BIBR 1048 Dose Range Finding Study in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip or Knee Replacement Surgery

Study Overview
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Brief Summary
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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.

Official Title
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BIBR 1048 Dose Range Finding Study in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip or Knee Replacement Surgery

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* Drug: Enoxaparin
* Drug: BIBR 1048
* Drug: BIBR 1048
* Drug: BIBR 1048
* Drug: BIBR 1048


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Patients scheduled to undergo a primary elective total hip or knee replacement. Male of female being 18 years or older. Patients weighing at least 40 kg. Written informed consent for study participation. Exclusion criteria Bleeding diathesis, constitutional or acquired coagulation disorders. Major surgery or trauma(e.g., hip fracture) within the last 3 months. Cardiovascular disease Any history of haemorrhagic stroke, intracranial or intraocular bleeding or cerebral ischaemic attacks lasting more than 24 hours and / or with cardiovascular pathological findings. Deep vein thrombosis(DVT), gastrointestinal or pulmonary bleeding, gastric or duodenal ulcer within the last year. History of or acute intracranial disease Liver disease Renal disease Use of long-term anticoagulants or antiplatelet drugs within 7 days prior to hip/knee replacement operation. 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 Known allergy to contrast media Thrombocytopenia Allergy against heparin. Active malignant disease or current cytostatic treatment. Treatment with an investigational drug in the past month. Leg amputee Known alcohol or drug abuse

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBR 1048 50 mg bis in die(b.i.d)<br>BIBR 1048 50 mg b.i.d twice a day plus two capsules of placebo matching BIBR 1048 0 mg twice a day plus one placebo matching enoxaparin 0 mg once a day for the treatment period | Drug: BIBR 1048<br>* 50 mg b.i.d BIBR 1048 capsule twice a day for 5-10 days of treatment period<br>|
| Experimental: BIBR 1048 150 mg b.i.d<br>BIBR 1048 150 mg b.i.d twice a day plus two capsules of placebo matching BIBR 1048 0 mg twice a day plus placebo matching enoxaparin 0 mg once a day for the treatment period | Drug: BIBR 1048<br>* 150 mg b.i.d BIBR 1048 capsule twice a day for 5-10 treatment period<br>|
| Experimental: BIBR 1048 225 mg b.i.d<br>BIBR 1048 225 mg b.i.d twice a day plus two capsules of placebo matching BIBR 1048 0 mg twice a day plus placebo matching enoxaparin 0 mg once a day for the treatment period | Drug: BIBR 1048<br>* 225 mg b.i.d BIBR 1048 capsule twice a day for 5-10 treatment period<br>|
| Experimental: BIBR 1048 300 mg quaque die(q.d)<br>BIBR 1048 150 mg q.d once a day plus placebo matching BIBR 1048 0 mg twice a day plus placebo matching enoxaparin 0 mg once a day for the treatment period | Drug: BIBR 1048<br>* 300 mg q.d BIBR 1048 capsule for 5-10 treatment period<br>|
| Active Comparator: Enoxaparin 40 mg subcutaneous(s.c)<br>placebo matching BIBR 1048 0 mg twice a day plus enoxaparin 40 mg s.c once a day for the treatment period | Drug: Enoxaparin<br>* Enoxaparin 40 mg s.c once a day for 5-10 days of treatment period<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Treatment period (up to day 8+/-2 days visit) | 
| Number of Participants With Major Bleeding Events (MBE) |  | From approximately 14 days prior to surgery to 4-6 weeks post surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Treatment period (up to day 8+/-2 days visit) | 
| 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 | Treatment period (up to day 10) | 
| 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 | Treatment period (up to day 8+/-2 days visit) | 
| Volume of Blood Loss | Volume of blood loss was to be analysed using an analysis of variance (ANOVA), which included treatment and centre. | Day 1 (Day of surgery) | 
| 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. | Day 1 (Day of surgery) | 
| 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. | Treatment period (up to day 8+/-2 days visit) | 
| 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 | Screening to end of treatment | 
| 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 | Day 1 to end of treatment | 
| 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. | up to day 8+/-2 days visit |