Hemorrhage
Conditions
Brief summary
To investigate safety, tolerability, PK and PD of BI 655075 and to establish the BI 655075 dose(s) effective to reverse prolongation of blood coagulation time by dabigatran
Interventions
DRUGBI 655075
DRUGPlacebo
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
45 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy midage male and female volunteers, age =45 and =64 years, BMI range: =18.5 and =29.9 kg/m2 * Healthy elderly male and female volunteers, age =65 and =80 years, BMI range: =18.5 and = 32 kg/m2 * Male and female volunteers with mild renal impairment (CLcrd 60-90 (mL/min)) in relatively good health, age =45 and =80 years, BMI range: =18.5 and =32 kg/m2 Moderate renal impaired (CLcrd =30 to \<60 mL/min according Cockcroft&Gault formula in relatively good health, age =45 and =80 years, BMI range: =18.5 and =32 kg/m2
Exclusion criteria
* Any finding of the medical examination (including BP, PR and ECG) deviating from normal and of clinical relevance * Any evidence of a clinically relevant concomitant disease (other than mild renal impairment in the respective group) A significant disease is defined as a disease which in the opinion of the investigator * put the volunteer at risk because of participation in the study * may influence the results of the study * may influence the volunteer¿s ability to participate in the study * is not in a stable condition Diabetic, hypercholesterolemia or hypertensive subjects can be entered in this trial if the disease is not significant according to these criteria * Surgery of the gastrointestinal tract (except appendectomy) * Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or neurological disorders * History of relevant orthostatic hypotension, fainting spells or blackouts. * Chronic or relevant acute infections * History of relevant allergy/hypersensitivity (including allergy to drug or its excipients)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | End of last infusion and 10 minutes after completion of last infusion of BI 655075 | Percentage of subjects with at least one assay value from diluted thrombin time (dTT) or ecarin clotting time (ECT) reversed within 10min after completion of infusion. Reversal was defined as return to baseline, where the threshold for reversal to baseline was determined using PK/PD correlation between unbound sum dabigatran and the clotting parameters ECT and dTT. Measured at the end of the infusion and 10 min later. |
| The Percentage of Subjects With Drug-related Adverse Events | From baseline up to the start of follow-up period (from Day 1 to Day 35) | The percentage of subjects with possibly drug-related AEs (as defined by the investigator) during the treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | From 0 to 74h post of last DE dose (details in description) | Urinary excretion of sum dabigatran from the time point t1 to t2 at steady state. PK Urine sampling time: Urine sampling relative to first DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h. Ae0-26,ss was not measured in Period 3 (re-exposure period). Ae0-74,ss was not measured in healthy subjects aged 45 to 64 years. |
| AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | From Day 4 to Day 9 (details in description) | AUC0-infinity. PK/PD sampling time: (p=predose, D=day) 1. single medium or high dose, healthy subjects(HS) mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00. 2. single low or high dose, HS elderly or mild renal impaired: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8: 9:00;D9: 9:00. 3. high 2 doses, moderate renal impaired: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8:9:00; D9:9:00. |
| Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | from 0 to 6 hours of post Ida dose (details in description) | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time point 6 h). PK Urine sampling time: Urine sampling relative to DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h. |
| Cmax (Maximum Measured Concentration of the Ida in Plasma) | From Ida administration to 4 days post dose (details in description) | Cmax. PK/PD sampling time: (p=predose, D=day) 1. single medium or high dose, HS mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00. 2. single low or high dose, healthy elderly or mild RI: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8: 9:00;D9: 9:00. 3. high 2 doses, moderate RI: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8:9:00; D9:9:00. |
| AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | from 2h to12h of post DE dose at steady state (details in description) | PK/PD sampling time:(d=dose,D=Day,p=predose) 1. single medium or high dose,healthy, mid-age (45-64 yrs): D4: 7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00, 01:00; D5:9:00p,11:00,21:00p; D6:9:00p, 21:00p; D7:9:00p, 11:00. 2. single low or high dose,healthy elder or mild renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00;D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00. 3. high 2 doses, moderate renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,9:55p,10:00,10:10,10:30,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00; D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00. |
Countries
Belgium
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Total Subjects Group The total subjects group contains the following sub-groups: high dose (5 g idarucizumab), healthy, aged 45-64 yrs: high dose (5 g idarucizumab), healthy elderly, aged 65-80 yrs: high dose (5 g idarucizumab), mild renal impairment (RI), aged 45-80 yrs: high dose (2.5 g + 2.5 g idarucizumab), with moderate RI, aged 45-80 yrs: medium dose (2.5 g idarucizumab), healthy, aged 45-64 yrs: low dose (1 g idarucizumab), healthy elderly, aged 65-80 yrs: low dose (1 g idarucizumab), with mild RI, aged 45-80 yrs. | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Total Subjects Group |
|---|---|
| Age, Continuous | 63.8 years STANDARD_DEVIATION 9.2 |
| Sex: Female, Male Female | 19 Participants |
| Sex: Female, Male Male | 27 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 13 / 46 | 4 / 14 | 1 / 12 | 2 / 26 | 3 / 14 | 3 / 12 | 0 / 26 |
| serious Total, serious adverse events | 0 / 46 | 0 / 14 | 0 / 12 | 0 / 26 | 0 / 14 | 0 / 12 | 0 / 26 |
Outcome results
Primary
Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time
Percentage of subjects with at least one assay value from diluted thrombin time (dTT) or ecarin clotting time (ECT) reversed within 10min after completion of infusion. Reversal was defined as return to baseline, where the threshold for reversal to baseline was determined using PK/PD correlation between unbound sum dabigatran and the clotting parameters ECT and dTT. Measured at the end of the infusion and 10 min later.
Time frame: End of last infusion and 10 minutes after completion of last infusion of BI 655075
Population: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | at least one time point, dTT | 0.0 percentage of participants |
| Placebo | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | both time points, dTT | 0.0 percentage of participants |
| Placebo | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | at least one time point, ECT | 0.0 percentage of participants |
| Placebo | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | both time points, ECT | 0.0 percentage of participants |
| Idarucizumab (Ida) | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | both time points, ECT | 100.0 percentage of participants |
| Idarucizumab (Ida) | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | at least one time point, dTT | 100.0 percentage of participants |
| Idarucizumab (Ida) | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | at least one time point, ECT | 100.0 percentage of participants |
| Idarucizumab (Ida) | Reversal of Dabigatran-induced Prolongation of Blood Coagulation Time | both time points, dTT | 100.0 percentage of participants |
Primary
The Percentage of Subjects With Drug-related Adverse Events
The percentage of subjects with possibly drug-related AEs (as defined by the investigator) during the treatment period.
Time frame: From baseline up to the start of follow-up period (from Day 1 to Day 35)
Population: Treated Set (TS): All randomised subjects who received at least 1 dose of trial medication were included in the treated set.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Percentage of Subjects With Drug-related Adverse Events | 13.0 percentage of participants |
Secondary
Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h)
Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time point 6 h). PK Urine sampling time: Urine sampling relative to DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h.
Time frame: from 0 to 6 hours of post Ida dose (details in description)
Population: PKS-Ida: The PKS-Ida included all treated subjects who have received at least 1 dose of idarucizumab and who provided data for at least 1 secondary or other PK endpoint in any treatment period, which was judged as evaluable for PK and was not affected by (important) protocol violations relevant to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 13.5 umol | Geometric Coefficient of Variation 32.6 |
| 220 mg/5 g HS 45-64 Yrs | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 33.5 umol | Geometric Coefficient of Variation 60 |
| 220 mg/1 g HS 65-80 Yrs | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 1.97 umol | Geometric Coefficient of Variation 69 |
| 220 mg/5 g HS 65-80 Yrs | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 41.6 umol | Geometric Coefficient of Variation 13.7 |
| 150 mg/1 g Mild Renal Impairment (RI) | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 2.60 umol | Geometric Coefficient of Variation 46.7 |
| 150 mg/5 g Mild RI (CL 60-90) | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 33.4 umol | Geometric Coefficient of Variation 48.9 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | Ae0-6 (Amount of Ida Eliminated in Urine From the Time Point 0 to Time Point 6 h) | 31.3 umol | Geometric Coefficient of Variation 89 |
Secondary
Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2)
Urinary excretion of sum dabigatran from the time point t1 to t2 at steady state. PK Urine sampling time: Urine sampling relative to first DE administration: Planned times 72:00 - 73:55h, 73:55 - 80:00h, 80:00 - 86:00h, 86:00 - 98:00h, 98:00 - 122:00h, 122:00 - 146:00h; additional sampling for renal impaired: 146:00 - 170:00; 170:00 - 194:00h. Ae0-26,ss was not measured in Period 3 (re-exposure period). Ae0-74,ss was not measured in healthy subjects aged 45 to 64 years.
Time frame: From 0 to 74h post of last DE dose (details in description)
Population: Pharmacokinetic Set - DE (PKS-DE): The PKS-DE included all treated subjects who have received at least 1 dose of DE and who provided data for at least 1 secondary or further PK endpoint in any treatment period, which was judged as evaluable for PK and was not affected by protocol violations relevant to the statistical evaluation of PK endpoints.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 6080 μg | Geometric Coefficient of Variation 26.5 |
| Placebo | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | NA μg | — |
| Idarucizumab (Ida) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 7460 μg | Geometric Coefficient of Variation 21 |
| Idarucizumab (Ida) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | NA μg | — |
| 220 mg/1 g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 7560 μg | Geometric Coefficient of Variation 47.2 |
| 220 mg/1 g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | NA μg | — |
| 220 mg/5 g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 7790 μg | Geometric Coefficient of Variation 43.9 |
| 220 mg/5 g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | NA μg | — |
| 150 mg/1 g Mild Renal Impairment (RI) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 8490 μg | Geometric Coefficient of Variation 29.4 |
| 150 mg/1 g Mild Renal Impairment (RI) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 10700 μg | Geometric Coefficient of Variation 22 |
| 150 mg/5 g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 10300 μg | Geometric Coefficient of Variation 40.8 |
| 150 mg/5 g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 8870 μg | Geometric Coefficient of Variation 41.8 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 13900 μg | Geometric Coefficient of Variation 26.1 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 7460 μg | Geometric Coefficient of Variation 39.6 |
| 220 mg/Plc. 5g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 10600 μg | Geometric Coefficient of Variation 21.9 |
| 220 mg/Plc. 5g HS 65-80 Yrs | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 12800 μg | Geometric Coefficient of Variation 20.6 |
| 150 mg/1g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 5800 μg | Geometric Coefficient of Variation 39 |
| 150 mg/1g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 7760 μg | Geometric Coefficient of Variation 38.8 |
| 150 mg/Plc. 1g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 7170 μg | Geometric Coefficient of Variation 45.8 |
| 150 mg/Plc. 1g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 6040 μg | Geometric Coefficient of Variation 44.7 |
| 150 mg/5g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 9730 μg | Geometric Coefficient of Variation 35.3 |
| 150 mg/5g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 4020 μg | Geometric Coefficient of Variation 58.3 |
| 150 mg/Plc. 5g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 6280 μg | Geometric Coefficient of Variation 38.4 |
| 150 mg/Plc. 5g Mild RI (CL 60-90) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 7690 μg | Geometric Coefficient of Variation 39.1 |
| 150 mg /2*2.5g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 4760 μg | Geometric Coefficient of Variation 26.7 |
| 150 mg /2*2.5g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 11100 μg | Geometric Coefficient of Variation 24.5 |
| 150 mg /Plc. 2*2.5g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-74,ss(N=0,0,0,0,0,8,8,8,8,6,6,6,6,6,6) | 10800 μg | Geometric Coefficient of Variation 30.4 |
| 150 mg /Plc. 2*2.5g Moderate RI (CL 30-60) | Aet1-t2, ss (Amount of DE Eliminated in Urine From the Time Point t1 to Time Point t2) | Ae0-26,ss(N=6,6,0,6,6,8,8,8,8,6,6,6,6,6,6) | 8880 μg | Geometric Coefficient of Variation 29.8 |
Secondary
AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity)
AUC0-infinity. PK/PD sampling time: (p=predose, D=day) 1. single medium or high dose, healthy subjects(HS) mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00. 2. single low or high dose, HS elderly or mild renal impaired: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8: 9:00;D9: 9:00. 3. high 2 doses, moderate renal impaired: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for renal impaired: D8:9:00; D9:9:00.
Time frame: From Day 4 to Day 9 (details in description)
Population: Pharmacokinetic Set -Ida (PKS-Ida): included all treated subjects who have received at least 1 dose of idarucizumab and who provided data for at least 1 secondary or other PK endpoint in any treatment period, which was judged as evaluable for PK and was not affected by protocol violations relevant to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 22200 nmol*h/L | Geometric Coefficient of Variation 12.7 |
| Idarucizumab (Ida) | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 20600 nmol*h/L | Geometric Coefficient of Variation 10.6 |
| 220 mg/5 g HS 45-64 Yrs | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 37000 nmol*h/L | Geometric Coefficient of Variation 18.4 |
| 220 mg/1 g HS 65-80 Yrs | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 8560 nmol*h/L | Geometric Coefficient of Variation 15.2 |
| 220 mg/5 g HS 65-80 Yrs | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 43900 nmol*h/L | Geometric Coefficient of Variation 18.7 |
| 150 mg/1 g Mild Renal Impairment (RI) | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 10700 nmol*h/L | Geometric Coefficient of Variation 14.1 |
| 150 mg/5 g Mild RI (CL 60-90) | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 53100 nmol*h/L | Geometric Coefficient of Variation 11.1 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | AUC0-infinity (Area Under the Concentration-time Curve of Idarucizumab (Ida) in Plasma Over the Time Interval From 0 Extrapolated to Infinity) | 67900 nmol*h/L | Geometric Coefficient of Variation 11.6 |
Secondary
AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h)
PK/PD sampling time:(d=dose,D=Day,p=predose) 1. single medium or high dose,healthy, mid-age (45-64 yrs): D4: 7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00, 01:00; D5:9:00p,11:00,21:00p; D6:9:00p, 21:00p; D7:9:00p, 11:00. 2. single low or high dose,healthy elder or mild renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00;D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00. 3. high 2 doses, moderate renal impaired: D4:7:00p,8:55p,9:00,9:10,9:30,9:55p,10:00,10:10,10:30,11:00,13:00,15:00,19:00,21:00,01:00;D5:9:00;D6:9:00; D7:9:00; additional sampling for renal impaired: D8:9:00;D9:9:00.
Time frame: from 2h to12h of post DE dose at steady state (details in description)
Population: PKS-DE: The PKS-DE included all treated subjects who have received at least 1 dose of DE and who provided data for at least 1 secondary or further PK endpoint in any treatment period, which was judged as evaluable for PK and was not affected by (important) protocol violations relevant to the statistical evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 18.5 ng*h/mL | Geometric Coefficient of Variation 75.7 |
| Idarucizumab (Ida) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 924 ng*h/mL | Geometric Coefficient of Variation 25.6 |
| 220 mg/5 g HS 45-64 Yrs | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 36.0 ng*h/mL | Geometric Coefficient of Variation 125 |
| 220 mg/1 g HS 65-80 Yrs | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 10.6 ng*h/mL | Geometric Coefficient of Variation 11.3 |
| 220 mg/5 g HS 65-80 Yrs | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 933 ng*h/mL | Geometric Coefficient of Variation 39.2 |
| 150 mg/1 g Mild Renal Impairment (RI) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 284 ng*h/mL | Geometric Coefficient of Variation 66.3 |
| 150 mg/5 g Mild RI (CL 60-90) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 1220 ng*h/mL | Geometric Coefficient of Variation 40 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 11.6 ng*h/mL | Geometric Coefficient of Variation 23.8 |
| 220 mg/Plc. 5g HS 65-80 Yrs | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 1270 ng*h/mL | Geometric Coefficient of Variation 32.8 |
| 150 mg/1g Mild RI (CL 60-90) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 100 ng*h/mL | Geometric Coefficient of Variation 192 |
| 150 mg/Plc. 1g Mild RI (CL 60-90) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 929 ng*h/mL | Geometric Coefficient of Variation 56 |
| 150 mg/5g Mild RI (CL 60-90) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 10.0 ng*h/mL | Geometric Coefficient of Variation 0.0828 |
| 150 mg/Plc. 5g Mild RI (CL 60-90) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 876 ng*h/mL | Geometric Coefficient of Variation 40.5 |
| 150 mg /2*2.5g Moderate RI (CL 30-60) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 10.2 ng*h/mL | Geometric Coefficient of Variation 3.95 |
| 150 mg /Plc. 2*2.5g Moderate RI (CL 30-60) | AUC2-12, ss (Area Under the Concentration-time Curve of Unbound Sum Dabigatran (DE) in Plasma at Steady State Over the Time Interval From 2 to 12h) | 1440 ng*h/mL | Geometric Coefficient of Variation 32.3 |
Secondary
Cmax (Maximum Measured Concentration of the Ida in Plasma)
Cmax. PK/PD sampling time: (p=predose, D=day) 1. single medium or high dose, HS mid-age (45-64 yrs): D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00p, 21:00. D6: 9:00. 2. single low or high dose, healthy elderly or mild RI: D4: 8:55p, 9:00,9:10,9:30,10:00,11:00,13:00,15:00,19:00,21:00,01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8: 9:00;D9: 9:00. 3. high 2 doses, moderate RI: D4: 8:55p, 9:00, 9:10,9:30,9:55p, 10:00,10:10,10:30,11:00, 13:00, 15:00, 19:00, 21:00, 01:00; D5: 9:00; D6: 9:00; D7: 9:00; additional sampling for RI: D8:9:00; D9:9:00.
Time frame: From Ida administration to 4 days post dose (details in description)
Population: PKS-Ida
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 15700 nmol/L | Geometric Coefficient of Variation 14.3 |
| Idarucizumab (Ida) | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 14900 nmol/L | Geometric Coefficient of Variation 12 |
| 220 mg/5 g HS 45-64 Yrs | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 25000 nmol/L | Geometric Coefficient of Variation 16.9 |
| 220 mg/1 g HS 65-80 Yrs | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 5790 nmol/L | Geometric Coefficient of Variation 16.4 |
| 220 mg/5 g HS 65-80 Yrs | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 28300 nmol/L | Geometric Coefficient of Variation 28.9 |
| 150 mg/1 g Mild Renal Impairment (RI) | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 6940 nmol/L | Geometric Coefficient of Variation 19.4 |
| 150 mg/5 g Mild RI (CL 60-90) | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 32100 nmol/L | Geometric Coefficient of Variation 17.4 |
| 150 mg /2*2.5 g Moderate RI (CL 30-60) | Cmax (Maximum Measured Concentration of the Ida in Plasma) | 25600 nmol/L | Geometric Coefficient of Variation 11.6 |