To Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 1467335 Following Multiple Dose Administration Over 28 Days: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 1467335 Following Multiple Dose Administration Over 28 Days (NCT02733627), a randomized phase 1 study. The primary outcome is Number of Subjects With Investigator Defined Drug-related Adverse Events.

2. Clinical Question

3. Trial Design

This was a Phase 1, randomized, double-blind, parallel-group, placebo-controlled trial of BI 1467335. Its official title describes multiple rising oral doses in healthy male and female participants, with placebo control within dose groups. The registry lists three active dose groups—10 mg, 15 mg, and 20 mg—and a placebo group. Each group had 9 participants in the primary endpoint results, and the registry reports enrollment of 36.

The primary objective was to investigate safety and tolerability following multiple rising doses over 28 days. The secondary objectives were to explore pharmacokinetics and target-engagement biomarkers after multiple dosing. The registry lists Cmax, AUC0-24, Cmax,28, and AUC0-24,28 among the secondary outcomes. Numerical results for those measures are not reported in the registry record.

The primary endpoint population was the treated set, defined as all participants who received at least 1 dose of trial medication. The endpoint observation period ran from the first day of study drug administration until 20 days after the last dose, up to 48 days. The record identifies the study as completed. It reports a start date of 2016-07-07 and a primary completion date of 2017-07-12.

Randomization and double masking are recorded, but details such as the allocation procedure, concealment methods, and how masking was maintained are not reported in the registry record. The record also does not describe the schedule of dose escalation, dose-group assignment process, or other operational features beyond the stated design and doses. Those details should not be inferred from the phrase “multiple rising doses.”

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 to participate in trial. Subjects attended specialist sites to ensure that they (the subjects) met all implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial drug if any of the specific entry criteria was violated.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated set (TS): All participants who received at least 1 dose of trial medication.

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 participants who received at least 1 dose of trial medication.

6. Primary Endpoint

The registry lists the primary outcome as Number of Subjects With Investigator Defined Drug-related Adverse Events, measured over From first day of study drug administration until 20 days after last dose of study drug administration, up to 48 days..

The primary endpoint counts participants with investigator-defined drug-related adverse events. It is a participant count, rather than a count of all event episodes: a participant contributes to the endpoint if at least one qualifying event is recorded. The endpoint is described as applying to the treated set, meaning participants who received at least 1 dose of trial medication.

The registry gives the safety observation period as beginning on the first day of study drug administration and continuing until 20 days after the last dose, up to 48 days. It reports 3 participants in the 10 mg group, 4 in the 15 mg group, 6 in the 20 mg group, and 4 in the placebo group with investigator-defined drug-related adverse events. Each group had 9 participants in the posted results.

In general, a participant-level safety endpoint is useful in an early trial because it summarizes how many people experienced an event considered relevant to the study treatment. It does not convey how many events each affected participant experienced, how long events lasted, or how severe they were. Investigator attribution is also a judgment about relationship, not proof of cause. The registry record does not provide event-level detail for this primary endpoint or a statistical comparison of the groups.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

What does the primary count represent?

The primary measure is a binary participant-level outcome summarized as a count: whether a participant had an investigator-defined drug-related adverse event during the observation period. A binary outcome has two possible states for each participant, such as event recorded or no event recorded. The registry reports the number with an event for each group and the number of participants in each group. It does not give event-level totals, participant-level records, or a statistical comparison for this endpoint.

Counting participants is different from counting episodes. If one participant had multiple qualifying events, the participant would still be counted once in a participant-level measure. The registry’s endpoint description specifies the number of subjects with such adverse events. It does not report whether multiple episodes, recurrence, severity, or duration were separately analyzed for this primary endpoint. Those features cannot be recovered from the group counts alone.

How should the group counts be read?

The primary counts are 3 of 9 at 10 mg, 4 of 9 at 15 mg, 6 of 9 at 20 mg, and 4 of 9 with placebo. The denominator matters: it identifies the number of participants in the group from which the count arose. A count should not be interpreted in isolation, and comparisons based on small groups are inherently sensitive to the outcome status of individual participants. No additional rates or contrasts are needed to state the posted results, and the registry record does not report inferential statistics for these comparisons.

In general, a confidence interval describes a range of values compatible with data under a specified statistical procedure and assumptions. It can convey uncertainty around an estimate more fully than a point estimate alone. No confidence intervals for the primary group results are reported in the registry record. A p-value, when used, addresses compatibility of data with a specified null model; it is not a measure of clinical importance or the probability that a hypothesis is true. No p-values for the primary comparisons are reported in the registry record.

What would an adjusted comparison add?

In general, a comparative analysis can estimate how outcomes differ between treatment groups while accounting for features specified in the analysis plan. Such an analysis might be useful when the scientific question concerns a contrast rather than a description of each group. The registry record does not report an adjusted analysis, the covariates that might be included, or a model for the primary endpoint. It also does not report a prespecified hypothesis test comparing each dose with placebo. Consequently, the posted counts should not be recast as results from an unreported model.

For binary outcomes, methods may be chosen according to the design, event frequency, and intended estimand. General options include direct comparisons of group proportions or regression models. The choice affects the estimate and its uncertainty, and sparse data can challenge some approximations. This is general statistical context only; the analysis method used by the sponsor is not reported in the registry record for this primary outcome. No newly calculated comparison is warranted from the posted summaries.

What does the planning illustration mean?

The registry describes planning illustrations based on the observed effect, with a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. The intended effect is a stated fraction of the observed effect. In general, a planning calculation asks what sample size might be needed under assumptions about the target effect and analysis. It is a prospective scenario, not a result observed in participants.

Such illustrations do not establish that the trial was designed around those assumptions. The record does not report the trial’s own sample-size justification, nor does it report that the sample size was selected to achieve a particular power for the primary safety endpoint. Sample-size planning is also distinct from observed power, which should not be used as a substitute for an estimate and its uncertainty. The registry’s illustrative approach should therefore be read only as a set of conditional planning scenarios, not as evidence about the probability that the study detected a treatment effect.

Why can over-dispersion matter?

General explanation: when count data vary more than a model assumes, standard errors based on that model may be too small, making uncertainty appear less than it is. Over-dispersion is relevant to certain count-data analyses, particularly when modeling event totals. The primary endpoint is reported as participants with an event, not as a count of all event episodes, and the registry does not report a model that would allow assessment of over-dispersion. This concept should not be used to infer an unreported analysis or limitation specific to the sponsor’s method.

The secondary outcomes include Cmax, AUC0-24, Cmax,28, and AUC0-24,28. These are pharmacokinetic measures listed by the registry, but their numerical results and analysis methods are not reported in the registry record. The record also does not report numerical target-engagement biomarker results. Without the outcome estimates and their uncertainty, no statistical interpretation of those secondary measures can be made.

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("BI 1467335 10 mg (Low Dose)", "BI 1467335 15 mg (Medium Dose)", "BI 1467335 20 mg (High Dose)", "Placebo")
n      <- c(9, 9, 9, 9)
events <- c(3, 4, 6, 4)
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  BI 1467335 10 mg (Low Dose)  9  3  33.3  7.5  70.1  12.1  64.6  12.2  65.2
ARM  BI 1467335 15 mg (Medium Dose)  9  4  44.4  13.7  78.8  18.9  73.3  18.7  73.8
ARM  BI 1467335 20 mg (High Dose)  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8
ARM  Placebo  9  4  44.4  13.7  78.8  18.9  73.3  18.7  73.8

11. Multiplicity, Missing Data and Analysis Populations

The trial had a primary safety endpoint and secondary objectives involving pharmacokinetics and target-engagement biomarkers. The registry lists Cmax, AUC0-24, Cmax,28, and AUC0-24,28 as secondary outcomes. It records 5 outcome measures and 4 analyses. The registry record does not describe a multiplicity strategy for interpreting results across doses, outcomes, time points, or analyses. It does not report whether any adjustment, hierarchy, or other prespecified approach was used to address multiple statistical questions.

In general, examining several outcomes or contrasts can increase the chance of finding an apparently notable result by chance if each is interpreted independently. Multiplicity procedures are ways to manage that issue, but the appropriate approach depends on the aims and analysis plan. No particular procedure should be presumed for this study. Numerical secondary outcome results and their inferential analyses are not reported in the registry record, limiting assessment of either individual findings or a broader set of comparisons.

The primary endpoint population is identified as the treated set, defined as participants who received at least 1 dose of trial medication. This clarifies the population used for the stated endpoint, but the registry record does not report how missing outcome data were handled, whether any participants had missing primary endpoint assessments, or whether sensitivity analyses were conducted. It also does not report imputation methods or rules for excluding observations.

Randomization and double masking are recorded, but the record does not specify the analysis population used for each secondary outcome or the detailed statistical analysis plan. These omissions do not establish that the trial lacked such procedures; they mean that the procedures are not reported in the registry record. Interpretation should remain bounded by the population definition and results actually posted.

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 summary reports 0 affected participants among 9 at risk in each group: placebo, 10 mg, 15 mg, and 20 mg. The record also reports 0 deaths in each group. No serious adverse event terms are listed in the registry record.

These figures describe what was recorded during the trial; they do not demonstrate that serious events are impossible or that the underlying risk is zero. With 9 participants per group, the absence of a recorded event provides limited information about uncommon outcomes. The registry record does not post uncertainty intervals for these counts or a formal comparison of serious-event rates.

Serious adverse events are a separate category from the primary endpoint of investigator-defined drug-related adverse events. “Serious” describes one classification of an event, while “drug-related” reflects an investigator’s attribution. The primary endpoint counts were 3, 4, 6, and 4 participants across the 10 mg, 15 mg, 20 mg, and placebo groups, respectively; those counts should not be interpreted as serious adverse event counts. The other adverse-event counts also represent a separate summary and should not be conflated with serious events.

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

The results establish that the registry recorded investigator-defined drug-related adverse events in 3 participants at 10 mg, 4 at 15 mg, 6 at 20 mg, and 4 with placebo, with 9 participants in each group. They also establish that the registry reports 0 serious adverse events and 0 deaths in each group. These are descriptive findings from a randomized, double-blind, placebo-controlled Phase 1 study of healthy participants.

The results do not, on their own, establish a causal effect of BI 1467335 on adverse events. Randomization and masking support a controlled design, but the posted counts lack a reported inferential comparison and uncertainty estimates. A difference in observed counts is not by itself proof of a difference in the underlying event risk. Nor does a zero count establish absence of risk beyond the participants and observation period represented in this trial.

The findings do not answer whether adverse event patterns vary reliably by dose. The observed counts do not form a simple increasing sequence across all dose groups, and the registry does not report a statistical dose-response analysis. Attribution to study drug is investigator-defined; it is not equivalent to demonstrated causation. Participant counts also omit details about the number, duration, severity, and clinical course of events unless those are separately reported.

The study’s objectives included pharmacokinetics and target-engagement biomarkers, but numerical results for those measures are not reported in the registry record. The primary safety counts therefore do not establish exposure levels, biomarker engagement, or the relation between exposure and safety outcomes. The posted data also do not support conclusions about longer-term outcomes, populations beyond the healthy male and female participants studied, or clinical effectiveness.

The planning illustrations are not observed evidence of power and are not a substitute for uncertainty estimates. The registry record does not report the trial’s own sample-size justification or detailed inferential analysis plan. Accordingly, the narrowest defensible interpretation is a description of the recorded endpoint and serious-event counts in this study, with uncertainty and generalizability left unresolved by the posted results.

14. Why This Trial Matters Statistically

Early trials often emphasize safety and tolerability while characterizing exposure and biological response. This study’s stated primary objective was to investigate safety and tolerability after multiple rising oral doses over 28 days, and its secondary objectives were to explore pharmacokinetics and target-engagement biomarkers. That combination illustrates why the interpretation of a Phase 1 trial should distinguish its objectives from the kinds of conclusions that a small, early-stage study can support.

Statistically, the group structure provides a placebo reference alongside three dose groups, with 9 participants in each group. The posted primary endpoint is a participant count, which is straightforward to describe but carries substantial uncertainty when group sizes are limited. Stating the denominator alongside each count is essential. A descriptive pattern across dose groups may motivate questions, but without reported uncertainty and a prespecified comparative analysis it cannot settle them.

The separate safety classifications also matter. Investigator-defined drug-related events, other adverse events, serious adverse events, and deaths are not interchangeable endpoints. Keeping them distinct prevents a reader from treating the primary count as a serious-event count or assuming that investigator attribution establishes causality. The registry’s separate counts make clear that different summaries answer different safety questions.

Finally, the record illustrates the boundary between an outcome listing and a complete statistical report. It names pharmacokinetic outcomes and reports safety counts, but numerical secondary results, detailed methods, missing-data procedures, multiplicity handling, and the trial’s sample-size rationale are not reported in the registry record. Recognizing those gaps is part of sound statistical interpretation: the available evidence can be described accurately without extending it to claims the record cannot 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 trial enrolled 36 participants, with 9 in each of the three BI 1467335 groups and 9 in the placebo group. These group sizes limit the amount of information available for comparing relatively uncommon safety outcomes. The registry record does not report confidence intervals or formal comparative analyses for the primary endpoint, so the precision of group differences is not available.

The participants were described as healthy male and female subjects. Further demographic detail, including age and other characteristics, is not reported in the registry record. Findings in this study therefore should not be assumed to describe other populations. The trial was Phase 1 and focused on safety, tolerability, pharmacokinetics, and pharmacodynamics; it was not described as an effectiveness trial.

The treatment period was described as 28 days, and the primary safety observation period extended until 20 days after the last dose, up to 48 days. The record does not provide longer-term follow-up results. It also does not report event-level details for the primary endpoint, including severity, duration, recurrence, or participant-level patterns. The investigator-defined relationship to study drug is an attribution, not a direct measure of causality.

Numerical results for the listed pharmacokinetic measures and target-engagement biomarkers are not reported in the registry record. Detailed methods for the primary analysis, missing-data handling, multiplicity, and sample-size justification are also not reported. These omissions constrain interpretation of both the safety counts and the broader set of stated objectives.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: To Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BI 1467335 Following Multiple Dose Administration Over 28 Days — NCT02733627.
• 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

The registry identifies NCT02733627 as a completed Phase 1 randomized, double-blind, parallel-group, placebo-controlled trial of multiple rising oral doses of BI 1467335 in healthy male and female participants. Enrollment was 36. The active groups received 10 mg, 15 mg, or 20 mg, with a placebo group; each group had 9 participants in the primary results.

The primary endpoint was the number of participants with investigator-defined drug-related adverse events, assessed from the first day of study drug administration until 20 days after the last dose, up to 48 days. The reported counts were 3 at 10 mg, 4 at 15 mg, 6 at 20 mg, and 4 with placebo. Serious adverse events and deaths were reported as 0 in every group.

The registry lists pharmacokinetic secondary outcomes and describes target-engagement biomarkers as a secondary objective, but numerical results for these measures are not reported in the registry record. The registry record also does not report detailed inferential methods, missing-data procedures, multiplicity handling, or the trial’s own sample-size justification.