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

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ClinicalTrials.gov Identifier: NCT01184989
Recruitment Status : Completed
First Posted : August 19, 2010
Results First Posted : May 23, 2014
Last Update Posted : September 25, 2018
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Conditions Arthroplasty, Replacement
Prevention of Venous Thromboembolism
Moderate Renal Impairment (CrCl 30-50 mL/Min)
Intervention Drug: Dabigatran etexilate
Enrollment 142
Recruitment Details  
Pre-assignment Details 30 patients did not receive any study medication.
Arm/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description

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.

142 patients were enrolled for the study, but only 112 were treated. Therefore, the number of started patients corresponds to the ones that were actually treated.

Period Title: Overall Study
Started 112 [1]
Completed 100
Not Completed 12
Reason Not Completed
Adverse Event             11
Withdrawal by Subject             1
[1]
Treated Patients
Arm/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description 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.
Overall Number of Baseline Participants 112
Hide Baseline Analysis Population Description
Treated Set (TS): Patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 112 participants
79.1  (6.5)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 112 participants
Female
78
  69.6%
Male
34
  30.4%
1.Primary Outcome
Title Dabigatran Concentration in Plasma, Estimated From Local Hemoclot®
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 99
Overall Number of Units Analyzed
Type of Units Analyzed: Measurements
320
Measure Type: Number
Unit of Measure: measurements estimated as above LLOQ
136
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patients Treated With Dabigatran Etexilate
Comments Estimated local measurements are compared to HPLC-MS/MS measurements. The comparison was done for the 136 quantifiable measurements.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioavailability analysis
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Geometric Mean
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 102.16
Confidence Interval 90%
97.640 to 106.893
Parameter Dispersion
Type: Standard Deviation
Value: 22.8
Estimation Comments Dispersion value is actually the intraindividual gCV.
2.Primary Outcome
Title Dabigatran Concentration in Plasma, Estimated From Central Hemoclot®
Hide Description

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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 97
Overall Number of Units Analyzed
Type of Units Analyzed: Measurements
1158
Measure Type: Number
Unit of Measure: measurements estimated as above LLOQ
468
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Patients Treated With Dabigatran Etexilate
Comments Estimated central measurements are compared to HPLC-MS/MS measurements. The comparison was done for the 468 quantifiable measurements.
Type of Statistical Test Non-Inferiority or Equivalence
Comments Bioavailability analysis
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method Geometric Mean
Comments [Not Specified]
Method of Estimation Estimation Parameter Ratio
Estimated Value 92.37
Confidence Interval 90%
90.079 to 94.719
Parameter Dispersion
Type: Standard Deviation
Value: 23.5
Estimation Comments The Dispersion Value is actually the intraindividual gCV.
3.Primary Outcome
Title Dabigatran Concentration in Plasma, Measured With HPLC-MS/MS
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description:
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.
Overall Number of Participants Analyzed 96
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: ng/mL
before intake(N=96)
47.5
(84.7%)
after 1h(N=93)
87.8
(81.9%)
after 2h(N=91)
147
(85.2%)
after 4h(N=88)
157
(84.8%)
after 8h(N=93)
119
(78.1%)
after 24h(N=86)
47.7
(90.5%)
Time Frame Up to 14 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Patients Treated With Dabigatran Etexilate
Hide Arm/Group Description 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.
All-Cause Mortality
Patients Treated With Dabigatran Etexilate
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Patients Treated With Dabigatran Etexilate
Affected / at Risk (%)
Total   10/112 (8.93%) 
Cardiac disorders   
Atrial fibrillation  1  1/112 (0.89%) 
Acute myocardial infarction  1  1/112 (0.89%) 
Gastrointestinal disorders   
Gastric ulcer  1  2/112 (1.79%) 
Haematemesis  1  2/112 (1.79%) 
Gastritis haemorrhagic  1  1/112 (0.89%) 
Infections and infestations   
Diverticulitis  1  1/112 (0.89%) 
Pyelonephritis  1  1/112 (0.89%) 
Urinary tract infection  1  1/112 (0.89%) 
Urosepsis  1  1/112 (0.89%) 
Injury, poisoning and procedural complications   
Wound secretion  1  1/112 (0.89%) 
Surgical and medical procedures   
Post procedural drainage  1  1/112 (0.89%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Patients Treated With Dabigatran Etexilate
Affected / at Risk (%)
Total   99/112 (88.39%) 
Blood and lymphatic system disorders   
Anaemia  1  7/112 (6.25%) 
Gastrointestinal disorders   
Nausea  1  45/112 (40.18%) 
Vomiting  1  37/112 (33.04%) 
Constipation  1  11/112 (9.82%) 
General disorders   
Oedema peripheral  1  9/112 (8.04%) 
Pyrexia  1  7/112 (6.25%) 
Injury, poisoning and procedural complications   
Wound haematoma  1  6/112 (5.36%) 
Investigations   
Haemoglobin decreased  1  11/112 (9.82%) 
Musculoskeletal and connective tissue disorders   
Arthralgia  1  23/112 (20.54%) 
Nervous system disorders   
Dizziness  1  14/112 (12.50%) 
Renal and urinary disorders   
Urinary retention  1  7/112 (6.25%) 
Vascular disorders   
Hypotension  1  11/112 (9.82%) 
Haematoma  1  6/112 (5.36%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MEDDRA 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Any publication of the result of this trial must be consistent with the Boehringer Ingelheim publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim Pharmaceuticals
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01184989     History of Changes
Other Study ID Numbers: 1160.86
2010-018723-26 ( EudraCT Number: EudraCT )
First Submitted: August 16, 2010
First Posted: August 19, 2010
Results First Submitted: March 3, 2014
Results First Posted: May 23, 2014
Last Update Posted: September 25, 2018