Arthroplasty, Replacement, Moderate Renal Impairment (CrCl 30-50 mL/Min), Prevention of Venous Thromboembolism
Conditions
Brief summary
To supplement the current evidence of the effect of Pradaxa® (dabigatran etexilate) on coagulation parameters, including a calibrated thrombin time test, in patients with moderate renal impairment undergoing elective total hip- or knee-replacement surgery, this PK/PD study will be conducted.
Interventions
DRUGDabigatran etexilate
once daily approved dose by EMEA and Health Canada
Sponsors
Boehringer Ingelheim
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients scheduled for primary unilateral elective total knee or hip replacement, male or female being 18 years or older 2. Moderate renal impairment (CrCl 30-50 mL/min) 3. Written informed consent 4. Caucasian patients
Exclusion criteria
1. Patients weighing less than 40 kg. 2. Patients requiring chronic treatment with anticoagulants (e.g. vitamin K antagonists; e.g. patients with atrial fibrillation, patients with artificial heart valves, etc.). 3. Patients who in the investigator's judgment were perceived as having an excessive risk of bleeding, for example: Constitutional or acquired coagulation disorders History of bleeding diathesis Clinically relevant bleeding (gastrointestinal, pulmonary, intraocular or urogenital bleeding) within 3 months of enrolment Major surgery or trauma (e.g. hip fracture) within 3 months of enrolment History of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count \<100 000 cells/microliter at randomization Any history of hemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm Any arteriovenous malformations, vascular aneurysms or major intraspinal or intracerebral vascular abnormalities Presence of malignant neoplasms at higher risk of bleeding Known or suspected oesophageal varices Symptomatic or endoscopically documented gastroduodenal ulcer disease in the previous 30 days Treatment with anticoagulants, clopidogrel, ticlopidine, abciximab, aspirin \>162.5 mg/day or non-steroidal anti-inflammatory drug (NSAID) with t1/2\>12 hours within 7 days prior to hip or knee replacement surgery OR anticipated need while the patient was receiving study medication and prior to 24 hours after the last administration of study medication (COX-2 selective inhibitors are allowed) because of anticipated need of quinidine, verapamil or other restricted medication during the treatment period 4. Recent unstable cardiovascular disease (in the investigator's opinion) such as uncontrolled hypertension, that was ongoing at the time of enrolment or history of myocardial infarction within 3 months of enrolment. 5. Ongoing treatment for VTE. 6. Liver disease expected to have any potential impact on survival (i.e. hepatitis B or C, cirrhosis) or ALT/AST \>3x upper limit of normal range (ULN). This did not include Gilbert's syndrome or hepatitis A with complete recovery. 7. Known severe renal insufficiency (CrCl \<30 mL/min) and patients with mild renal insufficiency (CrCl \>50 mL/min) or normal renal function. 8. Planned anaesthesia with post-operative indwelling epidural catheters. 9. Pre-menopausal women (last menstruation \<=1 year prior to signing informed consent), who were: Pregnant Nursing Of child-bearing potential and were NOT practicing acceptable methods of birth control, or did NOT plan to continue practicing an acceptable method throughout the study. Acceptable methods of birth control included intrauterine device; oral, implantable or injectable contraceptives and surgical sterility 10. Hypersensitivity to dabigatran etexilate or to any of excipients. 11. Participation in a clinical trial within 30 days of enrolment. 12. Known alcohol or drug abuse which would interfere with completion of the study; patients considered unreliable by the investigator concerning the requirements for follow-up during the study and/or compliance with study drug administration. 13. Previous participation in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dabigatran Concentration in Plasma, Estimated From Local Hemoclot® | Screening, day of surgery 1 hour (h) and 2h after drug intake (di) for late finalization of surgery, 4h and 8h after di for early finalization of surgery, 15 minutes (min) before di at days 2, 3, 4, 5 and 6, at day 6 also 1h, 2h, 4h, 8h and 24 after di | The Hemoclot® test kit measures the dTT (diluted Thrombin time). In the present trial, as a first step, the dTT in calibration samples that had known Dabigatran concentrations was measured locally with the Hemoclot® test kit, and a linear calibration curve was fitted to the data from the calibration samples. Thereafter, for each patient at each time-point, the dTT was measured with the Hemoclot® kit and the Dabigatran concentration was read off from the calibration curve. These estimated concentrations are compared with concentrations measured in parallel with HPLC-MS/MS. As the trial objective is the method comparison and not the detection of the absolute concentrations of either of the methods, the result is reported as a relative bioavailability \[%\], see Statistical Analysis 1 below. Only concentrations \>= LLOQ (Lower Limit of concentration) are included in the quantitative comparison. |
| Dabigatran Concentration in Plasma, Estimated From Central Hemoclot® | Screening, day of surgery 1 hour (h) and 2h after drug intake (di) for late finalization of surgery, 4h and 8h after di for early finalization of surgery, 15 minutes (min) before di at days 2, 3, 4, 5 and 6, at day 6 also 1h, 2h, 4h, 8h and 24 after di | The Hemoclot® test kit measures the dTT (diluted Thrombin time). In the present trial, as a first step, the dTT in calibration samples that had known Dabigatran concentrations was measured centrally with the Hemoclot® test kit, and a linear calibration curve was fitted to the data from the calibration samples. Thereafter, for each patient at each time-point, the dTT was measured with the Hemoclot® kit and the Dabigatran concentration was read off from the calibration curve. These estimated concentrations are compared with concentrations measured in parallel with HPLC-MS/MS. As the trial objective is the method comparison and not the detection of the absolute concentrations of either of the methods, the result is reported as a relative bioavailability \[%\], see Statistical Analysis 1 below. Only concentrations \>= LLOQ (Lower Limit of concentration) are included in the quantitative comparison. |
| Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | At day 6 before drug intake (di), at 1h, 2h, 4h, 8h and 24h after di | Dabigatran Concentration in Plasma, measured with HPLC-MS/MS - Most relevant timepoints are reported here, ie timepoints of day 6 |
Countries
Austria, Canada, Czechia, Finland, Netherlands, Sweden
Participant flow
Pre-assignment details
30 patients did not receive any study medication.
Participants by arm
| Arm | Count |
|---|---|
| Patients Treated With Dabigatran Etexilate Patients treated with Dabigatran Etexilate 150mg once daily. At the day of surgery the treatment will be initiated 1-4 h post surgery with 75mg. | 112 |
| Total | 112 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 11 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Patients Treated With Dabigatran Etexilate |
|---|---|
| Age, Continuous | 79.1 years STANDARD_DEVIATION 6.5 |
| Sex: Female, Male Female | 78 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 99 / 112 |
| serious Total, serious adverse events | 10 / 112 |
Outcome results
Primary
Dabigatran Concentration in Plasma, Estimated From Central Hemoclot®
The Hemoclot® test kit measures the dTT (diluted Thrombin time). In the present trial, as a first step, the dTT in calibration samples that had known Dabigatran concentrations was measured centrally with the Hemoclot® test kit, and a linear calibration curve was fitted to the data from the calibration samples. Thereafter, for each patient at each time-point, the dTT was measured with the Hemoclot® kit and the Dabigatran concentration was read off from the calibration curve. These estimated concentrations are compared with concentrations measured in parallel with HPLC-MS/MS. As the trial objective is the method comparison and not the detection of the absolute concentrations of either of the methods, the result is reported as a relative bioavailability \[%\], see Statistical Analysis 1 below. Only concentrations \>= LLOQ (Lower Limit of concentration) are included in the quantitative comparison.
Time frame: Screening, day of surgery 1 hour (h) and 2h after drug intake (di) for late finalization of surgery, 4h and 8h after di for early finalization of surgery, 15 minutes (min) before di at days 2, 3, 4, 5 and 6, at day 6 also 1h, 2h, 4h, 8h and 24 after di
Population: Correct calculation set: all patients of the Per Protocol set (PPS) (patients with at least one pair of observations for both PD and PK parameters without important protocol violations) and additionally all patients of the TS whom the only reason for not being in the PPS was the non-influential forbidden concomitant medication or vomiting
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Estimated From Central Hemoclot® | 468 measurements estimated as above LLOQ |
Comparison: Estimated central measurements are compared to HPLC-MS/MS measurements. The comparison was done for the 468 quantifiable measurements.90% CI: [90.079, 94.719]Geometric Mean
Primary
Dabigatran Concentration in Plasma, Estimated From Local Hemoclot®
The Hemoclot® test kit measures the dTT (diluted Thrombin time). In the present trial, as a first step, the dTT in calibration samples that had known Dabigatran concentrations was measured locally with the Hemoclot® test kit, and a linear calibration curve was fitted to the data from the calibration samples. Thereafter, for each patient at each time-point, the dTT was measured with the Hemoclot® kit and the Dabigatran concentration was read off from the calibration curve. These estimated concentrations are compared with concentrations measured in parallel with HPLC-MS/MS. As the trial objective is the method comparison and not the detection of the absolute concentrations of either of the methods, the result is reported as a relative bioavailability \[%\], see Statistical Analysis 1 below. Only concentrations \>= LLOQ (Lower Limit of concentration) are included in the quantitative comparison.
Time frame: Screening, day of surgery 1 hour (h) and 2h after drug intake (di) for late finalization of surgery, 4h and 8h after di for early finalization of surgery, 15 minutes (min) before di at days 2, 3, 4, 5 and 6, at day 6 also 1h, 2h, 4h, 8h and 24 after di
Population: Correct calculation set: all patients of the Per Protocol set (PPS) (patients with at least one pair of observations for both PD and PK parameters without important protocol violations) and additionally all patients of the TS whom the only reason for not being in the PPS was the non-influential forbidden concomitant medication or vomiting
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Estimated From Local Hemoclot® | 136 measurements estimated as above LLOQ |
Comparison: Estimated local measurements are compared to HPLC-MS/MS measurements. The comparison was done for the 136 quantifiable measurements.90% CI: [97.64, 106.893]Geometric Mean
Primary
Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS
Dabigatran Concentration in Plasma, measured with HPLC-MS/MS - Most relevant timepoints are reported here, ie timepoints of day 6
Time frame: At day 6 before drug intake (di), at 1h, 2h, 4h, 8h and 24h after di
Population: Correct calculation set: all patients of the Per Protocol set (PPS) (patients with at least one pair of observations for both PD and PK parameters without important protocol violations) and additionally all patients of the TS whom the only reason for not being in the PPS was the non-influential forbidden concomitant medication or vomiting
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | before intake(N=96) | 47.5 ng/mL | Geometric Coefficient of Variation 84.7 |
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | after 1h(N=93) | 87.8 ng/mL | Geometric Coefficient of Variation 81.9 |
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | after 2h(N=91) | 147 ng/mL | Geometric Coefficient of Variation 85.2 |
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | after 4h(N=88) | 157 ng/mL | Geometric Coefficient of Variation 84.8 |
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | after 8h(N=93) | 119 ng/mL | Geometric Coefficient of Variation 78.1 |
| Patients Treated With Dabigatran Etexilate | Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS | after 24h(N=86) | 47.7 ng/mL | Geometric Coefficient of Variation 90.5 |