Clinical trial NCT02283294
Conditions: Transient Ischemic Attack Stroke Atrial Fibrillation
Sponsor: University of South Florida
Start date: 2015-04-01; Completion date: 2019-06-01
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate if Apixaban will decrease the complication of having another stroke for people who have atrial fibrillation if initiated earlier than standard of care.

Detailed description:
This is an Open label, randomized, active control, parallel-group pilot trial to examine the effect of initiation of APIXABAN at days 0-3 (TIA), days 3-5 (small stroke) and days 7-9 (medium stroke) to decrease fatal and/or recurrent stroke/TIA in 120 subjects who have suffered a recent( 0 to 48 hours from symptoms) TIA, or small to medium ischemic stroke compared to standard of care warfarin treatment regimen. Subjects will be randomly assigned in a 1:1 ratio to one of two treatment arms (apixaban or warfarin). Subjects will be followed for a total of 180 days during from screening through monthly follow-up visits.

Arms: arm 1: Apixaban twice a day for 180 days with drug initiation day 0-3 (TIA), day 3-5(small stroke) or day 7- 9 (medium stroke) respectively arm 2: standard of care warfarin starting at day 7±5 (TIA) or day 14 ±5 (small to medium ischemic stroke).
Interventions: intervention 1: Apixaban intervention 2: Warfarin
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_SAP_000.pdf: 
i 
 
Protocol version 11 
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Title: 
Apixaban for Early Prevention of Recurrent Embolic Stroke and 
Hemorrhagic Transformation (AREST) 
 
 
Drug or Device 
Name(s): 
Apixaban 
FDA IND: 
Exempt 
BMS Protocol # 
CV185-370 
IRB Protocol #: 
Pro00019754 
NCT # 
NCT02283294 
 
 
Study Principal Investigator  
Guilherme Oliveira, MD 
Department of Internal Medicine 
Division of Cardiovascular Sciences  
University of South Florida 
 
Study Co-Principal Investigator 
David Rose, MD 
Department of Neurology  
University of South Florida 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
Table of Contents ................................................................................................................................ ii 
Abbreviations and Definitions of Terms ........................................................................................... v 
1 
BACKGROUND INFORMATION AND RATIONALE .............................................................. 8 
1.1 
INTRODUCTION ............................................................................................................................................. 8 
1.2 
FINDINGS FROM PRE-CLINICAL AND CLINICAL STUDIES ................................................................................. 8 
1.3 
NAME AND DESCRIPTION OF INVESTIGATIONAL PRODUCT OR DESCRIPTION OF INTERVENTION 17 ............... 9 
1.4 
SELECTION OF DRUGS AND DOSAGES ......................................................................................................... 10 
1.4.1 
Apixaban ......................................................................................................................... 10 
1.4.2 
Warfarin .......................................................................................................................... 10 
1.5 
COMPLIANCE STATEMENT .......................................................................................................................... 10 
2 
STUDY GOVERNANCE ............................................................................................................... 10 
2.1 
EXECUTIVE COMMITTEE ............................................................................................................................. 10 
2.2 
DATA AND SAFETY MONITORING BOARD ................................................................................................... 11 
2.3 
STROKE ADJUDICATION COMMITTEE (SACCO) ......................................................................................... 11 
2.3.1 
Adjudicators .................................................................................................................... 11 
2.3.2 
Stroke/TIA Subtype Classification18, 19 ............................................................................ 11 
2.3.3 
Examination .................................................................................................................... 12 
2.3.4 
Stroke Disability .............................................................................................................. 12 
2.4 
ATRIAL FIBRILLATION REVIEW COMMITTEE .............................................................................................. 12 
2.4.1 
Members .......................................................................................................................... 12 
2.4.2 
Atrial Fibrillation Classifications and Diagnosis 10 ....................................................... 12 
3 
STUDY OBJECTIVES ................................................................................................................... 13 
3.1 
RESEARCH HYPOTHESIS .............................................................................................................................. 13 
3.2 
PRIMARY OBJECTIVE .................................................................................................................................. 13 
3.3 
SECONDARY OBJECTIVES ............................................................................................................................ 13 
4 
INVESTIGATIONAL PLAN ......................................................................................................... 14 
4.1 
GENERAL SCHEMA OF STUDY DESIGN ........................................................................................................ 14 
4.1.1 
Screening Phase .............................................................................................................. 15 
4.2 
STUDY DURATION, ENROLLMENT AND NUMBER OF SITES .......................................................................... 15 
4.2.1 
Duration of Study ............................................................................................................ 15 
4.2.2 
Total Number of Study Sites/Total Number of Subjects Projected .................................. 15 
4.3 
STUDY POPULATION ................................................................................................................................... 15 
4.3.1 
Inclusion Criteria ............................................................................................................ 15 
4.3.2 
Exclusion Criteria ........................................................................................................... 17 
4.3.3 
Women of Childbearing Potential ................................................................................... 18 
5 
STUDY DESIGN AND INTERVENTION ................................................................................... 18 
5.1 
SCREENING VISIT ........................................................................................................................................ 18 
5.2 
BASELINE VISIT/RANDOMIZATION.............................................................................................................. 19 
5.3 
TREATMENT PHASE .................................................................................................................................... 19 
5.4 
END OF STUDY ............................................................................................................................................ 20 
5.5 
STUDY ASSESSMENTS (SEE FIGURE 1) ........................................................................................................ 20 
5.6 
UNSCHEDULED VISITS ................................................................................................................................ 20 
5.6.1 
Super-therapeutic/Sub-therapeutic INR .......................................................................... 20 


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5.6.2 
Adverse Events ................................................................................................................ 20 
5.7 
SUBJECT COMPLETION/EARLY WITHDRAWAL ............................................................................................ 20 
5.8 
CONCOMITANT MEDICATION ...................................................................................................................... 21 
6 
STUDY PROCEDURES ................................................................................................................. 21 
6.1 
VISIT 1 SCREENING VISIT/BASELINE/RANDOMIZATION (CAN OCCUR ON SAME DAY) ................................. 21 
6.2 
RANDOMIZATION ........................................................................................................................................ 21 
6.3 
DRUG INITIATION (MAY BE SAME AS RANDOMIZATION DEPENDING ON GROUP AND STUDY ARM) ............... 21 
6.4 
TREATMENT VISITS ..................................................................................................................................... 22 
6.5 
END OF STUDY ............................................................................................................................................ 23 
6.6 
EARLY WITHDRAWAL (EW) ....................................................................................................................... 23 
7 
STUDY ENDPOINTS AND EVALUATIONS ............................................................................. 23 
7.1 
PRIMARY ENDPOINT ................................................................................................................................... 23 
7.2 
SECONDARY ENDPOINTS ............................................................................................................................. 24 
7.3 
BASELINE EVALUATION (SEE ALSO SCHEDULE OF EVENTS) ........................................................................ 24 
7.3.1 
Physical Examination ..................................................................................................... 24 
7.3.2 
Vital Signs ....................................................................................................................... 24 
7.3.3 
Laboratory Evaluations .................................................................................................. 24 
7.4 
EFFICACY AND SAFETY EVALUATIONS (SEE ALSO SCHEDULE OF EVENTS) .................................................. 24 
7.4.1 
Diagnostic Tests, Scales, Measures, etc.......................................................................... 24 
7.4.2 
Safety criteria for suspension of dosing .......................................................................... 27 
8 
STATISTICAL CONSIDERATIONS ........................................................................................... 27 
8.1 
STATISTICAL METHODS .............................................................................................................................. 27 
8.1.1 
Baseline Data .................................................................................................................. 27 
8.1.2 
Efficacy Analysis/Primary Aim ....................................................................................... 27 
 
8.1.3 
Safety Analysis/Secondary Aim ....................................................................................... 28 
8.1.4 
Potential Confounders .................................................................................................... 28 
8.1.5 
Sample Size and Power. .................................................................................................. 28 
8.1.6 
Randomization ................................................................................................................ 29 
8.2 
INTERIM ANALYSIS ..................................................................................................................................... 29 
9 
STUDY MEDICATION ................................................................................................................. 29 
9.1 
PACKAGING ................................................................................................................................................ 29 
9.1.1 
Warfarin .......................................................................................................................... 29 
9.1.2 
Apixaban ......................................................................................................................... 29 
9.2 
LABELING ................................................................................................................................................... 30 
9.3 
DOSING ....................................................................................................................................................... 30 
9.3.1 
Warfarin .......................................................................................................................... 30 
9.3.2 
Apixaban. ........................................................................................................................ 30 
9.4 
TREATMENT COMPLIANCE AND ADHERENCE.............................................................................................. 30 
9.5 
DRUG ACCOUNTABILITY............................................................................................................................. 30 
10 
SAFETY MANAGEMENT ............................................................................................................ 31 
10.1 
CLINICAL ADVERSE EVENTS ....................................................................................................................... 31 
10.2 
ADVERSE EVENT REPORTING ..................................................................................................................... 31 
10.3 
DEFINITION OF AN ADVERSE EVENT ........................................................................................................... 31 
10.4 
DEFINITION OF A SERIOUS ADVERSE EVENT (SAE) .................................................................................... 31 
10.4.1 
Serious Adverse Event Collecting and Reporting ........................................................... 32 
10.4.2 
Relationship of SAE to study drug or other intervention ................................................ 33 
10.4.3 
Definition of Severity ...................................................................................................... 34 
10.5 
IRB/IEC NOTIFICATION OF SAES ............................................................................................................... 34 
10.5.1 
SAE Reconciliation ......................................................................................................... 34 


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10.5.2 
Follow-up report ............................................................................................................. 35 
10.5.3 
Non-Serious Adverse Events ........................................................................................... 35 
10.5.4 
Non-Serious Event Collecting and Reporting ................................................................. 35 
10.6 
HEALTH  AUTHORITY REPORTING (US FDA IND) ..................................................................................... 35 
10.7 
LABORATORY TEST ABNORMALITIES ......................................................................................................... 36 
10.8 
PREGNANCY ................................................................................................................................................ 36 
10.9 
OVERDOSE .................................................................................................................................................. 36 
10.10 
DRUG INDUCED LIVER INJURY (DILI) ........................................................................................................ 36 
10.11 
OTHER SAFETY CONSIDERATIONS .............................................................................................................. 37 
10.12 
MEDICAL EMERGENCIES ............................................................................................................................. 37 
11 
STUDY ADMINISTRATION ........................................................................................................ 37 
11.1 
TREATMENT ASSIGNMENT METHODS ......................................................................................................... 37 
11.2 
DATA COLLECTION AND MANAGEMENT ..................................................................................................... 37 
11.2.1 
Sources of Materials ....................................................................................................... 37 
11.3 
38 
CONFIDENTIALITY ........................................................................................................................................................ 38 
11.4 
REGULATORY AND ETHICAL CONSIDERATIONS .......................................................................................... 38 
11.4.1 
Risks to subjects .............................................................................................................. 38 
11.4.2 
Potential Risks ................................................................................................................ 38 
11.4.3 
Risk Assessment............................................................................................................... 39 
11.4.4 
Potential Benefits of Trial Participation ......................................................................... 39 
11.5 
INFORMED CONSENT ................................................................................................................................... 39 
11.6 
PAYMENT TO SUBJECTS/FAMILIES .............................................................................................................. 39 
11.7 
PUBLICATION .............................................................................................................................................. 39 
12 
REFERENCES ................................................................................................................................ 40 
13 
APPENDICES ................................................................................................................................. 41 
13.1 
MODIFIED RANKIN SCALE .......................................................................................................................... 41 
13.2 
NIHSS ........................................................................................................................................................ 41 
13.3 
SS- QOL ..................................................................................................................................................... 42 
13.4 
WARFARIN DOSING PROTOCOL .................................................................................................................. 46 
 
 


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ABBREVIATIONS AND DEFINITIONS OF TERMS 
°C 
 
Degrees centigrade 
AE 
 
Adverse event 
AF 
 
Atrial Fibrillation 
ALT 
AST 
aPTT 
 
Alanine aminotransferase 
Aspartate aminotransferase  
Activated Partial Thromboplastin Time 
BMS 
CMP 
CBC  
CK 
CMB 
 
Bristol-Myers Squibb 
Complete metabolic panel 
Complete blood count 
Creatine kinase  
Cerebral Microbleeds 
CT  
DSMB 
E.G. 
EKG 
 
Computed Tomography  
Data and Safety Monitoring Board 
For Example 
Electrocardiogram 
EOS 
 
End of Study 
EW 
 
Early  Withdrawal 
FDA 
 
Food and Drug Administration 
GRE 
 
Gradient Recovery Echo 
INR 
IRB 
LAR 
 
International Normalization Ratio 
Institutional Review Board 
Legally Authorized Representative 
MRI 
 
Magnetic Resonance Imaging 
mRS 
 
Modified Rankin Scale 
NIHSS 
 
National Institute of Health Stroke Scale 
NVAF 
NSAE 
PI 
 
Non-Valvular Atrial Fibrillation 
Non Serious Adverse Event 
Principal Investigator 
SS-QOL 
 
Stroke Specific Quality of Life Scale 
SACCO 
 
SWI 
 
Stroke Adjudication Committee for Classification and 
Organization 
Susceptibiltiy Weighted Imaging 
TEE 
TSH 
 
Trans-Esophageal Echocardiogram 
Thyroid Stimulating Hormone 
TIA 
ULNS 
 
Transient Ischemic Attack 
Upper Limit of Normal 
USF 
 
University of South Florida 
WOCBP 
 
Women of Child Bearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Schedule of Study Procedures 
TIA -Apixaban group 
Screen/ 
Baseline 
Treatment 
Initiation 
Maintenance╪ 
End of 
Study 
30day 
PC 
Early 
Withdrawal 
Unsch 
Visit Number 
1  
2 
3 
4 
5 
6 
7 
8 
9 
10 
Study Days (Visit Window) 
0 
β  
(See also 
table 2) 
14 (±3) 
30(±5) 
60(±10
) 
90(±10
) 
120(±1
0) 
150(±1
0) 
180 
(±10) 
210±10
) 
  
  
Informed Consent 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
 
 
 
General Medical 
History/Demographics 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs§ 
 
 
 
 
 
 
 
 
 
 
 
 
mRS 
 
 
 
 
 
 
 
 
 
 
 
 
NIHSS 
 
 
 
 
 
 
 
 
 
 
 
 
SS-QOL 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test╪ 
 
╪ 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Lab Evaluation* 
** 
 
 
 
 
 
 
 
 
 
 
 
PT/INR ( Warfarin arm only) 
 
 
 
 
 
 
 
 
 
 
 
 
TEE 
† 
 
 
 
 
 
 
 
 
 
 
 
Event Monitor (prior to DC) 
 
 
 
 
 
 
 
 
 
 
 
 
Carotid Ultrasound 
 
 
 
 
 
 
 
 
 
 
 
 
MRI or CT scan 
 
 
 
 
 
 
 
 
 
 
 
 
Record AE/SAEs 
 
 
 
 
 
 
 
 
 
 
 
 
Prior and con. medications/procedures 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense Study Drug 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Compliance 
 
 
 
 
 
 
 
 
 
 
 
Non-study anticoagulation initiation 
 
 
 
 
 
 
 
 
 
 
 
 
β drug initatiation will be as follows:  TIA: Apixaban arm day 0-3/Warfarin arm day 7(±5): Small stroke: Apixaban arm day 3-5/Warfarin arm day 14(±5): Medium stroke: Apixaban arm day 7-9/Warfarin arm day 
14(±5) 
* Results of existing tests will be obtained from subject’s hospital chart to assess eligibility. If tests results are not available labs will be performed at the visit. See section 6 for a detailed description of 
what this entails. 
 
 
§ Vitals: BP, HR,, weight,  (RR and Temperature are optional, height obtained at baseline only) 
 
** Labs for inclusion/exclusion criteria will include CMP, CBC with diff and platelets, Creatinine, PT/INR, LFTs and Lipid panel.  
† performed prior to discharge  


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╪ All WOCBP MUST have a negative pregnancy test within 24 hours before receiving apixaban. The minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy 
test is positive, the subject must not receive apixaban and must not be enrolled in the study.¥ Study day at screening is day of event  
 
 
Dosing Category 
Apixaban dose initiation window 
TIA 
Day 0-3 
Small Stroke 
Day 3-5 
Medium Stroke 
Day 7-9 
 
 
Dosing Category 
Warfarin dose initiation window 
TIA 
Day 7 (+/- 5) 
Small Stroke 
Day 14 (+/- 5) 
Medium Stroke 
Day 14 (+/- 5) 
 
 
Table 2 
 
 
 
 
 
 
 


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1 
BACKGROUND INFORMATION AND RATIONALE 
1.1 Introduction 
Non-Valvular Atrial Fibrillation (NVAF) is a growing problem with prevalence in the United 
States of approximately 5 million, up to half of whom are unaware that they have the most 
common cardiac arrhythmia. Patients with AF are at five time’s greater risk for having a 
stroke than those in normal sinus rhythm1, 2.  Current clinical practice prohibits early use of 
anticoagulation following stroke even when etiology is suspected as embolic3, 4. Furthermore, 
strokes in patients with atrial fibrillation have been shown to be associated with increased 
morbidity and mortality1, 2. 
Several recent trials with novel anticoagulation (table 3) have shown stroke prevention 
efficacy equal to or superior to warfarin with over a fifty percent reduction in intracranial 
bleed; however they excluded subjects with a stroke within seven or less days  5, 6, 7, 8, 9. 
The results from these pivotal trials are listed below: 
 
Rely 
Rocket AF 
Aristotle 
Engage AF 
 
Warfarin 
Dabigatran 
150mg 
Warfarin 
Rivaroxaban 
Warfarin 
Apixaban 
Warfarin 
Edoxaban 
60mg 
Stroke 
Per year 
1.69 % 
1.11% 
2.2 %  
1.7%  
1.6% 
1.27% 
1.50 % 
1.18% 
Hemorrhagic 
stroke per 
year 
0.38% 
0.10%  
0.7 %  
0.5 %  
0.47% 
0.24% 
0.47% 
0.26% 
Major Bleed 
Per year 
3.36 %  
3.11 %  
14.5% * 
14.9% * 
2.09% 
2.13% 
3.43 % 
2.75 % 
Intracranial 
Bleed Per 
Year 
0.74% 
0.30% 
0.70 % 
0.50 % 
0.80 %. 
0.33 % 
0.85 % 
0.39 % 
Table3* total bleed rate accounted for not just major bleed 
This study is being conducted to evaluate if anticoagulation treatment with Apixaban, initated 
earlier then the recommended guidelines of within 14 days after embolic stroke for patients 
with atrial fibrillation is associated with decreased risk for recurrent embolic stroke without 
increasing the risk of hemorrhagic transformation compared to conventional treatment (i.e. no 
anticoagulation treatment within 14 days of stroke10, 11.  
 
1.2 Findings from pre-clinical and clinical studies 
 
Currently, there are limited data regarding the early start of anticoagulation therapy following 
embolic stroke. 
 
In the review of our local stroke database from October 2011 until December 2013, we 
examined the records of 336 small to medium stroke patients admitted to Tampa General 
Hospital with an ischemic stroke secondary to atrial fibrillation.  The average age in our study 
population was 75.3 ± 1.83 years of age.  Stroke risk was similar to other AF groups in the 
literature, possessing an average CHADS2 score of 2.6 ± 0.26 on admission; average 
CHA2DS2-VASc score was 4.4 ± 0.4.  Average hospital stay was 9.8 ± 1.49 days.  We 
observed a 24.7% ± 6.2% mortality rate in our population prior to discharge.  In addition, 
stroke survivors had a 5.1% recurrent non-fatal stroke risk.  Patients with disabling or fatal 


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strokes were of a more advanced age than those who survived without severe disability (78.0 ± 
1.96 years vs 69.7 ± 3.50 years, p <0.001).Our data indicate that the risk of fatal to recurrent 
stroke is approximately 25 % with standard treatment (initiating anticoagulation 
approximately seven to fourteen days after signs and symptoms) for this group of patients 12. 
 
The HAEST trial indicated that low molecular weight heparin results in a reduction in 
mortality and disability when used early (30 hours post stroke)in the treatment of ischemic 
stroke; however, this benefit is offset by an increased risk of intracranial hemorrhage 3, 13, 14  
 
The previous studies on novel anticoagulation (NOAC) excluded subjects with a stroke/TIA 
within seven or less days; however, these randomized trials consistently demonstrated a lower 
risk of intracranial bleed compared to traditional anticoagulants ( see table 2) 5, 6, 7, 8, 9.  
 
ARISTOTLE followed a limited number of subjects (44) who suffered a stroke/TIA, between 
7 and 14 days prior to randomization to treatment with either Apixaban or warfarin. There was 
only 1 subject in the warfarin group who suffered a major bleed 5, 15. There were no recurrent 
stroke or systemic embolism in any of the 44 patients.  
 
Recently investigators have reported the use of Dabigatran given within 24 hours of a 
TIA/minor stroke onset in a population of non-AF patients and have found it to demonstrate 
no significant increase in hemorrhagic transformation in this population 16.  
 
Based on these limited data, we propose to examine the potential advantage of  a treatment 
regimen of Apixaban at 0-3 days after TIA, 3-5 days after small ischemic stroke and 7-9 days 
after medium  stroke in patients with atrial fibrillation 
 
 
1.3 
Name and Description of Investigational Product or Description of Intervention 17 
Apixaban, a factor Xa (FXa) inhibitor, is chemically described as 1-(4-methoxyphenyl)-7-oxo-
6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-
carboxamide. Its molecular formula is C25H25N5O4, which corresponds to a molecular 
weight of 459.5. Apixaban has the following structural formula: 
 
 
 
 
 
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does not 
ionize; its aqueous solubility across the physiological pH range is ~0.04 mg/mL 17. 
This study is an open label, randomized,  active controlled pilot study of Apixaban in subjects 
with NVAF who have, within 48 hours from signs and symptoms, been diagnosed with a TIA 
or a Small to Medium Ischemic Stroke as defined by the SACCO (see section 2.3 ) .  


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In this study 120 patients with NVAF who have had a recent small or medium stroke or TIA 
(within 0-48 hours)  will receive Apixaban twice a day for 180 days with drug initiation day 0-
3 (TIA), day 3-5(small stroke) or day 7- 9 (medium stroke) respectively or receive standard of 
care warfarin starting at day 7±5 (TIA) or day 14 ±5  (small to medium ischemic stroke).  
1.4 
Selection of Drugs and Dosages 
1.4.1 
Apixaban 
The dosage of Apixaban is based on the clinical findings of studies in human subjects and its 
FDA approved dosage for patients with nonvalvular atrial fibrillation. Patients will receive 
5mg dosage twice a day or 2.5 mg if they have any 2 of the following characteristics: 
 
• age ≥80 years 
• body weight ≤60 kg 
• serum creatinine ≥1.5 mg/dL 
 
 
Coadministration with CYP3A4 and P-glycoprotein inhibitors: For patients receiving 
Apixaban 5 mg twice daily when Apixaban is coadministered with drugs that are strong dual 
inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole, 
itraconazole, ritonavir, clarithromycin), the recommended dose is 2.5 mg twice daily [ patients 
already taking 2.5 mg twice daily, coadministration of Apixaban with strong dual inhibitors of 
CYP3A4 and P- glycoprotein should be avoided 17. 
 
1.4.2 
Warfarin 
Standard of care arm will be on Warfarin which will be locally sourced and commercial drug 
supply provided by Primary Investigator. See appendix 13.4 for dosing guidelines. 
 
 
1.5 
Compliance Statement  
This study will be conducted in full accordance with all applicable Institutional Policies of 
participating sites and Procedures and all applicable Federal and state laws and regulations 
including 45 CFR 46, 21 CFR Parts 50, 54, 56, 312, 314 and 812 and the Good Clinical 
Practice: Consolidated Guideline approved by the International Conference on Harmonisation 
(ICH). Any episode of noncompliance will be documented. 
The investigators will perform the study in accordance with this protocol, will obtain consent, 
and will report adverse events in accordance with IRB Policies and Procedures and all federal 
requirements. Collection, recording, and reporting of data will be accurate and will ensure the 
privacy, health, and welfare of research subjects during and after the study.  
 
2 
STUDY GOVERNANCE 
2.1 
Executive Committee 
The Executive Committee will be composed of a group of clinical experts responsible for 
ensuring that study design, execution and management are of the highest quality. The 
Executive Committee will monitor progress of study enrollment, make recommendations in 
collaboration with the sponsor based on the Stroke Adjudication Committee and DSMB 
Committee input, and oversee the presentation and publication of the trial results. The 
committee will convene regularly by teleconference and/or face-to-face meetings to discuss 
and report on the ongoing conduct of the study in collaboration with the sponsor. 
The chairman of the Executive Committee will serve as the third member to both the stroke 
adjudication and atrial fibrillation committees to meet consensus if necessary.  


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2.2 
Data and Safety Monitoring Board 
The DSMB is responsible for safeguarding the interests of study participants, assessing the 
safety and efficacy of study procedures, and for monitoring the overall conduct of the study. 
The recommendations will be forwarded to the Executive Committee and the sponsor for final 
decision.  
The DSMB is an independent group advisory to the executive board and is required to provide 
recommendations about continuing, and stopping the study. In addition, the DSMB is asked to 
make recommendations, as appropriate, about the benefit/risk ratio of procedures and 
participant burden 
 
The DSMB will convene annually and at the milestones of  40 and 80 patients  enrolled as 
well as at study conclusion to review safety data.  
 
 
Notification of and referral for abnormal findings Data will be collected by the research team. 
Study data will be entered into the data collection forms or recorded electronically as they are 
collected during the study visit. The PIs will monitor all data for any inconsistencies or 
irregularity. If unanticipated adverse events or SAE of importantce (symptomatic hemorrhagic 
transformation)  are observed, they will be reported to the DSMB within 24 hours. All other 
AE’s will be reported during scheduled meetings and to the IRB according to standard AE 
reporting policies. The Principal Investigator will forward all decisions to the regulatory 
authority as appropriate.  
2.3 
Stroke Adjudication Committee (SACCO) 
The Stroke Adjudication Committee will review and adjudicate all stroke endpoints. The 
committee will not be blinded to patient and study medication arm during the review of each 
stroke endpoint case.  
2.3.1 
Adjudicators 
W. Scott Burgin, MD 
David Z. Rose, MD 
Swetha Renati, MD 
Department of Neurology 
University of South Florida 
Ryan Murtagh, MD 
Department of Radiology 
             University of South Florida 
2.3.2 
Stroke/TIA Subtype Classification18, 19 
2.3.2.1 
Ischemic Stroke 
Defined as an acute symptomatic focal cerebral or retinal dysfunction caused by an 
infarction of central nervous system tissue. 
1. a. Acute infarcts are classified as small, medium or large based on size of the 
largest ischemic lesion: 
a. small = lesion in the anterior or posterior circulation <1.5 cm. 
b. medium = equal to or greater than 1.5cm but less than a complete territory 
infarct lesion in a cortical superficial branch of the anterior cerebral artery 
(ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), or 
in a branch of MCA or PCA, or lesion in internal border-zone territories.  
c. large posterior = lesion involving complete PCA territory, or lesion of 
cerebellum 1.5 cm or larger or any lesion of the brain stem. 


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d. large anterior = lesion involving complete ACA or MCA territory, or 
lesion involving >1 artery territory  
 
e. All classifications are based of the measurement of the largest lesion size  
with preferred sequencing to be GRE on MRI (but all effort should be 
used to maintain the same modality of sequencing and magnet strength 
used at baseline 
2.Subacute/chronic or 'old' infarcts (i.e. more than 2 weeks) are noted but not 
classified. 
3.Transient Ischemic Attack (TIA) 
defined as an acute symptomatic focal cerebral, spinal, or retinal dysfunction 
in which symptoms resolve (typically in less than 1 day) without acute 
damage on neuroimaging. 
 
2.3.2.2 
Hemorrhagic Stroke 
Defined as an acute symptomatic focal or global cerebral dysfunction caused by a 
nontraumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage; or 
asymptomatic neuroimaging-positivity, including greater than three cerebral  
microbleeds found with GRE-sequenceing and/or CT hyperintensities 
2.3.2.3 
Undetermined Stroke  
Undetermined stroke is defined as a stroke with insufficient information to allow 
categorization as A or B. 
2.3.3 
Examination 
Outpatient (in clinic) or Inpatient (in hospital) physical neuro-examination at day 14, 30, 
60, 90, 120, 150 and 180 
2.3.4 
Stroke Disability  
Stroke disability should be measured by a reliable and valid scale in all cases, 
modified Rankin Scale (mRS) and NIHSS  at day 14, 30, 60, 90, 120, 150 and 180 
(see appendix 13.1 and 13.2) 
2.4 Atrial Fibrillation Review Committee 
The Atrial Fibrillation Adjudication Committee will provide Atrial Fibrillation 
Classifications and Diagnosis prior to randomization on subjects with new onset 
atrial fibrillation if the local PI is in doubt of diagnosis. All patients will be 
reviewed by the Atrial Fibrillation Review Committee at the end of the study.  
2.4.1 
Members 
Michael Fradley, MD 
Department of Cardiovascular Sciences 
University of South Florida 
2.4.2 
Atrial Fibrillation Classifications and Diagnosis 10 
2.4.2.1 
Definition 
a. Non Valvular Atrial fibrillation (NVAF) is defined as a supraventricular 
tachyarrhythmia with rapid, uncoordinated atrial electrical activity and 
irregular ventricular responses in the presence of intact atrioventricular (AV) 
conduction.  ECG, Holter, telemetry, or event monitor characteristics include: 


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1) irregular R-R intervals (when AV conduction is present), 2) absence of 
distinct repeating P waves, and 3) irregular atrial activity. 
b.  Premature atrial contractions (PACs) with underlying sinus rhythm or 
organized atrial supraventricular tachyarrhythmias such as atrial tachycardia 
or atrial flutter will not constitute a diagnosis of AF 
2.4.2.2 
Classification 
a. 
Paroxysmal – Atrial fibrillation that terminates spontaneously or with intervention 
within seven days of onset. Episodes may recur with variable frequency. 
b. Persistent – Atrial fibrillation that is sustained for more than 7 days.  Episodes often 
require pharmacologic or electrical cardioversion to restore sinus rhythm. 
c. 
Long-standing persistent – Atrial fibrillation that has lasted for more than 12 
months. 
d. Permanent – Persistent atrial fibrillation where a joint decision by the patient and 
clinician has been made to no longer pursue a rhythm control strategy. 
e. Non valvular Atrial fibrillation – AF in the absence of rheumatic mitral stenosis, a 
mechanical valve  
 
2.4.2.3 
Atrial Fibrillation Diagnosis 
a. 
Known past medical history of atrial fibrillation (as documented in patient’s medical 
record) 
b. Newly diagnosed atrial fibrillation lasting at least 10 seconds as documented by 12-lead 
electrocardiogram, rhythm strip, telemetry monitoring, Holter/event recorder monitoring. 
c. 
Pacemaker/ICD/implantable loop recorder interrogation – Electrograms must be used to 
make the diagnosis (marker channels and mode switch episodes are not sufficient or 
appropriate).  Electrograms should be reviewed by a member of the Atrial Fibrillation 
Adjudication Committee 
 
3 
STUDY OBJECTIVES 
3.1 
Research Hypothesis 
Early anticoagulation treatment regimen with Apixaban at 0-3 days after TIA, 3-5 days 
after small ischemic stroke and 7 to 9days after medium ischemic stroke for patients with 
atrial fibrillation will result in a decreased incidence for recurrent ischemic stroke and 
without significant increase in risk of  intracranial hemorrhage compared to conventional 
treatment for TIA, small and medium sized strokes.  
 
3.2 
Primary Objective 
In patients with atrial fibrillation with recent cerebral ischemic symptoms (0-48 hours), to 
evaluate whether the treatment regimen with Apixaban (Three subgroups: TIA: day 0-3; 
small stroke: day 3-5; medium stroke: day 7-9) compared with standard of care treatment 
regimen with warfarin (Three subgroups: TIA: day 7±5; Small or medium stroke: day 
14±5) reduces the composite endpoint of fatal stroke, recurrent ischemic stroke or TIA at 
30 and 180 days. (See figure 1) 
 
3.3 
Secondary Objectives 
In patients with atrial fibrillation with recent cerebral ischemic symptoms (0-48 hours), 
to evaluate whether the treatment regimen of early Apixaban (Three subgroups: TIA: 
day 0-3; small stroke: day 3-5; medium stroke: day 7-9) compared with standard of care 
treatment with warfarin (three subgroups: TIA: day 7±5; Small or medium stroke: day 
14±5) does not increase the number of intracranial hemorrhage assessed by MRI/CT by 
30 and 180 days. 


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Additional information will be collected on: 
o Quality of Life 
o Modified Rankin Score 
o NIH Stroke Scale 
o Echocardiography 
o AF Burden (Event Monitor data). 
     
4 
INVESTIGATIONAL PLAN 
 
4.1 General Schema of Study Design 
This will be a multi-center, open label, randomized, active control, parallel-group pilot trial to 
examine the effect of  initiation of APIXABAN at days 0-3 (TIA), days 3-5 (small stroke) and 
days 7-9 (medium stroke) to decrease fatal and/or  recurrent stroke/TIA in 120 subjects who 
have suffered a  recent( 0 to 48 hours from symptoms)  TIA, or small to medium ischemic 
stroke as defined by appendix 13.1 compared to standard of care warfarin treatment regimen.  
Subjects will be randomly assigned in a 1:1 ratio to one of two treatment arms (apixaban or 
warfarin). Subjects will be followed for a total of 180 days from screening through follow-up.  
 
 
 
 
Figure 1 


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4.1.1 
Screening Phase 
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  All 
subjects will have a diagnosis of NVAF with TIA or small to moderate embolic stroke.  
Subject consent will be obtained prior to any study related procedures being performed, 
including discontinuation of current therapy. All females of child bearing age will have a urine 
pregnancy test.  Labs to assess liver and kidney function and an EKG will be obtained from 
the patients’ hospital record or obtained at screening if not available at time of consent.  A 
physical exam will be obtained at screening and at various points throughout the study.  
The screening and baseline/randomization visit may be combined as long as all 
inclusion/exclusion criteria have been met prior to randomization.  Otherwise, if these reports 
are not available at the time of screening then randomization and study initiation can be 
combined into one visit.  
 
 
4.2 Study Duration, Enrollment and Number of Sites 
 
4.2.1 
Duration of Study 
The study duration per subject will be approximately 180 days. The active treatment phase is 
dependent on the dosing category (TIA, small or medium ischemic stroke) that the subject is 
placed in and which treatment regimen the patient is randomized into.  
 
4.2.2 
Total Number of Study Sites/Total Number of Subjects 
Projected 
The study will be conducted at University of South Florida (USF Health’s South Center for 
Advanced Health Care, USF Health’s Morsani Center for Advance Health Care , Tampa 
General Hospital), University of Louisville (hospital and clinic), University of California Los 
Angeles (hospital and clinic), and Bayfront Cardiovascular Sciences for a total of 4 enrolling 
sites.  
 
Recruitment will stop when approximately 120 subjects meeting eligibility criteria are 
enrolled.  To account for drop-outs as well as screen-failures up to 125 subjects will be 
consented and randomized.  
 
 
4.3 Study Population 
 Adult patients with the diagnosis of atrial fibrillation and recent TIA or ischemic small to 
medium stroke . Recent TIA will be defined as up to 3 days from signs and symptoms, recent 
small stroke will be up to 5 days from signs and symptoms and recent medium stroke will up 
to 9 days from signs and symptoms. 
4.3.1 
Inclusion Criteria  
 
1. Signed Written Informed Consent 
• 
Before any study procedures are performed, subjects will have the details 
of the study described to them, and they will be given a written informed 
consent document to read. Then, if subjects consent to participate in the 
study, they will indicate that consent by signing and dating the informed 
consent document in the presence of study personnel. 
 


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2. Males and Females 18 years of age and over. 
 
3. History of Nonvalvular Atrial Fibrillation (NVAF) by documentation in the 
medical history or newly diagnosed nonvalvular Atrial Fibrillation at time of 
study randomization by ECG, device or telemetry (see section 2.4.2) 
 
4. Diagnosis of a recent TIA or small or medium ischemic stroke . Recent TIA is 
defined as up to 3 days from signs and symptoms, recent small stroke will 
be up to 5 days from signs and symptoms and recent medium stroke will up 
to 9 days from signs and symptoms.  (See section 2.3.2) 
 
5. Women of child-bearing potential must use a reliable method of contraception and 
must provide a negative pregnancy test at entry into the study and within 24 hours 
of study treatment initiation.  
 
6. WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study drug Apixaban plus 5 half-lives (approximately 3 
days) plus 30 days (duration of ovulatory cycle) for a total of 33 days post-
treatment completion. 
 
7. Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with Apixaban plus 5 
half-lives (approximately 3 days) plus 90 days (duration of sperm turnover) for a 
total of 93 days post-treatment completion. 
 
8. Azoospermic males and WOCBP who are continuously not heterosexually active 
are exempt from contraceptive requirements.  However they must still undergo 
pregnancy testing as described in this section. 
 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy 
Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on 
the use of highly effective methods of contraception. Highly effective methods of contraception 
have a failure rate of < 1% when used consistently and correctly. 
At a minimum, subjects must agree to the use of one method of highly effective contraception 
as listed below: 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide 
• Hormonal  methods  of  contraception  including  combined  oral  contraceptive  pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena by 
WOCBP subject or male subject’s WOCBP partner Female partners of male subjects 
participating  in  the  study  may  use  hormone  based  contraceptives  as  one  of  the 
acceptable methods of contraception since they will not be receiving study drug  
• IUDs, such as ParaGard
™ 
• Tubal ligation 
• Vasectomy. 
• Complete Abstinence* 
 


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*Complete abstinence is defined as complete avoidance of heterosexual intercourse and is an 
acceptable form of contraception for all study drugs. Female subjects must continue to have 
pregnancy tests. Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence 
 
 
4.3.2 
Exclusion Criteria 
 
1. Hemorrhagic stroke 
 
2. Large ischemic stroke 
 
 
3. History of major bleeding within the last 6 months from time of subject 
enrollment (e.g. GI bleed). 
 
4. History of intracranial bleed  
 
a. Traumatic intracranial bleed within one year of randomization. 
(Traumatic ICH greater than one year of randomization is not an 
exclusion).  
 
5. Current or history of bleeding disorders (e.g. blood dycrasias) 
 
6. Blood Pressure of 180/100 mmHg on hypertensive therapy day of randomization 
per PI discretion 20.  
 
7. Current illicit drug use and/or chronic alcohol use per PI discretion. 
 
8. Severe liver disease (AST/ALT 2x upper limit). 
 
9. Patients with  kidney disease meeting criteria to take 2.5 mg twice daily  who are 
taking strong dual inhibitors of CYP3A4 and P-glycoprotein (e.g. ketoconazole, 
itraconazole, ritonavir, clarithromycin) . 
 
10. Any other suspected etiology for stroke (e.g. ipsilateral carotid disease). 
 
11.  Greater than 3 Cerebral Micro-bleeds (CMB) on gradient recovery echo (GRE) or 
evidence of intracranial hemorrhage on CT at time of randomization. (SWI 
sequencing may be used if GRE sequencing is not obtainable)  
12. Therapeutically anti-coagulated at time of admission (INR at admission greater 
than 2.0 on warfarin or took two consecutive doses of NOAC). 
 
13. Absolute indication for use of warfarin only.( e.g. Mechanical Valve) 
 
14. Absolute indication for anticoagulation prior to randomization window. (e.g. 
DVT) 
 
15. Hemoglobin less than 9 gm/dl and/or platelet count less than 100 K/uL. 
 
16. Requires dual antiplatelet therapy. 
 


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17. Daily use of NSAIDS  
 
18. Pregnancy or lactation. 
 
19. Any use of an investigational product within the past 30 days. 
 
20. Prisoners or subjects who are involuntarily incarcerated. 
 
21. Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness.  
 
22. Concurrent participation in another clinical study where use of an investigational 
product is used 
 
Subjects that do not meet all of the enrollment criteria may not be enrolled. Any violations of these 
criteria will be reported in accordance with IRB Policies and Procedures.  
 
4.3.3 
Women of Childbearing Potential 
A Women of childbearing potential (WOCBP) is defined as any female who has experienced menarche 
and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) and is not 
postmenopausal. Menopause is defined as 12 months of amenorrhea in a woman over age 45 years in 
the absence of other biological or physiological causes. In addition, females under the age of 55 years 
must have a serum follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause. 
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially suppressed 
FSH levels and may require a washout period in order to obtain a physiologic FSH level. The duration 
of the washout period is a function of the type of HRT used. The duration of the washout period below 
are suggested guidelines and the investigators should use their judgement in checking serum FSH levels. 
If the serum FSH level is >40 mIU/ml at any time during the washout period, the woman can be 
considered postmenopausal : 
• 
1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 
4 week minimum for transdermal products 
• 
8 week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. 
 
5 
STUDY DESIGN AND INTERVENTION  
5.1 
Screening Visit 
Potential subjects will be screened using the protocol inclusion and exclusion criteria.  All subjects 
will have a diagnosis of AF with TIA or small to medium ischemic stroke.  
Subject consent will be obtained prior to any study related procedures being performed. All females of 
child bearing age will have a urine pregnancy test within 24 hours of starting study drug.  Labs to 
assess liver and kidney function and an EKG will be obtained from the patients’ hospital record or 
obtained at screening.  A physical exam will be obtained at screening. The screening and 
baseline/randomization may be combined as long as all inclusion/exclusion criteria have been met 
prior to randomization.  Otherwise, if these reports are not available at the time of screening, patients 


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will be required to return for a separate assessment visit after these items are obtained. Drug initiation 
visit may take place in hospital or as a clinic visit.  
5.2 
Baseline Visit/Randomization 
The baseline/randomization visit will be performed up to 48 hours after signs and symptoms of stroke 
or TIA, and will be combined with the screening visit as long as all inclusion/exclusion criteria have 
met prior to randomization.  
After subjects have been screened and enrolled in the study, baseline assessments will be performed. 
Patients will be stratified according to their type of stroke ( TIA, small or medium stroke) and 
randomized 1:1 in each group to ensure for equal number of subjects for each three types. Treatment 
with APIXABAN 5mg or 2.5mg based on clinical characteristics defined in section 1.4  or Warfarin ( 
target INR 2-3) will begin based on the randomization treatment regimen. Study treatment regimen is 
initiated based off of TIA or stroke size. Subjects in the Warfarin arm will return to clinic with 
unscheduled INR checks until they reached the standard INR of 2.0 to 3.0. 
Hypertension will be treated per the AHA/ASA guidelines and are described below: 
Goals for target blood pressure level or reduction from pretreatment baseline are uncertain and should 
be individualized, but it is reasonable to achieve a systolic pressure less than 140 mm Hg and a 
diastolic pressure less than 90 mm Hg. For patients with a recent lacunar stroke, it might be reasonable 
to target a systolic blood pressure of less than 130 mm Hg. 20 
Resumption of Blood Pressure therapy is indicated for previously treated patients with hypertension.  
5.3 
Treatment Phase  
A study visit for the initiation of treatment will be conducted based on dosing category of TIA, Small 
stroke or medium stroke. See table 2 below and figure 1: 
 
 
 
Dosing Category 
Apixaban dose initiation window 
TIA 
Day 0-3 
Small Stroke 
Day 3-5 
Medium Stroke 
Day 7-9 
 
 
Dosing Category 
Warfarin dose initiation window 
TIA 
Day 7 (+/-5) 
Small Stroke 
Day 14 (+/-5) 
Medium Stroke 
Day 14( +/-5) 
Table 2 
Subjects will maintain the maximum dose for approximately 180 days (depending on dosing category) 
with study visits at drug initiation, day 14, 30, 60, 90, 120, 150 and 180. Patients will undergo drug 
accountability, AE/SAE assessment, and any concomitant medication changes. 


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5.4 
End of Study 
A final visit will be conducted at day 180 in person. Study medication will be collected at this visit and 
the patient will be started on standard of care therapy. Decisions regarding anticoagulation will be 
based off the subject’s individual needs as assessed by the Principal Investigator or Sub-Investigator. 
30 days after the EOS a phone call will be made to assess for AE’s or SAE’s that may have occurred 
during that time frame.  
5.5 
Study Assessments (See figure 1) 
The NIHSS and mRS Stroke will be obtained at screening and days 14, 30, 60, 90, 120, 150 and 180.  
MRI (or CT for subjects with contraindication to MRI) will be obtained at day 14 and EOS or Early 
Withdrawal (EW).  
The  Stroke Specific Quality of Life Scale (SS-QOL) will be conducted on screening day and again on 
day 30 and at EOS or EW.  
5.6 
Unscheduled Visits 
 
5.6.1 
Super-therapeutic/Sub-therapeutic INR 
If the subject is not within therapeutic range they will be expected to return to clinic for an 
unscheduled visit to check the INR value until therapeutic range is met per the warfarin dosing 
protocol. These visits will be scheduled per PI discretion.  
 
5.6.2 
Adverse Events 
If the subject reports an adverse event that requires medical investigation an unscheduled visit will be 
arranged. This can be arranged through the site coordinator. All medically relevant diagnostic tests 
will be performed at that time. 
 
5.7 
Subject Completion/Early Withdrawal 
It will be documented whether or not each subject completed the clinical study. A subject is considered 
to have completed the study if he/she has taken all study medications for 6 months and has completed 6 
month study assessments or withdrew from the study due to the occurrence of a recurrent embolic stroke 
, hemorrhagic transformation or death. If a subject does not complete the treatment phase, their data will 
be used for efficacy and for any safety analysis.   
 
It is understood that withdrawals may occur during a trial. Each subject has the right to withdraw from 
the trial at any time for any reason without affecting the right to treatment by the investigator. Subjects 
who do not complete the treatment phase for other reasons then mentioned above , should be followed 
at  day 14 and EOS visits,  if possible. At minimum these patients should have a monthly phone call to 
asses AE/SAE and vital status if they are unable to continue follow-up in clinic.  
 
 
Subjects needing to withdraw prior to the completion of the study and who do not agree to continue in 
follow-up should return to the clinic for completion of early withdrawal procedures, as outlined in 
table 1.  
Reasons that a subject may discontinue the study include the following: 
- Adverse events including recurrent stroke or hemorrhagic transformation 
- Intercurrent illnesses 
- Any significant new medical condition 
- Protocol violation 
- Non-compliance to study medication regimen 


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- Use of any investigational drug other than the study medication 
- Intake of prohibited medication  
- Pregnancy 
- Subject withdrew consent or lost to follow-up 
- Other (reason to be documented) 
 
Withdrawals due to intercurrent illnesses or AEs will be fully documented in the CRF with the addition 
of supplementary information if available and/or appropriate. Withdrawals due to non-attendance will 
be followed-up by the investigator to obtain the reason for non-attendance. 
 
5.8 
Concomitant Medication 
Concomitant medication documentation will begin as soon as the subject takes the first dose of study 
medication. All concomitant medications used through the end of the study will be recorded. The dates 
of administration, dosage, and reason for use will be included. Subjects will be allowed to continue on 
concomitant medications. Any study related side effect (e.g., nausea) requiring medication 
management must be approved by the investigator prior to consumption. 
 
 
 
6 
STUDY PROCEDURES 
 
6.1 
Visit 1 Screening Visit/Baseline/Randomization (can occur on same day) 
• 
Signing an informed consent form prior to any study related activities 
• 
Confirmation of Atrial Fibrillation either at admission or in subjects medical history 
• 
Physical exam including vitals 
• 
Body weight and height 
• 
Review MRI results to determine diagnosis of TIA or determine size of Ischemic stroke 
• 
Review of labs, echocardiogram, and EKG reports or draw labs and conduct EKG/ECHO if 
needed. 
• 
Obtain medical history with demographics 
• 
Schedule carotid ultrasound or CTA angiogram of the neck if not done at admission 
• 
Schedule TEE if not done at admission (optional) 
• 
Review of concomitant medications and procedures 
• 
Obtain mRS, NIHSS and SS-QOL scales 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Review of all inclusion/exclusion criteria  
• 
Treat any patient with hypertension according the current guidelines. (see  section 5.2)   
 
6.2 
Randomization 
• 
Confirm subject group selection based of the SACC recommendations, (TIA, Small ischemic 
stroke, Medium ischemic stroke) and must confirm subjects meets all inclusion criteria and no 
exclusion criteria prior to randomization. 
• 
Randomize Subject  
• 
Discuss treatment arm with patient 
 
6.3 
Drug Initiation (may be same as randomization depending on group and study arm)  
• 
Urine pregnancy test if not done within 24 hours of this visit 
• 
Dispense study medication 


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• 
Provide patient education regarding treatment regimen.  
• 
Apply event monitor within 14 days from randomization 
• 
Assess AE/SAE’s 
• 
Assess concomitant medication changes 
• 
Schedule next visit 
• 
INR for Warfarin arm 
 
6.4 
Treatment visits 
Visit day 14 (+/-3) 
• 
Physical exam 
• 
Vital Signs 
• 
Urine pregnancy test if required 
• 
ECG 
• 
NIHSS, mRS 
• 
MRI or CT scan  
• 
INR for Warfarin arm 
• 
Assess Drug Compliance 
• 
Dispense study medication 
• 
Provide patient education 
• 
Assess AE/SAE’s 
• 
Assess concomitant medication /procedure changes 
• 
Schedule next visit 
 
Visit day 30 (+/-5) and 90 (+/- 10) 
• 
Physical exam 
• 
Vital Signs 
• 
Collect Laboratory assessments including  INR for Warfarin arm 
• 
Urine pregnancy test if required 
• 
ECG 
• 
NIHSS and mRS 
• 
SS-QOL only at day 30  
• 
Assess Drug Compliance 
• 
Dispense study medication 
• 
Provide patient education 
• 
Assess concomitant medication /procedure changes 
• 
Assess AE/SAE’s  
• 
Schedule next visit 
 
Visit day 60, 120, 150 (+/- 10) 
• 
Physical exam 
• 
Vital Signs 
• 
Collect INR for Warfarin arm 
• 
Urine pregnancy test if required 
• 
ECG 
• 
NIHSS , mRS 


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• 
Assess Drug Compliance 
• 
Dispense study medication 
• 
Provide patient education 
• 
Assess concomitant medication /procedure changes 
• 
Assess AE/SAE’s  
• 
Schedule next visit 
 
6.5 
End of Study (+/- 10) 
• 
Physical exam 
• 
Vital Signs 
• 
Collect Laboratory assessments including  INR for Warfarin arm 
• 
Urine pregnancy test if required 
• 
MRI or CT scan  
• 
ECG 
• 
NIHSS ,mRS and SS-QOL 
• 
Assess Drug Compliance 
• 
Provide patient education 
• 
Assess concomitant medication /procedure changes 
• 
Assess AE/SAE’s  
• 
Start on non-study Anticoagulation therapy 
 
6.6 
Early Withdrawal (EW) 
• 
Physical exam 
• 
Vital Signs 
• 
Collect Laboratory assessments including  INR for Warfarin arm 
• 
Urine pregnancy test if required 
• 
MRI or CT scan  
• 
ECG 
• 
NIHSS ,mRS and SS-QOL 
• 
Assess Drug Compliance 
• 
Provide patient education 
• 
Assess concomitant medication /procedure changes 
• 
Assess AE/SAE’s  
• 
Start on non-study Anticoagulation therapy 
 
7 
 STUDY ENDPOINTS AND EVALUATIONS  
7.1 
Primary Endpoint 
Endpoint data will start at randomization up to 180 days. These composite endpoints include: 
 
• 
Fatal stroke  
• 
Recurrent Ischemic stroke  
• 
New hemorrhagic stroke 
 
 
 


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7.2 
Secondary Endpoints 
 
• 
Any intracranial bleeds assessed by MRI/CT scan at day 14 and EOS or at outcome event.  
• 
Any major bleeds defined as clinically overt bleeding that was accompanied by one or more of 
the following: a decrease in hemoglobin of 2 g/dL or more; a transfusion of 2 or more units of 
packed red blood cells; bleeding that occurred in at least one of the following critical sites: 
intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with 
compartment syndrome, retroperitoneal; or bleeding that was fatal. Intracranial hemorrhage 
included intracerebral (hemorrhagic stroke), subarachnoid, and subdural bleeds.2 
 
 
7.3 
Other Endpoints of Interest  
• Understanding the natural progression of ischemic stroke patients with NVAF within 
the first 14 days status post initial stroke event (i.e. stroke or TIA) 
• Effect of the addition of anti-epileptic medications during hospital admission on 
outcomes in patients with embolic stroke secondary to AF 
• Factors attributing to the addition of anti-epileptic medications during hospital 
admission in patients with embolic stroke secondary to AF  
• Factors affecting stroke specific quality of life in patients with embolic stroke 
secondary to AF 
 
7.4 
Baseline Evaluation (see also schedule of events) 
 
7.4.1 
Physical Examination 
A complete medical history including demographic characteristics (age, gender, and race/ethnicity) 
will be collected at screening. Complete physical and neurologic examinations will be performed at 
screening 
7.4.2 
Vital Signs 
Heart rate, blood pressure will be performed at every study visit (temperature, and respirations are 
optional) 
 
7.4.3 
Laboratory Evaluations  
Evidence of clinical laboratory evaluation within 72 hours of  hospital admission will be required at 
screening. This will include Creatinine (CPT 82575), complete metabolic panel (CPT 80053), 
complete blood count with differential and platelets (CPT 85025),, Lipid Panel (CPT 80061) and 
PT/INR (CPT 85730), urine HCG (CPT 81025) if indicated, aPTT (CPT 85730 ), TSH (CPT 84443 ) 
 
All WOCBP MUST have a negative pregnancy test within 24 hours before receiving apixaban. The 
minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the 
pregnancy test is positive, the subject must not receive apixaban and must not be enrolled in the study. 
In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect 
they might be pregnant (e.g., missed or late menstrual period) at any time during study participation. 
 
See schedule of events 
 
 
7.5 
Efficacy and Safety Evaluations (see also schedule of events) 
 
7.5.1 
Diagnostic Tests, Scales, Measures, etc. 
 


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MRI w/o contrast (GRE  sequencing preferred but all effort should be used to maintain the same 
modality of sequencing and magnet strength from baseline  or CT w/o contrast –  
Will be performed, along with the NIHSS, to measure the size of ischemic stroke at screening. It will 
also be used for follow-up assessments to indicate any early hemorrhagic transformation or micro-
embolic strokes. Patients who are unable to have a MRI due to contraindication (i.e. implantable 
pacemaker) will have be allowed to use CT with the NIHSS.    
• 
TIA- will have no ischemic changes 
• 
Acute infarcts are classified as small, medium or large based on size of the largest ischemic 
lesion: 
 
small = lesion in the anterior or posterior circulation <1.5 cm. 
 
medium = equal to or greater than 1.5cm but less than a complete territory 
infarct lesion in a cortical superficial branch of the anterior cerebral artery 
(ACA), middle cerebral artery (MCA), posterior cerebral artery (PCA), or in a 
branch of MCA or PCA, or lesion in internal border-zone territories.  
 
large posterior = lesion involving complete PCA territory, or lesion of 
cerebellum 1.5 cm or larger or any lesion of the brain stem. 
 
large anterior = lesion involving complete ACA or MCA territory, or lesion 
involving >1 artery territory  
 
• 
All classifications are based of the measurement of the largest lesion size. 
TEE-  
Will be obtained or scheduled prior to discharge on all patients or will be scheduled as part of their 
evaluation for potential cardiac sources of emboli. In addition to imaging specifically of left atrium 
thrombus; measurements will be obtained for left atrial size, left atrium appendage, velocity, left 
ventricle size and function and other significant myocardial or valvular heart disease.  
 
Carotid ultrasound-  
Will be performed on all patients to rule out ipsilateral carotid disease during the screening visit.   
 
Laboratory evaluations- 
Will be obtained from all patients at screening, day 30, day 90 and day 180. Additional lab 
measurements for the warfarin group will be obtained monthly and at unscheduled visits if warranted 
by the warfarin dosing protocol.  
 
Event Monitor- 
Will be obtained on all patients in order to characterize the atrial fibrillation burden to assess potential 
relationship to outcome events. The event monitor be started within 14 days (+3) from randomization 
and maintained for 30 days.  
 
NIH Stroke Scale (NIHSS)- see appendix 13.2   
Will be used with all patients to provide a rate of worsening, i.e., progression of the index stroke event 
assessed by deterioration in clinical symptoms and/or an increase in the score on the NIHSS. The 
NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute cerebral 
infarction on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, 
motor strength, ataxia, dysarthria, and sensory loss.  The total score can range from 0-42. The 
breakdown of the scoring is described below: 
 
0 = no stroke  
1-4 = minor stroke 
5-15 = moderate stroke 
15-20 = moderate/severe stroke 
21-42 = severe stroke 


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This scale will be administered at screening/baseline, day 14, 30, 60, 90, 120, 150, 180, and early 
withdrawal.  
 
 
 
Modified Rankin Scale (mRS)- see appendix 13.1 
Will be used with all patients to measure severity of stroke and overall disability of patients, this scale 
will also administered on screening/baseline, day 14, 30, 60, 90, 120, 150, 180, and early withdrawal.  
The breakdown of scoring is described below: 
 
Scale 
Disability 
0 
No symptoms at all 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities 
2 
Slight disability; unable to carry out all previous activities, but able to look after own affairs without assistance 
3 
Moderate disability; requiring some help, but able to walk without assistance 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to bodily needs without assistance 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
6 
Dead 
 
 
 
Stoke Specific Quality of Life Scale (SS-QOL)-See appendix 13.3 
The SS-QOL is a self-report questionnaire consisting of 49 items in the 12 domains of energy, family 
roles, language, mobility, mood, personality, self-care, social roles, thinking, upper extremity function, 
vision, and work/productivity. The domains are scored separately, and a total score is also provided. The 
psychometric properties of the SS-QOL have been validated in patients with ischemic stroke and 
intracerebral hemorrhage. 
 
Physical  
Weight will be recorded in pounds (lb) and height in inches (in). 
Physical examination will include assessment of the head, eyes, ears, nose, throat, heart, chest, lungs, 
abdomen, extremities, peripheral pulses, skin and any other physical conditions of note. 
 
Vital Signs 
Blood pressure will be measured in all subjects in either the sitting or supine position.  
 
Pregnancy Testing 
Sexually active Women of Child-Bearing Potential (WOCBP) must use an effective method of birth 
control during the course of the study, in a manner such that risk of failure is minimized.  
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during 
study participation and the potential risk factors for an unintentional pregnancy. The subject must sign 
an informed consent form documenting this discussion. 
Electrocardiogram (ECG) 
12-lead ECG recordings will be obtained from primary care or performed at screening and examined for 
gross abnormalities. ECGs will be conducted at various points throughout the study as shown in section 
5  
 
Clinical Laboratory Evaluations 
The following labs will be obtained at varies time points in the study as shown in section  6.  


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Complete metabolic panel which includes liver enzymes and creatinine, complete blood count with 
differential and platelets, PT/INR and if indicated urine HCG  
 
 
 
 
7.5.2 
Safety criteria for suspension of dosing 
For subjects experiences adverse events the following criteria will be used to determine whether the 
individual or the entire trial should be discontinued. 
For individual patients 
In the event of a Grade 3 or higher adverse event attributable to treatment with APIXABAN and not 
related to the underlying disease, administration of APIXABAN will be suspended in the patient to 
allow analysis and determination whether to continue the treatment, alter dosing regimen or to exclude 
the patient from further participation in the study;  if there is any increase  in cerebral microbleeds 
(CMB)  at day 14, in either arm, all study medication will be suspended until a repeat MRI is 
performed 48 hours from day 14 MRI. Study medication will be restarted in clinically stable 
individuals. In subjects who have a CT scan at day 14 and have a asymptomatic intracranial 
hemorrhage, all study medication will be suspended until a repeat CT is performed at 48 hours from 
the day 14 scan. Sstudy medication will be restarted in clinically stable individuals. If subjects 
experience any symptomatic hemorrhagic transformation in either arm, study medication will be 
suspended. All subjects will continued to be followed up monthly either by phone or clinic contact 
until the end of study.  
 
For all patients 
In the event of five or more patients experiencing a symptomatic hemorrhagic transformation in the 
APIXABAN arm and not related to the underlying disease, dosing will be suspended in all patients to 
allow analysis and determination whether to continue the treatment, alter dose regimen or to terminate 
the study. 
 
8 
STATISTICAL CONSIDERATIONS 
 
8.1 
Statistical Methods 
. 
8.1.1 
Baseline Data  
Baseline and demographic characteristics will be summarized by standard descriptive summaries (e.g. 
means and standard deviations for continuous variables such as age and percentages for categorical 
variables such as gender).  Non-parametric analyses will be used in situations where the variables are 
not normally distributed. Baseline comparisons will be performed to test if there is any residual 
unbalance between the treatment and the control groups on demographic and other influential clinical 
variables.  ANOVA or nonparametric ANOVA will be used to test continuous variables such as AGE. 
Chi-square or Fisher’s Exact test will be used to test categorical variables such as GENDER. If a 
covariate is unbalanced, it will be included in the regression model for the multivariable analysis as a 
control variable 
 
8.1.2 
Efficacy Analysis/Primary Aim 
For the main outcomes, the proportion of patients with any primary outcome (fatal stroke, recurrent 
ischemic stroke, transient ischemic attack) will be computed along with the 95% confidence interval 
for the differences in treatment arms.  


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 The primary outcome is defined as any component of the composite primary outcome occurred within 
30 and 180 days or otherwise had adequate follow-up.  Logistic regression models will be fitted with 
the primary outcome as the dependent variable and the SUBGROUP: (1) Apixaban TIA: day 0-3; (2). 
Apixaban small stroke: day 3-5; (3). Apixaban medium stroke: day 7-9; (4) warfarin TIA: day 7±5; (5) 
warfarin small stroke: day 14±5; (6) warfarin medium stroke: day 14±5 as the primary independent 
variable.   The overall treatment effect will be assessed by the ESTIMATE and LSMEANS of all the 
Apixaban groups to all the warfarin groups.  Comparison between individual subgroups will be 
assessed by constructing different ESTIMATE. For example, (1) Apixaban TIA versus (5) warfarin 
Small stroke: day 14±5.  These analyses will be implemented by using SAS 9.2 PROC LOGISTIC 
which has the ESTIMATE and the LSMEANS statements for the group comparisons. P<0.05 is used 
for the overall treatment effects. All other subsequent subgroup testing will be adjusted for multiple 
comparisons by using PROC PLM.  
8.1.3 
Safety Analysis/Secondary Aim 
The outcome will be measured at 30 and 180 days for all 6 subgroups: all coded as 0 or 1 at both 
follow-up points. 
The analysis plan for this aim is very similar to that for the Primary Aim except the outcome here is 
defined as intracranial hemorrhage (which is coded as a 0 and 1 variable), and (2) the hypotheses for 
the outcomes are directional and therefore one-sided tests will be performed. AE incidence will be 
summarized along with the corresponding 95% confidence intervals. 
8.1.4 
Potential Confounders 
Age and sex as well as a variety of clinical variables (e.g. CHADS2-VASc, CHA2DS2) that are risk 
factors for embolic stroke, and their associations with fatal or recurrent embolic stroke or hemorrhagic 
cerebral bleed will be examined. Other clinically relevant variables that are shown to differ between 
treatment regimens at enrollment will also be examined as potential confounders. 
 For missing data, both an intent-to-treat analysis (in which subjects are analyzed according to their 
randomized assignment) and a per-protocol analysis (in which subjects not treated according to their 
randomized assignment and/or with other major protocol violations are removed from this analysis) 
will be conducted. Sensitivity analyses to assess the effect of missing outcome data on the primary 
result will be conducted 
8.1.5 
Sample Size and Power 
As a pilot, open-label study, this project is intended to generate data to be used in the development of 
future, larger studies. A total of 120 patients are expected to be available and eligible to participate in 
this study and up to 125 may be screened in order to yield 120 randomized participants.  
 
Review of our database indicates the risk of fatal or recurrent stroke in patients with atrial fibrillation 
is approximately 20% with standard treatment 9. To calculate expected power in this study, this 
established risk was used as the basis for estimates that could be expected with this treatment if it is 
successful. Given the parameters of conducting a 2-sided test with alpha = .05, and equal allocation to 
treatment and control groups (50 patients per group), power calculations were conducted using various 
ratios of outcomes (i.e. fatal or recurrent stroke) in the control group compared to the experimental 
group. The following results were obtained: 
 
Power 
Detectable outcome  
Risk in control / 
Risk in experimental 
80% power 
2.30 


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90% power 
2.52 
99% power 
3.00 
 
 
8.1.6 
Randomization 
Randomization of treatment was calculated in SAS 9.4 using a stratified, blocked PLAN procedure. 
For the 120 subjects to be randomized to either apixaban or warfarin, a random seed number was 
generated. Each subgroup of stroke type (small stroke, medium stroke and TIA) was randomized 
implementing block randomization using four blocks of 10. The treatment allocation was created by an 
unblinded statistician and given to the TGH research pharmacy. Blinded study envelopes are provided   
to study team members for randomization. 
 
8.2 
Interim Analysis 
Due the small size and brief duration of the study no interim analyses are planned.  
 
 
9 
STUDY MEDICATION 
 
Apixaban is a white to pale-yellow powder. At physiological pH (1.2–6.8), apixaban does not ionize; 
its aqueous solubility across the physiological pH range is ~0.04 mg/mL 17.  
 
Crystalline warfarin sodium occurs as a white, odorless, crystalline powder that is discolored by  
light. It is very soluble in water, freely soluble in alcohol, and very slightly soluble in chloroform and 
ether 21. 
 
 
9.1 
Packaging 
 
9.1.1 
Warfarin  
Will be purchased by the Principal Investigator in and packaging will be based on 
manufacturer.  
 
9.1.2 
Apixaban  
Formulation and packaging details are below:  
 
Product 
Description and 
Dosage Form 
Potency 
Primary 
Packaging 
(Volume)/ 
Label Type 
 
Appearance 
Storage Conditions 
(per label) 
Apixaban 
Tablet 
2.5 mg 
Bottles of 60/ 
Marketed label 
 
yellow, round, biconvex, 
film-coated tablets with 
“893” debossed on one 
side and “2½” on the 
other side. 
Store at 20°C to 25°C 
(68°F-77°F); excursions 
permitted between 15°C 
and 30°C (59°F-86°F) 


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9.2 
Labeling 
Apixaban and Warfarin bottles will be labeled by the PI with subject number, visit number at which 
they are to be dispensed, the medication name, pill strength and directions detailing dosing for study 
subjects. 
9.3 
Dosing 
9.3.1 
Warfarin 
Warfarin will be dosed per the Dosage protocol found in appendix 13.4. 
9.3.2 
Apixaban. 
The dosage of Apixaban is based on the clinical findings of studies in human subjects and its FDA 
approved dosage for patients with non-valvular atrial fibrillation. Patients will receive 5mg dosage 
twice a day or 2.5 mg if they have any 2 of the following characteristics: 
 
• age ≥80 years 
• body weight ≤60 kg 
• serum creatinine ≥1.5 mg/dL 
 
 
Coadministration with CYP3A4 and P- glycoprotein inhibitors: For patients receiving 
Apixaban 5 mg twice daily when Apixaban is coadministered with drugs that are 
strong dual inhibitors of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) 
(e.g., ketoconazole, itraconazole, ritonavir, clarithromycin), the recommended dose is 
2.5 mg twice daily [ patients already taking 2.5 mg twice daily, coadministration of Apixaban with 
strongdual inhibitors of CYP3A4 and P- glycoprotein should be avoided 
 
If a dose of Apixaban is not taken at the scheduled time, the dose should be taken as  
soon as possible on the same day and twice-daily administration should be resumed.  
The dose should not be doubled to make up for a missed dose. 
 
9.4 
Treatment Compliance and Adherence 
Subjects will be instructed to return all medication bottles (empty or partially used) at each study visit. 
The number of pills used will be counted and compared to the expected use to track treatment 
compliance.  
 
Study medication will be counted to assess compliance at each clinic visit starting at day 14.  Subjects 
who take between 75% and 125% of the prescribed dose will be considered compliant.  Subjects who 
fall outside this range will be counseled and re-instructed on dosing procedures.  Dose modifications 
along with the reasons for the modifications will be recorded on the CRF for each visit. 
9.5 
Drug Accountability 
Records of study drug receipt and disposition will be maintained by the study sites including records 
of receipts, investigational drug orders, dispensing records, and disposition forms.  These records will 
Apixaban 
Tablet 
5 mg 
Bottles of 60/ 
Marketed label 
 
pink, oval-shaped, 
biconvex, film-coated 
tablets with “894” 
debossed on one side 
and “5” on the other 
side. 
Store at 20°C to 25°C 
(68°F-77°F); excursions 
permitted between 15°C 
and 30°C (59°F-86°F) 


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be used to ensure that the investigational drug will not be distributed to any person who is not a study 
subject under the terms and conditions set forth in this protocol.  The study medication is to be 
prescribed by the Investigator or designee and may not be used for any purpose other than that 
described in this protocol. 
 
10 SAFETY MANAGEMENT 
10.1 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study.  
 
10.2 Adverse Event Reporting 
All AEs that occur will be reported to the IRB. All SAEs will be reported to the IRB in accordance 
with IRB policies. AEs that are not serious will be summarized in narrative or other format and 
submitted to the IRB at the time of continuing review. 
 
10.3 Definition of an Adverse Event 
An Adverse Event  
[AE] is defined as any new untoward medical occurrence or worsening of a pre existing medical 
condition in a patient or clinical investigation subject administered an investigational (medicinal) 
product and that does not necessarily have a causal relationship with this treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for 
example), symptom, or disease temporally associated with the use of investigational product, whether 
or not considered related to the investigational product. 
 
• 
The causal relationship to study drug is determined by a physician and should be used to 
assess     
• 
all adverse events (AEs). The causal relationship can be one of the following: 
o Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
o Not Related: There is not a reasonable causal relationship between study drug   
administration and the AE. 
 
• 
The term “reasonable causal relationship” means there is evidence to suggest a causal 
relationship.  
• 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more adverse events). 
 
10.4 Definition of a Serious Adverse Event (SAE) 
            Serious Adverse Event (SAE) is any untoward medical occurrence at any dose that:  
• 
results in death 
• 
is life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were 
more severe) 
• 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE*: below for exceptions) 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
is an important medical event, defined as a medical event that may not be immediately life-
threatening or result in death or hospitalization but, based on appropriate medical and scientific 


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judgment, may jeopardize the subject or may require intervention (e.g., medical, surgical) to 
prevent one of the other serious outcomes listed above. Examples of such events include but are 
not limited to intensive treatment in an emergency department or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization.  
− 
Potential drug-induced liver injury (DILI) is also considered an important medical event--
see the DILI section below for a definition of a potential DILI event. 
Suspected transmission of an infectious agent (eg, pathogenic or non-pathogenic) via the study drug is 
an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events 
must be handled as SAEs 
*NOTE: The following hospitalizations are not considered SAEs:  
− 
A visit to the emergency room or other hospital department lasting less than 24 hours that does not 
result in admission (unless considered an “important medical event” or a life-threatening event) 
− 
Elective surgery planned before signing consent 
− 
Admissions as per protocol for a planned medical/surgical procedure 
− 
Routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
− 
Medical/surgical admission other than remedying ill health state that was planned before study entry. 
Appropriate documentation is required in these cases 
− 
Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (eg, lack of housing, economic inadequacy, caregiver 
respite, family circumstances, administrative reason) 
 
10.4.1 Serious Adverse Event Collecting and Reporting  
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures. All SAEs must be collected that occur during the screening period and within 
30 days of discontinuing dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on the SAE Report Form; Pregnancies on a Pregnancy 
Surveillance Form. 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 


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If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours to the BMS (or designee) using the 
same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
 
10.4.2 Relationship of SAE to study drug or other intervention 
 
Assessment of Severity 
The severity of each SAE will be assessed as described in the following table: 
 
Assessment Definition 
1 = Mild: Discomfort noted, but no disruption of normal daily activities; slightly bothersome; relieved 
with or without symptomatic treatment 
 
2 = Moderate: Discomfort sufficient to reduce or affect normal daily activity to some degree; 
bothersome; interferes with activities, only partially relieved with symptomatic treatment 
 
3 = Severe: Discomfort sufficient to reduce or affect normal daily activity considerably; prevents regular 
activities; not relieved with symptomatic treatment 
 
For each solicited symptom, the subject will be asked if they sought medical advice (i.e. contact with a 
member of medical personnel) for this symptom. 
 
Assessment of Causality 
The investigator will attempt to explain each SAE and assess its causal relationship, if any, to the Study 
Medication . The degree of certainty with which an SAE can be attributed to  Study Medication (or 
alternative causes, e.g. natural history of the underlying diseases, concomitant therapy, etc.) will be 
determined by how well the event can be understood in terms of one or more of the following: 
-Reaction of similar nature having previously been observed with this type of medication. 
-The event having often been reported in literature for similar types of medication. 
 
The investigator will assess causality of all AEs, using the following method: 
 
In your opinion, is there a reasonable possibility that the AE may have been caused by the study 
medication? 
 
• 
No.  
o Unrelated: there is no suspicion that there is a relationship between Study 
Medication and AE, there are other more likely causes and the Study Medication 
is not suspected to have contributed to the AE. 
 
• 
Yes. 
o  Related: there is suspicion of a relationship between the study medication  and 
AE (without determining the extent of probability); there are no other more likely 
causes and study medication is suspected to have contributed to the AE. 
 


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Events considered related to the study medication will be further classified as follows: 
 
Probable-- AE cannot be reasonably explained by other factors (i.e. clinical condition,  
                  environmental/toxic factors or other treatments) 
Possible--  AE can be reasonably explained by other factors (as mentioned above) 
Unlikely-- AE occurs within an unusual time frame of administration of study medication 
 and can also be  reasonably explained by other factors (as mentioned above) 
 
Non-serious and serious AEs will be evaluated as 2 distinct types of events given their different medical 
nature. If an event meets the criteria to be determined "serious", it will be examined by the investigator 
to the extent to be able to determine ALL contributing factors applicable to each SAE. 
 
Other possible contributors include: 
-Underlying disease 
-Other medication 
-Protocol required procedure 
-Other cause (specify) 
 
10.4.3 Definition of Severity 
All AEs will be graded if possible by the Common Terminology Criteria for Adverse Events v4.03 
(CTCAE). The severity of AEs that cannot be graded by CTCAE version 4.0 will be categorized as 
follows: 
Grade 1 – Transient or mild discomfort; no limitation in activity; no medical intervention/therapy 
required. 
Grade 2 – Mild to moderate limitation in activity, some assistance may be needed; no or minimal 
medical intervention/therapy required.  
Grade 3 – Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required, hospitalizations possible. 
Grade 4 – Extreme limitation in activity, significant assistance required; significant medical 
intervention/therapy required hospitalization or hospice care probable. 
Grade 5 – Death. 
 
10.5 IRB/IEC Notification of SAEs 
The investigator will promptly notify the IRB of all SAEs and other unanticipated problems related to 
research using the applicable IRB reporting form(s). External SAEs that are unexpected and related to 
the study intervention will be reported as they are received, within 24 hours of receipt, using the 
External SAE form (if applicable).  
All Serious Adverse Events (SAEs) that occur following the subject’s written consent to participate in 
the study through 30 days of discontinuation of dosing must be reported to BMS Worldwide Safety. 
10.5.1 SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Frequency of reconciliation will beevery three months and once once 
prior to study database lock. BMS GPV&E will e-mail upon request from the investigator, the 
GPV&E reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bms.com. The data elements listed on the GPV&E reconciliation report will be 


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used for case identification purposes. If the investigator determines a case was not transmitted to 
BMS GPV&E, the case will be sent immediately 
10.5.2 Follow-up report 
If an SAE has not resolved at the time of the initial report, a follow-up report including all relevant 
new or reassessed information (e.g., concomitant medication, medical history) will be submitted to 
the IRB. All SAE will be followed until either resolved or stable.  
 
 
10.5.3 Non-Serious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
10.5.4 Non-Serious Event Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information should begin at initiation of study 
drug. Nonserious adverse event information should also be collected from the start of a placebo lead-
in period or other observational period intended to establish a baseline status for the subjects.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become 
serious. Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study drug, or those that are present at the end of study treatment as appropriate.  
Nonserious Adverse Events are provided to BMS via annual safety reports (if applicable), and 
interim or final study reports. 
 
10.6 Health Authority Reporting (US FDA IND) 
Investigators must adhere to local Health Authority Reporting Requirements. For studies conducted 
under an investigator sponsored US FDA IND, provide details of the following: 
 
Any event that is both serious and unexpected must be reported to the Food and Drug Administration 
(FDA) as soon as possible and no later than 7 days (for a death or life-threatening event) or 15 days 
(for all other SAEs) after the investigator’s or institution’s initial receipt of the information.  
 
BMS will be provided with a simultaneous copy of all adverse events filed with the FDA. SAEs 
should be reported on MedWatch Form 3500A, which can be accessed at: 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH  
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 


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10.7 Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as appropriate: 
• 
Any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
Any laboratory test result abnormality that required the subject to have study drug 
discontinued or interrupted  
• 
Any laboratory test result abnormality that required the subject to receive specific corrective 
therapy.  
• 
It is expected that wherever possible, the clinical rather than the laboratory term will be used 
by the reporting investigator (eg, use the term anemia rather than low hemoglobin value).  
• 
Laboratory test abnormalities are provided to BMS via annual safety reports (if applicable), 
and interim or final study reports 
 
10.8 Pregnancy  
If, following initiation of the investigational product, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of investigational product exposure, including 
during at least 5 half-lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for subject safety).  
The investigator must immediately notify WorldwideSafety@BMS.com of this event via the 
Pregnancy Surveillance Form within 24 hours and in accordance with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on a Pregnancy Surveillance 
Form. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to BMS. 
Information on this pregnancy may also be collected on the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy follow-
up procedures should be considered if indicated. 
 
10.9 Overdose  
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
SAEs. 
10.10 Drug Induced Liver Injury (DILI) 
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur 
prior to the reporting of a potential DILI event. All occurrences of potential DILIs, meeting the defined 
criteria, must be reported as SAEs. 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase), 
AND 
3. No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including, but not limited to, viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic 


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10.11 Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x 
rays, and any other potential safety assessments, whether or not these procedures are required by the 
protocol, should also be recorded as a nonserious or serious adverse event, as appropriate, and reported 
accordingly 
10.12 Medical Emergencies 
If medical emergencies arise during the study, the subject will contact the Doctor on call for the study. 
This individual will then triage the situation and direct the subject to a local hospital or appropriate site 
for immediate medical care, or arrange for urgent care for the next day when medically appropriate. 
 
 
11 STUDY ADMINISTRATION 
 
11.1 Treatment Assignment Methods  
Subjects will be randomized at a 1:1 ratio for each treatment arm.  
 
11.2 Data Collection and Management 
 
The biostatistician will be responsible for design of the randomization scheme, creation of analytical 
databases, and the statistical analysis plan. The PI and study staff will be blinded to the randomization 
scheme.  
 
Data review, coding and query processing will be done through interaction with USF and site 
personnel. Queries will be generated in real-time as the data are entered.  
 
The cycle of data entry, review, query identification/resolution, and correction occurs over the course 
of the study period until all subjects have completed the study.  
 
Forms and data collection 
Study personnel will enter subject information and data into source document worksheets that 
correspond to an electronic database containing all subject study data.  
 
It is the investigator’s responsibility to ensure that entries are proper and complete.  
 
11.2.1 Sources of Materials 
Data from study visits will be recorded on clinical research forms (CRF) and entered into a secure 
electronic database. All study records will be kept confidential and each subject will be assigned a 
unique study identification number which will be used on all research records. The identity of patients 
will only be known to site personnel and the PI. Original records will be kept in locked files at each 
site and copies of these records will be kept in a locked drawer in a secure office at the PI’s site. 
Subject information will not be released without the subject’s written consent except to the IRB, FDA 
and other regulatory monitoring bodies as necessary.  
Data to be recorded for this study include CT/MRI confirmation of stroke; EKG, physical exams; vital 
signs; copies of baseline labs and EKG reports (if available within previous 6 months); medical 
history; concomitant medications; Records will be retained in secure storage for 7 years after the study 
concludes.  


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11.3  
Confidentiality 
Enrollment or non-enrollment in the study will not affect the subject’s clinical care in any way. All 
participation is voluntary. All data will be kept confidential except as required by law and kept in a 
secure data at each study site. All source documents will be stored in locked cabinets with access only 
for the principal investigator and co-investigators. Subjects will be identified by identification numbers 
not by personal identifiers. Subject information will be anonymized in publications and only the 
personnel involved in the studies may be able to link results with actual subjects.  
 
11.4 Regulatory and Ethical Considerations 
This study will be conducted in accordance with Good Clinical Practice (GCP), as defined by the 
International Conference on Harmonisation (ICH) and in accordance with the ethical principles 
underlying European Union Directive 2001/20/EC and the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50). 
The study will be conducted in compliance with the protocol. The protocol, any amendments, and the 
subject informed consent will receive Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) approval/favorable opinion before initiation of the study. 
All potential serious breaches must be reported to Bristol Myers Squibb (BMS) immediately. A 
serious breach is a breach of the conditions and principles of GCP in connection with the study or the 
protocol, which is likely to affect, to a significant degree, the safety or physical or mental integrity of 
the subjects of the study or the scientific value of the study. 
Study personnel involved in conducting this study will be qualified by education, training, and 
experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been invoked or where 
there has been scientific misconduct or fraud (eg, loss of medical licensure; debarment). 
11.4.1 Risks to subjects 
Human Subjects Involvement and Characteristics 
This pilot study will enroll 120 patients with NVAF and TIA or small to moderate strokes. The 
diagnosis of Atrial Fibrillation must be confirmed either by EKG at admission or past medical history. 
The diagnosis of TIA or Embolic stroke is will be confirmed with CT or MRI reads at time of 
admission.  Adult patients of any race and ethnicity age  18 years and older will be included  for this 
study.  
Inclusion of Women and Minorities 
Both male and female subjects will participate in the study. 
There are no existing data supporting or negating significant differences in the effects of the study 
interventions among race/ethnicity subgroups.  
Inclusion of Children 
This study will not be including children as the diagnosis of non-valvular atrial fibrillation with TIA or 
embolic stoke does not usually occur in this population.  
11.4.2 Potential Risks 
The risks of anticoagulation have been well documented with the risk benefit ratios of anticoagulation 
in the treatment of atrial fibrillation being in favor for using these agents. 15, 20 


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11.4.3 Risk Assessment 
In the present study, the risk of serious side effects will be minimized by close follow-up of the subject 
during followup phase and at study visits after starting APIXABAN and warfarin treatment arms.   
 
The risks of the other study procedures are generally small. Clinical outcome measures questionnaires 
(mRS, NIHSS, SS-QOL) are non-invasive and are very similar to standard clinical evaluation.  
 
A standard venous blood draw is of minimal risk.  There is a risk of pain at the insertion of the needle; 
this is only for a short time. There are low risks of fainting and infection. All venipunctures will be 
performed by a trained phlebotomist. All precautions will be taken to reduce the risks. No adverse events 
are expected. 
 
 
11.4.4 Potential Benefits of Trial Participation 
The principal objective of this study is to examine the effects of APIXABAN as an early treatment for 
recurrent embolic stroke prevention for subjects with NVAF after a TIA or small to moderate stroke. 
Study medication will be provided to patients free of charge for the duration of the study. It is possible, 
however, that a subject may not derive any benefit at all from participation in the study. Participation 
may help future patients by yielding important information on risks of Apixaban as an early prevention 
for embolic stroke.  
 
 
11.5 Informed Consent 
Informed consent will be obtained from all patients prior to the initiation of any study procedures. The 
consent will be obtained by the institution investigator and research coordinator. The study purpose, 
protocol and potential risks and benefits will be presented to the patient by the investigator and the 
patient will be permitted time to ask questions. The patient will have the opportunity to take the 
consent form home and discuss it with a friend or family member before signing the consent form. All 
subjects will be given a copy of the informed consent form and a signed copy will also be retained on 
site as part of the study files. One copy of the signed and dated consent will be retained by the 
investigator and one will be provided to the subject. The protocol and model informed consent will be 
reviewed by the University of South Florida IRB prior to distribution to each investigative site for IRB 
submission.  
In some cases the subject may not be able to provide inform consent and a Legal Authorized 
Representative (LAR) will be used. The PI or Co-PI will determine the cognitive impairment of 
participants and when the use of the LAR is necessary. The signed consent form will be kept on file at 
the originating site and each subject will receive a copy of this document as well. Consent will be 
obtained prior to the initiation of any study related procedures.  
 
11.6 Payment to Subjects/Families 
In the present study there will be no payment to subjects. A small travel stipend will be given to 
subjects as appropriate.  
 
11.7 Publication 
It is expected that the Principal Investigators will submit the data for publication when the study is 
complete and has been evaluated. 
 
 
 
 


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12 REFERENCES 
1. Wolf PA, Abbott RD, and Kannel WB. Atrial fibrillation as an independent risk factor for stroke: 
the Framingham Study. Stroke, 1991, 22: 983-88 
2. Gage BF, Waterman AD, Shannon W, et al. Validation of Clinical Classificatin Schemes for 
Predicting Stroke: Results From the National Registry of Atrial Fibrillaion. JAMA, 2001, 285;22: 
2864-2870. 
3. Saxena R, Lewis S, Berge, et al. Risk of Early Death and Recurrent Stroke and Effect of Heparin 
in 3169 Patients With Acute Ischemic Stroke and Atrial Fibrillation in the International Stroke 
Trial. Stroke, 2001, 32: 2333-37. 
4. Lip GY and Edwards SJ. Stroke Prevention with aspirin, warfarin and ximelagatran in patients 
with non-valvular atrial fibrillatin: A systematic review and meta-analysis. 2006; 118, 321-33 
5. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus Warfarin in Patients with Atrial 
Fibrillation. N Eng J Med, 2011, 365;11 981-92 Available from nejm.org.  
6. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial 
Fibrillation. N Eng J Med, 2011, 365;10: 883-91. Available from nejm.org.  
7. Connolly SJ, Ezekowitz MD, Yusuf S et al. Dabigatran versus Warfarin in Patients with Atrial 
Fibrillation. N Eng J Med, 2009, 361; 12: 1139-51. Available from nejm.org.  
8. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in Patients with Atrial 
Fibrillation. N Eng J Med, 2013, 369; 22: 2093-2104. Available from nejm.org.  
9. Connolly SJ, Eikleboom J, Campbell J, et al. Apixaban in Patients with Atrial Fibrillation. N Eng J 
Med, 2011, 364;9: 806-17. Available from nejm.org.  
10. January CT, Wann LS, Alpert JS, et al.  2014 AHA/ACC/HRS Guideline for the Management of 
Patients With Atrial Fibrillation:  Executive Summary.  JACC.  2014 
11. Kernan WN, Ovbiagele B, Black HR. Guidelines for the prevention of Stroke in Patients With 
Storke and Transient Ischemic Attack A guideline for Healthcare Professionals From the 
American Heart Association/American Stroke Association. Stroke, 2014; 45:2130-236. Available 
from http://stroke.ahajournals.com 
12. Martin RC, Labovitz AJ, et al. High Recurrence and Increased Mortality in Ischemic Strokes 
secondary to Atrial Fibrillation. Circ. submitted 2014 
13. Berge E, Abdelnoor M, Sandset PM, et al. Low Molecular weight heparin versus aspirin in 
patients with acute ischemic stroke and atrial fibrillation: a double-blind randomised study. 
Lancet, 2000;355: 1205-10 
14. Bath PMW, Iddenden R, Bath FJ. Low-Molecular –Weight Heparins and Heparinoids in Acute 
Ischemic Stroke A Meta-Analysis of Randomized Controlled Trials. Stroke, 2000, 31:1770-78.  
15. Easton JD, Lopes RD, Bahit, MC, et al. Apixaban compared with warfarin in patients with atrial 
fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the 
ARISTOTLE trial. Lancet Neurol. 2012 Jun;11(6):503-11. 
16. Butcher KS, Kate M, Gioia L, et al. Safety and Feasibility of Acute Dabigatran Therapy in Minor 
Ischemic Stroke Patients Without Atrial Fibrillation. [PowerPoint] San Diego, CA: International 
Stroke Conference; 2014 
17. EliquisTM (Apixaban) package insert. Princeton (NJ): Bristol-Myers Squibb Company; Aug 2014  
18. Mar.Wardlaw, JM, Dennis, MS, Lindley, RI, et al. The validity of a simple clinical classification 
of acute ischaemic stroke. J Neurol, 1996; 243:274-79. 
19. Sims, JR, Rezai Ghariai, L, Schaefer, PW,et al. ABC/2 for rapid clinical estimate of infact, 
perfusion, and mismatch volumes. Neurology, 2009; 72:2104-10 


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20. James PA, Oparil S, Carter BL, et al. 2014 Evidence-Based Guidelines for the Management of 
High Blood Pressure in Adults reports from the panel members appointed to the eighth joint 
national committee (JNC8). JAMA, 2013 
21. CoumadinTM(Warfarin) package insert. Pinceton (NJ): Bristo-Myers Squibb Company; 2011 Oct. 
 
 
 
13 APPENDICES 
13.1 Modified Rankin Scale 
 
 
 
Score 
Description 
 
0 
No symptoms at all 
 
1 
No significant disability despite symptoms; able to carry out all usual duties and activities 
 
2 
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance 
 
3 
Moderate disability; requiring some help, but able to walk without assistance 
 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance 
 
5 
Severe disability; bedridden, incontinent and requiring constant nursing care and attention 
 
6 
Dead 
 
 
 
TOTAL (0–6): 
  
 
 
 
 
 
 
 
13.2 NIHSS 
NIH Stroke Scale (NIHSS) score is available at: 
http://www.ninds.nih.gov/doctors/NIH_Stroke_Scale.pdf 
 
 
 


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13.3 SS- QOL 
 
 
Scoring: each item shall be scored with the following key 
Total help - Couldn't do it at all - Strongly agree 
1 
A lot of help - A lot of trouble - Moderately agree 
2 
Some help - Some trouble - Neither agree nor disagree 
3 
A little help - A little trouble - Moderately disagree 
4 
No help needed - No trouble at all - Strongly disagree 
5 
Energy 
1. I felt tired most of the time. 
2. I had to stop and rest during the day. 
3. I was too tired to do what I wanted to do. 
Family Roles 
1. I didn't join in activities just for fun with my family. 
2. I felt I was a burden to my family. 
3. My physical condition interfered with my personal life. 
Language 
1. Did you have trouble speaking? For example, get stuck, stutter, stammer, or slur your words? 
  
 
2. Did you have trouble speaking clearly enough to use the telephone? 
3. Did other people have trouble in understanding what you said? 
4. Did you have trouble finding the word you wanted to say? 
5. Did you have to repeat yourself so others could understand you? 
Mobility 
1. Did you have trouble walking? (If patient can't walk, go to question 4 and score questions 2-3 as 
1.) 


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2. Did you lose your balance when bending over to or reaching for something? 
3. Did you have trouble climbing stairs? 
4. Did you have to stop and rest more than you would like when walking or using a wheelchair? 
  
 
5. Did you have trouble with standing? 
6. Did you have trouble getting out of a chair? 
 
 
Mood 
1. I was discouraged about my future. 
2. I wasn't interested in other people or activities. 
3. I felt withdrawn from other people. 
4. I had little confidence in myself. 
5. I was not interested in food. 
Personality 
1. I was irritable. 
2. I was inpatient with others. 
3. My personality has changed. 
Self Care 
1. Did you need help preparing food? 
2. Did you need help eating? For example, cutting food or preparing food? 
3. Did you need help getting dressed? For example, putting on socks or shoes, buttoning buttons, or 
zipping? 
4. Did you need help taking a bath or a shower? 
5. Did you need help to use the toilet? 
Social Roles 
1. I didn't go out as often as I would like. 
2. I did my hobbies and recreation for shorter periods of time than I would like. 
3. I didn't see as many of my friends as I would like. 
4. I had sex less often than I would like. 
5. My physical condition interfered with my social life. 
Thinking 
1. It was hard for me to concentrate. 


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2. I had trouble remembering things. 
3. I had to write things down to remember them. 


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Upper Extremity Function 
1. Did you have trouble writing or typing? 
2. Did you have trouble putting on socks? 
3. Did you have trouble buttoning buttons? 
4. Did you have trouble zipping a zipper? 
5. Did you have trouble opening a jar? 
Vision 
1. Did you have trouble seeing the television well enough to enjoy a show? 
2. Did you have trouble reaching things because of poor eyesight? 
3. Did you have trouble seeing things oﬀ to one side? 
Work/Productivity 
1. Did you have trouble doing daily work around the house? 
2. Did you have trouble finishing jobs that you started? 
3. Did you have trouble doing the work you used to do? 
TOTAL SCORE 
Reference 
Williams LS, Weinberger M, Harris LE, Clark DO, Biller J. Development of a stroke-specific quality of life scale. Stroke 1999 
Jul;30(7):1362-9. 
 
 
 
 


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13.4 Warfarin Dosing Protocol 


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