Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep Vein Thrombosis - The EINSTEIN DVT Study

Venous Thrombosis 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: NCT00440193
• Other study ID #: 11702a
• Secondary ID: 2006-004495-1311
• Status: Completed
• Phase: Phase 3
• First received: February 23, 2007
• Last updated: January 26, 2014
• Start date: March 2007
• Est. completion date: April 2010

Study information

• Verified date: January 2014
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: Australia: 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 CommitteeEuropean 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 ControlIsrael: Ethics CommissionIsrael: Ministry of HealthItaly: Ethics CommitteeItaly: National Institute 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 AgencyPhilippines: Bureau of Food and DrugsPhilippines: Ethics CommitteePoland: Ethics CommitteePoland: Office for Registration of Medicinal Products, Medical Devices and Biocidal ProductsSingapore: Health Sciences AuthoritySouth 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 DVT without symptomatic PE (Einstein-DVT).

Description:

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

The treatment period was followed by an observational period of 30 days starting the day after the last intake of study medication, regardless of the actual duration of study drug administration. Participants who did not complete the treatment period also entered the observational period. It was also possible that participants did not enter the observational period, e.g. due to withdrawal of consent or termination of study participation. Participants who were transferring from study 11702 DVT (NCT00440193) to the extension study 11899 (NCT00439725) did not enter the observational period.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3449
• Est. completion date: April 2010
• Est. primary completion date: April 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Confirmed acute symptomatic proximal DVT without symptomatic PE

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

• Thrombosis
• Venous Thrombosis

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

References & Publications (8)

Bamber L, Wang MY, Prins MH, Ciniglio C, Bauersachs R, Lensing AW, Cano SJ. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis. Thromb Haemost. 2013 Oct;110(4):7 — View Citation

Cano SJ, Lamping DL, Bamber L, Smith S. The Anti-Clot Treatment Scale (ACTS) in clinical trials: cross-cultural validation in venous thromboembolism patients. Health Qual Life Outcomes. 2012 Sep 26;10:120. doi: 10.1186/1477-7525-10-120. — View Citation

Cohen AT, Dobromirski M. The use of rivaroxaban for short- and long-term treatment of venous thromboembolism. Thromb Haemost. 2012 Jun;107(6):1035-43. doi: 10.1160/TH11-12-0859. Epub 2012 Feb 28. Review. — View Citation

EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral riv — 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 Venous Thromboembolism [VTE] (i.e. the Composite of Recurrent Deep Vein Thrombosis [DVT] or Fatal or Non-fatal Pulmonary Embolism [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), 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 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 or 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 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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