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Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation (TripleAXEL)

Primary Purpose

Ischemic Stroke, Transient Ischemic Attack

Status
Completed
Phase
Phase 2
Locations
Korea, Republic of
Study Type
Interventional
Intervention
Rivaroxaban
Warfarin
Sponsored by
Asan Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Ischemic Stroke focused on measuring stroke, TIA

Eligibility Criteria

19 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: All of below

  • Acute ischemic stroke or TIA presumed to be cardioembolic origin (within 5 days from stroke onset) with mild severity: infarct size on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere
  • Atrial fibrillation including paroxysmal atrial fibrillation: atrial fibrillation must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary).
  • Age ≥19 years
  • Informed consent

Exclusion Criteria: Any of below

  • Chronic renal failure (GFR less than 30ml/min) or severe hepatic impairment
  • Significant hemorrhagic transformation (parenchymal hematoma type I or II by the ECASS definition)
  • Stroke mechanism of presumed small vessel occlusion: single small subcortical infarct in the perforating artery territory
  • Large hemispheric or cerebellar infarction; larger than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere
  • Mechanical valve requiring warfarin therapy
  • Active internal bleeding
  • Prior history of symptomatic intracranial bleeding

    : patients with asymptomatic bleedings or microbleedings on MRI are eligible for inclusion

  • Major surgery or major trauma within 30 days that might be associated with increased bleeding risk
  • Clinically significant gastrointestinal bleeding within 6 months
  • Intravenous tissue plasminogen activator use or mechanical embolectomy within 48 hours plus 'significant hemorrhagic transformation as described above (exclusion criteria 2)' or 'large hemispheric infarction or cerebellar infarction as described above (exclusion criteria 4)'

    : patients achieving successful reperfusion without hemorrhage nor large infarction are eligible for enrollment

  • Severe anemia: hemoglobin <10 g/dL
  • Bleeding diathesis; thrombocytopenia (<90,000/µL, prolonged PT (INR>1.7)
  • Sustained uncontrolled hypertension: SBP >180 mmHg or DBP >100 mmHg
  • Severe devastating illness, such terminal cancer, hepatic failure; therefore, the participants have a life expectancy less than 6 months.
  • Planned invasive procedure with potential for uncontrolled bleeding, including major surgery

Sites / Locations

  • Asan Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Rivaroxaban

Warfarin

Arm Description

Rivaroxaban group for 1 month : initial 5 days after randomization rivaroxaban 10mg QD will be administered. Rivaroxaban 20mg QD, but 15mg in case of Cr CL will be administered for remaining 25 days.

Patients allocated to warfarin receive warfarin plus aspirin 100mg until INR value exceed 1.7 followed by warfarin monotherapy with target INR value of 2.5 [2.0 - 3.0].

Outcomes

Primary Outcome Measures

Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging
Intracranial bleeding: symptomatic hemorrhage confirmed by CT or MRI or asymptomatic hemorrhage on follow-up GRE or SWI imaging at 1 month Recurrent ischemic lesion: symptomatic ischemic stroke confirmed by relevant neuroimagings or asymptomatic recurrent ischemic lesion on follow-up or FLAIR imaging at 1 month

Secondary Outcome Measures

The Number of Patients With Intracranial Bleeding
Intracranial bleeding confirmed by relevant neuroimagings
The Number of Patients With Recurrent Ischemic Lesion
Recurrent ischemic lesion confirmed by relevant neuroimagings
Length of Hospitalization
Time to event will be calculated
Number of Participants With Modified Rankin Score of 0 or 1 at Week 4
modified Rankin Score 0 : No symptoms at all : No significant disability despite symptoms; able to carry out all usual duties and activities : Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance : Moderate disability; requiring some help, but able to walk without assistance : Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance : Severe disability; bedridden, incontinent and requiring constant nursing care and attention : Dead

Full Information

First Posted
January 17, 2014
Last Updated
December 14, 2016
Sponsor
Asan Medical Center
Collaborators
Bayer
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1. Study Identification

Unique Protocol Identification Number
NCT02042534
Brief Title
Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation
Acronym
TripleAXEL
Official Title
Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation: Acute Stroke With Xarelto to Reduce Intracranial Bleeding, Recurrent Embolic Stroke, and Hospital Stay, Phase 2, Conceptual Multicenter Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Completed
Study Start Date
January 2014 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Asan Medical Center
Collaborators
Bayer

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Rationale Acute ischemic stroke due to atrial fibrillation (AF) carries a high risk for early recurrence. In acute stage, guidelines recommend aspirin, but do not recommend anticoagulation due to the increased risk of intracranial bleeding. Since, aspirin has a limited efficacy of preventing recurrent stroke in AF, expert consensus suggests early anticoagulation in non-severe stroke with AF. The current practice for acute ischemic stroke patients with AF is delayed warfarin administration with aspirin use for non-minor stroke or immediate warfarin administration (sometimes with heparin bridging) for minor stroke. However, conventional anticoagulation with warfarin in acute ischemic stroke with AF has the following limitations: 1) risk of intracranial bleeding particularly in acute stage, 2) delayed action and transient paradoxical thrombogenic tendency due to the inhibition of protein C, resulting in the risk of early recurrent embolic stroke, and 3) prolongation of hospitalization waiting for full anticoagulation. In contrast, as compared to warfarin, rivaroxaban is advantageous for reduced risk of intracranial bleeding and immediate anticoagulation efficacy. Goal The current trial will examine whether early initiation (within 5 days from stroke onset) of rivaroxaban as compared to conventional warfarin would reduce intracranial bleeding, recurrent embolic stroke, and hospital stay in patients with acute ischemic stroke due to AF.
Detailed Description
Primary endpoint: Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion within 1 month after randomization (rivaroxaban vs conventional warfarin)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Ischemic Stroke, Transient Ischemic Attack
Keywords
stroke, TIA

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
195 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rivaroxaban
Arm Type
Experimental
Arm Description
Rivaroxaban group for 1 month : initial 5 days after randomization rivaroxaban 10mg QD will be administered. Rivaroxaban 20mg QD, but 15mg in case of Cr CL will be administered for remaining 25 days.
Arm Title
Warfarin
Arm Type
Active Comparator
Arm Description
Patients allocated to warfarin receive warfarin plus aspirin 100mg until INR value exceed 1.7 followed by warfarin monotherapy with target INR value of 2.5 [2.0 - 3.0].
Intervention Type
Drug
Intervention Name(s)
Rivaroxaban
Other Intervention Name(s)
Xarelto
Intervention Description
Rivaroxaban group receive oral rivaroxaban 10 mg once daily for 5 consecutive days, followed by 20 mg or 15 mg in patients with a calculated creatinine clearance of 30-49 ml/min. The dosage of rivaroxaban is leveraged from results of ROCKET-AF trial, where 20 mg of rivaroxaban was shown to offer balanced efficacy and safety.
Intervention Type
Drug
Intervention Name(s)
Warfarin
Intervention Description
To harmonize the warfarin regimen across the sites, fixed algorithm was used in dose calculation, both loading and maintenance, and age, sex, ethnicity, race, weight, height, smoking history, presence of liver disease, indication, baseline INR, target INR and concomitant medication were considered as cofactors (http://www.warfarindosing.org/Source/InitialDose.aspx). Investigators will manage anticoagulation with warfarin per routine clinical care.
Primary Outcome Measure Information:
Title
Number of Participants With Intracranial Bleeding and/or Recurrent Ischemic Lesion as Confirmed by MRI Imaging
Description
Intracranial bleeding: symptomatic hemorrhage confirmed by CT or MRI or asymptomatic hemorrhage on follow-up GRE or SWI imaging at 1 month Recurrent ischemic lesion: symptomatic ischemic stroke confirmed by relevant neuroimagings or asymptomatic recurrent ischemic lesion on follow-up or FLAIR imaging at 1 month
Time Frame
1 month after randomization
Secondary Outcome Measure Information:
Title
The Number of Patients With Intracranial Bleeding
Description
Intracranial bleeding confirmed by relevant neuroimagings
Time Frame
at 1 month
Title
The Number of Patients With Recurrent Ischemic Lesion
Description
Recurrent ischemic lesion confirmed by relevant neuroimagings
Time Frame
at 1 month
Title
Length of Hospitalization
Description
Time to event will be calculated
Time Frame
at 1month
Title
Number of Participants With Modified Rankin Score of 0 or 1 at Week 4
Description
modified Rankin Score 0 : No symptoms at all : No significant disability despite symptoms; able to carry out all usual duties and activities : Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance : Moderate disability; requiring some help, but able to walk without assistance : Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance : Severe disability; bedridden, incontinent and requiring constant nursing care and attention : Dead
Time Frame
at 1 month

10. Eligibility

Sex
All
Minimum Age & Unit of Time
19 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: All of below Acute ischemic stroke or TIA presumed to be cardioembolic origin (within 5 days from stroke onset) with mild severity: infarct size on DWI less than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere Atrial fibrillation including paroxysmal atrial fibrillation: atrial fibrillation must be documented by ECG evidence (e.g., 12-lead ECG, rhythm strip, Holter, pacemaker interrogation) within 30 days before randomization. This could be obtained from a notation in the subject's record (e.g., medical chart, hospital discharge summary). Age ≥19 years Informed consent Exclusion Criteria: Any of below Chronic renal failure (GFR less than 30ml/min) or severe hepatic impairment Significant hemorrhagic transformation (parenchymal hematoma type I or II by the ECASS definition) Stroke mechanism of presumed small vessel occlusion: single small subcortical infarct in the perforating artery territory Large hemispheric or cerebellar infarction; larger than 1/3 of MCA territory, 1/2 of ACA territory, 1/2 of PCA territory, and 1/2 of one cerebellar hemisphere Mechanical valve requiring warfarin therapy Active internal bleeding Prior history of symptomatic intracranial bleeding : patients with asymptomatic bleedings or microbleedings on MRI are eligible for inclusion Major surgery or major trauma within 30 days that might be associated with increased bleeding risk Clinically significant gastrointestinal bleeding within 6 months Intravenous tissue plasminogen activator use or mechanical embolectomy within 48 hours plus 'significant hemorrhagic transformation as described above (exclusion criteria 2)' or 'large hemispheric infarction or cerebellar infarction as described above (exclusion criteria 4)' : patients achieving successful reperfusion without hemorrhage nor large infarction are eligible for enrollment Severe anemia: hemoglobin <10 g/dL Bleeding diathesis; thrombocytopenia (<90,000/µL, prolonged PT (INR>1.7) Sustained uncontrolled hypertension: SBP >180 mmHg or DBP >100 mmHg Severe devastating illness, such terminal cancer, hepatic failure; therefore, the participants have a life expectancy less than 6 months. Planned invasive procedure with potential for uncontrolled bleeding, including major surgery
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sun Uck Kwon, PhD.
Organizational Affiliation
Asan Medical Center
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Keun-Sik Hong, PhD
Organizational Affiliation
InjeUniversityIlsanPaikHospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Young Jae Kim, PhD
Organizational Affiliation
Ewha Womans University Mokdong Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Yang Ha Hwang, PhD
Organizational Affiliation
Kyungpook National University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Jaekwan Cha, PhD
Organizational Affiliation
Dong-A University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Woo-Keun Seo, PhD
Organizational Affiliation
Korea University Guro Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Eung-Gyu Kim, PhD
Organizational Affiliation
InjeUniversityBusanPaikHospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Byung-Woo Yoon, PhD
Organizational Affiliation
Seoul National University Hospital
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kyung-Ho Yu, PhD
Organizational Affiliation
Hallym University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Asan Medical Center
City
Seoul
ZIP/Postal Code
138-736
Country
Korea, Republic of

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28892526
Citation
Hong KS, Kwon SU, Lee SH, Lee JS, Kim YJ, Song TJ, Kim YD, Park MS, Kim EG, Cha JK, Sung SM, Yoon BW, Bang OY, Seo WK, Hwang YH, Ahn SH, Kang DW, Kang HG, Yu KH; Phase 2 Exploratory Clinical Study to Assess the Effects of Xarelto (Rivaroxaban) Versus Warfarin on Ischemia, Bleeding, and Hospital Stay in Acute Cerebral Infarction Patients With Non-valvular Atrial Fibrillation (Triple AXEL) Study Group. Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2017 Oct 1;74(10):1206-1215. doi: 10.1001/jamaneurol.2017.2161.
Results Reference
derived
PubMed Identifier
25346499
Citation
Hong KS, Choi YJ, Kwon SU; Triple AXEL Investigators. Rationale and design of Triple AXEL: trial for early anticoagulation in acute ischemic stroke patients with nonvalvular atrial fibrillation. Int J Stroke. 2015 Jan;10(1):128-33. doi: 10.1111/ijs.12386. Epub 2014 Oct 26. Erratum In: Int J Stroke. 2016 Jul;11(5):NP63.
Results Reference
derived

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Rivaroxaban Versus Warfarin in Acute Ischemic Stroke With Atrial Fibrillation

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