A Study in Healthy Japanese Men to Test How Different Doses of BI 1323495 Are Tolerated and How Itraconazole Influences the Amount of BI 1323495 in the Blood: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Japanese Men to Test How Different Doses of BI 1323495 Are Tolerated and How Itraconazole Influences the Amount of BI 1323495 in the Blood (NCT04619251), a randomized phase 1 study. The primary outcome is SRD and MD Part: Number of Participants With Drug-related Adverse Events (AEs).

2. Clinical Question

3. Trial Design

This was a completed phase 1 study with randomized allocation, single masking, and a sequential model. The registry reports an enrollment of 74 and lists healthy participants as the condition. The trial included distinct single-rising-dose (SRD), multiple-dose (MD), and drug-drug interaction (DDI) parts. These parts addressed related but not identical questions, so their groups should not be treated as if they were arms in one common comparison.

In the SRD part, PM participants received single doses of BI 1323495 at 10 mg, 30 mg, or 100 mg. EM participants received single doses of 30 mg, 70 mg, or 150 mg. Placebo participants were pooled across dose groups in the arm description, and randomization within each dose group was in a 3:1 ratio of test treatment to placebo. The registry describes a single-blind, randomized, placebo-controlled design for these parts.

The MD part included PM participants assigned to 30 mg twice daily or 60 mg once daily, alongside placebo. Dosing continued through Day 11, with the 30 mg twice-daily group receiving a morning dose only on Day 11. The DDI part was open-label and used a two-period fixed sequence in PM participants, with BI 1323495 alone in one period and BI 1323495 with itraconazole in another. This sequence is not described as a randomized crossover.

The primary safety endpoint applied only to the SRD and MD parts. The DDI objective concerned relative bioavailability, while the SRD and MD parts also addressed safety, tolerability, and pharmacokinetics; pharmacodynamics was an objective for the MD part only. The registry lists July 30, 2021 as the primary completion date and reports the study as completed.

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. Administrations of BI 1323495 was separated by a wash-out phase of at least 11 days.

Only the first 6 of 11 groups are shown.

Period 1

Period 2

Analysis population for the primary outcome, as defined in the registry: Treated set (TS): The treated set includes all subjects who were randomised (SRD and MD part) and treated with at least one dose of trial drug. As pre-specified in the protocol this endpoint only includes the SRD and MD part of the 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.

Population: Treated set (TS): The treated set includes all subjects who were randomised (SRD and MD part) / allocated (DDI part) and treated with at least one dose of trial drug. The treatment assignment will be determined based on the first treatment the subjects received. The treated set will be used for safety analyses.

Only the first 6 of 12 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as SRD and MD Part: Number of Participants With Drug-related Adverse Events (AEs), measured over Up to 7 days (for SRD part), up to 17 days (for MD part)..

The primary endpoint was the number of participants with drug-related adverse events in the SRD and MD parts. It was assessed through up to 7 days for the SRD part and up to 17 days for the MD part. The analysis population was the treated set: participants randomized in those parts who received at least one dose of trial drug.

A participant count is a binary-event summary at the individual level: each participant either had at least one event meeting the endpoint definition or did not. It is not a count of the total number of adverse-event episodes. The endpoint description specifically concerns events considered drug-related, so it should not be conflated with the separate adverse-event summary of other events.

This type of endpoint is used in early-phase studies to describe the occurrence of safety events during the defined observation period and across the tested dose groups. The group counts allow readers to see how many treated participants were reported with a drug-related event. They do not, by themselves, establish that an event was caused by treatment, nor do they quantify event severity or duration. Those details are not reported in the registry record.

The primary endpoint did not include the DDI part. Although the registry lists pharmacokinetic outcomes for that part, no numerical results for those outcomes appear in the posted results included in the record. The primary endpoint therefore does not answer whether itraconazole changed BI 1323495 exposure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The endpoint is a count of participants with at least one drug-related adverse event, not a measurement of how many total event episodes occurred. For a binary endpoint, each participant contributes an event status. A group count communicates the number meeting the endpoint, while the group size indicates how many participants were included in that reported arm. In this trial, the posted results give those counts separately by dose, genotype group, and trial part.

What does a confidence interval add?

General statistical explanation: a confidence interval expresses the uncertainty around an estimated quantity under a specified statistical method. For a treatment comparison, an interval can show which effect sizes remain compatible with the data and the analysis assumptions. A point estimate alone does not show that uncertainty. The registry record does not report a confidence interval or treatment-effect estimate for the primary endpoint, so the precision of a between-group effect cannot be assessed from the posted counts alone.

Why are the group counts descriptive?

The arms have small and differing group sizes, and the SRD dose groups are separated by genotype. The MD schedules also differ from one another, while placebo participants are reported in their own group. These features mean that reading the counts as a direct dose comparison would require assumptions about which groups are comparable and what contrast is intended. A statistical model or pre-specified contrast might address such questions, but the analysis plan for the primary endpoint is not reported in the registry record.

General statistical explanation: for binary outcomes, methods can compare event probabilities or model the odds of an event, but the chosen method should reflect the design and the intended estimand. When counts are sparse, standard large-sample approximations may be unreliable; exact or other methods may be considered depending on the analysis plan. No inferential method for the primary endpoint is reported in the registry record, so no particular model should be assumed to have been used.

What is the role of the pharmacokinetic outcomes?

The registry lists secondary pharmacokinetic outcomes including area under the concentration-time curve and maximum measured concentration for the SRD and MD parts, and area under the curve for the DDI part. These outcomes describe drug concentration over time or a peak measured concentration. The listed outcome names are not numerical findings. Their numerical results, estimates of variability, and analysis details are not reported in the registry record. The stated DDI objective was relative bioavailability for BI 1323495 given alone versus with itraconazole, but the posted primary safety counts cannot answer that pharmacokinetic question.

General statistical explanation: pharmacokinetic summaries often need to account for the scale and distribution of concentration measures. When measurements are right-skewed, logarithmic-scale analyses may be used, and geometric summaries may be more suitable than arithmetic summaries. The registry record does not report the transformations, model, or summary approach used for the listed pharmacokinetic outcomes; those methods should not be inferred from the outcome names.

How should planning calculations be understood?

The planning illustration uses stated assumptions: a two-sided significance level of 0.05, equal allocation, a normal approximation, and an effect expressed as a fraction of the observed effect. Such calculations describe hypothetical sample sizes for a future design under those assumptions. They are not the trial's observed power, do not show that a planned sample size was adequate, and do not recover the protocol's original rationale. The trial's own sample-size justification is not reported in the registry record. A sample-size calculation based on the observed effect is also uncertain because the observed effect itself may be imprecise.

General statistical explanation: power is a design property calculated for a specified effect, variability, significance threshold, and analysis. It is not a post hoc certificate that a result is meaningful. In a small study, a non-significant comparison could reflect limited precision, while a seemingly large difference could be unstable. Because the registry does not report a primary-endpoint comparison or its analysis method, interpretation should stay with the observed counts and their limitations rather than infer significance or power.

The trial was sequential, but the registry record does not report whether any interim analyses or formal dose-escalation decision rules were used. The sequence of dose groups alone does not establish the statistical rules governing progression. Those details, like endpoint-specific missing-data procedures and multiplicity adjustments, are 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("SRD Part: PM Subjects, BI1323495 10mg", "SRD Part: PM Subjects, BI1323495 30mg", "SRD Part: PM Subjects, BI1323495 100mg", "SRD Part: EM Subjects, BI1323495 30mg", "SRD Part: EM Subjects, BI1323495 70mg", "SRD Part: EM Subjects, BI1323495 150mg")
n      <- c(6, 6, 6, 3, 3, 3)
events <- c(1, 2, 1, 0, 1, 0)
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: PM Subjects, BI1323495 10mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SRD Part: PM Subjects, BI1323495 30mg  6  2  33.3  4.3  77.7  9.7  70.0  9.9  71.0
ARM  SRD Part: PM Subjects, BI1323495 100mg  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  SRD Part: EM Subjects, BI1323495 30mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2
ARM  SRD Part: EM Subjects, BI1323495 70mg  3  1  33.3  0.8  90.6  6.1  79.2  6.8  80.6
ARM  SRD Part: EM Subjects, BI1323495 150mg  3  0  0.0  0.0  70.8  0.0  56.1  0.6  60.2

11. Multiplicity, Missing Data and Analysis Populations

The study had multiple parts, dose groups, genotypes, and outcomes. The registry lists 10 outcome measures and 3 analyses, and it names seven secondary outcomes, many of them pharmacokinetic measures. Examining multiple outcomes or comparisons can increase the chance of a false-positive finding if each is tested without adjustment. Whether any multiplicity procedure was planned or applied is not reported in the registry record.

The primary safety endpoint is restricted to the SRD and MD parts. The DDI part had a distinct bioavailability objective, so combining its participants with the primary safety groups would not match the endpoint's stated scope. The registry does not report a unified analysis that compares all trial arms, nor does it report a treatment-effect estimate for the primary endpoint.

The primary analysis population is the treated set. It includes participants randomized in the SRD and MD parts who received at least one dose. The registry does not report a separate intention-to-treat analysis or a per-protocol analysis for this endpoint.

Missing-data handling is not reported in the registry record. The record also does not state whether any participants had incomplete follow-up, whether endpoint status was unavailable for anyone, or what assumptions would have been used for missing observations. The posted group counts therefore should not be interpreted as proof that all randomized participants had complete outcome ascertainment. Any exclusion or imputation beyond the stated treated-set definition cannot be inferred.

The registry also does not report a pre-specified statistical analysis plan for the primary endpoint, a method for adjusting comparisons across doses or genotypes, or a plan for handling multiple secondary pharmacokinetic outcomes. Those absences limit reconstruction of how the trial was intended to distinguish confirmatory questions from descriptive ones.

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 adverse-event summary reports serious adverse events separately from other adverse events. Across the listed SRD, MD, and DDI groups, the number of participants affected by serious adverse events was 0, and the number of deaths was 0. The registry lists no top serious-event terms. These are the posted counts for the groups and should be read as such, rather than as a guarantee that serious events are impossible or as a measure of risk outside the trial.

The other-adverse-event counts differ by group. For example, the SRD summary lists 1 of 9 placebo participants, 1 of 6 PM participants at 10 mg, 2 of 6 at 30 mg, and 4 of 6 at 100 mg as affected. For the SRD EM groups, the counts are 2 of 3 at 30 mg, 1 of 3 at 70 mg, and 0 of 3 at 150 mg. In the MD part, the counts are 2 of 9 at 30 mg twice daily, 4 of 9 at 60 mg once daily, and 1 of 6 with placebo. These are not all the same endpoint as the primary count of drug-related adverse events.

The DDI summary reports other adverse events for 4 of 14 participants receiving BI 1323495, 1 of 14 receiving itraconazole, and 4 of 14 receiving the combination. The summary does not provide enough detail to identify event types, severity beyond the separate serious-event category, or causal attribution for these counts. The small groups and different parts make simple cross-group comparisons especially uncertain.

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

The primary results show how many participants in each SRD and MD arm were reported with drug-related adverse events during the specified follow-up windows. These counts are useful descriptive safety information from a completed early-phase study. They identify that events were reported in some groups and not in others, with the exact counts varying across the small dose and genotype groups.

They do not establish whether BI 1323495 caused an event. The endpoint records the sponsor's classification of drug-related events, but the registry record does not provide event descriptions or adjudication details for this outcome. The counts also do not show event severity, duration, recurrence, or clinical consequences. No serious adverse events or deaths were reported in the listed group summaries, but small group sizes and limited observation periods constrain what can be concluded from that finding.

The primary results do not establish a comparative treatment effect. No estimate, confidence interval, or inferential test for the primary endpoint is reported in the registry record. The data therefore do not support a claim that one dose, genotype group, or dosing schedule had a higher or lower event risk than another. Differences in the counts are descriptive, and the groups are not all interchangeable comparisons.

The results also do not answer the DDI pharmacokinetic question. The registry names outcomes related to exposure and maximum concentration, but numerical findings for those outcomes are not reported in the registry record. It is therefore not possible from the posted figures to quantify the relative bioavailability of BI 1323495 alone versus with itraconazole.

Finally, the study was conducted in healthy male participants, with the SRD and MD parts focused on Japanese participants and UGT2B17 genotype groups. The results should not be extended beyond the populations and conditions studied on the basis of these counts alone. The posted information is a bounded description of trial observations, not a general estimate for other populations or circumstances.

14. Why This Trial Matters Statistically

This trial illustrates why the structure of an early-phase study matters when interpreting its results. It combined single-dose escalation, repeated dosing, genotype-defined groups, placebo controls, and a separate drug-interaction sequence. Each component addresses a distinct question. Reading all arms as one large comparison would obscure those design differences and could lead to contrasts the trial was not designed to estimate.

The primary endpoint is a participant-level binary safety outcome, and the posted results are counts rather than modeled effects. Such counts are straightforward to understand, but their interpretation depends on group size, endpoint definition, follow-up, and analysis population. Here, the groups are small, and the endpoint applies only to the SRD and MD parts. That makes precision and the distinction between observation and inference particularly important.

The record also demonstrates the difference between naming an outcome and reporting a result. Several pharmacokinetic outcomes are listed, and the DDI objective is described, but numerical findings for those questions are not reported in the registry record. The presence of outcome definitions does not establish the size or direction of any pharmacokinetic effect.

Finally, planning calculations based on an observed effect should be kept separate from the original design. Such illustrations can support discussion of future study sizes under explicit assumptions, but they are not observed power and do not disclose the original sample-size rationale. This distinction helps prevent descriptive early-phase findings from being presented as more precise or definitive than the available statistics support.

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 most direct limitation is the size of the individual groups: several SRD arms include 3 participants, and other primary endpoint groups include 6 or 9. Event counts in groups this small provide limited precision, and the registry record does not report confidence intervals for the primary endpoint. A zero count in a group is therefore not evidence that the event risk is zero.

The primary endpoint is limited to drug-related adverse events in the SRD and MD parts. The separate DDI part is excluded, and its main objective concerned relative bioavailability. Consequently, the primary safety results do not summarize all trial participants or address the DDI pharmacokinetic objective. Numerical results for the listed secondary pharmacokinetic outcomes are not reported in the registry record.

The groups also differ in genotype, dose, and dosing schedule. The SRD arms include PM and EM participants at different doses; the MD regimens include twice-daily and once-daily dosing. The registry reports counts by arm but does not provide an adjusted analysis that accounts for these distinctions or a formal dose-response analysis. A comparison across those groups would therefore require assumptions not specified in the record.

Further limitations include the absence of a reported primary-endpoint statistical analysis plan, multiplicity procedure, missing-data approach, or sample-size justification. Event descriptions and details of severity and attribution are not reported in the registry record. The design's single-blind SRD and MD parts and open-label DDI part also differ in masking, while the posted safety summaries do not indicate how knowledge of treatment assignment was addressed in event assessment.

The study population was healthy male Japanese participants in the SRD and MD parts, with genotype-defined groups; the DDI part involved healthy male PM participants. The record does not establish how these findings apply to other populations or settings.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study in Healthy Japanese Men to Test How Different Doses of BI 1323495 Are Tolerated and How Itraconazole Influences the Amount of BI 1323495 in the Blood — NCT04619251.
• Registry record last updated 2024-03-27; status last verified 2024-03.
• Results first posted 2024-02-22.
• 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

NCT04619251 is a completed phase 1 randomized, single-blind, sequential study sponsored by Boehringer Ingelheim, with 74 participants enrolled. It examined single rising doses and multiple doses of BI 1323495 in healthy male Japanese PM and EM participants, with placebo groups, and included an open-label fixed-sequence DDI part in PM participants involving itraconazole.

The primary endpoint counted participants with drug-related adverse events in the SRD and MD parts, assessed through up to 7 days and up to 17 days, respectively. The posted arm counts range from 0 of 3 to 2 of 6 in the SRD groups and from 1 of 6 to 3 of 9 in the MD and placebo groups. The listed adverse-event summary reports 0 participants with serious adverse events and 0 deaths in each group.

No inferential comparison for the primary endpoint, numerical pharmacokinetic results, missing-data method, multiplicity approach, or sample-size justification is reported in the registry record. The posted safety counts are descriptive and should be interpreted in light of the small, distinct groups and the trial's early-phase scope.