Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism - The EINSTEIN PE Study

This study has been completed.
Sponsor:
Collaborator:
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00439777
First received: February 23, 2007
Last updated: January 25, 2014
Last verified: January 2014
  Purpose

This is a multicenter, randomized, open-label, assessor-blind, event-driven, non-inferiority program for efficacy with a study treatment duration of 3, 6 or 12 months in patients with confirmed acute symptomatic pulmonary embolism (PE) with or without symptomatic Deep-Vein Thrombosis (DVT) (Einstein-PE).


Condition Intervention Phase
Pulmonary Embolism
Drug: Rivaroxaban (Xarelto, BAY59-7939)
Drug: Enoxaparin overlapping with and followed by VKA
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism

Resource links provided by NLM:


Further study details as provided by Bayer:

Primary Outcome Measures:
  • Percentage of Participants With Symptomatic Recurrent Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [PE]) Until the Intended End of Study Treatment [ Time Frame: 3-, 6-, or 12-month study treatment period ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.


Secondary Outcome Measures:
  • Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment [ Time Frame: 3-, 6-, or 12-month study treatment period ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment [ Time Frame: 3-, 6-, or 12-month study treatment period ] [ Designated as safety issue: No ]
    Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose) [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: Yes ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Clinically relevant bleeding included major bleeding (overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of 2 or more units of packed red blood cells or whole blood, occurring in a critical site or contributing to death) and non-major bleeding associated with medical intervention, unscheduled physician contact, (temporary) cessation of study treatment, discomfort for the participants such as pain, or impairment of activities of daily life.

  • Percentage of Participants With All Deaths [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: Yes ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either autopsy, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose) [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: Yes ]
    All pre-defined vascular events (ST segment elevation myocardial infarction, non ST segment elevation myocardial infarction, unstable angina, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism or vascular death) were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based results/films/images of confirmatory testing, and/or case summaries.


Other Outcome Measures:
  • Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment [ Time Frame: 3-, 6- or 12-month study treatment period ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.

  • Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period [ Time Frame: Up to 30 days after the last intake of study medication ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for fatal PE) or unexplained death for which DVT/PE could not be ruled out (for fatal PE), and/or case summaries.

  • Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period [ Time Frame: Up to 30 days after the last intake of study medication ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound (for DVT), venography (for DVT), spiral computed tomography (CT) scanning (for PE), pulmonary angiography (for PE), ventilation/perfusion lung scan (for PE), lung scintigraphy (for PE), autopsy (for deaths), results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period [ Time Frame: Up to 30 days after the last intake of study medication ] [ Designated as safety issue: No ]
    Net clinical benefit 1: composite of recurrent DVT or non-fatal or fatal PE, and major bleeding. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death. Net clinical benefit was considered greater in those participants with fewer composite events. All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With Recurrent DVT During Observational Period [ Time Frame: Up to 30 days after the last intake of study medication ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment. Events were assessed based on either compression ultrasound, venography, results/films/images of confirmatory testing, and/or case summaries.

  • Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period [ Time Frame: Up to 30 days after the last intake of study medication ] [ Designated as safety issue: No ]
    All events were adjudicated and confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral computed tomography scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, autopsy or unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries. Major bleeding was overt bleeding associated with 2 g/dL or greater fall in hemoglobin, leading to a transfusion of ≥2 units, occurring in a critical site or contributing to death.


Enrollment: 4833
Study Start Date: March 2007
Study Completion Date: December 2011
Primary Completion Date: September 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Rivaroxaban (Xarelto, BAY59-7939)
Participants received 15 mg rivaroxaban (oral) twice daily (b.i.d.) for 3 weeks, followed by 20 mg once daily (o.d.)
Drug: Rivaroxaban (Xarelto, BAY59-7939)
During the first 3 weeks patients will receive 15 mg rivaroxaban twice-daily. Thereafter, patients will receive rivaroxaban 20 mg once-daily. Rivaroxaban will be administered orally and should be taken with food.
Active Comparator: Enoxaparin/VKA
Participants received enoxaparin (subcutaneous) 1.0 mg/kg b.i.d. for minimal 5 days, plus vitamin K antagonist (VKA) at individually titrated doses to achieve a target international normalized ratio (INR) of 2.5 (range: 2.0 - 3.0)
Drug: Enoxaparin overlapping with and followed by VKA
Enoxaparin 1.0 mg/kg twice daily with a minimal duration of 5 days. This 5 days treatment could include the period up to 36 hr before randomization if enoxaparin twice-daily was used. VKA should be started as soon as possible but not later than 48 hours after randomization.

Detailed Description:

Within the US 'Johnson & Johnson Pharmaceutical Research & Development, L.L.C.' is sponsor.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Confirmed acute symptomatic proximal PE with or without symptomatic DVT

Exclusion Criteria:

  • Legal lower age limitations (country specific)
  • Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of DVT and/or PE
  • Other indication for VKA than DVT and/or PE
  • The pre-randomization anti-coagulant treatment (Criteria # 4) has been prolonged from 36 hours to a maximum of 48 hours.
  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: NCT00439777

  Show 305 Study Locations
Sponsors and Collaborators
Bayer
Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
Investigators
Study Director: Bayer Study Director Bayer
  More Information

Additional Information:
Publications:

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00439777     History of Changes
Other Study ID Numbers: 11702b, 2006-004495-13
Study First Received: February 23, 2007
Results First Received: November 22, 2012
Last Updated: January 25, 2014
Health Authority: Andorra: Ministeri de Salut i Benestar
Australia: Department of Health and Ageing Therapeutic Goods Administration
Austria: Ethikkommission
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: Ethics Committee
Brazil: National Committee of Ethics in Research
Brazil: National Health Surveillance Agency
Canada: Ethics Review Committee
Canada: Health Canada
China: Ethics Committee
China: Food and Drug Administration
Czech Republic: Ethics Committee
Czech Republic: State Institute for Drug Control
Denmark: Danish Medicines Agency
Denmark: Ethics Committee
Estonia: The State Agency of Medicine
European Union: European Medicines Agency
Finland: Ethics Committee
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
France: Institutional Ethical Committee
Germany: Ethics Commission
Germany: Federal Institute for Drugs and Medical Devices
Hong Kong: Department of Health
Hong Kong: Ethics Committee
Hungary: Institutional Ethics Committee
Hungary: National Institute of Pharmacy
India: Drugs Controller General of India
India: Institutional Review Board
Indonesia: National Agency of Drug and Food Control
Ireland: Irish Medicines Board
Ireland: Research Ethics Committee
Israel: Ethics Commission
Israel: Ministry of Health
Italy: Ethics Committee
Italy: National Institute of Health
Latvia: Institutional Review Board
Latvia: State Agency of Medicines
Lithuania: Bioethics Committee
Lithuania: State Medicine Control Agency - Ministry of Health
Malaysia: The National Pharmaceutical Control Bureau (NPCB)
Netherlands: Independent Ethics Committee
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
New Zealand: Health and Disability Ethics Committees
New Zealand: Medsafe
Norway: Ethics Committee
Norway: Norwegian Medicines Agency
Peru: Ethics Committee
Peru: General Directorate of Pharmaceuticals, Devices, and Drugs
Peru: Instituto Nacional de Salud
Peru: Ministry of Health
Philippines: Bureau of Food and Drugs
Philippines: Ethics Committee
Poland: Ethics Committee
Poland: Office for Registration of Medicinal Products, Medical Devices and Biocidal Products
Portugal: Health Ethic Committee
Portugal: National Pharmacy and Medicines Institute
Singapore: Health Sciences Authority
Slovakia: State Institute for Drug Control
South Africa: Human Research Ethics Committee
South Africa: Medicines Control Council
South Africa: National Health Research Ethics Council
South Korea: Institutional Review Board
South Korea: Korea Food and Drug Administration (KFDA)
Spain: Ethics Committee
Spain: Spanish Agency of Medicines
Sweden: Institutional Review Board
Sweden: Medical Products Agency
Switzerland: Ethikkommission
Switzerland: Swissmedic
Taiwan: Center for Drug Evaluation
Taiwan: Institutional Review Board
Thailand: Ethical Committee
Thailand: Food and Drug Administration
Thailand: National Research Council of Thailand (NCRT)
Thailand: Medical Council of Thailand (MCT)
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United Kingdom: Research Ethics Committee
United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
Embolism
Pulmonary Embolism
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Rivaroxaban
Anticoagulants
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on October 02, 2014