Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 691751 in Healthy Asian Male Volunteers: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 691751 in Healthy Asian Male Volunteers (NCT02057835), a randomized phase 1 study. The primary outcome is Percentage of Participants With Drug Related Adverse Events.

2. Clinical Question

3. Trial Design

This completed Phase 1 trial studied BI 691751 in healthy Chinese and Japanese male volunteers. Its stated focus was safety, tolerability, and pharmacokinetics after single rising oral doses. The registry describes a randomized, double-blind, placebo-controlled, parallel design. The reported treatment groups include placebo and BI 691751 doses of 5mg, 10mg, 30mg, and 60mg for each ethnic group.

The registry lists enrollment of 64 participants. The primary outcome is reported for the treated set, with the listed group sizes and results presented separately by ethnicity and treatment. The registry record does not explain how participants were assigned to the ethnic or dose groups, or whether any dose-escalation decisions depended on earlier observations. Such details should not be inferred from the phrase “single rising oral doses.”

The primary outcome is the percentage of participants with drug-related adverse events, assessed from administration through 31 days after administration. Registered secondary outcomes concern pharmacokinetics: maximum measured concentration, time to maximum concentration, and areas under the concentration-time curve. Some are described as overall outcomes. Numeric results for those secondary outcomes are not included in the registry entries used for this account.

The study began in 2014-03, had primary completion in 2014-05, and is listed as completed. These design features describe a small, early-phase investigation in healthy volunteers. They do not establish how BI 691751 would perform in patients with atherosclerotic disease, the population mentioned in the development rationale.

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 10 groups are shown.

Overall Study

Reasons for not completing this period:

Analysis population for the primary outcome, as defined in the registry: Treated set

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 which included all subjects who were documented to have taken study medication.

Only the first 6 of 11 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Participants With Drug Related Adverse Events, measured over From drug administration until 31 days after drug administration, 31 days.

The primary endpoint measures the percentage of participants in the treated set who experienced an adverse event judged to be drug-related. The registry specifies observation from drug administration until 31 days after drug administration. This is a safety and tolerability outcome: it records whether an event occurred and was considered related to treatment during the stated period. It does not, by itself, describe the event’s severity, duration, clinical importance, or the certainty of the attribution.

In early-phase research, tracking adverse events is one way to characterize tolerability while a drug is being studied in people. A percentage allows the reported frequency to be expressed relative to the participants in each group. Interpretation depends on the group size, the event definition, the observation period, and how relatedness was assessed. The registry gives the primary endpoint title, treated-set population, and timeframe, but details of the relatedness assessment and any adjudication process are not reported in the registry record.

The posted primary outcome is 0.0 for every listed placebo and BI 691751 group, across the Chinese and Japanese groups. This describes the reported endpoint values; it does not establish that the underlying event risk is exactly zero. With relatively small group sizes, an absence of recorded drug-related events can coexist with uncertainty about the frequency of uncommon events. The record does not post confidence intervals for these percentages.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry describes a randomized, double-blind, parallel, placebo-controlled Phase 1 design. Randomization is intended to make treatment groups comparable on average, while blinding can reduce the influence of expectations on reporting or assessment. These are general features of trial design; the registry record does not describe the randomization procedure, concealment method, or who was blinded. A parallel design means treatment groups are compared rather than the same participant receiving each study condition in sequence, but the operational details are not reported in the registry record.

What does the primary percentage represent?

The primary measure is the percentage of participants in the treated set with drug-related adverse events during the period from administration through 31 days after administration. In general, a binary outcome classifies each participant according to whether the event occurred. The group percentage is a summary of those classifications. The record reports the percentage and group size for each treatment and ethnic group; it does not provide the underlying event-level data or further detail about how drug relatedness was determined.

For every listed group, the reported percentage is 0.0. When an observed event count is zero, a difference between groups cannot be estimated from those observed percentages in the usual way as a nonzero contrast. The registry explicitly indicates that a two-arm comparison is missing or not estimable for this endpoint. Accordingly, there is no posted comparative estimate, confidence interval, or p-value to interpret. The absence of a numerical comparison is not evidence that the groups are equivalent.

Why are confidence intervals useful?

In general, a confidence interval describes the range of effect estimates that are reasonably compatible with the observed data under a specified statistical model. It conveys uncertainty that a point estimate alone cannot show. For rare or absent events in small groups, uncertainty can remain substantial even when the observed percentage is at its lower bound. No confidence intervals for the primary endpoint are reported in the registry record, so its precision cannot be assessed from an interval estimate.

A p-value, when reported, addresses how compatible data are with a specified null hypothesis under a statistical model. It does not measure the probability that a treatment is safe or unsafe, and it does not quantify the size or clinical importance of an effect. No primary comparison p-value is posted for these values. A lack of an estimable contrast is different from a result showing no statistically significant difference.

What do the planning assumptions mean?

The registry’s planning description specifies a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation. It says that a planning illustration would target a stated fraction of the observed effect. Such calculations, when available, are hypothetical design exercises: they describe the number of participants per arm that might be needed under their assumptions. They are not observed power and do not change the results of the completed trial.

For this binary percentage endpoint, the registry notes that values are missing or not estimable for a two-arm comparison. Consequently, a usable observed effect is not available for the stated comparison-based planning approach. No planning sample-size figure for this endpoint should be interpreted as a result of the trial. The protocol’s original sample-size justification is not reported in the registry record.

Why can over-dispersion matter?

In general, over-dispersion means that variation in observed data is greater than a model assumes. It can make standard errors too small if the model does not account for that extra variation, leading to confidence intervals that are too narrow and tests that are too optimistic. This concern is often relevant to outcomes such as counts or clustered observations. The posted primary endpoint is a binary percentage, and the registry record does not report an over-dispersion analysis or a model-based comparison. No specific over-dispersion adjustment can therefore be attributed to this trial.

The registry lists pharmacokinetic outcomes including maximum measured concentration, time to maximum measured concentration, and concentration-time areas. In general, these measures describe different aspects of drug exposure over time: a peak concentration, when the peak occurs, and accumulated concentration over a defined interval. Their interpretation depends on the sampling schedule, assay, handling of values below quantification, and analysis method. Those methods and the numerical outcome results are not reported in the registry record for this account. No pharmacokinetic conclusion should be inferred from the adverse-event percentages.

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("Chinese: Placebo", "Chinese: BI 691751 5mg", "Chinese: BI 691751 10mg", "Chinese: BI 691751 30mg", "Chinese: BI 691751 60mg", "Japanese: Placebo")
n      <- c(8, 6, 6, 6, 6, 8)
events <- c(0, 0, 0, 0, 0, 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  Chinese: Placebo  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6
ARM  Chinese: BI 691751 5mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Chinese: BI 691751 10mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Chinese: BI 691751 30mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Chinese: BI 691751 60mg  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  Japanese: Placebo  8  0  0.0  0.0  36.9  0.0  32.4  0.3  33.6

11. Multiplicity, Missing Data and Analysis Populations

The registry lists 10 secondary outcomes, including maximum measured concentration, time to maximum concentration, and area-under-the-curve measures. Some outcomes are also listed with an overall version. When several outcomes or group comparisons are examined, the chance of at least one apparently notable result can increase. Statistical approaches to address this multiplicity may include prespecified outcome hierarchies or adjusted testing. The approach for this trial is not reported in the registry record.

The record does not post a primary two-arm comparison estimate or test because values are missing or not estimable for the binary percentage endpoint. It lists zero analyses in the analysis record. This absence of posted analyses means the registry does not provide inferential results to evaluate; it does not establish that no analyses were conducted outside the posted record. Interim analyses and any multiplicity adjustment are not reported in the registry record.

The primary population is identified as the treated set. The record does not describe how participants with missing outcome information were handled, whether any imputation was used, or whether all treated participants contributed complete follow-up. Missing-data procedures and the amount or pattern of missingness are not reported in the registry record. The listed group sizes and percentages should therefore be read as the posted summaries, without assuming a particular missing-data strategy.

The registry record also does not report a statistical analysis plan, details of prespecified comparisons, or whether subgroup analyses were planned. It is not possible to determine from the posted information how the many listed treatment, ethnic-group, and pharmacokinetic summaries were prioritized analytically.

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 safety summary lists zero serious adverse events in the placebo group and in each BI 691751 dose group. The corresponding numbers at risk are 16 for placebo and 12 for each listed dose group. These figures describe the serious-adverse-event summary and should not be substituted for the primary drug-related adverse-event endpoint, which is reported separately by ethnicity and treatment.

The same safety summary lists other adverse events affecting 6 participants in the placebo group, 6 at 5mg, 4 at 10mg, 3 at 30mg, and 7 at 60mg. These are counts, not percentages. The registry does not identify these “other” events as drug-related, and the counts should not be interpreted as a causal comparison between treatment groups. The specific event terms and their severity are not included in the registry entries.

Deaths are recorded as null in the safety data, so deaths are not reported in the registry record. The serious-event summary does not establish that no adverse events of any kind occurred; it indicates zero serious adverse events in the listed groups. As with the primary outcome, group sizes are limited, and observed counts alone do not precisely characterize the possibility of uncommon events.

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

The posted results show that the registry recorded 0.0 for the primary percentage of participants with drug-related adverse events in each listed placebo and BI 691751 group. The primary outcome covers the period from administration through 31 days afterward and uses the treated set. The serious adverse event summary separately lists zero serious events in each treatment group, while reporting counts of other adverse events.

These findings describe what was recorded for this trial, in its healthy Chinese and Japanese male volunteers and under its stated follow-up period. They do not establish that the true frequency of drug-related events is zero. The group sizes are small, no confidence intervals are posted, and the registry does not provide an estimable two-arm comparison for the primary endpoint. The observed values cannot show that treatment groups are equivalent or that the risks are the same.

The trial’s registered secondary outcomes concern pharmacokinetics, but their numerical results are not reported in the registry record. The safety figures cannot answer questions about concentration, exposure, dose response, or differences between Chinese and Japanese participants. Likewise, the study’s healthy-volunteer population differs from patients with established atherosclerotic disease, the population discussed in the development rationale. The results do not establish safety or efficacy in that patient population.

The registry identifies the study as a completed Phase 1 investigation of single oral doses. Its results therefore have a specific scope: the listed groups, the recorded endpoint, and the stated observation period. They do not determine what might happen with repeated dosing, longer exposure, or use in other populations. Clinical conclusions require consideration of the complete evidence base; these registry summaries alone cannot answer broader treatment questions.

14. Why This Trial Matters Statistically

This trial illustrates a basic challenge in interpreting early-phase safety data: a result at the lower bound of a percentage measure can look definitive while providing limited information about the underlying event frequency. The registry reports 0.0 for every listed primary endpoint group, but the group sizes are small and confidence intervals are not posted. The data therefore describe the observed record, while leaving uncertainty about events that may be uncommon.

The trial also shows why outcome definitions matter. The primary endpoint is specifically about adverse events considered drug-related, whereas the safety summary separately reports serious events and other adverse events. Those categories answer different questions. Keeping them distinct avoids treating every adverse event as drug-caused or conflating seriousness with relatedness.

Its design provides placebo comparisons within Chinese and Japanese volunteer groups across multiple doses. Yet the posted primary outcome does not support a numerical two-arm comparison. This distinction is important: a randomized design can support comparisons in principle, but a particular endpoint may still yield no estimable contrast from the posted data. A design label alone does not guarantee a precise or interpretable effect estimate.

Finally, the registered pharmacokinetic outcomes show that the investigation was not limited to adverse-event monitoring. Concentration and exposure measures can inform the characterization of a drug in early development, but their numerical results and methods are not reported in the record. The study is statistically informative as an example of how design, endpoint, population, and reporting completeness jointly define what can be concluded.

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 outcome is reported as percentages by treatment and ethnic group, but no confidence intervals or comparative estimates are posted. Because the registry identifies the two-arm comparison as missing or not estimable, the results do not quantify differences between placebo and BI 691751. Equal observed percentages should not be interpreted as evidence of equivalence.

The group sizes are limited, and the record gives no precision estimates for the zero primary endpoint values. The follow-up window extends through 31 days after administration, so these results do not describe events beyond that period. The study concerns single oral doses in healthy Chinese and Japanese male volunteers; findings cannot automatically be generalized to patients, women, other populations, or repeated dosing.

The registry does not report details of how drug-relatedness was assessed, how missing outcome data were handled, or what statistical methods were prespecified. The numerical results for the registered pharmacokinetic outcomes are not reported in the record. The serious adverse event data list counts, while deaths are not reported in the registry record. The “other” adverse-event counts do not establish causality and are not accompanied by event-level descriptions.

The registry lists enrollment of 64, while the primary summaries use treatment-specific group sizes in the treated set. The record does not explain the relationship between enrollment and each analysis denominator. No conclusions about the trial’s original sample-size justification, interim monitoring, or multiplicity strategy can be drawn from the information reported.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability and Pharmacokinetics of Single Rising Oral Doses of BI 691751 in Healthy Asian Male Volunteers — NCT02057835.
• Registry record last updated 2015-12-16; status last verified 2015-11.
• Results first posted 2015-12-16.
• 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

NCT02057835 is a completed Phase 1, randomized, double-blind, placebo-controlled, parallel study of single oral doses of BI 691751 in healthy Chinese and Japanese male volunteers. The registry lists enrollment of 64 and study dates from 2014-03 to primary completion in 2014-05.

The primary endpoint is the percentage of treated participants with drug-related adverse events through 31 days after administration. The posted value is 0.0 in every listed placebo and dose group. A two-arm comparison is not estimable in the posted record. The safety summary separately reports zero serious adverse events by treatment group and counts of other adverse events.

Registered secondary outcomes concern pharmacokinetics, but numerical results for those outcomes are not reported in the registry record. Confidence intervals, missing-data methods, multiplicity handling, and the original sample-size justification are also not reported.