Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Oral Doses of BI 1026706 in Male and Female Healthy Subjects and Patients With Osteoarthritis of the Knee: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Oral Doses of BI 1026706 in Male and Female Healthy Subjects and Patients With Osteoarthritis of the Knee (NCT02126826), 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 randomized, double-blind, parallel-group phase I trial of multiple rising oral doses of BI 1026706. The official title describes the study as placebo-controlled within dose groups. The record lists healthy subjects and patients with osteoarthritis of the knee; the groups are reported separately by population and dose. Overall enrollment was 58.

The healthy-volunteer groups were placebo, 50mg BI 1026706, 100mg BI 1026706 and 300mg BI 1026706. Their reported group sizes were 9.0 participants in each arm. The osteoarthritis groups were placebo, 200mg BI 1026706 and 100mg BI 1026706 BID; their reported group sizes were 5.0, 9.0 and 8.0 participants, respectively. These are distinct reported arms, not a single pooled treatment comparison.

The trial started on 2014-05-28, had primary completion on 2014-10-01 and is listed as completed. Its stated aims included assessment of safety and tolerability after repeated rising doses, exploration of pharmacokinetics, and assessment of pharmacodynamics in osteoarthritis patients. Secondary outcomes listed in the registry concern measured concentration, timing of peak concentration and concentration-time exposure, including steady-state measures.

The registry record does not report the sequence-generation procedure, allocation concealment, details of how masking was maintained, or the dose-escalation decision process. It also does not report a sample-size justification or enough detail to establish the planned statistical comparisons. The design labels indicate randomization, double masking and parallel groups, but do not by themselves provide those additional procedural details.

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 7 groups are shown.

Overall Study

Reasons for not completing this period:

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

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) which included all randomised patients and healthy subjects who received at least 1 dose of study medication.

Only the first 6 of 8 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Drug Related Adverse Events, measured over From first drug administration until 3 days after last drug administration, 15 days.

The primary endpoint is the percentage of participants in the treated set who experienced drug-related adverse events. The registry describes the events as adverse events judged to be related to study drug. The timeframe runs from first drug administration until 3 days after the last drug administration and is stated as 15 days. The endpoint is reported separately for the placebo and BI 1026706 arms.

A percentage expresses the share of participants in a group who had at least one qualifying event, rather than the number of events experienced. It is therefore a participant-level summary, not a measure of how often events occurred or how severe they were. The endpoint is relevant to the stated safety and tolerability aim because it describes how frequently drug-related events were recorded during the defined observation period. It does not, on its own, identify the type, severity, duration or clinical importance of those events.

The posted results give percentages and group sizes but do not report confidence intervals for these percentages. The registry record does not report the criteria used to judge whether an event was drug-related or the procedure for collecting and adjudicating events. Those details would be important for interpreting the endpoint, but cannot be inferred from the percentage alone.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The primary outcome is binary at the participant level: a participant either had a drug-related adverse event during the defined period or did not. The registry reports this outcome as a percentage in each arm. In general, a percentage makes groups of different sizes easier to describe on a common scale, but it does not show how much uncertainty surrounds the estimate. An uncertainty interval would indicate a range of values compatible with the observed data under a stated statistical method. Such intervals are not reported for these primary results.

What can a percentage tell us?

A participant percentage summarizes how common the recorded endpoint was within an arm. It does not give the total number of events, because a participant may have more than one event and the endpoint counts participants with events rather than event episodes. It also does not distinguish event types or grades. The primary endpoint is explicitly restricted to events considered drug-related, so it is not interchangeable with a count of all adverse events.

Some statistical comparisons for binary outcomes use a difference in percentages or a ratio of event probabilities. Such comparisons require a clearly defined pair of groups and an analysis method. The registry results list multiple dose arms and separate placebo groups for healthy volunteers and patients with osteoarthritis. The record does not identify a single pooled comparison or report a formal analysis of these arms. Consequently, a reader should treat the percentages as arm-specific descriptions, not as proof of a comparative effect.

Why does group context matter?

Randomization supports fair comparisons when the groups being compared arise from the same randomized framework and the analysis follows the intended allocation. Here, placebo control is described as occurring within dose groups, and the reported results separate healthy volunteers from osteoarthritis patients. The populations and treatment schedules are not identical across all arms. A broad comparison that combines arms could obscure those design distinctions. The registry record does not report whether any pooled analysis was planned.

In general, randomization does not remove uncertainty in small groups. Results in a group with few participants can be sensitive to the experience of individual participants. Double masking can reduce some forms of bias in treatment administration or assessment, but the registry record does not give enough operational detail to assess how masking was maintained or whether it was successful. These general design considerations do not alter the reported percentages; they help define what those percentages can support.

What role do confidence intervals and tests play?

A confidence interval expresses statistical uncertainty around an estimate under the assumptions of the method used. A test addresses a specified hypothesis or contrast and produces evidence relative to that hypothesis. Neither replaces consideration of the design, outcome definition or size of the groups. No confidence intervals, test statistics or p-values for the primary endpoint are reported in the registry record. It is therefore not possible to use the posted primary results to assess a formal significance test or to quantify comparative precision.

The registry record does not report the statistical analysis plan, including the method for comparing proportions, any adjustment variables, or rules for handling missing endpoint information. These details matter because different methods can yield different estimates or uncertainty measures, particularly when groups are small. No such method should be assumed in the absence of a report.

How should planning calculations be read?

General sample-size planning asks how many participants per arm might be needed to detect a chosen effect under specified assumptions. The planning illustration associated with this analysis is based on the observed effect, not on the original trial design. It uses a two-sided significance level of 0.05, equal allocation between two arms and a normal approximation, with the effect to detect expressed as a stated fraction of the observed effect. Such calculations are illustrations for future planning, not evidence that the trial had a particular power and not a report of the number of participants actually analyzed.

In general, using an effect observed in a small study as the planning target can be unstable: the observed estimate may differ from the underlying effect. Planning results also depend on the selected effect fraction and assumptions about allocation and analysis. They should not be confused with observed power, which does not provide a useful substitute for reporting the estimate and its uncertainty. The registry record does not report the rationale used to choose the original enrollment or whether the trial was designed to test a formal efficacy or safety hypothesis.

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("Placebo HV", "50mg BI 1026706 HV", "100mg BI 1026706 HV", "300mg BI 1026706 HV", "Placebo OA", "200mg BI 1026706 OA")
n      <- c(9, 9, 9, 9, 5, 9)
events <- c(2, 2, 1, 6, 3, 5)
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  Placebo HV  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6
ARM  50mg BI 1026706 HV  9  2  22.2  2.8  60.0  6.3  54.7  6.7  55.6
ARM  100mg BI 1026706 HV  9  1  11.1  0.3  48.2  2.0  43.5  2.5  44.5
ARM  300mg BI 1026706 HV  9  6  66.7  29.9  92.5  35.4  87.9  34.8  87.8
ARM  Placebo OA  5  3  60.0  14.7  94.7  23.1  88.2  22.3  88.2
ARM  200mg BI 1026706 OA  9  5  55.6  21.2  86.3  26.7  81.1  26.2  81.3

11. Multiplicity, Missing Data and Analysis Populations

The registry lists the primary safety endpoint and 7 secondary outcomes. The secondary outcomes concern pharmacokinetic measures, including maximum measured concentration, time to maximum concentration and area under the concentration-time curve, with measures listed for steady state as well. The study description also states that pharmacodynamics in osteoarthritis patients was to be assessed. The registry entries available for these results do not include the numerical findings for those secondary measures.

When a study assesses multiple outcomes or makes multiple treatment comparisons, the chance of at least one apparently unusual result can increase. Statistical methods sometimes address this multiplicity by defining a hierarchy, adjusting significance thresholds or identifying outcomes as exploratory. The registry record does not report a multiplicity strategy, a hierarchy of tests, or which comparisons were planned for formal inference. The reported safety percentages should therefore be read as descriptive, without assuming an adjustment or an unreported confirmatory testing framework.

The primary outcome population is identified as the treated set. The record does not report how participants with missing event information were handled, whether all treated participants contributed to each endpoint, or how incomplete follow-up affected the analysis. Missing-data methods and analysis populations for the secondary outcomes are not reported in the registry record.

The record also does not report a statistical analysis plan, rules for censoring or exclusions, or whether any interim analyses took place. These omissions limit assessment of how the outcome summaries were produced and whether the methods were specified before results were known. The planning illustration uses stated assumptions for a hypothetical two-arm calculation; it is not the original trial's design justification. The original sample-size rationale is 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 registry's adverse-event listing reports 0 participants with serious adverse events judged related to study drug in each arm. This is specifically a count of serious events considered related; it should not be interpreted as evidence that no serious adverse events of any kind occurred. The serious-event totals, whether events were unrelated, and details of event types are not reported in the registry record. Death counts are also not reported in the registry record.

The listing separately gives counts for other adverse events: 5 for placebo HV, 3 for 50mg BI 1026706 HV, 2 for 100mg BI 1026706 HV, 6 for 300mg BI 1026706 HV, 3 for placebo OA, 6 for 200mg BI 1026706 OA and 4 for 100mg BI 1026706 BID OA. These counts should be kept distinct from the primary endpoint percentages. The registry entries do not specify whether these other-event counts refer to participants with at least one event or to event episodes, nor do they give event details or a relation-to-treatment breakdown for this listing.

In general, a count of participants with serious events and a count of all adverse events answer different safety questions. Neither can be substituted for the drug-related adverse-event percentage without matching definitions and denominators. The registry's summary does not establish that an event was caused by treatment merely because it occurred during the trial.

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

The results describe the percentage of treated participants in each reported arm who had an adverse event judged related to study drug during the stated observation period. They show variation across the dose groups and between the healthy-volunteer and osteoarthritis populations. Because the groups are small and the registry does not report confidence intervals or formal comparisons, the percentages do not quantify the precision of between-group differences.

The results do not establish that BI 1026706 caused or prevented a particular event, and they do not demonstrate a pattern of increasing or decreasing events with dose. The observed values are not a substitute for event-level information, severity descriptions, or a complete account of serious adverse events. The separate serious-event listing reports no serious events judged related in the listed groups, but it does not report all serious-event totals or deaths.

This was a phase I study with stated aims focused on safety and tolerability, pharmacokinetics and pharmacodynamics. The primary outcome addresses only one part of safety, and its period of observation is limited to the timeframe stated in the registry. It does not address longer-term effects. The registry's listed secondary pharmacokinetic outcomes indicate the kinds of measures planned, but numerical findings for them are not included in the record summarized in these results.

The record also does not report a prespecified inferential analysis for the primary endpoint, missing-data handling, a multiplicity strategy or the original sample-size rationale. Without those details, interpretation should remain descriptive. The findings can be read as a record of the observed endpoint percentages in these particular trial groups, not as a definitive estimate of comparative safety or a basis for clinical decisions.

14. Why This Trial Matters Statistically

This trial illustrates why safety outcomes need careful definition. The primary endpoint is not simply any adverse event: it is the percentage of treated participants whose events were judged drug-related. A separate registry listing distinguishes serious events judged related from other adverse events. Keeping these measures separate avoids treating different event definitions as if they were interchangeable.

The design also highlights the importance of reading group labels alongside results. Healthy volunteers and osteoarthritis patients appear in separate arms, with different dose schedules represented in the osteoarthritis groups. Comparing every active arm with every placebo arm as though there were a single common population would ignore the structure described in the registry. The reported dose groups are useful descriptive units, but the record does not establish which pairwise comparisons were intended for inference.

Small group sizes make transparent reporting of uncertainty particularly valuable. Percentages give an accessible summary, but without confidence intervals or formal comparisons readers cannot assess the precision of differences from the posted endpoint data. This limitation is distinct from whether randomization and masking were used: the registry reports both, but those design features do not replace uncertainty estimates or analysis details.

Finally, the registry's stated aims span safety, pharmacokinetics and pharmacodynamics, while the primary result is a safety percentage. The study therefore provides a useful example of how one outcome can answer only a defined part of a broader research question. Clear outcome-specific interpretation prevents descriptive safety findings from being stretched into claims about other outcomes or clinical benefit.

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 reported as percentages without confidence intervals, test results or a stated comparative estimate. This limits assessment of precision and makes it impossible to determine from the registry record whether any differences were evaluated using a formal statistical procedure. The record does not report the method for judging drug relatedness, event collection procedures or detailed event classifications.

The primary endpoint is reported for the treated set, but the registry record does not explain the handling of missing data, withdrawals or participants who may not have completed the observation period. It does not report a detailed analysis population definition beyond the treated-set label. The serious-adverse-event listing reports related serious events but does not provide total serious-event counts, event terms or death counts.

The arms include healthy volunteers and osteoarthritis patients, and the osteoarthritis groups have different dose schedules from the healthy-volunteer groups. These distinctions restrict direct interpretation of cross-arm differences as dose effects. The record does not report a planned comparison structure, adjustment for population differences, multiplicity handling, or the statistical analysis plan.

The trial is described as phase I, and the primary observation period is stated as 15 days. The record therefore does not report longer-term safety findings. Although pharmacokinetic and pharmacodynamic aims and secondary outcomes are listed, their numerical results are not included in the registry record used for this statistical interpretation. The original sample-size rationale and any interim-analysis plan are not reported in the registry record.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Multiple Rising Oral Doses of BI 1026706 in Male and Female Healthy Subjects and Patients With Osteoarthritis of the Knee — NCT02126826.
• Registry record last updated 2019-03-25; status last verified 2018-12.
• Results first posted 2019-03-25.
• 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

NCT02126826 is a completed randomized, double-blind, parallel-group phase I trial of repeated rising oral doses of BI 1026706, with placebo control within dose groups. It enrolled 58 male and female healthy subjects and patients with osteoarthritis of the knee. The primary endpoint was the percentage of treated participants with drug-related adverse events during the stated 15-day timeframe.

Reported percentages varied across the healthy-volunteer and osteoarthritis arms. The registry's adverse-event listing records 0 serious adverse events judged related in each arm, but does not report total serious-event or death counts. Confidence intervals, formal primary comparisons, missing-data methods, multiplicity handling and the original sample-size rationale are not reported in the registry record. The posted endpoint results are descriptive and do not establish comparative effects or longer-term safety.