A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 730357 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 How Itraconazole Influences the Amount of BI 730357 in the Blood (NCT03782987), a non-randomized phase 1 study. The primary outcome is Area Under the Concentration-time Curve of the BI 730357 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz).

2. Clinical Question

This is a pharmacokinetic interaction question, not a test of clinical benefit. The endpoint concerns the amount of BI 730357 measured in plasma over time after dosing. The intended comparison is between the same BI 730357 dose administered under two conditions: alone and alongside itraconazole. In a crossover study, the conditions are arranged as treatment periods, making within-participant comparisons relevant in principle. However, the record identifies the allocation as nonrandomized and the treatment sequence as BI 730357 alone in period 1 followed by the combination in period 2. Thus, the comparison also coincides with treatment-period order. The registry record does not report an effect estimate, confidence interval, or test result for the primary endpoint. It therefore does not establish from the posted results how large or precise the exposure contrast was.

3. Trial Design

The registry describes a completed Phase 1, open-label, nonrandomized, one-way crossover study in healthy men. BI 730357 was administered alone in treatment period 1, identified as Reference, and with itraconazole in treatment period 2, identified as Test. The record lists an enrollment of 14. It reports a start date of 2019-01-10 and a primary completion date of 2019-03-11.

In the Reference period, participants received a 50 mg BI 730357 tablet orally on Day 1. In the Test period, they received the same stated BI 730357 dose on Day 1 together with 20 mL of 10 mg/mL itraconazole oral solution. Itraconazole was administered once daily for 12 days, from Day -3 to Day 9. The registry describes plasma sampling within 3 hours before BI 730357 administration and at multiple post-dose times in both periods, with additional sampling in period 2. These measurements support calculation of the concentration-time exposure endpoint.

The design allows the two treatment conditions to be compared within the study’s crossover structure, but the registry does not report randomized treatment order. The stated sequence places the BI 730357-alone period first and the combination period second. Because treatment condition and period order are aligned, the record does not establish that any observed contrast would be separable from period or sequence effects. Masking was absent, as expected from the listed NONE designation, and the study is described as open-label.

The registry does not report a sample-size justification, protocol-level statistical plan, interim analyses, or details of how period effects were addressed. It identifies a pharmacokinetic analysis population that included subjects with at least 1 primary or secondary pharmacokinetic parameter not excluded for relevant protocol deviations or pharmacokinetic non-evaluability. The record does not state how many participants ultimately contributed an evaluable primary endpoint.

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 participants were screened for eligibility to participate in the trial. Participants attended specialist site which would then ensured that all participants met all inclusion/exclusion criteria. Participants were not to be entered to trial if any one of the specific entry criteria were not met.

Period 1

Washout Period

Period 2

Analysis population for the primary outcome, as defined in the registry: Pharmacokinetic (PK) parameter set (PKS): The PKS included all subjects of the TS who provided at least 1 primary or secondary PK parameter that was not excluded due to relevant protocol deviations 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 received at least 1 dose of trial medication.

6. Primary Endpoint

The registry lists the primary outcome as Area Under the Concentration-time Curve of the BI 730357 in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz), measured over Pharmacokinetic samples were taken within 3 hours (h) before administration of BI 730357 and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 12, 24, 34, 47, 71, 119 and 167 h in both periods and additionally at 215 and 263 h only for period 2..

The primary endpoint is the area under the plasma concentration-time curve for BI 730357 from time 0 to the last quantifiable data point, abbreviated AUC0-tz in the registry. It is expressed in nanomole-hours per litre. The endpoint combines concentration measurements across the observed post-dose period into a measure of plasma exposure. The registry describes the endpoint as a geometric mean with standard error as its dispersion measure.

Exposure measures are used in pharmacokinetic studies because they describe drug concentration over time rather than relying on a single blood sample. AUC0-tz uses observations through the last quantifiable concentration. The registry also lists AUC from 0 extrapolated to infinity as a secondary outcome, which extends the exposure concept beyond the last measured quantifiable point using an extrapolation. The primary endpoint’s listed sampling schedule includes measurements in both treatment periods and additional later samples in period 2.

For the clinical question, the relevant quantity would be a contrast in BI 730357 exposure between administration alone and administration with itraconazole. The record does not report the geometric means, a treatment contrast, a confidence interval, or a statistical test result for AUC0-tz. Consequently, the endpoint definition can be explained, but the magnitude and precision of the observed contrast cannot be assessed from the registry record. The endpoint is a pharmacokinetic measure; by itself it does not describe a clinical outcome or establish a clinical effect.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is a pharmacokinetic exposure measure. Concentration-time data are collected after dosing, and the area under the concentration-time curve summarizes exposure across a defined time interval. AUC0-tz ends at the last quantifiable data point, so it is tied to the observed concentration profile and the quantifiability of the samples. The registry states that the measure is summarized as a geometric mean and gives standard error as the dispersion measure. It does not report the values for either treatment condition.

Why use a geometric mean?

General statistical context: pharmacokinetic measurements are often positive and may have a right-skewed distribution, with some values appreciably larger than others. A geometric mean summarizes multiplicative variation and is often used for such outcomes. Comparisons of geometric means are naturally interpreted as relative contrasts, rather than absolute differences in the original measurement units. This general rationale does not establish which model or transformation was used in this trial. The statistical model and the exact form of the reported treatment contrast are not reported in the registry record.

What does standard error describe?

General statistical context: a standard error describes the sampling uncertainty of an estimate under a statistical model. It is not the same as the spread of individual participant measurements. A standard error can help construct an interval estimate when the analysis and assumptions are known, but it does not by itself show the full uncertainty in a contrast between two conditions. The record names standard error as the dispersion measure for the geometric mean but does not give numerical standard errors, confidence intervals, or a test result for the primary outcome.

How does crossover structure affect interpretation?

General statistical context: crossover designs can compare conditions within the same participants. Pairing can reduce the influence of stable between-participant differences, because each participant can serve as their own reference. A crossover analysis must also account appropriately for the paired structure and may need to consider period, sequence, or carryover effects. Here the registry identifies a nonrandomized, one-way crossover and specifies BI 730357 alone in period 1 followed by the combination in period 2. The record does not report the analysis model, treatment sequence randomization, carryover assessment, or period-effect handling. Consequently, the general advantages of crossover designs should not be mistaken for confirmation that these issues were addressed in a particular way.

What is over-dispersion?

General statistical context: over-dispersion occurs when the variability in observed data is greater than a statistical model expects. If not accommodated, uncertainty estimates can be too small and statistical tests can appear more conclusive than warranted. The registry does not report whether over-dispersion was assessed or relevant to the analysis. For a continuous pharmacokinetic endpoint, the applicable distributional and model assumptions would need to be evaluated from the analysis methods and data; those details are not reported in the registry record.

What can be said about planning calculations?

General statistical context: a sample-size calculation for a future study depends on a target effect, variability assumptions, a significance level, allocation, and the intended analysis. The record’s planning assumptions describe a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation, with the target effect defined as a stated fraction of the observed effect. Such calculations are planning illustrations, not observed power and not evidence that the completed study had a particular probability of detecting an effect. The numerical planning estimates and observed primary effect are not reported in the registry record. No conclusion about the adequacy of the study’s sample size can be drawn from the assumptions alone.

The registry identifies 3 outcome measures and 3 analyses, but it does not provide details of the statistical models, covariates, handling of missing observations, multiplicity procedures, or inferential results for the primary outcome. The pharmacokinetic analysis population is described as including subjects who had at least 1 primary or secondary parameter not excluded because of relevant protocol deviations or pharmacokinetic non-evaluability. This definition specifies an eligibility principle for the analysis set, not the number with an evaluable primary endpoint or the exact method used to estimate the treatment contrast.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists 3 outcome measures and 3 analyses. It identifies AUC0-tz as the primary endpoint and lists AUC from 0 extrapolated to infinity as a secondary outcome. Details of the remaining outcome measures and analyses are not reported in the registry record. The record does not describe a testing hierarchy, an adjustment for multiple comparisons, or whether any multiplicity procedure was planned. Without those details, the relationship between the primary and secondary analyses and the interpretation of any tests cannot be assessed.

The pharmacokinetic analysis population is described as including subjects from the trial who provided at least 1 primary or secondary pharmacokinetic parameter that was not excluded because of relevant protocol deviations or pharmacokinetic non-evaluability. This definition indicates that some observations could be excluded for those stated reasons. The number included in the primary analysis, the reasons for any exclusions, and the handling of missing or non-quantifiable measurements are not reported in the registry record. The record also does not describe imputation or sensitivity analyses.

The registry does not report a statistical analysis plan, model specification, confidence intervals, or primary endpoint test results. It is therefore not possible to determine from this record how multiplicity, missing measurements, or exclusions affected the reported inference. These omissions matter because an endpoint definition alone does not specify how the final estimate and its uncertainty were obtained. The registry’s analysis-population description should not be taken to imply that all enrolled participants contributed an evaluable primary endpoint.

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 three safety groups: BI 730357 alone, itraconazole, and BI 730357 with itraconazole. Each group has 14 participants listed as at risk for serious adverse events and other adverse events. The serious adverse event count is 0 in each group. The record lists other adverse events for 1 participant in the BI 730357-alone group, 5 in the itraconazole group, and 8 in the combination group. It lists 0 deaths in each group and no top serious adverse event terms.

These are registry counts for the listed groups, not a comparative estimate of treatment risk. The record does not provide event-level descriptions, severity breakdowns, exposure-adjusted rates, or a statistical comparison. Because the study is nonrandomized and the treatment conditions are ordered by period, the group counts should not be read as a randomized safety comparison. Zero reported serious events means none were listed in these group entries; it does not establish that an event is impossible or characterize risks beyond the study record. The adverse event entries also do not answer the primary pharmacokinetic question.

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

This trial addresses a focused pharmacokinetic question: whether BI 730357 exposure differs when the drug is administered with multiple doses of itraconazole rather than alone. It defines exposure using AUC0-tz, a plasma concentration-time measure, and describes a crossover arrangement in healthy men. The registry record also gives details of the dosing conditions and sampling schedule.

What the record does not provide is the numerical primary endpoint result. It does not report the condition-specific geometric means, a contrast between conditions, a confidence interval, or a statistical test result. Without these, the direction, magnitude, and precision of the exposure difference cannot be stated. In particular, the endpoint name and study objective are not evidence that exposure increased or decreased.

The study design also limits the conclusions that can be drawn from the record. Treatment order was not randomized: BI 730357 alone was administered in period 1 and the combination in period 2. This makes the treatment condition coincide with the period. A within-participant design can address stable individual differences in an appropriate analysis, but the registry does not describe how period effects or other potential design concerns were handled.

The findings, as recorded, concern pharmacokinetic measurements and safety counts in healthy male subjects. They do not establish clinical benefit, clinical harm, or outcomes in other populations. The adverse event counts are descriptive and do not substitute for the missing primary endpoint estimate. The registry lists no serious adverse events in the named groups, while other adverse events are recorded; neither fact determines the pharmacokinetic contrast.

Accordingly, the most defensible reading is that the record documents the study question, treatment schedule, endpoint, analysis-population definition, and selected safety counts, but not the primary result needed to quantify the interaction. Any stronger conclusion would require results and analysis details that are not reported in the registry record.

13. Why This Trial Matters Statistically

This study illustrates why a clearly stated pharmacokinetic question and a clearly defined endpoint are not enough to interpret a trial’s result. The registry specifies AUC0-tz, its unit, the geometric-mean summary, and the sampling schedule. Those details explain what was intended to be measured. Yet the absence of the endpoint estimates and their uncertainty prevents readers from quantifying the treatment contrast or judging its precision.

The crossover structure also highlights the distinction between a design feature and a statistical result. Comparing treatment conditions within participants can be useful in general because it can account for stable differences between individuals. But this study’s nonrandomized, one-way sequence places the alone condition in period 1 and the combination condition in period 2. Interpretation therefore depends on how the analysis handles the fact that treatment and period are aligned. The registry does not report that analytic detail.

The record further shows why safety counts and pharmacokinetic results answer different questions. Counts of serious and other adverse events describe reported safety observations; they do not quantify plasma exposure. Likewise, an exposure endpoint does not by itself establish a clinical outcome. Keeping these evidence types separate avoids treating one as a substitute for the other.

Finally, planning illustrations should be distinguished from results. A sample-size calculation based on an observed effect and stated assumptions is a planning aid, not observed power and not a replacement for an effect estimate with an uncertainty interval. For statistical interpretation, readers need the estimate, its precision, the analysis method, and enough information to understand exclusions and multiplicity. Those details are not reported in the registry record for the primary comparison.

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 main limitation for interpreting the primary question is that the registry record does not report the AUC0-tz estimates or a treatment contrast. It also does not report a confidence interval, standard error values, or a test result. The direction, size, and precision of the pharmacokinetic comparison therefore cannot be evaluated from the posted record.

The allocation is listed as nonrandomized, and the treatment sequence is specified: BI 730357 alone in period 1 and BI 730357 with itraconazole in period 2. Treatment condition and period are consequently aligned. The record does not describe methods for addressing period effects, carryover, or sequence-related issues. Masking was absent, and the study is described as open-label.

The registry states that the pharmacokinetic analysis population included subjects with at least 1 eligible primary or secondary parameter, excluding parameters for relevant protocol deviations or pharmacokinetic non-evaluability. It does not report how many participants contributed an evaluable primary endpoint, what exclusions occurred, or how missing and non-quantifiable samples were handled. Details of the statistical model and multiplicity procedures are also not reported in the registry record.

The study was conducted in healthy male subjects, as described in the record. Its population and pharmacokinetic purpose limit what can be inferred about other populations or clinical outcomes. The safety entries are counts without event-level detail or a reported statistical comparison. These record-specific limitations do not show that the analyses were inadequate; they identify information that is not available in the registry record for independent interpretation.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: A Study in Healthy Men to Test How Itraconazole Influences the Amount of BI 730357 in the Blood — NCT03782987.
• Registry record last updated 2023-07-12; status last verified 2022-08.
• Results first posted 2023-07-12.
• 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

NCT03782987 is a completed Phase 1, open-label, nonrandomized, one-way crossover study sponsored by Boehringer Ingelheim. It enrolled 14 healthy male subjects. The record gives a start date of 2019-01-10 and a primary completion date of 2019-03-11.

The study compared a 50 mg oral dose of BI 730357 given alone in period 1 with the same BI 730357 dose given with itraconazole in period 2. Itraconazole was administered once daily from Day -3 to Day 9. The primary endpoint was AUC0-tz for BI 730357 in plasma, summarized as a geometric mean with standard error. The registry record does not report the primary endpoint estimates or inferential results.

Safety entries list 0 serious adverse events and 0 deaths in each named group. Other adverse events are listed in the BI 730357-alone, itraconazole, and combination groups. These counts are descriptive and do not provide the missing pharmacokinetic comparison.