Venous Thromboembolism
Conditions
Brief summary
The primary objective of this study is to establish the dose-response relationship with regard to efficacy and safety of BIBR 1048 (50 mg bis in die(b.i.d), 150 mg b.i.d, 225 mg b.i.d. and 300 mg quaque die(q.d) ) in preventing venous thromboembolism(VTE) in patients undergoing primary elective total hip and knee replacement.
Interventions
DRUGEnoxaparin
Enoxaparin 40 mg s.c once a day for 5-10 days of treatment period
DRUGBIBR 1048
50 mg b.i.d BIBR 1048 capsule twice a day for 5-10 days of treatment period
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients scheduled to undergo a primary elective total hip or knee replacement. 2. Male of female being 18 years or older. 3. Patients weighing at least 40 kg. 4. Written informed consent for study participation.
Exclusion criteria
1. Bleeding diathesis, constitutional or acquired coagulation disorders. 2. Major surgery or trauma(e.g., hip fracture) within the last 3 months. 3. Cardiovascular disease 4. Any history of haemorrhagic stroke, intracranial or intraocular bleeding or cerebral ischaemic attacks lasting more than 24 hours and / or with cardiovascular pathological findings. 5. Deep vein thrombosis(DVT), gastrointestinal or pulmonary bleeding, gastric or duodenal ulcer within the last year. 6. History of or acute intracranial disease 7. Liver disease 8. Renal disease 9. Use of long-term anticoagulants or antiplatelet drugs within 7 days prior to hip/knee replacement operation. 10. Pre-menopausal women who are not surgically steriles, are nursing and are of child-bearing potential and are not practising acceptable methods of birth control 11. Known allergy to contrast media 12. Thrombocytopenia 13. Allergy against heparin. 14. Active malignant disease or current cytostatic treatment. 15. Treatment with an investigational drug in the past month. 16. Leg amputee 17. Known alcohol or drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Venous Thromboembolic (VTE) Events | Treatment period (up to day 8+/-2 days visit) | Deep vein thrombosis (DVT) (proximal and distal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic DVT confirmed by venography during the treatment period or PE confirmed by objective testing |
| Number of Participants With Major Bleeding Events (MBE) | From approximately 14 days prior to surgery to 4-6 weeks post surgery | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Proximal DVT | Treatment period (up to day 8+/-2 days visit) | Deep venous thrombosis (DVT) (proximal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic proximal DVT confirmed by venography during the treatment period |
| Volume of Blood Loss | Day 1 (Day of surgery) | Volume of blood loss was to be analysed using an analysis of variance (ANOVA), which included treatment and centre. |
| Rate of Transfusions Due to Bleedings | Day 1 (Day of surgery) | Percentage of patients requiring transfusions due to bleeding .Rate of need of transfusion were to be analysed using a logistic regression with treatment and centre. |
| Number of Participants With VTE Events and All Cause Mortality | Treatment period (up to day 8+/-2 days visit) | Deep venous thrombosis (DVT) (proximal and distal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic DVT confirmed by venography during the treatment period or Pulmonary Embolism (PE) confirmed by objective testing and all deaths. |
| Laboratory Analyses | Screening to end of treatment | Number of patients with possible clinically significant abnormalities, i.e. with values out of normal range. Normal ranges are defined as: Haematocrit \[%\]: (0.35-0.45) for women and (0.39-0.51) for men Haemoglobin \[g/dL\]: (11.6-15.4) for women and (13.2-17.3) for men White Blood Cell count \[10\^9/L\]: (4-10.3) for women and (3.9-10.3) for men Platelets \[10\^9/L\]: (145-420) for women and men Sodium \[mmol/L\]: (135-146) for women and men Potassium \[mmol/L\]: (3.5-5) for women and men Aspartate aminotransferase (AST) \[U/L\]: (11-37) for women and (11-39) for men Alanine aminotransferase (ALT) \[U/L\]: (8-43) for women and (8-45) for men Alkaline Phosphatase \[U/L\]: (36-118) for women and (35-123) for men Creatinine \[mg/dL\]: (0.57-1.06)for women and (0.72-1.3) for men Bilirubin, total \[mg/dL\]: (0.22-1.28) for women and men Uric acid \[mg/dL\]: (2.4-6.47) for women and men |
| Plasma Concentration (Cmax) of Dabigatran | Day 1 to end of treatment | Maximum plasma concentration of Dabigatran (at steady-state) and Pre-dose plasma concentrations at steady state. Cmax represents the maximum concentration of Dabigatran in plasma. Cmax,ss represents the maximum concentration of Dabigatran in plasma at steady state. Cpre,ss represents pre-dose concentration of Dabigatran in plasma at steady state |
| Area Under the Plasma Concentration-time Curve During a Dosing Interval | up to day 8+/-2 days visit | Area under the plasma concentration-time curve during a dosing interval (at steady-state). The AUC0-12h (for b.i.d. treatment regimens) and AUC0-24h (300 mg q.d.) after the first dose on day of surgery calculated by extrapolation using the elimination rate constant, reported only if the extrapolated fraction of AUC was less than 30 % of the total AUC. |
| Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Treatment period (up to day 8+/-2 days visit) | Number of participants with Clinically Significant, minor or any bleeding events. Clinically significant bleeding events are defined as * Spontaneous skin haematoma larger than \>25 cm² * Wound haematoma \>100 cm² * Spontaneous nose bleed \>5 minutes * Macroscopic haematurea, either spontaneous or lasting more than 24 hours if associated with an intervention * Spontaneous rectal bleeding (more than spot on toilet paper) * Gingival bleeding \>5 minutes * Any other bleeding event considered as clinically significant by the investigator All other bleeding events that did not fulfil the criteria of MBE or clinically significant bleeding event were classified as minor bleeding events. |
| Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | Treatment period (up to day 10) | Deep venous thrombosis (DVT) (proximal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic proximal DVT confirmed by venography during the treatment period or PE confirmed by objective testing plus VTE related mortality |
Countries
Austria, Belgium, Czechia, Denmark, Finland, France, Hungary, Italy, Netherlands, Norway, South Africa, Sweden
Participant flow
Recruitment details
There were 1973 patients enrolled/randomised in this trial but only 1949 started treatment
Participants by arm
| Arm | Count |
|---|---|
| BIBR 1048 50 mg Bid Dabigatran 50 mg bid (twice daily) oral | 389 |
| BIBR 1048 150 mg Bid Dabigatran 150 mg bid (twice daily) oral | 390 |
| BIBR 1048 225 mg Bid Dabigatran 225 mg bid (twice daily) oral | 393 |
| BIBR 1048 300 mg qd Dabigatran 300 mg qd (once daily) oral | 385 |
| Enoxaparin 40 mg qd Enoxaparin 40 mg qd (once daily) subcutaneous injection | 392 |
| Total | 1,949 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 13 | 31 | 18 | 23 | 14 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other | 13 | 10 | 7 | 10 | 7 |
| Overall Study | Protocol Violation | 6 | 8 | 6 | 7 | 4 |
| Overall Study | Withdrawal by Subject | 6 | 7 | 7 | 11 | 6 |
Baseline characteristics
| Characteristic | BIBR 1048 50 mg Bid | BIBR 1048 150 mg Bid | BIBR 1048 225 mg Bid | BIBR 1048 300 mg qd | Enoxaparin 40 mg qd | Total |
|---|---|---|---|---|---|---|
| Age, Customized | 66.07 years STANDARD_DEVIATION 10.23 | 65.86 years STANDARD_DEVIATION 10.77 | 65.87 years STANDARD_DEVIATION 10.63 | 66.47 years STANDARD_DEVIATION 10.37 | 65.03 years STANDARD_DEVIATION 11.03 | 65.86 years STANDARD_DEVIATION 10.61 |
| Sex: Female, Male Female | 223 Participants | 252 Participants | 229 Participants | 246 Participants | 241 Participants | 1191 Participants |
| Sex: Female, Male Male | 166 Participants | 138 Participants | 164 Participants | 139 Participants | 151 Participants | 758 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 242 / 389 | 267 / 390 | 256 / 393 | 267 / 385 | 258 / 392 |
| serious Total, serious adverse events | 25 / 389 | 29 / 390 | 21 / 393 | 33 / 385 | 31 / 392 |
Outcome results
Primary
Number of Participants With Major Bleeding Events (MBE)
Time frame: From approximately 14 days prior to surgery to 4-6 weeks post surgery
Population: Safety Set (SAFE) population. This included all randomised patients who were treated and who had any available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With Major Bleeding Events (MBE) | 1 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Major Bleeding Events (MBE) | 16 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Major Bleeding Events (MBE) | 15 participants |
| BIBR 1048 300 mg qd | Number of Participants With Major Bleeding Events (MBE) | 18 participants |
| Enoxaparin 40 mg qd | Number of Participants With Major Bleeding Events (MBE) | 8 participants |
Comparison: BIBR 1048 225 mg bid vs. BIBR 1048 50 mg bid, same methodology as for primary endpointp-value: 0.007795% CI: [2.077, 120.474]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 50 mg bid, same methodology as for primary endpointp-value: 0.006295% CI: [2.229, 128.238]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 300 mg qd, same methodology as for primary endpointp-value: 0.719295% CI: [0.567, 2.276]Regression, Logistic
Comparison: BIBR 1048 50 mg bid vs. Enoxaparin 40 mg qd, same methodology as for primary endpointp-value: 0.047295% CI: [0.015, 0.974]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. Enoxaparin 40 mg qd, same methodology as for primary endpointp-value: 0.104395% CI: [0.862, 4.868]Regression, Logistic
Comparison: BIBR 1048 225 mg bid vs. Enoxaparin 40 mg qd, same methodology as for primary endpointp-value: 0.144895% CI: [0.799, 4.597]Regression, Logistic
Primary
Number of Participants With Venous Thromboembolic (VTE) Events
Deep vein thrombosis (DVT) (proximal and distal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic DVT confirmed by venography during the treatment period or PE confirmed by objective testing
Time frame: Treatment period (up to day 8+/-2 days visit)
Population: Full Analysis Set (FAS) population. This included all randomised patients who had at least one subcutaneous injection and one oral dose of study medication and with confirmed VTE data post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With Venous Thromboembolic (VTE) Events | 86 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Venous Thromboembolic (VTE) Events | 49 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Venous Thromboembolic (VTE) Events | 39 participants |
| BIBR 1048 300 mg qd | Number of Participants With Venous Thromboembolic (VTE) Events | 47 participants |
| Enoxaparin 40 mg qd | Number of Participants With Venous Thromboembolic (VTE) Events | 72 participants |
Comparison: BIBR 1048 225 mg bid vs. BIBR 1048 50 mg bid comparison. The primary objective of the trial was to establish a dose relationship among BIBR 1048 doses studied in the prevention of VTE. The statistical model was a logistic regression which included treatment and centre..p-value: <0.000195% CI: [0.244, 0.577]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 50 mg bid comparison. The primary objective of the trial was to establish a dose relationship among BIBR 1048 doses studied in the prevention of VTE. The statistical model was a logistic regression which included treatment and centre..p-value: 0.001595% CI: [0.344, 0.778]Regression, Logistic
Comparison: BIBR 1048 300 mg qd vs. BIBR 1048 150 mg bid comparison. Secondary analysis to compare once daily dosing vs. twice daily dosing. . The statistical model was a logistic regression which included treatment and centre.p-value: 0.785695% CI: [0.599, 1.473]Regression, Logistic
Comparison: BIBR 1048 225 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.000795% CI: [0.302, 0.727]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.040195% CI: [0.427, 0.98]Regression, Logistic
Comparison: BIBR 1048 50 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.244695% CI: [0.859, 1.817]Regression, Logistic
Secondary
Area Under the Plasma Concentration-time Curve During a Dosing Interval
Area under the plasma concentration-time curve during a dosing interval (at steady-state). The AUC0-12h (for b.i.d. treatment regimens) and AUC0-24h (300 mg q.d.) after the first dose on day of surgery calculated by extrapolation using the elimination rate constant, reported only if the extrapolated fraction of AUC was less than 30 % of the total AUC.
Time frame: up to day 8+/-2 days visit
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BIBR 1048 50 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval (N=13,12,21,72,0) | 229 ng*h/mL | Geometric Coefficient of Variation 88.1 |
| BIBR 1048 50 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval at steady-state | 350 ng*h/mL | Geometric Coefficient of Variation 66.8 |
| BIBR 1048 150 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval at steady-state | 1250 ng*h/mL | Geometric Coefficient of Variation 64.8 |
| BIBR 1048 150 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval (N=13,12,21,72,0) | 636 ng*h/mL | Geometric Coefficient of Variation 56.2 |
| BIBR 1048 225 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval (N=13,12,21,72,0) | 605 ng*h/mL | Geometric Coefficient of Variation 91.6 |
| BIBR 1048 225 mg Bid | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval at steady-state | 1910 ng*h/mL | Geometric Coefficient of Variation 64.9 |
| BIBR 1048 300 mg qd | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval (N=13,12,21,72,0) | 1610 ng*h/mL | Geometric Coefficient of Variation 82.5 |
| BIBR 1048 300 mg qd | Area Under the Plasma Concentration-time Curve During a Dosing Interval | AUC during a dosing interval at steady-state | 2450 ng*h/mL | Geometric Coefficient of Variation 76.1 |
Secondary
Laboratory Analyses
Number of patients with possible clinically significant abnormalities, i.e. with values out of normal range. Normal ranges are defined as: Haematocrit \[%\]: (0.35-0.45) for women and (0.39-0.51) for men Haemoglobin \[g/dL\]: (11.6-15.4) for women and (13.2-17.3) for men White Blood Cell count \[10\^9/L\]: (4-10.3) for women and (3.9-10.3) for men Platelets \[10\^9/L\]: (145-420) for women and men Sodium \[mmol/L\]: (135-146) for women and men Potassium \[mmol/L\]: (3.5-5) for women and men Aspartate aminotransferase (AST) \[U/L\]: (11-37) for women and (11-39) for men Alanine aminotransferase (ALT) \[U/L\]: (8-43) for women and (8-45) for men Alkaline Phosphatase \[U/L\]: (36-118) for women and (35-123) for men Creatinine \[mg/dL\]: (0.57-1.06)for women and (0.72-1.3) for men Bilirubin, total \[mg/dL\]: (0.22-1.28) for women and men Uric acid \[mg/dL\]: (2.4-6.47) for women and men
Time frame: Screening to end of treatment
Population: Safety Set (SAFE) population. This included all randomised patients who were treated and who had any available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBR 1048 50 mg Bid | Laboratory Analyses | Creatinine increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Platelets decrease (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Bilirubin, total increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Uric Acid increase (N=340,334,344,327,352) | 3 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Alkaline phosphatase incr. (N=340,334,344,327,352) | 1 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | White blood cell ct. decr.(N=325,324,339,320,340) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Platelets increase (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Potassium decrease (N=340,334,344,326,352) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Haemoglobin decrease (N=325,324,339,320,340) | 122 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | ALT increase (N=340,334,344,327,352) | 6 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Haematocrit decrease (N=325,324,339,320,340) | 16 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Sodium decrease (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | Potassium increase (N=340,334,344,326,352) | 0 participants |
| BIBR 1048 50 mg Bid | Laboratory Analyses | AST increase (N=340,334,344,327,352) | 1 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Haemoglobin decrease (N=325,324,339,320,340) | 129 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Potassium decrease (N=340,334,344,326,352) | 0 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Haematocrit decrease (N=325,324,339,320,340) | 15 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Alkaline phosphatase incr. (N=340,334,344,327,352) | 2 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Potassium increase (N=340,334,344,326,352) | 2 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Bilirubin, total increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | White blood cell ct. decr.(N=325,324,339,320,340) | 0 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Uric Acid increase (N=340,334,344,327,352) | 4 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Creatinine increase (N=340,334,344,327,352) | 2 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Platelets decrease (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | ALT increase (N=340,334,344,327,352) | 5 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Platelets increase (N=325,324,339,320,340) | 1 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | Sodium decrease (N=340,334,344,327,352) | 2 participants |
| BIBR 1048 150 mg Bid | Laboratory Analyses | AST increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | AST increase (N=340,334,344,327,352) | 2 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Haematocrit decrease (N=325,324,339,320,340) | 14 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Haemoglobin decrease (N=325,324,339,320,340) | 148 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | White blood cell ct. decr.(N=325,324,339,320,340) | 2 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Platelets decrease (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Platelets increase (N=325,324,339,320,340) | 1 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Sodium decrease (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Potassium decrease (N=340,334,344,326,352) | 1 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Potassium increase (N=340,334,344,326,352) | 1 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | ALT increase (N=340,334,344,327,352) | 3 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Alkaline phosphatase incr. (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Creatinine increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Bilirubin, total increase (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 225 mg Bid | Laboratory Analyses | Uric Acid increase (N=340,334,344,327,352) | 4 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | ALT increase (N=340,334,344,327,352) | 8 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | AST increase (N=340,334,344,327,352) | 3 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | White blood cell ct. decr.(N=325,324,339,320,340) | 1 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Platelets decrease (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Haematocrit decrease (N=325,324,339,320,340) | 14 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Haemoglobin decrease (N=325,324,339,320,340) | 129 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Uric Acid increase (N=340,334,344,327,352) | 2 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Bilirubin, total increase (N=340,334,344,327,352) | 1 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Alkaline phosphatase incr. (N=340,334,344,327,352) | 0 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Platelets increase (N=325,324,339,320,340) | 0 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Potassium decrease (N=340,334,344,326,352) | 0 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Potassium increase (N=340,334,344,326,352) | 2 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Creatinine increase (N=340,334,344,327,352) | 1 participants |
| BIBR 1048 300 mg qd | Laboratory Analyses | Sodium decrease (N=340,334,344,327,352) | 1 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Sodium decrease (N=340,334,344,327,352) | 0 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Platelets increase (N=325,324,339,320,340) | 0 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | AST increase (N=340,334,344,327,352) | 9 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Platelets decrease (N=325,324,339,320,340) | 1 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Haematocrit decrease (N=325,324,339,320,340) | 22 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | ALT increase (N=340,334,344,327,352) | 20 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Alkaline phosphatase incr. (N=340,334,344,327,352) | 3 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Creatinine increase (N=340,334,344,327,352) | 1 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | White blood cell ct. decr.(N=325,324,339,320,340) | 0 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Uric Acid increase (N=340,334,344,327,352) | 3 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Haemoglobin decrease (N=325,324,339,320,340) | 142 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Potassium decrease (N=340,334,344,326,352) | 2 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Bilirubin, total increase (N=340,334,344,327,352) | 0 participants |
| Enoxaparin 40 mg qd | Laboratory Analyses | Potassium increase (N=340,334,344,326,352) | 1 participants |
Secondary
Number of Participants With Clinically Significant, Minor or Any Bleeding Events
Number of participants with Clinically Significant, minor or any bleeding events. Clinically significant bleeding events are defined as * Spontaneous skin haematoma larger than \>25 cm² * Wound haematoma \>100 cm² * Spontaneous nose bleed \>5 minutes * Macroscopic haematurea, either spontaneous or lasting more than 24 hours if associated with an intervention * Spontaneous rectal bleeding (more than spot on toilet paper) * Gingival bleeding \>5 minutes * Any other bleeding event considered as clinically significant by the investigator All other bleeding events that did not fulfil the criteria of MBE or clinically significant bleeding event were classified as minor bleeding events.
Time frame: Treatment period (up to day 8+/-2 days visit)
Population: Safety Set (SAFE) population. This included all randomised patients who were treated and who had any available data
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Clinically significant bleeding events | 9 participants |
| BIBR 1048 50 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Any bleeding events | 26 participants |
| BIBR 1048 50 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Minor bleeding events | 18 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Minor bleeding events | 31 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Clinically significant bleeding events | 16 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Any bleeding events | 61 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Minor bleeding events | 38 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Clinically significant bleeding events | 20 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Any bleeding events | 65 participants |
| BIBR 1048 300 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Clinically significant bleeding events | 19 participants |
| BIBR 1048 300 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Any bleeding events | 62 participants |
| BIBR 1048 300 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Minor bleeding events | 37 participants |
| Enoxaparin 40 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Minor bleeding events | 25 participants |
| Enoxaparin 40 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Clinically significant bleeding events | 10 participants |
| Enoxaparin 40 mg qd | Number of Participants With Clinically Significant, Minor or Any Bleeding Events | Any bleeding events | 43 participants |
Secondary
Number of Participants With Proximal DVT
Deep venous thrombosis (DVT) (proximal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic proximal DVT confirmed by venography during the treatment period
Time frame: Treatment period (up to day 8+/-2 days visit)
Population: Full Analysis Set (FAS) population. This included all randomised patients who had at least one subcutaneous injection and one oral dose of study medication and with confirmed VTE data post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With Proximal DVT | 15 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Proximal DVT | 9 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Proximal DVT | 5 participants |
| BIBR 1048 300 mg qd | Number of Participants With Proximal DVT | 6 participants |
| Enoxaparin 40 mg qd | Number of Participants With Proximal DVT | 17 participants |
Comparison: BIBR 1048 225 mg bid vs. BIBR 1048 50 mg bid, same methodology as primary endpoint.p-value: 0.03695% CI: [0.118, 0.931]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 50 mg bid, same methodology as primary endpoint.p-value: 0.388495% CI: [0.293, 1.611]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 300 mg qd, same methodology as primary endpoint.p-value: 0.367495% CI: [0.215, 1.766]Regression, Logistic
Comparison: BIBR 1048 50 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.566395% CI: [0.393, 1.668]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.167895% CI: [0.242, 1.28]Regression, Logistic
Comparison: BIBR 1048 225 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.011395% CI: [0.097, 0.743]Regression, Logistic
Secondary
Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality
Deep venous thrombosis (DVT) (proximal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic proximal DVT confirmed by venography during the treatment period or PE confirmed by objective testing plus VTE related mortality
Time frame: Treatment period (up to day 10)
Population: Full Analysis Set (FAS) population. This included all randomised patients who had at least one subcutaneous injection and one oral dose of study medication and with confirmed VTE data post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | 15 participants |
| BIBR 1048 150 mg Bid | Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | 11 participants |
| BIBR 1048 225 mg Bid | Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | 5 participants |
| BIBR 1048 300 mg qd | Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | 6 participants |
| Enoxaparin 40 mg qd | Number of Participants With Proximal DVT, PE (Pulmonary Embolism) and VTE Related Mortality | 17 participants |
Comparison: BIBR 1048 225 mg bid vs. BIBR 1048 50 mg bid, same methodology as primary endpoint.p-value: 0.037395% CI: [0.199, 0.938]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 50 mg bid, same methodology as primary endpoint.p-value: 0.665995% CI: [0.374, 1.875]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 300 mg qd, same methodology as primary endpoint.p-value: 0.188295% CI: [0.183, 1.397]Regression, Logistic
Comparison: BIBR 1048 50 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.556695% CI: [0.39, 1.66]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.325395% CI: [0.307, 1.48]Regression, Logistic
Comparison: BIBR 1048 225 mg bid vs. Enoxaparin 40 mg qd, same methodology as primary endpoint.p-value: 0.011495% CI: [0.097, 0.744]Regression, Logistic
Secondary
Number of Participants With VTE Events and All Cause Mortality
Deep venous thrombosis (DVT) (proximal and distal) as detected by routine bilateral venography on day 8 +/- 2, plus symptomatic DVT confirmed by venography during the treatment period or Pulmonary Embolism (PE) confirmed by objective testing and all deaths.
Time frame: Treatment period (up to day 8+/-2 days visit)
Population: Full Analysis Set (FAS) population. This included all randomised patients who had at least one subcutaneous injection and one oral dose of study medication and with confirmed VTE data post surgery
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Number of Participants With VTE Events and All Cause Mortality | 86 participants |
| BIBR 1048 150 mg Bid | Number of Participants With VTE Events and All Cause Mortality | 49 participants |
| BIBR 1048 225 mg Bid | Number of Participants With VTE Events and All Cause Mortality | 39 participants |
| BIBR 1048 300 mg qd | Number of Participants With VTE Events and All Cause Mortality | 47 participants |
| Enoxaparin 40 mg qd | Number of Participants With VTE Events and All Cause Mortality | 72 participants |
Comparison: BIBR 1048 225 mg bid vs. BIBR 1048 50 mg bid comparison. The primary objective of the trial was to establish a dose relationship among BIBR 1048 doses studied in the prevention of VTE. The statistical model was a logistic regression which included treatment and centre..p-value: <0.000195% CI: [0.244, 0.577]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. BIBR 1048 50 mg bid comparison. The primary objective of the trial was to establish a dose relationship among BIBR 1048 doses studied in the prevention of VTE. The statistical model was a logistic regression which included treatment and centre..p-value: 0.001595% CI: [0.344, 0.778]Regression, Logistic
Comparison: BIBR 1048 300 mg qd vs. BIBR 1048 150 mg bid comparison. Secondary analysis to compare once daily dosing vs. twice daily dosing. . The statistical model was a logistic regression which included treatment and centre.p-value: 0.785695% CI: [0.599, 1.473]Regression, Logistic
Comparison: BIBR 1048 225 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.000795% CI: [0.302, 0.727]Regression, Logistic
Comparison: BIBR 1048 150 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.040195% CI: [0.427, 0.98]Regression, Logistic
Comparison: BIBR 1048 50 mg bid vs. Enoxaparin 40 mg qd comparison. Secondary analysis, active control used as reference. The statistical model was a logistic regression which included treatment and centre.p-value: 0.244695% CI: [0.859, 1.817]Regression, Logistic
Secondary
Plasma Concentration (Cmax) of Dabigatran
Maximum plasma concentration of Dabigatran (at steady-state) and Pre-dose plasma concentrations at steady state. Cmax represents the maximum concentration of Dabigatran in plasma. Cmax,ss represents the maximum concentration of Dabigatran in plasma at steady state. Cpre,ss represents pre-dose concentration of Dabigatran in plasma at steady state
Time frame: Day 1 to end of treatment
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| BIBR 1048 50 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax (N=88, 83, 84, 96, 0) | 24.5 ng/mL | Geometric Coefficient of Variation 115 |
| BIBR 1048 50 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cpre at steady-state | 19.6 ng/mL | Geometric Coefficient of Variation 70.7 |
| BIBR 1048 50 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax at steady-state (N=87, 74, 79, 85, 0) | 48.0 ng/mL | Geometric Coefficient of Variation 64.6 |
| BIBR 1048 150 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax (N=88, 83, 84, 96, 0) | 60.5 ng/mL | Geometric Coefficient of Variation 97.3 |
| BIBR 1048 150 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cpre at steady-state | 70.3 ng/mL | Geometric Coefficient of Variation 87.3 |
| BIBR 1048 150 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax at steady-state (N=87, 74, 79, 85, 0) | 165 ng/mL | Geometric Coefficient of Variation 63.6 |
| BIBR 1048 225 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax at steady-state (N=87, 74, 79, 85, 0) | 257 ng/mL | Geometric Coefficient of Variation 62.7 |
| BIBR 1048 225 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cmax (N=88, 83, 84, 96, 0) | 79.9 ng/mL | Geometric Coefficient of Variation 94.7 |
| BIBR 1048 225 mg Bid | Plasma Concentration (Cmax) of Dabigatran | Cpre at steady-state | 113 ng/mL | Geometric Coefficient of Variation 80.9 |
| BIBR 1048 300 mg qd | Plasma Concentration (Cmax) of Dabigatran | Cmax (N=88, 83, 84, 96, 0) | 132 ng/mL | Geometric Coefficient of Variation 81.6 |
| BIBR 1048 300 mg qd | Plasma Concentration (Cmax) of Dabigatran | Cpre at steady-state | 38.0 ng/mL | Geometric Coefficient of Variation 85.9 |
| BIBR 1048 300 mg qd | Plasma Concentration (Cmax) of Dabigatran | Cmax at steady-state (N=87, 74, 79, 85, 0) | 271 ng/mL | Geometric Coefficient of Variation 75.2 |
Secondary
Rate of Transfusions Due to Bleedings
Percentage of patients requiring transfusions due to bleeding .Rate of need of transfusion were to be analysed using a logistic regression with treatment and centre.
Time frame: Day 1 (Day of surgery)
Population: Safety Set (SAFE) population. This included all randomised patients who were treated and who had any available data
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BIBR 1048 50 mg Bid | Rate of Transfusions Due to Bleedings | 0.26 Percentage of patients |
| BIBR 1048 150 mg Bid | Rate of Transfusions Due to Bleedings | 5.38 Percentage of patients |
| BIBR 1048 225 mg Bid | Rate of Transfusions Due to Bleedings | 4.07 Percentage of patients |
| BIBR 1048 300 mg qd | Rate of Transfusions Due to Bleedings | 4.94 Percentage of patients |
| Enoxaparin 40 mg qd | Rate of Transfusions Due to Bleedings | 3.57 Percentage of patients |
p-value: 0.006395% CI: [2.221, 128.142]Regression, Logistic
p-value: 0.002595% CI: [2.983, 167.268]Regression, Logistic
p-value: 0.797395% CI: [0.483, 1.75]Regression, Logistic
p-value: 0.009795% CI: [0.009, 0.522]Regression, Logistic
p-value: 0.237595% CI: [0.758, 3.058]Regression, Logistic
p-value: 0.710495% CI: [0.55, 2.403]Regression, Logistic
Secondary
Volume of Blood Loss
Volume of blood loss was to be analysed using an analysis of variance (ANOVA), which included treatment and centre.
Time frame: Day 1 (Day of surgery)
Population: Safety Set (SAFE) population. This included all randomised patients who were treated and who had any available data
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BIBR 1048 50 mg Bid | Volume of Blood Loss | 523.3 ml | Standard Deviation 845.8 |
| BIBR 1048 150 mg Bid | Volume of Blood Loss | 1538.4 ml | Standard Deviation 1474.5 |
| BIBR 1048 225 mg Bid | Volume of Blood Loss | 631.4 ml | Standard Deviation 720.9 |
| BIBR 1048 300 mg qd | Volume of Blood Loss | 910.3 ml | Standard Deviation 918.3 |
| Enoxaparin 40 mg qd | Volume of Blood Loss | 945.5 ml | Standard Deviation 651.3 |