A Study in Healthy Men to Test Whether BI 425809 Influences the Amount of Midazolam in the Blood: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study in Healthy Men to Test Whether BI 425809 Influences the Amount of Midazolam in the Blood (NCT05258110), a na phase 1 study. The primary outcome is Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).

2. Clinical Question

The study description says the purpose was to assess the potential impact of steady-state BI 425809 on CYP3A clinically by evaluating midazolam pharmacokinetics. Midazolam is identified in the registry summary as a recommended CYP3A4 substrate. The primary endpoint therefore focuses on the amount of midazolam measured in plasma over time, rather than on a clinical symptom or health outcome.

The registry record does not report the numerical primary endpoint results, so the magnitude and precision of any difference between treatments are not available in the record. It also does not report a numerical estimate of the treatment effect or a confidence interval. The study question can be described from its design and endpoint, but the posted record does not support a conclusion about the direction or size of the observed pharmacokinetic change.

3. Trial Design

This was a Phase 1, open-label, two-period, one-sequence trial. The registry lists the allocation as not applicable and the model as sequential. It records enrollment of 15 and identifies the study population as healthy male subjects. The trial is marked completed, with a start date of 2022-03-18 and a primary completion date of 2022-05-31.

In Period 1, all participants received a single oral dose of 2 mg midazolam solution alone on Day 1 as the reference treatment. The arm description also states that participants received one 10 mg film-coated tablet of iclepertin (BI 425809) orally once daily over 21 days, from Day -20 until Day 1 of the period described in the record. The registry names a midazolam-plus-iclepertin test treatment. The available arm description ends before fully specifying the remainder of the schedule, so further sequencing or timing details are not reported in the registry record.

Open-label means that treatment assignment was not masked in the study description. The one-sequence design means the treatments were not assigned in a randomized order. Consequently, this is not a randomized comparison with a parallel control group. A within-participant sequence can make pharmacokinetic comparisons possible, but interpretation depends on the actual order, timing, and analysis. Those details, beyond the stated schedule, are not reported in the registry record.

The primary outcome was midazolam AUC0-tz, expressed in hours*nanomole/Liter (h*nmol/L). Blood plasma concentrations were scheduled to be measured within 1 hour before administration and at 30 minutes, 1h, 1h 30 min, 2h, 3h, 4h, 6h, 8h, 10h, and 12h afterward. The registry also lists AUC0-∞ as a secondary outcome. Although the registry records three outcome measures and three analyses, their full details and numerical results are not reported in the registry record.

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.

Period 1

Wash-out period

Reasons for not completing this period:

Period 2

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic parameter analysis set (PKS): The PKS included all subjects in the treated set who provided at least one pharmacokinetics (PK) endpoint defined as primary or secondary and was not excluded due to protocol deviation relevant to evaluation of PK or due to PK non-evaluability.

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 subjects who were treated with at least one dose of trial drug. The TS was used for all safety analyses.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve of Midazolam in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz), measured over Plasma concentrations of midazolam were measured within 1 hour (h) before and at 30 minutes (min), 1h, 1h 30 min, 2h, 3h, 4h, 6h, 8h, 10h, and 12h after administration of midazolam alone or in combination with iclepertin (BI 425809)..

The primary endpoint is the area under the concentration-time curve of midazolam in plasma from time 0 to the last quantifiable data point, called AUC0-tz. It combines the measured plasma concentrations across the stated sampling period into a measure of midazolam exposure. The unit is hours*nanomole/Liter (h*nmol/L).

Pharmacokinetic exposure is useful when the question concerns whether another drug may alter how much of a substrate drug is present in the body over time. Here, the registry describes midazolam as a recommended CYP3A4 substrate and states that the study aimed to assess the potential impact of BI 425809 on CYP3A clinically. AUC0-tz addresses exposure over the observed concentration-time interval, rather than only a single concentration at one sampling time.

The registry specifies geometric least squares means as the endpoint parameter and standard error as its dispersion measure. These describe a group-level estimate and its statistical precision; they are not a display of the spread of individual concentrations. The record does not include the numerical estimates, standard errors, treatment contrast, or confidence interval. AUC0-∞ is listed as a secondary outcome, but its numerical result is also not reported in the registry record.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry reports a pharmacokinetic endpoint summarized as a geometric least squares mean with standard error. It does not report the numerical estimates or a full statistical analysis plan. The concepts below explain how such summaries are generally used; they do not establish which additional procedures were used in this trial.

What does AUC measure?

For a drug concentration-time profile, area under the curve (AUC) summarizes concentration over time. AUC0-tz covers the interval from time 0 through the last quantifiable concentration. It uses information from multiple scheduled samples rather than relying on one concentration alone. The registry specifies plasma sampling within 1 hour before dosing and at 30 minutes, 1h, 1h 30 min, 2h, 3h, 4h, 6h, 8h, 10h, and 12h after midazolam administration. AUC0-∞, listed as a secondary outcome, refers to an area extrapolated to infinity; its numerical result is not reported in the registry record.

AUC is a pharmacokinetic exposure measure, not a direct measure of clinical benefit or harm. Its interpretation depends on the drug, the treatment context, the measurement schedule, and the study question. In this trial, the registry states that midazolam was used to assess the potential impact of BI 425809 on CYP3A clinically. The endpoint alone does not demonstrate a mechanism or establish a clinical consequence.

What is a geometric least squares mean?

As a general statistical concept, a geometric mean summarizes values on a multiplicative scale and is often useful for quantities that are positive and right-skewed, such as pharmacokinetic measurements. A least squares mean is a model-based group summary. The registry names geometric least squares means but does not report the model specification, transformations, covariates, or adjustment factors. Therefore, the record does not allow readers to determine precisely how the posted summaries were estimated.

In many analyses, geometric summaries are connected to modeling on a logarithmic scale, then expressed back on the original scale. That general practice should not be mistaken for a description of this trial's exact analysis: the model details are not reported in the registry record. Nor should a geometric mean be interpreted as the arithmetic average of participant-level AUC values.

What does standard error describe?

Standard error describes uncertainty in an estimated summary. It is distinct from the standard deviation, which describes dispersion among individual observations. A smaller standard error, considered in context, generally indicates a more precisely estimated group summary. The registry identifies standard error as the dispersion measure for the primary endpoint, but does not give its numerical value. Consequently, precision cannot be assessed from the record.

A confidence interval is a general way to express uncertainty around an estimate, showing a range of values compatible with the data and method under stated assumptions. No confidence interval for the primary contrast is reported in the registry record. Without an estimate and interval, readers cannot assess which effect sizes remain compatible with the posted primary results.

Why does the sequence matter?

In a parallel randomized trial, participants are assigned to different treatment groups, and randomization is intended to balance prognostic characteristics on average. This trial is listed as sequential, one-sequence, open-label, with allocation marked not applicable. It is therefore not a randomized comparison. The registry describes midazolam alone as the reference treatment and midazolam with iclepertin as the test treatment, but those labels do not make the treatments randomized or equivalent to independent control and intervention arms.

In a sequential pharmacokinetic study, observations under different treatment conditions may be compared within the same study sequence. General considerations can include whether the treatment timing is appropriate, whether drug effects persist into later periods, and how period effects are handled. These considerations are not claims that a problem occurred. The full schedule and the methods used to address such issues are not reported in the registry record, so their impact cannot be assessed.

What can the reported analysis counts establish?

The record lists three outcome measures and three analyses. Those counts indicate that multiple outcomes or analyses were registered, but do not describe their full definitions, statistical models, or results. The primary endpoint is identified as AUC0-tz; AUC0-∞ is named as a secondary outcome. The remaining details are not reported in the registry record.

When multiple outcomes or comparisons are considered, multiplicity can increase the chance of at least one apparently notable finding if each is evaluated separately. Statistical plans may address this through prespecified outcome hierarchy or adjustment methods. The registry record does not report a multiplicity strategy, so none should be assumed. Likewise, no interim analysis plan, sample-size justification, or trial-specific significance threshold is reported in the registry record.

The record includes planning assumptions for illustrative sample-size calculations based on an observed effect, with a two-sided significance level of 0.05, equal allocation, and a normal approximation. These are planning illustrations, not evidence of the trial's design justification or observed power. The record does not report the actual trial sample-size rationale, and an observed-effect illustration cannot substitute for the missing endpoint estimate and its uncertainty.

10. Multiplicity, Missing Data and Analysis Populations

The registry records three outcome measures and three analyses. It identifies AUC0-tz as the primary endpoint and AUC0-∞ as a secondary outcome, but the full descriptions and numerical results for all outcomes are not reported in the registry record. The record does not describe a prespecified hierarchy among outcomes, a multiplicity adjustment, or how any multiple analyses were interpreted.

As a general statistical issue, evaluating multiple outcomes or comparisons can increase the chance of a nominally notable result arising by chance when each is treated separately. A trial may address this through a defined testing hierarchy or an adjustment procedure. Since neither is reported, it is not possible to determine whether or how multiplicity was handled. No p-value for the primary comparison is reported in the registry record.

The primary analysis population is described as the pharmacokinetic parameter analysis set. It included treated subjects who provided at least one primary or secondary pharmacokinetic endpoint and were not excluded because of a protocol deviation relevant to pharmacokinetic evaluation or pharmacokinetic non-evaluability. The record does not give the number included in this set for the primary endpoint or describe exclusions by treatment condition.

Missing-data methods and the handling of individual unquantifiable or unavailable concentration measurements are not reported in the registry record. The registry identifies the last quantifiable data point in AUC0-tz, but does not explain how missing samples or other incomplete profiles were handled. Interim analyses, sample-size justification, and a detailed statistical plan are also not reported.

11. 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 lists serious adverse events separately for three treatment groups. It records 0 affected among 15 at risk for midazolam alone, 0 among 14 at risk for iclepertin alone, and 0 among 12 at risk for iclepertin with midazolam. Deaths are recorded as 0 in each group. The record lists no serious adverse-event terms.

For other adverse events, the registry records 0 affected among 15 at risk with midazolam alone, 5 among 14 at risk with iclepertin alone, and 1 among 12 at risk with iclepertin plus midazolam. These are the counts reported for the groups; they are not a randomized comparison. The record does not provide event-term details in the registry record for this summary.

These figures describe recorded events in this trial and should be read separately from the pharmacokinetic endpoint. Zero recorded serious events does not establish that serious events cannot occur, and the group counts do not by themselves establish a causal treatment effect. The record does not report additional detail needed to assess event timing, severity beyond the serious/non-serious classification, or attribution.

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

This trial was designed to assess whether iclepertin (BI 425809) could influence midazolam pharmacokinetics, using midazolam as a CYP3A4 substrate. The primary outcome was AUC0-tz, an exposure measure based on plasma concentrations over time. The record also names AUC0-∞ as a secondary outcome and specifies the primary endpoint's summary format.

What the registry record does not provide is the numerical primary endpoint result. It therefore does not allow readers to determine whether midazolam AUC0-tz was higher, lower, or similar between the reference and test treatments, or how precise any contrast was. No treatment contrast, confidence interval, or primary-comparison p-value is reported in the registry record. A study purpose and endpoint definition are not substitutes for numerical findings.

The design was open-label and sequential, with one sequence and allocation marked not applicable. It was not a randomized, like-for-like control comparison. The record's treatment labels identify the conditions being assessed, but do not support interpreting the groups as randomized arms. The treatment schedule as recorded is incomplete, and full analysis details are not reported.

The safety counts show no recorded serious adverse events or deaths in the listed groups, while other adverse events are recorded in the iclepertin-alone and combination groups. These observations describe the recorded trial data; they do not answer the primary pharmacokinetic question or establish causation.

Accordingly, the record supports understanding what the trial set out to measure and how its primary endpoint was defined. It does not support a quantitative conclusion about the treatment effect, its uncertainty, or its clinical implications.

13. Why This Trial Matters Statistically

This trial illustrates a focused pharmacokinetic question: whether exposure to a probe drug, midazolam, differs when it is administered with iclepertin. AUC0-tz is suited to summarizing measured concentration over time, while the registry's reference and test treatment labels make the intended contrast clear.

It also illustrates why an endpoint definition is not enough to interpret a result. The registry identifies a geometric least squares mean and standard error, but does not report the numerical estimates or uncertainty for the primary endpoint. Without those values, readers cannot judge the size or precision of the treatment contrast. The record reports the question and measurement framework, but not the numerical evidence required to answer the question.

The sequential, one-sequence design is another important statistical feature. It differs from a randomized parallel comparison, and the registry explicitly notes that the arms are not a like-for-like control comparison. Design labels and treatment names should therefore be read in context rather than treated as evidence of random assignment.

Finally, the record distinguishes pharmacokinetic outcomes from safety counts. Serious adverse-event and death counts are reported, as are counts for other adverse events, but these do not replace the missing exposure results. Together, these features show how study purpose, design, outcome definition, numerical reporting, and safety data each contribute different parts of a statistical interpretation.

14. 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 principal limitation of the registry record for interpreting the stated question is the absence of numerical results for AUC0-tz. The treatment-specific geometric least squares means, standard errors, contrast, and confidence interval are not reported in the registry record. The listed secondary AUC0-∞ outcome also lacks a numerical result.

The trial was open-label, sequential, and conducted in one sequence, rather than randomized. The registry cautions that the treatment arms are not a like-for-like control comparison. The available treatment description ends before fully specifying the schedule, and further details about sequence timing are not reported in the registry record.

Although the pharmacokinetic analysis set is defined, the record does not report how many participants contributed to each endpoint analysis, or how missing or non-evaluable concentration data were handled. The model specification, covariates, estimation details, and any methods for addressing period or carryover effects are not reported. Multiplicity procedures and interim analyses are also not reported in the registry record.

The population is described as healthy male subjects, and the record does not establish how results would apply to other populations. The safety figures are counts from the listed groups; they do not supply detailed event terms or establish causality. These limitations constrain interpretation of both the pharmacokinetic comparison and the broader meaning of the trial.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study in Healthy Men to Test Whether BI 425809 Influences the Amount of Midazolam in the Blood — NCT05258110.
• Registry record last updated 2026-03-30; status last verified 2023-03.
• Results first posted 2026-03-30.
• 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.

18. Record Summary

NCT05258110 is a completed Phase 1, open-label, sequential, two-period, one-sequence trial in healthy male subjects. The registry records enrollment of 15. It describes a reference treatment of a single oral 2 mg dose of midazolam and a test treatment involving midazolam with iclepertin (BI 425809), which was administered orally as a 10 mg tablet once daily over 21 days.

The primary endpoint was midazolam AUC0-tz, summarized as a geometric least squares mean with standard error. AUC0-∞ was listed as a secondary outcome. Numerical primary and secondary outcome results are not reported in the registry record. Serious adverse events and deaths were recorded as 0 in each listed group; other adverse events were recorded in the iclepertin-alone and combination groups.

The record does not report a detailed statistical analysis plan, multiplicity approach, missing-data methods, or full treatment schedule. Its design is not a randomized, like-for-like comparison.