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

Pulmonary Embolism Clinical Trial

Official title:

Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00439777
• Other study ID #: 11702b
• Secondary ID: 2006-004495-13
• Status: Completed
• Phase: Phase 3
• First received: February 23, 2007
• Last updated: January 25, 2014
• Start date: March 2007
• Est. completion date: December 2011

Study information

• Verified date: January 2014
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Andorra: Ministeri de Salut i BenestarAustralia: Department of Health and Ageing Therapeutic Goods AdministrationAustria: EthikkommissionAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsBrazil: Ethics CommitteeBrazil: National Committee of Ethics in ResearchBrazil: National Health Surveillance AgencyCanada: Ethics Review CommitteeCanada: Health CanadaChina: Ethics CommitteeChina: Food and Drug AdministrationCzech Republic: Ethics CommitteeCzech Republic: State Institute for Drug ControlDenmark: Danish Medicines AgencyDenmark: Ethics CommitteeEstonia: The State Agency of MedicineEuropean Union: European Medicines AgencyFinland: Ethics CommitteeFinland: Finnish Medicines AgencyFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)France: Institutional Ethical CommitteeGermany: Ethics CommissionGermany: Federal Institute for Drugs and Medical DevicesHong Kong: Department of HealthHong Kong: Ethics CommitteeHungary: Institutional Ethics CommitteeHungary: National Institute of PharmacyIndia: Drugs Controller General of IndiaIndia: Institutional Review BoardIndonesia: National Agency of Drug and Food ControlIreland: Irish Medicines BoardIreland: Research Ethics CommitteeIsrael: Ethics CommissionIsrael: Ministry of HealthItaly: Ethics CommitteeItaly: National Institute of HealthLatvia: Institutional Review BoardLatvia: State Agency of MedicinesLithuania: Bioethics CommitteeLithuania: State Medicine Control Agency - Ministry of HealthMalaysia: The National Pharmaceutical Control Bureau (NPCB)Netherlands: Independent Ethics CommitteeNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)New Zealand: Health and Disability Ethics CommitteesNew Zealand: MedsafeNorway: Ethics CommitteeNorway: Norwegian Medicines AgencyPeru: Ethics CommitteePeru: General Directorate of Pharmaceuticals, Devices, and DrugsPeru: Instituto Nacional de SaludPeru: Ministry of HealthPhilippines: Bureau of Food and DrugsPhilippines: Ethics CommitteePoland: Ethics CommitteePoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsPortugal: Health Ethic CommitteePortugal: National Pharmacy and Medicines InstituteSingapore: Health Sciences AuthoritySlovakia: State Institute for Drug ControlSouth Africa: Human Research Ethics CommitteeSouth Africa: Medicines Control CouncilSouth Africa: National Health Research Ethics CouncilSouth Korea: Institutional Review BoardSouth Korea: Korea Food and Drug Administration (KFDA)Spain: Ethics CommitteeSpain: Spanish Agency of MedicinesSweden: Institutional Review BoardSweden: Medical Products AgencySwitzerland: EthikkommissionSwitzerland: SwissmedicTaiwan: Center for Drug EvaluationTaiwan: Institutional Review BoardThailand: Ethical CommitteeThailand: Food and Drug AdministrationThailand: National Research Council of Thailand (NCRT)Thailand: Medical Council of Thailand (MCT)United Kingdom: Medicines and Healthcare Products Regulatory AgencyUnited Kingdom: Research Ethics CommitteeUnited States: Food and Drug AdministrationUnited States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

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).

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 4833
• Est. completion date: December 2011
• Est. primary completion date: September 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Embolism
• Pulmonary Embolism

Intervention

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.
• 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.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Bayer	Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Countries where clinical trial is conducted

United States,  Andorra,  Australia,  Austria,  Belgium,  Brazil,  Canada,  China,  Czech Republic,  Denmark,  Estonia,  Finland,  France,  Germany,  Hong Kong,  Hungary,  India,  Indonesia,  Ireland,  Israel,  Italy,  Korea, Republic of,  Latvia,  Lithuania,  Malaysia,  Netherlands,  New Zealand,  Norway,  Philippines,  Poland,  Puerto Rico,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (5)

EINSTEIN–PE Investigators, Büller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A. Oral riva — View Citation

Prins MH, Lensing AW, Bauersachs R, van Bellen B, Bounameaux H, Brighton TA, Cohen AT, Davidson BL, Decousus H, Raskob GE, Berkowitz SD, Wells PS; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thr — View Citation

Prins MH, Lensing AW. Derivation of the non-inferiority margin for the evaluation of direct oral anticoagulants in the treatment of venous thromboembolism. Thromb J. 2013 Jul 6;11(1):13. doi: 10.1186/1477-9560-11-13. — View Citation

van Bellen B, Bamber L, Correa de Carvalho F, Prins M, Wang M, Lensing AW. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin. 2014 May;30(5):829-37 — View Citation

Wang Y, Wang C, Chen Z, Zhang J, Liu Z, Jin B, Ying K, Liu C, Shao Y, Jing Z, Meng IL, Prins MH, Pap AF, Müller K, Lensing AW; Chinese EINSTEIN Investigators. Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chin — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment	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.	3-, 6- or 12-month study treatment period	No
Other	Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period	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.	Up to 30 days after the last intake of study medication	No
Other	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period	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.	Up to 30 days after the last intake of study medication	No
Other	Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period	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.	Up to 30 days after the last intake of study medication	No
Other	Percentage of Participants With Recurrent DVT During Observational Period	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.	Up to 30 days after the last intake of study medication	No
Other	Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period	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.	Up to 30 days after the last intake of study medication	No
Primary	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	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.	3-, 6-, or 12-month study treatment period	No
Secondary	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment	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.	3-, 6-, or 12-month study treatment period	No
Secondary	Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment	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.	3-, 6-, or 12-month study treatment period	No
Secondary	Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment	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.	3-, 6- or 12-month study treatment period	No
Secondary	Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment	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.	3-, 6- or 12-month study treatment period	No
Secondary	Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)	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.	3-, 6- or 12-month study treatment period	Yes
Secondary	Percentage of Participants With All Deaths	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.	3-, 6- or 12-month study treatment period	Yes
Secondary	Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)	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.	3-, 6- or 12-month study treatment period	Yes

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