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Treatment of Patients Undergoing Primary Unilateral Elective Total Knee or Hip Replacement With Dabigatran Etexilate

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01184989
First received: August 16, 2010
Last updated: June 3, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Arthroplasty, Replacement,
Prevention of Venous Thromboembolism,
Moderate Renal Impairment (CrCl 30-50 mL/Min)
Drug: Dabigatran etexilate
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Pharmacokinetics/Dynamics Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: An Open Label, Non-comparative, Pharmacokinetic and Pharmacodynamic Study to Evaluate the Effect of Dabigatran Etexilate on Coagulation Parameters Including a Calibrated Thrombin Time Test in Patients With Moderate Renal Impairment (Creatinine Clearance 30-50 ml/Min) Undergoing Primary Unilateral Elective Total Knee or Hip Replacement Surgery

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Dabigatran Concentration in Plasma, Estimated From Local Hemoclot® [ 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 ] [ Designated as safety issue: No ]

    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® [ 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 ] [ Designated as safety issue: No ]

    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 [ Time Frame: At day 6 before drug intake (di), at 1h, 2h, 4h, 8h and 24h after di ] [ Designated as safety issue: No ]
    Dabigatran Concentration in Plasma, measured with HPLC-MS/MS - Most relevant timepoints are reported here, ie timepoints of day 6


Enrollment: 142
Study Start Date: August 2010
Study Completion Date: April 2013
Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Dabigatran etexilate
open label, once daily dose approved by EMEA and Health Canada
Drug: Dabigatran etexilate
once daily approved dose by EMEA and Health Canada

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01184989

Locations
Austria
1160.86.43001 Boehringer Ingelheim Investigational Site
Graz, Austria
1160.86.43003 Boehringer Ingelheim Investigational Site
Wien, Austria
Canada, Alberta
1160.86.01001 Boehringer Ingelheim Investigational Site
Red Deer, Alberta, Canada
Canada, Nova Scotia
1160.86.01002 Boehringer Ingelheim Investigational Site
Halifax, Nova Scotia, Canada
Canada, Prince Edward Island
1160.86.01003 Boehringer Ingelheim Investigational Site
Charlottetown, Prince Edward Island, Canada
Czech Republic
1160.86.42002 Boehringer Ingelheim Investigational Site
Prague 5, Czech Republic
Finland
1160.86.35801 Boehringer Ingelheim Investigational Site
Jyväskylä, Finland
Netherlands
1160.86.31002 Boehringer Ingelheim Investigational Site
Hilversum, Netherlands
Sweden
1160.86.46002 Boehringer Ingelheim Investigational Site
Hässleholm, Sweden
1160.86.46001 Boehringer Ingelheim Investigational Site
Mölndal, Sweden
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided

Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01184989     History of Changes
Other Study ID Numbers: 1160.86, 2010-018723-26
Study First Received: August 16, 2010
Results First Received: March 3, 2014
Last Updated: June 3, 2014
Health Authority: Austria: Medicines and Medical Devices Agency
Canada: Health Canada
Czech Republic: State Institute for Drug Control
Finland: Finnish Medicines Agency
Netherlands: Central Committee Research Involving Human Subjects
Sweden: Regional Ethical Review Board

Additional relevant MeSH terms:
Renal Insufficiency
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism and Thrombosis
Kidney Diseases
Thrombosis
Urologic Diseases
Vascular Diseases
Dabigatran
Anticoagulants
Antithrombins
Enzyme Inhibitors
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Serine Proteinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on November 24, 2014