Once - Daily Oral Direct Factor Xa Inhibitor Rivaroxaban In The Long-Term Prevention Of Recurrent Symptomatic Venous Thromboembolism In Patients With Symptomatic Deep-Vein Thrombosis Or Pulmonary Embolism. The Einstein-Extension Study

Venous Thromboembolism Clinical Trial

Official title:

Once-daily Oral Direct Factor Xa Inhibitor Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic Venous Thromboembolism in Patients With Symptomatic Deep-vein Thrombosis or Pulmonary Embolism. The Einstein-Extension Study

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00439725
• Other study ID #: 11899
• Secondary ID: 2006-004494-96
• Status: Completed
• Phase: Phase 3
• First received: February 23, 2007
• Last updated: October 28, 2014
• Start date: February 2007
• Est. completion date: September 2009

Study information

• Verified date: October 2014
• Source: Bayer
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This is a multicenter, randomized, double-blind, placebo-controlled, event-driven, superiority study for efficacy. Patients with confirmed symptomatic DVT (deep vein thrombosis) or PE (pulmonary embolism) who completed 6 or 12 months of treatment with rivaroxaban or VKA (vitamin K antagonist) are eligible for this trial (Einstein-Extension study).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1197
• Est. completion date: September 2009
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Patients with confirmed symptomatic PE or DVT who have been treated for 6 or 12 months with VKA or rivaroxaban

Exclusion Criteria:

• Legal lower age limitations (country specific)

• Indication for VKA other than DVT and/or PE

• Patients in whom anticoagulant treatment for their index PE or DVT should be continued

• Childbearing potential without proper contraceptive measures, pregnancy or breast feeding. Proper contraceptive measures are defined as a method of contraception with a failure rate < 1 % during the course of the study (including the observational period). These methods of contraception according to the note for guidance on non-clinical safety studies for the conduct of human trials for pharmaceuticals (CPMP [Committee for Proprietary Medicinal Products]/ICH [International Conference on Harmonization]/286/95, modification) include consistent and correct use of hormone containing implants and injectables, combined oral contraceptives, hormone containing intrauterine devices, surgical sterilization, sexual abstinence and vasectomy

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Pulmonary Embolism
• Thromboembolism
• Venous Thromboembolism
• Venous Thrombosis

Intervention

Drug:
• Rivaroxaban (Xarelto, BAY59-7939)
Patients randomized to rivaroxaban will receive rivaroxaban 20 mg once-daily.
• Placebo
Patients allocated to placebo will receive a matching placebo tablet once daily.

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,  Singapore,  South Africa,  Spain,  Sweden,  Switzerland,  Taiwan,  Thailand,  United Kingdom, 

References & Publications (2)

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percentage of Participants With Death (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 autopsy, results/films/images of confirmatory testing, and/or case summaries.	6- or 12-month study treatment period	No
Other	Percentage of Participants With Death (PE Cannot be Excluded) 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 unexplained death for which DVT/PE could not be ruled out, results/films/images of confirmatory testing, and/or case summaries.	6- or 12-month study treatment period	No
Other	Percentage of Participants With Symptomatic 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 either spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, results/films/images of confirmatory testing, and/or case summaries.	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.	30 days observational period after last intake of study medication	No
Other	Percentage of Participants With Symptomatic Recurrent 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 spiral computed tomography (CT) scanning, pulmonary angiography, ventilation/perfusion lung scan, lung scintigraphy, results/films/images of confirmatory testing, and/or case summaries.	30 days observational period after 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.	30 days observational period after last intake of study medication	No
Other	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions 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.	30 days observational period after last intake of study medication	No
Other	Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events During Observational Period	Events were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on either compression ultrasound, venography, spiral CT 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 or more units, occurring in a critical site or contributing to death.	30 days observational period after last intake of study medication	No
Other	Percentage of Participants With Recurrent VTE (PE or 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 (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), results/films/images of confirmatory testing, and/or case summaries.	30 days observational period after 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 or venography, results/films/images of confirmatory testing, and/or case summaries.	30 days observational period after 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. For definition of DVT/PE, kindly refer to the link in the Protocol section.	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), or lung scintigraphy (for PE), and/or case summaries.	6- or 12-month study treatment period	No
Secondary	Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE, All Cause Mortality, Strokes and Myocardial Infarctions 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), results/films/images of confirmatory testing, and/or case summaries.	6- or 12-month study treatment period	No
Secondary	Percentage of Participants With Net Clinical Benefit as Composite of Recurrent DVT or Non-fatal or Fatal PE and Major Bleeding Events 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.	6- or 12-month study treatment period	No
Secondary	Percentage of Participants With Recurrent VTE (PE or 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 (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), results/films/images of confirmatory testing, and/or case summaries.	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.	6- or 12-month study treatment period	No
Secondary	Percentage of Participants With Major Bleeding	All events were adjudicated and confirmed by a central independent adjudication committee (CIAC) blinded to treatment. Major bleeding event was overt bleeding associated with a 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. Treatment-emergent [after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days)] events and all events post randomization were reported.	6- or 12-month study treatment period	Yes
Secondary	Percentage of Participants With Clinically Relevant Bleeding	All events adjudicated/confirmed by CIAC blinded to treatment. Clinically relevant bleeding included major bleeding (definition: see outcome 7) 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 daily life activities. Treatment-emergent events (after intake of 1st study medication tablet as randomized up to 2 days after stop of study medication ['time window: 2 days']) and all events post randomization were reported	6- or 12-month study treatment period	Yes
Secondary	Percentage of Participants With All Death	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. Treatment-emergent events and all events post randomization were reported. Treatment-emergent: after intake of first tablet of study medication as randomized but not more than 2 days after stop of study medication (referred to as time window: 2 days)	6- or 12-month study treatment period	Yes
Secondary	Percentage of Participants With Other Vascular Events	All pre-defined vascular events (acute coronary syndromes, ischemic stroke, transient ischemic attack, non-central nervous system systemic embolism and vascular death) were adjudicated/confirmed by a central independent adjudication committee blinded to treatment, based on results/films/images of confirmatory testing, and/or case summaries. On treatment events and all events post randomization were reported. On treatment: after intake of first tablet of study medication as randomized but not more than 1 day after stop of study medication (referred to as time window: 1 day)	6- or 12-month study treatment period	Yes

External Links

•   Click here and search for drug information provided by the FDA.
•   Click here and search for information of Bayer products for Europe
•   Click here and search for information on any recalls, market or product safety alerts by the FDA which might have occurred with this product.
•   Click here to find results for studies related to Bayer Healthcare products.
•   Click here to find the definition for Deep Vein Thrombosis [DVT].
•   Click here to find the definition for Pulmonary Embolism [PE].