Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000222448
Ethics application status
Approved
Date submitted
19/04/2007
Date registered
24/04/2007
Date last updated
6/02/2020
Date data sharing statement initially provided
6/02/2020
Date results information initially provided
6/02/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
The effect of oral rivaroxaban in treating and in the long term prevention in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism.
Scientific title
The effect of oral direct factor Xa inhibitor rivaroxaban in treating (Bay 59-7939 / 11702) and in the long term prevention (Bay 59-7939 / 11899) in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism.
Secondary ID [1] 358 0
ClinicalTrials.org: NCT00439725
Secondary ID [2] 359 0
ClinicalTrials.org: NCT00439777
Universal Trial Number (UTN)
Trial acronym
Einstein VTE III and Einstein Extension
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Deep vein thrombosis 1752 0
Pulmonary embolism 1753 0
Condition category
Condition code
Cardiovascular 1844 1844 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Patients allocated to the rivaroxaban arm of the prevention trial (Bay 59-7939 / 11702) will receive rivaroxaban 15 mg twice daily orally for a total of 3 weeks and thereafter patients will receive rivaroxaban 20 mg once daily.

Patients from both the rivaroxaban and enoxaparin treatment arms will be treated for 3, 6 or 12 months depending on the risk profile of the patients and the preference of the investigator.

Patients continuing in the extension study (Bay 59-7939 / 11899) will receive rivaroxaban or matching placebo 20 mg orally once daily. Treatment duration will be 6 or 12 months and should be indicated prior to randomisation.
Intervention code [1] 1712 0
Treatment: Drugs
Comparator / control treatment
Patients allocated to the comparator arm will receive enoxaparin 1.0 mg / kg twice daily for at least 5 days in combination with vitamin K antagonist given subcutaneously. Enoxaparin will continue until the International Normalised Ratio is greater than or equal to 2.0 on two consecutive occasions, with an advised overlap with VKA for 4 to 5 days.
Control group
Active

Outcomes
Primary outcome [1] 2583 0
The primary efficacy outcome is symptomatic recurrent venous thromboembolism (VTE).
Timepoint [1] 2583 0
Measured at the first occurrence from time of randomisation, then once a month until the end of the follow up period.
Secondary outcome [1] 4443 0
Clinically relevant bleeding.
Timepoint [1] 4443 0
Measured at the first occurrence from time of randomisation, then once a month until the end of the follow up period.

Eligibility
Key inclusion criteria
Inclusion criteria for Bay 59-7939 / 11702. Confirmed acute symptomatic proximal deep vein thrombosis or confirmed acute symptomatic pulmonary embolism.
Active bleeding.Inclusion criteria for Bay 59-7939 / 11899.Confirmed acute symptomatic deep vein thrombosis or pulmonary embolism who have been treated for 6 or 12 months with vitamin K antagonist.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Exclusion criteria for 11702Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent to treat the current episode of deep vein thrombosis (DVT) and/or pulmonary embolism (PE).Other indication for VKA other than DVT and/or PE. More than 36 hours pre-randomisation treatment with therapeutic dosages of low molecular weight heparin / fondaparinux or more than a single dose of VKA prior to randomisation.Significant renal or liver disease.
Exclusion criteria for 11899Other indication for VKA other than DVT and/or PE.Significant renal or liver disease.Systolic blood pressure greater than 180 mmHg or diastolic greater than 110 mmHgActive bleeding. Bacterial endocarditis.Active bleeding or high risk for bleeding.Life expectancy less than 3 months.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
An interactive voice response system (IVRS) will be used to allocate treatments.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated random code.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
The extension trial (Bay 59-7939 / 11899) is a double blind (patients, assessors, clinician and data analyst), placebo controlled trial for patients with confirmed symptomatic deep vein thrombosis or pulmonary embolism who completed 6 or 12 months of treatment with rivaroxaban.
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
24/04/2007
Actual
22/03/2007
Date of last participant enrolment
Anticipated
Actual
12/03/2011
Date of last data collection
Anticipated
Actual
1/12/2011
Sample size
Target
5193
Accrual to date
Final
8257
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,WA,VIC
Recruitment outside Australia
Country [1] 520 0
United States of America
State/province [1] 520 0

Funding & Sponsors
Funding source category [1] 1991 0
Commercial sector/Industry
Name [1] 1991 0
Bayer Australia Limited
Country [1] 1991 0
Australia
Funding source category [2] 1992 0
Commercial sector/Industry
Name [2] 1992 0
Johnson and Johnson Pharmaceutical Research Development
Country [2] 1992 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Bayer Australia Limited
Address
875 Pacific Highway Pymble NSW 2073
Country
Australia
Secondary sponsor category [1] 1803 0
Commercial sector/Industry
Name [1] 1803 0
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Collaborator 11702b)
Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Collaborator 11899)
Address [1] 1803 0
Raritan, New Jersey
Country [1] 1803 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3698 0
The Queen Elizabeth Hospital
Ethics committee address [1] 3698 0
Ethics committee country [1] 3698 0
Australia
Date submitted for ethics approval [1] 3698 0
Approval date [1] 3698 0
19/03/2007
Ethics approval number [1] 3698 0
2007018
Ethics committee name [2] 3699 0
The Gold Coast Hospital
Ethics committee address [2] 3699 0
Ethics committee country [2] 3699 0
Australia
Date submitted for ethics approval [2] 3699 0
Approval date [2] 3699 0
28/03/2007
Ethics approval number [2] 3699 0
200715

Summary
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 PE with or without symptomatic DVT (Einstein-PE). (11702b)

This is a multicenter, randomized, double-blind, placebo-controlled, event-driven, superiority study for efficacy. Patients with confirmed symptomatic DVT or PE who completed 6 or 12 months of treatment with rivaroxaban or VKA are eligible for this trial (Einstein-Extension study). (11899)
Trial website
Trial related presentations / publications
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.

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 rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.1056/NEJMoa1007903. Epub 2010 Dec 3.


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 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.

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.

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.

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 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.

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.

Public notes

Contacts
Principal investigator
Name 27815 0
Address 27815 0
Country 27815 0
Phone 27815 0
Fax 27815 0
Email 27815 0
Contact person for public queries
Name 10901 0
Professor Tim Brighton
Address 10901 0
Department of Haematology
Prince of Wales Hospital
Barker Street
Randwick NSW 2031
Country 10901 0
Australia
Phone 10901 0
+61 2 93829013
Fax 10901 0
+61 2 93829116
Email 10901 0
tim.brighton@sesaihs.health.nsw.gov.au
Contact person for scientific queries
Name 1829 0
Professor Tim Brighton
Address 1829 0
Department of Haematology
Prince of Wales Hospital
Barker Street
Randwick NSW 2031
Country 1829 0
Australia
Phone 1829 0
+61 2 93829013
Fax 1829 0
+61 2 93829116
Email 1829 0
tim.brighton@sesaihs.health.nsw.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually

Documents added automatically
No additional documents have been identified.