Dabigatran Etexilate Compared With Enoxaparin in Prevention of Venous Thromboembolism (VTE) Following Total Hip Arthroplasty

Venous Thromboembolism Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00657150
• Other study ID #: 1160.64
• Secondary ID: 2007-002630-11
• Status: Completed
• Phase: Phase 3
• First received: March 27, 2008
• Last updated: June 23, 2014
• Start date: March 2008

Study information

• Verified date: December 2013
• Source: Boehringer Ingelheim
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: Dept of Health and Ageing Therapeutic Goods AdminAustria: Bundesamt für Sicherheit im Gesundheitswesen, A-1030 ViennaBelgium: Federal Agency for Medicines and Health Products, FAMHPCanada: Health Canada, Therapeutic Products DirectorateCzech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10Denmark: The Danish Medicines AgencyFinland: Finnish Medicines AgencyGermany: Federal Institute for Drugs and Medical DevicesHungary: National Institute of Pharmacy, H-1051 BudapestIndia: Drug Control General of IndiaItaly: Comitato Etico dell'IRCCS Istituti Ortopedici Rizzoli di BolognaNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)New Zealand: Multicentre Ethics Committee/MedsafeNorway: Norwegian Medicines Agency (Statens Legemiddelverk)Poland: Registration Medicinal Product Medical Device Biocidal ProductSouth Africa: Medicines Control CouncilSpain: Spanish Agency of MedicinesSweden: Forskningsetikkommitteen, 58185 LinkopingUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 2055
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

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

Related Conditions & MeSH terms

• Thromboembolism
• Venous Thromboembolism

Intervention

Drug:
• Enoxaparin
40 mg once daily
• Dabigatran etexilate
220 mg once daily

Locations

Country	Name	City	State
Australia	1160.64.2002 Boehringer Ingelheim Investigational Site	Box HIll	Victoria
Australia	1160.64.2003 Boehringer Ingelheim Investigational Site	Daws Park	South Australia
Australia	1160.64.2004 Boehringer Ingelheim Investigational Site	Nedlands	Western Australia
Australia	1160.64.2001 Boehringer Ingelheim Investigational Site	Windsor	Victoria
Austria	1160.64.4004 Boehringer Ingelheim Investigational Site	Graz
Austria	1160.64.4002 Boehringer Ingelheim Investigational Site	Linz
Austria	1160.64.4003 Boehringer Ingelheim Investigational Site	Wels
Austria	1160.64.4001 Boehringer Ingelheim Investigational Site	Wien
Belgium	1160.64.5004 Boehringer Ingelheim Investigational Site	Brussel
Belgium	1160.64.5002 Boehringer Ingelheim Investigational Site	Deurne
Belgium	1160.64.5005 Boehringer Ingelheim Investigational Site	Lanaken
Belgium	1160.64.5001 Boehringer Ingelheim Investigational Site	Leuven
Canada	1160.64.6012 Boehringer Ingelheim Investigational Site	Ajax	Ontario
Canada	1160.64.6003 Boehringer Ingelheim Investigational Site	Belleville	Ontario
Canada	1160.64.6004 Boehringer Ingelheim Investigational Site	Cambridge	Ontario
Canada	1160.64.6009 Boehringer Ingelheim Investigational Site	Edmonton,	Alberta
Canada	1160.64.6008 Boehringer Ingelheim Investigational Site	Kitchener	Ontario
Canada	1160.64.6011 Boehringer Ingelheim Investigational Site	Oshawa	Ontario
Canada	1160.64.6002 Boehringer Ingelheim Investigational Site	Red Deer	Alberta
Canada	1160.64.6005 Boehringer Ingelheim Investigational Site	Sarnia	Ontario
Canada	1160.64.6007 Boehringer Ingelheim Investigational Site	Stratford	Ontario
Canada	1160.64.6013 Boehringer Ingelheim Investigational Site	Windsor	Ontario
Czech Republic	1160.64.7004 Boehringer Ingelheim Investigational Site	Chomutov
Czech Republic	1160.64.7005 Boehringer Ingelheim Investigational Site	Jihlava
Czech Republic	1160.64.7003 Boehringer Ingelheim Investigational Site	Kolin
Czech Republic	1160.64.7001 Boehringer Ingelheim Investigational Site	Plzen
Czech Republic	1160.64.7002 Boehringer Ingelheim Investigational Site	Prague 8
Denmark	1160.64.8004 Boehringer Ingelheim Investigational Site	Frederiksberg
Denmark	1160.64.8003 Boehringer Ingelheim Investigational Site	Herlev
Denmark	1160.64.8001 Boehringer Ingelheim Investigational Site	Hørsholm
Denmark	1160.64.8002 Boehringer Ingelheim Investigational Site	Silkeborg
Finland	1160.64.9002 Boehringer Ingelheim Investigational Site	Jyväskylä
Finland	1160.64.9001 Boehringer Ingelheim Investigational Site	Oulu
Finland	1160.64.9003 Boehringer Ingelheim Investigational Site	Tampere
Germany	1160.64.1104 Boehringer Ingelheim Investigational Site	Garmisch-Partenkirchen
Germany	1160.64.1101 Boehringer Ingelheim Investigational Site	Mainz
Germany	1160.64.1103 Boehringer Ingelheim Investigational Site	Markgröningen
Germany	1160.64.1102 Boehringer Ingelheim Investigational Site	Rheinfelden
Hungary	1160.64.1201 Boehringer Ingelheim Investigational Site	Gyula
Hungary	1160.64.1203 Boehringer Ingelheim Investigational Site	Kecskemét
Hungary	1160.64.1202 Boehringer Ingelheim Investigational Site	Szeged
Hungary	1160.64.1204 Boehringer Ingelheim Investigational Site	Székesfehérvár
India	1160.64.9105 Boehringer Ingelheim Investigational Site	Ahmedabad
India	1160.64.9112 Boehringer Ingelheim Investigational Site	Andhra Pradesh
India	1160.64.9109 Boehringer Ingelheim Investigational Site	Andhra Predesh
India	1160.64.9103 Boehringer Ingelheim Investigational Site	Bangalore
India	1160.64.9108 Boehringer Ingelheim Investigational Site	Bangalore
India	1160.64.9107 Boehringer Ingelheim Investigational Site	Baroda
India	1160.64.9110 Boehringer Ingelheim Investigational Site	Mangalore
India	1160.64.9104 Boehringer Ingelheim Investigational Site	Mohali
India	1160.64.9111 Boehringer Ingelheim Investigational Site	New Delhi
India	1160.64.9106 Boehringer Ingelheim Investigational Site	Pune
India	1160.64.9101 Boehringer Ingelheim Investigational Site	Ramdaspeth Nagpur
India	1160.64.9102 Boehringer Ingelheim Investigational Site	Secunderabad
India	1160.64.9113 Boehringer Ingelheim Investigational Site	Vadodara
Italy	1160.64.1401 Boehringer Ingelheim Investigational Site	Bologna
Italy	1160.64.1405 Boehringer Ingelheim Investigational Site	Parma
Italy	1160.64.1402 Boehringer Ingelheim Investigational Site	Pavia
Italy	1160.64.1407 Boehringer Ingelheim Investigational Site	Reggio Emilia
Italy	1160.64.1403 Boehringer Ingelheim Investigational Site	Roma
Italy	1160.64.1404 Boehringer Ingelheim Investigational Site	Torino
Netherlands	1160.64.1503 Boehringer Ingelheim Investigational Site	Amsterdam
Netherlands	1160.64.1507 Boehringer Ingelheim Investigational Site	Amsterdam
Netherlands	1160.64.1501 Boehringer Ingelheim Investigational Site	Hilversum
Netherlands	1160.64.1506 Boehringer Ingelheim Investigational Site	Hoofddorp
Netherlands	1160.64.1510 Boehringer Ingelheim Investigational Site	Leiden
Netherlands	1160.64.1505 Boehringer Ingelheim Investigational Site	Sittard
Netherlands	1160.64.1508 Boehringer Ingelheim Investigational Site	Zwolle
New Zealand	1160.64.3001 Boehringer Ingelheim Investigational Site	Takapuna Auckland
Norway	1160.64.1603 Boehringer Ingelheim Investigational Site	Ålesund
Norway	1160.64.1601 Boehringer Ingelheim Investigational Site	Bodø
Norway	1160.64.1606 Boehringer Ingelheim Investigational Site	Elverum
Norway	1160.64.1604 Boehringer Ingelheim Investigational Site	Lillehammer
Norway	1160.64.1605 Boehringer Ingelheim Investigational Site	Tynset
Poland	1160.64.1702 Boehringer Ingelheim Investigational Site	Krakow
Poland	1160.64.1704 Boehringer Ingelheim Investigational Site	Krakow
Poland	1160.64.1705 Boehringer Ingelheim Investigational Site	Lodz
Poland	1160.64.1703 Boehringer Ingelheim Investigational Site	Piekary Slaskie
Poland	1160.64.1701 Boehringer Ingelheim Investigational Site	Warsaw
South Africa	1160.64.1801 Boehringer Ingelheim Investigational Site	Bryanston
South Africa	1160.64.1804 Boehringer Ingelheim Investigational Site	Cape Western Province
South Africa	1160.64.1802 Boehringer Ingelheim Investigational Site	Plumstead
Spain	1160.64.1904 Boehringer Ingelheim Investigational Site	Alcorcón (Madrid)
Spain	1160.64.1906 Boehringer Ingelheim Investigational Site	Barcelona
Spain	1160.64.1908 Boehringer Ingelheim Investigational Site	Fuenlabrada
Spain	1160.64.1901 Boehringer Ingelheim Investigational Site	Madrid
Spain	1160.64.1907 Boehringer Ingelheim Investigational Site	Madrid
Spain	1160.64.1905 Boehringer Ingelheim Investigational Site	Valencia
Sweden	1160.64.2101 Boehringer Ingelheim Investigational Site	Göteborg
Sweden	1160.64.2112 Boehringer Ingelheim Investigational Site	Halmstad
Sweden	1160.64.2105 Boehringer Ingelheim Investigational Site	Hässleholm
Sweden	1160.64.2109 Boehringer Ingelheim Investigational Site	Kalmar
Sweden	1160.64.2103 Boehringer Ingelheim Investigational Site	Kungälv
Sweden	1160.64.2106 Boehringer Ingelheim Investigational Site	Lidköping
Sweden	1160.64.2102 Boehringer Ingelheim Investigational Site	Motala
Sweden	1160.64.2108 Boehringer Ingelheim Investigational Site	Stockholm
Sweden	1160.64.2111 Boehringer Ingelheim Investigational Site	Uppsala
Sweden	1160.64.2107 Boehringer Ingelheim Investigational Site	Varberg
United States	1160.64.01010 Boehringer Ingelheim Investigational Site	Aurora	Colorado
United States	1160.64.01007 Boehringer Ingelheim Investigational Site	Charleston	South Carolina
United States	1160.64.01012 Boehringer Ingelheim Investigational Site	Clearwater	Florida
United States	1160.64.01013 Boehringer Ingelheim Investigational Site	Conway	South Carolina
United States	1160.64.01009 Boehringer Ingelheim Investigational Site	Englewood	Colorado
United States	1160.64.01002 Boehringer Ingelheim Investigational Site	Houston	Texas
United States	1160.64.01005 Boehringer Ingelheim Investigational Site	La Jolla	California
United States	1160.64.01006 Boehringer Ingelheim Investigational Site	Lexington	Kentucky
United States	1160.64.01003 Boehringer Ingelheim Investigational Site	Missoula	Montana
United States	1160.64.01011 Boehringer Ingelheim Investigational Site	Spokane	Washington

Sponsors (1)

Lead Sponsor	Collaborator
Boehringer Ingelheim

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Belgium,  Canada,  Czech Republic,  Denmark,  Finland,  Germany,  Hungary,  India,  Italy,  Netherlands,  New Zealand,  Norway,  Poland,  South Africa,  Spain,  Sweden, 

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 venography), symptomatic DVT (confirmed by venous duplex, 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.	28-35 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	28-35 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	28-35 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	28-35 days	No
Secondary	Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period	Symptomatic Deep Vein Thrombosis, confirmed by venous duplex, ultrasound, venography or autopsy, and as adjudicated by the VTE events committee	28-35 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	28-35 days	No
Secondary	Number of Participants Who Died During Treatment Period	All cause death, as adjudicated by the VTE events committee	28-35 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 venography), symptomatic DVT (confirmed by venous duplex, 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 >=25 cm²; wound hematoma >=100 cm²; spontaneous nose bleed >5 min; macroscopic hematuria spontaneous or >24 hours if associated with an intervention; spontaneous rectal bleeding; gingival bleeding >5 min; any other bleeding event considered clinically relevant by the investigator; Any bleeding events were defined as major, clinically-relevant and minor bleeding events. Minor bleeding events were defined as all other bleeding events that did not fulfil the criteria from above.	28-35 days	Yes
Secondary	Blood Transfusion	Number of treated and operated patients with required blood transfusion on day of surgery.	Day 1	No
Secondary	Volume of Blood Loss	Volume of blood loss for treated and operated patients during surgery.	Day 1	No
Secondary	Laboratory Analyses	Frequency of patients with possible clinically significant abnormalities.	First administration to end of study	No

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