BIBR 1048 in the Prevention of Venous Thromboembolism in Patients Undergoing Primary Elective Total Hip Replacement Surgery

Study Overview
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Brief Summary
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To determine the therapeutic window of BIBR 1048 in order to select doses for further studies in the development plan. Twice daily regimen will be tested for most dose levels and once daily administration will also be evaluated when appropriate.

Official Title
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Multicenter, Open-label, Ascending Dose Study of BIBR 1048 in the Prevention of Venous Thromboembolism in Patients Undergoing Primary Elective Total Hip Replacement Surgery. Bistro I

Conditions
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Venous Thromboembolism

Intervention / Treatment
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* 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 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 three months. Patients with previous hip fractures associated with plate revisions at any time will be excluded Cardiovascular disease including uncontrolled hypertension at time of enrolment or history of myocardial infarction within the last 6 months Any history of haemorrhagic stroke, intracranial or intraocular bleeding or cerebral ischaemic attacks Known history of deep venous thrombosis (DVT) Gastrointestinal or pulmonary bleeding within the last year Known liver disease Aspartate transaminase (AST) or Alanine transaminase (ALT) > 3 x ULN) Known renal disease (serum creatinine > 1.5 x ULN) Use of long- term anticoagulants, antiplatelet drugs, or fibrinolytics within 7 days prior to hip replacement operation (also contraindicated during the period of prophylaxis) Women of childbearing potential Known allergy to radiopaque contrast media Known thrombocytopenia (prior platelet count below 100,000 cells/microliter) Active malignant disease Current H2 blocker or proton pump inhibitor treatment 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: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BIBR 1048<br>Ascending doses (in mg) given twice daily | Drug: BIBR 1048<br>* Ascending doses (in mg) given twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of venous thrombolic events |  | Up to day 10 after hip surgery | 
| Changes from baseline in activated partial thromboplastin time (aPTT) |  | From baseline (day -14 to day -1 before treatment) until last day of treatment (up to day 10) | 
| Changes from baseline in ecarin clotting time (ECT) |  | From baseline (day -14 to day -1 before treatment) until last day of treatment (up to day 10) | 
| Changes from baseline in thrombin time (TT) |  | From baseline (day -14 to day -1 before treatment) until last day of treatment (up to day 10) | 
| Rate of major bleeding events during treatment phase |  | Start of treatment (day 0) until end of treatment (up to day 10) | 
| Cpre,ss (predose plasma concentrations at steady state) |  | baseline and predose from day 1 to last treatment day | 
| Cmax,ss (maximum plasma concentration at steady state (day 4)) |  | Day 4 | 
| Tmax,ss (time to reach Cmax,ss) |  | baseline, day 0 before and 4 hours after, day 1 to 4 before and 2 h after treatment, day 5 to last treatment day before treatment | 
| CLtot/f (total clearance of drug from plasma after oral administration) |  | baseline, day 0 before and 4 hours after, day 1 to 4 before and 2 h after treatment, day 5 to last treatment day before treatment | 
| AUCss (area under the plasma concentration curve of one dosing interval at steady state) |  | baseline, day 0 before and 4 hours after, day 1 to 4 before and 2 h after treatment, day 5 to last treatment day before treatment | 
| PTF (percent peak trough fluctuation for the last dosing interval) |  | baseline, day 0 before and 4 hours after, day 1 to 4 before and 2 h after treatment, day 5 to last treatment day before treatment | 
| Cmax,ss (maximum plasma concentration at steady state (day 4)) |  | Day 4 before and 0.5, 1, 2, 4 , 8, 12 , 14 h after treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Venous thromboembolism diagnosed during the follow-up period |  | Up to 6 weeks after surgery (day 42) |