A Study to Test How Well Healthy Men Tolerate Different Doses of BI 706321: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for A Study to Test How Well Healthy Men Tolerate Different Doses of BI 706321 (NCT03971695), a randomized phase 1 study. The primary outcome is Part I: Percentage of Subjects With Drug-related Adverse Events.

2. Clinical Question

3. Trial Design

This was a phase 1, randomized, single-blind, parallel-group study of BI 706321 in healthy male subjects. The registry lists the study as completed, with enrollment of 73. Part I investigated safety, tolerability, and pharmacokinetics after single rising oral doses. It included oral solution doses of 0.3 mg, 0.6 mg, and 1.2 mg, capsule doses of 2 mg, 4 mg, 8 mg, 15 mg, and 25 mg, and matching placebo groups. The oral doses in Part I were taken with 240 mL of water after an overnight fast of at least 10 hours.

Part II addressed formulation and food effects rather than the Part I dose sequence. It included 4 mg tablets after fasting, 4 mg tablets after a high-fat, high-calorie breakfast, and 4 mg capsules after fasting. The registry describes these as a test formulation under fasted conditions, a fed tablet condition, and a fasted capsule reference. Its stated objectives included comparing relative bioavailability after tablets and capsules under fasted conditions and investigating the effect of food on tablet bioavailability.

The primary safety result is for Part I, not a combined safety estimate across both parts. The primary outcome population was the treated set: participants randomized and treated with at least 1 dose of trial drug, assigned according to the first treatment received. The registry reports a single-blind design but does not identify which study personnel or participants were masked. Further details of sequence generation, concealment, and the allocation process 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.

Only the first 6 of 13 groups are shown.

Part I and Period 1 of Part II

End of Part I and Part II - Washout

Reasons for not completing this period:

Part II - Period 2

Part II - Washout (of at Least 12 Days)

Analysis population for the primary outcome, as defined in the registry: Treated set (TS): The TS included all subjects who were randomised and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the subjects received.

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 randomised and treated with at least 1 dose of trial drug. The treatment assignment was determined based on the first treatment the subjects received.

Only the first 6 of 14 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Part I: Percentage of Subjects With Drug-related Adverse Events, measured over Between intake of trial medication and the individual subject's end of trial, up to 22 days..

The primary endpoint is the percentage of Part I subjects with drug-related adverse events. It captures whether participants experienced an adverse event that was considered related to trial medication during the period from intake of trial medication to the individual subject’s end of trial, up to 22 days. This is a binary outcome at the participant level: a participant either is or is not counted as having at least one event meeting the endpoint definition.

In an early-phase study focused on safety and tolerability, this endpoint gives a direct descriptive account of the frequency of events judged related to treatment across dose and placebo groups. Percentages allow groups of different sizes to be read on a common scale, while the underlying group sizes remain important for understanding how much information each estimate contains. With small groups, one participant’s outcome can materially affect a percentage, so the values should not be treated as precise estimates of event frequency in a broader population.

The endpoint is not a complete account of safety. It does not, by itself, describe event type, severity, duration, timing, or the clinical reasoning behind attribution. Serious adverse events and other adverse-event counts are reported separately in the registry. The primary endpoint is also distinct from the pharmacokinetic outcomes, which concern drug concentration and exposure rather than adverse-event occurrence. The registry does not report a confidence interval or an inferential comparison for the primary endpoint.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

Reading a percentage endpoint. General: a binary endpoint records whether each participant meets a defined event criterion. The group percentage is the share of participants in that group who meet the criterion. It describes observed event frequency in that group; it does not by itself quantify how much the treatment changed risk relative to a comparator. The denominator matters because percentages from small groups are less stable than percentages from large groups. The Part I group sizes were small, ranging from 5.0 to 9.0 in the posted primary results.

Uncertainty and comparisons. General: a confidence interval describes a range of values compatible with the data under a specified statistical procedure. It conveys uncertainty around an estimate, rather than guaranteeing that the underlying value lies within a particular range. No confidence intervals for the primary percentages are reported in the registry record. The record also flags the two-arm comparison as missing or not estimable for this binary percentage endpoint. Consequently, the observed percentages should not be interpreted as a formal test of treatment differences, and no comparative precision can be assessed from the posted primary result.

For a randomized trial, a between-group comparison can help separate a treatment contrast from background event occurrence, but the design alone does not supply the result of that comparison. Here, both placebo groups had nonzero drug-related adverse-event percentages, and some active-treatment groups also had nonzero percentages. The registry does not provide an inferential estimate that combines these observations into a treatment-versus-placebo effect. No p-value or adjusted analysis for the primary endpoint is reported in the registry record.

Multiplicity. General: multiplicity arises when several outcomes, doses, or comparisons are examined. If many hypotheses are tested without an appropriate strategy, the chance of at least one apparently notable result can increase. This study had multiple dose groups, a placebo group for each formulation context, and pharmacokinetic outcomes in addition to safety outcomes. However, a prespecified multiplicity strategy or hierarchy for interpreting these endpoints is not reported in the registry record. The observed values should therefore be read as group-level descriptions, not as a selected set of confirmatory findings.

Analysis population and missingness. The primary population is the treated set, defined in the registry as participants randomized and treated with at least 1 dose of trial drug, with treatment assignment based on the first treatment received. This definition identifies who was included in the endpoint population; it does not establish how missing endpoint observations were handled. The registry record does not report a missing-data method, the extent of missing primary endpoint data, or sensitivity analyses for missingness.

Planning calculations. General: sample-size calculations can illustrate the number of participants per arm that might be needed to detect a specified effect under stated assumptions. Such a calculation is prospective planning information, not a measure of the probability that the completed study detected an effect. The posted planning illustration uses a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect defined as a stated fraction of the observed effect. It is explicitly based on the observed effect rather than the trial’s own design. Those assumptions do not establish the actual sample-size rationale, which is not reported in the registry record. The illustration is not observed power and should not be used to claim that the study was adequately powered or underpowered.

Design-specific caution. General: a parallel-group study assigns participants to one treatment group for the relevant comparison, whereas a crossover design compares treatments within the same participant. This trial is listed as parallel group; the Part II conditions are described as test and reference treatments, but the registry entries available for the primary safety endpoint do not establish a crossover analysis. Pharmacokinetic comparisons and the Part I safety endpoint answer different questions and should not be conflated. The registry lists four secondary outcomes and six analyses, but does not report a full statistical analysis plan, the model used for each analysis, or how all planned comparisons were to be interpreted.

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("Part I - Placebo Oral Solution", "Part I - 0.3 mg BI 706321 Oral Solution", "Part I - 0.6 mg BI 706321 Oral Solution", "Part I - 1.2 mg BI 706321 Oral Solution", "Part I - Placebo Capsules", "Part I - 2 mg BI 706321 Capsules")
n      <- c(6, 6, 6, 5, 9, 6)
events <- c(1, 1, 0, 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  Part I - Placebo Oral Solution  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part I - 0.3 mg BI 706321 Oral Solution  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Part I - 0.6 mg BI 706321 Oral Solution  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Part I - 1.2 mg BI 706321 Oral Solution  5  0  0.0  0.0  52.2  0.0  43.4  0.4  45.9
ARM  Part I - Placebo Capsules  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  Part I - 2 mg BI 706321 Capsules  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

Multiplicity is relevant because the study included several Part I doses, two placebo presentations, and additional Part II formulation and food conditions. It also listed pharmacokinetic outcomes alongside the safety endpoint. When many outcomes or comparisons are assessed, results can be difficult to interpret without a prespecified strategy for prioritizing hypotheses and accounting for repeated testing. The registry record does not report such a strategy, an outcome hierarchy, or whether any multiplicity adjustment was planned. The primary endpoint percentages should therefore be read descriptively rather than as a set of confirmatory dose comparisons.

The primary analysis population is the treated set. The record defines this as participants who were randomized and received at least 1 dose of trial drug, with assignment based on the first treatment received. It does not report the number of participants with missing primary endpoint data, a method for handling missing outcomes, or sensitivity analyses. The stated population definition alone does not answer whether every randomized participant contributed an observed endpoint value.

For the primary binary endpoint, the registry indicates that values were missing or not estimable for a two-arm comparison. This prevents interpretation of the results as a formal treatment-versus-placebo estimate. The registry record does not explain the specific reason the comparison could not be estimated. It also does not report an analysis plan describing which comparisons were primary for statistical inference, whether analyses were adjusted for other factors, or how deviations from the intended analysis were handled.

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 serious-adverse-event data report zero serious adverse events in each listed treatment group, including placebo, and zero deaths. For example, the Part I treatment groups show zero serious events among their respective at-risk counts, and the Part II groups likewise report zero. These are observed counts during the registry’s safety reporting, not proof that serious events cannot occur. When groups are small, an observed count of zero leaves substantial uncertainty about the frequency of uncommon events.

The registry separately reports other adverse events. In Part I, those affected counts vary across the placebo and BI 706321 groups; the BI 706321 Total Part I row reports 15 affected among 46 at risk, while Placebo Total reports 6 among 15 at risk. Part II reports 4 affected among 12 at risk for BI 706321 Total Part II. These are counts of participants affected by other adverse events, not counts of drug-related events for the primary endpoint. The registry record does not provide serious event terms because none are listed, and it does not provide event-level narratives in these figures. The safety findings apply to the recorded trial conditions and follow-up, not to other populations or longer-term exposure.

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

The results describe drug-related adverse-event percentages in small Part I groups of healthy male subjects after single oral doses of BI 706321 or matching placebo. They show that the posted percentages were not identical across groups, and that nonzero values occurred in both placebo and active-treatment groups. The percentages are useful as descriptive safety observations within this study, alongside the separately reported serious and other adverse-event counts.

They do not establish that a particular dose is safe or unsafe, that BI 706321 caused or prevented a specific event, or that the event frequency would be the same in another population. The trial was phase 1 and focused on safety, tolerability, and pharmacokinetics in healthy male subjects. The primary endpoint covered a defined period of up to 22 days, and the registry record does not provide longer-term safety results in the primary endpoint information.

The percentages also do not prove a dose-response relationship. Although some higher-dose capsule groups had nonzero drug-related event percentages, the results across dose groups are not uniformly ordered, and no formal trend test or inferential dose comparison is reported. The registry does not report an estimable two-arm comparison for the binary primary endpoint or confidence intervals around the percentages. Differences observed across groups may reflect chance variation, especially with the small group sizes.

The zero serious adverse-event counts and zero deaths are reassuring only as descriptions of what was observed in these groups during the recorded study. They cannot rule out uncommon harms. The Part II formulation and food-effect objectives concern pharmacokinetics and should not be interpreted as results of the Part I primary safety comparison. The registry record does not report enough statistical detail to support broader causal or confirmatory claims.

14. Why This Trial Matters Statistically

This study illustrates a common statistical challenge in early-phase clinical research: safety outcomes may be reported across several small dose groups, while the central need is to describe events and identify patterns that merit further study. The posted group percentages make the observed variation visible, but the small denominators mean that each value has limited precision. A percentage alone can look more definitive than the underlying amount of information warrants.

It also illustrates why descriptive results and inferential comparisons are different. Randomization supports comparisons by reducing systematic differences between groups on average, but a valid design does not automatically produce a precise estimate. Here, the registry reports no estimable two-arm comparison for the primary binary endpoint and does not report confidence intervals. The group values therefore support a description of what was recorded, not a conclusion that an apparent difference is statistically reliable.

Multiplicity matters in dose-ranging studies because several dose groups and outcomes can create many possible comparisons. A clear prespecified analysis strategy helps distinguish exploratory observations from confirmatory claims. Such a strategy is not reported in the registry record. The registry’s planning illustration is also distinct from the original study design: it is based on the observed effect and is not observed power.

Finally, the study separates safety questions from pharmacokinetic questions. Event percentages concern tolerability over the specified period, while exposure measures concern drug concentrations over time. Keeping those endpoints distinct prevents a pharmacokinetic comparison from being mistaken for evidence about clinical safety. These principles apply broadly when interpreting early-phase studies with multiple doses and small treatment groups.

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 results are based on small Part I groups, with reported group sizes from 5.0 to 9.0. Estimates from groups of this size are inherently imprecise, and the registry does not report confidence intervals for the percentages. A zero percentage in a group does not mean the underlying event risk is zero.

The primary endpoint is limited to drug-related adverse events as defined by the registry and is reported as a percentage. The record does not provide event terms, severity classifications, timing, duration, or the process used to determine whether an event was related to trial medication. The separate safety data report serious events and other adverse events, but they do not replace a detailed account of the primary endpoint events.

The study population was healthy male subjects. The registry record does not establish how these results apply to other populations, or to treatment over longer periods or at doses not studied. Part I used single doses, and the primary endpoint timeframe was up to 22 days. Part II included formulation and food conditions, but the primary endpoint result is for Part I.

The record does not report a formal statistical comparison, confidence intervals, a dose-trend analysis, or the full statistical analysis plan. It also does not explain why the two-arm comparison for the binary endpoint was missing or not estimable. Details about missing primary outcome data and their handling are not reported in the registry record. These omissions limit the ability to assess precision, robustness, and the extent to which the displayed group percentages support comparative conclusions.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: A Study to Test How Well Healthy Men Tolerate Different Doses of BI 706321 — NCT03971695.
• Registry record last updated 2025-09-18; status last verified 2025-08.
• Results first posted 2025-09-18.
• 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

The registry describes a completed, randomized, single-blind, parallel-group phase 1 study of BI 706321 in healthy male subjects, with enrollment of 73. Part I evaluated single oral doses of BI 706321 as an oral solution and capsules, with matching placebo groups. Its primary endpoint was the percentage of subjects with drug-related adverse events during follow-up up to 22 days. Part II evaluated tablet and capsule formulations under fasted conditions and tablets after a high-fat, high-calorie breakfast, with pharmacokinetic objectives.

Part I percentages varied across dose and placebo groups, but the groups were small. The registry does not report an estimable two-arm comparison or confidence intervals for the primary binary endpoint. Serious adverse events and deaths were reported as zero in the listed safety groups. These findings are descriptive and do not establish comparative safety or a dose-response relationship. The registry lists four secondary outcomes and six analyses; further details of the statistical plan, multiplicity strategy, and missing-data handling are not reported in the registry record.