Dabigatran Etexilate vs Enoxaparin in Prevention of Venous Thromboembolism (VTE) Post Total Knee Replacement

Arthroplasty, Replacement, Knee Clinical Trial

Official title:

A Phase III, Randomized, Parallel-group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Two Different Dose Regimens (75mg Day 1 Followed by 150 mg Day 2-completion, and 110 mg Day 1 Followed by 220 mg Day 2-completion) of Dabigatran Etexilate Administered Orally (Capsules), Compared to Enoxaparin 30 mg Twice a Day Subcutaneous for 12 - 15 Days in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Knee Replacement Surgery

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00152971
• Other study ID #: 1160.24
• Status: Completed
• Phase: Phase 3
• First received: September 8, 2005
• Last updated: April 22, 2014
• Start date: November 2004

Study information

• Verified date: April 2014
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada:Great Britain:Mexico:United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

To determine the comparative efficacy and safety of two different doses (75mg day 1 followed by 150 mg day 2-completion, and 110 mg day 1 followed by 220 mg day 2-completion) of dabigatran administered orally (capsules), compared to enoxaparin 30 mg twice a day subcutaneous, in prevention of venous thromboembolism in patients with primary elective total knee replacement surgery

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2615
• Est. primary completion date: June 2006
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion criteria INCLUSION CRITERIA

1. Patients scheduled to undergo a primary, unilateral elective total knee repla cement.

2. Male or female 18 years of age or older.

3. Patients weighing at least 40 kg.

4. Written informed consent prior to the start of study participation.

Exclusion criteria EXCLUSION CRITERIA

1. History of bleeding diathesis.

2. Constitutional or acquired coagulation disorders that in the investigator's judgment puts the patient at excessive risk for bleeding.

3. Major surgery or trauma (e.g. hip fracture) within the last 3 months.

4. Recent unstable cardiovascular disease, such as uncontrolled hypertension at the time of enrollment (investigator's judgment) or history of myocardial infarction within the last 3 months.

5. Spinal or epidural anesthesia, for which more than 3 attempts (sticks) at placement were made, or the placement was traumatic.

Please note that patients, who are not excluded under this criterion, are to have the catheter pulled at the completion of surgery.

6. Any history of hemorrhagic stroke or any of the following intracranial pathologies:

bleeding, neoplasm, arteriovenous (AV) malformation or aneurysm.

7. History of VTE or pre-existing condition requiring anticoagulant therapy.

8. Clinically relevant bleeding (e.g. gastrointestinal, pulmonary, intraocular or urogenital bleeding) within the last 6 months.

9. Gastric or duodenal ulcer within the last 6 months.

10. Liver disease expected to have any potential impact on survival (e.g. hepatitis B or C, cirrhosis, but not Gilbert's syndrome or hepatitis A with complete recovery).

11. Elevated AST or ALT >2x upper limit of normal, based on central lab results or local lab results within 1 month before enrollment.

12. Known severe renal insufficiency (CrCl < 30 mL/min). In order to determine patient inclusion/exclusion, creatinine clearance (CrCl) needs to be calculated only if serum creatinine is elevated or renal insufficiency is suspected.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Arthroplasty, Replacement, Knee
• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Dabigatran Dose 1 - day 2 to completion
low dose regimen taken once daily
• Dabigatran Dose 1 - day 1
low dose regimen taken once daily
• Dabigatran Dose 2 - day 2 to completion
high dose regimen taken once daily
• Dabigatran Dose 2 - day 1
high dose regimen taken once daily
• Enoxaparin
30 mg subcutaneously twice daily

Locations

Country	Name	City	State
Canada	1160.24.02021 Rouge Valley Health System	Ajax	Ontario
Canada	1160.24.02008 Orthopaedic Surgery	Barrie	Ontario
Canada	1160.24.02016 Orthopaedic Surgery	Brantford	Ontario
Canada	1160.24.02010 Joseph Brant Memorial Hospital	Burlington	Ontario
Canada	1160.24.02013 Queen Elizabeth Hospital	Charlottetown	Prince Edward Island
Canada	1160.24.02031 University of Alberta Hospital	Edmonton	Alberta
Canada	1160.24.02036 2B2.37 Walter Mackenizie Centre	Edmonton	Alberta
Canada	1160.24.02007 Orthopaedics 4NE	Fredericton	New Brunswick
Canada	1160.24.02001 73 Delhi Street	Guelph	Ontario
Canada	1160.24.02014 565 Sanatorium Road	Hamilton	Ontario
Canada	1160.24.02032 Kelowna General Hospital	Kelowna	British Columbia
Canada	1160.24.02004 Grand River Hospital	Kitchener	Ontario
Canada	1160.24.02028 NHS- Greater Niagara General Site	Niagara Falls	Ontario
Canada	1160.24.02022 Lakeridge Health Oshawa	Oshawa	Ontario
Canada	1160.24.02017 1053 Carling Avenue	Ottawa	Ontario
Canada	1160.24.02026 Ottawa Hospital - General Campus	Ottawa	Ontario
Canada	1160.24.02024 Red Deer Regional Hospital	Red Deer	Alberta
Canada	1160.24.02015 York Central Hospital Research	Richmond Hill	Ontario
Canada	1160.24.02027 Atlantic Health Sciences Corporation	Saint John	New Brunswick
Canada	1160.24.02009 2863 Ellesmere Road	Scarborough	Ontario
Canada	1160.24.02029 Niagara Health System St. Catharine's General Site	St. Catherine's	Ontario
Canada	1160.24.02003 46 General Hospital Drive	Stratford	Ontario
Canada	1160.24.02033 Thunder Bay Regional Hospital	Thunder Bay	Ontario
Canada	1160.24.02002 Toronto East General Hospital Fracture Clinic	Toronto	Ontario
Canada	1160.24.02023 North York General Hospital	Toronto	Ontario
Canada	1160.24.02030 St. Joseph's Health Centre	Toronto	Ontario
Canada	1160.24.02034 Hematology/Oncology Research	Vancouver	British Columbia
Canada	1160.24.02006 206-477 King Street	Welland	Ontario
Canada	1160.24.02035 Humber River Regional Hospital	Weston	Ontario
Canada	1160.24.02011 Windsor Regional Hospital	Windsor	Ontario
Canada	1160.24.02012 Hotel Dieu Grace Hospital	Windsor	Ontario
Canada	1160.24.02025 Grace General Hospital	Winnipeg	Manitoba
Mexico	1160.24.05009 Traumatologia, Planta Baja	Guadalajara, Jalisco
Mexico	1160.24.05004	México
United Kingdom	1160.24.44001 Ravenscourt Park Hospital	London
United States	1160.24.01012 Anderson Orthopedic Clinic	Alexandria	Virginia
United States	1160.24.01063 Resurgens Orthopaedics	Atlanta	Georgia
United States	1160.24.01072 Resurgeons Orthopedics	Atlanta	Georgia
United States	1160.24.01031 Colorodo Orthopedic Consultants, PC	Aurora	Colorado
United States	1160.24.01032 Seton Medical Center	Austin	Texas
United States	1160.24.01070 Sinai Hospital of Baltimore	Baltimore	Maryland
United States	1160.24.01020 Bay Pines VA Medical Center	Bay Pines	Florida
United States	1160.24.01002 The Orthopedic and Neurological Center of the Cascades	Bend	Oregon
United States	1160.24.01074 Capstone Clinical Trials, Inc.	Birmingham	Alabama
United States	1160.24.01028 Intermountain Research Center	Boise	Idaho
United States	1160.24.01024 Pulmonary Associates of Brandon Clinical Research	Brandon	Florida
United States	1160.24.01016	Charleston	South Carolina
United States	1160.24.01014 Charlotte Orthopedic Specialists	Charlotte	North Carolina
United States	1160.24.01035 Wellington Orthopedics and Sports Medicine	Cincinnati	Ohio
United States	1160.24.01030 Alliance Research, Inc.	Clearwater	Florida
United States	1160.24.01073 Coastal Orthopedic Associates, PA	Conway	South Carolina
United States	1160.24.01003 Texas Orthopedic Associates	Dallas	Texas
United States	1160.24.01090 VA Medical Center	Dallas	Texas
United States	1160.24.01039 Florida Orthopedic Associates	Deland	Florida
United States	1160.24.01027 Advanced Orthopedic and Sports Medicine Specialists, PC	Denver	Colorado
United States	1160.24.01022 Iowa Orthopedic Clinic	Des Moines	Iowa
United States	1160.24.01041 Core Orthopedic Medical Center	Encinitas	California
United States	1160.24.01023 Orthopedic Physicians of Colorado, PC	Engelwood	Colorado
United States	1160.24.01034 Glendale Adventist Medical Center	Glendale	California
United States	1160.24.01036 Orthopaedic Associates of South Broward, PA	Hollywood	Florida
United States	1160.24.01026 James Muntz, MD	Houston	Texas
United States	1160.24.01033 Bone and Joint Clinic of Houston	Houston	Texas
United States	1160.24.01076 Discovery Alliance	Houston	Texas
United States	1160.24.01059 Rockhill Orthopaedics	Kansas City	Missouri
United States	1160.24.01005 Scripps Clinical Ctr for Orthopedic Rsrch & Educ	La Jolla	California
United States	1160.24.01056 Southern Orthopaedic Specialists	Lawrencville	Georgia
United States	1160.24.01008 Bluegrass Orthopedic/Musculoskeletal Research, LLC	Lexington	Kentucky
United States	1160.24.01025 Martin, Bowen, Hefley Knee and Sports	Little Rock	Arkansas
United States	1160.24.01053 OrthoArkansas, PA	Little Rock	Arkansas
United States	1160.24.01085 Martin, Bowen, Hefley Knee and Sports	Little Rock	Arkansas
United States	1160.24.01077 Long Beach VA Healthcare system	Long Beach	California
United States	1160.24.01018 Gill Research Center	Lubbock	Texas
United States	1160.24.01010 MIMA Century Research Associates	Melbourne	Florida
United States	1160.24.01062 Miami Institute for Joint Reconstruction	Miami	Florida
United States	1160.24.01042 Center for Joint Care	Missoula	Montana
United States	1160.24.01079 West AL Research, Inc	Northport	Alabama
United States	1160.24.01006 VA Medical Center	Oklahoma City	Oklahoma
United States	1160.24.01064 Orthopedic Specialty Institute	Orange	California
United States	1160.24.01040 Southern Clinical Research Consultants	Orlando	Florida
United States	1160.24.01067 Baptist Clinical Research	Pensacola	Florida
United States	1160.24.01046 Boehringer Ingelheim Investigational Site	Philadelphia	Pennsylvania
United States	1160.24.01001 Boehringer Ingelheim Investigational Site	Pinellas Park	Florida
United States	1160.24.01017 Boehringer Ingelheim Investigational Site	Pinellas Park	Florida
United States	1160.24.01019 Boehringer Ingelheim Investigational Site	Pinellas Park	Florida
United States	1160.24.01069 Correspondence and Pateint vists	Plano	Texas
United States	1160.24.01029 Coastal Medical Research	Port Orange	Florida
United States	1160.24.01015 Unlimited Research, LP	San Antonio	Texas
United States	1160.24.01052 Swedish Medical Center	Seattle	Washington
United States	1160.24.01057 Orthopedic Specialty Clinic of Spokane, PLLC	Spokane	Washington
United States	1160.24.01082 MultiCare Health System	Tacoma	Washington
United States	1160.24.01038 James A. Haley VA Hospital	Tampa	Florida
United States	1160.24.01007 Ortho Associates	Towson	Maryland
United States	1160.24.01047 Tucson Orhtopaedic Institute	Tucson	Arizona
United States	1160.24.01044 Tulsa Bone and Joint Associates	Tulsa	Oklahoma

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Canada,  Mexico,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period	Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy).; All of these components and all deaths were centrally adjudicated by the VTE events committee, which was not aware of the treatment allocation of the patients.	First administration until 12-15 days	No
Secondary	Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period	Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period	Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants With Total Deep Vein Thrombosis During Treatment Period	Total Deep Vein Thrombosis as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period	Symptomatic Deep Vein Thrombosis, confirmed by venous compression ultrasound, venography or autopsy, and as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants With Pulmonary Embolism During Treatment Period	Pulmonary embolism confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy, and as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants Who Died During Treatment Period	All cause death, as adjudicated by the VTE events committee	First administration until 12-15 days	No
Secondary	Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period	Total Venous Thromboembolic Event (VTE) includes both proximal and distal deep vein thrombosis (DVT) (detected by routine bilateral venography), symptomatic DVT (confirmed by venous compression ultrasound, venography or autopsy) and pulmonary embolism (PE) (confirmed by pulmonary V-Q scintigraphy, chest x-ray, pulmonary angiography, spiral CT or autopsy).	3 months	No
Secondary	Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period	Major bleeding events were defined as; fatal; clinically overt associated with loss of haemoglobin >=20g/L in excess of what was expected; clinically overt leading to the transfusion of >=2 units packed cells or whole blood in excess of what was expected; symptomatic retroperitoneal, intracranial, intraocular or intraspinal; requiring treatment cessation; leading to re-operation; Clinically-relevant was defined as; spontaneous skin hematoma greater than or equal to 25 cm²; wound hematoma greater than or equal to 100 cm²; spontaneous nose bleed lasting longer than 5 min; macroscopic hematuria spontaneous or lasting longer than 24 hours if associated with an intervention; spontaneous rectal bleeding (more than a spot on toilet paper); gingival bleeding lasting longer than 5 min; any other bleeding event considered clinically relevant by the investigator; Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.	First administration until 12-15 days	Yes

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