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| Name | Class |
|---|---|
| Bayer | INDUSTRY |
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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.
Primary endpoint: Composite of MRI-defined intracranial bleeding and recurrent ischemic lesion within 1 month after randomization (rivaroxaban vs conventional warfarin)
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rivaroxaban | Experimental | 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. |
|
| Warfarin | Active Comparator | 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]. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Rivaroxaban | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 1 month after randomization |
| Measure | Description | Time Frame |
|---|---|---|
| The Number of Patients With Intracranial Bleeding | Intracranial bleeding confirmed by relevant neuroimagings | at 1 month |
| The Number of Patients With Recurrent Ischemic Lesion | Recurrent ischemic lesion confirmed by relevant neuroimagings |
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Inclusion Criteria: All of below
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
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| Name | Affiliation | Role |
|---|---|---|
| Sun Uck Kwon, PhD. | Asan Medical Center | Principal Investigator |
| Keun-Sik Hong, PhD | InjeUniversityIlsanPaikHospital | Principal Investigator |
| Young Jae Kim, PhD | Ewha Womans University Mokdong Hospital | Principal Investigator |
| Yang Ha Hwang, PhD | Kyungpook National University Hospital | Principal Investigator |
| Jaekwan Cha, PhD | Dong-A University Hospital | Principal Investigator |
| Woo-Keun Seo, PhD | Korea University Guro Hospital | Principal Investigator |
| Eung-Gyu Kim, PhD | InjeUniversityBusanPaikHospital | Principal Investigator |
| Byung-Woo Yoon, PhD | Seoul National University Hospital | Principal Investigator |
| Kyung-Ho Yu, PhD | Hallym University Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Asan Medical Center | Seoul | 138-736 | South Korea |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 28892526 | Derived | 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. | |
| 25346499 |
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| ID | Title | Description |
|---|---|---|
| FG000 | Rivaroxaban | 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. Rivaroxaban: 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. |
| FG001 | Warfarin | 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]. Warfarin: 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
Modified Intention-to-treat analysis : The subject who is measured for the primary end point with IP is administered more than at least once after randomization
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| ID | Title | Description |
|---|---|---|
| BG000 | Rivaroxaban | 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. Rivaroxaban: 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. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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 |
| Posted | Number | Participants | 1 month after randomization |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rivaroxaban | Safety population : 98 (patients) 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. Rivaroxaban: 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. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Vertigo positional | Ear and labyrinth disorders | MedDRA 17.0 | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | MedDRA 17.0 | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Sun U. Kwon, MD, PhD, Prof | Asan Medical Center, University of Ulsan | 82-2-3010-3960 | sukwon@amc.seoul.kr |
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| ID | Term |
|---|---|
| D000083242 | Ischemic Stroke |
| D002546 | Ischemic Attack, Transient |
| D020521 | Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D000069552 | Rivaroxaban |
| D014859 | Warfarin |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D009025 | Morpholines |
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|
|
| Warfarin | Drug | 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. |
|
| at 1 month |
| Length of Hospitalization | Time to event will be calculated | at 1month |
| Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | modified Rankin Score 0 : No symptoms at all
| at 1 month |
| Derived |
| 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. |
| BG001 | Warfarin | 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]. Warfarin: 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. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Gender | Count of Participants | Participants |
|
| Body Mass Index | Mean | Standard Deviation | kg/㎡ |
|
| OG001 | Warfarin | 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]. Warfarin: 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. |
|
|
| Secondary | The Number of Patients With Intracranial Bleeding | Intracranial bleeding confirmed by relevant neuroimagings | Modified ITT | Posted | Number | Participants | at 1 month |
|
|
|
|
| Secondary | The Number of Patients With Recurrent Ischemic Lesion | Recurrent ischemic lesion confirmed by relevant neuroimagings | Modified ITT | Posted | Number | Participants | at 1 month |
|
|
|
|
| Secondary | Length of Hospitalization | Time to event will be calculated | Posted | Mean | Standard Deviation | days | at 1month |
|
|
|
|
| Secondary | Number of Participants With Modified Rankin Score of 0 or 1 at Week 4 | modified Rankin Score 0 : No symptoms at all
| Modified ITT (mRS 0,1 at Week 4, n(%) | Posted | Number | participants | at 1 month |
|
|
|
|
| 6 |
| 98 |
| 46 |
| 98 |
| EG001 | Warfarin | Safety population : 90 (patients) 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]. Warfarin: 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. | 5 | 90 | 51 | 90 |
| Atrial fibrillation | Cardiac disorders | MedDRA 17.0 | Systematic Assessment |
|
| Gastrooesophageal reflux disease | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Large intestine polyp | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| International normalised ratio increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Laboratory test abnormal | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Arthritis | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Cerebral infarction | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Stroke in evolution | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Pulmonary hypertension | Respiratory, thoracic and mediastinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Constipation | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nausea | Gastrointestinal disorders | MedDRA 17.0 | Systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA 17.0 | Systematic Assessment |
|
| International normalised ratio increased | Investigations | MedDRA 17.0 | Systematic Assessment |
|
| Decreased appetite | Metabolism and nutrition disorders | MedDRA 17.0 | Systematic Assessment |
|
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | MedDRA 17.0 | Systematic Assessment |
|
| Dizziness | Nervous system disorders | MedDRA 17.0 | Systematic Assessment |
|
| Delirium | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Depression | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Insomnia | Psychiatric disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypertension | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
| Hypotension | Vascular disorders | MedDRA 17.0 | Systematic Assessment |
|
| Others | Social circumstances | MedDRA 17.0 | Systematic Assessment |
|
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D002545 | Brain Ischemia |
| D010078 |
| Oxazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D015110 | 4-Hydroxycoumarins |
| D003374 | Coumarins |
| D001578 | Benzopyrans |
| D011714 | Pyrans |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |