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
DRUGPlacebo to dose
placebo
DRUGIdarucizumab
short infusion
DRUGPlacebo to Idarucizumab
Placebo to Idarucizumab
DRUGdabigatran
2 capsules dabigatran
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
20 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
1\. Healthy Japanese male subjects
Exclusion criteria
1\. Any relevant deviation from healthy conditions
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | From first drug administration until 13 weeks after the last drug administration, upto 98 days (Part-I) & upto 108 days (Part-II) | Percentage of subjects with drug-related adverse events in Part 1 and Part 2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 (Part I) and Day 11 (Part II). Time frame are provided in detail in the Description section | Area under the concentration-time curve of the dabigatran in plasma at steady state over the time interval 2 hours-12 hours. Time Frame: For dose group 5 to 7 (Day 1 to 3-Part-I):74hours (h), 74.5h, 75h, 76h, 78h, 80h, 82h, 84h, For dose group 8 (Day 1 to 3-Part-I): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h and For dose group 5-7 (Day11 to Day13-Part II):242h, 242.167h, 242.5h, 243h, 244h,246h, 248h, 250h, 252h. For dose group 8 (Day11 to Day13-Part II):242h, 242.083h, 242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h. |
| Cmax for Idarucizumab in the Part I & Part II. | Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section | Maximum measured concentration of the analyte in plasma for idarucizumab Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h. |
| AUC0-inf for Idarucizumab in the Part I & Part II. | Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section | Area under the concentration-time curve of the analyte in plasma for idarucizumab over the time interval from 0 extrapolated to infinity. Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h. |
| Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | 0-2 h, 2-6 h, 6-10 h, 10-12 h,12-14h, 14-26 h, 26-50 h, 50-74 h after drug administration of dabigatran etexilate on Day 4 and Day 11. | Amount of analyte eliminated in urine at steady state from the time point 0 hours to time point 74 hours. |
| Ae0-73 for the Dose Group 4 in the Part I | For dose group 4 (day1 to day4-Part-1): 0-7h, 7-13h, 13-25h, 25-49h, 49-73h | Amount of the analyte excreted in urine over the time interval 0-73 |
| AUEC2-12 | Day 4 and Day 11 (Part II); Time frame are provided in detail in the Description section | Area under the effect curve over the time interval from 2 to 12h, AUEC2-12 on Days 4 and 11 for diluted thrombin time (dTT). For dose groups 5 to 7(day4-Part-II): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h on day 4. For dose groups 5 to 7(day11-Part-II): 242h, 242.083h, 242.167h, 242.5h, 243h, 244h, 246h, 248h, 250h, 252h. For dose groups 8(day4-Part-II): 74.5 h, 78 h, 84 h on day 4. For dose groups 8(day11-Part-II): 242h, 242.083h,242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h on day 11. AUEC is calculated by multiplying the ratio (Value at each time point/Ebase, unit of Vaue is \[s\] and Ebase is value \[s\] at baseline) by time. Therefore, Unit for AUEC2-12 is \[h\]. |
| Ae0-72 for Idarucizumab in the Part I & Part II. | Day 1 to 4 (Part I) and Day 11 to 14 (Part II); Time frame are provided in detail in the Description section | Amount of idarucizumab eliminated in urine over the time interval 0-72. Time frame: For dose groups 1 to 3 (day1 to day4-Part-1):0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-72 h. For dose groups 5 to 7 (day 11 to day14-Part-II): 0-4 h, 4-8 h, 8-10 h, 10-12 h,12-24 h, 24-48 h, and 48-72 h. For dose groups 8 (day11 to day14-Part-II): 0-4h, 4-8 h, 8-10 h, 10-24 h, 24-48 h, 48-72 h. |
Countries
Japan
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Placebo_5m (Part I) Subject received a single intravenous infusion of matching placebo to idarucizumab once daily for 5min on Day 1. | 6 |
| Placebo_1h (Part I) Subject received a single intravenous infusion of matching placebo to idarucizumab once daily for 1h (hour) on Day 1. | 2 |
| BI1000mg_5m (Dose group1 - Part I) Subject received a single intravenous infusion of idarucizumab 1000mg for 5min on Day 1. | 6 |
| BI2000mg_5m (Dose group2 - Part I) Subject received a single intravenous infusion of idarucizumab 2000mg for 5min on Day 1. | 6 |
| BI4000mg_5m (Dose group3 - Part I) Subject received a single intravenous infusion of idarucizumab 4000mg for 5min on Day 1. | 6 |
| BI8000mg_1h (Dose group4 - Part I) Subject received a single intravenous infusion of idarucizumab 8000mg for 1h on Day 1. | 6 |
| DE+Placebo_5m (Part II) Subject received a multiple oral doses of dabigatran etexilate 220 mg twice daily(b.i.d.) from Days 1 to 3 and once daily(q.d)on Day 4 and from Days 8 to 10 and once daily(q.d)on Day 11,followed with a single intravenous infusion of matching placebo to idarucizumab for 5min, approximately 2h after the last dose of dabigatran etexilate on Day 11. | 9 |
| DE+Placebo+Placebo (Part II) Subject received multiple oral doses of dabigatran etexilate 220 mg b.i.d. from Days 1 to 3 and q.d on Day 4 and from Days 8 to 10 and q.d on Day 11, followed with a single intravenously infusion of two doses of matching placebo to Idarucizumab for 5 min + 5 min, with a 15 min infusion interval between two doses, approximately 2 h after the last dose of dabigatran etexilate on Day 11. | 3 |
| DE+1000mg_5m (Dose group5 - Part II) Subject received multiple oral doses of dabigatran etexilate 220 mg b.i.d.from Days 1 to 3 and q.d on Day 4 and from Days 8 to 10 and q.d on Day 11, followed with a single intravenously infusion of Idarucizumab 1000 mg for 5 min, approximately 2 h after the last dose of dabigatran etexilate on Day 11. | 9 |
| DE+2000mg_5m (Dose group6 - Part II) Subject received multiple oral doses of dabigatran etexilate 220 mg b.i.d.from Days 1 to 3 and q.d on Day 4 and from Days 8 to 10 and q.d on Day 11, followed with a single intravenously infusion of Idarucizumab 2000 mg for 5 min, approximately 2 h after the last dose of dabigatran etexilate on Day 11. | 9 |
| DE+4000mg_5m (Dose group7 - Part II) Subject received multiple oral doses of dabigatran etexilate 220 mg b.i.d.from Days 1 to 3 and q.d on Day 4 and from Days 8 to 10 and q.d on Day 11, followed with a single intravenously infusion of Idarucizumab 4000 mg for 5 min, approximately 2 h after the last dose of dabigatran etexilate on Day 11. | 9 |
| DE+2500mg+2500mg (Dose group8 - Part II) Subject received multiple oral doses of dabigatran etexilate 220 mg b.i.d.from Days 1 to 3 and q.d on Day 4 and from Days 8 to 10 and q.d on Day 11, followed with intravenously infusion of two doses of Idarucizumab 2500mg+2500mg for 5 min+5 min, with a 15 min infusion interval between two doses, approximately 2 h after the last dose of dabigatran etexilate on Day 11. | 9 |
| Total | 80 |
Baseline characteristics
| Characteristic | 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) | DE+Placebo_5m (Part II) | DE+Placebo+Placebo (Part II) | DE+1000mg_5m (Dose group5 - Part II) | DE+2000mg_5m (Dose group6 - Part II) | DE+4000mg_5m (Dose group7 - Part II) | DE+2500mg+2500mg (Dose group8 - Part II) | Total |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 28.7 Years STANDARD_DEVIATION 10.5 | 32.5 Years STANDARD_DEVIATION 4.9 | 31.5 Years STANDARD_DEVIATION 10.9 | 27.8 Years STANDARD_DEVIATION 7.7 | 31.5 Years STANDARD_DEVIATION 8.3 | 32.2 Years STANDARD_DEVIATION 8.1 | 24.7 Years STANDARD_DEVIATION 3.3 | 29.7 Years STANDARD_DEVIATION 5 | 23.8 Years STANDARD_DEVIATION 3.1 | 25.7 Years STANDARD_DEVIATION 3.1 | 25.4 Years STANDARD_DEVIATION 2.7 | 24.4 Years STANDARD_DEVIATION 1.4 | 27.3 Years STANDARD_DEVIATION 6.4 |
| 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 |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 6 Participants | 6 Participants | 6 Participants | 6 Participants | 9 Participants | 3 Participants | 9 Participants | 9 Participants | 9 Participants | 9 Participants | 80 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 |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 1 / 6 | 0 / 2 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 3 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
| serious Total, serious adverse events | 0 / 6 | 0 / 2 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 6 | 0 / 9 | 0 / 3 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 |
Outcome results
Primary
Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2
Percentage of subjects with drug-related adverse events in Part 1 and Part 2.
Time frame: From first drug administration until 13 weeks after the last drug administration, upto 98 days (Part-I) & upto 108 days (Part-II)
Population: Treated set (TS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo_5m (Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 16.7 Percentage of participants |
| Placebo_1h (Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| BI1000mg_5m (Dose group1 - Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| BI2000mg_5m (Dose group2 - Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| BI4000mg_5m (Dose group3 - Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| BI8000mg_1h (Dose group4 - Part I) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+Placebo_5m (Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+Placebo+Placebo (Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+1000mg_5m (Dose group5 - Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+2000mg_5m (Dose group6 - Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+4000mg_5m (Dose group7 - Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
| DE+2500mg+2500mg (Dose group8 - Part II) | Percentage of Subjects With Drug-related Adverse Events in Part 1 and Part 2 | 0.0 Percentage of participants |
Secondary
Ae0-72 for Idarucizumab in the Part I & Part II.
Amount of idarucizumab eliminated in urine over the time interval 0-72. Time frame: For dose groups 1 to 3 (day1 to day4-Part-1):0-4 h, 4-8 h, 8-12 h, 12-24 h, 24-48 h, 48-72 h. For dose groups 5 to 7 (day 11 to day14-Part-II): 0-4 h, 4-8 h, 8-10 h, 10-12 h,12-24 h, 24-48 h, and 48-72 h. For dose groups 8 (day11 to day14-Part-II): 0-4h, 4-8 h, 8-10 h, 10-24 h, 24-48 h, 48-72 h.
Time frame: Day 1 to 4 (Part I) and Day 11 to 14 (Part II); Time frame are provided in detail in the Description section
Population: PKS set. Ae 0-72 data is not available for BI8000mg\_1h (Dose group 4 - Part I) due to longer infusion time resulting different urine collection interval. Instead, Ae 0-73 is presented for BI8000mg\_1h as separate endpoint.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo_5m (Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 1.54 μmol | Geometric Coefficient of Variation 54.9 |
| Placebo_1h (Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 6.10 μmol | Geometric Coefficient of Variation 165 |
| BI1000mg_5m (Dose group1 - Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 20.5 μmol | Geometric Coefficient of Variation 52.4 |
| BI2000mg_5m (Dose group2 - Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 4.21 μmol | Geometric Coefficient of Variation 35.1 |
| BI4000mg_5m (Dose group3 - Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 13.8 μmol | Geometric Coefficient of Variation 12.5 |
| BI8000mg_1h (Dose group4 - Part I) | Ae0-72 for Idarucizumab in the Part I & Part II. | 42.6 μmol | Geometric Coefficient of Variation 16.4 |
| DE+Placebo_5m (Part II) | Ae0-72 for Idarucizumab in the Part I & Part II. | 51.5 μmol | Geometric Coefficient of Variation 18.1 |
Secondary
Ae0-73 for the Dose Group 4 in the Part I
Amount of the analyte excreted in urine over the time interval 0-73
Time frame: For dose group 4 (day1 to day4-Part-1): 0-7h, 7-13h, 13-25h, 25-49h, 49-73h
Population: PKS set. The results from dose group 4 has been disclosed, because only dose group 4 had 1hr infusion, Ae 0-73 was reported, instead of Ae0-72.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo_5m (Part I) | Ae0-73 for the Dose Group 4 in the Part I | 69.1 μmol | Geometric Coefficient of Variation 25 |
Secondary
Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II)
Amount of analyte eliminated in urine at steady state from the time point 0 hours to time point 74 hours.
Time frame: 0-2 h, 2-6 h, 6-10 h, 10-12 h,12-14h, 14-26 h, 26-50 h, 50-74 h after drug administration of dabigatran etexilate on Day 4 and Day 11.
Population: PKS set: This subject set included all subjects who received the idarucizumab and who had at least one pharmacokinetic parameter. For the Part 2, subjects who had the emesis with onset at or before twice the median tmax of dabigatran were not included in this set.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo_5m (Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 11 | 9690 μg | Geometric Coefficient of Variation 27.7 |
| Placebo_5m (Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 4 | 9250 μg | Geometric Coefficient of Variation 42 |
| Placebo_1h (Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 4 | 12800 μg | Geometric Coefficient of Variation 21.6 |
| Placebo_1h (Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 11 | 12500 μg | Geometric Coefficient of Variation 32 |
| BI1000mg_5m (Dose group1 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 11 | 13100 μg | Geometric Coefficient of Variation 30.1 |
| BI1000mg_5m (Dose group1 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 4 | 11700 μg | Geometric Coefficient of Variation 45.7 |
| BI2000mg_5m (Dose group2 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 4 | 8810 μg | Geometric Coefficient of Variation 33.8 |
| BI2000mg_5m (Dose group2 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 11 | 9310 μg | Geometric Coefficient of Variation 41 |
| BI4000mg_5m (Dose group3 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 4 | 11000 μg | Geometric Coefficient of Variation 32.9 |
| BI4000mg_5m (Dose group3 - Part I) | Ae0-74,ss on Days 4 and 11 for Sum Dabigatran (Part II) | Day 11 | 10600 μg | Geometric Coefficient of Variation 28.1 |
Secondary
AUC0-inf for Idarucizumab in the Part I & Part II.
Area under the concentration-time curve of the analyte in plasma for idarucizumab over the time interval from 0 extrapolated to infinity. Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h.
Time frame: Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo_5m (Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 9150 nmol*h/L | Geometric Coefficient of Variation 15 |
| Placebo_1h (Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 19500 nmol*h/L | Geometric Coefficient of Variation 17.8 |
| BI1000mg_5m (Dose group1 - Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 37600 nmol*h/L | Geometric Coefficient of Variation 14.4 |
| BI2000mg_5m (Dose group2 - Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 76800 nmol*h/L | Geometric Coefficient of Variation 14.8 |
| BI4000mg_5m (Dose group3 - Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 8590 nmol*h/L | Geometric Coefficient of Variation 14.2 |
| BI8000mg_1h (Dose group4 - Part I) | AUC0-inf for Idarucizumab in the Part I & Part II. | 19200 nmol*h/L | Geometric Coefficient of Variation 18.5 |
| DE+Placebo_5m (Part II) | AUC0-inf for Idarucizumab in the Part I & Part II. | 34500 nmol*h/L | Geometric Coefficient of Variation 16.6 |
| DE+Placebo+Placebo (Part II) | AUC0-inf for Idarucizumab in the Part I & Part II. | 43300 nmol*h/L | Geometric Coefficient of Variation 8.25 |
Secondary
AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II).
Area under the concentration-time curve of the dabigatran in plasma at steady state over the time interval 2 hours-12 hours. Time Frame: For dose group 5 to 7 (Day 1 to 3-Part-I):74hours (h), 74.5h, 75h, 76h, 78h, 80h, 82h, 84h, For dose group 8 (Day 1 to 3-Part-I): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h and For dose group 5-7 (Day11 to Day13-Part II):242h, 242.167h, 242.5h, 243h, 244h,246h, 248h, 250h, 252h. For dose group 8 (Day11 to Day13-Part II):242h, 242.083h, 242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h.
Time frame: Day 4 (Part I) and Day 11 (Part II). Time frame are provided in detail in the Description section
Population: PKS set
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo_5m (Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 | 909 ng*h/mL | Geometric Coefficient of Variation 56.2 |
| Placebo_5m (Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 11 | 909 ng*h/mL | Geometric Coefficient of Variation 34.8 |
| Placebo_1h (Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 | 1260 ng*h/mL | Geometric Coefficient of Variation 25 |
| Placebo_1h (Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 11 | 330 ng*h/mL | Geometric Coefficient of Variation 109 |
| BI1000mg_5m (Dose group1 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 | 1010 ng*h/mL | Geometric Coefficient of Variation 54.1 |
| BI1000mg_5m (Dose group1 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 11 | 82.2 ng*h/mL | Geometric Coefficient of Variation 149 |
| BI2000mg_5m (Dose group2 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 11 | 10.1 ng*h/mL | Geometric Coefficient of Variation 1.86 |
| BI2000mg_5m (Dose group2 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 | 802 ng*h/mL | Geometric Coefficient of Variation 46.8 |
| BI4000mg_5m (Dose group3 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 4 | 1100 ng*h/mL | Geometric Coefficient of Variation 25.6 |
| BI4000mg_5m (Dose group3 - Part I) | AUC2-12,ss on Days 4 and 11 for Unbound Sum Dabigatran (Part II). | Day 11 | 10.0 ng*h/mL | Geometric Coefficient of Variation 0.0213 |
Secondary
AUEC2-12
Area under the effect curve over the time interval from 2 to 12h, AUEC2-12 on Days 4 and 11 for diluted thrombin time (dTT). For dose groups 5 to 7(day4-Part-II): 74h, 74.5h, 75h, 76h, 78h, 80h, 82h, 84h on day 4. For dose groups 5 to 7(day11-Part-II): 242h, 242.083h, 242.167h, 242.5h, 243h, 244h, 246h, 248h, 250h, 252h. For dose groups 8(day4-Part-II): 74.5 h, 78 h, 84 h on day 4. For dose groups 8(day11-Part-II): 242h, 242.083h,242.25h, 242.333h, 243.333h, 244h, 246h, 248h, 252h on day 11. AUEC is calculated by multiplying the ratio (Value at each time point/Ebase, unit of Vaue is \[s\] and Ebase is value \[s\] at baseline) by time. Therefore, Unit for AUEC2-12 is \[h\].
Time frame: Day 4 and Day 11 (Part II); Time frame are provided in detail in the Description section
Population: Pharmacodynamic set (PDS): The PDS comprised all subjects in the TS who provided at least 1 evaluable predose and 1 on-treatment pharmacodynamic observation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo_5m (Part I) | AUEC2-12 | Day 11 | 15.8 h | Standard Deviation 1.93 |
| Placebo_5m (Part I) | AUEC2-12 | Day 4 | 16.3 h | Standard Deviation 2.3 |
| Placebo_1h (Part I) | AUEC2-12 | Day 4 | 18.0 h | Standard Deviation 1.79 |
| Placebo_1h (Part I) | AUEC2-12 | Day 11 | 12.5 h | Standard Deviation 1.74 |
| BI1000mg_5m (Dose group1 - Part I) | AUEC2-12 | Day 4 | 17.4 h | Standard Deviation 4 |
| BI1000mg_5m (Dose group1 - Part I) | AUEC2-12 | Day 11 | 11.2 h | Standard Deviation 2.23 |
| BI2000mg_5m (Dose group2 - Part I) | AUEC2-12 | Day 4 | 15.5 h | Standard Deviation 2.17 |
| BI2000mg_5m (Dose group2 - Part I) | AUEC2-12 | Day 11 | 9.95 h | Standard Deviation 0.206 |
| BI4000mg_5m (Dose group3 - Part I) | AUEC2-12 | Day 4 | 17.3 h | Standard Deviation 2.02 |
| BI4000mg_5m (Dose group3 - Part I) | AUEC2-12 | Day 11 | 10.0 h | Standard Deviation 0.131 |
Secondary
Cmax for Idarucizumab in the Part I & Part II.
Maximum measured concentration of the analyte in plasma for idarucizumab Time frame: For dose group 1 to 3 (Day 1 to 3-Part-I): predose, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 6h, 8h, 10h, 12h, 16h, 24h, 48h. For dose group 4 (Day 1 to 3-Part-I): predose, -0.5h, 0 (end of infusion), 0.033h, 0.083h, 0.167h, 0.25h, 0.5h, 0.75h, 1h, 1.5h, 2h, 3h, 4h, 6h, 8h, 12h, 16h, 24h, 48h. For dose group 5-7 (Day11 to Day13-Part II): predose, 242h (end of infusion), 242.033h, 242.083h, 242.167h, 242.25h, 242.5h, 242.75h, 243h, 243.5h, 244h, 244.5h, 245h, 246h, 248h, 250h, 252h, 254h, 258h, 266h, 290h.For dose group 8 (day11 to Day13-Part II): predose, 242h (end of infusion), 242.083h, 242.25h, 242.333h, 242.367h, 242.5h, 242.833h, 243.333h, 244h, 245h, 246h, 248h, 252h, 254h, 266h, 290h, 314h.
Time frame: Day 1 to 3 (Part I) and Day 11 to 13 (Part II); Time frame are provided in detail in the Description section
Population: PKS set
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo_5m (Part I) | Cmax for Idarucizumab in the Part I & Part II. | 6810 nmol/L | Geometric Coefficient of Variation 10.1 |
| Placebo_1h (Part I) | Cmax for Idarucizumab in the Part I & Part II. | 15700 nmol/L | Geometric Coefficient of Variation 10.9 |
| BI1000mg_5m (Dose group1 - Part I) | Cmax for Idarucizumab in the Part I & Part II. | 28100 nmol/L | Geometric Coefficient of Variation 14.3 |
| BI2000mg_5m (Dose group2 - Part I) | Cmax for Idarucizumab in the Part I & Part II. | 37600 nmol/L | Geometric Coefficient of Variation 6.88 |
| BI4000mg_5m (Dose group3 - Part I) | Cmax for Idarucizumab in the Part I & Part II. | 9510 nmol/L | Geometric Coefficient of Variation 33.8 |
| BI8000mg_1h (Dose group4 - Part I) | Cmax for Idarucizumab in the Part I & Part II. | 17600 nmol/L | Geometric Coefficient of Variation 16.8 |
| DE+Placebo_5m (Part II) | Cmax for Idarucizumab in the Part I & Part II. | 30200 nmol/L | Geometric Coefficient of Variation 17.7 |
| DE+Placebo+Placebo (Part II) | Cmax for Idarucizumab in the Part I & Part II. | 30100 nmol/L | Geometric Coefficient of Variation 11.5 |