainty. The posted values should therefore be read as estimates for their groups, not as exact underlying risks.

What would a group comparison require?

A comparison of proportions needs a defined contrast, such as a particular dose group against its placebo group, and a method for estimating uncertainty around that contrast. A test or interval would also depend on assumptions about the data and the planned analysis. The registry does not report a primary-endpoint comparison, confidence interval, or statistical test. The descriptive percentages cannot be turned into a reported inferential result by simply comparing their printed values.

General statistical methods for binary outcomes may use a binomial model, with the number of participants having an event related to the number assessed. The model’s assumptions and the chosen interval or test affect the uncertainty estimate, especially with small samples. If there are meaningful differences in event rates beyond ordinary binomial variation, a model that allows over-dispersion can sometimes better represent the observed variability. This is a general consideration; the registry does not report using a binomial model, testing for over-dispersion, or fitting another model for the primary endpoint.

How should the multiple groups be handled?

Multiple dose and age groups create several possible pairwise comparisons. If many comparisons are tested, the chance of finding an apparently unusual result by chance can increase. Methods that control multiplicity can address that issue, but their choice depends on the questions specified in advance and the testing strategy. The registry record does not report whether a multiplicity adjustment was planned or used, nor does it identify a primary pairwise contrast among the reported groups. The endpoint percentages are therefore descriptive and should not be treated as a collection of confirmatory tests.

The registry lists nine outcome measures and 11 analyses, and identifies six secondary outcomes. Those counts do not, by themselves, disclose the analysis hierarchy or which outcomes were included in any adjustment procedure. The registry does not report the full statistical analysis plan, the handling of missing endpoint data, or the methods used for the pharmacokinetic outcomes.

What do planning calculations mean?

Planning sample-size calculations are hypothetical illustrations of how many participants per arm might be needed to detect a specified effect under stated assumptions. They are not evidence about the probability that this completed study detected an effect, and they are not observed power. The planning assumptions described for the illustrations include a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect expressed as a fraction of the observed effect. Those assumptions do not constitute the trial’s own design justification.

For this binary percentage endpoint, the registry record indicates that values were missing or not estimable for a two-arm comparison. Consequently, no numerical recalculated comparison or planning estimate for this endpoint is available. The record does not report the sponsor’s original sample-size justification or any interim analysis plan. The absence of a reported calculation should not be read as evidence that the study had adequate or inadequate power; it means the relevant design information is not reported in the registry record.

10. Exact Estimates for Each Arm

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

R code and output

arm    <- c("Placebo - BI 425809- Young Healthy Subjects (YH)", "Placebo - BI 425809- Elderly Healthy Subjects (EH)", "BI 425809 - 10 Milligram (mg) Multiple Dose in YH", "BI 425809 - 25 mg Multiple Dose in YH", "BI 425809 - 25 mg Multiple Dose in EH", "BI 425809 - 50 mg Multiple Dose in YH")
n      <- c(15, 6, 9, 9, 9, 9)
events <- c(7, 3, 4, 6, 6, 6)
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  Placebo - BI 425809- Young Healthy Subjects (YH)  15  7  46.7  21.3  73.4  24.8  69.9  24.7  70.1
ARM  Placebo - BI 425809- Elderly Healthy Subjects (EH)  6  3  50.0  11.8  88.2  18.8  81.2  18.4  81.6
ARM  BI 425809 - 10 Milligram (mg) Multiple Dose in YH  9  4  44.4  13.7  78.8  18.9  73.3  18.7  73.8
ARM  BI 425809 - 25 mg Multiple Dose in YH  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8
ARM  BI 425809 - 25 mg Multiple Dose in EH  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8
ARM  BI 425809 - 50 mg Multiple Dose in YH  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8

11. Multiplicity, Missing Data and Analysis Populations

The registry identifies the percentage of participants with drug-related adverse events in Part I as the primary outcome and lists six secondary outcomes, including adverse-event and pharmacokinetic measures. It also reports nine outcome measures and 11 analyses. The record does not explain how those outcomes and analyses were organized into a testing hierarchy, which comparisons were prespecified, or whether any adjustment for multiple testing was used. Without that information, the primary percentages are most appropriately treated as descriptive rather than as results from a documented confirmatory testing strategy.

The analysis population for the primary outcome is the treated set: randomized participants documented to have received at least one dose of trial drug. The registry does not report how many randomized participants were excluded from this population, the number with missing endpoint information, or how missing observations were handled. It also does not describe an intention-to-treat analysis or another analysis population for this endpoint.

These omissions affect interpretation. If outcome status is unavailable for some participants, the approach to those records can influence a percentage. The registry does not say whether missing status was treated as no event, excluded from the denominator, or handled by another method. It also does not report sensitivity analyses that would show whether conclusions change under alternative assumptions.

The record does not report interim analyses, stopping rules, a prespecified statistical analysis plan, or a sample-size justification. Their absence from the registry entry does not establish whether they were or were not conducted; these details are not reported in the registry record. The posted results should therefore be read with the analysis population definition and these reporting gaps in mind.

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 registry’s serious-event figures list zero participants with serious events attributed to study drug in each reported group, and zero deaths in each group. This is a statement about the counts recorded in the posted safety data; it is not proof that the underlying risk is zero. The group sizes are limited, so an event that did not occur in these participants could still occur in a broader population.

The serious-event attribution figures should not be confused with the primary endpoint. The primary outcome includes drug-related adverse events generally, while the serious-event field concerns serious events recorded as related. The registry does not provide serious-event terms, and its list of top serious terms is empty. It also does not describe how seriousness or relatedness was assessed. Accordingly, the zero attributed counts should not be expanded into a claim that no serious event of any kind occurred.

Other adverse events were reported in every listed Part I group. The primary percentages describe participants with drug-related events, whereas the adverse-event counts distinguish participants at risk from those affected. Event counts are not equivalent to counts of event episodes, and the registry does not describe repeat-event handling. These safety summaries are limited to the reported study groups and observation periods.

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

The posted results describe the proportion of participants in each Part I group who were recorded as having drug-related adverse events during the specified follow-up period. They show variation across the reported placebo, dose, and age groups. They also show that drug-related events were reported in the placebo groups. These observations are descriptive; the registry does not report a formal estimate or test comparing a BI 425809 group with placebo for the primary endpoint.

The results do not establish that a dose caused a particular event, that one dose is safer than another, or that an observed difference between groups is statistically reliable. The record supplies no confidence intervals for the primary percentages and no analysis plan describing adjustments for dose, age, or multiple comparisons. Small group sizes make the proportions sensitive to the experience of individual participants, further limiting precision.

The safety endpoint also does not answer the study’s pharmacokinetic questions. Part II compared a single morning dose with a single evening dose in an open crossover design, but the primary outcome is from Part I. The listed secondary outcomes include pharmacokinetic measures, but those do not alter the interpretation of the primary safety percentages.

Finally, the study involved healthy volunteers, with separate young and elderly categories, and the registry does not report age thresholds or additional demographic detail in the registry record describing the results. The estimates should not be treated as direct evidence about other populations or clinical settings. They describe what was recorded in these study groups, over the registry’s stated observation period, with uncertainty that cannot be quantified from the posted primary endpoint results alone.

14. Why This Trial Matters Statistically

This trial illustrates how a safety endpoint can be presented as percentages across several small dose and age groups. Such a display can be useful for describing what was observed, but it does not automatically provide a statistical comparison. A reader needs to distinguish the group-level proportions from a treatment effect estimate, and to consider the uncertainty around each proportion.

The design also combines different questions. Part I examined multiple doses against placebo within dose groups under a randomized, double-blind description. Part II examined administration timing with an open crossover design and focused on pharmacokinetics. Keeping those objectives separate prevents a safety result from being mistaken for a pharmacokinetic comparison, or a result from one part from being attributed to the other.

The endpoint highlights the role of clear outcome definitions. “Drug-related adverse event” depends not only on whether an event was recorded, but also on how it was classified and which participants were included in the denominator. The registry defines the treated set but does not explain attribution criteria or missing-data handling. Those details matter for interpreting a reported percentage.

Finally, the record shows why statistical reporting should include precision estimates, prespecified comparisons, and multiplicity methods when many groups and outcomes are involved. Their absence does not invalidate the descriptive data, but it limits the strength of conclusions that can be drawn from them. The result is best understood as a set of safety summaries rather than a definitive comparative 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 primary endpoint is reported as percentages without confidence intervals, standard errors, or a formal comparison. That leaves the precision of the estimates unclear and prevents a direct assessment of uncertainty in differences between groups. The registry does not describe the criteria for classifying an event as drug-related, the method of event collection, or the handling of multiple events for one participant.

Group sizes are limited, and the results are divided by dose and age category. The registry does not report an adjusted analysis that accounts for these group features or a prespecified primary contrast. It also does not report whether multiplicity was addressed across the several outcomes and analyses. The lack of a documented analysis plan means the results cannot be evaluated against a stated inferential strategy.

Missing-data information is not reported in the registry record. There is no reported count of participants with unavailable endpoint status or description of their handling. The treated-set definition is available, but the registry does not provide enough information to determine whether all treated participants contributed to each percentage.

There is also a duration inconsistency in the registry descriptions: the title and brief summary refer to multiple dosing for 12 days, while several arm descriptions say administration over 14 days. The record does not reconcile the difference. The primary endpoint’s stated follow-up is from first dose until 11 days after the last dose, up to 25 days, but further details of the observation schedule are not reported.

Finally, the results are from healthy volunteers and may not represent other populations. The registry does not report the age thresholds defining young and elderly participants. These limitations do not change the recorded percentages, but they constrain precision, comparison, and generalizability.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, and Pharmacokinetics of Multiple Rising Doses of BI 425809 Tablets for 12 Days to Young and Elderly Healthy Male and Female Volunteers and Comparison of Pharmacokinetics of a Single Oral Dose of BI 425809 (Morning Versus Evening) — NCT02337283.
• Registry record last updated 2026-05-13; status last verified 2026-04.
• Results first posted 2026-05-13.
• 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

NCT02337283 is a completed Phase I randomized study sponsored by Boehringer Ingelheim, with registry enrollment of 96. Its two parts addressed multiple-dose BI 425809 safety and pharmacokinetics in young and elderly healthy volunteers, and single-dose morning-versus-evening pharmacokinetics in young healthy volunteers. The primary endpoint was the percentage of participants with drug-related adverse events in Part I, from first dose until 11 days after the last dose, up to 25 days.

The posted Part I results give group-specific event percentages for placebo and several BI 425809 dose regimens. They do not include confidence intervals or a formal primary-endpoint comparison. The registry defines the treated set but does not report missing-data handling, a sample-size justification, multiplicity procedures, or a full statistical analysis plan. Serious events attributed to study drug and deaths are recorded as zero in each listed group; those counts should be interpreted in light of the limited group sizes and the registry’s reporting detail.