Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BI 655075 (Idarucizumab) Administered Alone or With Dabigatran Etexilate in Japanese Healthy Subjects: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BI 655075 (Idarucizumab) Administered Alone or With Dabigatran Etexilate in Japanese Healthy Subjects (NCT02028780), a randomized phase 1 study. The primary outcome is Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2.

2. Clinical Question

3. Trial Design

This was a randomized, double-blind, parallel Phase I trial with placebo control. The official title describes two parts in healthy Japanese male volunteers: Part I investigated safety, tolerability, and pharmacokinetics of different doses of BI 655075; Part II explored the effective dose to reverse dabigatran anticoagulant activity. Enrollment was 80. The study start is recorded as 2014-01, primary completion as 2014-08, and status as completed.

In Part I, participants received single rising intravenous doses of idarucizumab or placebo. The dose groups include BI1000mg 5m, BI2000mg 5m, BI4000mg 5m, and BI8000mg 1h, alongside two placebo groups distinguished by administration duration. Part II included dabigatran plus placebo groups and groups receiving dabigatran with idarucizumab. The registry describes a short infusion with two dabigatran capsules for the combination arm description. Its listed Part II dose groups include 1000mg, 2000mg, 4000mg, and 2500mg+2500mg idarucizumab regimens.

The primary safety endpoint covers the period from first drug administration until 13 weeks after the last drug administration, up to 98 days in Part I and up to 108 days in Part II. The registry gives group-level treated-set percentages rather than a single pooled estimate. Further details of randomization procedures, allocation concealment, dose escalation rules, and the timing of specific assessments 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: Randomised, double-blind within dose groups, placebo controlled, sequential rising order, single centre trial. This study has two phases ie., Observation phase (Single administration of placebo or BI study drug and 6-14 days follow up) and Follow up phase (End of observation phase to 92-98 days after administration of Placebo or BI study drug).

Only the first 6 of 12 groups are shown.

Observation Phase

Follow up Phase

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): : This subject set included all subjects who received the idarucizumab or placebo.

Only the first 6 of 13 groups are shown.

6. Primary Endpoint

The registry lists the primary outcome as Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2, measured over From first drug administration until 13 weeks after the last drug administration, upto 98 days (Part-I) & upto 108 days (Part-II).

The primary endpoint is the percentage of subjects with drug-related adverse events in Part I and Part II. It is a binary participant-level outcome: each treated participant is classified according to whether a drug-related adverse event was recorded during the stated follow-up period. The registry identifies the analysis population as the treated set.

This type of endpoint is used to describe the frequency of events considered related to study drug exposure. Reporting a percentage makes groups of different sizes easier to read side by side, but a percentage alone does not show how uncertain an estimate is. The registry gives no confidence intervals for these group results, so their precision cannot be judged directly from an interval estimate.

The recorded percentages are 16.7% in Placebo 5m (Part I), and 0.0% in each of the other listed groups. Those other groups include Placebo 1h and the idarucizumab dose groups in Part I, as well as the dabigatran-plus-placebo and dabigatran-plus-idarucizumab groups in Part II. The arm sizes are small, ranging from 2.0 to 9.0 participants per group. Consequently, each percentage summarizes a limited number of observations, and should be read as a description of these trial groups rather than as a precise estimate for a broader population.

The endpoint does not itself measure pharmacokinetic exposure or anticoagulant reversal. Those were addressed in secondary outcomes, including measures of dabigatran and idarucizumab exposure and AUEC2-12. Numerical results for those outcomes are not reported in the registry record.

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 recorded during the stated period or did not. The registry reports the proportion as a percentage for each treatment group. This is a suitable descriptive format for an event-frequency outcome, but interpretation depends on the denominator as well as the percentage. The reported group sizes are small, so even a percentage of 0.0% should be understood as an observed result in that group, not proof that the event cannot occur.

What does a confidence interval add?

In general, a confidence interval expresses the uncertainty around an estimated quantity under a statistical model. For a binary outcome, it would give a range of values compatible with the observed event data and the method used to construct the interval. Wider intervals generally indicate less precision. No confidence intervals are reported for these primary endpoint percentages, so readers cannot use the registry results to assess that uncertainty quantitatively. No standard errors or other measures of dispersion are listed either.

What can be concluded without a treatment comparison?

The posted results are group-level percentages. The registry reports no analyses for the endpoint and identifies that values are missing or not estimable for a two-arm comparison. Therefore, there is no reported estimate of a difference between idarucizumab and placebo, no test of a treatment effect, and no p-value for the primary outcome. A visual or numerical contrast between two percentages is not equivalent to a formal inferential comparison. In general, such a comparison requires an explicitly defined estimand, an analysis method, and an account of uncertainty.

The trial uses several dose groups across two parts rather than a single two-group contrast. A pooled comparison would require decisions about which groups and regimens to combine, and how to handle the different contexts of idarucizumab alone and idarucizumab after dabigatran. Those decisions are not reported in the registry record. No group pooling or recalculation is appropriate from the posted summary percentages alone.

Why do small groups matter?

In general, estimates from small samples are sensitive to individual outcomes. When few participants contribute to a percentage, a change in one participant's outcome can alter the reported proportion noticeably. Small groups also limit the amount of information available about uncommon events. The arm sizes range from 2.0 to 9.0 participants. The registry does not give interval estimates that would show the precision of the percentages, and the absence of a recorded event in a group should not be interpreted as a precise estimate of zero underlying risk.

The trial's overall enrollment is 80, but the posted endpoint results are divided among multiple groups. Overall enrollment does not make each group estimate precise; group-level sample sizes determine the information available for each percentage. The registry does not explain differences between total enrollment and the numbers reported for individual endpoint groups, nor does it report whether any participants were excluded from the treated set or had missing endpoint assessments.

What is the role of the secondary outcomes?

The registry lists secondary outcomes related to dabigatran exposure, unbound dabigatran, idarucizumab concentration and exposure, and AUEC2-12. These outcomes address pharmacokinetic or pharmacodynamic questions distinct from the primary adverse-event percentage. Their presence indicates that the trial was designed to examine more than event frequency, but their numerical results are not reported in the registry record. The primary endpoint results therefore cannot substitute for those outcome data.

In general, pharmacokinetic measures describe drug concentration or exposure over time, while pharmacodynamic measures describe effects related to drug activity. The registry's outcome names identify measures such as Cmax, AUC0-inf, Ae0-72, Ae0-73, Ae0-74,ss, and AUC2-12,ss. Without the corresponding posted estimates, time points, and analysis details, these measures cannot be interpreted quantitatively. The stated objective of exploring an effective dose to reverse dabigatran anticoagulant activity is an objective, not a result by itself.

What is not specified?

The registry does not report the statistical analysis plan, the sample-size justification, a prespecified hypothesis-testing procedure, or methods for handling multiplicity. It also does not report interim analyses. These omissions matter because they prevent assessment of how the reported endpoints and groups were prioritized, how uncertainty was to be quantified, and whether any planned analyses differed from the descriptive results posted. No assumptions about those procedures can be made from the outcome percentages alone.

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_5m (Part I)", "Placebo_1h (Part I)", "BI1000mg_5m (Dose group1 - Part I)", "BI2000mg_5m (Dose group2 - Part I)", "BI4000mg_5m (Dose group3 - Part I)", "BI8000mg_1h (Dose group4 - Part I)")
n      <- c(6, 2, 6, 6, 6, 6)
events <- c(1, 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  Placebo_5m (Part I)  6  1  16.7  0.4  64.1  3.0  56.4  3.7  57.9
ARM  Placebo_1h (Part I)  2  0  0.0  0.0  84.2  0.0  65.8  0.8  70.8
ARM  BI1000mg_5m (Dose group1 - Part I)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  BI2000mg_5m (Dose group2 - Part I)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  BI4000mg_5m (Dose group3 - Part I)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0
ARM  BI8000mg_1h (Dose group4 - Part I)  6  0  0.0  0.0  45.9  0.0  39.0  0.4  41.0

11. Multiplicity, Missing Data and Analysis Populations

The trial includes a primary safety endpoint, multiple dose groups, two study parts, and seven listed secondary outcomes. This creates several possible summaries and comparisons. The statistical approach for controlling multiplicity, if any, is not reported in the registry record. No inferential analyses or p-values are posted for the primary endpoint, so there is no basis for interpreting the percentages as a set of multiplicity-adjusted or unadjusted hypothesis tests.

The registry identifies the primary endpoint population as the treated set. It does not describe other analysis populations or state how participants were assigned to a population. The rules for handling missing endpoint observations, withdrawals, incomplete follow-up, or participants with uncertain event attribution are not reported in the registry record. The group-level results do not state how missing observations, if any, were handled.

In general, missing-data methods can affect an estimated event percentage when outcome status is unavailable. A complete-case approach, an imputation method, or another rule can lead to different interpretations, so the handling needs to be specified to assess the analysis. No such rule is available in the registry record. Likewise, the registry does not state how drug-relatedness was determined or whether event adjudication procedures were used. These gaps limit reproducibility and prevent a full assessment of the endpoint analysis.

The secondary outcomes are listed, but their numerical results are not reported in the registry record. Thus, multiplicity cannot be assessed from outcome results, and the pharmacokinetic and pharmacodynamic findings cannot be reviewed alongside the safety percentages.

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 lists zero serious events in every reported group, with the at-risk group sizes ranging from 2 to 9 participants. In the terms used by the registry, this means no serious adverse events were recorded among the participants counted at risk in those groups during the reported safety observation. It does not show that serious events are impossible or estimate their frequency precisely beyond these observed groups.

The death counts are not reported in the registry record. The separate other-adverse-event summary lists one event in Placebo 5m (Part I) and zero in each of the other groups. That category is not the same as the primary endpoint of drug-related adverse events, and these figures should not be treated as interchangeable. The registry does not give enough detail to link the event categories or determine whether the same participant contributed to more than one summary.

Because this is a small Phase I study in healthy volunteers, the safety figures are descriptive of the participants and follow-up recorded in the trial. They do not provide a precise estimate of uncommon harms or a formal comparison of safety between regimens.

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

The registry results describe drug-related adverse-event percentages across the listed groups in a Phase I study of healthy Japanese male volunteers. The only nonzero primary endpoint percentage is 16.7% in Placebo 5m (Part I); every other reported group has 0.0%. The figures show what was recorded in these treated groups during the specified safety follow-up. They are not accompanied by confidence intervals, p-values, or comparative estimates.

These results do not establish that idarucizumab caused fewer or more drug-related adverse events than placebo. The groups are small, no inferential comparison is posted, and the different regimens and trial parts are not combined into a single analysis. A zero percentage is an observed count outcome in a limited group, not evidence that the true event probability is zero. The findings also do not establish whether a difference in percentages, if any, is due to treatment rather than chance or other factors.

The primary endpoint addresses safety, not the pharmacokinetic or pharmacodynamic objectives. Although the registry lists outcomes intended to characterize idarucizumab and dabigatran exposure and to explore reversal of dabigatran anticoagulant activity, numerical results for those outcomes are not reported in the registry record. The safety endpoint alone cannot establish the degree or timing of reversal, an effective dose, or a pharmacokinetic profile.

The serious-adverse-event summary records no serious events in the listed groups, while deaths are not reported in the registry record. This is a limited description of events during the trial, not a guarantee that serious events cannot occur. The small volunteer groups and absence of reported uncertainty measures make the safety percentages imprecise for broader inference. These results should therefore be read as early-stage descriptive evidence about observed events in this particular trial, not as a definitive comparison or a conclusion about use in patients.

14. Why This Trial Matters Statistically

Phase I trials often focus on early safety, tolerability, and pharmacokinetics. This study is statistically notable because it reports those aims across a range of idarucizumab regimens, first alone and then after dabigatran, while also including placebo groups. That staged structure raises distinct questions: safety after idarucizumab alone is not identical to safety when dabigatran is also being administered, and the different dose groups should not automatically be treated as interchangeable.

The primary outcome illustrates why percentages need to be interpreted with their denominators. A percentage is easy to read, but the group sizes are small and vary across arms. Without confidence intervals or formal comparisons, the posted percentages communicate observed event frequency but not a precise treatment contrast. The absence of inferential analyses is especially relevant when many dose groups and outcomes are listed: readers cannot determine whether a planned comparison or multiplicity strategy was used.

The trial also demonstrates the distinction between a study objective and a posted result. The record states an objective to explore the effective dose for reversing dabigatran anticoagulant activity and lists relevant pharmacokinetic and pharmacodynamic outcomes. However, the corresponding numerical results are not reported in the registry record. The adverse-event endpoint cannot stand in for those data.

For biostatistical interpretation, the key lesson is to keep the estimand, population, outcome, and level of evidence aligned. The results describe treated-set drug-related adverse events by group. They do not provide a treatment-effect estimate, a precise risk estimate, or a conclusion about reversal. Keeping those boundaries clear prevents descriptive safety observations from being mistaken for a comparative or mechanistic finding.

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.

Several features of the trial constrain interpretation of the posted safety results. The study enrolled healthy Japanese male volunteers, and the results do not describe patients receiving dabigatran in clinical care. The registry reports small group sizes, from 2.0 to 9.0 participants, across multiple regimens. The percentages therefore summarize limited group experience and cannot precisely characterize uncommon events.

The endpoint results are descriptive. No confidence intervals, p-values, or inferential analyses are reported, and the registry notes that values for a two-arm comparison are missing or not estimable. There is no posted estimate of the difference between an idarucizumab regimen and its comparator. The results should not be read as evidence of equivalence or as a formal demonstration that event rates differ.

The registry does not report the statistical analysis plan, sample-size justification, missing-data rules, multiplicity procedures, interim analyses, or details of how drug-relatedness was determined. The primary population is identified as the treated set, but additional analysis-population definitions are not reported in the registry record. The secondary outcomes are listed without numerical results, limiting assessment of the stated pharmacokinetic and pharmacodynamic objectives. Death counts are also not reported in the registry record.

Finally, the study's two parts address different dosing contexts, and the posted figures should be understood by group rather than treated as a pooled estimate. The registry does not report a pooled analysis or explain how results across parts would be combined. These limitations mean the available results provide a narrow, descriptive account of recorded adverse events rather than a complete comparative evaluation.

16. Related Tutorials

17. Related Statistical Calculators

18. Sources

• ClinicalTrials.gov: Study to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of BI 655075 (Idarucizumab) Administered Alone or With Dabigatran Etexilate in Japanese Healthy Subjects — NCT02028780.
• Registry record last updated 2016-02-11; status last verified 2016-01.
• Results first posted 2016-02-11.
• 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

This completed randomized, double-blind, parallel Phase I trial enrolled 80 healthy Japanese male volunteers. Part I studied single rising doses of idarucizumab alone; Part II explored idarucizumab after dabigatran. The primary endpoint was the percentage of treated participants with drug-related adverse events during follow-up.

The reported percentage was 16.7% in Placebo 5m (Part I) and 0.0% in every other listed group. Group sizes were small. The registry reports no inferential analyses or confidence intervals for this endpoint. Serious adverse events were not recorded in the listed groups; death counts are not reported in the registry record. Numerical results for the listed secondary outcomes are also not reported in the registry record, limiting interpretation of the pharmacokinetic and pharmacodynamic objectives.