Clinical trial NCT00657150: Dabigatran Etexilate Compared With Enoxaparin in Prevention of Venous Thromboembolism (VTE) Following Total Hip Arthroplasty
Official title: A Phase III Randomised, Parallel Group, Double-blind, Active Controlled Study to Investigate the Efficacy and Safety of Orally Administered 220 mg Dabigatran Etexilate Capsules (110 mg Administered on the Day of Surgery Followed by 220 mg Once Daily) Compared to Subcutaneous 40 mg Enoxaparin Once Daily for 28-35 Days, in Prevention of Venous Thromboembolism in Patients With Primary Elective Total Hip Arthroplasty Surgery. (RE-NOVATE II)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Venous Thromboembolism
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2008-04-14
Enrollment: 2055
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The primary objective of the trial is to demonstrate non-inferiority of 220 mg oral dabigatran etexilate compared to 40 mg subcutaneous enoxaparin administered once daily. Safety and efficacy will be compared between the treatment groups.


Eligibility criteria: Inclusion criteria:

* Patients scheduled to undergo primary, unilateral, elective total hip arthroplasty.
* Male or female 18 years of age or older.
* Patients giving written informed consent for study participation.

Exclusion criteria:

* Patients weighing less than 40 kg.
* History of bleeding diathesis.
* Patients who in the investigators judgement are perceived as having an excessive risk of bleeding, for example, constitutional or acquired coagulation disorders or because of anticipated need of quinidine, verapamil or other restricted medication during the treatment period (see Section 4.2.2).
* Major surgery or trauma (e.g., hip fracture) within 3 months of enrolment.
* Recent unstable cardiovascular disease (in the investigators opinion) such as uncontrolled hypertension, that is ongoing at the time of enrolment or history of myocardial infarction within 3 months of enrolment.
* Any history of haemorrhagic stroke or any of the following intracranial pathologies: bleeding, neoplasm, Atriovenous (AV) malformation or aneurysm.
* Ongoing treatment for Venous Thromboembolism (VTE).
* Clinically relevant bleeding (gastrointestinal, pulmonary, intraocular or urogenital bleeding) within 6 months of enrolment.
* Gastric or duodenal ulcer within one year of enrolment.
* Liver disease expected to have any potential impact on survival (ie, hepatitis B or C, cirrhosis). This does not include Gilberts syndrome or hepatitis A with complete recovery.
* Active liver disease or liver disease decreasing survival (e.g, acute hepatitis, chronic active hepatitis, cirrhosis) or Alanine Aminotransferase (ALT) \>3 x ULN.
* Known severe renal insufficiency (CrCl \<30 ml/min). Note: CrCl should be calculated only if serum creatinine is elevated or renal insufficiency is suspected. See Appendix 10.1 for calculation.
* Elevated creatinine that, in the investigators opinion, contraindicates venography.
* Treatment with anticoagulants, clopidogrel, ticlopidine, abciximab, aspirin \>162.5 mg/day or NSAID with t 1/2 \>12 hours within 7 days prior to hip replacement surgery OR anticipated need while the patient is receiving study medication and prior to 24 hours after the last administration of any blinded study medication (COX-2 selective inhibitors are allowed).
* Anticipated required use of intermittent pneumatic compression and electric stimulation of lower limb.
* Pre-menopausal women (last menstruation within 1 year prior to signing informed consent) who:

  * Are pregnant.
  * Are nursing.
  * Are of child-bearing potential and are NOT practicing acceptable methods of birth control, or do NOT plan to continue practicing an acceptable method throughout the study. Acceptable methods of birth control include intrauterine device; oral, implantable or injectable contraceptives and surgical sterility.
* Known allergy to radio opaque contrast media.
* History of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count \<100,000 cells/microliter at randomisation.
* Allergy to heparins or dabigatran etexilate.
* Active malignant disease or current cytostatic treatment. Patients should be disease free for at least 5 years.
* Participation in a clinical trial within 30 days of randomisation.
* Leg amputee.
* Known alcohol or drug abuse which would interfere with completion of the study.
* Contraindications to enoxaparin.
* Previous participation in this study.

Primary outcomes:
measure: Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period
timeFrame: 28-35 days
Secondary outcomes:
measure: Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants With Total Deep Vein Thrombosis During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants With Pulmonary Embolism During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants Who Died During Treatment Period
timeFrame: 28-35 days
measure: Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period
timeFrame: 3 months
measure: Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period
timeFrame: 28-35 days
measure: Blood Transfusion
timeFrame: Day 1
measure: Volume of Blood Loss
timeFrame: Day 1
measure: Laboratory Analyses
timeFrame: First administration to end of study
Other outcomes:
Locations:
city: La Jolla
country: United States
facility: 1160.64.01005 Boehringer Ingelheim Investigational Site
state: California
city: Aurora
country: United States
facility: 1160.64.01010 Boehringer Ingelheim Investigational Site
state: Colorado
city: Englewood
country: United States
facility: 1160.64.01009 Boehringer Ingelheim Investigational Site
state: Colorado
city: Clearwater
country: United States
facility: 1160.64.01012 Boehringer Ingelheim Investigational Site
state: Florida
city: Lexington
country: United States
facility: 1160.64.01006 Boehringer Ingelheim Investigational Site
state: Kentucky
city: Missoula
country: United States
facility: 1160.64.01003 Boehringer Ingelheim Investigational Site
state: Montana
city: Charleston
country: United States
facility: 1160.64.01007 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Conway
country: United States
facility: 1160.64.01013 Boehringer Ingelheim Investigational Site
state: South Carolina
city: Houston
country: United States
facility: 1160.64.01002 Boehringer Ingelheim Investigational Site
state: Texas
city: Spokane
country: United States
facility: 1160.64.01011 Boehringer Ingelheim Investigational Site
state: Washington
city: Daws Park
country: Australia
facility: 1160.64.2003 Boehringer Ingelheim Investigational Site
state: South Australia
city: Box HIll
country: Australia
facility: 1160.64.2002 Boehringer Ingelheim Investigational Site
state: Victoria
city: Windsor
country: Australia
facility: 1160.64.2001 Boehringer Ingelheim Investigational Site
state: Victoria
city: Nedlands
country: Australia
facility: 1160.64.2004 Boehringer Ingelheim Investigational Site
state: Western Australia
city: Graz
country: Austria
facility: 1160.64.4004 Boehringer Ingelheim Investigational Site
city: Linz
country: Austria
facility: 1160.64.4002 Boehringer Ingelheim Investigational Site
city: Wels
country: Austria
facility: 1160.64.4003 Boehringer Ingelheim Investigational Site
city: Wien
country: Austria
facility: 1160.64.4001 Boehringer Ingelheim Investigational Site
city: Brussel
country: Belgium
facility: 1160.64.5004 Boehringer Ingelheim Investigational Site
city: Deurne
country: Belgium
facility: 1160.64.5002 Boehringer Ingelheim Investigational Site
city: Lanaken
country: Belgium
facility: 1160.64.5005 Boehringer Ingelheim Investigational Site
city: Leuven
country: Belgium
facility: 1160.64.5001 Boehringer Ingelheim Investigational Site
city: Edmonton,
country: Canada
facility: 1160.64.6009 Boehringer Ingelheim Investigational Site
state: Alberta
city: Red Deer
country: Canada
facility: 1160.64.6002 Boehringer Ingelheim Investigational Site
state: Alberta
city: Ajax
country: Canada
facility: 1160.64.6012 Boehringer Ingelheim Investigational Site
state: Ontario
city: Belleville
country: Canada
facility: 1160.64.6003 Boehringer Ingelheim Investigational Site
state: Ontario
city: Cambridge
country: Canada
facility: 1160.64.6004 Boehringer Ingelheim Investigational Site
state: Ontario
city: Kitchener
country: Canada
facility: 1160.64.6008 Boehringer Ingelheim Investigational Site
state: Ontario
city: Oshawa
country: Canada
facility: 1160.64.6011 Boehringer Ingelheim Investigational Site
state: Ontario
city: Sarnia
country: Canada
facility: 1160.64.6005 Boehringer Ingelheim Investigational Site
state: Ontario
city: Stratford
country: Canada
facility: 1160.64.6007 Boehringer Ingelheim Investigational Site
state: Ontario
city: Windsor
country: Canada
facility: 1160.64.6013 Boehringer Ingelheim Investigational Site
state: Ontario
city: Chomutov
country: Czech Republic
facility: 1160.64.7004 Boehringer Ingelheim Investigational Site
city: Jihlava
country: Czech Republic
facility: 1160.64.7005 Boehringer Ingelheim Investigational Site
city: Kolin
country: Czech Republic
facility: 1160.64.7003 Boehringer Ingelheim Investigational Site
city: Plzen
country: Czech Republic
facility: 1160.64.7001 Boehringer Ingelheim Investigational Site
city: Prague 8
country: Czech Republic
facility: 1160.64.7002 Boehringer Ingelheim Investigational Site
city: Frederiksberg
country: Denmark
facility: 1160.64.8004 Boehringer Ingelheim Investigational Site
city: Herlev
country: Denmark
facility: 1160.64.8003 Boehringer Ingelheim Investigational Site
city: Hørsholm
country: Denmark
facility: 1160.64.8001 Boehringer Ingelheim Investigational Site
city: Silkeborg
country: Denmark
facility: 1160.64.8002 Boehringer Ingelheim Investigational Site
city: Jyväskylä
country: Finland
facility: 1160.64.9002 Boehringer Ingelheim Investigational Site
city: Oulu
country: Finland
facility: 1160.64.9001 Boehringer Ingelheim Investigational Site
city: Tampere
country: Finland
facility: 1160.64.9003 Boehringer Ingelheim Investigational Site
city: Garmisch-Partenkirchen
country: Germany
facility: 1160.64.1104 Boehringer Ingelheim Investigational Site
city: Mainz
country: Germany
facility: 1160.64.1101 Boehringer Ingelheim Investigational Site
city: Markgröningen
country: Germany
facility: 1160.64.1103 Boehringer Ingelheim Investigational Site
city: Rheinfelden
country: Germany
facility: 1160.64.1102 Boehringer Ingelheim Investigational Site
city: Gyula
country: Hungary
facility: 1160.64.1201 Boehringer Ingelheim Investigational Site
city: Kecskemét
country: Hungary
facility: 1160.64.1203 Boehringer Ingelheim Investigational Site
city: Szeged
country: Hungary
facility: 1160.64.1202 Boehringer Ingelheim Investigational Site
city: Székesfehérvár
country: Hungary
facility: 1160.64.1204 Boehringer Ingelheim Investigational Site
city: Ahmedabad
country: India
facility: 1160.64.9105 Boehringer Ingelheim Investigational Site
city: Andhra Pradesh
country: India
facility: 1160.64.9112 Boehringer Ingelheim Investigational Site
city: Andhra Predesh
country: India
facility: 1160.64.9109 Boehringer Ingelheim Investigational Site
city: Bangalore
country: India
facility: 1160.64.9103 Boehringer Ingelheim Investigational Site
city: Bangalore
country: India
facility: 1160.64.9108 Boehringer Ingelheim Investigational Site
city: Baroda
country: India
facility: 1160.64.9107 Boehringer Ingelheim Investigational Site
city: Mangalore
country: India
facility: 1160.64.9110 Boehringer Ingelheim Investigational Site
city: Mohali
country: India
facility: 1160.64.9104 Boehringer Ingelheim Investigational Site
city: New Delhi
country: India
facility: 1160.64.9111 Boehringer Ingelheim Investigational Site
city: Pune
country: India
facility: 1160.64.9106 Boehringer Ingelheim Investigational Site
city: Ramdaspeth Nagpur
country: India
facility: 1160.64.9101 Boehringer Ingelheim Investigational Site
city: Secunderabad
country: India
facility: 1160.64.9102 Boehringer Ingelheim Investigational Site
city: Vadodara
country: India
facility: 1160.64.9113 Boehringer Ingelheim Investigational Site
city: Bologna
country: Italy
facility: 1160.64.1401 Boehringer Ingelheim Investigational Site
city: Parma
country: Italy
facility: 1160.64.1405 Boehringer Ingelheim Investigational Site
city: Pavia
country: Italy
facility: 1160.64.1402 Boehringer Ingelheim Investigational Site
city: Reggio Emilia
country: Italy
facility: 1160.64.1407 Boehringer Ingelheim Investigational Site
city: Roma
country: Italy
facility: 1160.64.1403 Boehringer Ingelheim Investigational Site
city: Torino
country: Italy
facility: 1160.64.1404 Boehringer Ingelheim Investigational Site
city: Amsterdam
country: Netherlands
facility: 1160.64.1503 Boehringer Ingelheim Investigational Site
city: Amsterdam
country: Netherlands
facility: 1160.64.1507 Boehringer Ingelheim Investigational Site
city: Hilversum
country: Netherlands
facility: 1160.64.1501 Boehringer Ingelheim Investigational Site
city: Hoofddorp
country: Netherlands
facility: 1160.64.1506 Boehringer Ingelheim Investigational Site
city: Leiden
country: Netherlands
facility: 1160.64.1510 Boehringer Ingelheim Investigational Site
city: Sittard
country: Netherlands
facility: 1160.64.1505 Boehringer Ingelheim Investigational Site
city: Zwolle
country: Netherlands
facility: 1160.64.1508 Boehringer Ingelheim Investigational Site
city: Takapuna Auckland
country: New Zealand
facility: 1160.64.3001 Boehringer Ingelheim Investigational Site
city: Bodø
country: Norway
facility: 1160.64.1601 Boehringer Ingelheim Investigational Site
city: Elverum
country: Norway
facility: 1160.64.1606 Boehringer Ingelheim Investigational Site
city: Lillehammer
country: Norway
facility: 1160.64.1604 Boehringer Ingelheim Investigational Site
city: Tynset
country: Norway
facility: 1160.64.1605 Boehringer Ingelheim Investigational Site
city: Ålesund
country: Norway
facility: 1160.64.1603 Boehringer Ingelheim Investigational Site
city: Krakow
country: Poland
facility: 1160.64.1702 Boehringer Ingelheim Investigational Site
city: Krakow
country: Poland
facility: 1160.64.1704 Boehringer Ingelheim Investigational Site
city: Lodz
country: Poland
facility: 1160.64.1705 Boehringer Ingelheim Investigational Site
city: Piekary Slaskie
country: Poland
facility: 1160.64.1703 Boehringer Ingelheim Investigational Site
city: Warsaw
country: Poland
facility: 1160.64.1701 Boehringer Ingelheim Investigational Site
city: Bryanston
country: South Africa
facility: 1160.64.1801 Boehringer Ingelheim Investigational Site
city: Cape Western Province
country: South Africa
facility: 1160.64.1804 Boehringer Ingelheim Investigational Site
city: Plumstead
country: South Africa
facility: 1160.64.1802 Boehringer Ingelheim Investigational Site
city: Alcorcón (Madrid)
country: Spain
facility: 1160.64.1904 Boehringer Ingelheim Investigational Site
city: Barcelona
country: Spain
facility: 1160.64.1906 Boehringer Ingelheim Investigational Site
city: Fuenlabrada
country: Spain
facility: 1160.64.1908 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1160.64.1901 Boehringer Ingelheim Investigational Site
city: Madrid
country: Spain
facility: 1160.64.1907 Boehringer Ingelheim Investigational Site
city: Valencia
country: Spain
facility: 1160.64.1905 Boehringer Ingelheim Investigational Site
city: Göteborg
country: Sweden
facility: 1160.64.2101 Boehringer Ingelheim Investigational Site
city: Halmstad
country: Sweden
facility: 1160.64.2112 Boehringer Ingelheim Investigational Site
city: Hässleholm
country: Sweden
facility: 1160.64.2105 Boehringer Ingelheim Investigational Site
city: Kalmar
country: Sweden
facility: 1160.64.2109 Boehringer Ingelheim Investigational Site
city: Kungälv
country: Sweden
facility: 1160.64.2103 Boehringer Ingelheim Investigational Site
city: Lidköping
country: Sweden
facility: 1160.64.2106 Boehringer Ingelheim Investigational Site
city: Motala
country: Sweden
facility: 1160.64.2102 Boehringer Ingelheim Investigational Site
city: Stockholm
country: Sweden
facility: 1160.64.2108 Boehringer Ingelheim Investigational Site
city: Uppsala
country: Sweden
facility: 1160.64.2111 Boehringer Ingelheim Investigational Site
city: Varberg
country: Sweden
facility: 1160.64.2107 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Eriksson BI, Dahl OE, Rosencher N, Clemens A, Hantel S, Feuring M, Kreuzer J, Huo M, Friedman RJ. Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials. Thromb J. 2015 Nov 17;13:36. doi: 10.1186/s12959-015-0067-8. eCollection 2015.
citation: Eriksson BI, Dahl OE, Huo MH, Kurth AA, Hantel S, Hermansson K, Schnee JM, Friedman RJ; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011 Apr;105(4):721-9. doi: 10.1160/TH10-10-0679. Epub 2011 Jan 12.