Cardiovascular Diseases, Kidney Failure, Chronic
Conditions
Brief summary
The current study will allow the assessment of pharmacokinetics, pharmacodynamics, elimination rate and clearance of dabigatran etexilate during and following haemodialysis in ESRD patients.
Interventions
DRUGDabigatran etexilate
150 mg capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
21 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* End stage renally disease (ESRD), undergoing haemodialysis * ESRD patients in relatively good health * Age 21 - 60 years inclusive * Signed and dated written informed consent prior to admission to the study
Exclusion criteria
* Clinically relevant laboratory or physical examination abnormalities (except for renal function tests or deviation of clinical laboratory values) that are related to renal impairment * Moderate and severe concurrent liver function impairment * Surgery of gastrointestinal tract (except appendectomy or herniotomy) or evidence of significant gastrointestinal motility problems * Recent or contemplated diagnostic or therapeutic procedures with potential for uncontrollable bleeding * Intake of medication, which influences the blood clotting * Subjects not able to understand and comply with protocol requirements, instructions and protocol-stated restrictions * For women with childbearing potential: no reliable contraception * Participation in another trial with an investigational drug (\<2 months prior to administration or during trial) * Scheduled to receive a donor kidney transplant during the course of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dialysis Clearance of Dabigatran | 4 hours | Dialysis clearance of dabigatran from blood (CLD,b) and dialysis clearance of dabigatran from plasma (CLD) were calculated and indicate how quickly dabigatran is cleared out from blood or plasma. |
| Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis | 4 hours | Extent of dabigatran that is removed from blood during one complete 4-hour cycle of dialysis was computed by the difference of plasma concentration at the start and at the end of dialysis relative to the start concentration and is therefore measured as a percentage. |
| Plasma Concentration Extraction Ratio | 4 hours | Plasma concentration extraction ratio was measured directly at the dialysis machine and computed as the difference of the predialysis plasma concentration and the postdialysis plasma concentration relative to the predialysis concentration on the percentage scale (minimum: 0 percent of extraction (worst), maximum: 100 percent of extraction). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Coagulation Parameters | Day 3 | Assessment of blood coagulation parameters 'activated partial thromboplastin time' (aPTT) and 'factor IIa inhibition' (anti-FIIa) measured with the diluted thrombin time assay. Time to the formation of a fibrin clot (coagulation) is measured in seconds. |
| Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Days 2 and 3 | Area under the concentration-time curve of total and free dabigatran in plasma over the time interval from 0 to 8 hours after the second and third administration of dabigatran. |
| Additional Safety Parameters | 2 periods of 5 days each | By study design abnormalities could be due to dialysis or Dabigatran. |
| Safety and Tolerability | 2 periods of 5 days each | Tolerability refers to the number of non-tolerable patients as assessed through the subjective examination of adverse events (AE). Safety refers to the number of patients with treatment emergent AEs. These numbers are presented on the overall Dabigatran treatment. |
| Maximum Plasma Concentrations of Dabigatran (Cmax) | Days 2 and 3 | Maximum measured concentration of total and free dabigatran in plasma after the second and third administration of dabigatran. |
| Time to Maximum Plasma Concentration (Tmax) | Day 3 | Time to maximum plasma concentration of total and free dabigatran in plasma after the third administration of dabigatran. |
Countries
Germany
Participant flow
Pre-assignment details
This was an open-label, 2-period, fixed-sequence, multiple dose trial. On Day 1, all patients were treated with Dabigatran 150 mg, on day 2, with 110 mg at 10:00, and on day 3, 75 mg 8 h before dialysis. The target blood flow rate on day 3 of period 1 was 200mL/min, whilst that in period 2 was 400mL/min.
Participants by arm
| Arm | Count |
|---|---|
| Dabigatran Dabigatran treated patients | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Dabigatran |
|---|---|
| Age, Continuous | 38.3 Years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 7 |
| serious Total, serious adverse events | 0 / 7 |
Outcome results
Primary
Dialysis Clearance of Dabigatran
Dialysis clearance of dabigatran from blood (CLD,b) and dialysis clearance of dabigatran from plasma (CLD) were calculated and indicate how quickly dabigatran is cleared out from blood or plasma.
Time frame: 4 hours
Population: Pharmacokinetic set (PKS) includes all evaluable patients of the treated set who received at least one dose of dabigatran etexilate and who provide at least one observation for at least one Pharmacokinetic (PK) endpoint without important protocol violations relevant to the evaluation of PK.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Dialysis Clearance of Dabigatran | Total dabigatran clearance (CLD,b) from blood | 161 mL/min | Geometric Coefficient of Variation 5.01 |
| Dabigatran P1 | Dialysis Clearance of Dabigatran | Total dabigatran clearance (CLD) from plasma | 120 mL/min | Geometric Coefficient of Variation 5.09 |
| Dabigatran P1 | Dialysis Clearance of Dabigatran | Free dabigatran clearance (CLD,b) from blood | 167 mL/min | Geometric Coefficient of Variation 4.6 |
| Dabigatran P1 | Dialysis Clearance of Dabigatran | Free dabigatran clearance (CLD) from plasma | 124 mL/min | Geometric Coefficient of Variation 4.48 |
| Dabigatran P2 | Dialysis Clearance of Dabigatran | Free dabigatran clearance (CLD) from plasma | 190 mL/min | Geometric Coefficient of Variation 3.68 |
| Dabigatran P2 | Dialysis Clearance of Dabigatran | Total dabigatran clearance (CLD,b) from blood | 241 mL/min | Geometric Coefficient of Variation 3.08 |
| Dabigatran P2 | Dialysis Clearance of Dabigatran | Free dabigatran clearance (CLD,b) from blood | 251 mL/min | Geometric Coefficient of Variation 2.17 |
| Dabigatran P2 | Dialysis Clearance of Dabigatran | Total dabigatran clearance (CLD) from plasma | 183 mL/min | Geometric Coefficient of Variation 4.3 |
Primary
Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis
Extent of dabigatran that is removed from blood during one complete 4-hour cycle of dialysis was computed by the difference of plasma concentration at the start and at the end of dialysis relative to the start concentration and is therefore measured as a percentage.
Time frame: 4 hours
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis | Total Dabigatran | 48.8 Percentage | Geometric Coefficient of Variation 10.9 |
| Dabigatran P1 | Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis | Free Dabigatran | 49.7 Percentage | Geometric Coefficient of Variation 9.1 |
| Dabigatran P2 | Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis | Total Dabigatran | 59.3 Percentage | Geometric Coefficient of Variation 6.69 |
| Dabigatran P2 | Extent Cleared From Circulation (Plasma) During 1 Complete Cycle of Dialysis | Free Dabigatran | 59.3 Percentage | Geometric Coefficient of Variation 6.13 |
Primary
Plasma Concentration Extraction Ratio
Plasma concentration extraction ratio was measured directly at the dialysis machine and computed as the difference of the predialysis plasma concentration and the postdialysis plasma concentration relative to the predialysis concentration on the percentage scale (minimum: 0 percent of extraction (worst), maximum: 100 percent of extraction).
Time frame: 4 hours
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Plasma Concentration Extraction Ratio | Total Dabigatran | 79.9 Percentage | Geometric Coefficient of Variation 9.01 |
| Dabigatran P1 | Plasma Concentration Extraction Ratio | Free Dabigatran | 82.6 Percentage | Geometric Coefficient of Variation 8.21 |
| Dabigatran P2 | Plasma Concentration Extraction Ratio | Total Dabigatran | 61.4 Percentage | Geometric Coefficient of Variation 9.54 |
| Dabigatran P2 | Plasma Concentration Extraction Ratio | Free Dabigatran | 63.7 Percentage | Geometric Coefficient of Variation 8.6 |
Secondary
Additional Safety Parameters
By study design abnormalities could be due to dialysis or Dabigatran.
Time frame: 2 periods of 5 days each
Population: TS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran P1 | Additional Safety Parameters | Electrocardiogram (ECG) abnormalities | 0 Participants |
| Dabigatran P1 | Additional Safety Parameters | Vital sign abnormalities | 0 Participants |
| Dabigatran P1 | Additional Safety Parameters | Physical finding abnormalities | 0 Participants |
| Dabigatran P1 | Additional Safety Parameters | Laboratory abnormalities: Haematology | 0 Participants |
| Dabigatran P1 | Additional Safety Parameters | Laboratory abnormalities: Clinical chemistry | 0 Participants |
Secondary
Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h)
Area under the concentration-time curve of total and free dabigatran in plasma over the time interval from 0 to 8 hours after the second and third administration of dabigatran.
Time frame: Days 2 and 3
Population: Pharmacokinetic set (PKS) includes all evaluable patients of the TS who received at least 1 dose of dabigatran etexilate, who provided at least 1 observation for at least 1 Pharmacokinetics (PK) endpoint, and who did not have important protocol violations relevant to the evaluation of PK
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Total Dabigatran on Day 2 | 1230 ng*hr/mL | Geometric Coefficient of Variation 57.1 |
| Dabigatran P1 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Total Dabigatran on Day 3 | 1280 ng*hr/mL | Geometric Coefficient of Variation 54.4 |
| Dabigatran P1 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Free Dabigatran on Day 2 | 907 ng*hr/mL | Geometric Coefficient of Variation 51.6 |
| Dabigatran P1 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Free Dabigatran on Day 3 | 839 ng*hr/mL | Geometric Coefficient of Variation 41.3 |
| Dabigatran P2 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Free Dabigatran on Day 3 | 752 ng*hr/mL | Geometric Coefficient of Variation 58 |
| Dabigatran P2 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Total Dabigatran on Day 2 | 1140 ng*hr/mL | Geometric Coefficient of Variation 39.4 |
| Dabigatran P2 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Free Dabigatran on Day 2 | 802 ng*hr/mL | Geometric Coefficient of Variation 44.1 |
| Dabigatran P2 | Area Under the Curve Exposure to Dabigatran During the First 8 Hours Post Dose (AUC0-8h) | Total Dabigatran on Day 3 | 1180 ng*hr/mL | Geometric Coefficient of Variation 50.2 |
Secondary
Coagulation Parameters
Assessment of blood coagulation parameters 'activated partial thromboplastin time' (aPTT) and 'factor IIa inhibition' (anti-FIIa) measured with the diluted thrombin time assay. Time to the formation of a fibrin clot (coagulation) is measured in seconds.
Time frame: Day 3
Population: TS
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Coagulation Parameters | Activated partial thromboplastin time (aPTT) | 46.91 sec | Standard Deviation 12.22 |
| Dabigatran P1 | Coagulation Parameters | Factor IIa inhibition (anti-FIIa) | 43.27 sec | Standard Deviation 7.99 |
| Dabigatran P2 | Coagulation Parameters | Activated partial thromboplastin time (aPTT) | 44.26 sec | Standard Deviation 10.98 |
| Dabigatran P2 | Coagulation Parameters | Factor IIa inhibition (anti-FIIa) | 43.09 sec | Standard Deviation 5.38 |
Secondary
Maximum Plasma Concentrations of Dabigatran (Cmax)
Maximum measured concentration of total and free dabigatran in plasma after the second and third administration of dabigatran.
Time frame: Days 2 and 3
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Total Dabigatran on Day 2 | 194 ng/mL | Geometric Coefficient of Variation 53.1 |
| Dabigatran P1 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Total Dabigatran on Day 3 | 176 ng/mL | Geometric Coefficient of Variation 54.1 |
| Dabigatran P1 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Free Dabigatran on Day 2 | 150 ng/mL | Geometric Coefficient of Variation 47.3 |
| Dabigatran P1 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Free Dabigatran on Day 3 | 119 ng/mL | Geometric Coefficient of Variation 43.7 |
| Dabigatran P2 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Free Dabigatran on Day 3 | 105 ng/mL | Geometric Coefficient of Variation 57.3 |
| Dabigatran P2 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Total Dabigatran on Day 2 | 171 ng/mL | Geometric Coefficient of Variation 36.2 |
| Dabigatran P2 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Free Dabigatran on Day 2 | 126 ng/mL | Geometric Coefficient of Variation 38.1 |
| Dabigatran P2 | Maximum Plasma Concentrations of Dabigatran (Cmax) | Total Dabigatran on Day 3 | 159 ng/mL | Geometric Coefficient of Variation 50.2 |
Secondary
Safety and Tolerability
Tolerability refers to the number of non-tolerable patients as assessed through the subjective examination of adverse events (AE). Safety refers to the number of patients with treatment emergent AEs. These numbers are presented on the overall Dabigatran treatment.
Time frame: 2 periods of 5 days each
Population: TS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Dabigatran P1 | Safety and Tolerability | Treatment emergent adverse events | 2 Participants |
| Dabigatran P1 | Safety and Tolerability | Assessment of tolerability by the investigator | 0 Participants |
Secondary
Time to Maximum Plasma Concentration (Tmax)
Time to maximum plasma concentration of total and free dabigatran in plasma after the third administration of dabigatran.
Time frame: Day 3
Population: PKS
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dabigatran P1 | Time to Maximum Plasma Concentration (Tmax) | Total Dabigatran | 1.49 h | Geometric Coefficient of Variation 38.4 |
| Dabigatran P1 | Time to Maximum Plasma Concentration (Tmax) | Free Dabigatran | 1.35 h | Geometric Coefficient of Variation 38.4 |
| Dabigatran P2 | Time to Maximum Plasma Concentration (Tmax) | Total Dabigatran | 2.13 h | Geometric Coefficient of Variation 74.1 |
| Dabigatran P2 | Time to Maximum Plasma Concentration (Tmax) | Free Dabigatran | 1.83 h | Geometric Coefficient of Variation 27.3 |