Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose(s) Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran: Complete Statistical Analysis

1. Trial at a Glance

This page covers the registry results for Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose(s) Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran (NCT01955720), a randomized phase 1 study. The primary outcome is Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time.

2. Clinical Question

The trial’s stated purpose was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 655075, and to establish dose(s) effective to reverse dabigatran-related prolongation of blood coagulation time. That purpose combines questions about drug exposure, biological response, and safety. The primary endpoint focuses on reversal in clotting assays rather than a clinical bleeding or thrombotic outcome. The listed condition is hemorrhage, but the enrolled population is described as volunteers; a clinical patient benefit question is not reported in the registry record.

3. Trial Design

This was a Phase Ib, randomized, double-blind, placebo-controlled, two-way crossover study. The registry lists enrollment of 46 and describes the study as completed. In a crossover design, participants receive more than one treatment condition in sequence, allowing outcomes under different conditions to be compared within the same participant. This general feature can account for stable differences between people, but interpretation depends on the sequence, timing, and adequacy of separation between treatment periods. Those protocol details are not reported in the registry record.

The arm descriptions identify four participant groups: healthy subjects aged 45-64, healthy elderly subjects aged 65-80 year, participants with mild renal impairment aged 45-80 years, and participants with mod renal impairment aged 45-80 years. Each description refers to sequential crossover to placebo or BI 655075. The registry does not specify the number of participants in each group, the sequence assigned to each participant, or whether every group received the same dose levels.

The adverse-event record lists dabigatran etexilate and low (1g), medium (2.5g), and high (5g) idarucizumab dose groups, together with corresponding placebo dose groups. These safety group counts should be read as the registry presents them; they do not establish that each listed group is a separate, parallel randomized arm. The crossover structure means treatment observations may be repeated within participants. The registry does not report a treatment-period diagram or explain the relationship between the safety group denominators and the four participant groups.

The listed primary outcome was measured at the end of the last infusion and 10 minutes after completion of that infusion. Secondary outcomes included plasma and urine pharmacokinetic measures for idarucizumab and dabigatran-related measures. The primary completion date, start date, and more detailed visit schedule do not add information about the statistical analysis. In particular, methods for handling sequence, period, carryover, and within-participant correlation 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.

Overall Study

Analysis population for the primary outcome, as defined in the registry: PD Set (PDS): The PDS included all subjects from the TS who had at least 1 evaluable predose and on-treatment coagulation test measurement value for at least 1 coagulation test and who did not have important protocol violation relevant to the evaluation of PD.

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

6. Primary Endpoint

The registry lists the primary outcome as Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time, measured over End of last infusion and 10 minutes after completion of last infusion of BI 655075.

The primary endpoint is the percentage of participants with at least one dTT or ECT assay value judged to have reversed within 10min after the infusion. Reversal was defined as a return to baseline. The registry says the threshold for return to baseline was determined using a pharmacokinetic/pharmacodynamic correlation between unbound sum dabigatran and the clotting parameters ECT and dTT. Measurements were made at the end of infusion and 10 minutes later.

This endpoint is a pharmacodynamic measure: it describes a change in a laboratory measure related to dabigatran’s anticoagulant activity. A binary endpoint of this kind classifies each eligible participant according to whether the defined reversal criterion was met. Reporting a percentage can make the proportion meeting the criterion straightforward to interpret, but the percentage alone does not show how quickly an individual response began, how long it lasted, or whether a clinical event changed.

Using both dTT and ECT permits the endpoint definition to use either assay, as specified in the registry. The criterion is tied to a baseline threshold derived from the stated PK/PD relationship rather than an independently reported clinical outcome. The record does not give the assay-specific results, the threshold values, the observed percentage meeting the endpoint, or uncertainty intervals. It therefore does not allow readers to assess the magnitude or precision of the primary endpoint result.

7. Why No Re-analysis Is Shown

8. Statistical Interpretation

9. Statistical Methods Explained

The registry identifies a binary percentage endpoint: whether a participant had at least one qualifying dTT or ECT assay value return to baseline under the specified definition. General statistical explanation: a binary outcome reduces each participant’s result to one of two categories, such as criterion met or not met. A percentage describes the proportion in the first category, but it is most informative when accompanied by its denominator and an uncertainty interval. Neither the observed primary endpoint percentages nor confidence intervals are reported in the registry record.

What would an interval estimate add?

General statistical explanation: a confidence interval expresses uncertainty around an estimated effect using the data and a stated statistical procedure. A narrow interval indicates greater precision than a wide interval, while neither width alone nor statistical significance establishes clinical importance. Because the registry does not report a primary endpoint estimate or interval, the precision of the reversal result cannot be assessed from this record.

How does crossover allocation affect interpretation?

General statistical explanation: in a crossover study, a participant can contribute observations under more than one treatment condition. A within-participant comparison can account for characteristics that remain stable across treatment periods. However, treatment order, period effects, carryover, and correlation between repeated observations may matter. The registry describes randomization, double masking, and crossover, but does not report the specific statistical model or how these design features were handled. No model should be presumed from the design label alone.

The primary analysis population is the PD Set. It includes participants from the TS who had at least one evaluable predose and on-treatment coagulation test measurement for at least one coagulation test and did not have an important protocol violation relevant to the pharmacodynamic evaluation. This is a defined analysis population rather than an assertion that every enrolled participant contributed to the endpoint. The registry does not explain the TS abbreviation or report the PD Set size.

What do the sample-size assumptions mean?

General statistical explanation: sample-size planning estimates how many participants may be needed to detect a specified effect under stated assumptions. The registry describes planning illustrations based on the observed effect, a two-sided significance level of 0.05, equal allocation between two arms, and a normal approximation; the effect to detect is a stated fraction of the observed effect. Such illustrations are planning exercises, not observed power and not necessarily the assumptions used to design the trial. For time-to-event outcomes, the description refers to total events; for other outcomes, it refers to participants per arm. The record does not report a trial-specific sample-size justification or numerical planning illustrations in the registry record. Those illustrations cannot be used to infer the study’s original design rationale.

General statistical explanation: when outcome variability exceeds what a simple model assumes, standard errors can be underestimated and confidence intervals can be too narrow. This is called over-dispersion. It is relevant to some count outcomes, but the primary outcome is described as a percentage based on a binary classification, and the registry does not report a model or an over-dispersion assessment. It would therefore be inappropriate to claim that over-dispersion was tested or adjusted for in this study.

What can be learned from the safety counts?

The adverse-event record separates serious events from other events and gives numbers at risk and numbers affected for each listed group. General statistical explanation: counts are descriptive; an inferential comparison requires a defined estimand and method that account for the design, exposure, and any repeated observations. In a crossover study, participants may appear under more than one treatment condition, so treating all group counts as independent samples may be inappropriate. The registry does not report an inferential safety analysis, event-level timing, or a method for accounting for repeated treatment periods.

The record lists zero serious events affected in the groups. A zero count does not show that the underlying event risk is exactly zero; it indicates that no affected participants were recorded in those listed groups. The precision of a risk estimate depends on the denominator and analysis approach, and no interval estimates are reported. The separate group denominators should not be summed to create a unique-participant total because the crossover structure and overlap are not clarified.

What is absent from the analysis record?

The registry lists seven outcome measures and zero analysis entries. It does not report endpoint estimates, p-values, confidence intervals, adjusted analyses, subgroup analyses, or missing-data methods. Statistical methods for multiplicity and the handling of sequence or period effects are also not reported in the registry record. This absence prevents an independent assessment of the analysis procedure and its uncertainty; it should not be interpreted as evidence that a particular procedure was or was not used outside the registry record.

10. Multiplicity, Missing Data and Analysis Populations

The registry lists one primary outcome and seven outcome measures in total, including secondary pharmacokinetic measures. It reports zero analysis entries and does not provide a set of outcome estimates or tests. A multiplicity procedure, such as a hierarchy for testing outcomes or an adjustment to control the chance of false-positive findings across multiple tests, is not reported in the registry record. With no posted inferential results, it is not possible to determine whether multiplicity was addressed in the analysis or what effect it had on interpretation.

The primary outcome population is the PD Set, defined by evaluable predose and on-treatment coagulation measurements and the absence of an important protocol violation relevant to pharmacodynamic evaluation. The record does not report the number of participants in this set, how many were excluded, or the reasons for exclusion. It does not state how missing outcome measurements were handled, whether any imputation was used, or whether analyses were conducted under more than one missing-data assumption.

These gaps matter because the enrolled count and the analyzed population may not be identical. In a crossover study, missing measurements in one treatment period can also affect whether a participant contributes to a within-person comparison. The registry does not report the extent of missingness by treatment, period, assay, or participant group. No conclusion about the direction or size of any resulting bias can be drawn without those details.

Likewise, the record does not report whether there were prespecified subgroup analyses by age or renal impairment, or how any such analyses were handled statistically. The group descriptions alone do not establish that subgroup effects were estimated. These omissions limit assessment of the analysis populations and the reliability of comparisons across outcomes or participant categories.

11. 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 reports serious-event counts and other-event counts separately. For serious events, zero affected participants are listed for dabigatran etexilate (0 of 46), low (1g) idarucizumab (0 of 14), medium (2.5g) idarucizumab (0 of 12), high (5g) idarucizumab (0 of 26), low (1g) placebo (0 of 14), medium (2.5g) placebo (0 of 12), and high (5g) placebo (0 of 26). The record lists no serious-event terms.

Other-event counts are 13 of 46 for dabigatran etexilate, 4 of 14 for low (1g) idarucizumab, 1 of 12 for medium (2.5g) idarucizumab, 2 of 26 for high (5g) idarucizumab, 3 of 14 for low (1g) placebo, 3 of 12 for medium (2.5g) placebo, and 0 of 26 for high (5g) placebo. These are counts, not adjusted comparisons. Because the study used a crossover design, participants could contribute to more than one condition; the listed groups should not be treated as independent populations without further information.

The record does not report event definitions beyond the serious-versus-other categories, event timing, severity details for other events, or statistical comparisons. It also does not report death counts as numerical values. A zero recorded serious-event count is not proof of zero risk, and the count pattern alone cannot establish a treatment-related difference.

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

The record establishes that the trial was designed to assess whether BI 655075 could reverse dabigatran-related prolongation of blood coagulation time, alongside safety, tolerability, pharmacokinetic, and pharmacodynamic questions. It defines the primary endpoint using return to baseline in at least one dTT or ECT assay value, with the reversal threshold tied to a stated PK/PD relationship. These details clarify what investigators intended to measure.

The record does not report the primary endpoint results. It therefore cannot support a numerical statement about the percentage meeting the reversal criterion, the difference between BI 655075 and placebo, or the precision of such a difference. The listed safety counts describe serious and other events by registry group, but they do not by themselves establish a causal contrast. Nor do the listed secondary outcome names provide evidence about the observed pharmacokinetic results.

The trial enrolled volunteers and includes participant groups categorized by age and renal impairment. The registry does not report a clinical outcome such as a change in bleeding events or another patient-centered endpoint. A laboratory reversal measure should not be conflated with a demonstrated change in clinical outcomes. General statistical interpretation: a surrogate or pharmacodynamic measure can be useful for describing a biological response, but evidence about that measure alone does not quantify effects on outcomes it does not directly measure.

The trial’s randomized, double-blind crossover design is relevant to how its comparisons should be analyzed. Yet the registry record does not report the statistical model, treatment-sequence handling, endpoint estimates, missing-data approach, or multiplicity strategy. Readers should distinguish the design and endpoint definitions that are reported from the results and analysis details that are absent. No conclusion about efficacy, safety differences, or the size of a treatment effect can be drawn from the posted record’s endpoint description alone.

13. Why This Trial Matters Statistically

This trial is statistically notable for combining a crossover design with a pharmacodynamic endpoint defined through laboratory assays. A crossover can support comparisons within participants, but it also makes the treatment sequence and repeated-measure structure important. The registry identifies randomization, double masking, and crossover allocation, yet does not describe the analysis used to account for those features. This illustrates why a design label is not enough to evaluate an estimate: the analysis must match the way observations were collected.

The primary outcome is a binary classification based on whether at least one assay value met a baseline-reversal threshold. Its interpretation depends on the assay definition, the threshold-setting approach, and the timing of measurements. The record describes these elements at a high level, including a PK/PD correlation used to determine the threshold. It does not give assay-level results or the observed proportion meeting the endpoint, so the statistical quantity of interest is defined but not estimable from the posted results.

The safety record also illustrates a common interpretive issue. Group-specific event counts can look directly comparable, but crossover exposure means the same participants may contribute under different conditions. Without event timing, exposure detail, and an analysis that accounts for within-participant data, simple differences in counts cannot be treated as independent treatment effects.

Finally, the registry’s lack of analysis entries makes the distinction between trial purpose, endpoint specification, and reported evidence especially important. Clear outcome definitions help readers understand the intended question; they do not replace results, uncertainty estimates, or analysis methods. The record therefore supports understanding of the statistical design and measurement strategy, while leaving the central treatment-effect estimate unreported.

14. 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 main limitation for interpreting the primary question is that no observed primary endpoint results are reported. There are no percentages, denominators by treatment condition, effect estimates, confidence intervals, or p-values for reversal of dabigatran-related coagulation-time prolongation. The registry defines the criterion and measurement timing, but the result itself is not reported in the registry record.

The registry gives limited detail about the crossover implementation. The order of treatments, period duration, washout interval, dose sequence, and handling of potential period or carryover effects are not reported. The group descriptions identify age and renal-impairment categories, but do not provide group sizes or show whether every group received each dose level. These omissions make the relationship between participant groups and the listed safety groups difficult to assess.

The adverse-event results are descriptive and do not include reported inferential comparisons. The record does not clarify whether each denominator represents unique participants or treatment exposures, and it does not give event-level timing or details for other events. This is particularly relevant when interpreting counts from a crossover trial.

The record also does not report missing-data methods, the analyzed PD Set size, multiplicity procedures, or a trial-specific sample-size justification. Although the sample-size assumptions describe planning illustrations, numerical illustrations and the original design rationale are not reported in the registry record. The registry does not provide enough information to assess the precision of the primary endpoint or whether the study was planned around a particular effect size.

Finally, the primary outcome is pharmacodynamic, and no clinical endpoint results are reported. The posted record therefore cannot establish effects on clinical outcomes beyond the laboratory measures it specifies.

15. Related Tutorials

16. Related Statistical Calculators

17. Sources

• ClinicalTrials.gov: Safety, Tolerability, PK and PD of BI 655075 and Establishment of BI 655075 Dose(s) Effective to Reverse Prolongation of Blood Coagulation Time by Dabigatran — NCT01955720.
• 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.

18. Record Summary

NCT01955720 is a completed Phase Ib randomized, double-blind, placebo-controlled, two-way crossover study with enrollment of 46. It investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of BI 655075, also listed as idarucizumab, in relation to dabigatran etexilate. Participant groups included healthy subjects and participants with mild or moderate renal impairment.

The primary endpoint was the percentage of participants with at least one dTT or ECT assay value returning to baseline under a threshold based on a stated PK/PD correlation. The assessment was specified at the end of the last infusion and 10 minutes after completion. The registry record does not report the primary endpoint results or a statistical comparison.

Safety figures list zero serious events in the reported groups and varying counts of other events. Seven outcome measures are listed, but the record reports zero analysis entries. It does not report the statistical analysis model, missing-data methods, multiplicity handling, or trial-specific sample-size justification. The record therefore describes the trial question, design, endpoint, and safety counts, but does not permit estimation of the primary treatment effect or its precision.