Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12607000214437
Ethics application status
Approved
Date submitted
27/03/2007
Date registered
19/04/2007
Date last updated
11/02/2020
Date data sharing statement initially provided
11/02/2020
Date results information initially provided
11/02/2020
Type of registration
Retrospectively registered

Titles & IDs
Public title
A study comparing the efficacy and safety of once-daily oral rivaroxaban with warfarin for the prevention of stroke and embolism in patients with atrial fibrillation.
Scientific title
A Prospective, Randomized, Double-Blind, Parallel-Group, Multicenter, Non-inferiority Study Comparing the Efficacy and Safety of Rivaroxaban (BAY 59-7939) With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Subjects With Non-Valvular Atrial Fibrillation
Secondary ID [1] 357 0
ClinicalTrials.org: NCT00403767
Universal Trial Number (UTN)
Trial acronym
ROCKET
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Non-central nervous system systemic embolism in subjects with non-valvular atrial fibrillation. 1741 0
Stroke 1742 0
Condition category
Condition code
Stroke 1833 1833 0 0
Ischaemic

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is comparing the efficacy and safety of rivaroxaban with warfarin for the prevention of stroke and non-central nervous system systemic embolism in subjects with non-valvular atrial fibrillation. Those subjects assigned to rivaroxaban will receive rivaroxaban 20 mg orally once daily, plus warfarin placebo titrated to a sham International Normalised Ratio. Subjects with moderate renal impairment at screening (defined as calculated creatinine clearance between 30 and 49 ml/min inclusive) will receive a dose adaptation to rivaroxaban 15 mg once daily.
The duration of the treatment period for a given subject will depend on the time required to accrue the required number of adjudicated primary efficacy endpoint events. As a result, the time on study drug will vary from subject to subject, however the expected maximum duration of the study is 32 months, but may extend to 4 years.
Intervention code [1] 1669 0
Prevention
Comparator / control treatment
Those subjects assigned to warfarin will receive warfarin orally once daily titrated to a target INR of 2.5, plus rivaroxaban placebo.
Control group
Active

Outcomes
Primary outcome [1] 2565 0
Primary efficacy outcome is the composite of stroke and non-central nervous system systemic embolism.
Timepoint [1] 2565 0
Measured at the first occurrence from time of randomisation, then every 4 weeks to the end of follow-up period. That is an expected maximum of 32 months, but may extend to 4 years.
Secondary outcome [1] 4421 0
Individual components of the composite primary outcome; vascular death; myocardial infarctiion; disabling stroke; and all-cause mortality.
Timepoint [1] 4421 0
Measured at the first occurrence from time of randomisation, then every 4 weeks to the end of follow-up period. That is an expected maximum of 32 months, but may extend to 4 years.

Eligibility
Key inclusion criteria
Subjects must have documented atrial fibrillation on 2 separate occasions within 6 months before screening.History of prior stroke, transient ischemic attack or non-neurologic systemic embolism believed to be cardiac in origin, OR at least two of the following risk factors: heart failure, hypertension, age 75 years or greater, diabetes mellitus.
Minimum age
18 Years
Maximum age
Not stated
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Significant mitral stenosis.Transient atrial fibrillation caused by a reversible disorder.Active internal bleeding.Severe disabling stroke.History of intracranial bleeding.Haemorrhagic disorders.

Study design
Purpose of the study
Prevention
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
The packaging and dosage will be such that the different treatment groups will appear identical. An interactive voice response system (IVRS) will be used to accomplish a blind allocation.
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
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
14/12/2006
Actual
14/12/2006
Date of last participant enrolment
Anticipated
Actual
5/06/2009
Date of last data collection
Anticipated
Actual
3/09/2010
Sample size
Target
14269
Accrual to date
Final
14268
Recruitment in Australia
Recruitment state(s)
ACT,NSW,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 496 0
United States of America
State/province [1] 496 0

Funding & Sponsors
Funding source category [1] 1982 0
Commercial sector/Industry
Name [1] 1982 0
Bayer Australia Limited
Country [1] 1982 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Bayer Australia Limited
Address
875 Pacific Highway, Pymble NSW 2073
Country
Australia
Secondary sponsor category [1] 1795 0
Commercial sector/Industry
Name [1] 1795 0
Johnson & Johnson Pharmaceutical Research & Development L.L.C.
Address [1] 1795 0
One Johnson & Johnson Plaza
New Brunswick, New Jersey, 08933
Country [1] 1795 0
United States of America

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 3680 0
Rivercity Private Hospital-Redcliffe-Caboolture Health Service District Ethics Committee
Ethics committee address [1] 3680 0
Redcliffe-Caboolture Health Service District Ethics Committee
Level 2, Redcliffe Hospital,
Anzac Ave
Redcliffe QLD 4020
Ethics committee country [1] 3680 0
Australia
Date submitted for ethics approval [1] 3680 0
Approval date [1] 3680 0
06/12/2006
Ethics approval number [1] 3680 0
06/Dec/06
Ethics committee name [2] 3681 0
Peninsula Clinical Research Centre-Redcliffe-Caboolture Health Service District Ethics Committee
Ethics committee address [2] 3681 0
Redcliffe-Caboolture Health Service District Ethics Committee
Level 2, Redcliffe Hospital,
Anzac Ave
Redcliffe QLD 4020
Ethics committee country [2] 3681 0
Australia
Date submitted for ethics approval [2] 3681 0
Approval date [2] 3681 0
14/02/2007
Ethics approval number [2] 3681 0
06/Dec/06
Ethics committee name [3] 3682 0
Caboolture Clinical Research Centre-Redcliffe-Caboolture Health Service District Ethics Committee
Ethics committee address [3] 3682 0
Redcliffe-Caboolture Health Service District Ethics Committee
Level 2, Redcliffe Hospital,
Anzac Ave
Redcliffe QLD 4020
Ethics committee country [3] 3682 0
Australia
Date submitted for ethics approval [3] 3682 0
Approval date [3] 3682 0
14/02/2007
Ethics approval number [3] 3682 0
06/Dec/06

Summary
Brief summary
The purpose of this study is to demonstrate that the efficacy and safety of 20 mg once daily rivaroxaban in preventing thromboembolic events in subjects with atrial fibrillation not related to mitral valve stenosis. Subjects with moderate renal impairment at screening (defined as calculated creatinine clearance between 30 and 49 ml/min inclusive) will receive a dose adaptation to rivaroxaban 15 mg once daily.
Trial website
Trial related presentations / publications
Ungar L, Rodriguez F, Hellkamp AS, Becker RC, Berkowitz SD, Breithardt G, Fox KAA, Hacke W, Halperin JL, Hankey GJ, Nessel CC, Singer DE, Patel MR, Piccini JP, Mahaffey KW. Patient-Reported Satisfaction and Study Drug Discontinuation: Post-Hoc Analysis of Findings from ROCKET AF. Cardiol Ther. 2019 Dec;8(2):283-295. doi: 10.1007/s40119-019-00146-6. Epub 2019 Aug 2.

Quinn GR, Hellkamp AS, Hankey GJ, Becker RC, Berkowitz SD, Breithardt G, Fava M, Fox KAA, Halperin JL, Mahaffey KW, Nessel CC, Patel MR, Piccini JP, Singer DE. Selective Serotonin Reuptake Inhibitors and Bleeding Risk in Anticoagulated Patients With Atrial Fibrillation: An Analysis From the ROCKET AF Trial. J Am Heart Assoc. 2018 Aug 7;7(15):e008755. doi: 10.1161/JAHA.118.008755.

Chen ST, Hellkamp AS, Becker RC, Berkowitz SD, Breithardt G, Fox KAA, Hacke W, Halperin JL, Hankey GJ, Mahaffey KW, Nessel CC, Piccini JP, Singer DE, Patel MR, Melloni C. Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF. Eur Heart J Qual Care Clin Outcomes. 2019 Apr 1;5(2):145-152. doi: 10.1093/ehjqcco/qcy040.

Chen ST, Hellkamp AS, Becker RC, Berkowitz SD, Breithardt G, Fox KAA, Hacke W, Halperin JL, Hankey GJ, Mahaffey KW, Nessel CC, Piccini JP, Singer DE, Patel MR. Impact of polyvascular disease on patients with atrial fibrillation: Insights from ROCKET AF. Am Heart J. 2018 Jun;200:102-109. doi: 10.1016/j.ahj.2018.02.013. Epub 2018 Feb 27.

Leef GC, Hellkamp AS, Patel MR, Becker RC, Berkowitz SD, Breithardt G, Halperin JL, Hankey GJ, Hacke W, Nessel CC, Singer DE, Fox KAA, Mahaffey KW, Piccini JP. Safety and Efficacy of Rivaroxaban in Patients With Cardiac Implantable Electronic Devices: Observations From the ROCKET AF Trial. J Am Heart Assoc. 2017 Jun 14;6(6). pii: e004663. doi: 10.1161/JAHA.116.004663.

Balla SR, Cyr DD, Lokhnygina Y, Becker RC, Berkowitz SD, Breithardt G, Fox KAA, Hacke W, Halperin JL, Hankey GJ, Mahaffey KW, Nessel CC, Piccini JP, Singer DE, Patel MR. Relation of Risk of Stroke in Patients With Atrial Fibrillation to Body Mass Index (from Patients Treated With Rivaroxaban and Warfarin in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation Trial). Am J Cardiol. 2017 Jun 15;119(12):1989-1996. doi: 10.1016/j.amjcard.2017.03.028. Epub 2017 Mar 29.

Sun Y, Hu D, Stevens S, Lokhnygina Y, Becker RC, Berkowitz SD, Breithardt G, Hacke W, Halperin JL, Hankey GJ, Mahaffey KW, Nessel CC, Piccini JP, Singer DE, Fox KAA, Patel MR. Efficacy and safety of rivaroxaban versus warfarin in patients from mainland China with nonvalvular atrial fibrillation: A subgroup analysis from the ROCKET AF trial. Thromb Res. 2017 Aug;156:184-190. doi: 10.1016/j.thromres.2017.04.010. Epub 2017 Apr 13.

Lindner SM, Fordyce CB, Hellkamp AS, Lokhnygina Y, Piccini JP, Breithardt G, Mahaffey KW, Singer DE, Hacke W, Halperin JL, Hankey GJ, Berkowitz SD, Nessel CC, Becker RC, Fox KA, Patel MR; ROCKET AF Steering Committee and Investigators. Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin: A ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis. Circulation. 2017 Mar 7;135(10):1001-1003. doi: 10.1161/CIRCULATIONAHA.116.024666.

Fordyce CB, Hellkamp AS, Lokhnygina Y, Lindner SM, Piccini JP, Becker RC, Berkowitz SD, Breithardt G, Fox KA, Mahaffey KW, Nessel CC, Singer DE, Patel MR; ROCKET AF Steering Committee and Investigators. On-Treatment Outcomes in Patients With Worsening Renal Function With Rivaroxaban Compared With Warfarin: Insights From ROCKET AF. Circulation. 2016 Jul 5;134(1):37-47. doi: 10.1161/CIRCULATIONAHA.116.021890. Erratum in: Circulation. 2016 Aug 23;134(8):e114.

Pokorney SD, Piccini JP, Stevens SR, Patel MR, Pieper KS, Halperin JL, Breithardt G, Singer DE, Hankey GJ, Hacke W, Becker RC, Berkowitz SD, Nessel CC, Mahaffey KW, Fox KA, Califf RM; ROCKET AF Steering Committee & Investigators; ROCKET AF Steering Committee Investigators. Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation: Data From ROCKET AF. J Am Heart Assoc. 2016 Mar 8;5(3):e002197. doi: 10.1161/JAHA.115.002197.

Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP, Lokhnygina Y, Halperin JL, Singer DE, Hankey GJ, Hacke W, Becker RC, Nessel CC, Mahaffey KW, Califf RM, Fox KA, Patel MR; ROCKET AF Steering Committee & Investigators. Native valve disease in patients with non-valvular atrial fibrillation on warfarin or rivaroxaban. Heart. 2016 Jul 1;102(13):1036-43. doi: 10.1136/heartjnl-2015-308120. Epub 2016 Feb 17.

Piccini JP, Hellkamp AS, Washam JB, Becker RC, Breithardt G, Berkowitz SD, Halperin JL, Hankey GJ, Hacke W, Mahaffey KW, Nessel CC, Singer DE, Fox KA, Patel MR. Polypharmacy and the Efficacy and Safety of Rivaroxaban Versus Warfarin in the Prevention of Stroke in Patients With Nonvalvular Atrial Fibrillation. Circulation. 2016 Jan 26;133(4):352-60. doi: 10.1161/CIRCULATIONAHA.115.018544. Epub 2015 Dec 16.

Bansilal S, Bloomgarden Z, Halperin JL, Hellkamp AS, Lokhnygina Y, Patel MR, Becker RC, Breithardt G, Hacke W, Hankey GJ, Nessel CC, Singer DE, Berkowitz SD, Piccini JP, Mahaffey KW, Fox KA; ROCKET AF Steering Committee and Investigators. Efficacy and safety of rivaroxaban in patients with diabetes and nonvalvular atrial fibrillation: the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF Trial). Am Heart J. 2015 Oct;170(4):675-682.e8. doi: 10.1016/j.ahj.2015.07.006. Epub 2015 Jul 17.

Washam JB, Stevens SR, Lokhnygina Y, Halperin JL, Breithardt G, Singer DE, Mahaffey KW, Hankey GJ, Berkowitz SD, Nessel CC, Fox KA, Califf RM, Piccini JP, Patel MR; ROCKET AF Steering Committee and Investigators. Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF). Lancet. 2015 Jun 13;385(9985):2363-70. doi: 10.1016/S0140-6736(14)61836-5. Epub 2015 Mar 6.

Singer DE, Hellkamp AS, Yuan Z, Lokhnygina Y, Patel MR, Piccini JP, Hankey GJ, Breithardt G, Halperin JL, Becker RC, Hacke W, Nessel CC, Mahaffey KW, Fox KA, Califf RM; ROCKET AF Investigators. Alternative calculations of individual patient time in therapeutic range while taking warfarin: results from the ROCKET AF trial. J Am Heart Assoc. 2015 Mar 3;4(3):e001349. doi: 10.1161/JAHA.114.001349.

Girgis IG, Patel MR, Peters GR, Moore KT, Mahaffey KW, Nessel CC, Halperin JL, Califf RM, Fox KA, Becker RC. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF. J Clin Pharmacol. 2014 Aug;54(8):917-27. doi: 10.1002/jcph.288. Epub 2014 Mar 26.

Sherwood MW, Douketis JD, Patel MR, Piccini JP, Hellkamp AS, Lokhnygina Y, Spyropoulos AC, Hankey GJ, Singer DE, Nessel CC, Mahaffey KW, Fox KA, Califf RM, Becker RC; ROCKET AF Investigators. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF). Circulation. 2014 May 6;129(18):1850-9. doi: 10.1161/CIRCULATIONAHA.113.005754. Epub 2014 Feb 19.
Goodman SG, Wojdyla DM, Piccini JP, White HD, Paolini JF, Nessel CC, Berkowitz SD, Mahaffey KW, Patel MR, Sherwood MW, Becker RC, Halperin JL, Hacke W, Singer DE, Hankey GJ, Breithardt G, Fox KA, Califf RM; ROCKET AF Investigators. Factors associated with major bleeding events: insights from the ROCKET AF trial (rivaroxaban once-daily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation). J Am Coll Cardiol. 2014 Mar 11;63(9):891-900. doi: 10.1016/j.jacc.2013.11.013. Epub 2013 Dec 4.

Mahaffey KW, Wojdyla D, Hankey GJ, White HD, Nessel CC, Piccini JP, Patel MR, Berkowitz SD, Becker RC, Halperin JL, Singer DE, Califf RM, Fox KA, Breithardt G, Hacke W. Clinical outcomes with rivaroxaban in patients transitioned from vitamin K antagonist therapy: a subgroup analysis of a randomized trial. Ann Intern Med. 2013 Jun 18;158(12):861-8. doi: 10.7326/0003-4819-158-12-201306180-00003.

van Diepen S, Hellkamp AS, Patel MR, Becker RC, Breithardt G, Hacke W, Halperin JL, Hankey GJ, Nessel CC, Singer DE, Berkowitz SD, Califf RM, Fox KA, Mahaffey KW. Efficacy and safety of rivaroxaban in patients with heart failure and nonvalvular atrial fibrillation: insights from ROCKET AF. Circ Heart Fail. 2013 Jul;6(4):740-7. doi: 10.1161/CIRCHEARTFAILURE.113.000212. Epub 2013 May 30.

Singer DE, Hellkamp AS, Piccini JP, Mahaffey KW, Lokhnygina Y, Pan G, Halperin JL, Becker RC, Breithardt G, Hankey GJ, Hacke W, Nessel CC, Patel MR, Califf RM, Fox KA; ROCKET AF Investigators. Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc. 2013 Feb 19;2(1):e000067. doi: 10.1161/JAHA.112.000067.

Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, Hankey GJ, Hacke W, Becker RC, Nessel CC, Mahaffey KW, Fox KA, Califf RM, Breithardt G; ROCKET AF Steering Committee & Investigators. Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol. 2013 May 14;61(19):1998-2006. doi: 10.1016/j.jacc.2013.02.025. Epub 2013 Mar 14.

Piccini JP, Stevens SR, Chang Y, Singer DE, Lokhnygina Y, Go AS, Patel MR, Mahaffey KW, Halperin JL, Breithardt G, Hankey GJ, Hacke W, Becker RC, Nessel CC, Fox KA, Califf RM; ROCKET AF Steering Committee and Investigators. Renal dysfunction as a predictor of stroke and systemic embolism in patients with nonvalvular atrial fibrillation: validation of the R(2)CHADS(2) index in the ROCKET AF (Rivaroxaban Once-daily, oral, direct factor Xa inhibition Compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation) and ATRIA (AnTicoagulation and Risk factors In Atrial fibrillation) study cohorts. Circulation. 2013 Jan 15;127(2):224-32. doi: 10.1161/CIRCULATIONAHA.112.107128. Epub 2012 Dec 3.

Hankey GJ, Patel MR, Stevens SR, Becker RC, Breithardt G, Carolei A, Diener HC, Donnan GA, Halperin JL, Mahaffey KW, Mas JL, Massaro A, Norrving B, Nessel CC, Paolini JF, Roine RO, Singer DE, Wong L, Califf RM, Fox KA, Hacke W; ROCKET AF Steering Committee Investigators. Rivaroxaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of ROCKET AF. Lancet Neurol. 2012 Apr;11(4):315-22. doi: 10.1016/S1474-4422(12)70042-X. Epub 2012 Mar 7.

Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KA, Califf RM; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.
ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010 Mar;159(3):340-347.e1. doi: 10.1016/j.ahj.2009.11.025.
Public notes

Contacts
Principal investigator
Name 27772 0
Dr Head of Development, CV and UROL
Address 27772 0
Johnson & Johnson Pharmaceutical Research & Development LLC
One Johnson & Johnson Plaza
New Brunswick, New Jersey 08933
Country 27772 0
United States of America
Phone 27772 0
+1 732 524 0400
Fax 27772 0
Email 27772 0
Not available
Contact person for public queries
Name 10858 0
Ms Judith Ruijter
Address 10858 0
PAREXEL International
PO Box 351
North Ryde BC NSW 1670
Country 10858 0
Australia
Phone 10858 0
+61 2 88700533
Fax 10858 0
+61 2 88700503
Email 10858 0
[email protected]
Contact person for scientific queries
Name 1786 0
Dr Dr. Ahmad Hidayat
Address 1786 0
APEX International Clinical Research - Indonesia Office
Ariobimo Sentral 3th Floor Suite 303
Jl. HR. Rasuna Said Kav.X-2 No.5
Jakarta 12950
Country 1786 0
Indonesia
Phone 1786 0
+21 2525740 ext. 371
Fax 1786 0
+62 21 2525883
Email 1786 0
[email protected]

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
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.