Clinical trial NCT00439777: Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Pulmonary Embolism - The EINSTEIN PE Study
Official title: Oral Direct Factor Xa Inhibitor Rivaroxaban in Patients With Acute Symptomatic Deep-Vein Thrombosis or Pulmonary Embolism
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Embolism
Lead sponsor: Bayer
Sponsor class: INDUSTRY
Collaborators: name: Johnson & Johnson Pharmaceutical Research & Development, L.L.C.
First posted: 2007-02-26
Enrollment: 4833
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).

Detailed description: Within the US 'Johnson \& Johnson Pharmaceutical Research \& Development, L.L.C.' is sponsor.

Eligibility 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.

Primary outcomes:
measure: 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
timeFrame: 3-, 6-, or 12-month study treatment period
Secondary outcomes:
measure: Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality Until the Intended End of Study Treatment
timeFrame: 3-, 6-, or 12-month study treatment period
measure: Percentage of Participants With an Event for Net Clinical Benefit 1 Until the Intended End of Study Treatment
timeFrame: 3-, 6-, or 12-month study treatment period
measure: Percentage of Participants With Recurrent PE Until the Intended End of Study Treatment
timeFrame: 3-, 6- or 12-month study treatment period
measure: Percentage of Participants With Recurrent DVT Until the Intended End of Study Treatment
timeFrame: 3-, 6- or 12-month study treatment period
measure: Percentage of Participants With Clinically Relevant Bleeding, Treatment-emergent (Time Window: Until 2 Days After Last Dose)
timeFrame: 3-, 6- or 12-month study treatment period
measure: Percentage of Participants With All Deaths
timeFrame: 3-, 6- or 12-month study treatment period
measure: Percentage of Participants With Other Vascular Events, On-treatment (Time Window: Until 1 Day After Last Dose)
timeFrame: 3-, 6- or 12-month study treatment period
Other outcomes:
measure: Percentage of Participants With the Individual Components of Efficacy Outcomes Until the Intended End of Study Treatment
timeFrame: 3-, 6- or 12-month study treatment period
measure: Percentage of Participants With Symptomatic Recurrent VTE (i.e. the Composite of Recurrent DVT or Fatal or Non-fatal PE) During Observational Period
timeFrame: Up to 30 days after the last intake of study medication
measure: Percentage of Participants With the Composite Variable Comprising Recurrent DVT, Non-fatal PE and All Cause Mortality During Observational Period
timeFrame: Up to 30 days after the last intake of study medication
measure: Percentage of Participants With an Event for Net Clinical Benefit 1 During Observational Period
timeFrame: Up to 30 days after the last intake of study medication
measure: Percentage of Participants With Recurrent DVT During Observational Period
timeFrame: Up to 30 days after the last intake of study medication
measure: Percentage of Participants With the Individual Components of Efficacy Outcomes During Observational Period
timeFrame: Up to 30 days after the last intake of study medication
Locations:
city: Little Rock
country: United States
state: Arkansas
city: Redlands
country: United States
state: California
city: Bay Pines
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Miami
country: United States
state: Florida
city: Idaho Falls
country: United States
state: Idaho
city: Covington
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Chesterfield
country: United States
state: Missouri
city: Albuquerque
country: United States
state: New Mexico
city: Chapel Hill
country: United States
state: North Carolina
city: Greensboro
country: United States
state: North Carolina
city: Greensboro
country: United States
state: North Carolina
city: Oklahoma City
country: United States
state: Oklahoma
city: Camp Hill
country: United States
state: Pennsylvania
city: Pittsburgh
country: United States
state: Pennsylvania
city: San Antonio
country: United States
state: Texas
city: Murray
country: United States
state: Utah
city: Salt Lake City
country: United States
state: Utah
city: Fredericksburg
country: United States
state: Virginia
city: Spokane
country: United States
state: Washington
city: Tacoma
country: United States
state: Washington
city: Escaldes - Engordany
country: Andorra
city: Garran
country: Australia
state: Australian Capital Territory
city: Gosford
country: Australia
state: New South Wales
city: Kogarah
country: Australia
state: New South Wales
city: Lismore
country: Australia
state: New South Wales
city: St Leonards
country: Australia
state: New South Wales
city: Sydney
country: Australia
state: New South Wales
city: Sydney
country: Australia
state: New South Wales
city: Sydney
country: Australia
state: New South Wales
city: Brisbane
country: Australia
state: Queensland
city: Redcliffe
country: Australia
state: Queensland
city: Southport
country: Australia
state: Queensland
city: Woolloongabba
country: Australia
state: Queensland
city: Adelaide
country: Australia
state: South Australia
city: Woodville South
country: Australia
state: South Australia
city: Launceston
country: Australia
state: Tasmania
city: Box Hill
country: Australia
state: Victoria
city: Clayton
country: Australia
state: Victoria
city: Geelong
country: Australia
state: Victoria
city: Melbourne
country: Australia
state: Victoria
city: Melbourne
country: Australia
state: Victoria
city: Fremantle
country: Australia
state: Western Australia
city: Perth
country: Australia
state: Western Australia
city: Graz
country: Austria
state: Steiermark
city: Feldkirch
country: Austria
state: Vorarlberg
city: Innsbruck
country: Austria
city: Linz
country: Austria
city: Wien
country: Austria
city: Wien
country: Austria
city: Wien
country: Austria
city: Aalst
country: Belgium
city: Bruxelles - Brussel
country: Belgium
city: Bruxelles - Brussel
country: Belgium
city: Duffel
country: Belgium
city: Genk
country: Belgium
city: Gent
country: Belgium
city: Hasselt
country: Belgium
city: Leuven
country: Belgium
city: Liege
country: Belgium
city: Lier
country: Belgium
city: Namur
country: Belgium
city: Yvoir
country: Belgium
city: Zottegem
country: Belgium
city: Curitiba
country: Brazil
state: Parana
city: Londrina
country: Brazil
state: Parana
city: Botucatu
country: Brazil
state: Sao Paulo
city: Sorocaba
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: São Paulo
country: Brazil
state: Sao Paulo
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Winnipeg
country: Canada
state: Manitoba
city: London
country: Canada
state: Ontario
city: Ottawa
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Guangzhou
country: China
state: Guangdong
city: Guangzhou
country: China
state: Guangdong
city: Guangzhou
country: China
state: Guangdong
city: Nanning
country: China
state: Guangxi
city: Harbin
country: China
state: Heilongjiang
city: Wuhan
country: China
state: Hubei
city: Suzhou
country: China
state: Jiangsu
city: Shenyang
country: China
state: Liaoning
city: Hangzhou
country: China
state: Zhejiang
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Beijing
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Shanghai
country: China
city: Kladno
country: Czech Republic
city: Ostrava-Poruba
country: Czech Republic
city: Ostrava
country: Czech Republic
city: Prague 5
country: Czech Republic
city: Praha 1
country: Czech Republic
city: Praha 2
country: Czech Republic
city: Rakovnik
country: Czech Republic
city: Usti nad Lebem
country: Czech Republic
city: Aarhus C
country: Denmark
city: Braedstrup
country: Denmark
city: Frederiksberg
country: Denmark
city: Tallinn
country: Estonia
city: Tampere
country: Finland
city: Turku
country: Finland
city: Agen Cedex 9
country: France
city: Amiens
country: France
city: Angers Cedex 01
country: France
city: Arras
country: France
city: Besancon
country: France
city: Bordeaux
country: France
city: Brest Cedex
country: France
city: Castelnau Le Lez
country: France
city: Clamart
country: France
city: Clermont Ferrand
country: France
city: Colombes Cedex
country: France
city: Dijon
country: France
city: Grenoble
country: France
city: Limoges
country: France
city: Metz-tessy
country: France
city: Montpellier Cedex
country: France
city: Nantes
country: France
city: Nice
country: France
city: Orthez
country: France
city: Paris Cedex 15
country: France
city: Paris
country: France
city: Paris
country: France
city: Paris
country: France
city: Paris
country: France
city: Pierre Benite
country: France
city: Roanne
country: France
city: Rouen Cedex
country: France
city: Saint Etienne
country: France
city: Strasbourg Cedex
country: France
city: Toulon
country: France
city: Toulouse
country: France
city: Valenciennes Cedex
country: France
city: Vandoeuvre Les Nancy
country: France
city: Vernon
country: France
city: Bruchsal
country: Germany
state: Baden-Württemberg
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: Heidelberg
country: Germany
state: Baden-Württemberg
city: Karlsbad
country: Germany
state: Baden-Württemberg
city: Neckargemünd
country: Germany
state: Baden-Württemberg
city: Tübingen
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state: Baden-Württemberg
city: Augsburg
country: Germany
state: Bayern
city: München
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state: Bayern
city: München
country: Germany
state: Bayern
city: Würzburg
country: Germany
state: Bayern
city: Darmstadt
country: Germany
state: Hessen
city: Frankfurt
country: Germany
state: Hessen
city: Frankfurt
country: Germany
state: Hessen
city: Greifswald
country: Germany
state: Mecklenburg-Vorpommern
city: Rotenburg
country: Germany
state: Niedersachsen
city: Essen
country: Germany
state: Nordrhein-Westfalen
city: Paderborn
country: Germany
state: Nordrhein-Westfalen
city: Witten
country: Germany
state: Nordrhein-Westfalen
city: Mainz
country: Germany
state: Rheinland-Pfalz
city: Halle
country: Germany
state: Sachsen-Anhalt
city: Magdeburg
country: Germany
state: Sachsen-Anhalt
city: Dresden
country: Germany
state: Sachsen
city: Nordhausen
country: Germany
state: Thüringen
city: Berlin
country: Germany
city: Bottrop
country: Germany
city: Hamburg
country: Germany
city: Hong Kong
country: Hong Kong
city: Wanchai
country: Hong Kong
city: Budapest
country: Hungary
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: Kecskemet
country: Hungary
city: Kistarcsa
country: Hungary
city: Miskolc
country: Hungary
city: Szekszard
country: Hungary
city: Szentes
country: Hungary
city: Szombathely
country: Hungary
city: Zalaegerszeg
country: Hungary
city: Kochi
country: India
state: Kerala
city: Hyderabad
country: India
city: New Delhi
country: India
city: Pune
country: India
city: Bandung
country: Indonesia
city: Jakarta
country: Indonesia
city: Jakarta
country: Indonesia
city: Medan
country: Indonesia
city: Semarang
country: Indonesia
city: Ballinasloe
country: Ireland
state: Co. Galway
city: Afula
country: Israel
city: Ashkelon
country: Israel
city: Haifa
country: Israel
city: Haifa
country: Israel
city: Haifa
country: Israel
city: Holon
country: Israel
city: Jerusalem
country: Israel
city: Kfar Saba
country: Israel
city: Petach Tikva
country: Israel
city: Rehovot
country: Israel
city: Safed
country: Israel
city: Tel Aviv
country: Israel
city: Rozzano
country: Italy
state: Milano
city: Bologna
country: Italy
city: Chieti
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Milano
country: Italy
city: Padova
country: Italy
city: Palermo
country: Italy
city: Parma
country: Italy
city: Pavia
country: Italy
city: Piacenza
country: Italy
city: Reggio Emilia
country: Italy
city: Varese
country: Italy
city: Venezia
country: Italy
city: Seoul
country: Korea, Republic of
state: Korea
city: Daegu
country: Korea, Republic of
city: Seoul
country: Korea, Republic of
city: Taegu
country: Korea, Republic of
city: Liepaja
country: Latvia
city: Kaunas
country: Lithuania
city: Vilnius
country: Lithuania
city: Selangor
country: Malaysia
city: Amsterdam
country: Netherlands
city: Arnhem
country: Netherlands
city: Enschede
country: Netherlands
city: Groningen
country: Netherlands
city: Hoofddorp
country: Netherlands
city: Maastricht
country: Netherlands
city: Zwolle
country: Netherlands
city: Auckland
country: New Zealand
city: Auckland
country: New Zealand
city: Auckland
country: New Zealand
city: Christchurch
country: New Zealand
city: Palmerston North
country: New Zealand
city: Wellington South
country: New Zealand
city: Fredrikstad
country: Norway
city: Oslo
country: Norway
city: Rud
country: Norway
city: Trondheim
country: Norway
city: Quezon City
country: Philippines
city: Quezon City
country: Philippines
city: Bialystok
country: Poland
city: Krakow
country: Poland
city: Lodz
country: Poland
city: Lublin
country: Poland
city: Poznan
country: Poland
city: Poznan
country: Poland
city: Torun
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Wroclaw
country: Poland
city: San Juan
country: Puerto Rico
city: Singapore
country: Singapore
city: Singapore
country: Singapore
city: Johannesburg
country: South Africa
state: Gauteng
city: Johannesburg
country: South Africa
state: Gauteng
city: Johannesburg
country: South Africa
state: Gauteng
city: Pretoria
country: South Africa
state: Gauteng
city: Pretoria
country: South Africa
state: Gauteng
city: Pretoria
country: South Africa
state: Gauteng
city: Roodepoort
country: South Africa
state: Gauteng
city: Cape Town
country: South Africa
state: Western Cape
city: Somerset West
country: South Africa
state: Western Cape
city: Worcester
country: South Africa
state: Western Cape
city: Terrassa
country: Spain
state: Barcelona
city: Valladolid
country: Spain
state: Castilla - León
city: Palma de Mallorca
country: Spain
state: Illes Baleares
city: Requena
country: Spain
state: Valencia
city: Barcelona
country: Spain
city: Barcelona
country: Spain
city: Girona
country: Spain
city: Madrid
country: Spain
city: Pamplona
country: Spain
city: Borås
country: Sweden
city: Göteborg
country: Sweden
city: Göteborg
country: Sweden
city: Jönköping
country: Sweden
city: Stockholm
country: Sweden
city: Sundsvall
country: Sweden
city: Genéve 14
country: Switzerland
state: Genève 14
city: Chur
country: Switzerland
state: Graubünden
city: Lausanne
country: Switzerland
state: Vaud
city: Lausanne
country: Switzerland
state: Waadt
city: Bern
country: Switzerland
city: Luzern
country: Switzerland
city: Zürich
country: Switzerland
city: Taichung
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Taipei
country: Taiwan
city: Bangkok
country: Thailand
city: Chiang Mai
country: Thailand
city: Pathumwan, Bangkok
country: Thailand
city: Plymouth
country: United Kingdom
state: Devon
city: Isleworth
country: United Kingdom
state: London
city: London
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: EINSTEIN-PE Investigators; Buller 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 rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012 Apr 5;366(14):1287-97. doi: 10.1056/NEJMoa1113572. Epub 2012 Mar 26.
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.
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 thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013 Sep 20;11(1):21. doi: 10.1186/1477-9560-11-21.
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, Muller K, Lensing AW; Chinese EINSTEIN Investigators. Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies. Thromb J. 2013 Dec 16;11(1):25. doi: 10.1186/1477-9560-11-25.
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. doi: 10.1185/03007995.2013.879439. Epub 2014 Jan 22.
citation: Ten Cate H, Lensing AWA, Weitz JI, Middeldorp S, Beyer-Westendorf J, Kubitza D, Brighton T, Raskob GE, Mismetti P, Prandoni P, Gebel M, Prins MH. The prothrombin time does not predict the risk of recurrent venous thromboembolism or major bleeding in rivaroxaban-treated patients. Thromb Res. 2018 Oct;170:75-83. doi: 10.1016/j.thromres.2018.08.008. Epub 2018 Aug 15.
citation: Di Nisio M, Vedovati MC, Riera-Mestre A, Prins MH, Mueller K, Cohen AT, Wells PS, Beyer-Westendorf J, Prandoni P, Bounameaux H, Kubitza D, Schneider J, Pisters R, Fedacko J, Fontes-Carvalho R, Lensing AW. Treatment of venous thromboembolism with rivaroxaban in relation to body weight. A sub-analysis of the EINSTEIN DVT/PE studies. Thromb Haemost. 2016 Sep 27;116(4):739-46. doi: 10.1160/TH16-02-0087. Epub 2016 Aug 18.
citation: Wells PS, Gebel M, Prins MH, Davidson BL, Lensing AW. Influence of statin use on the incidence of recurrent venous thromboembolism and major bleeding in patients receiving rivaroxaban or standard anticoagulant therapy. Thromb J. 2014 Nov 26;12:26. doi: 10.1186/1477-9560-12-26. eCollection 2014.
citation: Prins MH, Lensing AW, Brighton TA, Lyons RM, Rehm J, Trajanovic M, Davidson BL, Beyer-Westendorf J, Pap AF, Berkowitz SD, Cohen AT, Kovacs MJ, Wells PS, Prandoni P. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol. 2014 Oct;1(1):e37-46. doi: 10.1016/S2352-3026(14)70018-3. Epub 2014 Sep 28.
citation: Bauersachs RM, Lensing AW, Prins MH, Kubitza D, Pap AF, Decousus H, Beyer-Westendorf J, Prandoni P. Rivaroxaban versus enoxaparin/vitamin K antagonist therapy in patients with venous thromboembolism and renal impairment. Thromb J. 2014 Nov 24;12:25. doi: 10.1186/1477-9560-12-25. eCollection 2014.
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.