Conditions: Stroke
Keywords: Atrial Cardiopathy Cryptogenic stroke Ischemic stroke Apixaban Aspirin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1015
Healthy volunteers: no

Brief summary:
Objectives

* Primary: To test the hypothesis that apixaban is superior to aspirin for the prevention of recurrent stroke in patients with cryptogenic ischemic stroke and atrial cardiopathy.
* Secondary: To test the hypothesis that the relative efficacy of apixaban over aspirin increases with the severity of atrial cardiopathy.

Detailed description:
ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of apixaban versus aspirin in patients who have evidence of atrial cardiopathy and a recent stroke of unknown cause. Eleven hundred subjects will be recruited over 2.5 years at up to 200 sites in and out of the NINDS StrokeNet consortium. Subjects will be followed for a minimum of 1.5 years and a maximum of 7 years for the primary efficacy outcome of recurrent stroke and the primary safety outcomes of symptomatic intracranial hemorrhage and major hemorrhage other than intracranial hemorrhage.

Arms:
arm 1: Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Apixaban arm 2: Patients with a recent embolic stroke of undetermined source (ESUS) and evidence of atrial cardiopathy will receive Aspirin

Interventions: intervention 1: Apixaban intervention 2: Aspirin
Intervention descriptions: intervention 1: 5 mg by mouth twice daily (2.5 mg for subjects meeting standard criteria for an adjusted dose). intervention 2: Aspirin 81 mg by mouth once daily.

Protocol document:
Prot_000.pdf: 
AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke
Protocol Identifying Number: NCT03192215
Principal Investigators:
Hooman Kamel, MD
Mitchell S.V. Elkind, MD, MS
W.T. Longstreth Jr, MD, MPH
David L. Tirschwell, MD, MSc
Randolph S. Marshall, MD
Funded by: NINDS
Supported by: BMS-Pfizer Partnership and Roche Diagnostics
Version Number: v6
17 Aug 2022


2
Table of Contents
LIST OF ABBREVIATIONS..........................................................................................................5
STATEMENT OF COMPLIANCE..................................................................................................7
PROTOCOL SUMMARY ............................................................................................................9
SCHEMATIC OF STUDY DESIGN ..............................................................................................10
1
KEY ROLES ......................................................................................................................11
2
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE .........................................12
2.1
BACKGROUND............................................................................................................................................................12
2.2
RATIONALE.................................................................................................................................................................13
2.3
POTENTIAL RISKS AND BENEFITS...................................................................................................................13
2.3.1
KNOWN POTENTIAL RISKS........................................................................................................................13
2.3.2
KNOWN POTENTIAL BENEFITS...............................................................................................................14
3
OBJECTIVES AND PURPOSE.............................................................................................14
4
STUDY DESIGN AND ENDPOINTS.....................................................................................15
4.1
DESCRIPTION OF THE STUDY DESIGN...........................................................................................................15
4.2
STUDY ENDPOINTS..................................................................................................................................................15
4.2.1
PRIMARY ENDPOINTS..................................................................................................................................15
4.2.2
SECONDARY ENDPOINTS............................................................................................................................15
4.2.3
EXPLORATORY ENDPOINTS ......................................................................................................................15
4.2.4
DEFINITIONS OF PRIMARY AND SECONDARY ENDPOINTS .......................................................15
4.2.5
ADJUDICATION OF ENDPOINTS...............................................................................................................16
5
STUDY ENROLLMENT AND WITHDRAWAL.......................................................................16
5.1
PARTICIPANT INCLUSION CRITERIA ..............................................................................................................16
5.2
PARTICIPANT EXCLUSION CRITERIA..............................................................................................................17
5.3
INFORMED CONSENT FOR SCREENING AND RANDOMIZATION........................................................18
5.4
ATRIAL CARDIOPATHY CRITERIA REQUIRED FOR RANDOMIZATION...........................................19
5.5
STRATEGIES FOR RETENTION AND RECRUITMENT...............................................................................19
5.5.1
TIME PERIOD FOR RECRUITMENT.........................................................................................................19
5.5.2
INCLUSION OF WOMEN AND MINORITIES.........................................................................................20
5.6
PARTICIPANT WITHDRAWAL OR TERMINATION ....................................................................................20
5.6.1
REASONS FOR WITHDRAWAL OR TERMINATION..........................................................................20
5.6.2
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION.........................................21
5.7
PREMATURE TERMINATION OR SUSPENSION OF STUDY ....................................................................21
6
STUDY AGENT.................................................................................................................22
6.1
STUDY AGENT AND CONTROL DESCRIPTION.............................................................................................22
6.1.1
ACQUISITION ....................................................................................................................................................22
6.1.2
FORMULATION, APPEARANCE, PACKAGING, AND LABELING...................................................22
6.1.3
PRODUCT STORAGE AND STABILITY....................................................................................................22
6.1.4
DISTRIBUTION.................................................................................................................................................22
6.1.5
DOSING ................................................................................................................................................................22
6.1.6
ADMINISTRATION..........................................................................................................................................23
6.1.7
LABORATORY MONITORING AND DOSE ADJUSTMENTS/INTERRUPTIONS.......................23
6.1.8
TRACKING OF DOSE.......................................................................................................................................23
6.2
STUDY DRUG ACCOUNTABILITY PROCEDURES.........................................................................................23
7
STUDY PROCEDURES AND SCHEDULE..............................................................................24
7.1
STUDY PROCEDURES/EVALUATIONS.............................................................................................................24
7.1.1
STUDY-SPECIFIC PROCEDURES ...............................................................................................................24
7.1.2
STANDARD-OF-CARE STUDY PROCEDURES ......................................................................................25


3
7.2
STUDY SCHEDULE....................................................................................................................................................26
7.2.1
SCREENING........................................................................................................................................................26
7.2.2
RANDOMIZATION...........................................................................................................................................28
7.2.3
FOLLOW-UP.......................................................................................................................................................28
7.2.4
FINAL STUDY VISIT........................................................................................................................................29
7.2.5
UNSCHEDULED VISIT....................................................................................................................................29
7.2.6
SCHEDULE OF EVENTS TABLE .................................................................................................................30
7.3
CONCOMITANT AND PROHIBITED MEDICATIONS...................................................................................31
7.3.1
ANTIPLATELET MEDICATIONS................................................................................................................31
7.3.2
ANTICOAGULANT MEDICATIONS ...........................................................................................................31
7.3.3
STRONG INDUCERS AND INHIBITORS OF CYP3A4 AND P-gp....................................................31
7.4
DETECTION AND MANAGEMENT OF ATRIAL FIBRILLATION.............................................................31
7.5
INTERRUPTION OF STUDY DRUG FOR ELECTIVE INVASIVE PROCEDURES.................................32
7.6
MANAGEMENT OF BLEEDING ............................................................................................................................32
7.7
MANAGEMENT OF ACUTE ISCHEMIC STROKE IN SUBJECTS ON STUDY DRUG...........................32
7.8
VASCULAR RISK FACTOR MANAGEMENT.....................................................................................................33
7.9
PARTICIPANT ACCESS TO STUDY DRUG AFTER STUDY CLOSURE....................................................33
8
ASSESSMENT OF SAFETY.................................................................................................33
8.1
SPECIFICATION OF SAFETY PARAMETERS..................................................................................................33
8.1.1
DEFINITION OF ADVERSE EVENTS ........................................................................................................34
8.1.2
DEFINITION OF SERIOUS ADVERSE EVENTS.....................................................................................34
8.1.3
ADVERSE EVENTS OF SPECIAL INTEREST..........................................................................................35
8.1.4
UNANTICIPATED PROBLEMS AND UNANTICIPATED EVENTS .................................................36
8.2
CLASSIFICATION OF AN ADVERSE EVENT ...................................................................................................36
8.2.1
SEVERITY OF EVENT.....................................................................................................................................36
8.2.2
RELATIONSHIP TO STUDY AGENT..........................................................................................................37
8.2.3
EXPECTEDNESS...............................................................................................................................................37
8.3
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP ..........................37
8.4
REPORTING PROCEDURES...................................................................................................................................38
8.4.1
ADVERSE EVENT REPORTING..................................................................................................................38
8.4.2
SAFETY REPORTING......................................................................................................................................38
8.4.3
UNANTICIPATED EVENT REPORTING..................................................................................................39
8.5
STUDY OVERSIGHT..................................................................................................................................................39
8.6
STUDY HALTING RULES ........................................................................................................................................40
9
CLINICAL MONITORING ..................................................................................................40
10
STATISTICAL CONSIDERATIONS ...................................................................................40
10.1
STATISTICAL AND ANALYTICAL PLAN ..........................................................................................................40
10.2
STATISTICAL HYPOTHESES.................................................................................................................................41
10.3
ANALYSIS DATASETS..............................................................................................................................................41
10.4
DESCRIPTION OF STATISTICAL METHODS..................................................................................................41
10.4.1
GENERAL APPROACH ...................................................................................................................................41
10.4.2
ANALYSIS OF THE PRIMARY AND SECONDARY ENDPOINTS.....................................................41
10.4.3
SAFETY ANALYSES.........................................................................................................................................41
10.4.4
PLANNED INTERIM ANALYSES................................................................................................................42
10.4.5
ADDITIONAL SUBGROUP ANALYSES.....................................................................................................42
10.4.6
EXPLORATORY AND SENSITIVITY ANALYSES ..................................................................................42
10.5
SAMPLE SIZE...............................................................................................................................................................42
10.5.1
ASSUMPTIONS..................................................................................................................................................42
10.5.2
SAMPLE SIZE CALCULATION.....................................................................................................................42


4
10.6
MEASURES TO MINIMIZE BIAS ..........................................................................................................................43
10.6.1
ENROLLMENT, RANDOMIZATION, AND MASKING PROCEDURES...........................................43
10.6.2 
BREAKING THE STUDY BLIND..................................................................................................................43
11
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA.................................................43
12
QUALITY ASSURANCE AND QUALITY CONTROL............................................................44
13
ETHICS/PROTECTION OF HUMAN SUBJECTS ................................................................44
13.1
ETHICAL STANDARD ..............................................................................................................................................44
13.2
INSTITUTIONAL REVIEW BOARD.....................................................................................................................44
13.3
INFORMED CONSENT PROCESS.........................................................................................................................45
13.3.1
CONSENT AND OTHER INFORMATION DOCUMENTS PROVIDED TO PARTICIPANTS....45
13.3.2
CONSENT PROCEDURES AND DOCUMENTATION...........................................................................45
13.3.3
USE OF SURROGATES FOR CONSENT....................................................................................................45
13.4
PARTICIPANT AND DATA CONFIDENTIALITY............................................................................................47
13.4.1
CONFIDENTIALITY AND DATA STORAGE ...........................................................................................47
13.4.2
RESEARCH USE OF STORED HUMAN SAMPLES................................................................................47
13.5
FUTURE USE OF STORED SPECIMENS............................................................................................................48
14
DATA HANDLING AND RECORD KEEPING.....................................................................49
14.1
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES.............................................................49
14.2
STUDY RECORDS RETENTION............................................................................................................................50
14.3
PROTOCOL DEVIATIONS.......................................................................................................................................50
14.4
PUBLICATION AND DATA SHARING POLICY ...............................................................................................50
15
STUDY ADMINISTRATION............................................................................................51
15.1
OVERVIEW...................................................................................................................................................................51
15.2
STUDY MANAGEMENT CORES (NCC and CCC)............................................................................................51
15.3
DATA MANAGEMENT CORE (NDMC) ..............................................................................................................52
15.4
EXECUTIVE COMMITTEE ......................................................................................................................................52
15.5
TRIAL OPERATIONS COMMITTEE ....................................................................................................................52
15.6
PUBLICATIONS COMMITTEE ..............................................................................................................................52
15.7
ANCILLARY STUDIES COMMITTEE ..................................................................................................................52
16
CONFLICT OF INTEREST POLICY....................................................................................53
17
LITERATURE REFERENCES ............................................................................................53
CHANGE LOG.........................................................................................................................56


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LIST OF ABBREVIATIONS
AE
Adverse event
AF
Atrial fibrillation/flutter
AHA/ASA
American Heart Association/American Stroke Association
ALT
Alanine aminotransferase
ARCADIA
AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke
AST
Aspartate aminotransferase
BMI
Body mass index
CALM
Center for Advanced Laboratory Medicine at Columbia University Medical Center
CCC
Canadian Coordinating Center
CFR
Code of Federal Regulations
cIRB
StrokeNet central institutional review board
CRF
Case report form
CT
Computed tomography
CTA
CT angiogram
CTCAE
Common Terminology Criteria for Adverse Events
CUMC
Columbia University Medical Center
DSMB
Data and safety monitoring board
ECG
Electrocardiogram
eCrCl
Estimated creatinine clearance
ESUS
Embolic stroke of undetermined source
FDA
Food and Drug Administration
FDAAA
FDA Amendments Act
GFR
Glomerular filtration rate
GI
Gastrointestinal
GCP
Good clinical practices
GLP
Good laboratory practices
GMP
Good manufacturing practices
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonization
ICMJE
International Committee of Medical Journal Editors
ID
Identification
IRB
Institutional review board
INR
International normalized ratio
MOP
Manual of procedures
MRA
MR angiogram
MRI
Magnetic resonance imaging
MRS
Modified Rankin Scale
MSM
Medical safety monitor
NCC
NIH StrokeNet National Coordinating Center
NDMC
NIH StrokeNet National Data Management Center
NIH
National Institutes of Health
NIHSS
National Institutes of Health Stroke Scale
NINDS
National Institute of Neurological Disorders and Stroke


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NOAC
Non-vitamin K antagonist oral anticoagulant drug
NT-proBNP
Amino terminal pro-B-type natriuretic peptide
OHRP
Office of Human Research Protections
PHI
Protected health information
PI
Principal Investigator
PM
Project manager
PROMIS
Patient-Reported Outcomes Measurement Information System 
PT
Prothrombin time
PTFV1
P-wave terminal force in ECG lead V1
PTT
Partial thromboplastin time
PUDS
Public use data sets
QC
Quality control
QVSFS
Questionnaire for Verification of Stroke-Free Status
REB
Research ethics board
SAE
Serious adverse event
SAP
Statistical analysis plan
SOP
Standard operating procedure
TEE
Transesophageal echocardiogram
TTE
Transthoracic echocardiogram
UP
Unanticipated problem


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STATEMENT OF COMPLIANCE
The trial will be conducted in accordance with the International Council for Harmonization (ICH) E6, the 
Code of Federal Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NINDS Terms 
of Award. The co-Principal Investigators (co-PIs) will assure that no deviation from or changes to the 
protocol will take place without prior agreement from NINDS and documented approval from the 
central institutional review board (cIRB) and/or other applicable IRB/REBs with study oversight, except 
where necessary to eliminate an immediate hazard to the trial participants. All personnel involved in the 
conduct of this study have completed human subjects protection training.
We agree to ensure that all staff members involved in the conduct of this study are informed about their 
obligations in meeting the above commitments. 
PI: Hooman Kamel, MD
Signed: _____________________________________ 
Date: 17 Aug 2022
PI: Mitchell S.V. Elkind, MD, MS
Signed: _____________________________________ 
Date: 17 Aug 2022
PI: W.T. Longstreth, Jr, MD, MPH
Signed: _____________________________________ 
Date: 17 Aug 2022
PI: David Tirschwell, MD, MSc
Signed: _____________________________________ 
Date: 17 Aug 2022
PI: Randolph S. Marshall, MD
Signed: _____________________________________ 
Date: 17 Aug 2022


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AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke
Protocol Identifying Number: NCT03192215
PROTOCOL ACCEPTANCE FORM / SIGNATURE PAGE
Version: 6
Date: 17 Aug 2022
By signing below I confirm that:
1. I have read this protocol and it contains all necessary details for 
conducting this study
AND
2. I agree to conduct the trial in compliance with this protocol and to 
adhere to all regulations that govern the conduct of the study.
Principal Investigator’s Signature 
Date
Principal Investigator’s Name (Print)
Site Name


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PROTOCOL SUMMARY
Title:
AtRial Cardiopathy and Antithrombotic Drugs In prevention After 
cryptogenic stroke.
Précis: 
ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, 
active-control, phase 3 clinical trial of apixaban versus aspirin in patients 
who have evidence of atrial cardiopathy and a recent stroke of unknown 
cause. Eleven hundred subjects will be recruited at up to 200 sites in the 
United States and Canada. Subjects will be followed for a minimum of 1.5 
years for the primary efficacy outcome of recurrent stroke and the primary 
safety outcomes of symptomatic intracranial hemorrhage and major 
hemorrhage other than intracranial hemorrhage.
Objectives:
Primary: To test the hypothesis that apixaban is superior to aspirin for the 
prevention of recurrent stroke in patients with cryptogenic ischemic 
stroke and atrial cardiopathy.
Secondary: To test the hypothesis that the relative efficacy of apixaban 
over aspirin increases with the severity of atrial cardiopathy.
Endpoints:
Primary efficacy outcome: Recurrent stroke of any type (ischemic, 
hemorrhagic, or of undetermined type).
Primary safety outcomes: (A) Symptomatic intracranial hemorrhage 
(including symptomatic hemorrhagic transformation of an ischemic 
stroke), and (B) major hemorrhage other than intracranial hemorrhage.
Secondary efficacy outcomes: (A) Composite outcome of recurrent 
ischemic stroke or systemic embolism, and (B) composite outcome of 
recurrent stroke of any type or death from any cause.
Secondary safety outcome: All-cause mortality. 
Population: 
1,100 patients with a recent embolic stroke of undetermined source (ESUS) 
and evidence of atrial cardiopathy.
Phase:
Phase 3.
Number of sites:
Up to 200.
Study agent:
Active agent: Apixaban (trade name Eliquis®) 5 mg by mouth twice daily 
(2.5 mg twice daily if standard criteria for adjusted dose are met).
Active control: Aspirin 81 mg by mouth once daily.
Study duration:
7 years.
Participant duration:
Minimum of 1.5 years and maximum of 7 years.


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SCHEMATIC OF STUDY DESIGN


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1
KEY ROLES
Contact PI
Randolph S. Marshall, MD
rsm2@cumc.columbia.edu
Co-PI
Mitchell S. V. Elkind, MD, MS
mse13@cumc.columbia.edu
Protocol PI 
Hooman Kamel, MD
hok9010@med.cornell.edu
Co-PI, Director of Eligibility Core and Recruitment Core
David Tirschwell, MD
tirsch@uw.edu
Co-PI, Director of Outcomes Adjudication Core
W.T. Longstreth, Jr, MD, MPH
wl@uw.edu
Blinded Statistician
Richard Kronmal, PhD
kronmal@uw.edu
StrokeNet NCC PI
Joseph Broderick, MD
broderjp@ucmail.uc.edu
StrokeNet NDMC PI 
Jordan Elm, PhD
elmj@musc.edu
NINDS Project Scientists
Scott Janis, PhD
janiss@ninds.nih.gov
Canadian Sites Lead PI
David Gladstone, MD, PhD
David.gladstone@sunnybrook.ca
Canadian Stroke Consortium Chair
Mike Sharma, MD, Msc
Mike.sharma@phri.ca
Canadian Coordination Centre (CCC) Lead PI
Jeff Healey, MD, Msc
Jeff.healey@phri.ca
A full list of key personnel and their contact information is provided in the Manual of Operations.


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2
INTRODUCTION: BACKGROUND AND SCIENTIFIC RATIONALE
2.1
BACKGROUND
In one-third of ischemic strokes, a specific cause cannot be identified.1 Many of these cryptogenic 
strokes appear to arise from a distant embolic source.2 Recent evidence suggests that some cryptogenic 
strokes may arise from left atrial thromboembolism that goes unrecognized because it has not 
manifested with atrial fibrillation/flutter (AF). In the ASSERT study, which showed that even a single 6-
minute episode of subclinical AF was associated with a heightened risk of stroke,3 31% of patients with 
both subclinical AF and stroke had no episodes of AF during a median 8 months of continuous cardiac 
monitoring before the stroke, only manifesting AF for the first time after the stroke.4 These findings 
were closely replicated in the more recent IMPACT trial.5 Such a lack of temporal relationship between 
AF and stroke undermines the concept that AF itself directly causes cardiac embolism, and is more 
consistent with AF as a marker of a diseased left atrium characterized by inflammation, endothelial 
dysfunction, fibrosis, contractile dysfunction, structural derangement, or some combination of these 
factors. Supporting this possibility, other markers of left atrial abnormality are associated with stroke in 
the absence of AF. Clinical diagnoses of paroxysmal supraventricular tachycardia have been associated 
with stroke risk in patients without AF.6 More recently, increased P-wave terminal force in 
electrocardiogram (ECG) lead V1 (PTFV1)—a well-established marker of left atrial abnormality7—has 
been associated with stroke even in the absence of AF.8-11 Left atrial size on echocardiogram has also 
been correlated with stroke risk in the absence of AF.12-15 Lastly, serum levels of NT-pro-BNP, a marker of 
cardiac myonecrosis and elevated filling pressures, correlate with stroke risk independent of AF.16,17 
These data suggest that an underlying atrial cardiopathy may provide the substrate for thrombus 
formation and embolization even in the absence of AF.18 These observations may also explain why fewer 
than one-third of patients with cryptogenic stroke in the CRYSTAL-AF trial manifested AF even after 3 
years of continuous heart-rhythm monitoring.19 
In parallel with these new insights about cryptogenic stroke, new therapeutic options for stroke 
prevention have become available. Non-vitamin K antagonist oral anticoagulant (NOAC) drugs such as 
apixaban may be more effective than aspirin for treatment of cryptogenic stroke. A benefit is especially 
likely in cryptogenic stroke patients with atrial cardiopathy because of parallels with AF and because an 
analysis of data from the WARSS/APASS studies suggests that cryptogenic stroke patients with one 
marker of atrial cardiopathy (elevated NT-proBNP) and no obvious AF benefit from anticoagulant 
therapy.20 Apixaban is a particularly attractive choice because it has a low bleeding risk,21,22 lowers 
mortality more than warfarin in patients with AF,23 and is the only NOAC drug with a Class 1A 
recommendation in recent AHA/ASA guidelines.24 
Among patients with causes of cryptogenic stroke other than atrial cardiopathy, data are less compelling 
on the efficacy of anticoagulant therapy.25 Many cryptogenic strokes may be due to artery-to-artery 
embolism from non-stenotic and unrecognized large-artery atherosclerosis.26-28 In patients with stroke 
from known intracranial atherosclerosis, the WASID trial found no benefit of warfarin over aspirin29 and 
the SAMMPRIS trial found historically low rates of recurrence with dual antiplatelet therapy.30 The ARCH 
trial demonstrated a trend towards fewer recurrent strokes with antiplatelet therapy compared to 
anticoagulant therapy in those with aortic arch atheroma.31 These data suggest that new oral 
anticoagulant agents are unlikely to be superior to antiplatelet therapy in cryptogenic stroke patients 
without atrial cardiopathy. 


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2.2
RATIONALE
These data justify a randomized trial of apixaban versus aspirin specifically in patients with cryptogenic 
stroke who have evidence of atrial cardiopathy. This trial design will address several important 
knowledge gaps. First, it will advance our understanding of stroke pathophysiology by assessing whether 
atrial cardiopathy is a valid therapeutic target, which may set the stage for a primary prevention trial. 
Second, this trial will advance our understanding of optimal secondary stroke prevention therapy. One 
industry-sponsored trial (NAVIGATE-ESUS) that compared rivaroxaban to aspirin in patients with 
cryptogenic stroke was stopped early for futility. Another industry-sponsored trial (RESPECT-ESUS) is 
comparing dabigatran versus aspirin in patients with cryptogenic stroke. By including all cryptogenic 
stroke patients and by including those with up to 6 minutes of AF per day, these trials have mixed 
patients with heterogeneous stroke mechanisms. These trials may thus fail to show an overall benefit 
(as in NAVIGATE-ESUS), or may show an overall benefit driven mostly by patients with known AF and 
atrial cardiopathy, resulting in an overly broad indication for anticoagulant therapy. In the first instance, 
our trial may ensure that a valuable treatment in a specifically targeted subgroup will not be 
prematurely abandoned. In the second instance, the results of our trial would provide a compelling 
rationale to perform subgroup analyses of the industry-sponsored trials and conduct future trials to 
determine the risks and benefits of anticoagulant therapy across biologically distinct subgroups of stroke 
patients. Given the expense and risks of bleeding associated with anticoagulant drugs, it is imperative to 
define as precisely as possible the groups of stroke patients who would and would not benefit from their 
use. Therefore, our approach comports well with the general move toward precision medicine.
2.3
POTENTIAL RISKS AND BENEFITS
2.3.1
KNOWN POTENTIAL RISKS
Major hemorrhage. Both treatment arms (apixaban versus aspirin) will involve antithrombotic 
medications that necessarily increase the risk for hemorrhage. Despite its associated bleeding risks, the 
benefit of aspirin in secondary stroke prevention has long been established to outweigh these risks, and 
aspirin receives a Class I, Level of Evidence A recommendation in American Heart Association guidelines 
on secondary stroke prevention.24 Apixaban is a much newer drug than aspirin, and as an anticoagulant 
drug, it has a theoretically higher risk of bleeding than an antiplatelet drug such as aspirin. However, in 
the secondary stroke prevention substudy of the AVERROES trial, which enrolled a comparable 
population of patients as in our proposed trial, the rate of major hemorrhage was not significantly 
higher with apixaban compared to aspirin.32
Recurrent stroke. A 7% annual risk of recurrent stroke is anticipated. It is hypothesized that patients in 
the intervention arm (apixaban) will face a 40% lower relative risk of recurrent stroke compared to those 
in the active-control arm receiving standard therapy (aspirin).
Delay of or exclusion from treatment with thrombolytic drugs for recurrent ischemic stroke. Patients 
actively taking oral anticoagulant drugs such as apixaban are generally excluded from treatment with 
intravenous thrombolysis for acute ischemic stroke. 
Discovery of incidental conditions. This risk is expected to be low because the only diagnostic test that 
will be performed solely for the purposes of the proposed trial is the collection of a blood sample that 
will be assayed for NT-proBNP. NT-proBNP can reflect ventricular as well as atrial dysfunction, but all 


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patients will undergo echocardiography and those with significant heart failure will be excluded prior to 
the collection of this blood sample. Therefore, an elevated NT-proBNP level in this study will be most 
likely to reflect atrial cardiopathy rather than another incidental condition. The other diagnostic tests 
used in this trial—echocardiography and ECG—will have been done as part of standard care and will 
have been interpreted by clinicians at each site, so that usual clinical protocols will be in place to 
document and manage incidental findings.
Loss of confidentiality. It is expected that this risk will be low because of numerous safeguards that will 
be in place, including standard data management procedures at the NDMC.
Discomfort from phlebotomy. Patients who consent to screening for atrial cardiopathy will need to 
undergo collection of a blood sample for an NT-proBNP assay. Discomfort from this procedure will be 
minimized by adding on this blood sample to already-scheduled phlebotomies for routine, clinically 
indicated laboratory tests whenever possible.
Allergic reaction or liver injury. It is expected that these risks will be low based on existing data.
2.3.2
KNOWN POTENTIAL BENEFITS
A successful outcome in the proposed trial would have immediate implications for secondary stroke 
prevention by identifying a new group of stroke patients who benefit from anticoagulant therapy. Such a 
result would answer a significant unmet need by providing robust evidence to guide directed treatments 
for cryptogenic stroke.2 Such a result would also have near-term implications for primary stroke 
prevention. Any success of anticoagulant therapy in reducing stroke risk in this high-risk population with 
atrial cardiopathy would suggest the possibility of benefit in patients with atrial cardiopathy and no 
history of stroke. If anticoagulation can prevent recurrent stroke from atrial cardiopathy, it should also 
prevent stroke from occurring in the first place. Thus, validation of atrial cardiopathy as a therapeutic 
target may set the stage for primary prevention trials. These likely potential benefits, for which we have 
compelling preliminary data, are highly likely to outweigh the potential risks of the interventions in this 
trial, both of which involve FDA-approved antithrombotic agents in widespread clinical use and with 
good safety data in comparable populations.32 In addition to the benefits to public health, this 
information could also be of benefit to individual participants in the study, as their own future 
secondary stroke prevention treatment after the completion of this trial would be influenced by its 
results. 
3
OBJECTIVES AND PURPOSE
The primary aim is to test the hypothesis that apixaban is superior to aspirin for the prevention of 
recurrent stroke in subjects with cryptogenic ischemic stroke and atrial cardiopathy.
The secondary aim is to test the hypothesis that the relative efficacy of apixaban over aspirin increases 
with the severity of atrial cardiopathy.


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4
STUDY DESIGN AND ENDPOINTS
4.1
DESCRIPTION OF THE STUDY DESIGN
Multicenter, biomarker-driven, randomized, double-blind, active-control, phase 3 clinical trial of 
apixaban versus aspirin.
4.2
STUDY ENDPOINTS
4.2.1
PRIMARY ENDPOINTS
Efficacy: Recurrent stroke of any type (ischemic, hemorrhagic, or of undetermined type).
Safety: (A) Symptomatic intracranial hemorrhage (including symptomatic hemorrhagic transformation 
of an ischemic stroke), and (B) major hemorrhage other than intracranial hemorrhage.
4.2.2
SECONDARY ENDPOINTS
Efficacy: (A) Composite of recurrent ischemic stroke or systemic embolism, and (B) composite of 
recurrent stroke of any type or death from any cause.
Safety: All-cause mortality.
4.2.3
EXPLORATORY ENDPOINTS
See the manual of procedures (MOP) for definitions of other endpoints used for exploratory analyses: 
AF, any intracranial hemorrhage, major hemorrhage including any intracranial hemorrhage, 
symptomatic hemorrhagic transformation of an ischemic stroke, transient ischemic attack, myocardial 
infarction, minor hemorrhage, systemic embolism, symptomatic deep venous thrombosis, symptomatic 
pulmonary embolism, ischemic vascular death, and hemorrhagic vascular death.
4.2.4
DEFINITIONS OF PRIMARY AND SECONDARY ENDPOINTS
Stroke: 

Composite of ischemic stroke, hemorrhagic stroke, or stroke of 
undetermined type.
Ischemic stroke: 

Rapid onset of a new focal neurological deficit: 1) imaging or 
other evidence of infarction in a part of the central nervous 
system consistent with symptoms OR 2) lasting >24 hours 
without imaging evidence of infarction, AND 3) not attributable 
to a non-ischemic etiology, such as intracranial hemorrhage, 
edema, infection, trauma, tumor, seizure, severe metabolic 
disease, or degenerative neurological disease. 
Hemorrhagic stroke: 

Acute extravasation of blood into the brain parenchyma, 
subarachnoid space, or intraventricular space, judged to be non-
traumatic and not in the area of an acute or subacute ischemic 
infarct but associated with and identified as the predominant 


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cause of new neurologic symptoms, including headache, or 
leading to death. 
Stroke of undetermined 
type: 

Rapid onset of a new focal neurological deficit: 1) lasting >24 
hours AND 2) not meeting criteria for ischemic stroke or 
hemorrhagic stroke AND 3) not attributable to a non-vascular 
etiology, such as edema, infection, trauma, tumor, seizure, 
severe metabolic disease, or degenerative neurological disease. 
Symptomatic intracranial 
hemorrhage: 

Any extravascular blood within the cranium, including subdural 
and epidural blood, associated with and identified as the 
predominant cause of new neurologic symptoms, including 
headache, or leading to death.
Major hemorrhage other 
than intracranial 
hemorrhage: 

Clinically overt bleeding accompanied by a 2 g/dL decrease in 
the hemoglobin level during a 24-hour period, transfusion of 2 
units of whole blood or red cells, involvement of a critical non-
intracranial site (intraspinal, intraocular, pericardial, 
intraarticular, intramuscular with compartment syndrome, or 
retroperitoneal), or death.33 
Systemic embolism: 

Clinical history consistent with an acute loss of blood flow to a 
peripheral artery or arteries and supported by evidence of 
embolism from surgical specimens, autopsy, angiography, or 
other objective testing.
4.2.5
ADJUDICATION OF ENDPOINTS
Study endpoints will be adjudicated using procedures defined in the MOP and approved by the NINDS-
appointed DSMB. Regulatory reporting of SAEs and AEs of special interest will not be delayed for this 
adjudication to occur. 
5
STUDY ENROLLMENT AND WITHDRAWAL
5.1
PARTICIPANT INCLUSION CRITERIA

Age 45 years.

Clinical diagnosis of ischemic stroke + brain imaging to rule out hemorrhagic stroke.

Modified Rankin Scale (MRS) score 4.

Ability to be randomized no later than 180 days after stroke onset. 

ESUS, defined as all of the following2:
-
Stroke that is not lacunar. Lacunar is defined as a subcortical (this includes pons and 
midbrain) infarct in the distribution of the small, penetrating cerebral arteries whose largest 
dimension is ≤1.5 cm on CT, ≤2.0 cm on MRI diffusion images, or ≤1.5 cm on MRI T2-
weighted images. The following are not considered lacunes: multiple simultaneous small 


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deep infarcts, lateral medullary infarcts, and cerebellar infarcts. Patients with a clinical 
lacunar stroke syndrome and no infarct on imaging are excluded.
-
Absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis of the 
artery supplying the area of ischemia. Patients must undergo vascular imaging of the 
extracranial and intracranial vessels using either catheter angiography, CT angiogram (CTA), 
MR angiogram (MRA), or ultrasound, as considered appropriate by the treating physician 
and local principal investigator. Training will be provided to the investigators that will 
encourage the use of CTA and MRA over ultrasound for the evaluation of patients to 
minimize operator-dependent variation. 
-
No major-risk cardioembolic source of embolism, including AF, intracardiac thrombus, 
mechanical prosthetic cardiac valve, atrial myxoma or other cardiac tumors, moderate or 
severe mitral stenosis, myocardial infarction within the last 4 weeks, left ventricular ejection 
fraction <30%, valvular vegetations, or infective endocarditis. Patent foramen ovale is not an 
exclusion unless it is determined to be causally related to the stroke. All patients must 
undergo electrocardiogram, transthoracic or transesophageal echocardiography (TTE or 
TEE), and at least 24 hours of cardiac rhythm monitoring (Holter monitor or telemetry or 
equivalent). Additional cardiac imaging, such as cardiac MRI or cardiac CT, will be performed 
at the discretion of the local treating physician and principal investigator. Additional cardiac 
rhythm monitoring, such as monitored cardiac outpatient telemetry (MCOT) or an 
implanted cardiac monitor, will be at the discretion of the treating physician and local 
principal investigator. Although standard-of-care echocardiography will be used to make 
diagnoses of cryptogenic stroke and for atrial cardiopathy criteria, these echocardiograms 
will be centrally read as well to confirm local readings and provide feedback to local sites.
-
No other specific cause of stroke identified, such as arteritis, dissection, migraine, 
vasospasm, drug abuse, or hypercoagulability. Special testing, such as toxicological screens, 
serological testing for syphilis, and tests for hypercoagulability, will be performed at the 
discretion of the treating physician and local principal investigator. Training will be provided 
to local investigators to consider obtaining hypercoagulability tests among patients with 
patent foramen ovale.
5.2
PARTICIPANT EXCLUSION CRITERIA

History of AF, AF on 12-lead ECG, or any AF of any duration during heart-rhythm monitoring 
prior to randomization. 

Clear indication for treatment-dose anticoagulant therapy, such as venous thromboembolism or 
a mechanical heart valve.

Left ventricular ejection fraction <30%.

Definite indication for antiplatelet agent (e.g., aspirin or clopidogrel after implantation of a 
coronary artery stent). 

History of spontaneous intracranial hemorrhage.

Chronic kidney disease with serum creatinine ≥2.5 mg/dL. For Canadian sites only, estimated 
creatinine clearance (eCrCl) <15 mL/min is also an exclusion criterion.

Active hepatitis or hepatic insufficiency with Child-Pugh score B or C (see MOP for definition).

Clinically significant bleeding diathesis.

Anemia (hemoglobin <9 g/dL) or thrombocytopenia (<100 x 109/L) that is chronic in the 
judgment of the investigator.


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
GI bleeding within the past year considered clinically significant by the investigator.

Pregnancy risk:

Female patient who is known to be pregnant.

Female patient who is sexually active and premenopausal without a negative pregnancy 
test performed after stroke onset. 

Female patient who is sexually active and premenopausal, and who does not commit to 
adequate birth control. 

Male patient who is sexually active with a premenopausal female partner, and who does 
not commit to adequate birth control.

Known allergy or intolerance to aspirin or apixaban.

Concomitant participation in another clinical trial involving a drug or acute stroke intervention.

Considered by the investigator to have a condition that precludes follow-up or safe participation 
in the trial.

Inability to obtain written, informed consent from patient or surrogate for trial participation.
5.3
INFORMED CONSENT FOR SCREENING AND RANDOMIZATION
If a patient fulfills all of the inclusion/exclusion criteria, they or their surrogate will be approached for 
consent per the process described in Section 7.2.1 and according to local regulations. 
Written consent should preferably be obtained in person. This can be done using a paper form or a 
HIPAA-compliant method for eConsent (e.g., REDCap). If consent cannot be obtained in person, written 
consent can be obtained via a HIPAA-compliant method per the following procedure:
•
Contact the patient or surrogate by telephone or other HIPAA-compliant telehealth technology.
•
Transmit the entire consent form so that the patient or surrogate has it available to read during 
the discussion.
•
Provide a comprehensive explanation of the purpose, procedures, and possible risks/benefits of 
the study in language that is understandable to a non-medically trained person; explain the 
participant responsibilities and the fact that participation is voluntary; that the participant may 
withdraw from the study at any time; and that the decision not to participate or to withdraw will 
not affect the patient’s care in any way. Provide ample opportunity for the patient or surrogate 
to ask questions and to consider the decision. 
•
If the patient or surrogate expresses a sustained interest, give instructions about how the 
patient or surrogate needs to sign and date the consent form and how to transmit the signed 
form back.
•
The patient or surrogate should return the entire signed and dated informed consent form back 
at which point the person obtaining consent should sign and date the form and transmit a copy 
of the fully signed consent form back to the patient or surrogate for his/her records. The 
informed consent form is not valid and study enrollment cannot proceed unless all pages are 
received and appropriately filled out/signed/dated by the patient or surrogate.
Patients who provide consent at this stage will be considered consented but not randomized. Patients 
will be randomized only if they meet ≥1 of the atrial cardiopathy criteria below.


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Reconsenting Process
If changes are made to the consent during the course of the trial, the cIRB or other IRB/REBs with study 
oversight will determine whether active subjects will need to be re-consented. Ideally re-consenting 
should be done in person and mirror the initial consenting process. Because some subjects in the 
ARCADIA trial may have phone follow up visits before or in lieu of in person visits, the procedure below 
should be followed if it is necessary to mail a new consent to a subject:
1.
Contact the person that you are planning to re-consent by phone and explain that you need to 
re-consent them. Explain why you need to re-consent them, make arrangements for mailing 
them the new consent and a time to schedule the re-consenting call. Ask them not to sign the 
consent until the time of the re-consenting call.
2.
Mail 2 copies of the consent to the participant with instruction not to sign the form until the re-
consent call has been made. Include a self-addressed stamped envelope for the participant to 
return one of the signed consents to the researcher. The person obtaining the verbal consent 
would have signed their part of the consent before mailing (they would need to make a note 
that the date they entered is the date they mailed the consent to the participant).
3.
The study staff will have the consent process discussion with the participant on the phone and 
answer any questions the participant may have. Both parties will have the consent in front of 
them during the call and reference it during the re-consenting process (same as would be done 
in-person). Ensure that all of the participant’s questions have been answered. 
4.
Record documentation of this entire conversation and the verbal phone consent. Have the 
participant sign both of the consents and mail one signed consent back to the site. 
5.
The site would then document the process used and the date they received the fully signed 
consent from the participant. 
6.
Reconsenting can be done via eConsent as allowed by location regulations and IRB/REB 
requirements.
5.4
ATRIAL CARDIOPATHY CRITERIA REQUIRED FOR RANDOMIZATION
To be eligible for randomization, patients must meet criteria for atrial cardiopathy in addition to the 
inclusion/exclusion criteria above. Atrial cardiopathy is defined as ≥1 of the following:

PTFV1 >5,000 μV*ms on 12-lead ECG (ECG criterion).

Serum NT-proBNP >250 pg/mL (NT-proBNP criterion).

Left atrial diameter index ≥3 cm/m2 on echocardiogram (i.e., severe left atrial enlargement) 
(ECHO criterion).
5.5
STRATEGIES FOR RETENTION AND RECRUITMENT
5.5.1
TIME PERIOD FOR RECRUITMENT
Subject recruitment is planned to be carried out over a maximum of 6 years. Study subjects will be 
followed for a minimum of 1.5 years. 


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5.5.2
INCLUSION OF WOMEN AND MINORITIES
Inclusion or exclusion of subjects will not differ based on sex/gender, and the aim is to recruit similar 
numbers of men and women. The absence of an upper age limit will aid recruitment of women given 
that they are generally older than men at the time of a first cardiovascular event such as stroke.
Inclusion or exclusion of subjects will not differ based on race/ethnicity. To ensure representative 
enrollment of minority groups, site PIs and their clinical research staff will be trained and periodically 
reminded to:

Be mindful of cultural, historical, social, and political factors that may influence minority 
participation. It should be noted that many individuals (particularly certain racial/ethnic groups) 
need clarification on what a clinical trial is; understanding of what type of research is being 
conducted; who is conducting the research study, benefits to individuals and the community; 
place of worship’s encouragement, etc.

Emphasize that the goal is to recruit patients regardless of race or ethnicity.

Clearly explain that the purpose of informed consent is to protect, not relinquish, participants’ 
rights.

Provide time if necessary between screening and randomization for patients to reflect and 
discuss participation with family.

Emphasize the proven track record of the study drugs.

Emphasize the trial’s potential to help find better treatments to prevent stroke.

Mitigate concern about randomization by clearly explaining its rationale and highlighting the 
possibility of cross over if clinically indicated.

Emphasize that participants will be kept up to date on scientific developments in this field 
throughout their participation in the trial.

Think about modes of communication for outreach and retention, such as follow-up phone calls, 
social media campaigns, text messaging, to identify what works best for the 
community/population (as allowed by local regulations).

Provide translation services or bilingual staff, if needed for recruiting populations for which 
English is not the primary language.

Use motivational interviewing techniques as a method to improve communication between the 
research coordinator and patient population to enhance recruitment efforts. This includes 
investigators and staff taking the time to understand the patient’s personal circumstances that 
may well affect enrollment and follow-up.
5.6
PARTICIPANT WITHDRAWAL OR TERMINATION
5.6.1
REASONS FOR WITHDRAWAL OR TERMINATION
An investigator may discontinue study drug if, in the investigator’s opinion, any clinical AE, laboratory 
abnormality, or other medical condition or situation occurs such that continued use would not be in the 
best interest of the participant. Additionally, participants are free to discontinue study drug at any time. 
Subjects who discontinue study drug will continue to be followed and study data collected through the 
end of the study.  
Alternatively, participants are free to withdraw entirely from participation in the study at any time. 
Subjects who withdraw consent for study participation will not be followed and further study data will 


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not be collected. Every effort must be made to undertake protocol-specified safety follow-up 
procedures to capture SAEs, clinical outcomes, and AEs of special interest prior to study discontinuation.  
If a subject wishes to withdraw from active participation in the study, sites should request permission to 
contact the patient at less frequent intervals (every 6 months or 12 months, depending on subject 
preference) via telephone or other HIPAA-compliant telehealth technology. If the subject declines this 
option, sites should request permission to contact the subject’s physicians or family members for follow-
up (if allowed by local regulations) and to periodically remotely review the subject’s electronic medical 
record and claims data. If the subject declines this option, sites should ask permission for ongoing 
remote monitoring of the subject’s status via the electronic medical record and claims data. If granted, 
permission for one or more of the above options should be documented in writing and retained in the 
study subject’s file in a secure and confidential manner. Sites should contact subjects’ physicians/family 
(as allowed by location regulations) and/or review all available medical records of such patients every 3 
months (as per subject’s follow up window) and make their best effort at ascertaining the subject’s 
stroke and vital status. Regardless of the method chosen for modified follow-up, the appropriate CRFs 
should be completed every 3 months using available information from at least the electronic medical 
record. If there is no available follow-up information of any kind for 1 year, the subject should be 
reported as officially lost to follow-up. 
At the end of the trial, publicly available vital records will be used to attempt to verify the vital status of 
any subjects withdrawn from the study or lost to follow-up.
5.6.2
HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION
All randomized participants will be analyzed according to the intention-to-treat principle and therefore 
will be analyzed in the group they were assigned to regardless of premature discontinuation of study 
drug, withdrawal from the study, or changes in study treatment.
5.7
PREMATURE TERMINATION OR SUSPENSION OF STUDY
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause. Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to site investigators, NINDS, and the StrokeNet Data 
and Safety Monitoring Board (DSMB). If the study is prematurely terminated or suspended, the co-PIs 
will promptly inform the cIRB and other IRB/REBs with study oversight and will provide the reason(s) for 
the termination or suspension. 
Circumstances that may warrant termination or suspension include but are not limited to: 

Determination of unexpected, significant, or unacceptable risk to participants. 

Insufficient compliance to protocol requirements. 

Data that are not sufficiently complete and/or evaluable. 

Demonstration of efficacy or futility (see Section 10.4.4).
The study may resume once concerns about safety, protocol compliance, and data quality are addressed 
and satisfy any concerns of NINDS, the DSMB, and the cIRB and other IRB/REBs with study oversight.


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6
STUDY AGENT
6.1
STUDY AGENT AND CONTROL DESCRIPTION
6.1.1
ACQUISITION
Study drug and matching placebo will be supplied by the BMS-Pfizer Partnership. Study drug will be sent 
from BMS-Pfizer to the NCC Central Pharmacy, which will label the study drug bottles, distribute study 
drug to the sites (via a central depot for Canadian sites) as they are released to enroll, and resupply sites 
with study drug as recruitment progresses.   
6.1.2
FORMULATION, APPEARANCE, PACKAGING, AND LABELING
Study treatments to be administered are active apixaban or matching placebo and active aspirin or 
matching placebo. Blinding will be provided by the use of the same color of formulations, same drug 
packaging, and same method of drug administration in every subject.
6.1.3
PRODUCT STORAGE AND STABILITY
Study product should be stored under controlled room temperature at 15°C to 25°C (59°F-77°F). The 
NCC Central Pharmacy must be notified of known temperature excursions beyond this range. Excursions 
must be reviewed by the study team before product that has experienced a known excursion may be 
used. Excursions must be reported immediately, preferably within 48 hours of occurrence to the NCC 
Central Pharmacy.
6.1.4
DISTRIBUTION
Local site pharmacies will distribute study drugs to enrolled participants every 3 months either in person 
or by mail depending on each site’s local practice in accordance with local laws and regulations. Study 
drug will be provided in 90-day supply bottles, with a buffer of 10-day supply of extra pills to account for 
a delayed resupply visit. At the time of each resupply, subjects will return unused study drug to the 
investigator/coordinator. 
6.1.5
DOSING 
Active treatment will be either apixaban 5 mg or aspirin 81 mg. An adjusted dose of apixaban 2.5 mg will 
be used for subjects with 2 of the following: age 80 years, body weight 60 kg, or known serum 
creatinine 1.5 mg/dL. For Canadian sites only, an adjusted dose of apixaban 2.5 mg will be used for 
subjects with eCrCl 15-24 mL/min regardless of other factors, as per national regulatory requirements. 
Thus, there will be six possible study tablets: apixaban 5 mg (regular dose), apixaban 2.5 mg (adjusted 
dose), apixaban 5 mg placebo, apixaban 2.5 mg placebo, aspirin 81 mg, and aspirin placebo. This dosing 
schema is consistent with previous trials of stroke prevention in AF.21,32 Aspirin will be used as the active 
control agent since it is the proven, standard-of-care antithrombotic drug recommended for patients 
with stroke.24 


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6.1.6
ADMINISTRATION
All subjects will be randomized to receive active treatment with either active apixaban or active aspirin. 
Study treatments will be supplied in a double-dummy fashion as aspirin 81 mg or matching placebo, and 
as apixaban 5 mg (2.5 mg for the adjusted dose) or matching placebo.  Study participants will take 1 
tablet of aspirin or placebo once daily by mouth from Bottle 1 and 1 tablet of apixaban or placebo twice 
daily by mouth from Bottle 2. Starting at the randomization visit and then at regular intervals thereafter 
until study completion, subjects will be provided with two high-density polyethylene pill bottles. 
Depending on the treatment assignment, Bottle 1 will contain placebo aspirin and Bottle 2 will contain 
active apixaban, or Bottle 1 active aspirin and Bottle 2 will contain placebo apixaban.
The first doses of study medication must be initiated within 48 hours of randomization. 
If a dose of study drug is not taken at the scheduled time, the dose should be taken as soon as possible 
on the same day, except if less than 6 hours from the next dose, then the missed dose should be skipped 
and the usual schedule of administration should be resumed. The dose should not be doubled to make 
up for a missed dose. 
6.1.7
LABORATORY MONITORING AND DOSE ADJUSTMENTS/INTERRUPTIONS
The U.S. FDA package insert for apixaban does not recommend regular monitoring of laboratory 
parameters such as creatinine or liver function tests. Thus, such tests are not required as part of this 
study in the United States. For Canadian sites only, laboratory determination of renal function must 
occur at least once per year as part of standard care, as per national regulatory requirements. All site 
investigators and study coordinators will be educated, via training at the start of the study and regular 
study newsletters, that a reduced dose of apixaban study drug is required if subjects meet the dose 
adjustment criteria. The MOP provides details on switching doses if necessary.
6.1.8
TRACKING OF DOSE
Study drug adherence will be assessed using pill counts at each study visit. For subjects who have 
intentionally stopped study drug, the reason for discontinuation or temporary interruption will be 
collected (e.g., elective procedure, new contraindication to treatment, etc).
6.2
STUDY DRUG ACCOUNTABILITY PROCEDURES
Upon receipt of the study drug, the site pharmacist or designee will inspect the study drug supply and 
confirm receipt of the study drug in the WebDCUTM, the study’s clinical trial management system. The 
pharmacist or pharmacy designee at each clinical site must also document in WebDCUTM study drug 
dispensing, return, and destruction. Drug accountability records and storage temperature logs may be 
inspected by the study monitor or subjected to inspection by relevant authorities.  


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7
STUDY PROCEDURES AND SCHEDULE
7.1
STUDY PROCEDURES/EVALUATIONS
7.1.1
STUDY-SPECIFIC PROCEDURES
Medical history: 

Obtained at baseline.

Should focus on inclusion/exclusion criteria and vascular 
comorbidities.

Can be obtained from up-to-date medical records and/or 
interview.
Vital signs:

Obtained at baseline.

Should include height and weight to allow calculation of the 
body mass index (BMI).
NIHSS:

Obtained at baseline. 
QVSFS:

Validated screening tool for identifying strokes.34

Obtained at the randomization visit and all follow-up visits.

Should be obtained via telephone if subjects cannot make in-
person study visits.

Should be obtained from a proxy if necessary.

Medical records should be reviewed to confirm reports of 
possible strokes.
mRS:

Obtained at baseline and at the q6-month follow-up visits by a 
certified investigator.

Should be obtained via telephone if subjects cannot make an 
in-person q6-month study visit.

Should be obtained from a proxy if necessary.
Blood sample:

Obtained at baseline and sent to Laboratory Core.

See MOP for instructions for collection and shipment. 
PROMIS scales:

Global Health Form and Physical Function Short Form.35

Obtained at the 12-month follow-up visit from subjects who are 
able to complete the forms themselves.
Clinical outcome events:

Obtained at all follow-up visits.

Should be obtained via telephone or other HIPAA-compliant 
telehealth technology if subjects cannot make in-person study 
visits.

Should be obtained from a proxy or medical records if 
necessary.


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SAEs and AEs of special 
interest:

Obtained at all follow-up visits until 30 days after permanent 
study drug discontinuation.

Should be obtained via telephone or other HIPAA-compliant 
telehealth technology if subjects cannot make in-person study 
visits.

Should be obtained from a proxy or medical records if 
necessary.
Medication adherence:

Pill counts should be documented at each follow-up visit.

Reasons for discontinuation/interruption should be 
documented if applicable.
Concomitant medications:

Subjects should be asked about antiplatelet and anticoagulant 
drugs at baseline and each follow-up visit.
7.1.2
STANDARD-OF-CARE STUDY PROCEDURES
Each of the tests below, which are all required to establish a diagnosis of ESUS, should ideally be 
performed after the index stroke. If necessary, tests that were done no earlier than 3 months prior to 
the index stroke can be used to establish ESUS and eligibility for consenting. Note that 12-lead ECGs or 
TTEs done before the index stroke cannot be used to assess atrial cardiopathy and qualification for 
randomization. 
Brain imaging:

Either CT or MRI is acceptable.
Vascular imaging:

Acceptable modalities include ultrasound, CTA, MRA, or 
catheter angiogram. 

Both the cervical and intracranial cerebral circulation must be 
evaluated.
12-lead ECG:

The first technically adequate ECG done after stroke onset 
should be used.

See MOP for instructions on uploading a copy of the ECG to 
WebDCUTM.
Continuous heart-rhythm 
monitoring:

≥24 hours required.

Either hospital telemetry or formal Holter monitoring is 
acceptable. 

Hospital telemetry does not require an automated AF detection 
algorithm if reviewed by investigators or other clinical staff. 
Review of ECG or heart-rhythm monitoring by an attending 
cardiologist at the site, if it occurs, is the gold standard for 
defining whether AF is present. Eligible patients must not be 
randomized until any heart-rhythm monitoring performed prior 
to the date of randomization is interpreted, to avoid 
randomizing patients with AF found before randomization.


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Echocardiogram:

Either TTE or TEE is acceptable to determine ESUS.

The first technically adequate TTE done after stroke onset 
should be used to assess for atrial cardiopathy.

See MOP for instructions on sending echocardiogram images.
Laboratory tests:

Chemistry: creatinine.

CBC: white blood cell count, hemoglobin, hematocrit, platelet 
count.

Pregnancy test, if applicable.
7.2
STUDY SCHEDULE
7.2.1
SCREENING
Study subjects are expected to be recruited from both the inpatient setting, such as from an acute 
stroke service, and the outpatient setting, such as from a stroke clinic. Ideally, the trial should be 
introduced to a potential subject by individuals who, by virtue of their position, would normally have 
access to the potential subject’s confidential information, for example the subject’s primary care 
physician or member of current treating team. Potential subjects who show an interest in study 
participation should be asked for their permission to be approached by the study team. The person who 
introduced the study to the potential subject should document this permission in the medical record.
If a study investigator was a treating physician for a potential subject who expresses interest in the 
study, or if a treating physician introduces the potential subject to the trial and that potential subject 
provides permission to be approached by study investigators or coordinators, that subject can be 
contacted about the trial by phone by a study team member.
If a potential subject was not introduced to the trial by a treating physician who asked for permission for 
ARCADIA investigators or coordinators to approach the patient, the steps below must be followed in 
sequence before a patient can be called about ARCADIA:
1.
If required at a site, a waiver of HIPAA authorization must be in place to screen medical records 
to identify potentially eligible subjects. 
2.
Permission to approach the patient must be obtained from the potential subject’s primary care 
physician or neurologist.
3.
Recruitment materials must be mailed to the potential subject, along with instructions to return 
a postcard or make a telephone call indicating that they do not wish to participate.
4.
If the potential subject does not indicate refusal to participate, the study team may call them 
about the study after the time indicated in the instructions. 
The investigators at each site will be required to maintain a screen failure log for patients with ESUS who 
are found ineligible to participate in the study, documenting the patients’ age, demographics, and the 
reason(s) for exclusion from the current study. The study coordinator at each site is required to enter 
the screen failure log data into WebDCUTM on a monthly basis. 


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Screening for Atrial Cardiopathy
Among patients who provide consent for trial participation, only those who meet at least one atrial 
cardiopathy criterion will be randomized. A hotline coordinated via the Eligibility Core will be available 
to help with reviewing screening data and determining eligibility. 

To determine whether a patient meets the ECHO criterion, the site investigator will determine 
from the report of the first available post-stroke TTE with a reported left atrial diameter 
whether the patient has severe left atrial enlargement, defined as left atrial diameter index ≥3 
cm/m2. If possible, echocardiograms should be sent via procedures outlined in the MOP to the 
Echocardiography Core at Columbia for additional measurements to be used in secondary 
analyses.

To determine whether a patient meets the ECG criterion, the first ECG done as part of the 
standard stroke evaluation will be used. A copy of this ECG will be sent via procedures outlined 
in the MOP to the ECG Core at Wake Forest for standardized measurement of PTFV1. The ECG 
Core will enter the assessment of PTFV1 into WebDCUTM within 2 business days of receipt of the 
ECG so that eligibility can be determined.

To determine whether a patient meets the BNP criterion, a blood sample will be sent via 
procedures outlined in the MOP to the study Laboratory Core at Columbia for NT-proBNP 
measurement. The Laboratory Core will enter the NT-proBNP measurement into WebDCUTM 
within 2 business days of receipt of the blood sample so that eligibility can be determined. 
Baseline Visit (Day 0-180 after stroke onset)

Ensure that required standard-of-care tests have been performed (see Section 7.1.2).

Review medical history, medications, and standard-of-care tests to confirm eligibility based on 
inclusion/exclusion criteria (see Sections 5.1 and 5.2).

Obtain informed consent of potential participant verified by signature on written informed 
consent form. 

Assess mRS score. If possible, record vital signs and NIHSS score. Collect baseline information 
such as medical history, imaging results, and Medicare information (beneficiary name, DOB, and 
ID) if applicable. All data will be entered into WebDCUTM except for the Medicare information 
which will be entered into a separate HIPAA-compliant electronic database (REDCap) and kept 
separate from the main WebDCUTM-collected data for an added level of protection.

Collect blood samples for NT-proBNP assay and potential future use and ship to Laboratory Core 
(see MOP).

Upload a copy of the first technically adequate post-stroke 12-lead ECG to WebDCUTM (see 
MOP).

If possible, send a copy of images of the first technically adequate post-stroke TTE to the 
Echocardiography Core (see MOP).

Schedule Randomization Visit. This visit can occur later during the index hospitalization or at a 
subsequent visit (randomization must occur on or before Day 180 after stroke onset).


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7.2.2
RANDOMIZATION
Randomization should occur as close to the first administration of study drug as possible. In general, 
randomization can occur as early as post-stroke day 3. However, randomization must be delayed until at 
least post-stroke day 14 for patients with severe strokes (initial NIHSS score ≥11), hemorrhagic 
transformation of the index stroke, or uncontrolled hypertension. For all strokes, randomization must 
occur no later than post-stroke day 180. The calendar day (12:00 a.m. through 11:59 p.m.) of stroke 
onset is considered post-stroke day 0. If the time of onset of the stroke is unclear, the day of the first 
presentation for medical care will be considered post-stroke day 0.
Randomization Visit (Day 3-180 after stroke onset)

Rescreen participants immediately prior to randomization. Review medical history, medications, 
QVSFS, and vital signs (if possible). Participants must continue to meet all inclusion and 
exclusion criteria at the time of randomization. None of the tests specified in Section 5.1 need to 
be repeated as part of the rescreening process; investigators should simply screen for interval 
events that would make the patient ineligible (e.g., development of spontaneous intracranial 
hemorrhage, AF, recurrent stroke). If any of the tests in Section 5.1 have been repeated as part 
of standard clinical care, those results should be reviewed to ensure continued eligibility. 

Once it is determined that a patient meets all the randomization criteria, the site investigator or 
their designee will log on to WebDCUTM to enter the required randomization data. The database 
will generate the randomization which will correlate to the appropriate study drug to be 
retrieved from the study pharmacy. 

Those who are not considered eligible for randomization due to the absence of all of the three 
atrial cardiopathy biomarkers may be followed in the future as part of ancillary studies, for 
clinical outcomes through telephone calls and review of medical records and insurance claims. 
Permission for follow up of this group is included in the study consent form.

If randomization cannot be performed during an in-person visit, randomization can be 
performed during a visit using telephone or other HIPAA-compliant telehealth technology 
(please see MOP for details).
7.2.3
FOLLOW-UP
Follow-Up Visit 1 (30 ± 7 days after randomization)

Contact participants via telephone or other HIPAA-compliant telehealth technology and assess 
eligibility for study medication, study drug safety, clinical outcome events, SAEs and AEs of 
special interest as indicated depending on patient’s follow-up and study treatment status, 
medication adherence, and concomitant medications.
Follow-up Visit 2 (90 days ± 5 days after randomization)

Schedule in-person visit (or televisit if necessary) to assess eligibility for study medication, study 
drug safety, clinical outcome events, SAEs and AEs of special interest as indicated depending on 
patient’s follow-up and study treatment status, medication adherence, and concomitant 
medications. Televisits must be via telephone or other HIPAA-compliant telehealth technology.


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Follow-up Visit 3 (180 days ± 5 days after randomization)

Schedule in-person visit (or televisit if necessary) to assess eligibility for study medication, study 
drug safety, mRS, clinical outcome events, SAEs and AEs of special interest as indicated 
depending on patient’s follow-up and study treatment status, medication adherence, and 
concomitant medications. Televisits must be via telephone or other HIPAA-compliant telehealth 
technology.
Follow-up Visit 4 (270 days ± 5 days after randomization)

Schedule in-person visit (or televisit if necessary) to assess eligibility for study medication, study 
drug safety, clinical outcome events, SAEs and AEs of special interest as indicated depending on 
patient’s follow-up and study treatment status, medication adherence, and concomitant 
medications. Televisits must be via telephone or other HIPAA-compliant telehealth technology.
Follow-up Visit 5 (360 days ± 5 days after randomization)

Schedule in-person visit (or televisit if necessary) to assess eligibility for study medication, study 
drug safety, mRS, clinical outcome events, SAEs and AEs of special interest as indicated 
depending on patient’s follow-up and study treatment status, medication adherence, 
concomitant medications, ambulatory status, and PROMIS quality-of-life scales. Televisits must 
be via telephone or other HIPAA-compliant telehealth technology.
Follow-up Visits 6 and beyond (through completion of subject participation, minimum 540 days) 

Schedule in-person visits (or televisits if necessary) every 180 days ± 5 days to assess eligibility 
for study medication, study drug safety, mRS, clinical outcome events, SAEs and AEs of special 
interest as indicated depending on patient’s follow-up and study treatment status, medication 
adherence, and concomitant medications. Televisits must be via telephone or other HIPAA-
compliant telehealth technology. Medication resupply will need to occur at the 3-month mid-
point. Sites are also required every 3 months to assess clinical outcome events, as well as SAEs 
and AEs of special interest as indicated depending on patient’s follow-up and study treatment 
status. This can be in-person or via telephone or other HIPAA-compliant telehealth technology.
7.2.4
FINAL STUDY VISIT
At the end of the study, or at the time of subject withdrawal from the study or premature treatment 
discontinuation, the site investigator will be responsible for choosing and initiating appropriate 
antithrombotic therapy. Subjects should be treated at least with aspirin (or open-label anticoagulation if 
they have documented AF). There will also be a close-out telephone visit 30 days after the end of study 
drug treatment to ascertain SAEs, clinical outcome events, and AEs of special interest (details in MOP).
7.2.5
UNSCHEDULED VISIT
An unscheduled visit should be arranged for SAEs, clinical outcome events, AEs of special interest, or 
other developments that in the opinion of the site investigator necessitate an in-person evaluation to 
ensure the subject’s safe ongoing participation in the study. 


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7.2.6
SCHEDULE OF EVENTS TABLE
Procedure
B
R
30 ±7
days*
90 ±5 
days
180 ±5 
days
270 ±5 
days
360 ±5 
days
q180 ±5 
days#
afterward
Close 
out$
Eligibility check^
x
x
x
x
x
x
x
x
Consent
x
Randomization form
x
Medical history
x
x
QVSFS
x
x
x
x
x
x
x
Modified Rankin Scale
x
x
x
x
Vital signs
x
x
NIHSS
x
Brain imaging
o
Vascular imaging
o
12-lead ECG
o
≥24 hrs cardiac monitoring
o
Echocardiogram
o
Serum chemistry
o
||
Complete blood count
o
Pregnancy test, if applicable
o
Blood sample to core lab
x
ECG to core lab
x
Echo to core lab
x
PROMIS Global Health 
x
PROMIS Phys. Func. Short 
x
Ambulatory status
x
Safety assessment
x
x
x
x
x
x
x
Study drug safety
x
x
x
x
x
x
Medication adherence 
x
x
x
x
x
x
Medication resupply 
x
x
x
x
x
Concomitant med. 
x
x
x
x
x
x
x
x
B = Baseline visit; R = Randomization visit; QVSFS = Questionnaire for Verification of Stroke-Free Status.
* Telephone visit.
# This visit includes medication resupply at mid-point (3 months) which will require assessing QVSFS, clinical 
outcomes, as well as SAEs and AEs of special interest as indicated depending on patient’s follow-up and study 
treatment status. These should occur within ±5 days of the 3-month mark. 
$ Telephone visit 30 days after study drug discontinuation. 
^ After randomization, eligibility check will involve ensuring continued suitability for study drug administration.
o Cost billed as standard of care.
x Cost covered by study.
|| For Canadian sites only, laboratory determination of renal function must be performed at least once per year as 
part of standard care, as per national regulatory requirements.


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7.3
CONCOMITANT AND PROHIBITED MEDICATIONS
7.3.1
ANTIPLATELET MEDICATIONS
If an antiplatelet agent is newly indicated after randomization (e.g., aspirin or clopidogrel after 
implantation of a coronary artery stent), then study drug must be stopped until the antiplatelet agent is 
stopped.
For subjects who were receiving antiplatelet therapy prior to their qualifying stroke, there is no high-
quality evidence to support switching to another antiplatelet agent empirically or based on the results of 
platelet resistance assays.24 Therefore, subjects receiving aspirin, clopidogrel, or aspirin/dipyridamole 
should be considered eligible for this trial and randomization to either aspirin or apixaban monotherapy. 
All baseline antiplatelet therapy must be stopped after randomization; the last dose of antiplatelet 
therapy allowed is on the day before randomization.
If the site investigator feels that a short course of dual antiplatelet therapy is indicated, randomization 
cannot occur until after this course is completed.
7.3.2
ANTICOAGULANT MEDICATIONS
The first dose of study drug cannot be given until at least 12 hours after the last dose of an 
anticoagulant (heparin, enoxaparin, etc), even if at a prophylactic dose. Guidelines from the AHA/ASA 
recommend prophylactic-dose anticoagulation for “treatment of immobilized subjects to prevent 
DVT.”36 For immobilized subjects who are receiving prophylactic-dose anticoagulation per these 
guidelines, randomization should be performed at a time such that study drug is not started until after 
discontinuation of prophylactic-dose anticoagulation.
After randomization, if open-label anticoagulant therapy is newly indicated at a full treatment dose, 
such as for newly diagnosed venous thromboembolism, or at a prophylactic dose during an intercurrent 
hospitalization and/or a rehabilitation stay, then study drug must be stopped until open-label 
anticoagulation is stopped.
7.3.3
STRONG INDUCERS AND INHIBITORS OF CYP3A4 AND P-gp
The concomitant use of strong inhibitors of CYP3A4 and P-gp, such as azole-antimycotics (e.g., 
ketoconazole, itraconazole, voriconazole, or posaconazole) or HIV protease inhibitors (e.g., ritonavir), 
can increase apixaban exposure. The concomitant use of strong inducers of CYP3A4 and P-gp (e.g., 
rifampin, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort) can reduce apixaban exposure. 
Concomitant use of strong inhibitors or inducers of CYP3A4 and P-gp is discouraged for U.S. sites. 
Concomitant use of strong inhibitors or inducers of CYP3A4 and P-gp is prohibited for Canadian sites, as 
per national regulatory requirements.
7.4
DETECTION AND MANAGEMENT OF ATRIAL FIBRILLATION
The use of continuous heart-rhythm monitoring after randomization is allowed. Subjects who, as part of 
standard-of-care follow-up/testing after randomization, manifest AF of any duration, as determined by 


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the judgment of the site investigator and treating physicians, should be switched to open-label 
anticoagulant therapy per the discretion of the site investigator and treating physicians. We recommend 
but do not mandate switching to open-label apixaban using the same dosing as the study protocol. 
These subjects will continue to be followed for outcome events in the study according to the intention-
to-treat paradigm.
7.5
INTERRUPTION OF STUDY DRUG FOR ELECTIVE INVASIVE PROCEDURES
Unblinding will not be performed for elective procedures. Investigators will be educated and reminded 
that subjects have a 50% chance of being on anticoagulation, and investigators will be provided with and 
referred to guidelines from the American Academy of Neurology on periprocedural management of 
antithrombotic medications in subjects with ischemic cerebrovascular disease.37 For further reference, 
the FDA label for apixaban states: “ELIQUIS should be discontinued at least 48 hours prior to elective 
surgery or invasive procedures with a moderate or high risk of unacceptable or clinically significant 
bleeding. ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive 
procedures with a low risk of bleeding or where the bleeding would be non-critical in location and easily 
controlled.” Site investigators and study coordinators will be educated about these guidelines through 
training at study initiation and through regular study newsletters.
7.6
MANAGEMENT OF BLEEDING
In cases of bleeding that do not meet the definition of serious bleeding, subjects should be advised to 
not take further doses of study drugs until the bleeding has stopped and the investigator judges that the 
benefits of resuming study drug outweigh the risk of recurrent bleeding. 
The following steps should be taken in all cases of serious bleeding:

Further doses of study drug should be held until the bleeding is controlled and the investigator 
judges that the benefits of resuming study drug outweigh the risk of recurrent bleeding.

Standard measures should be taken to control and mitigate the effects of bleeding, such as local 
control of the bleeding source if possible and administration of intravenous fluids and blood 
products as necessary.
If it is considered likely that bleeding cannot be managed with only the steps above, and that measures 
specific to reversal of apixaban are required, treating physicians and/or site investigator can perform 
unblinding by calling the study hotline. The MOP provides detailed guidance on management of serious 
bleeding in subjects assigned to apixaban.
7.7
MANAGEMENT OF ACUTE ISCHEMIC STROKE IN SUBJECTS ON STUDY DRUG
If intravenous thrombolysis is being considered for the acute treatment of recurrent ischemic stroke, the 
treating physicians and/or site investigators can call the study hotline for unblinding. After unblinding, 
subjects assigned to aspirin can be treated with intravenous thrombolysis if indicated per each site’s 
standard practice. 


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Subjects assigned to apixaban may be at an increased risk of bleeding if treated with intravenous 
thrombolysis unless all of the following conditions are met:

The subject or surrogate can confirm that no study drug has been taken for the past 48 hours;

The subject’s renal function is normal (GFR ≥60);

The subject’s INR and PTT values are normal;

Intravenous thrombolysis is otherwise indicated per the site’s standard practice. 
Unblinding should only occur for subjects who would be eligible for treatment only if they were on 
aspirin and not on apixaban. Unblinding is discouraged for subjects who are not eligible regardless of 
being on aspirin or apixaban, or subjects who meet all of the criteria above and may be able to receive 
thrombolysis while being on apixaban. 
7.8
VASCULAR RISK FACTOR MANAGEMENT
Investigators will be provided with and referred to the most recent guidelines from the AHA/ASA on 
secondary stroke prevention.24 Site investigators and study coordinators will be educated about these 
guidelines through training at study initiation and through regular study newsletters.
7.9
PARTICIPANT ACCESS TO STUDY DRUG AFTER STUDY CLOSURE
Study drug will not be provided free of charge to participants after study closure. Similarly, participants 
who switch to open-label anticoagulant therapy due to interval diagnosis of AF will no longer receive 
study drug free of charge. 
If a site identifies an event as a possible primary or secondary efficacy outcome, the subject will stop 
study medication. If the adjudication committee determines the event does not meet the primary or 
secondary efficacy outcome definition, the subject may resume treatment at the discretion of the site 
investigator and/or treating physician.
8
ASSESSMENT OF SAFETY
8.1
SPECIFICATION OF SAFETY PARAMETERS
Primary safety endpoints: (A) Symptomatic intracranial hemorrhage (including symptomatic 
hemorrhagic transformation of an ischemic stroke), and (B) major hemorrhage other than intracranial 
hemorrhage.
Secondary safety endpoints: All-cause mortality.
The following exploratory endpoints will also be recorded: AF, any intracranial hemorrhage, major 
hemorrhage including any intracranial hemorrhage, symptomatic hemorrhagic transformation of an 
ischemic stroke, transient ischemic attack, myocardial infarction, minor hemorrhage, systemic 
embolism, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, ischemic vascular 
death, and hemorrhagic vascular death. The endpoint of any intracranial hemorrhage will be 
subclassified as: 1) symptomatic versus asymptomatic, and 2) consisting of hemorrhagic transformation 
of the index brain infarct versus not.


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8.1.1
DEFINITION OF ADVERSE EVENTS
An AE is defined as any new untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation participant administered study drug and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (such as an abnormal laboratory finding), symptom, or disease temporally associated with the use 
of investigational product, whether or not considered related to the investigational product. Adverse 
events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. For the purposes of this trial, only AEs that meet the definition of serious, clinical 
outcomes, and AE of special interest will be reported.
8.1.2
DEFINITION OF SERIOUS ADVERSE EVENTS
An SAE is any untoward medical occurrence that at any dose: 

results in death;

is life-threatening (defined as an event in which the participant 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;

results in persistent or significant disability/incapacity;

is a congenital anomaly/birth defect;

is an important medical event (defined as a medical event(s) that may not be immediately life-
threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [e.g., medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above. Examples 
of such events include, but are not limited to, intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do not result in 
hospitalization.) 

results in suspected transmission of an infectious agent (e.g., pathogenic or nonpathogenic) via 
the study drug. 
The definition of SAE excludes the following hospitalizations: 

A visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered an important medical or life-threatening event);

Elective surgery, planned prior to signing consent;

Admissions as per protocol for a planned medical/surgical procedure;

Routine health assessment requiring admission for baseline/trending of health status (e.g., 
routine colonoscopy);

Medical/surgical admission other than to remedy ill health and planned prior to entry into the 
study (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 (e.g., lack of housing, economic inadequacy, 
caregiver respite, family circumstances, administrative reason).


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A life-threatening adverse event is defined as an event in which the participant was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death if it 
were more severe.
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse. Other study-
specific SAEs are defined in the MOP.
8.1.3
ADVERSE EVENTS OF SPECIAL INTEREST
Pregnancy, overdose, potential drug-induced liver injury, cancer, and COVID-19 are AEs of special 
interest and will be assessed and reported.  
Potential or suspected cases of liver injury:
This includes but is not limited to liver test abnormalities, jaundice, hepatitis, or cholestasis.
Pregnancy:
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant 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 (e.g., dose tapering if necessary for participant). 
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 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 will also be reported. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order for the 
investigators to collect any pregnancy surveillance information from the female partner, the female 
partner must sign an informed consent form for disclosure of this information. 
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. 
COVID-19:
COVID-19 is defined as the patient reporting or the medical record indicating that the patient was tested 
for SARS-CoV-2 and found to be positive.


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8.1.4
UNANTICIPATED PROBLEMS AND UNANTICIPATED EVENTS
The Office for Human Research Protections (OHRP) considers unanticipated problems (UPs) involving 
risks to participants or others to include, in general, any incident, experience, or outcome that meets all 
of the following criteria: 
 

Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the cIRB/IRB/REB-approved research 
protocol and informed consent document; and (b) the characteristics of the participant 
population being studied; 

Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 

Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
This study will use the OHRP definition of UP.
 
Unanticipated events include UPs, but may also include other events that do not rise to the level of UPs 
as outlined above. These include protocol deviations or other unexpected problems that do not 
necessarily pose a safety concern, and will be reported according to cIRB/IRB/REB requirements and 
StrokeNet Standard Operating Procedures as defined in detail in the MOP.
8.2
CLASSIFICATION OF AN ADVERSE EVENT
8.2.1
SEVERITY OF EVENT
The severity of SAEs, clinical outcome events, and AEs of special interest will be reported using the 
grading system outlined in the NCI Common Terminology Criteria for Adverse Events Version 4.03 
(CTCAE). The CTCAE provides a grading (severity) scale for each AE term and AEs are listed alphabetically 
within categories based on anatomy or pathophysiology. The CTCAE (v4.03) displays Grades 1-5 with 
unique clinical descriptions of severity for each AE based on this general guidance:
 
CTCAE Severity Grading Summary
Grade 1:
Mild AE
Grade 2:
Moderate AE
Grade 3:
Severe or Disabling AE
Grade 4:
Life-Threatening AE
Grade 5:
Death related to AE
 
The complete definitions of these grades are: 

Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated AE. 


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
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.).  

Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care activities of daily living 
(bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden).  

Grade 4: Life-threatening consequences; urgent intervention indicated.  

Grade 5: Death related to AE.
8.2.2
RELATIONSHIP TO STUDY AGENT
For each SAE, clinical outcome event, and AE of special interest, the relationship to the study treatment 
will be assessed and documented using the following algorithm:
8.2.3
EXPECTEDNESS
The independent Medical Safety Monitor (MSM) will be responsible for determining whether an SAE is 
expected or unexpected. An SAE will be considered unexpected if the nature, severity, or frequency of 
the event is not consistent with the risk information previously described for the study agent.
8.3
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP
The site investigator will regularly assess and report all clinical outcome events occurring after 
randomization until the last day of study participation. The site investigator will regularly assess and 
report all SAEs other than clinical outcome events, as well as all AEs of special interest, occurring after 
Algorithm to Determine Relatedness of Adverse Event to Study Agent
 
Not Related
The temporal relationship between treatment exposure and the adverse 
event is unreasonable or incompatible and/or adverse event is clearly due to 
extraneous causes (e.g., underlying disease, environment)
Must have both of the following 2 conditions, but may have reasonable or 
only tenuous temporal relationship to intervention:
 
Unlikely
1. Could readily have been produced by the subject’s clinical state, or 
environmental or other interventions.
2. Does not follow known pattern of response to intervention.
Must have at least 2 of the following 3 conditions:
 
Reasonable 
Possibility
1. Has a reasonable temporal relationship to intervention.
2. Could not readily have been produced by the subject’s clinical state or 
environmental or other interventions.
3. Follows a known pattern of response to intervention.
Must have all 3 of the following conditions:
 
Definitely
1. Has a reasonable temporal relationship to intervention.
2. Could not possibly have been produced by the subject’s clinical state or 
have been due to environmental or other interventions.
3. Follows a known pattern of response to intervention.


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randomization until 30 days after permanent study drug discontinuation. All such events will be 
captured on the appropriate CRF and entered into WebDCUTM. Information to be collected includes 
event description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), time of 
resolution/stabilization of the event, a description of the event, relevant history, and concomitant 
medications/procedures. All clinical outcome events, and all reportable SAEs and AEs of special interest, 
will be followed for outcome information until resolution or until 30 days after the subject’s 
participation in the study ends. The information in WebDCUTM will be updated as more information 
becomes available.
8.4
REPORTING PROCEDURES
8.4.1
ADVERSE EVENT REPORTING
This study is being conducted as an investigator-initiated, NINDS-funded protocol. The FDA has granted 
a waiver for an investigational new drug (IND) application. Thus, no formal safety reporting to FDA will 
be done. 
Only AEs that meet the definition of an SAE, clinical outcome event, or AE of special interest will be 
recorded and reported per the reporting timelines. All reporting will be done in accordance with 
StrokeNet Standard Operating Procedures for Safety Monitoring and Reporting as outlined in the 
administrative documents available on the website (https://www.nihstrokenet.org/docs/default-
source/default-document-library/adm13-safety-monitoring-and-reporting-12-19-16.pdf?sfvrsn=0). 
8.4.2
SAFETY REPORTING
Site Responsibilities
Site investigators or their designees must report SAEs, clinical outcome events, and AEs of special 
interest that occur during the time periods established in Section 8.3 through WebDCUTM within 24 
hours of site awareness of the event. The investigators are required to provide relevant information 
such as a description of the event, date/time of onset and resolution, severity, suspected relationship to 
the study treatment, and action taken. Supporting documentation of the event should be provided as 
soon as possible. Additional supporting documentation may be requested by the NCC and should also be 
provided as soon as possible.
All clinical outcome events, whether related or not related to study drug, must be collected from the 
time of randomization until the end of the study. All SAEs other than clinical outcome events, and AEs of 
special interest, whether related or not related to study drug, must be collected from the time of 
randomization until 30 days after permanent study drug discontinuation. 


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NDMC and NCC Responsibilities (Sites should ignore these two paragraphs)
All SAEs and AEs of special interest that occur during the time periods established in Section 8.3 will be 
reported to BMS via a Safety Report generated in WebDCUTM for review by their Global 
Pharmacovigilance group (GPV&E) in accordance with global regulatory reporting requirements. Such 
SAEs and AEs of special interest, whether related or unrelated to the study drug, must be reported to 
BMS by NDMC within 72 hours. These events must be recorded on an approved form and sent to the 
BMS SAE Email Address: Worldwide.Safety@BMS.com, SAE Fax Number: 609-818-3804, or other 
address as provided by BMS. If only limited information is initially available, follow-up reports are 
required. Note: Follow-up safety reports should include the same investigator term(s) initially 
reported. If an ongoing event changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up safety report should be sent within 72 hours to the BMS (or designee) 
using the same procedure used for transmitting the initial report. The NCC will reconcile the clinical 
database with safety events transmitted to BMS GPV&E. Reconciliation will occur every 3 months and 
once just prior to database lock/final study report. The investigator will request a safety data 
reconciliation report from aepbusinessprocess@bms.com or other address provided by BMS. BMS 
GPV&E will email, upon request from the investigator, the GPV&E reconciliation report. The data 
elements listed on the GPV&E safety data reconciliation report will be used for case identification 
purposes. If the investigator determines a case was not transmitted to BMS GPV&E, the case will be sent 
immediately.
Via a separate safety monitoring mechanism, the MSM will conduct an independent review of each SAE 
to determine its seriousness, relationship to the study treatment, and expectedness. If the MSM 
adjudicates the event to be serious, unexpected, and study related, the event will be reported 
expeditiously to the cIRB and other IRB/REBs with study oversight and to Health Canada according to 
local regulations via a Safety Report generated in WebDCUTM.
8.4.3
UNANTICIPATED EVENT REPORTING
Clinical sites will report unanticipated events, including UPs and protocol deviations, in the WebDCUTM 
per the guidelines listed in the MOP. Unanticipated events that are unexpected, related to study 
participation, and place the subject/others at increased risk will require prompt reporting to the cIRB 
and other IRB/REBs with study oversight and to Health Canada. All other unanticipated events which do 
meet the above criteria will be reported to the cIRB and other IRB/REBs with study oversight at the time 
of continuing review. 
8.5
STUDY OVERSIGHT
Safety oversight will be under the direction of the NIH StrokeNet DSMB, which is composed of 
individuals with the appropriate expertise in overseeing stroke clinical trials. The DSMB will meet at least 
semiannually to assess safety data on each arm of the study. The DSMB will review data quality and 
completeness, monitor fidelity to the study protocol, review the adequacy of participant recruitment 
and retention, review SAEs, clinical outcome events, and AEs of special interest and make 
recommendations to the NINDS and the study co-PIs concerning trial continuation, modification, or 
conclusion. 


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8.6
STUDY HALTING RULES
The MSM is responsible for ongoing monitoring of reports of SAEs by the clinical centers within 72 hours 
to ensure Good Clinical Practices (GCP) and to identify safety concerns quickly. The MSM may suggest 
protocol modifications to prevent the occurrence of particular SAEs, such as modifying the protocol to 
require frequent measurement of laboratory values predictive of the event or to improve expeditious 
identification of SAEs. To minimize bias, the MSM will evaluate SAEs blinded to treatment assignment. 
The NDMC will prepare regular reports concerning SAEs and submit them to the DSMB. In the event of 
unexpected SAEs or an unduly high rate of SAEs, the MSM will promptly contact the co-PIs and the 
NINDS Program Official and, if applicable, the NINDS DSMB liaison, who will notify the DSMB Chair. The 
DSMB will convene an ad hoc meeting by teleconference or in writing as soon as possible. The DSMB will 
provide recommendations for continuing or halting the study to the NIH and the study co-PIs.
9
CLINICAL MONITORING
Clinical site monitoring is conducted to ensure that the rights and well-being of human subjects are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with GCP, with applicable 
FDA regulations (21 CFR 312), and with the FDA’s “Guidance for Industry Oversight of Clinical 
Investigations — A Risk-Based Approach to Monitoring.” 

Monitoring for this study will be performed by the NDMC centrally, on site, and remotely. 

Per the study’s monitoring plan, monitoring will include a combination of on-site monitoring (to 
verify data entered into the WebDCU™ database against source documents and query 
inaccuracies between the source documents and WebDCU™ database), remote monitoring 
(source document verification, including verification of written consent, may be performed 
remotely by reviewing source documents that have been uploaded into WebDCU™ or via 
remote access to electronic medical records), and central monitoring (using web-based data 
validation rules, data manager review of entered data, statistical analysis, and on-going review 
of site metrics). 

The NDMC, study co-PIs, and the appropriate site PIs will be provided copies of monitoring 
reports within 30 days of site visits. 
Further details of clinical site monitoring are documented in the study’s Monitoring Plan. The 
Monitoring Plan describes in detail who will conduct the monitoring, at what frequency monitoring will 
be done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports. 
10
STATISTICAL CONSIDERATIONS
10.1
STATISTICAL AND ANALYTICAL PLAN
Statistical analysis details are documented in a formal statistical and analytical plan (SAP). The SAP will 
be finalized prior to the first site being released to enroll subjects. 


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10.2
STATISTICAL HYPOTHESES
Primary efficacy endpoint: The null hypothesis (H0) is that the hazard ratio comparing apixaban versus 
aspirin for the primary endpoint will be 1.
Secondary efficacy endpoint: The null hypothesis (H0) is that the hazard ratio comparing apixaban versus 
aspirin for the secondary endpoint will be 1.
10.3
ANALYSIS DATASETS
The analysis datasets will include:

Intention-to-treat analysis dataset, which will include all randomized participants.

Safety analysis dataset, which will include all participants who took at least one dose of study 
drug.

Per-protocol analysis dataset, which will include all randomized participants who do not have an 
eligibility violation and who received at least one dose of study drug.
10.4
DESCRIPTION OF STATISTICAL METHODS
10.4.1 GENERAL APPROACH
Efficacy outcomes will be analyzed in the intention-to-treat analysis dataset. Safety outcomes will be 
analyzed in the safety analysis dataset.
10.4.2 ANALYSIS OF THE PRIMARY AND SECONDARY ENDPOINTS
The log-rank statistic will be used to test the null hypothesis that the hazard ratio is 1, comparing 
apixaban to aspirin, at a two-tailed alpha level of 0.05.
10.4.3 SAFETY ANALYSES
A standard frequency table will be used to report the number (%) of SAEs, stratified by treatment group. 
Based on prior reports,32,38 the following approximate annual rates of major safety endpoints are 
expected:
Adverse Event
Apixaban
Aspirin
Symptomatic intracranial hemorrhage
1.5%
1.5%
Major hemorrhage other than intracranial hemorrhage
4.0%
3.0%
All-cause mortality
3.5%
3.5%
Log-rank tests will be utilized to assess the treatment group differences in the rates of: (1) first 
symptomatic intracranial hemorrhage; (2) first major hemorrhage other than intracranial hemorrhage; 
and (3) death from any cause. 


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10.4.4 PLANNED INTERIM ANALYSES
The ARCADIA investigators propose one interim analysis for efficacy (or harm) and futility to be 
performed when 1/2 of the expected events have occurred (75 events), with the details specified in the 
SAP.  
10.4.5 ADDITIONAL SUBGROUP ANALYSES
The primary efficacy and safety analyses will be stratified by age (<75 years versus ≥75 years), 
sex/gender, and race/ethnicity (non-Hispanic white versus others). Differential effects of apixaban 
versus aspirin across these subgroups are not anticipated and therefore the trial is not powered 
specifically for these subgroup analyses, but these analyses will allow any unexpectedly large variations 
to be identified.
10.4.6 EXPLORATORY AND SENSITIVITY ANALYSES
The SAP lists additional prespecified exploratory and sensitivity analyses, including analyses related to 
the secondary objective of the trial, which is to test the hypothesis that the relative efficacy of apixaban 
over aspirin increases with the severity of atrial cardiopathy.
10.5
SAMPLE SIZE
10.5.1 ASSUMPTIONS
The estimated sample size of 1,100 subjects is based on several important assumptions:

30-month uniform accrual period and 18-month minimum follow-up period;

7% annual risk of recurrent stroke of any type in aspirin-treated subjects;

40% relative reduction (hazard ratio, 0.6) in the stroke recurrence rate with apixaban compared 
to aspirin;

3% annual rate of cross-over from blinded aspirin to open-label apixaban because of AF 
detection;

3% annual rate of cross-over from blinded apixaban to open-label aspirin because of bleeding or 
other SAEs; and 

5% annual rate of loss to follow-up or death in each group.
10.5.2 SAMPLE SIZE CALCULATION 
Given the assumptions above, enrollment of 1,100 subjects (150 recurrent stroke events anticipated) 
will provide 80% power to demonstrate a statistically significant difference in the hazard for recurrent 
stroke with apixaban compared to aspirin at a two-sided alpha level of 0.05 while allowing for an interim 
look for efficacy (or harm) and futility. An O’Brien-Fleming type Lan-DeMets error spending function39 
will be used to perform one interim analysis at the halfway point of the trial. The sample size estimate 
assumes that the futility boundary will be nonbinding.


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10.6
MEASURES TO MINIMIZE BIAS
10.6.1 ENROLLMENT, RANDOMIZATION, AND MASKING PROCEDURES
Eligible patients will be allocated in a 1:1 ratio to apixaban or aspirin using a scheme that balances 
randomization by regional coordinating center. 
To maintain blinding, the BMS-Pfizer Partnership will provide the NCC Central Pharmacy with apixaban 
and aspirin tablets along with an equal number of matching placebo tablets. Site pharmacists and all 
investigators and subjects will be blinded throughout the course of the study. Switching to open-label 
anticoagulation, if indicated, should not result in unblinding of previous treatment status up until that 
point. Subjects who switch to open-label anticoagulation because of AF or other indication, or who 
switch to open-label antiplatelet therapy, will continue to be followed and will be analyzed according to 
the intention-to-treat principle with blinded outcome adjudication. Unblinding should only occur if a 
compelling clinical reason arises, such as active major bleeding or a pending decision on whether to 
administer intravenous thrombolysis for acute ischemic stroke, in which case the site investigator can 
perform emergency unblinding via procedures detailed in the MOP. In the case of unblinding, 
adjudication of any study endpoints that led to the unblinding will be performed centrally by 
adjudicators who remain blinded to the subject’s treatment status. Once a participant’s treatment is 
unblinded, that participant will no longer receive study drug.
10.6.2 BREAKING THE STUDY BLIND
This is a blinded study. All co-PIs, site study team members including site pharmacists, and study 
subjects will be fully blinded to treatment assignment. Unblinding is unlikely to be needed, but in the 
event that emergency unblinding is requested, unblinding procedures are specified in the MOP. The site 
investigator should only request unblinding when it is essential for the subject’s safety (e.g., when 
considering administration of intravenous thrombolysis for recurrent acute ischemic stroke, managing 
life-threatening bleeding, or undertaking emergency surgery). 
Participants will be provided with identification that includes study contact information and indicates 
that they are participating in a study of aspirin versus apixaban for recurrent stroke. This will be useful in 
the event of a medical emergency. A notification will also be sent to participants’ primary care 
physicians to inform them of their subject’s participation in this trial.
11
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with ICH E6 and regulatory and institutional requirements for the protection of 
confidentiality of participants. As part of participating in an NINDS-sponsored trial, each site will permit 
authorized representatives of NINDS and regulatory agencies to examine (and when permitted by 
applicable law, to copy) clinical records for the purposes of quality assurance reviews, audits, and 
evaluation of the study safety, progress, and data validity.
Data will be collected using CRFs whenever possible, but source data to be collected will also include 
copies of provider notes, laboratory results, and imaging reports. 


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Subjects’ participation in the study will be documented in the electronic medical record unless 
prohibited by local regulations. 
In an effort to review informed consent forms in a timely manner, enrolling sites will upload a PDF of the 
signed informed consent form into the password protected clinical trial management system, 
WebDCUTM. The PDF file will be linked to the Subject ID but will be stored on a secure server separate 
from the study’s CRF data. The secure server on which these files are stored is not backed up to prevent 
copies of files containing individually identifiable health information from being copied and stored on 
non-NDMC back up servers. The files on these servers can only be accessed by designated NDMC study 
personnel. NDMC staff will remotely monitor the informed consent forms and issues identified will be 
relayed to the clinical site for corrective and preventative action. After remote monitoring is complete, 
the PDF file containing the informed consent form will be permanently deleted from the secure server. If 
a subject must be re-consented, the process will repeat itself.
12
QUALITY ASSURANCE AND QUALITY CONTROL
Quality control (QC) procedures will be implemented beginning with the data entry system, and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following written procedures as detailed in the monitoring plan, the monitors will verify that the clinical 
trial is conducted and data are generated, documented (recorded), and reported in compliance with the 
protocol, GCP, and the applicable regulatory requirements (e.g., Good Laboratory Practices (GLP), Good 
Manufacturing Practices (GMP)). 
The investigational site will provide direct access to all trial-related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities.
13
ETHICS/PROTECTION OF HUMAN SUBJECTS
13.1
ETHICAL STANDARD
The co-PIs will ensure that this study is conducted in full conformity with Regulations for the Protection 
of Human Subjects of Research codified in 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH 
E6.
13.2
INSTITUTIONAL REVIEW BOARD
The protocol, informed consent form, recruitment materials, and all participant materials will be 
submitted to applicable central and local IRB/REBs for review and approval. Approval of both the 
protocol and the consent form will be obtained before any participant is enrolled. Any amendment to 
the protocol will require review and approval by the cIRBs/IRB/REBs before the changes are 
implemented to the study. All changes to the template consent form will be cIRB/IRB/REBs approved; a 
determination will be made regarding whether previously consented participants need to be re-
consented.


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13.3
INFORMED CONSENT PROCESS
13.3.1 CONSENT AND OTHER INFORMATION DOCUMENTS PROVIDED TO PARTICIPANTS
Consent forms describing in detail the study agent, study procedures, and risks will be given to the 
participant and written documentation of informed consent will be performed prior to starting 
intervention/administering study product. The following consent materials are submitted with this 
protocol: informed consent form with included HIPAA authorization form.
13.3.2 CONSENT PROCEDURES AND DOCUMENTATION
In accordance with FDA regulations (21 CFR 50) and ICH-GCP Consolidated Guidelines, cIRB/IRB/REB-
approved, informed consent is required from all patients prior to participating in this study. At the initial 
contact with a potential candidate, the investigative team (investigator or coordinator) will provide a 
comprehensive explanation of the purpose, procedures, possible risks/benefits of the study in language 
that is understandable to a non-medically trained person; as well as participant responsibilities and the 
fact that his/her participation is voluntary, that he or she may withdraw from the study at any time, and 
that the decision not to participate or to withdraw will not affect the patient’s care in any way. Potential 
participants will be given ample opportunity to ask questions and to consider their decision. If the 
patient expresses a sustained interest, a signed and dated written informed consent will be obtained. 
Patients with a known history of dementia will not provide self-consent, thereby minimizing the 
possibility of invalid informed consent. A copy of the consent form will be given to the participant, and 
another copy placed in his or her medical record unless prohibited by local regulations. The informed 
consent will be obtained by either the clinical site PI or other members of the study team who are 
qualified to perform this task and whose names are listed on the Delegation of Authority Log. Informed 
consent will be performed in a language in which the patient or surrogate (see below) is fluent. 
Participants will be asked to explain back the study to confirm their understanding of the study and its 
procedures. 
13.3.3 USE OF SURROGATES FOR CONSENT
Since this is a long-term secondary stroke prevention trial, the goal is to enroll subjects who will be able 
to participate actively in their care over the duration of the trial. However, recognizing that otherwise 
suitable subjects will often have neurological deficits that may impair their ability to provide written, 
informed consent, especially soon after their index stroke, the trial will allow inclusion of subjects via the 
use of surrogate consent. Loss of capacity to provide consent is a common, though hardly universal, 
feature in stroke patients. Neurologists and other physicians who care for stroke patients, as well as 
coordinators involved in stroke trials, are familiar with the signs and symptoms of stroke that can render 
a stroke patient unable to provide informed consent. All investigators and coordinators will be trained in 
the process of enrolling stroke patients using informed consent.
The use of surrogates for consent will conform with determinations required by federal regulations for 
the cognitively impaired:

45 CFR 46.111(a): Selection of subjects is equitable. Use of surrogate consent leads to inclusion 
of a more representative cohort of subjects with stroke and is therefore more equitable than 


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excluding subjects who are otherwise eligible except for their inability to provide consent 
themselves.

45 CFR 46.111(b): Additional safeguards have been included to protect their rights and welfare. 
Although the active treatment arm of this trial imposes a risk of injury from increased bleeding, 
compelling preliminary data exists to suggest that subjects receiving apixaban will benefit from 
improved stroke prevention and that the probability of benefit is greater than the probability of 
harm. Subjects assigned to aspirin will receive the current standard of care for stroke 
prevention. 

45 CFR 46.116: Informed consent must be obtained from the subject or the subject's legally 
authorized representative. 
Our protocol will be the following: First, the lack of capacity will be determined. Acute stroke patients 
frequently lack capacity due to language deficits, inattention to their health (neglect and anosognosia, 
or lack of awareness of their deficit), or other deficits. A trained study investigator will make these initial 
assessments and this process of determination of lack of capacity will be documented in the medical 
record. 
Second, once the patient is determined to lack capacity, a member of the investigative team will seek to 
identify a court-appointed legally authorized representative/guardian or appropriately executed health 
care proxy. This individual will serve as the legally authorized representative to provide surrogate 
consent.
Third, if no court-appointed legally authorized representative/guardian or appropriately executed health 
care proxy is available, then a member of the investigative team will obtain surrogate consent from 
another person on the following list: (a) the spouse (if not legally separated from the subject) or the 
domestic partner; (b) a son or daughter eighteen (18) years of age or older; (c) a parent; (d) a brother or 
sister eighteen (18) years of age or older; (e) a close friend (meaning a person eighteen [18] years of age 
or older who has maintained such regular contact with the subject as to be familiar with the subject’s 
activities, health, and beliefs). Determination of the appropriate individual to provide informed consent 
will be determined through means considered possible and appropriate by the study investigator or 
coordinator, including but not limited to presentation and review of documents, discussion with family 
members present, review of administrative and medical records, and discussion with the patient’s 
primary care physician, who is likely to know these individuals. The discussion will include the patient 
when possible, even if the patient is unable to provide formal consent due to language or other deficits. 
In this circumstance, the patient’s assent will be sought, when possible. In addition, the discussion will 
include multiple family members as appropriate in the investigator’s judgment, and agreement among 
family members will be sought. 
Finally, if a subject previously determined to lack capacity to consent regains capacity during the study, 
the investigator will obtain the consent of the individual for the remaining part of the study. 
Detailed procedures for determining subjects’ capacity for consent and obtaining consent from a 
surrogate, if necessary, are specified in the MOP. Investigators and coordinators will be trained in the 
use of surrogates for informed consent.


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13.4
PARTICIPANT AND DATA CONFIDENTIALITY
13.4.1 CONFIDENTIALITY AND DATA STORAGE
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
sponsor(s) and their agents. This confidentiality is extended to cover testing of biological samples in 
addition to clinical information relating to participants. Therefore, the study protocol, documentation, 
data, and other information generated will be held in strict confidence. No information about the study 
or data will be released to any unauthorized third party without prior written approval of the sponsor.
The study monitor, other authorized representatives of the sponsor, and representatives of the NDMC, 
applicable cIRB/IRB/REBs, and pharmaceutical company supplying study product may inspect all 
documents and records required to be maintained by the investigator, including but not limited to, 
medical records and pharmacy records for the participants in this study. The clinical study site will 
permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for the 
duration specified by the StrokeNet Standard Operating Procedure (SOP) or longer as dictated by 
applicable cIRB/IRB/REBs and local institutional regulations.
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored for the duration of the study and analysis at the NDMC. The study data 
entry and study management systems used by clinical sites and by the NDMC research staff will be 
secured and password protected. At the end of the study, all study databases will be de-identified and a 
Public Use Dataset (PUDS) will be archived at the NINDS data repository. 
13.4.2 RESEARCH USE OF STORED HUMAN SAMPLES
Intended Use: Samples collected from participants at the time of screening will be stored and will be 
used to assay NT-proBNP to determine eligibility for the study. Samples may also be used for other 
studies of stroke and cardiac disease (see Section 13.5 below). No genetic testing will be performed 
without further amendment of this protocol and informed consent form. 
Storage: The biobank repository will be kept at the Laboratory Core for the study, in the Center for 
Advanced Laboratory Medicine (CALM) at Columbia University Medical Center (CUMC), under the 
supervision of Dr. Marshall, Contact PI for the study, and Dr. Eldad Hod, a clinical pathologist and 
Director of CALM. A dedicated -80° C freezer will be used for this study. Drs. Marshall and Hod, and their 
delegates, will have responsibility for the integrity of the repository. Access to the repository for future 
research studies will be limited to those approved by the ARCADIA Executive Committee. 
Tracking: Samples and data will be stored using codes. Data will be kept in password-protected 
computers. Only investigators will have access to the samples and data. Study participants who request 
destruction of samples will be notified of compliance with such request and all supporting details will be 
maintained for tracking.


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13.5
FUTURE USE OF STORED SPECIMENS
All ARCADIA ancillary studies, including those that include the use of blood specimens, will be reviewed 
by the Publications and Executive Committees for approval. Specimens will be used only for purposes 
related to research described in this protocol, i.e., understanding the causes and optimal prevention, 
treatment, and outcomes of unexplained strokes. The purpose of the Executive and Publications 
Committee reviews will be to assure that future uses of subject specimens are consistent with the 
informed consent obtained at the time the specimen was collected. A letter of approval for use of 
biobank specimens will be provided to the ancillary study PI. Once approved and, if necessary, funded, 
Dr. Hod’s delegated staff will retrieve the samples for assays to be performed locally or for shipping to 
offsite laboratories as requested and appropriate for the particular study. Investigators who receive 
specimens from the study will sign forms to indicate that the samples are solely for their use and they 
will be expressly forbidden from transferring samples to any third parties. The CALM biosample 
repository will also be provided with a code-link that will allow linking the biological specimens with the 
phenotypic data from each participant, maintaining the masking of the identity of the participant.
Informed consent for collection and storage of blood samples for the biobank (i.e. blood samples above 
and beyond that needed to determine NT-pro BNP for study eligibility) is incorporated into the primary 
ARCADIA consent form, but as a separate section requiring separate approval. Participants will thus have 
the opportunity to participate in ARCADIA without participating in the biobank. No additional consent 
will be obtained so as to minimize inconvenience to the participant and the local investigator’s staff by 
collecting the blood samples at a single time. Because collection of a sample for the assay for NT-pro 
BNP is being performed to determine eligibility for randomization, the collection of limited additional 
samples for the purpose of this biobank is expected to cause minimal risk and inconvenience, thereby 
limiting the possibility for interference with the parent ARCADIA study. Participants can withdraw 
consent for research on stored specimens at any time and the specimens will be discarded; this 
information is also included in the consent form. However,  data already collected about the participants 
will be retained and analyzed even if the subjects choose to withdraw from the research. If a subject 
revokes authorization in writing for continued use or disclosure of blood sample data or protected 
health information (PHI) that was already obtained in the research, analysis of that data will continue 
only to the extent necessary to protect the integrity of the research study. Furthermore, withdrawal of 
consent with regard to biosample storage will not be possible after the study is completed. 
The privacy and confidentiality of the biobank will be ensured through the use of standard CALM 
procedures. All individuals who handle specimens will be trained in accordance with GCP and on specific 
modules related to the handling of biospecimens. This training will include safeguards to prevent 
accidental or inappropriate release of information. A list of those with access to the samples will be kept 
with Dr. Hod as Director of the CALM Laboratory. The samples themselves will be kept in a dedicated 
freezer in a locked room in the CALM Laboratory; access will be limited to Drs. Hod, Marshall, and their 
delegates. Any clinical data collected will be handled through WebDCUTM. Samples will be shipped to 
CALM to arrive during business hours. Samples will be accompanied by labels on tubes and a sample 
shipping form that will include no patient identifiers other than the study ID number. The samples will 
be stored at CALM using this study ID number only, and samples will be bar coded for ease of storage 
and retrieval. Any laboratory results will be provided to WebDCUTM. Further use of this information will 
be according to the study-wide procedures for maintenance of confidentiality and privacy. Depending 
on funding, analyses for ancillary studies may be performed by the NDMC, or, if they are performed 
locally by an ancillary study investigator, a limited data set, including key clinical variables needed for 


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the analyses, may be provided by the NDMC to enable the analyses to be performed. PHI will not be 
provided without further authorization by the Executive Committee. A Certificate of Confidentiality will 
be obtained prior to the beginning of enrollment.
Specimens will be destroyed 10 years after the publication of the primary manuscript describing the 
results of the ARCADIA study. Samples will be discarded in red medical waste bags specially made to 
contain medical or biohazardous waste and certification will be provided to the co-PIs and other 
requestors.
In the event that an ancillary study proposal is approved that uses the specimens and does not involve 
any investigators related to the main protocol, a sample use agreement will be required. In this case, to 
minimize the possibility that data in the biobank could be used to identify individuals in the study, we 
will add to the agreement an additional statement stating that the recipient may not attempt to identify 
subjects by any means. 
Specimens may be made available to commercial organizations. Commercial organizations will need to 
complete an ancillary study proposal form, which will be reviewed by the Executive and Publications 
Committees, which includes NINDS representation. Final agreements with commercial organizations will 
need to be reviewed with legal counsel of the study sponsor, as well, in the event of potential 
development of commercial products. 
14
DATA HANDLING AND RECORD KEEPING
14.1
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
PI. The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of 
the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data. Black ink is required to ensure clarity of reproduced copies. When making changes or 
corrections, cross out the original entry with a single line, and initial and date the change. DO NOT 
ERASE, OVERWRITE, OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL.
Copies of the electronic CRF (eCRF) will be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study. Data reported in the eCRF derived from source 
documents should be consistent with the source documents or the discrepancies should be explained 
and captured in a progress note and maintained in the participant’s official electronic study record. 
Clinical data will be entered into WebDCUTM. The data system includes password protection and internal 
quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Clinical data will be entered directly from the source documents.
14.2
STUDY RECORDS RETENTION


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Study documents should be retained for the duration specified by the StrokeNet SOP or for a longer 
period if required by local regulations. 
14.3
PROTOCOL DEVIATIONS
A protocol deviation is any noncompliance with the clinical trial protocol, GCP, or MOP requirements. 
The noncompliance may be either on the part of the participant, the investigator, or the study site staff. 
As a result of deviations, corrective action plans are to be developed by the site after review and 
approval by the NCC.
These practices are consistent with ICH E6: 

4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3.

5.1 Quality Assurance and Quality Control, section 5.1.1.

5.20 Noncompliance, sections 5.20.1, and 5.20.2. 
It is the responsibility of the site to use continuous vigilance to identify and report deviations within 10 
working days of identification of a protocol deviation meeting criteria for prompt reporting, or within 10 
working days of the scheduled protocol-required activity. These protocol deviations must be addressed 
in study source documents and reported via WebDCUTM for review by the ARCADIA Project Manager. All 
other protocol deviations must be reported to the applicable cIRB/IRB/REBs at the time of annual 
reviews. The site PI and study staff are responsible for knowing and adhering to applicable cIRB/IRB/REB 
requirements. Further details about the handling of protocol deviations are included in the MOP.
14.4
PUBLICATION AND DATA SHARING POLICY
This study will comply with the NIH Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. As required by International Committee of Medical Journal Editors (ICMJE) member journals 
and Section 801 of the Food and Drug Administration Amendments Act (FDAAA) of 2007, this trial will be 
registered prior to its initiation at clinicaltrials.gov, a public trials registry sponsored by the National 
Library of Medicine. The co-PIs will take specific steps to ensure compliance with NIH implementation of 
FDAAA.
Data generated through this project will be shared according to StrokeNet SOP ADM 04 regarding the 
Network Data Sharing Policy Data Sharing Policy. In summary, the goals of this Data and Resource 
Sharing Policy are to make available final data from StrokeNet clinical trials to the research community, 
while safeguarding the privacy of trial participants and protecting confidential and proprietary data. 
Upon database lock, the NDMC statisticians will generate data files from each data table corresponding 
to each electronic CRF in the database. In compliance with the HIPAA regulations, each data table will be 
stripped of any and all personal identifiers and will undergo a deidentification process. Furthermore, the 
NDMC statisticians will create a minimum number of derived variables that would be necessary to 
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Within 1 year from the acceptance of the primary manuscript for publication OR no later than 2 years 
from the database lock the PUDS will be submitted to the NINDS data repository, along with the final 
version of the study protocol, the data dictionary, and a user guide (or a “Readme” file) regarding the 
data files, including an explanation of any derived variables. Once PUDS are available, any researcher 
(study investigator or otherwise) wishing to receive them can contact the NINDS 
(CRLiaison@ninds.nih.gov). All manuscripts, abstracts, and press releases using the study data must 
acknowledge the StrokeNet investigators and the NINDS as the study sponsor with the relevant grant 
numbers.
In order to expedite and track external data sharing, the ARCADIA website will serve as a resource and 
informational site for potential external investigators and collaborators. The website will include the 
ARCADIA publication policy, the data sharing procedures and policies, timelines, and contact 
information. All published ARCADIA manuscripts, abstracts, and brief descriptions of ongoing projects 
will be posted on the website, maintained by the StrokeNet NCC.
15
STUDY ADMINISTRATION
15.1
OVERVIEW
This trial is being conducted as part of the NIH-funded StrokeNet network for stroke clinical trials. Trial 
administration will be handled by the StrokeNet NCC at the University of Cincinnati, and data 
management and monitoring by the NDMC at the Medical University of South Carolina. The ARCADIA 
co-PIs will have overall responsibility for study design, site selection, analysis and interpretation of final 
data, and dissemination of study results.
15.2
STUDY MANAGEMENT CORES (NCC and CCC)
For participating U.S. sites, the NCC will perform study management tasks such as site management and 
contracting, cIRB oversight, trial-wide communications, orchestration of training activities, coordination 
of site initiation visits, collection of regulatory documents, and site performance analyses. This core will 
also receive study drug from BMS-Pfizer, label drugs to maintain blinding, and distribute study drug to 
sites on a regular schedule.
For participating Canadian sites, the NCC will perform study management tasks such as trial-wide 
communications, review and approval of regulatory documents, and protocol support. The NCC will also 
receive study drug from BMS-Pfizer, label drugs to maintain blinding, and distribute study drug to the 
Canadian depot. The Canadian Coordinating Centre (CCC) will perform study management tasks such as 
site management and contracting, collection of regulatory documents, cIRB/IRB/REB oversight, 
orchestration of training activities, coordination of site initiation visits, and site performance analyses. 
The CCC will oversee distribution of study drug from the central Canadian depot to sites on a regular 
schedule.
15.3
DATA MANAGEMENT CORE (NDMC)
The study database will reside at Medical University of South Carolina according to the procedures 
governing the StrokeNet. This core consists of those responsible for maintenance of the database, logic 


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checks, edit requests, quality assurance, merging of datasets, creating and exporting data subsets, 
reliability and validity substudies, programming reports and data arrays needed for tracking enrollment 
and follow-up, and supporting other operational, project management, and analysis needs. This core will 
interface closely with the ARCADIA co-PIs, co-investigators, and all the committees. This core will 
provide unblinded reports to the DSMC for their meetings, and will provide a final locked database to 
the blinded study statistician after data collection and cleaning have been completed.
15.4
EXECUTIVE COMMITTEE
The Executive Committee will consist of the following voting members: the four ARCADIA co-PIs, the 
blinded study statistician, the study cardiologist, the PIs of the NCC and NDMC, the NINDS project 
scientist, the Canadian Sites Lead PI, and the CCC Lead PI. Key blinded members of the Trial Operations 
Committee will also attend. The Executive Committee in its entirety will meet twice annually, and more 
frequently as needed, to review and if necessary vote on key study issues, including but not limited to: 
1) approving modification of the protocol or operations manual, 2) reviewing study progress, 3) 
mediating budgetary disputes, 4) reviewing and approving issues surrounding local projects and ancillary 
studies, and 5) reviewing and approving all abstracts and publications. 
15.5
TRIAL OPERATIONS COMMITTEE
The Trial Operations Committee will include the four ARCADIA co-PIs, the PIs of the NCC and NDMC, the 
NINDS project scientist, the unblinded study statistician, and key members of the NCC, NDMC, CCC, and 
study Cores involved in study operations. Membership will also include individuals representing 
additional networks of study investigators that may join this trial. This committee will meet weekly to 
review recruitment and discuss execution, budget, and other day-to-day issues arising in the conduct of 
the trial. 
15.6
PUBLICATIONS COMMITTEE
Membership of the Publications Committee will be determined by the Executive Committee. The 
Publications Committee will convene quarterly, and more frequently as needed (i.e., during the 
dissemination phase after trial completion), to review and make recommendations to the Executive 
Committee with regard to: 1) paper proposals, 2) prioritization of analysis requests, 3) writing group 
membership and authorship issues, 4) other manuscript-related issues. This Committee will function in 
accordance with the StrokeNet SOP regarding publications policies.
15.7
ANCILLARY STUDIES COMMITTEE
Membership of the Ancillary Studies Committee will be determined by the Executive Committee. The 
Ancillary Studies Committee is responsible for soliciting and reviewing ancillary study proposals and 
interfacing with all approved ancillary study teams to ensure their coordination with the parent trial. As 
needed, the Ancillary Study Committee will interface with the study cores to ensure equitable 
distribution of samples and data, and with the Publications Committee to review proposed analyses and 
manuscripts. The Ancillary Study Committee will function in accordance with the StrokeNet SOP 
regarding ancillary studies.


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16
CONFLICT OF INTEREST POLICY
The independence of this study from any actual or perceived external influence is critical. Therefore any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or any 
aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived conflict 
of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the trial. The study leadership in conjunction with the NINDS has established policies and 
procedures for all study group members to disclose all conflicts of interest and will establish a 
mechanism for the management of all reported dualities of interest.
17
LITERATURE REFERENCES
1.
Marnane M, Duggan CA, Sheehan OC, et al. Stroke subtype classification to mechanism-specific 
and undetermined categories by TOAST, A-S-C-O, and Causative Classification system. Stroke. 
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2.
Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new 
clinical construct. Lancet Neurol. 2014;13(4):429-438.
3.
Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J 
Med. 2012;366(2):120-129.
4.
Brambatti M, Connolly SJ, Gold MR, et al. Temporal relationship between subclinical atrial 
fibrillation and embolic events. Circulation. 2014;129(21):2094-2099.
5.
Martin DT, Bersohn MM, Waldo AL, et al. Randomized trial of atrial arrhythmia monitoring to 
guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization 
devices. Eur Heart J. 2015;36(26):1660-1668.
6.
Kamel H, Elkind MS, Bhave PD, et al. Paroxysmal supraventricular tachycardia and the risk of 
ischemic stroke. Stroke. 2013;44(6):1550-1554.
7.
Hancock EW, Deal BJ, Mirvis DM, et al. AHA/ACCF/HRS recommendations for the 
standardization and interpretation of the electrocardiogram: part V: electrocardiogram changes 
associated with cardiac chamber hypertrophy: a scientific statement from the American Heart 
Association Electrocardiography and Arrhythmias Committee, Council on Clinical Cardiology; the 
American College of Cardiology Foundation; and the Heart Rhythm Society: endorsed by the 
International Society for Computerized Electrocardiology. Circulation. 2009;119(10):e251-261.
8.
Kamel H, Soliman EZ, Heckbert SR, et al. P-wave morphology and the risk of incident ischemic 
stroke in the Multi-Ethnic Study of Atherosclerosis. Stroke. 2014;45(9):2786-2788.
9.
Kamel H, O'Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial 
abnormality and stroke subtype in the Atherosclerosis Risk In Communities study. Ann Neurol. 
2015;78(5):670-678.
10.
Kamel H, Bartz TM, Longstreth WT, Jr., et al. Association between left atrial abnormality on ECG 
and vascular brain injury on MRI in the Cardiovascular Health Study. Stroke. 2015;46(3):711-716.
11.
Kamel H, Hunter M, Moon YP, et al. Electrocardiographic left atrial abnormality and risk of 
stroke: Northern Manhattan Study. Stroke. 2015;46(11):3208-3212.
12.
Benjamin EJ, D'Agostino RB, Belanger AJ, Wolf PA, Levy D. Left atrial size and the risk of stroke 
and death. The Framingham Heart Study. Circulation. 1995;92(4):835-841.
13.
Barnes ME, Miyasaka Y, Seward JB, et al. Left atrial volume in the prediction of first ischemic 
stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc. 2004;79(8):1008-1014.


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14.
Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial size and the risk of ischemic stroke in an 
ethnically mixed population. Stroke. 1999;30(10):2019-2024.
15.
Yaghi S, Moon YP, Mora-McLaughlin C, et al. Left atrial enlargement and stroke recurrence: the 
northern Manhattan stroke study. Stroke. 2015;46(6):1488-1493.
16.
Folsom AR, Nambi V, Bell EJ, et al. Troponin T, N-terminal pro-B-type natriuretic peptide, and 
incidence of stroke: the Atherosclerosis Risk In Communities study. Stroke. 2013;44(4):961-967.
17.
Cushman M, Judd SE, Howard VJ, et al. N-terminal pro-B-type natriuretic peptide and stroke risk: 
the Reasons for Geographic and Racial Differences in Stroke Cohort. Stroke. 2014;45(6):1646-
1650.
18.
Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial fibrillation and mechanisms of stroke: time for a 
new model. Stroke. 2016;47(3):895-900.
19.
Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N 
Engl J Med. 2014;370(26):2478-2486.
20.
Longstreth WT, Jr., Kronmal RA, Thompson JL, et al. Amino terminal pro-B-type natriuretic 
peptide, secondary stroke prevention, and choice of antithrombotic therapy. Stroke. 
2013;44(3):714-719.
21.
Connolly SJ, Eikelboom J, Joyner C, et al. Apixaban in patients with atrial fibrillation. N Engl J 
Med. 2011;364(9):806-817.
22.
Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral 
anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised 
trials. Lancet. 2014;383(9921):955-962.
23.
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial 
fibrillation. N Engl J Med. 2011;365(11):981-992.
24.
Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with 
stroke and transient ischemic attack: a guideline for healthcare professionals from the American 
Heart Association/American Stroke Association. Stroke. 2014;45(7):2160-2236.
25.
Dennis M. Embolic stroke of undetermined source: a therapeutic target? Lancet Neurol. 
2014;13(4):344-346.
26.
Freilinger TM, Schindler A, Schmidt C, et al. Prevalence of nonstenosing, complicated 
atherosclerotic plaques in cryptogenic stroke. JACC Cardiovasc Imaging. 2012;5(4):397-405.
27.
Gupta A, Gialdini G, Lerario MP, et al. Magnetic resonance angiography detection of abnormal 
carotid artery plaque in patients with cryptogenic stroke. J Am Heart Assoc. 2015;4(6):e002012.
28.
Gupta A, Gialdini G, Giambrone AE, et al. Association between nonstenosing carotid artery 
plaque on MR angiography and acute ischemic stroke. JACC Cardiovasc Imaging. 
2016;9(10):1228-1229.
29.
Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for 
symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352(13):1305-1316.
30.
Chimowitz MI, Lynn MJ, Derdeyn CP, et al. Stenting versus aggressive medical therapy for 
intracranial arterial stenosis. N Engl J Med. 2011;365(11):993-1003.
31.
Amarenco P, Davis S, Jones EF, et al. Clopidogrel plus aspirin versus warfarin in patients with 
stroke and aortic arch plaques. Stroke. 2014;45(5):1248-1257.
32.
Diener HC, Eikelboom J, Connolly SJ, et al. Apixaban versus aspirin in patients with atrial 
fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis 
from AVERROES, a randomised trial. Lancet Neurol. 2012;11(3):225-231.
33.
Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the S, Standardization 
Committee of the International Society on T, Haemostasis. Definition of major bleeding in 


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clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb 
Haemost. 2005;3(4):692-694.
34.
Meschia JF, Brott TG, Chukwudelunzu FE, et al. Verifying the stroke-free phenotype by 
structured telephone interview. Stroke. 2000;31(5):1076-1080.
35.
Katzan IL, Fan Y, Uchino K, Griffith SD. The PROMIS physical function scale: A promising scale for 
use in patients with ischemic stroke. Neurology. 2016;86(19):1801-1807.
36.
Jauch EC, Saver JL, Adams HP, Jr., et al. Guidelines for the early management of patients with 
acute ischemic stroke: a guideline for healthcare professionals from the American Heart 
Association/American Stroke Association. Stroke. 2013;44(3):870-947.
37.
Armstrong MJ, Gronseth G, Anderson DC, et al. Summary of evidence-based guideline: 
periprocedural management of antithrombotic medications in patients with ischemic 
cerebrovascular disease: report of the Guideline Development Subcommittee of the American 
Academy of Neurology. Neurology. 2013;80(22):2065-2069.
38.
Nam HS, Kim HC, Kim YD, et al. Long-term mortality in patients with stroke of undetermined 
etiology. Stroke. 2012;43(11):2948-2956.
39.
Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659-663.


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CHANGE LOG
Version
Date
Significant Revisions
1.1
7 July 2017

Added the composite outcome of stroke of any type or death from 
any cause as a secondary efficacy outcome (4.2.2).

Clarified inclusion and exclusion criteria (5.1 and 5.2).

Clarified that patients not eligible for randomization may still be 
followed as part of ancillary studies (7.2.2).

Revised schedule of assessments (7.2.6).

Clarified procedures for study drug administration after a potential 
primary endpoint (7.9).

Only SAEs will be recorded (8.1.1).

Clarified SAE reporting procedures from NDMC to BMS (8.4.2).

Certificate of confidentiality will be obtained (13.5).

Clarified reporting of protocol deviations (14.3).

Corrected typographical errors and made minor revisions 
throughout to improve clarity.
2.0
22 Sep 2017

Updated safety reporting language to distinguish between SAEs, 
clinical outcome events, and AEs of special interest, rather than 
lumping them together in one category.

Added clarification about study medication refills (7.2.3).
3.0
01 Dec 2017

Modified time of randomization based on stroke severity. In 
general, randomization can occur as early as post-stroke day 3. 
However, randomization must be delayed until at least post-stroke 
day 14 for patients with severe strokes (initial NIHSS score ≥11), 
hemorrhagic transformation of the index stroke, or uncontrolled 
hypertension (7.2.2).

Added information about buffer or number of extra pills provided. 
(6.14)

Added route of medication “by mouth” (6.16)

Clarified what patient should do for a missed dose of study 
medication (i.e., when to take and when to skip). (6.16)

Changed exclusion criteria to exclude patients with an indication for 
any antiplatelet therapy (5.2) and added requirement that study 
drug be stopped while any antiplatelet therapy is indicated after 
randomization (7.3.1). Clarified that all patients stopping study drug 
due to need for open-label anticoagulant or antiplatelet therapy 
will continued to be followed and analyzed according to the 
intention-to-treat principle (10.6.1).

Follow-up visit window (7.2.3 and 7.2.6) window of time reduced 
from +/-14 days to +/-5 days to prevent subjects from running out 
of study medication and to keep them within the guidelines for 
follow-up visits based on time of randomization.
4.0
05 Feb 2019

Changed number of sites from 120 to up to 200 (Protocol 
Summary).

Updated study team members (pgs 11,12) 


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
Clarified that mitral stenosis as an exclusion criterion applies only to 
moderate or severe mitral stenosis (5.1). 

Provided a procedure for obtaining written consent from 
surrogates via fax or other HIPAA-compliant method for 
transmitting written documents (5.3). 

Removed a general physical examination from study-specific 
procedures (7.1.1). 

Clarified that tests to establish ESUS must be performed no earlier 
than 3 months prior to the index stroke (7.1.2).

Clarified requirements for contacting potential subjects by phone 
(7.2.1).

Allowed follow-up visits via telephone or other HIPAA-compliant 
telehealth technology (7.2.3).

Clarified that study drug must be stopped if a site identifies an 
event as a possible primary efficacy outcome (7.9).
4.1
24 Apr 2019

Corrected an error in description of procedure for obtaining written 
consent from surrogates via fax or other HIPAA-compliant method 
for transmitting written documents (5.3).
4.1 
(Canada 
only)
22 Aug 2019

Updated personnel in Key Roles.

Throughout:  added U.S. and Canada to highlight that this is now a 
collaboration of sites in the two countries. 

List of Abbreviations: added REB (Regulatory Ethics Board)

Throughout: revised cIRB to applicable cIRB and other IRB/REBs 
with study oversight to include other Canadian regulatory bodies.

Section 8.4.2 Safety Reporting – we added reporting to Health 
Canada, cIRB and other IRB/REBs with study oversight according to 
local regulations.

Section 8.4.3 -- reporting of unanticipated events to the cIRB and 
other IRB/REBs with study oversight and to Health Canada.

Section 15.2 Study Management Cores – now includes Canadian 
Central Coordinating Center responsibilities
4.2 
(Canada 
only)
12 Sep 2019

Added an exclusion for eCrCl <15 mL/min (5.2).

Specified that subjects with eCrCl 15-24 mL/min will receive 
apixaban 2.5 mg twice daily, regardless of other dose adjustment 
criteria (6.1.5, 6.1.7).

Specified that laboratory determination of renal function must 
occur at least once per year as part of standard care (6.1.7).

Added strong inhibitors and inducers of CYP3A4 and P-gp to the list 
of prohibited medications (7.3.3).
5.0
3 Apr 2020

Incorporated all changes from Canadian protocol version 4.1 and 
4.2 into combined U.S./Canada version 5.0. 

Updated study/participant duration in Protocol Summary and 
Schematic of Study Design.

Streamlined and updated personnel list in Key Roles (Section 1).

Changed inclusion criteria to require randomization no later than 
180 days after stroke onset, rather than 120 days (5.1, 7.2.1, 7.2.2).  


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
Specified that remote consent can be obtained from patients as 
well as their surrogates (5.3).

Specified that eConsent can be used as allowed by local regulations 
and IRB/REB requirements (5.3).

Specified procedures for reconsenting subjects (5.3).

Updated time period of recruitment (5.5).

Clarified procedure for handling subject withdrawal from study 
(5.6.1).

First dose of study medication is now required within 48 hours of 
randomization, rather than 24 hours (6.1.5).

Clarified that study-specific procedures do not need to be 
performed in person (7.1.1, 7.2.1).

Clarified which echocardiogram should be used to determine the 
ECHO criterion for atrial cardiopathy (7.2.1).

Specified that remote randomization is allowed (7.2.2).

Added COVID-19 as an Adverse Event of Special Interest (8.1.3).

Updated membership of Executive Committee and clarified key 
issues to be reviewed by Executive Committee (15.4).

Updated membership of Trial Operations Committee (15.5).
5.1
12 Jan 2021

Clarified nature of exploratory endpoints (4.2, 8.1).

Clarified procedures for subjects who wish to withdraw from the 
study (5.6.1).

Changed the time period for assessment of SAEs other than clinical 
outcome events as well as AEs of special interest. These must now 
be reported from randomization until 30 days after permanent 
study drug discontinuation. Clinical outcome events will still be 
ascertained from randomization until the end of study participation 
(7.1, 7.2, 8.1, 8.3, and 8.4).

Clarified procedure for ascertaining presence of AF on ECG/heart-
rhythm monitoring (7.1.2).

Added procedure for collecting Medicare information (7.2).

Clarify that last dose of open-label antiplatelet therapy allowed is 
on the day before randomization (7.3.1).
6.0
17 Aug 2022

Updated Contact PI from Dr. Mitchell Elkind to Dr. Randolph 
Marshall.

Updated eligibility criteria in light of recently updated ESUS criteria 
which exclude PFO-associated stroke (5.1).

Minor clarification of follow-up and end-of-study visits (7.2.3., 
7.2.4).

Minor clarification of adjudication process after emergency 
unblinding (10.6.1).

SAP_001.pdf: 
 
 
 
AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke 
 
Clinicaltrial.gov: NCT03192215 
 
STATISTICAL ANALYSIS PLAN 
 
SAP Version 1.4 
Protocol Version 6 
Date: 15 Feb 2023 
 
 
 
Primary Trial Statistician, Blinded 
NDMC Trial Statistician, Unblinded 
Richard A. Kronmal, PhD 
School of Public Health 
University of Washington 
Seattle, WA 98101 
Christy Cassarly, PhD 
Department of Public Health Sciences 
Medical University of South Carolina 
Charleston, SC 29425 
 
 


 
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TABLE OF CONTENTS 
 
1 
LIST OF ABBREVIATIONS ................................................................................................. 4 
2 
KEY ROLES ...................................................................................................................... 5 
3 
STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS ................................................ 5 
4 
BACKGROUND AND RATIONALE ...................................................................................... 6 
5 
SYNOPSIS OF THE STUDY ................................................................................................ 7 
6 
OUTCOME VARIABLES .................................................................................................... 7 
6.1 
PRIMARY EFFICACY OUTCOME .......................................................................................................................... 7 
6.2 
SECONDARY EFFICACY OUTCOMES ................................................................................................................. 7 
6.3 
PRIMARY SAFETY OUTCOMES ............................................................................................................................ 7 
6.4 
SECONDARY SAFETY OUTCOMES ...................................................................................................................... 8 
7 
SAMPLE SIZE DETERMINATION FOR PRIMARY EFFICACY OBJECTIVE ................................. 8 
7.1 
SAMPLE SIZE ESTIMATION .................................................................................................................................. 8 
7.2 
REVISIONS TO THE GROUP SEQUENTIAL BOUNDARIES ........................................................................ 8 
8 
DEFINITION OF TARGET POPULATION AND STUDY SAMPLES ........................................... 9 
8.1 
TARGET POPULATION ............................................................................................................................................ 9 
8.2 
INTENT-TO-TREAT SAMPLE ................................................................................................................................ 9 
8.3 
SAFETY-ANALYSIS SAMPLE ................................................................................................................................. 9 
8.4 
PER-PROTOCOL SAMPLE....................................................................................................................................... 9 
9 
GENERAL STATISTICAL CONSIDERATIONS ...................................................................... 10 
9.1 
PARTICIPANT ACCOUNTABILITY .................................................................................................................... 10 
9.2 
RANDOMIZATION ................................................................................................................................................... 10 
9.3 
BLINDING ................................................................................................................................................................... 10 
9.4 
CENSORING PARTICIPANTS ............................................................................................................................... 12 
9.4.1 
PRIMARY OUTCOME .................................................................................................................................... 12 
9.4.2 
DEATH ................................................................................................................................................................ 12 
9.4.3 
CROSSOVER TO OPEN-LABEL DRUG .................................................................................................... 12 
9.4.4 
WITHDRAWN CONSENT AND LOSS TO FOLLOW-UP .................................................................... 12 
9.4.5 
SECONDARY AND SAFETY OUTCOMES ............................................................................................... 12 
9.5 
TREATMENT GROUP COMPARABILITY ........................................................................................................ 12 
9.6 
SITE EFFECTS ........................................................................................................................................................... 13 
9.7 
PARTICIPANT ADHERENCE ............................................................................................................................... 13 
10 
EFFICACY ANALYSIS ................................................................................................... 13 
10.1 
PRIMARY EFFICACY ANALYSIS ......................................................................................................................... 13 
10.1.1 
PARAMETER DESCRIPTION ..................................................................................................................... 13 
10.1.2 
STATISTICAL HYPOTHESES...................................................................................................................... 13 
10.1.3 
STATISTICAL MODEL .................................................................................................................................. 14 
10.1.4 
INTERIM ANALYSIS METHOD.................................................................................................................. 14 
10.1.5 
FINAL ANALYSIS METHOD ....................................................................................................................... 15 
10.1.6 
ADDITIONAL ANALYSES OF THE PRIMARY EFFICACY OUTCOME .......................................... 15 
10.2 
INTERACTION OF ATRIAL CARDIOPATHY SEVERITY AND TREATMENT EFFECT .................... 16 
10.2.1 
TESTS OF INTERACTION ............................................................................................................................ 16 
10.2.2 
IDENTIFICATION OF HIGH-RISK SUBGROUPS ................................................................................. 17 
10.2.3 
ADDITIONAL EXPLORATORY MODELING .......................................................................................... 17 
10.2.4 
STATISTICAL MODEL .................................................................................................................................. 17 
10.3 
SECONDARY EFFICACY ANALYSIS .................................................................................................................. 18 


 
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10.3.1 
PARAMETER DESCRIPTION ..................................................................................................................... 18 
10.3.2 
STATISTICAL HYPOTHESES...................................................................................................................... 18 
10.3.3 
EXPLORATORY EFFICACY ANALYSES .................................................................................................. 18 
10.3.4 
EXPLORATORY ENDPOINTS ..................................................................................................................... 19 
11 
SAFETY ANALYSES ..................................................................................................... 19 
11.1 
SAFETY MONITORING .......................................................................................................................................... 19 
11.2 
DESCRIPTIVE SUMMARY OF EVENTS ............................................................................................................ 19 
11.3 
ANALYSIS OF SAFETY OUTCOMES AT TRIAL COMPLETION ............................................................... 19 
11.3.1 
PRIMARY SAFETY ENDPOINTS ............................................................................................................... 20 
11.3.2 
SECONDARY SAFETY ENDPOINT ........................................................................................................... 20 
11.4 
ADJUDICATION OF SAFETY ENDPOINTS ...................................................................................................... 20 
12 
SUBGROUP ANALYSES ............................................................................................... 20 
13 
QUALITY-OF-LIFE ANALYSES....................................................................................... 20 
13.1 
QUALITY-OF-LIFE MEASURES........................................................................................................................... 20 
13.2 
ANALYSES OF QUALITY-OF-LIFE MEASURES ............................................................................................ 20 
14 
COST-EFFECTIVENESS ANALYSIS ................................................................................. 21 
15 
UPDATE OF TRIAL OPERATING PARAMETERS ............................................................. 21 
16 
CHANGE LOG ............................................................................................................. 22 
17 
REFERENCES .............................................................................................................. 23 


ARCADIA Statistical Analysis Plan 
 
Version 1.4 
 
 
15 Feb 2023 
 
 
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1 LIST OF ABBREVIATIONS
 
AE 
Adverse event 
AF 
Atrial fibrillation 
AHA/ASA 
American Heart Association/American Stroke Association 
ARCADIA 
AtRial Cardiopathy and Antithrombotic Drugs In prevention After cryptogenic stroke 
CRF 
Case report form 
CI 
Confidence interval 
DCU 
Data Coordination Unit 
DCR 
Data clarification request 
DSMB 
Data and safety monitoring board 
ECG 
Electrocardiogram 
ESUS 
Embolic stroke of undetermined source 
HR 
Hazard ratio 
ITT 
Intention to treat 
MOP 
Manual of procedures 
NCC 
NIH StrokeNet National Coordinating Center 
NDMC 
NIH StrokeNet National Data Management Center 
NIH 
National Institutes of Health 
NIHSS 
National Institutes of Health Stroke Scale 
NINDS 
National Institute of Neurological Disorders and Stroke 
NOAC 
Non-vitamin K antagonist oral anticoagulant drug 
NT-proBNP 
Amino terminal pro-B-type natriuretic peptide 
PI 
Principal Investigator 
PROMIS 
Patient-Reported Outcomes Measurement Information System  
PTFV1 
P-wave terminal force in ECG lead V1 
QVSFS 
Questionnaire for Verification of Stroke-Free Status 
RCC 
Regional Coordinating Center 
SAE 
Serious adverse event 
SD 
Standard deviation 
SOP 
Standard operating procedure 
 
 
 


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2 KEY ROLES
 
Primary Trial Statistician, Blinded 
NDMC Trial Statistician, Unblinded 
Richard A. Kronmal, PhD 
School of Public Health 
University of Washington 
Seattle, WA 98101 
Caitlyn Meinzer, PhD 
Department of Public Health Science 
Medical University of South Carolina, 
Charleston, SC, 29425 
 
 
 
Contact PI 
Protocol PI 
Mitchell S.V. Elkind, MD, MS 
Hooman Kamel, MD 
 
 
 
 
3 STATISTICAL ANALYSIS PLAN AND STATISTICAL REPORTS
 
This document provides the details of statistical analyses planned for the ARCADIA trial, including 
interim analyses for efficacy and futility. In addition, it discusses the statistical issues relevant to these 
analyses (e.g., sample data to be used, missing data, adjustments for multiplicity, etc.). 
 
The DCU generates two statistical reports: an open report to be distributed to the ARCADIA Executive 
Committee and the DSMB, and a closed report to be distributed only to the DSMB. The timing of these 
reports is determined in consultation with the DSMB. Reports will be sent from the DCU to the NINDS 
liaison two weeks in advance of the scheduled meeting.  
 
Each report provides cumulative summary statistics on enrollment; participant status in the study (e.g., 
number who completed each study visit assessment); baseline characteristics; protocol violations; data 
management/quality information (e.g., timeliness and completeness of data entry by the clinical sites; 
number of DCRs generated and resolved); and safety data, including SAEs by AE code, severity, 
expectedness (anticipated/unanticipated), and relatedness to the study medication. Aggregate rates of 
SAEs including atrial fibrillation/flutter and excluding clinical outcomes (stroke [ischemic, hemorrhagic, 
or undetermined type], symptomatic hemorrhagic transformation of ischemic stroke, intracranial 
hemorrhage excluding either hemorrhagic stroke or symptomatic hemorrhagic transformation of 
ischemic stroke, transient ischemic attack, major hemorrhage excluding intracranial hemorrhage, minor 
hemorrhage, myocardial infarction, systemic embolism, symptomatic deep venous thrombosis, and 
symptomatic pulmonary embolism) are provided in the open report; data on all other endpoints are 
restricted to the closed report. The statistics are provided for the overall study as well as by site or RCC, 
where appropriate, in the open report. For the closed report only, the statistics are also provided by 
treatment group (A vs B). If a report coincides in timing with a planned interim analysis, the analysis 
results are appended to the report. 
 


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The DCU also generates a blinded quarterly report to be distributed to the ARCADIA Executive 
Committee which contains updated aggregate data on enrollment, baseline, safety information, and loss 
to follow-up and crossovers. In addition, this report contains a table that shows what proportion of 
consented patients were randomized and on which atrial cardiopathy marker(s) these participants were 
deemed eligible, including summary statistics of the atrial cardiopathy marker values.  
 
4 BACKGROUND AND RATIONALE 
 
In one-third of ischemic strokes, a specific cause cannot be identified. Many of these cryptogenic strokes 
appear to arise from a distant embolic source. Recent evidence suggests that some cryptogenic strokes 
may arise from left atrial thromboembolism that goes unrecognized because it has not manifested with 
atrial fibrillation/flutter (AF). These data suggest that an underlying atrial cardiopathy may provide the 
substrate for thrombus formation and embolization even in the absence of AF.  
 
In parallel with these new insights about cryptogenic stroke, new therapeutic options for stroke 
prevention have become available. Non-vitamin K antagonist oral anticoagulant (NOAC) drugs such as 
apixaban may be more effective than aspirin for treatment of cryptogenic stroke. A benefit is especially 
likely in cryptogenic stroke patients with atrial cardiopathy because of parallels with AF and because an 
analysis of data from the WARSS/APASS studies suggests that cryptogenic stroke patients with one 
marker of atrial cardiopathy (elevated NT-proBNP) and no obvious AF benefit from anticoagulant 
therapy.1 Apixaban is a particularly attractive choice because it has a low bleeding risk,2,3 lowers 
mortality more than warfarin in patients with AF,4 and is the only NOAC drug with a Class 1A 
recommendation in recent AHA/ASA guidelines.5  
 
The ARCADIA trial is designed to address several important knowledge gaps. First, it will advance 
knowledge about stroke pathophysiology by assessing whether atrial cardiopathy is a valid therapeutic 
target, which may set the stage for a primary prevention trial. Second, this trial will advance knowledge 
about optimal secondary stroke prevention therapy. One industry-sponsored trial (NAVIGATE-ESUS) that 
compared rivaroxaban to aspirin in patients with cryptogenic stroke was stopped early for futility. 
Another industry-sponsored trial (RESPECT-ESUS) is comparing dabigatran versus aspirin in patients with 
cryptogenic stroke. By including all cryptogenic stroke patients and by including those with up to 6 
minutes of AF per day, these trials have mixed patients with heterogeneous stroke mechanisms. These 
trials may thus fail to show an overall benefit (as in NAVIGATE-ESUS), or may show an overall benefit 
driven mostly by patients with known AF and atrial cardiopathy, resulting in an overly broad indication 
for anticoagulant therapy. In the first instance, the ARCADIA trial may ensure that a valuable treatment 
in a specifically targeted subgroup will not be prematurely abandoned. In the second instance, the 
results of the ARCADIA trial would provide a compelling rationale to perform subgroup analyses of the 
industry-sponsored trials and conduct future trials to determine the risks and benefits of anticoagulant 
therapy across biologically distinct subgroups of stroke patients. Given the expense and risks of bleeding 
associated with anticoagulant drugs, it is imperative to define as precisely as possible the groups of 
stroke patients who would and would not benefit from their use. Therefore, the approach taken by the 
ARCADIA trial comports well with the general move toward precision medicine.  
 
 
 


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5 SYNOPSIS OF THE STUDY 
 
ARCADIA is a multicenter, biomarker-driven, randomized, double-blind, active controlled Phase III 
clinical trial of 1,100 participants, conducted at up to 200 enrolling sites. Participants will be followed for 
a minimum of 1.5 years. Patients who have evidence of atrial cardiopathy and a recent stroke of 
undetermined source by current criteria will be randomly assigned to apixaban or aspirin (active control 
therapy) in a 1:1 ratio. Atrial cardiopathy will be defined as one or more of the following biomarkers: P-
wave terminal force in electrocardiogram lead V1 >5,000 µV*ms, left atrial size index ≥3.0 cm/m2 on 
echocardiogram, and serum amino terminal pro-B-type natriuretic peptide >250 pg/mL. Standard heart-
rhythm monitoring will be performed before enrollment to exclude as thoroughly as possible those 
patients with atrial fibrillation. Therapy must be initiated within 3-180 days of enrolling stroke. The 
primary efficacy endpoint is time to recurrent stroke (ITT analysis). Secondary efficacy endpoints are 
time to (1) recurrent stroke or death and (2) recurrent ischemic stroke or systemic embolism. There will 
be a test of the interaction of the atrial cardiopathy selection variables with treatment arm for the 
primary outcome. The primary safety outcomes are: (1) symptomatic intracranial hemorrhage (including 
symptomatic hemorrhagic transformation of an ischemic stroke) and (2) major hemorrhage other than 
intracranial hemorrhage. Additional safety endpoints include all-cause mortality.  
 
6 OUTCOME VARIABLES 
 
6.1 PRIMARY EFFICACY OUTCOME 
 
The primary efficacy outcome is recurrent stroke of any type (ischemic, hemorrhagic, or of 
undetermined type). Possible stroke events will be centrally adjudicated, and the primary outcome 
measure will be defined as the centrally adjudicated stroke event, NOT the site determined event.  
 
If a site identifies an event as a possible primary efficacy outcome, the participant will stop study 
medication. If the adjudication committee determines the event meets the primary efficacy definition, 
the participant will stop participation in the study, including stopping study drug; otherwise they may 
stop, continue, or resume study drug at the discretion of the treating physician. 
 
6.2 SECONDARY EFFICACY OUTCOMES 
 
The secondary efficacy outcomes are: (A) composite of recurrent ischemic stroke or systemic embolism, 
and (B) composite of recurrent stroke of any type or death from any cause. Possible events will be 
centrally adjudicated, and the outcome measure will be defined as the centrally adjudicated event, NOT 
the site determined event. Note that recurrent ischemic stroke is a subset of the primary outcome 
definition and thus the participant would stop participation in the study, including stopping study drug. 
In the case of systemic embolism, the participant may continue in the trial until the end of follow-up or 
occurrence of the primary endpoint.  
 
6.3 PRIMARY SAFETY OUTCOMES 
 
The primary safety outcomes are: (A) symptomatic intracranial hemorrhage (including symptomatic 
hemorrhagic transformation of an ischemic stroke), and (B) major hemorrhage other than intracranial 


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hemorrhage. Symptomatic intracranial hemorrhage is defined as any extravascular blood within the 
cranium, including subdural and epidural blood, associated with and identified as the predominant 
cause of new neurologic symptoms, including headache, or leading to death. Major hemorrhage other 
than intracranial hemorrhage is defined as clinically overt bleeding accompanied by a 2 g/dL decrease 
in the hemoglobin level during a 24-hour period, transfusion of 2 units of whole blood or red cells, 
involvement of a critical non-intracranial site (intraspinal, intraocular, pericardial, intraarticular, 
intramuscular with compartment syndrome, or retroperitoneal), or death. 
 
Note that symptomatic intracranial hemorrhage may not meet the primary outcome definition of 
stroke, in which case the participant is eligible to continue in the trial; this is true for other safety 
outcomes as well. 
 
 
6.4 SECONDARY SAFETY OUTCOMES 
 
The secondary safety endpoint is all-cause mortality. Note that death is included as part of a composite 
secondary efficacy endpoint.  
 
7 SAMPLE SIZE DETERMINATION FOR PRIMARY EFFICACY OBJECTIVE 
 
7.1 SAMPLE SIZE ESTIMATION 
 
The primary outcome variable is the time to recurrent stroke of any type. Preliminary data suggest a 7% 
annual risk of recurrent stroke of any type in aspirin-treated patients, with a clinically relevant relative 
risk reduction of 40% (hazard ratio of 0.6, hazard rate of 4.2%) for patients treated with apixaban. Based 
on preliminary feasibility data and 120 sites, ARCADIA plans to recruit 1,100 participants during a 30-
month uniform accrual period and follow these participants to the end of the study (i.e., 18-month 
minimum follow-up period). In addition, it is anticipated that there will be a 3% annual rate of crossover 
from blinded aspirin to open-label anticoagulation due to AF detection, and a 3% annual rate of 
crossover from blinded apixaban to open-label antiplatelet therapy due to bleeding or other adverse 
events. Finally, it is estimated that there will be a 5% annual rate of loss to follow-up or death in each 
group.  
 
Given the assumptions above, enrollment of 1,100 participants (approximately 150 recurrent stroke 
events) will provide 80% power to demonstrate a statistically significant difference in the hazard for 
recurrent stroke with apixaban compared to aspirin at an alpha level of 0.05 while allowing for one 
interim look for efficacy (or harm) and futility after 1/2 of expected events have occurred (75 events). To 
maintain the power as planned and the overall alpha of the study at 0.05, an O’Brien-Fleming type Lan-
DeMets error spending function will be used. The sample size was calculated using the “Design: Survival 
Endpoint: Two-Sample Test – Parallel Design – Logrank” program in EAST® v6 software (Cytel 
Corporation) (Lan and DeMets, 1983).  
 
7.2 REVISIONS TO THE GROUP SEQUENTIAL BOUNDARIES 
 
It is possible that the information fraction at the interim analysis may be incorrect due to incorrect 
estimation of the total number of events in the trial. However, given this trial’s extremely conservative 
interim analysis boundaries, it is unlikely that such misestimation would substantively affect the final 


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test statistic. Furthermore, there is inherent difficulty in accurately estimating the total number of 
events even at the time of the interim analysis. Therefore, there will be no revisions to the group 
sequential boundaries. 
 
8 DEFINITION OF TARGET POPULATION AND STUDY SAMPLES 
 
8.1 TARGET POPULATION 
 
The population that will be randomized in the ARCADIA trial comprises patients 45 years of age and 
older who have a clinical diagnosis of embolic stroke of undetermined source (ESUS) within the prior 
180 days, a modified Rankin Scale score ≤4 at the time of screening, and at least one of the following 
criteria for atrial cardiopathy:  
• 
[ECG]: PTFV1 >5,000 μV*ms on 12-lead ECG. 
• 
[ECHO]: Left atrial size index ≥3 cm/m2 on echocardiogram. 
• 
[NT-proBNP]: Serum NT-proBNP >250 pg/mL. 
 
8.2 INTENT-TO-TREAT SAMPLE 
 
Under the ITT principle, the evaluable sample includes all participants who are randomized. Each 
participant will be analyzed according to the treatment group to which they were randomly assigned at 
the time of randomization. 
 
8.3 SAFETY-ANALYSIS SAMPLE 
 
The safety sample includes all participants who are randomized and receive at least one dose of study 
medication. The safety sample will include all safety outcomes from randomization until 30 days after 
permanent discontinuation of study drug. The primary safety analysis will define treatment arm as the 
treatment to which a participant was randomized. Additional sensitivity analyses will define a time-
dependent treatment covariate, and possibly a lagged time-dependent treatment covariate.   
 
8.4 PER-PROTOCOL SAMPLE 
 
In addition to the defined ITT analysis sample, a per-protocol sample is defined as a subset of the ITT 
sample. This sample will be used for sensitivity analyses of the primary and secondary efficacy 
outcomes. The per-protocol sample will include all randomized participants who do not have the 
following protocol deviations: 
• 
Eligibility violation. 
• 
Treatment never started. 
 
For these sensitivity analyses, treatment will first be defined as randomized, but a time-dependent 
treatment covariate with concurrent treatment effects may be considered.  
 
 
 


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9  GENERAL STATISTICAL CONSIDERATIONS 
 
9.1 PARTICIPANT ACCOUNTABILITY 
 
A flowchart will be created to present a summary of participants’ status. This flowchart will first list the 
number of patients who were eligible and consented to be screened for the biomarkers. Of consented 
patients, the chart will then delineate those who did not meet criteria for any of the three biomarkers, 
those who were positive for at least one biomarker but no longer eligible at the time of randomization 
or declined randomization or were not randomized for another reason, and those randomized to a 
treatment group. Then, within each treatment group, it will list the number of participants who were 
lost to follow-up, the number of participants who withdrew, and the number of participants who were 
included in the primary analysis.  
 
9.2 RANDOMIZATION 
 
Eligible participants will be allocated in a 1:1 ratio to apixaban or aspirin using a randomization method 
that controls the maximum tolerated imbalance within each RCC. Implementation details are provided 
in the randomization plan and validation documentation.  
 
A web-based central randomization system will be developed by the NDMC and installed on the 
WebDCU™ ARCADIA study website. The randomization algorithm and its implementation will be fully 
detailed in the ARCADIA Randomization Plan and the Randomization Validation documents. These 
documents will be developed prior to enrollment initiation and stored in a secure location at the NDMC. 
The documents will be archived with the study database at the end of the trial.  
 
The participant randomization system is fully integrated into the ARCADIA study database, and 
presented as a special CRF in the electronic data capture module. Data edit permission for the 
randomization CRF is centrally managed based on user groups. Site study team members are limited to 
viewing and editing data only for participants in their own site. Site enrollment status, participant 
eligibility, and site study drug availability are verified prior to the performance of participant 
randomization in order to protect data integrity. The participant randomization system checks the drug 
availability at both the site level and the individual participant level and triggers site study drug 
shipment and participant drug resupply requests accordingly. 
 
Participant treatment assignment information is masked by using the Study Drug ID, which is a globally 
unique no-sequence 6-digit number placed on each study drug kit. Access to treatment assignment 
information is prohibited for all blinded investigators. Authorized emergency unblinding for medical 
safety purposes is provided through a medical emergency hotline with one of the trial PIs responding to 
the treating physician. All cases of unblinding are recorded in the study database. 
 
9.3 BLINDING 
 
The study is conducted in a double-blinded manner. Study drug administration, clinical care, and 
outcomes assessments are made by the clinical site staff blinded to the treatment assignment. 
Participants will not be told of their actual treatment assignment until the trial is complete, at which 
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that requires unblinding. The Executive Committee and the MSM are also blinded to the treatment 
assignment. 
 
The NDMC biostatistician and statistical programmer will be partially unblinded; they know the 
participants’ group classification (A or B), but not whether A is apixaban or aspirin. During the course of 
the trial it may be necessary for them to become unblinded if the DSMB requests. The clinical 
adjudicators will attempt to remain blinded, but information in the narrative may on rare occasions 
unblind specific cases. The Executive Committee members are completely blinded.    
 
The DCU’s unblinded staff generates: (1) a hard copy list (obtained from the WebDCUTM) of study drug 
kit numbers and their corresponding study drug (apixaban or aspirin) as well as the lot numbers and 
expiration dates; and (2) two identical sealed envelopes that contain identification of treatment codes 
(e.g., A = apixaban, B = aspirin). Prior to initiation of the trial, one envelope is given to the NINDS liaison 
to the DSMB. Another is maintained in a locked file cabinet in a limited access central file room along 
with the hard copy list described in (1). 
 
The central pharmacy personnel at the StrokeNet NCC at the University of Cincinnati are completely 
unblinded. They have access to the WebDCUTM to match the study drug (apixaban or aspirin) to its 
corresponding study drug kit number.   
 
The DSMB (as well as the NINDS liaison to the DSMB) is partially unblinded. However, if it so wishes, it 
may be completely unblinded at any time during the trial. One of the sealed envelopes described in (2) 
above is given to the NINDS liaison to the DSMB prior to initiation of the trial. If the DSMB wishes to be 
unblinded on a particular participant only, the NINDS liaison to the DSMB can email the request to the 
NDMC biostatistician. 
 
In case of a medical emergency for a study participant who requires unblinding, clinical staff can become 
unblinded only to that participant’s treatment by calling the emergency hotline. Clinical staff would then 
request permission for unblinding to occur and provide a brief clinical summary to one of the 
responding trial PIs. The PI would perform unblinding via the WebDCU™ ARCADIA study website and 
inform the clinical staff. Unblinding should only occur if a compelling clinical reason arises, such as active 
major bleeding or a pending decision on whether to administer intravenous thrombolysis for acute 
ischemic stroke. Participants who undergo unblinding will stop study drug but continue to be followed 
as part of the study and will be analyzed according to the intention-to-treat principle. 
 
Details such as how kits will be labeled and how the study drug is blinded are provided in the Study Drug 
Plan. 
 
 
 


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9.4 CENSORING PARTICIPANTS 
 
9.4.1 PRIMARY OUTCOME 
 
Participants will be followed until the end of the trial follow-up period, which will be 18 months after 
enrollment of the last participant. Due to regulatory reasons, participants will have a final telephone 
visit 30 days after the trial follow-up period to assess SAEs related to discontinuation of study drug, but 
this 30-day period will not contribute to participants’ time-at-risk for the purposes of analysis. Under the 
ITT principle, all participants who are randomized are included in the analysis. Participants will be 
censored at the date of their last follow-up visit in cases of loss to follow-up or withdrawn consent, or at 
the date of death in cases of death.  
 
9.4.2 DEATH 
 
The primary analysis codes death as a censoring event. Sensitivity analyses will be conducted where 
death is treated as a competing risk. 
 
9.4.3 CROSSOVER TO OPEN-LABEL DRUG 
 
If a participant is known to have permanently crossed over onto open-label drug (e.g., an anticoagulant 
in the case of AF diagnosis, antiplatelet drug or no antithrombotic therapy in the case of bleeding events 
on apixaban, antiplatelet therapy for a new coronary event), the participant will continue to be followed 
and analyzed in the treatment group they are assigned. A sensitivity analysis using a time-dependent 
treatment effect, as well as an analysis accounting for pill count compliance data, will be considered. 
  
9.4.4 WITHDRAWN CONSENT AND LOSS TO FOLLOW-UP 
 
Using recommended methods,6 sensitivity analyses will be conducted to assess the effect of any 
censoring that occurs due to a participant being lost to follow-up or withdrawing consent. Based on 
other large stroke prevention trials, we anticipate no more than a 4% lost to follow up rate. At the time 
of each planned analysis (interim and final), the unblinded statistician will report the amount of missing 
primary outcome data. 
 
9.4.5 SECONDARY AND SAFETY OUTCOMES 
 
In cases where observation of the primary outcome precludes observation of secondary or safety 
outcomes, the primary analysis will treat the participant as censored. Sensitivity analyses will explore 
alternative modeling strategies, in particular competing risk, Markov models, or joint modeling 
approaches.  
 
9.5 TREATMENT GROUP COMPARABILITY  
 
A description of the baseline characteristics of trial participants will be presented by treatment group. 
Dichotomous variables will be summarized as number (%). Percentages will be calculated based on the 
number of participants with available data for that variable. Continuous variables will be summarized by 
the mean and SD. In the case of variables with missing values, the denominator will be stated in the 


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summary table or in a footnote to the summary table. The baseline characteristics of interest include 
age, sex, race, time from qualifying stroke, CHA2DS2-VASc score, weight, and the value of each of the 
biomarker inclusion criteria. Statistical significance of covariates will not be assessed. In addition, all of 
the above covariates, regardless of imbalances between groups, will be included as covariates in 
multivariable regression in a secondary analysis of the primary aim. 
  
9.6 SITE EFFECTS  
 
Several procedures have been incorporated into the study design (i.e., procedure manual, training and 
certification programs, protocol violation monitoring, blinding) to reduce trial site effects; however, 
possible effects will not be ignored for this trial. The distribution of demographics will be examined by 
RCC using means (SD) and proportions (95% CIs), and RCC and RCC*treatment interaction terms will be 
included as a random effect in a secondary analysis of the primary outcome. 
 
9.7 PARTICIPANT ADHERENCE 
 
Participants will be requested to bring in their study pill bottles at study visits for pill counts. For each 
visit interval, adherence by pill count will be measured as (# pills supplied - # remaining pills)/# pills 
supplied. Adherence will be classified as low (<60%), medium (60-79%), or high (≥80%). A sensitivity 
analysis of the primary endpoint will use a time-dependent compliance indicator to assess the impact of 
non-compliance on hazard of stroke. Note that participants are supplied with a buffer of 10 pills per 
bottle. The calculation listed above will adjust for the number of days between visits (i.e., a participant 
with 100% compliance and 90 days between study visits will be listed as 100% compliant). 
 
10 EFFICACY ANALYSIS 
 
10.1 PRIMARY EFFICACY ANALYSIS 
 
10.1.1 PARAMETER DESCRIPTION 
 
The primary efficacy analysis will use the ITT sample to assess time to recurrent stroke of any type. 
Censoring of participants is described in Section 0. 
 
10.1.2 STATISTICAL HYPOTHESES 
 
The null hypothesis (H0) is that the hazard ratio comparing apixaban versus aspirin for the primary 
endpoint will be 1. The alternative (HA) is that the hazard ratio is not 1. That is,  
 
H0: hapix(t) = hasp(t) 
 
versus  
HA: hapix(t) ≠ hasp(t) 
 
Where hapix(t) and hasp(t) are the hazard rates at time t for the apixaban and aspirin groups, respectively. 
The minimum effect size of clinical interest is a relative HR of 0.6. The estimated yearly event rate in the 
placebo group is assumed to be 7%.  
 


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10.1.3 STATISTICAL MODEL 
 
( )
( )
1
1
1
2
1
1
1
1
1
D
i
i
i
i
i
i
D
i
i
i
i
i
i
i
i
i
i
d
t
d
Y
Y
Z
Y
Y
Y
d
t
d
W
Y
Y
Y
W
=
=






=



−




−
−


−








 
 
Which has a standard normal distribution for large samples when H0 is true. Using this 
statistic, an α level test of the alternative hypothesis 
1
2
: h ( )
( )
A
H
t
h t

, for some t


, 
is rejected when 
/2
Z
Z

. Let W(t)=1 for all t, which represents the log-rank test.  
 
Efficacy Outcome 
Analysis Method to Compare Apixaban and 
Aspirin Groups (SAS® v9 Procedure) 
Log-Rank Test of Survival 
PROC PHREG 
 
To test the null hypothesis, we will use the log-rank test. 
In the above model, an event (Status) and event time (Time) are defined as follows: 
 
First Event 
Status 
Time 
Recurrent stroke of any type  
1 
Time of first stroke of any type 
Systemic embolism 
N/A (continue to follow) 
Death 
0 
Time of death 
Diagnosis of AF 
N/A (continue to follow) 
Study drug stopped 
N/A (continue to follow) 
Loss to follow-up or consent withdrawn 
0 
Last known contact  
Study team requires unblinding and 
recurrent stroke of any type has not yet 
occurred 
N/A (continue to follow) 
 
 
10.1.4 INTERIM ANALYSIS METHOD 
 
The study is designed using one interim look for both efficacy and futility for the primary outcome, and 
one final look, for a total of two planned analyses of the primary outcome. The interim analysis plan 
uses the error spending function method with O'Brien-Fleming type stopping guidelines. The error 
spending function distributes the type I and II error rates across the interim monitoring points giving the 
flexibility of changing the intervals of monitoring while still preserving the overall type I and II error 
rates. The O’Brien-Fleming type boundary is considered conservative as its boundaries make it difficult 
to terminate a study early by requiring extreme early evidence of efficacy or futility. It spends smaller 
amounts of alpha at the first look and gradually increases the spending as more information is acquired.  
The trial may be stopped for overwhelming efficacy of one treatment group over the other or for futility 
at the planned interim analyses if the test statistic crosses the respective boundaries.   
 
The prespecified plan is to conduct the first interim analysis after 75 cumulative adjudicated primary 
outcome events (estimated information fraction of ½), or approximately 800 participants have been 


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randomized. Assuming an accrual rate of 36.7 participants per month, it is anticipated that the first look 
will occur roughly 3.5 years from the start of enrollment. The interval may be altered if requested by the 
DSMB. The stopping boundaries are defined using the Lans-DeMets O’Brien-Fleming type spending 
functions (Lan and DeMets, 1983). The futility boundaries are derived as non-binding, meaning that if a 
futility boundary is crossed it can be overruled without inflation of the type I error rate. If the crossing of 
an efficacy boundary is overruled, then this decision can impact the type II error rate but not the type I 
error rate. EAST® v6 software (Cytel Corporation) was used for the boundary calculations. The following 
table lists the test statistics at a particular look. The NDMC will be responsible for conducting these 
analyses and compiling the reports for the DSMB. Since several factors need to be taken into 
consideration before stopping a study, safety and study progress will also be taken into consideration by 
the DSMB and Executive Committee when deciding whether to stop the study if an efficacy or futility 
boundary is crossed.   
 
Table. Nominal Critical Values and Alpha Levels for One Interim Analysis for Overwhelming Efficacy and 
Futility (O’Brien‐Fleming, two‐sided α = 0.05) 
 
Exp. # 
events 
under 
H0 
Cum. 
α 
Efficacy Boundary 
Cum. 
β 
Futility Boundary 
Z Scale 
HR 
Z Scale 
HR 
Interim 
Analysis 
75 
0.003 
|Z|>2.963 
HR>2.123 
-OR- 
HR<0.471 
0.04 
|Z|<0.356 
HR>0.914 
-AND- 
HR<1.095 
Final 
Analysis 
150 
0.05 
|Z|>1.969 
HR>1.424 
-or- 
HR<0.702 
0.20 
 
 
10.1.5 FINAL ANALYSIS METHOD 
 
The primary outcome analysis of the time to stroke of any type will use a log-rank test statistic to assess 
whether there is a difference in the hazard comparing apixaban to aspirin. Outcome differences will be 
analyzed under the ITT principle, so all randomized participants will be included in the primary analysis 
sample. To assess efficacy, the treatment groups will be compared with respect to the hazard of 
experiencing a primary outcome event. A log-rank test will be performed to compare the treatment 
group proportions using a cumulative two-tailed significance level of 0.05. An unadjusted HR will be 
reported with two-sided 95% CIs. At the final analysis, the null hypothesis will be rejected if the HR is 
greater than 1.424 or less than 0.702; we will fail to reject the null hypothesis at the 0.05 level of 
significance otherwise. 
 
10.1.6 ADDITIONAL ANALYSES OF THE PRIMARY EFFICACY OUTCOME 
 
10.1.6.1 Adjusting for Key Covariates 
 
In secondary analyses of the primary outcome, we will adjust for the prognostic variables listed in 
Section 9.5. A Cox proportional hazards model will be used, after the verification of variable and model 
assumptions and goodness-of-fit assessments accompanying each analysis. Schoenfeld residuals will be 
used to assess the assumption of proportional hazards, and if significant deviations are found, we will 


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analyze treatment effect according to time period. These secondary analyses will be reported in the 
paper reporting the primary results of the trial.  
 
10.1.6.2 Accounting for Crossover to Open-Label Therapy 
 
In a secondary analysis, we will censor participants at the time of AF detection, when they are switched 
to open-label anticoagulation. This analysis will be used to explore the utility of anticoagulation in 
participants with atrial cardiopathy before they have manifested AF and therefore remain “cryptogenic” 
based on the prevailing clinical paradigm. Alongside this analysis, we will also perform an alternative 
analysis treating AF as a competing risk rather than a censoring point, given very recent theoretical data 
suggesting that apixaban may reduce the risk of AF itself, not just stroke. Lastly, we will perform another 
alternative analysis setting the outcome as stroke of any type occurring before the time of AF detection. 
 
10.1.6.3 Accounting for Unblinding 
 
In a secondary analysis, we will censor participants at the time of unblinding, when they are switched to 
open-label antithrombotic therapy per the discretion of the treating physician.  
 
10.2 INTERACTION OF ATRIAL CARDIOPATHY SEVERITY AND TREATMENT EFFECT 
 
This secondary analysis will explore the relationship between the severity of atrial cardiopathy and the 
relative efficacy of apixaban over aspirin. The objective of this analysis is two-fold. First, it will be used to 
assess the degree to which the severity of atrial cardiopathy modifies the efficacy of anticoagulation. 
Second, it will be used, regardless of whether or not apixaban is superior to aspirin in the overall trial 
population, to identify high-risk subgroups of participants with severe atrial cardiopathy who 
substantially benefit from apixaban. 
 
10.2.1 TESTS OF INTERACTION 
 
A Cox regression model will be used to assess interactions between each of the three atrial cardiopathy 
biomarkers and treatment status. The dependent variable will be recurrent stroke of any type. 
Independent variables will be a categorical variable for treatment status (apixaban versus aspirin) and 
three continuous variables representing each atrial cardiopathy biomarker. The atrial cardiopathy 
biomarkers will be appropriately transformed if necessary (e.g., log-NT-proBNP). Two-way interaction 
terms will be included between the treatment status variable and each atrial cardiopathy biomarker 
variable.  
 
The z statistics for the individual interaction hazard ratios will be used to test the significance of the 
interaction terms. Each of the tests for the three biomarker-treatment interactions will be considered 
statistically significant if its individual P value is <0.016. This conservative P value is chosen to account 
for the multiple hypothesis testing in this exploratory analysis. Given the hypothesis test for the primary 
endpoint, the tests of the three interactions will exceed an experiment-wide alpha threshold of 0.05, but 
the alpha threshold of 0.016 for each interaction test will provide a conservative approach to the 
evaluation of interactions. Given that these tests of interaction are exploratory analyses, formal power 
calculations are not provided. 
 


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10.2.2 IDENTIFICATION OF HIGH-RISK SUBGROUPS 
 
If one or more of the interactions are statistically significant, a prediction score computed from the Cox 
model will be used to predict the degree of benefit of apixaban over aspirin in a given participant based 
on the severity of atrial cardiopathy. Such a risk score will be important regardless of the main findings 
of this trial. If Aim 1 is negative (no benefit of apixaban versus aspirin in the overall trial cohort), the 
prediction score will be used to identify subgroups of patients with severe atrial cardiopathy who may 
still benefit from apixaban despite the negative findings in the overall trial population. This would inform 
follow-up studies of antithrombotic therapy in patients with cryptogenic stroke. If Aim 1 is positive 
(apixaban proves superior to aspirin in the overall trial cohort), the prediction score will be used to 
assess whether absolute stroke risk reductions in the highest-risk atrial cardiopathy subgroups are large 
enough to justify a primary prevention trial.  
 
10.2.3 ADDITIONAL EXPLORATORY MODELING 
 
Since the effect of the atrial cardiopathy biomarkers or their interactions with the treatment assignment 
may be nonlinear, analyses will also be carried out using the generalized additive model in the Cox 
regression to allow for nonlinearities in the interactions of the biomarkers with treatment status. For 
this purpose, the approach and methodology described by Royston (Royston, 2000; Royston and 
Sauerbrei, 2004) and the associated functions available in Stata (MVRS and FP2) will be used. If there is 
evidence of important nonlinearities in the biomarker-treatment interactions, the risk score derived 
from this more complex model will be evaluated and compared to the linear model described in in 
11.2.2. Even if there is no effect modification of the atrial cardiopathy variables on the efficacy of 
apixaban versus aspirin, we will evaluate these markers as predictors of stroke risk in the full sample of 
participants in whom we have measured these markers and for whom we have follow-up for stroke 
events. We will construct a prediction risk score which will also include the other prognostic variables 
defined in Section 9.5. Such a risk score will potentially be valuable for identifying subgroups of patients 
with atrial cardiopathy in whom the absolute benefit of apixaban is high enough to justify a primary 
prevention trial. 
 
10.2.4 STATISTICAL MODEL 
 
The following is the right hand side of the full Cox proportional hazards model:   
0
1
2
3
4
5
6
7
*
*
*
Tx
ECG
Echo
BNP
Tx
ECG
Tx
Echo
Tx
BNP
j
j
I
X
X
X
I
X
I
X
I
X
X











=
+
+
+
+
+
+
+
+ 


 
Where ITX is an indicator with the value of 1 if the participant is on apixaban or 0 for aspirin, XECG, ECHO, BNP 
are the continuous values of the three biomarkers, and Xj are the values of other prognostic variables. 
 
From the full model, standard backward elimination regression modeling procedures will be used to 
identify the final model. Specifically, we will first test the interaction term: 
 
H0: β5 = 0 ; H0: β6 = 0; H0: β7 = 0 
 
If it is not statistically significant at  = 0.016, these terms will be dropped from the model and the 
covariates βj will be tested in a stepwise approach. For the risk-based modeling, the fitted estimates of 
the final model will be reported given a participant’s covariates, e.g. 

,
,
,
ECG
Echo
BNP
j
X
X
X
X
, under 
apixaban and under aspirin, as well as the hazard ratio.  


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10.3 SECONDARY EFFICACY ANALYSIS 
 
10.3.1 PARAMETER DESCRIPTION 
 
The secondary efficacy outcomes are: (A) composite of recurrent ischemic stroke or systemic embolism, 
and (B) composite of recurrent stroke of any type or death from any cause. Each of these two outcomes 
will be analyzed separately using the ITT sample (Section 8.2). 
 
10.3.2 STATISTICAL HYPOTHESES 
 
The set of statistical hypotheses can be stated in terms of hazard functions as: 
H0: hapix(t)=hasp(t) 
 
versus  
HA: hapix(t) ≠ hasp(t) 
 
Where hapix(t) and hasp(t) are the hazard rates for the apixaban and aspirin groups, respectively.  
 
STATISTICAL MODEL 
 
Each of the secondary efficacy outcomes will be analyzed using the same model as described for the 
primary efficacy analysis (Section 10.1), but the status and time of events will be defined as follows: 
 
Outcome: Composite of recurrent ischemic stroke or systemic embolism 
First Event 
Status 
Time 
Recurrent ischemic stroke  
1 
Time of first ischemic stroke 
Recurrent stroke of any type  
0 
Time of first stroke of any type 
Systemic embolism 
1 
Time of first systemic embolism 
Death 
0 
Time of death 
Diagnosis of AF 
N/A (continue to follow) 
Study drug stopped 
N/A (continue to follow) 
Loss to follow-up or consent withdrawn 
0 
Last known contact  
 
Outcome: Composite of recurrent stroke of any type or death from any cause 
First Event 
Status 
Time 
Recurrent stroke of any type  
1 
Time of first stroke of any type 
Systemic embolism 
N/A (continue to follow) 
Death 
1 
Time of death 
Diagnosis of AF 
N/A (continue to follow) 
Study drug stopped 
N/A (continue to follow) 
Loss to follow-up or consent withdrawn 
0 
Last known contact  
 
10.3.3 EXPLORATORY EFFICACY ANALYSES 
 
In a tertiary analysis, we will assess the effect of apixaban on the subset of ischemic stroke comprising 
only cardioembolic or cryptogenic stroke, as determined by Causative Classification of Stroke 
determinations performed by site investigators. 
 


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10.3.4 EXPLORATORY ENDPOINTS 
 
The following exploratory endpoints will also be recorded: AF, any intracranial hemorrhage, major 
hemorrhage including any intracranial hemorrhage, symptomatic hemorrhagic transformation of an 
ischemic stroke, transient ischemic attack, myocardial infarction, minor hemorrhage, systemic 
embolism, symptomatic deep venous thrombosis, symptomatic pulmonary embolism, ischemic vascular 
death, and hemorrhagic vascular death. The endpoint of any intracranial hemorrhage will be 
subclassified as: 1) symptomatic versus asymptomatic, and 2) consisting of hemorrhagic transformation 
of the index brain infarct versus not. 
 
11 SAFETY ANALYSES 
 
11.1 SAFETY MONITORING 
 
The MSM and DSMB will receive periodic safety reports of all SAEs. The detailed guidelines for 
monitoring for safety by the MSM, and the DSMB will be provided in a separate ARCADIA Safety 
Monitoring Plan. 
 
11.2 DESCRIPTIVE SUMMARY OF EVENTS 
 
All clinical safety endpoints and SAEs will be summarized by AE code (as provided on the AE CRF) in 
terms of frequency of the event, number of participants having the event, severity, and relatedness to 
the study treatment. Clinically important adverse events include: 
• 
Symptomatic intracranial hemorrhage (including symptomatic hemorrhagic transformation of an 
ischemic stroke). 
• 
Major hemorrhage other than intracranial hemorrhage. 
• 
All-cause mortality. 
 
The proportion of participants experiencing each of these events will be provided in the closed report to 
the DSMB by treatment arm with two-sided 95% CIs and unadjusted relative risks. Based on prior 
reports, the following approximate annual rates of major safety endpoints are expected: 
 
Adverse Event 
Apixaban 
Aspirin 
Symptomatic intracranial hemorrhage 
1.5% 
1.5% 
Major hemorrhage other than intracranial hemorrhage 
4.0% 
3.0% 
All-cause mortality 
3.5% 
3.5% 
 
Log-rank tests will be utilized to assess the treatment group differences in the rates of: (1) first 
symptomatic intracranial hemorrhage; (2) first major hemorrhage other than intracranial hemorrhage; 
and (3) death from any cause.  
 
11.3 ANALYSIS OF SAFETY OUTCOMES AT TRIAL COMPLETION 
 
All safety outcome measurements are analyzed using the safety sample (Section 8.3). Sensitivity 
analyses will be conducted using the ITT population. At the end of the study, the cumulative incidences 


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of the pre-specified safety events will be compared between the two treatment groups at a two-sided 
alpha level of 0.05. 
 
11.3.1 PRIMARY SAFETY ENDPOINTS 
 
The primary safety outcomes are: (A) symptomatic intracranial hemorrhage (including symptomatic 
hemorrhagic transformation of an ischemic stroke), and (B) major hemorrhage other than intracranial 
hemorrhage.  
 
11.3.2 SECONDARY SAFETY ENDPOINT 
 
The secondary safety endpoint is all-cause mortality. 
 
11.4 ADJUDICATION OF SAFETY ENDPOINTS 
 
Although regulatory reporting of possible SAEs will be based on the MSM determination of the event, 
for the publication of the final trial results analyses will use events as determined by the outcomes 
adjudication committee or site investigator (in the case of endpoints not adjudicated).  
 
12 SUBGROUP ANALYSES  
 
In prespecified subgroup analyses, the analyses in Sections 10.1 (primary efficacy analyses) and 11 
(safety analyses) will be stratified by age (75 years versus <75 years), sex/gender, race/ethnicity, and 
weight (<70 kg versus 70 kg). In particular, subgroup analyses of previous trials of anticoagulation in 
ESUS suggest a benefit in patients 75 years of age.7 
 
13 QUALITY-OF-LIFE ANALYSES 
 
13.1 QUALITY-OF-LIFE MEASURES 
 
Participants’ quality of life will be assessed at the Day 540 visit (18 months). Study investigators will elicit 
quality-of-life data from participants or their proxies using modules from PROMIS, a validated tool for 
assessing quality-of-life in patients with disorders including stroke. The Global Health Short Form v1.1 
and the Physical Function Short Form v1.2 will be used. Missing data for quality-of-life measures will not 
be imputed. 
 
13.2 ANALYSES OF QUALITY-OF-LIFE MEASURES 
 
The scores from each PROMIS domain will be compared between treatment groups using generalized 
linear mixed models which can account for correlation between the physical and global health forms.  
 
 
 


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14 COST-EFFECTIVENESS ANALYSIS 
 
The cost-effectiveness of treatment with apixaban as compared with aspirin in patients with cryptogenic 
stroke and atrial cardiopathy will be assessed using previously published methods (Kamel, Neurology, 
2012). In brief, a Markov decision model will be created based on the wholesale cost of apixaban and 
data from the ARCADIA trial. The model will quantify the cost and quality-adjusted life expectancy 
resulting from apixaban therapy compared with aspirin. The base case population will be a patient 
cohort with the mean age of the ARCADIA cohort and a history of prior stroke. The base case will include 
the following health states: No disability (history of transient ischemic attack or ischemic stroke with full 
recovery), ischemic stroke (fatal or resulting in moderate-to-severe, mild, or no disability), intracranial 
hemorrhage (fatal or resulting in moderate-to-severe or mild disability), recurrent stroke or combined 
stroke and intracranial hemorrhage, extracranial hemorrhage, myocardial infarction, and death. Model 
inputs on the rates of these adverse events (e.g., recurrent ischemic stroke, intracranial hemorrhage, 
major hemorrhage, myocardial infarction) will be taken directly from the average annual rates of these 
events in the apixaban versus aspirin arms of the ARCADIA trial. Costs and quality-of-life estimates will 
be based on previously published data as well as quality-of-life data from ARCADIA (see Section 13 
above). The model will adopt a societal perspective and will exclude costs unrelated to the treatment 
strategy in question (apixaban versus aspirin) or other disease states besides those listed above. Quality-
adjusted life expectancy and net costs will be quantified over 20 years or until death, whichever occurs 
first. Life-years and costs will be discounted at 3% per year and reported as quality-adjusted life-years 
(QALYs) and 2023 U.S. dollars (rounded to the nearest $100). TreeAge Pro software (TreeAge Software, 
Williamstown, Massachusetts) will be used to build the model and perform all analyses. 
 
15 UPDATE OF TRIAL OPERATING PARAMETERS  
 
As a trial with time-to-event outcome, the power can be affected by aspects other than the observed 
event rate (i.e. recruitment rate leading to decreased follow-up time for participants). At the 
recommendation of the DSMB, trial design modifications to rectify this problem may be considered, 
namely: 
• 
Increased follow-up period. 
• 
Increased sample size (i.e. observed accrual rate and increased accrual duration). 
• 
Increased number of sites. 
These estimates will be made using the assumptions above (Section 7), namely: 
• 
7% annual risk of recurrent stroke of any type in aspirin-treated participants. 
• 
Clinically relevant relative risk reduction of 40% (hazard ratio of 0.6, hazard rate of 4.2%) for 
participants treated with apixaban. 
• 
3% annual rate of crossover from blinded aspirin to open-label anticoagulation due to AF 
detection. 
• 
3% annual rate of crossover from blinded apixaban to open-label antiplatelet therapy due to 
bleeding or other adverse events. 
• 
4% annual rate of loss to follow-up or death in each group. 
 
 
 


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16 CHANGE LOG 
 
Date 
Relation to 
interim or other 
analysis 
Issue 
Trigger 
Solution 
3 Jan 2018 
Changes 
preceded start 
of recruitment 
Elimination of plan 
for sample size re-
estimation 
Not logistically 
feasible 
No sample size re-
estimation 
3 Jan 2018 
Changes 
preceded start 
of recruitment 
Elimination of plan 
for revision to 
group sequential 
boundaries 
Inherent difficulty 
in accurately 
estimating 
No plan for revision 
of group sequential 
boundaries 
3 Jan 2018 
Changes 
preceded start 
of recruitment 
Randomization 
method  
Balancing variables 
felt to be arbitrary 
Randomization will 
only control the 
maximum tolerated 
imbalance within 
each RCC 
9 Nov 2018 
Changes 
preceded first 
interim analysis 
Typographical 
error in Section 
7.1 
Loss-to-follow-
up/mortality rate 
incorrectly written 
as 4% 
Corrected to 5% 
31 Mar 2021 
Changes 
preceded first 
interim analysis 
Safety-analysis 
sample  
Protocol change 
Safety-analysis 
sample changed to 
include safety 
events from 
randomization 
through 30 days 
after permanent 
study drug 
discontinuation 
31 Mar 2021 
Changes 
preceded first 
interim analysis 
Subgroup analysis 
plan 
Recent preliminary 
data that efficacy of 
aspirin may vary by 
weight 
Subgroup analysis 
by weight added 
31 Mar 2021 
Changes 
preceded first 
interim analysis 
Miscellaneous 
Protocol change 
Several minor edits 
to maintain 
consistency with 
protocol 
29 Oct 2021 
Changes 
preceded first 
interim analysis 
Miscellaneous 
Clarifications ahead 
of interim analysis 
Several minor edits 
to maintain 
consistency with 
Manual of 
Procedures; clarified 
that log-log plots 
will be used to 
examine 


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proportional 
hazards assumption 
in secondary Cox 
models; added 
additional 
secondary analysis 
in section 10.1.6.2 
15 Feb 2023 
Changes 
preceded final 
analysis 
Subgroup analyses 
plan 
Recent preliminary 
data that efficacy of 
apixaban in ESUS 
may vary by age 
Subgroup analysis 
by age added; also 
clarified patient 
accountability 
flowchart and fixed 
typographical 
errors, including 
inadvertent 
holdover of section 
about adjusting for 
site effects in 
primary analysis 
 
17 REFERENCES 
 
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Longstreth WT, Jr., Kronmal RA, Thompson JL, Christenson RH, Levine SR, Gross R, Brey RL, 
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2. 
Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S, Flaker G, Avezum A, Hohnloser 
SH, Diaz R, et al. Apixaban in Patients with Atrial Fibrillation. N Engl J Med. 2011;364:806-817. 
3. 
Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, 
Weitz JI, Lewis BS, Parkhomenko A, et al. Comparison of the Efficacy and Safety of New Oral 
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4. 
Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, 
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Med. 2011;365:981-992. 
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6. 
Little RJ, D'Agostino R, Cohen ML, Dickersin K, Emerson SS, Farrar JT, Frangakis C, Hogan JW, 
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Diener H-C, Sacco RL, Easton JD, Granger CB, Bar M, Bernstein RA, Brainin M, Brueckmann M, 
Cronin L, Donnan G, et al. Antithrombotic Treatment of Embolic Stroke of Undetermined Source. 
Stroke. 2020;51:1758-1765.