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

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.

Study Overview

• Status: Completed
• Conditions: Venous Thromboembolism
• Intervention / Treatment: Drug: BIBR 1048; Drug: BIBR 1048; Drug: BIBR 1048; Drug: BIBR 1048; Drug: Enoxaparin

• Study Type: Interventional
• Enrollment (Actual): 1973
• Phase: Phase 2

Contacts and Locations

Study Locations

• Austria
  • Linz, Austria
    • 1160.19.43004 Krankenhaus der Barmherzigen Schwestern Linz
  • Wien, Austria
    • 1160.19.43002 Orthopädisches Spital Speising
  • Wr. Neustadt, Austria
    • 1160.19.43001 A.ö. Krankenhaus d. Statutarstadt Wiener Neustadt
• Belgium
  • Brussel, Belgium
    • 1160.19.32002 V.U.B. Jette
  • Gent, Belgium
    • 1160.19.32004 UZ Gent
  • Gent, Belgium
    • 1160.19.32005 Virga Jesseziekenhuis
  • Huy, Belgium
    • 1160.19.32006 Boehringer Ingelheim Investigational Site
  • La Louvière, Belgium
    • 1160.19.32007 C.H.U. de Tivoli
• Czech Republic
  • Brno-Bohunice, Czech Republic
    • 1160.19.42004 University Hospital Brno
  • Kladno, Czech Republic
    • 1160.19.42001 Hospital Kladno
  • Mlada Boleslav, Czech Republic
    • 1160.19.42006 Hospital Mlada Boleslav
  • Ostrava, Czech Republic
    • 1160.19.42003 University Hospital Ostrava
  • Plzen, Czech Republic
    • 1160.19.42005 University Hospital Plzen
  • Prague 8, Czech Republic
    • 1160.19.42009 University Hospital Na Bulovce
• Denmark
  • Frederiksberg, Denmark
    • 1160.19.45042 Orthopedic Surgical Clinic
  • Hellerup, Denmark
    • 1160.19.45045 Gentofte Hospital
  • Herlev, Denmark
    • 1160.19.45043 Herlev Hospital
  • Hørsholm, Denmark
    • 1160.19.45041 Hørsholm Sygehus
  • Silkeborg, Denmark
    • 1160.19.45044 Orthopedic Surgical Dept.
• Finland
  • Jyväskylä, Finland
    • 1160.19.35802 Keski-Suomen keskussairaala
  • Oulu, Finland
    • 1160.19.35801 Oulun yliopistollinen sairaala, Leikkaus- ja tehohoidon yks.
• France
  • Illkirch cedex, France
    • 1160.19.33004 Div
  • La Rochelle, France
    • 1160.19.33007 Clinique du Mail
  • Lyon cedex 03, France
    • 1160.19.33009 Hôpital Edouard Herriot
  • Saint-Etienne cedex 2, France
    • 1160.19.33006 Clinique Mutualiste
  • St Herblain cedex, France
    • 1160.19.33008 Clinique de l'Atlantique
• Hungary
  • Budapest, Hungary
    • 1160.19.36003 Sándor Péterfy Hospital
  • Gyula, Hungary
    • 1160.19.36001 Kálmán Pándy County Hospital
  • Kecskemét, Hungary
    • 1160.19.36004 Bács-Kiskun County Hospital
  • Szeged, Hungary
    • 1160.19.36002 Albert Szent-Györgyi Medical and Pharmacological Center
  • Székesfehérvár, Hungary
    • 1160.19.36005 Szent György Hospital
• Italy
  • Bergamo, Italy
    • 1160.19.39003 U. O. Ortopedia e Traumatologia
  • Bologna, Italy
    • 1160.19.39005 Modulo Coordinazione Dipartimentale di Ricerca e Anestesia
  • Milano, Italy
    • 1160.19.39002 Fondazione Centro S. Raffaele
  • Pavia, Italy
    • 1160.19.39001 IRCCS Policlinico San Matteo
  • Varese, Italy
    • 1160.19.39004 Ospedale di Circolo di Varese
• Netherlands
  • Amsterdam, Netherlands
    • 1160.19.31001 Boehringer Ingelheim Investigational Site
  • Hilversum, Netherlands
    • 1160.19.31003 Boehringer Ingelheim Investigational Site
  • Nijmegen, Netherlands
    • 1160.19.31005 Hengstdal 3
  • Sittard, Netherlands
    • 1160.19.31006 Boehringer Ingelheim Investigational Site
  • Zwolle, Netherlands
    • 1160.19.31004 Boehringer Ingelheim Investigational Site
• Norway
  • Bodø, Norway
    • 1160.19.47001 Nordlandssykehuset HF, Bodø
  • Bærum Postterminal, Norway
    • 1160.19.47004 Martina Hansens Hospital
  • Bærum Postterminal, Norway
    • 1160.19.47008 Martina Hansens Hospital
  • Elverum, Norway
    • 1160.19.47007 Sykehuset Innlandet HF, Avd. Elverum
  • Haugesund, Norway
    • 1160.19.47005 Haugesund sjukehus HF
  • Skien, Norway
    • 1160.19.47002 Sykehuset Telemark HF, Avd. Skien
  • Ålesund, Norway
    • 1160.19.47003 Helse Sunnmøre HF, Ålesund sykehus
• South Africa
  • Johannesburg, South Africa
    • 1160.19.27001 Dept. of Haematology
  • Johannesburg, South Africa
    • 1160.19.27002 Suite 203
• Sweden
  • Falköping, Sweden
    • 1160.19.46002 Kirurgavdelningen
  • Göteborg, Sweden
    • 1160.19.46001
  • Halmstad, Sweden
    • 1160.19.46004 Ortopediska kliniken, Länssjukhuset, Halmstad
  • Kalmar, Sweden
    • 1160.19.46003 Ortopediska kliniken, Länssjukhuset i Kalmar
  • Kungälvs, Sweden
    • 1160.19.46007 Kungälvs sjukhus
  • Lidköping, Sweden
    • 1160.19.46005 Kirurg Ortopediska kliniken, Sjukhuset i Lidköping
  • Linköping, Sweden
    • 1160.19.46008 Ortopediska Institutionen
  • Mölndal, Sweden
    • 1160.19.46009 Sahlgrenska Universitetssjukhuset, Mölndal
  • Varberg, Sweden
    • 1160.19.46006 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start: November 1, 2002
• Primary Completion (Actual): August 1, 2003

Study Registration Dates

• First Submitted: October 20, 2010
• First Submitted That Met QC Criteria: October 20, 2010
• First Posted (Estimate): October 21, 2010

Study Record Updates

• Last Update Posted (Estimate): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 8, 2014
• Last Verified: February 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Embolism and Thrombosis; Thromboembolism; Venous Thromboembolism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Fibrinolytic Agents; Fibrin Modulating Agents; Protease Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Dabigatran; Enoxaparin
• Other Study ID Numbers: 1160.19