Healthy
Conditions
Brief summary
The primary objective is to investigate the safety, tolerability and pharmacokinetics of BI 655075 following intravenous administration of single rising doses of BI 655075 when administered alone and after administration of dabigatran.
Interventions
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Healthy male subjects
Exclusion criteria
1\. Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Drug Related Adverse Events (AE) | AEs occurring until end of follow-up (Up to 3 months after last drug administration) | Frequency of subjects with related adverse events (AE) by treatment |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h | tmax (time from dosing to maximum measured concentration) for idarucizumab |
| AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h | AUC0-inf (area under the concentration-time curve from time 0 extrapolated to infinity) for idarucizumab |
| Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | Up to 7 hours | Aet1-t2 (amount of idarucizumab eliminated in urine from time point t1 to time point t2) Ae(0-7h) is presented for dose groups with 1 h infusion and Ae(0-4h) is presented for dose groups with 5 min infusion. |
| Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | Intervals 0-2, 2-6, 6-10, 10-12 hours on Day 3 post dabigatran treatment and -2 to -0:05, -0:05 to 4, 4-8, 8-10, 10-12, 12-24, 24-48, 48-72 on Day 4 post Idarucizumab treatment | Aet1-t2,ss (amount of dabigatran etexilate eliminated in urine from time point t1 to time point t2, at steady state) on Day 3 and Day 4 Ae(0-12h,ss) of sum dabigatran |
| Cmax (Maximum Measured Concentration) for Idarucizumab | -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h | Cmax (maximum measured concentration) for idarucizumab |
| AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h | AUC(2-12),ss ((area under the concentration-time curve for the idarucizumab in plasma from time point 2 to 12 h )) on Day 3 and Day 4 |
| AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | 2hours-12 hours | AUECt1-t2 (area under the effect curve from time point t1=2 hours to time point t2=12 hours) on Day 3 and Day 4 (determined under consideration of the baseline value). Ratio of above baseline AUEC(2-12) on Day 4 to above baseline AUEC(2-12) on Day 3 is presented. This endpoint was determined for Activated Partial Thromboplastin time (aPTT), Dithiothreitol (dTT), Thrombin time (TT) and Ecarin clotting time (ECT) |
| AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study | 2hours-12 hours | AUECt1-t2 (area under the effect curve from time point t1=2 hours to time point t2=12 hours) on Day 3 and Day 4 (determined under consideration of the baseline value). Ratio of above baseline AUEC(2-12) on Day 4 to above baseline AUEC(2-12) on Day 3 is presented. This endpoint was determined for Activated Partial Thromboplastin time (aPTT) and Dithiothreitol (dTT) |
| C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | 1.92 hours (h), 2 h, 2.5 h, 6 h and 12 h on Day 4 | Concentrations of unbound sum dabigatran in plasma after 1.92 to 12 h, at steady state of dabigatran, on Day 4 are presented. The endpoint refers to unbound sum dabigatran at several time points. The intended pharmacodynamic effect of idarucizumab is to reduce the concentration of this measure to levels below the lower limit of quantification (BLQ). BLQ values are not considered in the calculation of descriptive statistics; and therefore bias the result. This is the reason for applying the 2/3 rule to obtain reliable results. 2/3 rule states that, Statistics of PK parameters are only estimated when at least 2/3 of the data are evaluable. |
Countries
Belgium
Participant flow
Recruitment details
The study is conducted in two parts: Parts 1 and 2 had a single rising dose design; subjects in Part 3 received 2 single doses 1 h apart. Part 1: 8 subjects per dose group Part 2: 12 subjects per dose group Part 3: 12 subjects per dose group
Participants by arm
| Arm | Count |
|---|---|
| Placebo 1 h One single intravenous long infusion (1 h) of Idarucizumab Placebo
This is administered during Part 1 of the study | 21 |
| 20 mg Idarucizumab 1h Dose group 1: One single intravenous long infusion (1 h) of 20 mg Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 60 mg Idarucizumab 1h Dose group 2: One single intravenous long infusion (1 h) of 60 mg Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 200 mg Idarucizumab 1h Dose group 3: One single intravenous long infusion (1 h) of 200 mg Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 600 mg Idarucizumab 1h Dose group 4: One single intravenous long infusion (1 h) of 600 mg Idarucizumab verum
This is administered during Part 1 of the study | 5 |
| 1.2 g Idarucizumab 1h Dose group 5: One single intravenous long infusion (1 h) of 1.2 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 2 g Idarucizumab 1h Dose group 6: One single intravenous long infusion (1 h) of 2 g Idarucizumab verum
This is administered during Part 1 of the study | 12 |
| 3 g Idarucizumab 1h Dose group 7: One single intravenous long infusion (1 h) of 3 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 4 g Idarucizumab 1h Dose group 8: One single intravenous long infusion (1 h) of 4 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 6 g Idarucizumab 1h Dose group 9: One single intravenous long infusion (1 h) of 6 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 8 g Idarucizumab 1h Dose group 10: One single intravenous long infusion (1 h) of 8 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| Placebo 5min One single intravenous short infusion (5 min) of Idarucizumab Placebo
This is administered during Part 1 of the study | 6 |
| 1 g Idarucizumab 5min Dose group 11: One single intravenous short infusion (5 min) of 1 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 2 g Idarucizumab 5min Dose group 12: One single intravenous short infusion (5 min) of 2 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| 4 g Idarucizumab 5min Dose group 13: One single intravenous short infusion (5 min) of 4 g Idarucizumab verum
This is administered during Part 1 of the study | 6 |
| DE+ Placebo 5min One single intravenous short infusion (5 min) of Idarucizumab Placebo administered at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 2 of the study
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 9 |
| DE+ 1 g Idarucizumab 5min Dose group 14: One single intravenous short infusion (5 min) of 1 g Idarucizumab verum administered at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 2 of the study.
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 9 |
| DE+ 2 g Idarucizumab 5min Dose group 15: One single intravenous short infusion (5 min) of 2 g Idarucizumab verum administered at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 2 of the study.
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 9 |
| DE+ 4 g Idarucizumab 5min Dose group 16: One single intravenous short infusion (5 min) of 4 g Idarucizumab verum administered at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 2 of the study.
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 8 |
| DE+ Placebo+ Placebo Two short intravenous infusions (5 min each) of Idarucizumab Placebo administered at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 3 of the study
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 3 |
| DE+ 5 g + 2.5 g Idarucizumab Dose group 17: Two short intravenous infusions (5 min each) of 7.5 g Idarucizumab verum administered (5 g + 2.5 g 1 h later) at or close to the steady state of Dabigatran etexilate (DE) 220 mg.
This is administered during Part 3 of the study
DE is administered orally :
Day 1 to 3: twice daily; Day 4: once daily | 9 |
| Total | 157 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 | FG009 | FG010 | FG011 | FG012 | FG013 | FG014 | FG015 | FG016 | FG017 | FG018 | FG019 | FG020 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Placebo 1 h | 20 mg Idarucizumab 1h | 60 mg Idarucizumab 1h | 200 mg Idarucizumab 1h | 600 mg Idarucizumab 1h | 1.2 g Idarucizumab 1h | 2 g Idarucizumab 1h | 3 g Idarucizumab 1h | 4 g Idarucizumab 1h | 6 g Idarucizumab 1h | 8 g Idarucizumab 1h | Placebo 5min | 1 g Idarucizumab 5min | 2 g Idarucizumab 5min | 4 g Idarucizumab 5min | DE+ Placebo 5min | DE+ 1 g Idarucizumab 5min | DE+ 2 g Idarucizumab 5min | DE+ 4 g Idarucizumab 5min | DE+ Placebo+ Placebo | DE+ 5 g + 2.5 g Idarucizumab | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 30.3 years STANDARD_DEVIATION 7.8 | 29.8 years STANDARD_DEVIATION 6.6 | 35.2 years STANDARD_DEVIATION 5.5 | 36.2 years STANDARD_DEVIATION 8.8 | 36.6 years STANDARD_DEVIATION 4.5 | 32.0 years STANDARD_DEVIATION 8.9 | 30.3 years STANDARD_DEVIATION 8.5 | 32.7 years STANDARD_DEVIATION 4.2 | 35.3 years STANDARD_DEVIATION 9.5 | 34.5 years STANDARD_DEVIATION 8.8 | 35.2 years STANDARD_DEVIATION 9.1 | 34.5 years STANDARD_DEVIATION 11.2 | 34.7 years STANDARD_DEVIATION 8.5 | 31.8 years STANDARD_DEVIATION 5.4 | 36.0 years STANDARD_DEVIATION 8.3 | 30.9 years STANDARD_DEVIATION 8.9 | 31.3 years STANDARD_DEVIATION 7 | 31.1 years STANDARD_DEVIATION 8.3 | 31.9 years STANDARD_DEVIATION 9.1 | 30.0 years STANDARD_DEVIATION 2.6 | 29.9 years STANDARD_DEVIATION 9 | 32.4 years STANDARD_DEVIATION 7.9 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 21 Participants | 6 Participants | 6 Participants | 6 Participants | 5 Participants | 6 Participants | 12 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 9 Participants | 9 Participants | 8 Participants | 3 Participants | 9 Participants | 157 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk | EG015 affected / at risk | EG016 affected / at risk | EG017 affected / at risk | EG018 affected / at risk | EG019 affected / at risk | EG020 affected / at risk | EG021 affected / at risk | EG022 affected / at risk | EG023 affected / at risk | EG024 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 7 / 21 | 2 / 6 | 2 / 6 | 5 / 6 | 2 / 5 | 1 / 6 | 4 / 12 | 3 / 6 | 0 / 6 | 1 / 6 | 2 / 6 | 2 / 6 | 3 / 6 | 2 / 6 | 3 / 6 | 20 / 35 | 1 / 9 | 4 / 9 | 4 / 8 | 4 / 9 | 2 / 12 | 0 / 3 | 1 / 3 | 1 / 9 | 3 / 9 |
| serious Total, serious adverse events | 0 / 21 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 5 | 0 / 6 | 0 / 12 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 35 | 0 / 9 | 0 / 9 | 0 / 8 | 0 / 9 | 0 / 12 | 0 / 3 | 0 / 3 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Number of Subjects With Drug Related Adverse Events (AE)
Frequency of subjects with related adverse events (AE) by treatment
Time frame: AEs occurring until end of follow-up (Up to 3 months after last drug administration)
Population: Treated set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 20 mg Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 2 participants |
| 60 mg Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 200 mg Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 600 mg Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 1.2 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 2 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 3 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 2 participants |
| 4 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 6 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 8 g Idarucizumab 1h | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 1 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 1 participants |
| 2 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| 4 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ 1 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ 2 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ 4 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ 5 g + 2.5 g Idarucizumab | Number of Subjects With Drug Related Adverse Events (AE) | 1 participants |
| DE+ 2 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ 4 g Idarucizumab 5min | Number of Subjects With Drug Related Adverse Events (AE) | 0 participants |
| DE+ Placebo+ Placebo | Number of Subjects With Drug Related Adverse Events (AE) | 1 participants |
| DE+ 5 g + 2.5 g Idarucizumab | Number of Subjects With Drug Related Adverse Events (AE) | 1 participants |
Secondary
Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2)
Aet1-t2 (amount of idarucizumab eliminated in urine from time point t1 to time point t2) Ae(0-7h) is presented for dose groups with 1 h infusion and Ae(0-4h) is presented for dose groups with 5 min infusion.
Time frame: Up to 7 hours
Population: PKS (presented values are those subjects from the PKS with evaluable observations for this endpoint)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 60 mg Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 200 mg Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 600 mg Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 1.2 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 2 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 3 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 4 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | NA μmol | — |
| 6 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 36.1 μmol | Geometric Coefficient of Variation 50.1 |
| 8 g Idarucizumab 1h | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 39.5 μmol | Geometric Coefficient of Variation 395 |
| 1 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 2.23 μmol | Geometric Coefficient of Variation 76.3 |
| 2 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 8.00 μmol | Geometric Coefficient of Variation 73.1 |
| 4 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 32.6 μmol | Geometric Coefficient of Variation 23.6 |
| DE+ 1 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 1.71 μmol | Geometric Coefficient of Variation 90.6 |
| DE+ 2 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 11.0 μmol | Geometric Coefficient of Variation 23.4 |
| DE+ 4 g Idarucizumab 5min | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 33.6 μmol | Geometric Coefficient of Variation 30.5 |
| DE+ 5 g + 2.5 g Idarucizumab | Aet1-t2 (Amount of Idarucizumab Eliminated in Urine From Time Point t1 to Time Point t2) | 73.5 μmol | Geometric Coefficient of Variation 24.9 |
Secondary
Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran
Aet1-t2,ss (amount of dabigatran etexilate eliminated in urine from time point t1 to time point t2, at steady state) on Day 3 and Day 4 Ae(0-12h,ss) of sum dabigatran
Time frame: Intervals 0-2, 2-6, 6-10, 10-12 hours on Day 3 post dabigatran treatment and -2 to -0:05, -0:05 to 4, 4-8, 8-10, 10-12, 12-24, 24-48, 48-72 on Day 4 post Idarucizumab treatment
Population: PKS (presented values are those subjects from the PKS with evaluable observations for this endpoint)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 6600 μg | Geometric Coefficient of Variation 54.4 |
| 60 mg Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 6870 μg | Geometric Coefficient of Variation 37.8 |
| 200 mg Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 5160 μg | Geometric Coefficient of Variation 57.1 |
| 600 mg Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 3820 μg | Geometric Coefficient of Variation 86.9 |
| 1.2 g Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 3860 μg | Geometric Coefficient of Variation 39.1 |
| 2 g Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 6420 μg | Geometric Coefficient of Variation 38.7 |
| 3 g Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 5060 μg | Geometric Coefficient of Variation 55.1 |
| 4 g Idarucizumab 1h | Aet1-t2,ss (Amount of Dabigatran Etexilate Eliminated in Urine From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 for Sum Dabigatran | 4290 μg | Geometric Coefficient of Variation 35.2 |
Secondary
AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab
AUC0-inf (area under the concentration-time curve from time 0 extrapolated to infinity) for idarucizumab
Time frame: -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h
Population: PKS (presented values are those subjects from the PKS with evaluable observations for this endpoint)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 146 nmol*h/L | Geometric Coefficient of Variation 19.8 |
| 60 mg Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 426 nmol*h/L | Geometric Coefficient of Variation 11.6 |
| 200 mg Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 1950 nmol*h/L | Geometric Coefficient of Variation 129 |
| 600 mg Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 6970 nmol*h/L | Geometric Coefficient of Variation 75.4 |
| 1.2 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 8780 nmol*h/L | Geometric Coefficient of Variation 4.92 |
| 2 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 14500 nmol*h/L | Geometric Coefficient of Variation 15.9 |
| 3 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 22600 nmol*h/L | Geometric Coefficient of Variation 17.6 |
| 4 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 31000 nmol*h/L | Geometric Coefficient of Variation 12.9 |
| 6 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 41200 nmol*h/L | Geometric Coefficient of Variation 11.8 |
| 8 g Idarucizumab 1h | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 63800 nmol*h/L | Geometric Coefficient of Variation 15.6 |
| 1 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 7790 nmol*h/L | Geometric Coefficient of Variation 13.1 |
| 2 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 16400 nmol*h/L | Geometric Coefficient of Variation 16.8 |
| 4 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 25800 nmol*h/L | Geometric Coefficient of Variation 22.1 |
| DE+ 1 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 6480 nmol*h/L | Geometric Coefficient of Variation 17.1 |
| DE+ 2 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 16600 nmol*h/L | Geometric Coefficient of Variation 10.7 |
| DE+ 4 g Idarucizumab 5min | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 30900 nmol*h/L | Geometric Coefficient of Variation 14.1 |
| DE+ 5 g + 2.5 g Idarucizumab | AUC0-inf (Area Under the Concentration-time Curve From Time 0 Extrapolated to Infinity) for Idarucizumab | 62300 nmol*h/L | Geometric Coefficient of Variation 8.43 |
Secondary
AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4
AUC(2-12),ss ((area under the concentration-time curve for the idarucizumab in plasma from time point 2 to 12 h )) on Day 3 and Day 4
Time frame: 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h
Population: PKS (presented values are those subjects from the PKS with evaluable observations for this endpoint)
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 805 ng*h/mL | Geometric Coefficient of Variation 57.4 |
| 60 mg Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 754 ng*h/mL | Geometric Coefficient of Variation 45.6 |
| 200 mg Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 161 ng*h/mL | Geometric Coefficient of Variation 148 |
| 600 mg Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 20.9 ng*h/mL | Geometric Coefficient of Variation 199 |
| 1.2 g Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 11.9 ng*h/mL | Geometric Coefficient of Variation 44.3 |
| 2 g Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 786 ng*h/mL | Geometric Coefficient of Variation 40.1 |
| 3 g Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 542 ng*h/mL | Geometric Coefficient of Variation 98.9 |
| 4 g Idarucizumab 1h | AUCt1-t2,ss (Area Under the Concentration-time Curve for the Unbound Sum Dabigatran in Plasma From Time Point t1 to Time Point t2, at Steady State) on Day 3 and Day 4 | 10.0 ng*h/mL | Geometric Coefficient of Variation 0.344 |
Secondary
AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study
AUECt1-t2 (area under the effect curve from time point t1=2 hours to time point t2=12 hours) on Day 3 and Day 4 (determined under consideration of the baseline value). Ratio of above baseline AUEC(2-12) on Day 4 to above baseline AUEC(2-12) on Day 3 is presented. This endpoint was determined for Activated Partial Thromboplastin time (aPTT), Dithiothreitol (dTT), Thrombin time (TT) and Ecarin clotting time (ECT)
Time frame: 2hours-12 hours
Population: Pharmacodynamic set (PDS) : The PDS was used for all PD analyses and comprised all subjects in the TS who provided at least 1 evaluable predose and~1 on-treatment observation for calculating ratio (PD endpoint) and who had no important protocol violations relevant to the evaluation of PD.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | aPTT | 1.28 ratio | Standard Deviation 0.399 |
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | dTT | 1.01 ratio | Standard Deviation 0.484 |
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | TT | 1.08 ratio | Standard Deviation 0.361 |
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | ECT | 1.04 ratio | Standard Deviation 0.493 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | dTT | 0.26 ratio | Standard Deviation 0.245 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | TT | 0.32 ratio | Standard Deviation 0.28 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | ECT | 0.28 ratio | Standard Deviation 0.231 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | aPTT | 0.46 ratio | Standard Deviation 0.342 |
| 200 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | TT | 0.06 ratio | Standard Deviation 0.124 |
| 200 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | dTT | 0.06 ratio | Standard Deviation 0.094 |
| 200 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | ECT | 0.07 ratio | Standard Deviation 0.08 |
| 200 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | aPTT | 0.14 ratio | Standard Deviation 0.135 |
| 600 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | ECT | 0.03 ratio | Standard Deviation 0.013 |
| 600 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | dTT | 0.02 ratio | Standard Deviation 0.016 |
| 600 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | aPTT | 0.07 ratio | Standard Deviation 0.103 |
| 600 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 2 of the Study | TT | 0.00 ratio | Standard Deviation 0.007 |
Secondary
AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study
AUECt1-t2 (area under the effect curve from time point t1=2 hours to time point t2=12 hours) on Day 3 and Day 4 (determined under consideration of the baseline value). Ratio of above baseline AUEC(2-12) on Day 4 to above baseline AUEC(2-12) on Day 3 is presented. This endpoint was determined for Activated Partial Thromboplastin time (aPTT) and Dithiothreitol (dTT)
Time frame: 2hours-12 hours
Population: Pharmacodynamic set (PDS) : The PDS was used for all PD analyses and comprised all subjects in the TS who provided at least 1 evaluable predose and~1 on-treatment observation for calculating ratio (PD endpoint) and who had no important protocol violations relevant to the evaluation of PD.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study | aPTT | 1.68 ratio | Standard Deviation 0.534 |
| 20 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study | dTT | 1.02 ratio | Standard Deviation 1.036 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study | aPTT | 0.03 ratio | Standard Deviation 0.045 |
| 60 mg Idarucizumab 1h | AUECt1-t2 (Area Under the Effect Curve From Time Point t1 to Time Point t2) on Day 3 and Day 4 (Determined Under Consideration of the Baseline Value) for Part 3 of the Study | dTT | 0.01 ratio | Standard Deviation 0.029 |
Secondary
C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State)
Concentrations of unbound sum dabigatran in plasma after 1.92 to 12 h, at steady state of dabigatran, on Day 4 are presented. The endpoint refers to unbound sum dabigatran at several time points. The intended pharmacodynamic effect of idarucizumab is to reduce the concentration of this measure to levels below the lower limit of quantification (BLQ). BLQ values are not considered in the calculation of descriptive statistics; and therefore bias the result. This is the reason for applying the 2/3 rule to obtain reliable results. 2/3 rule states that, Statistics of PK parameters are only estimated when at least 2/3 of the data are evaluable.
Time frame: 1.92 hours (h), 2 h, 2.5 h, 6 h and 12 h on Day 4
Population: Pharmadynamic set (PDS) : The PDS was used for all PD analyses and comprised all subjects in the TS who provided at least 1 evaluable predose and~1 on-treatment observation for calculating ratio (PD endpoint) and who had no important protocol violations relevant to the evaluation of PD.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| 20 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | 79.2 ng/mL | Geometric Coefficient of Variation 44.6 |
| 20 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | 130 ng/mL | Geometric Coefficient of Variation 47.9 |
| 20 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | 123 ng/mL | Geometric Coefficient of Variation 40.8 |
| 20 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 119 ng/mL | Geometric Coefficient of Variation 38 |
| 20 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | 38.5 ng/mL | Geometric Coefficient of Variation 40.3 |
| 60 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | 1.59 ng/mL | Geometric Coefficient of Variation 10.7 |
| 60 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | 15.3 ng/mL | Geometric Coefficient of Variation 296 |
| 60 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | 18.2 ng/mL | Geometric Coefficient of Variation 71.1 |
| 60 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 136 ng/mL | Geometric Coefficient of Variation 51.8 |
| 60 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | NA ng/mL | — |
| 200 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | NA ng/mL | — |
| 200 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 200 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 200 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 96.2 ng/mL | Geometric Coefficient of Variation 33.3 |
| 200 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | NA ng/mL | — |
| 600 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | NA ng/mL | — |
| 600 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 600 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 600 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 135 ng/mL | Geometric Coefficient of Variation 47.6 |
| 600 mg Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | NA ng/mL | — |
| 1.2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 101 ng/mL | Geometric Coefficient of Variation 97.8 |
| 1.2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | 54.8 ng/mL | Geometric Coefficient of Variation 93.2 |
| 1.2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | 28.9 ng/mL | Geometric Coefficient of Variation 90.6 |
| 1.2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | 95.6 ng/mL | Geometric Coefficient of Variation 109 |
| 1.2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | 92.9 ng/mL | Geometric Coefficient of Variation 99.4 |
| 2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C6,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C12,ss (N= 9, 9, NA, NA, 2, NA) | NA ng/mL | — |
| 2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C1.92,ss (N= 9, 9, 9, 8, 2, 8) | 112 ng/mL | Geometric Coefficient of Variation 34 |
| 2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2.5,ss (N= 9, NA, NA, NA, 2, NA ) | NA ng/mL | — |
| 2 g Idarucizumab 1h | C1.92,ss, C2,ss, C2.5,ss, C6,ss, and C12,ss (Concentration of the Unbound Sum Dabigatran in Plasma at Steady State) | C2,ss (N= 9, 6, NA, NA, 2, NA) | NA ng/mL | — |
Secondary
Cmax (Maximum Measured Concentration) for Idarucizumab
Cmax (maximum measured concentration) for idarucizumab
Time frame: -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h
Population: Pharmacokinetic set (PKS) comprises of all subjects (with evaluable observations) in the TS who provided at least 1 PK endpoint and had no important protocol violations relevant to the evaluation of PK and additionally for Part 2 and 3 had no emesis with onset at or before twice the median tmax of dabigatran.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 20 mg Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 79.9 nmol/L | Geometric Coefficient of Variation 15.1 |
| 60 mg Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 257 nmol/L | Geometric Coefficient of Variation 11.1 |
| 200 mg Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 809 nmol/L | Geometric Coefficient of Variation 13.9 |
| 600 mg Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 2440 nmol/L | Geometric Coefficient of Variation 13.1 |
| 1.2 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 4520 nmol/L | Geometric Coefficient of Variation 9.72 |
| 2 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 7420 nmol/L | Geometric Coefficient of Variation 15.1 |
| 3 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 11700 nmol/L | Geometric Coefficient of Variation 10.4 |
| 4 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 15700 nmol/L | Geometric Coefficient of Variation 15.6 |
| 6 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 22100 nmol/L | Geometric Coefficient of Variation 12 |
| 8 g Idarucizumab 1h | Cmax (Maximum Measured Concentration) for Idarucizumab | 33900 nmol/L | Geometric Coefficient of Variation 13.2 |
| 1 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 6360 nmol/L | Geometric Coefficient of Variation 16.7 |
| 2 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 13600 nmol/L | Geometric Coefficient of Variation 23.4 |
| 4 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 21400 nmol/L | Geometric Coefficient of Variation 13.1 |
| DE+ 1 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 5410 nmol/L | Geometric Coefficient of Variation 13.5 |
| DE+ 2 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 12500 nmol/L | Geometric Coefficient of Variation 21.5 |
| DE+ 4 g Idarucizumab 5min | Cmax (Maximum Measured Concentration) for Idarucizumab | 25800 nmol/L | Geometric Coefficient of Variation 25.1 |
| DE+ 5 g + 2.5 g Idarucizumab | Cmax (Maximum Measured Concentration) for Idarucizumab | 35300 nmol/L | Geometric Coefficient of Variation 24.4 |
Secondary
Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab
tmax (time from dosing to maximum measured concentration) for idarucizumab
Time frame: -2 hours(h), -0.5h, 0h, 2min(m), 5m, 10m, 15m,30m, 45m, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h, 72h
Population: PKS (presented values are those subjects from the PKS with evaluable observations for this endpoint)
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| 20 mg Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.00 hours |
| 60 mg Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.03 hours |
| 200 mg Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.03 hours |
| 600 mg Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.10 hours |
| 1.2 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.967 hours |
| 2 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.984 hours |
| 3 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.00 hours |
| 4 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.06 hours |
| 6 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.03 hours |
| 8 g Idarucizumab 1h | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 1.08 hours |
| 1 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.117 hours |
| 2 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.142 hours |
| 4 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.167 hours |
| DE+ 1 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.117 hours |
| DE+ 2 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.200 hours |
| DE+ 4 g Idarucizumab 5min | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.117 hours |
| DE+ 5 g + 2.5 g Idarucizumab | Tmax (Time From Dosing to Maximum Measured Concentration) for Idarucizumab | 0.117 hours |