To Assess Safety, Tolerability and Pharmacokinetics of BI 416970 in Healthy Male Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for To Assess Safety, Tolerability and Pharmacokinetics of BI 416970 in Healthy Male Volunteers (NCT02093819), a randomized phase 1 study. The primary outcome is Percentage of Subjects With Drug-related Adverse Events.

2. Clinical Question

3. Trial Design

This was a completed phase 1 study sponsored by Boehringer Ingelheim, with registry identifier NCT02093819. The registry lists randomized allocation, single masking, and a parallel model. The official title adds detail: a partially randomised, single-blind, placebo-controlled study of single rising oral doses, an open-label, randomised, three-way crossover investigation of relative bioavailability, and an open-label, single-dose assessment among CYP2C9-genotyped volunteers. These descriptions indicate that the trial included more than one component, but the record does not report a full schedule linking participants, procedures, and analyses across those components.

The trial enrolled 60 healthy male volunteers. It started in 2014-04, reached primary completion in 2014-06, and is listed as completed. The single rising-dose part used BI 416970 tablets and included the dose groups from 10mg through 600mg, as well as a placebo group. The posted primary outcome was the percentage of participants with drug-related adverse events, recorded throughout the trial. The registry also identifies Cmax and AUC 0-infinity as secondary outcomes, reflecting the study’s pharmacokinetic objectives.

The posted arm sizes vary across the placebo and dose groups. The registry does not report the rationale for those group sizes, the randomization method, the allocation sequence, or whether the same participants contributed to more than one component. It also does not report detailed eligibility criteria beyond the healthy male volunteer description, the planned duration of follow-up, or the specific schedule of safety assessments. Those omissions limit reconstruction of the trial’s operational design from the registry record alone.

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.

Only the first 6 of 8 groups are shown.

Overall Study

Analysis population for the primary outcome, as defined in the registry: The PKS included 59 subjects of the TS who provided at least 1 value of the endpoints Cmax, AUC0-∞, or AUC0-tz.

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: This subject set included all subjects who were dispensed study medication and were documented to have taken ≥1 dose of study drug.

Only the first 6 of 9 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Drug-related Adverse Events, measured over AEs were recorded throughout the trial.

The primary endpoint was the percentage of subjects with drug-related adverse events. In plain terms, it describes the share of participants in each group who had at least one event judged to be related to the study drug. The registry says adverse events were recorded throughout the trial. It does not give a more detailed definition of “drug-related,” identify the assessor or adjudication process, or explain how events were attributed when participants received different study treatments.

A percentage is useful for describing how commonly an event outcome occurred in each treatment group while accounting for the number of participants in that group. This endpoint is relevant to a phase 1 study whose stated objectives include safety and tolerability. It is distinct from the pharmacokinetic outcomes, Cmax and AUC 0-infinity, which describe measured drug concentration and exposure rather than adverse events.

The registry posts a placebo percentage of 6.7% and percentages of 0.0% for the 10mg, 25mg, 50mg, 100mg, 200mg, and 600mg groups, and 20.0% for the 400mg group. The arm sizes are small, ranging from 5 to 15 participants. The posted percentages therefore describe the observed participants; by themselves, they do not provide a precise estimate of event frequency in a broader population. The record does not report confidence intervals for each individual group percentage.

7. Results Posted in the Registry

• BI 416970 25mg: 0.0% (0/10) versus 6.7% (1/15) on control; risk difference -6.7 percentage points (95% CI -19.3 to 6.0); unadjusted two-proportion z-test p = 0.405.

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a percentage endpoint and a risk-difference comparison for BI 416970 25mg versus placebo. The statistical explanation below distinguishes what those reported quantities mean from general principles that apply to this kind of outcome. Details of the complete analysis procedure are not reported in the registry record.

What does a percentage endpoint describe?

General: For a binary outcome, each participant is classified as having or not having the event under the outcome definition. The percentage is the number of participants with the event relative to the number assessed in the group, expressed on a percentage scale. It summarizes observed frequency; it does not describe the timing, duration, or severity of events unless those are separately recorded and analyzed. Here, the endpoint is drug-related adverse events recorded throughout the trial.

The registry gives the group sizes and percentages, but does not provide the event-count numerator for each primary-outcome arm directly in the primary outcome listing. The adverse-event summary separately reports counts for serious and other adverse events. Those categories should not be substituted for the primary endpoint, because the endpoint concerns drug-related events and the record does not state that the categories have the same definition or event-attribution rules.

What does a risk difference mean?

General: A risk difference subtracts the event proportion in one group from the event proportion in another group, using a stated direction for the contrast. A value of zero corresponds to equal observed proportions. Negative and positive values indicate the direction of the contrast; their interpretation depends on which group is subtracted from which. The registry’s posted estimate for BI 416970 25mg versus placebo is -0.067. In this comparison, it points to a lower observed event percentage in the 25mg group than in placebo.

The estimate is an effect measure on the proportion scale. It is not a relative risk and does not express how many times more or less likely an event was. No conversion to another effect measure is needed to interpret the posted result. The registry reports the risk difference and its interval directly.

How should the confidence interval and p-value be read?

General: A confidence interval communicates uncertainty around an estimate under the statistical procedure used. A wider interval indicates less precision than a narrower one. For a risk difference, an interval spanning zero includes values corresponding to no difference, as well as values on either side of zero. The 25mg-versus-placebo interval runs from -0.193 to 0.060 and spans zero. It therefore does not rule out no difference at the interval’s stated confidence level.

A p-value measures how incompatible the observed data are with a specified null model, under the assumptions of the test. It is not a measure of the size or clinical importance of an effect. The posted unadjusted p-value is 0.405. The registry does not report the test procedure, its assumptions, or whether any alternative test was considered. It also does not report an adjusted p-value for this comparison.

Why do small group sizes matter?

General: Estimates based on small groups are often imprecise because a small change in the number of participants with an event can make a substantial change to the group percentage. Sparse binary data can also make conventional approximations less dependable, depending on the method used. The registry’s group sizes range from 5 to 15, and several reported percentages are 0.0%. Such observed zeros mean no participants in those groups were recorded with the primary event according to the posted percentages; they do not prove that the underlying event probability is zero.

The registry does not state whether the comparison used an exact method, a normal approximation, or another procedure. A confidence interval cannot remove uncertainty created by sparse observations; it expresses uncertainty under the method used to calculate it. Without the analytic details, the posted estimate and interval can be described, but their computational assumptions cannot be independently assessed from the registry record.

What can be inferred about the analysis plan?

The registry identifies one primary endpoint, two named secondary pharmacokinetic outcomes, and four analyses. It does not report the full statistical analysis plan, any interim analyses, the sample-size justification, or a prespecified multiplicity strategy. These details matter because a study with several doses, outcomes, or comparisons may raise questions about which contrasts were planned and how uncertainty across them was handled. The record does not establish how those questions were addressed.

General: Planning calculations based on an observed effect are illustrations of what a future design might require under stated assumptions. They are not observed power and do not change what the current participants experienced. The registry’s stated sample-size assumptions describe a planning illustration using a two-sided significance level of 0.05, equal allocation, and a normal approximation, with the effect set as a stated fraction of the observed effect. That planning description is not the trial’s own sample-size justification, which is not reported in the registry record.

10. Confidence Intervals and Precision

The principal inferential result available for the primary endpoint is the comparison of BI 416970 25mg with placebo. Its estimated risk difference is -0.067, with a confidence interval from -0.193 to 0.060. The interval spans zero, so the data do not pin down the direction of the difference with high precision. Values on either side of zero remain compatible with the interval, under the method used to construct it.

Precision is also limited by the small group sizes. The placebo group had 15 participants and the 25mg group had 10. With few participants, observed binary outcomes can vary substantially from one sample to another. This is particularly relevant when event percentages are low or equal to 0.0%. A reported zero is an observed sample result, not a guarantee that an event cannot occur in a larger population.

The registry does not provide confidence intervals for each arm-specific percentage, and it does not identify the method used for the risk-difference interval. It is therefore not possible to assess from the record whether the interval used a method suited to sparse data or to compare alternative interval procedures. The reported p-value, 0.405, is unadjusted; the record does not state whether it was intended as a confirmatory test or how it relates to other analyses.

These limits do not make the results uninformative. They define the scope of what can be said: the observed percentages and the 25mg comparison can be described, while the precision remains limited and the interval allows a range of possible differences. The registry record does not support a precise estimate of event frequency in a wider population.

11. Multiplicity, Missing Data and Analysis Populations

The record lists one primary endpoint, Percentage of Subjects With Drug-related Adverse Events, and two secondary pharmacokinetic outcomes: Cmax and AUC 0-infinity. It also reports four analyses. The complete set of analyses and the relationships among them are not reported in the registry record. Nor does the record state whether the primary endpoint had a single prespecified comparison, whether dose groups were compared under a planned sequence, or whether multiplicity was addressed through adjustment or another strategy.

Multiplicity matters when several outcomes or contrasts are examined because the chance of observing at least one apparently notable result can rise as the number of analyses increases. General: A prespecified testing hierarchy or a suitable adjustment can help control that issue, but the appropriate approach depends on the study’s aims and analysis plan. Since the registry record does not report such a plan, the unadjusted p-value of 0.405 should be understood as the posted result for its stated comparison, without assuming an adjustment was or was not used elsewhere.

Missing-data handling is not reported in the registry record. The record does not state how participants with incomplete safety follow-up, missing outcome classifications, or withdrawal were handled in the primary endpoint analysis. The posted group sizes sum to the listed enrollment, but that fact alone does not establish that every enrolled participant had complete outcome information or show the analysis rules used.

The record identifies a PKS of 59 subjects from the TS who had at least one value for Cmax, AUC0-∞, or AUC0-tz. This describes a pharmacokinetic population and does not, by itself, define the analysis population for the primary safety outcome. The primary endpoint’s arm-level denominators are reported separately. The record does not explain the relationship between the TS and PKS abbreviations or state whether an intention-to-treat, per-protocol, or other named population was used for the safety analysis. Interim analyses, detailed analysis-population definitions, and the statistical analysis plan are not reported in the registry record.

12. Safety Results

The registry reports serious adverse events as affected participants divided by participants at risk.

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 zero serious events among the 15 participants in the placebo group and zero in each BI 416970 dose group. It also reports zero serious events among the 45 participants in the total BI 416970 treatment group and among the 60 participants in total treatment. These are event counts as recorded in the registry, not estimates that serious events are impossible.

The same summary distinguishes serious adverse events from “other” adverse events. It reports 1 other event in placebo, 1 in BI 416970 10 mg, 3 in 25 mg, 1 in 50 mg, 0 in 100 mg, 2 in 200 mg, 2 in 400 mg, and 1 in 600 mg. Across the total BI 416970 treatment group, the record reports 10 other events; across total treatment, it reports 11. These counts are separate from the primary endpoint’s percentage of participants with drug-related adverse events. The registry does not specify that “other” events correspond exactly to the primary endpoint definition.

Death figures are not reported in the registry record. The small group sizes and the trial’s limited observation context mean that zero observed serious events cannot rule out uncommon events. The record also does not provide event narratives or further detail on severity, timing, or attribution for the “other” events.

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

The posted results describe adverse-event percentages among the participants in a phase 1 study of BI 416970 in healthy male volunteers. The primary endpoint was the percentage of participants with drug-related adverse events recorded throughout the trial. Percentages varied across the dose groups, with 20.0% in the 400mg group and 0.0% in several other dose groups; the placebo percentage was 6.7%. These are observed group results, not a complete account of all possible safety outcomes.

The specific inferential comparison is between BI 416970 25mg and placebo. The estimated risk difference is -0.067, its confidence interval runs from -0.193 to 0.060, and the unadjusted p-value is 0.405. The interval includes zero. The result therefore leaves uncertainty about the direction and size of the difference. It does not demonstrate equivalence, and it does not establish that a difference is absent.

The findings do not establish that BI 416970 is safe or unsafe in other populations, with other dosing regimens, or over other observation periods. The participants were healthy male volunteers, and the registry describes single-dose and single rising-dose components. The record does not report a detailed follow-up schedule or enough information to characterize uncommon events. Nor do the primary safety results answer the pharmacokinetic questions: although Cmax and AUC 0-infinity are named as secondary outcomes, their numerical results are not reported in the registry record for this interpretation.

General: A small early-phase study can characterize observations in its enrolled sample and inform questions for further study, but the strength of conclusions depends on the design, size, outcome definitions, and completeness of reporting. For this trial, the posted evidence is best read as a set of group-level adverse-event descriptions plus one imprecise placebo comparison. It should not be extended into claims about clinical benefit, broad effectiveness, or the absence of risk.

14. Why This Trial Matters Statistically

This trial is statistically useful because it illustrates how early-phase safety data can look when outcomes are binary and treatment groups are small. A percentage is easy to read, but a value such as 0.0% can be misleading if it is treated as proof that the event cannot occur. The arm sizes, which range from 5 to 15, are essential context for interpreting those percentages. The comparison interval also makes uncertainty visible rather than reducing the result to a single estimate.

The trial includes several dose levels and more than one study component. That structure makes it important to distinguish a descriptive dose-group summary from a planned inferential comparison. The registry posts an estimate for BI 416970 25mg versus placebo, but does not report equivalent inferential comparisons for all dose groups or explain a multiplicity strategy. This is a reminder that the presence of many groups does not mean each possible contrast has the same evidential status.

The primary safety outcome is also different from the pharmacokinetic objectives. Cmax and AUC 0-infinity concern measured concentration and exposure, whereas drug-related adverse events concern participant outcomes. Keeping these outcome types separate prevents a pharmacokinetic objective from being mistaken for a safety result, or vice versa.

Finally, registry reporting details shape what can be assessed. The absence of a reported statistical analysis plan, missing-data approach, and sample-size justification limits evaluation of how the posted results were selected and calculated. The findings remain interpretable as recorded observations, but a careful reader should distinguish those observations from a complete inferential account of the trial.

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.
• Participant counts were reconstructed from posted percentages and arm sizes, so small rounding differences are possible.

Several features of the registry record constrain interpretation. The trial enrolled 60 healthy male volunteers, and the posted treatment groups are small. The results may not characterize event frequencies in other populations or settings. The record describes a single rising-dose component and additional crossover and genotype-assessment components, but does not provide enough operational detail to reconstruct how participants and outcomes were handled across all components.

The primary endpoint is described as drug-related adverse events, but the registry does not define the attribution process, provide detailed event criteria, or describe adjudication. It reports arm percentages without confidence intervals for each group. The one posted comparison has an interval, but the method used to calculate it is not identified. These gaps limit assessment of the endpoint’s measurement and the statistical reliability of the calculations.

The record does not report the sample-size justification, statistical analysis plan, interim analyses, missing-data methods, or multiplicity strategy. It is consequently unclear which analyses were prespecified and how incomplete observations or multiple comparisons were addressed. The PKS description relates to pharmacokinetic values and does not establish the analysis population for the primary safety endpoint.

The serious adverse event summary reports zero events, but sparse observations cannot rule out uncommon events. Death figures are not reported in the registry record. The “other” adverse event counts are listed separately, and the record does not clarify their exact relationship to drug-related events in the primary endpoint. Finally, numerical results for the named secondary pharmacokinetic outcomes are not reported in the information available for this interpretation. These limitations narrow the conclusions to the posted safety summaries and the 25mg-versus-placebo comparison.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: To Assess Safety, Tolerability and Pharmacokinetics of BI 416970 in Healthy Male Volunteers — NCT02093819.
• Registry record last updated 2016-03-22; status last verified 2016-02.
• Results first posted 2016-03-22.
• 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

NCT02093819 is a completed phase 1 trial sponsored by Boehringer Ingelheim, with 60 healthy male volunteers enrolled. The registry lists randomized allocation, single masking, and a parallel model, while the official title describes partially randomized, single-blind, placebo-controlled dose escalation and additional open-label components. The study began in 2014-04 and reached primary completion in 2014-06.

The primary endpoint was the percentage of participants with drug-related adverse events recorded throughout the trial. The posted percentages ranged from 0.0% to 20.0% across BI 416970 dose groups; the placebo percentage was 6.7%. The reported comparison of BI 416970 25mg with placebo estimated a risk difference of -0.067, with a confidence interval from -0.193 to 0.060 and an unadjusted p-value of 0.405. Serious adverse event counts were zero in each group. The record also names Cmax and AUC 0-infinity as secondary outcomes, but their numerical results are not reported in the information available for this interpretation.