Relative Bioavailability of BI 1467335 Tablet and Oral Solution, and Food Effect on Tablet in Healthy Male Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Relative Bioavailability of BI 1467335 Tablet and Oral Solution, and Food Effect on Tablet in Healthy Male Subjects (NCT02999191), a randomized phase 1 study. The primary outcome is AUC0-tz of BI 1467335.

2. Clinical Question

The trial was designed to address formulation and food-condition questions about pharmacokinetic exposure, rather than a clinical outcome. Its stated objective focused on relative bioavailability of the tablet compared with the oral solution under fasted conditions, alongside the effect of food on tablet bioavailability. The registry record does not report a clinical efficacy question, and the posted primary outcome is a pharmacokinetic measure.

3. Trial Design

This was a phase 1 randomized, open-label, single-dose, three-way crossover trial in healthy male subjects. The record lists an enrollment of 18 and a completed status. The recorded start date is 2017-01-10, and the primary completion date is 2017-03-15. The sponsor was Boehringer Ingelheim.

The three treatment conditions were BI 1467335 tablet under fasted conditions, BI 1467335 oral solution under fasted conditions, and BI 1467335 tablet under fed conditions. In a crossover design, participants receive more than one treatment condition in a sequence, so comparisons can be made within participants. This general feature can reduce the influence of stable differences between participants, although the record does not report the treatment sequences, washout arrangements, or the statistical handling of sequence and period effects.

Open-label means masking was not used, as also recorded in the trial details. Randomization was used, but the method of sequence generation and allocation concealment is not reported in the registry record. The record does not report the dose, exact timing of treatment periods, food composition, or participant-level adherence information.

For the primary pharmacokinetic outcome, the registry describes a Pharmacokinetic Set that includes treated subjects with at least one primary pharmacokinetic parameter not excluded because of a relevant protocol violation or a non-evaluable plasma concentration. The recorded group counts for AUC0-tz were 18 for the fasted tablet, 18 for the fasted solution, and 17 for the fed tablet. These are outcome-specific counts; they do not establish that each comparison used an identical set of participants. The registry record does not report reasons for the difference in the fed-tablet count.

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.

Treatment Period 1 [1 Day]

Wash-out Period 1 [21 Days]

Reasons for not completing this period:

Treatment Period 2 [1 Day]

Wash-out Period 2 [21 Days]

Analysis population for the primary outcome, as defined in the registry: PharmacoKinetic Set \[PKS\]: This subject set included all subjects in the Treated Set \[All subjects who received at least one dose of study medication\] who provided at least one primary PK parameter that was not excluded due to a relevant protocol violation \[PV\] or non-evaluable plasma concentrations. One subject did not receive the dose in period 2 \[Tablets, fed\].

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 \[TS\]: All subjects who received at least one dose of study medication.

6. Primary Endpoint

The registry lists the primary outcome as AUC0-tz of BI 1467335, measured over At -1:00h [hours (h): minutes (min)] before drug administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00 and 24:00 h:min after drug administration..

The primary endpoint was AUC0-tz of BI 1467335. AUC0-tz represents the area under the plasma concentration-time curve from time 0 to the last quantifiable data point. It summarizes measured drug concentration across the sampling period, rather than describing concentration at only one measurement time. For a bioavailability comparison, this is useful because it captures overall observed exposure over the defined interval.

Plasma sampling was scheduled at -1:00h before drug administration and at 0:15, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00, 8:00, 10:00, 12:00 and 24:00 h:min after administration. The record reports geometric means and geometric coefficients of variation for the treatment groups. A geometric mean is a measure of central tendency suitable for positive, often right-skewed pharmacokinetic measurements; the geometric coefficient of variation describes relative variability on a multiplicative scale.

The endpoint does not directly measure a clinical benefit or harm. It describes plasma exposure in the defined pharmacokinetic population. The registry record does not report a separate clinical endpoint alongside this primary pharmacokinetic measure.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The statistical methods can be understood by separating descriptive summaries from treatment comparisons. The geometric means and geometric coefficients of variation describe the AUC0-tz results within each treatment condition. The ANOVA ratio estimates and their confidence intervals address comparisons between specified conditions. These quantities answer related but different questions: a group summary describes an arm's observed exposure, while a ratio estimates a contrast between conditions.

Why use a geometric summary?

Pharmacokinetic measurements are positive and may vary proportionally rather than by a constant additive amount. A geometric mean summarizes central tendency on a multiplicative scale. The geometric coefficient of variation expresses relative dispersion on that scale, so it helps describe how variable the measurements were relative to their magnitude. It is not the same as a standard deviation in the original measurement units. The reported AUC group summaries are 2.24 for fasted tablets, 2.49 for fasted solution, and 3.9 for fed tablets; their geometric coefficients of variation are 101.0, 121.0, and 90.5, respectively.

What does ANOVA contribute?

ANOVA is a modeling approach for comparing means or transformed outcomes across treatment conditions. In pharmacokinetic analyses, a ratio can be estimated after a suitable transformation and then expressed on the original multiplicative scale. The registry identifies the reported method as ANOVA and the parameter as a ratio. It does not report the transformation, model terms, covariance structure, or diagnostic checks. Because this trial used a crossover design, treatment observations may be related within participants; the precise modeling of that relationship is not reported in the registry record.

How should the confidence intervals be read?

A confidence interval conveys the uncertainty around an estimated contrast under the analysis method. The fasted-tablet versus fasted-solution estimate is 89.90 with a 90% confidence interval from 73.304 to 110.25. The fed-tablet versus fasted-tablet estimate is 170.78 with a 90% confidence interval from 139.85 to 208.54. A confidence interval does not guarantee that the true value lies within its endpoints, nor does it show the distribution of individual responses. It gives an interval estimate whose interpretation depends on the model and its assumptions.

The registry does not report p values for these two comparisons. A p value and a confidence interval are different summaries of uncertainty, and neither alone establishes clinical importance. The record also does not state a prespecified equivalence or bioequivalence margin, so the reported intervals should not be labeled as demonstrating equivalence or non-equivalence based on a threshold that is not recorded.

Why can variability affect precision?

General statistical explanation: over-dispersion means that observations vary more than a model's assumed distribution or variance structure would predict. When variability is high, estimates can be less precise, and model-based uncertainty can be misleading if the variance assumptions are inappropriate. The geometric coefficients of variation indicate substantial relative variation in these group summaries, but the registry record does not provide individual data or model diagnostics to assess the fit or the treatment of variability. It is therefore not possible to independently evaluate whether the reported uncertainty fully reflects the data structure.

What does the crossover design change?

General statistical explanation: crossover studies compare treatments within participants, which can account for stable participant characteristics shared across treatment periods. Valid interpretation also depends on how treatment order, period effects, and possible carryover are handled. The registry identifies a randomized three-way crossover design, but does not report sequence details, washout duration, or the exact ANOVA terms. Those omissions limit independent assessment of the design-specific assumptions; they do not invalidate the posted sponsor analysis on their own.

The recorded outcome counts are 18 for the fasted tablet, 18 for the fasted solution, and 17 for the fed tablet. Counts in a crossover trial can reflect which outcome measurements were evaluable for each condition, but the specific reason for the difference is not reported in the registry record. The record's Pharmacokinetic Set description indicates that relevant protocol violations and non-evaluable concentrations could affect inclusion. The registry does not provide a participant flow or a detailed account of missing measurements, so the impact of exclusions cannot be assessed from these summaries alone.

10. Analyses Reported by the Sponsor

The registry reports two sponsor analyses using ANOVA. For the fasted tablet and fasted solution comparison, the ratio is 89.90 with a 90% confidence interval from 73.304 to 110.25. For the fed tablet and fasted tablet comparison, the ratio is 170.78 with a 90% confidence interval from 139.85 to 208.54. No p values are reported for these estimates.

A separate recalculated estimate for these comparisons is not reported in the registry record. The arm-level geometric means are descriptive summaries and are not a substitute for a model-based crossover contrast. A simple recalculation from group summaries would not reproduce the sponsor's ANOVA analysis because the record does not include the participant-level data or full model specification. The registry does not flag a discrepancy between a sponsor estimate and a recalculation. Accordingly, the posted sponsor analyses are the available inferential results, and there is no competing recalculated estimate to interpret alongside them.

The confidence intervals communicate uncertainty around the reported ratios. The record does not state a prespecified decision boundary for interpreting them, so the estimates should be described without assigning a formal equivalence conclusion.

11. Multiplicity, Missing Data and Analysis Populations

The registry reports a primary AUC0-tz outcome and two ANOVA comparisons: fasted tablet with fasted solution, and fed tablet with fasted tablet. It does not report whether these comparisons were prespecified as co-primary, whether one was confirmatory and the other supportive, or whether any adjustment for multiple comparisons was planned. A multiplicity strategy is not reported in the registry record.

Multiplicity matters when several hypotheses are tested because the chance of a false-positive finding can increase across a family of tests. The appropriate approach depends on the objectives and hierarchy of the analyses. Without a documented testing plan, the reported confidence intervals should be read as the intervals attached to the individual analyses, not assumed to have been adjusted for the full set of comparisons. The record does not report p values for the two posted comparisons.

Missing-data handling is also not described in detail. The Pharmacokinetic Set definition refers to treated participants with at least one primary pharmacokinetic parameter that was not excluded for a relevant protocol violation or non-evaluable plasma concentration. The recorded outcome counts are 18 for the fasted tablet, 18 for the fasted solution, and 17 for the fed tablet. The registry record does not report why the fed-tablet count differs, how missing concentration measurements were handled, or whether any sensitivity analysis was performed.

The record describes the treatment of protocol violations only in broad terms and does not provide a full list of exclusions or participant-level flow. It also does not report an intention-to-treat analysis population for this pharmacokinetic endpoint. The registry lists no posted secondary outcome results. An interim analysis plan, stopping rules, and any statistical analysis plan details beyond the reported ANOVA method are not reported in the registry record. These gaps restrict assessment of multiplicity control, missingness assumptions, and the relationship between the planned and reported analyses.

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 records no serious adverse events in any of the three treatment conditions: 0 of 18 participants in the fasted-tablet group, 0 of 18 in the fasted-solution group, and 0 of 17 in the fed-tablet group. Deaths were also recorded as 0 in each condition. These are the serious-event counts posted for the relevant group denominators.

The record separately lists other adverse events affecting 2 participants with fasted tablets, 5 with fasted solution, and 4 with fed tablets. Those counts are not serious adverse event counts and should not be combined with the serious-event summary. In a crossover study, the treatment-condition counts may include participants who contributed to more than one condition; the registry record does not give participant-level overlap for these safety summaries.

Zero reported serious events means none were recorded in the registry's safety results for these groups. It does not establish that no serious events could occur, nor does it quantify risks beyond the observed trial. The record does not provide further detail about event terms, timing, attribution, or the method used to collect adverse events. The small group counts and the study's healthy male population also limit how broadly these safety counts can be generalized.

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

The posted results characterize single-dose pharmacokinetic exposure for BI 1467335 in healthy male subjects under three conditions: tablet fasted, oral solution fasted, and tablet fed. AUC0-tz is the primary endpoint, and the record provides geometric mean summaries, relative variability summaries, and two ANOVA ratio estimates with 90% confidence intervals. The results therefore offer information about the measured exposure contrasts in this study population and setting.

They do not, by themselves, establish clinical benefit or harm. AUC0-tz is a pharmacokinetic measure, not a patient-centered outcome. The registry does not report clinical efficacy results, and it does not post secondary outcome results. No conclusion about use in a different population, repeated dosing, or other conditions follows from these data alone.

The estimates should also not be treated as proof of equivalence or lack of equivalence. Such a conclusion depends on a prespecified margin and an analysis plan; neither is reported in the registry record. The confidence intervals convey statistical uncertainty for the comparisons but cannot replace a decision criterion that is absent from the record.

Interpretation is bounded by the trial's size and scope, the outcome-specific counts, and the limited methodological detail available. The registry lists 18 enrolled participants, while AUC0-tz group counts are 18, 18, and 17. It does not explain the differing count or provide individual-level observations. The trial was open-label, although the primary endpoint is a laboratory pharmacokinetic measure. The record also does not report enough detail to evaluate the crossover model specification, missing-data assumptions, or multiplicity plan.

The most defensible reading is descriptive and comparative: the posted summaries and intervals quantify exposure estimates for the stated conditions, under the sponsor's reported ANOVA analyses. They do not answer broader clinical questions beyond the scope of this pharmacokinetic study.

14. Why This Trial Matters Statistically

This trial illustrates how a clinical study can have a narrow, well-defined statistical target without directly addressing a clinical outcome. The primary endpoint, AUC0-tz, summarizes plasma exposure across the observed concentration-time interval. The study's comparisons concern formulation and food conditions, so interpretation depends on distinguishing measured pharmacokinetic exposure from clinical effectiveness.

The crossover design is statistically important because each participant can contribute information under multiple conditions. This structure can make within-participant contrasts informative, but it also means that an analysis cannot be fully reconstructed from group geometric means alone. Understanding the estimated ratios requires the model, participant-level measurements, and design details. The registry identifies ANOVA but does not report enough model terms to assess those aspects independently.

The example also shows why point estimates should be read with their confidence intervals. The intervals indicate uncertainty around the reported ratios, while the group-level geometric coefficients of variation describe relative variability. Neither feature supplies a clinical decision threshold. Without a reported equivalence margin or multiplicity plan, statistical interpretation should remain close to the posted estimates rather than assigning a categorical conclusion.

Finally, the record makes visible the distinction between enrollment and outcome-specific analysis counts. The overall enrollment is 18, whereas the AUC group counts are 18, 18, and 17. A reader needs the participant flow and missing-data details to know why the counts differ and whether any exclusions could affect interpretation. Those explanations are not reported in the registry record. These are broadly useful statistical considerations when reading small pharmacokinetic crossover trials.

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.

Several trial-specific details needed to assess the comparisons are not reported in the registry record. The description identifies randomization and a three-way crossover, but does not give treatment sequences, washout arrangements, or the model terms used to account for treatment period and sequence. The record names ANOVA without specifying transformations, covariance assumptions, or diagnostics. These omissions prevent an independent reconstruction of the sponsor's analysis.

The outcome-specific count is 17 for the fed tablet and 18 for each fasted condition. The reason for this difference, the missing measurement pattern, and any sensitivity analyses are not reported. The Pharmacokinetic Set definition indicates that protocol violations or non-evaluable concentrations could affect inclusion, but the record does not provide participant-level flow or counts excluded for each reason.

The sample was limited to healthy male subjects, and the study assessed a single dose. The registry does not report the dose or other details needed to evaluate how the observed exposure estimates might relate to different dosing conditions. The open-label design is recorded, but blinding is not described beyond masking being absent. The record also does not report the food composition or timing details.

Finally, no equivalence margin, multiplicity plan, or p value is reported for the two ANOVA comparisons. The record does not provide a statistical analysis plan or interim analysis information. These are limitations of what can be assessed from the registry record; they do not establish that an unreported procedure was or was not conducted.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Relative Bioavailability of BI 1467335 Tablet and Oral Solution, and Food Effect on Tablet in Healthy Male Subjects — NCT02999191.
• Registry record last updated 2021-06-07; status last verified 2021-05.
• Results first posted 2021-06-07.
• 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

This completed phase 1 trial was a randomized, open-label, single-dose, three-way crossover study in healthy male subjects, with an enrollment of 18. It compared BI 1467335 tablet under fasted conditions, oral solution under fasted conditions, and tablet under fed conditions. The primary outcome was AUC0-tz, the area under the plasma concentration-time curve from 0 to the last quantifiable data point.

The registry reports geometric mean AUC0-tz values of 2.24 nmol*h/L for fasted tablets, 2.49 nmol*h/L for fasted solution, and 3.9 nmol*h/L for fed tablets. It also reports two ANOVA ratio estimates with 90% confidence intervals. No p values are reported. Serious adverse events and deaths were recorded as 0 in all three treatment conditions.

Important analysis details, including the full crossover model, missing-data handling, and multiplicity plan, are not reported in the registry record.