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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT00657150
First received: March 27, 2008
Last updated: June 23, 2014
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Venous Thromboembolism
Drug: Enoxaparin
Drug: Dabigatran etexilate
Phase 3

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

Resource links provided by NLM:


Further study details as provided by Boehringer Ingelheim:

Primary Outcome Measures:
  • Number of Participants With Total Venous Thromboembolic Event and All-cause Mortality During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • Number of Participants With Major Venous Thromboembolic Event and Venous Thromboembolic Event-related Mortality During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    Major Venous Thromboembolic Event (VTE) is defined as proximal DVT and PE, as adjudicated by the VTE events committee

  • Number of Participants With Proximal Deep Vein Thrombosis During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    Proximal Deep Vein Thrombosis as adjudicated by the VTE events committee

  • Number of Participants With Total Deep Vein Thrombosis During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    Total Deep Vein Thrombosis as adjudicated by the VTE events committee

  • Number of Participants With Symptomatic Deep Vein Thrombosis During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    Symptomatic Deep Vein Thrombosis, confirmed by venous duplex, ultrasound, venography or autopsy, and as adjudicated by the VTE events committee

  • Number of Participants With Pulmonary Embolism During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    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

  • Number of Participants Who Died During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: No ]
    All cause death, as adjudicated by the VTE events committee

  • Number of Participants With Total Venous Thromboembolic Event (VTE) and All-cause Mortality During the Follow-up Period [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    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).

  • Number of Participants With Bleeding Events (Defined According to Modified McMaster Criteria) During Treatment Period [ Time Frame: 28-35 days ] [ Designated as safety issue: Yes ]

    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.


  • Blood Transfusion [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Number of treated and operated patients with required blood transfusion on day of surgery.

  • Volume of Blood Loss [ Time Frame: Day 1 ] [ Designated as safety issue: No ]
    Volume of blood loss for treated and operated patients during surgery.

  • Laboratory Analyses [ Time Frame: First administration to end of study ] [ Designated as safety issue: No ]
    Frequency of patients with possible clinically significant abnormalities.


Enrollment: 2055
Study Start Date: March 2008
Primary Completion Date: September 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dabigatran etexilate
220 mg once daily
Drug: Dabigatran etexilate
220 mg once daily
Active Comparator: Enoxaparin
40 mg once daily
Drug: Enoxaparin
40 mg once daily

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00657150

  Show 108 Study Locations
Sponsors and Collaborators
Boehringer Ingelheim
Investigators
Study Chair: Boehringer Ingelheim Boehringer Ingelheim
  More Information

Additional Information:
No publications provided by Boehringer Ingelheim

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT00657150     History of Changes
Other Study ID Numbers: 1160.64, 2007-002630-11
Study First Received: March 27, 2008
Results First Received: November 18, 2010
Last Updated: June 23, 2014
Health Authority: Australia: Dept of Health and Ageing Therapeutic Goods Admin
Austria: Bundesamt für Sicherheit im Gesundheitswesen, A-1030 Vienna
Belgium: Federal Agency for Medicines and Health Products, FAMHP
Canada: Health Canada, Therapeutic Products Directorate
Czech Republic: State Institute for Drug Control (SUKL), CZ-100 41 Prague 10
Denmark: The Danish Medicines Agency
Finland: Finnish Medicines Agency
Germany: Federal Institute for Drugs and Medical Devices
Hungary: National Institute of Pharmacy, H-1051 Budapest
India: Drug Control General of India
Italy: Comitato Etico dell'IRCCS Istituti Ortopedici Rizzoli di Bologna
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
New Zealand: Multicentre Ethics Committee/Medsafe
Norway: Norwegian Medicines Agency (Statens Legemiddelverk)
Poland: Registration Medicinal Product Medical Device Biocidal Product
South Africa: Medicines Control Council
Spain: Spanish Agency of Medicines
Sweden: Forskningsetikkommitteen, 58185 Linkoping
United States: Food and Drug Administration

Additional relevant MeSH terms:
Thromboembolism
Venous Thromboembolism
Venous Thrombosis
Cardiovascular Diseases
Embolism and Thrombosis
Thrombosis
Vascular Diseases
Dabigatran
Anticoagulants
Antithrombins
Enzyme Inhibitors
Hematologic Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protease Inhibitors
Serine Proteinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on October 21, 2014