Stroke AF - Rate of Atrial Fibrillation Through 12 Months in Patients With Recent Ischemic Stroke of Presumed Known Origin
Phase: NA
Conditions: Stroke, Acute
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

 
 
Clinical Investigation Plan Title 
Stroke AF 
Clinical Investigation Plan Identifier 
Stroke AF 
Study Product 
Reveal LINQ™ Insertable Cardiac Monitor 
ClinicalTrials.gov Identifier 
NCT02700945 
Sponsor 
Medtronic 
8200 Coral Sea St NE 
Mounds View, MN U.S.A. 55112 
Document Title 
Stroke AF Clinical Investigation Plan  
Document Version (Date) 
4.0 (18-DEC-2018) 
 

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Clinical Investigation Plan 
 
Clinical Investigation Plan/Study Title  
 
Stroke AF 
 
 
Study Product Name 
 
Reveal LINQ™ Insertable Cardiac Monitor 
 
 
Sponsor/Local Sponsor 
 
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
1 (800) 328-2518 
 
 
Document Version 
 
4.0  
18 December 2018 
 
 
 
Confidentiality Statement 
The information contained in this document is confidential and the proprietary property of 
Medtronic. Any distribution, copying, or disclosure without the prior written authorization of 
Medtronic is strictly prohibited. Persons to whom the information is disclosed must know that it is 
confidential and that it may not be further disclosed by them. 
 
 
 
 

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Table of Contents  
 
Table of Contents ...................................................................................................................... 2 
Listing of Tables ........................................................................................................................ 6 
1. 
Glossary .............................................................................................................................. 7 
2. 
Synopsis ........................................................................................................................... 10 
3. 
Introduction ..................................................................................................................... 14 
3.1. Background ........................................................................................................................ 14 
3.2. Purpose .............................................................................................................................. 16 
4. 
Objectives and Endpoints ................................................................................................. 16 
4.1. Objectives .......................................................................................................................... 16 
4.1.1. 
Primary Objective(s) .............................................................................................................. 16 
4.1.2. 
Secondary Objective(s) .......................................................................................................... 17 
5. 
Study Design .................................................................................................................... 17 
5.1. Study Design ...................................................................................................................... 17 
5.1.1. 
Minimization of Bias .............................................................................................................. 17 
5.2. Duration ............................................................................................................................. 18 
5.3. Rationale ............................................................................................................................ 18 
6. 
Product Description.......................................................................................................... 19 
6.1. General .............................................................................................................................. 19 
6.2. Reveal LINQ System ............................................................................................................ 19 
6.3. Intended Population ............................................................................................................ 21 
6.4. Packaging ........................................................................................................................... 21 
6.5. Equipment .......................................................................................................................... 21 
6.6. Product Use ........................................................................................................................ 22 
6.7. Product Training Requirements ............................................................................................. 22 
6.7.1. 
Investigator / Investigation Site Selection ............................................................................ 22 
6.7.2. 
Site Activation ....................................................................................................................... 22 
6.8. Product Storage .................................................................................................................. 23 
6.9. Product Return .................................................................................................................... 23 

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7. 
Selection of Subjects ........................................................................................................ 23 
7.1. Study Population ................................................................................................................. 23 
7.2. Subject Enrollment .............................................................................................................. 23 
7.3. Inclusion Criteria ................................................................................................................. 24 
7.4. Exclusion Criteria................................................................................................................. 24 
8. 
Study Procedures ............................................................................................................. 25 
8.1. Schedule of Events .............................................................................................................. 25 
8.2. Subject Consent .................................................................................................................. 27 
8.3. Randomization and Treatment Assignment ............................................................................ 29 
8.4. Procedures and Data Collection ............................................................................................ 29 
8.4.1. 
Baseline ................................................................................................................................. 29 
8.4.2. 
Reveal LINQ ICM Insertion .................................................................................................... 30 
8.4.3. 
Scheduled Follow-up Visits/CareLink Transmissions ............................................................ 31 
8.4.3.1. 
Follow-up Visits ................................................................................................................. 32 
8.4.3.2. 
Follow-up Visits / Remote CareLink Transmissions ........................................................... 33 
8.4.4. 
Unscheduled Follow-up Visits ............................................................................................... 33 
8.4.5. 
Stroke/TIA Recurrence .......................................................................................................... 33 
8.4.6. 
System Modification ............................................................................................................. 33 
8.4.7. 
Study Exit ............................................................................................................................... 34 
8.5. Assessment of Safety .......................................................................................................... 35 
8.6. Recording Data ................................................................................................................... 35 
8.7. Deviation Handling .............................................................................................................. 36 
8.8. Subject Withdrawal or Discontinuation .................................................................................. 37 
9. 
Risks and Benefits ............................................................................................................ 37 
9.1. Potential Risks .................................................................................................................... 37 
9.2. Potential Benefits ................................................................................................................ 37 
9.3. Risk-Benefit Rationale .......................................................................................................... 37 
10. 
Adverse Events and Device Deficiencies ....................................................................... 38 
10.1. 
Adverse Event Assessment ............................................................................................. 38 
10.1.1. 
Adverse Events .................................................................................................................. 38 
10.1.2. 
Device Deficiencies ............................................................................................................ 39 

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10.1.3. 
Processing Updates and Resolution .................................................................................. 39 
10.2. 
Definitions/Classifications ............................................................................................... 39 
10.2.1. 
Adverse Event and Device Deficiency Definitions ............................................................. 39 
10.2.2. 
Adverse Events and Deficiency Classification .................................................................... 43 
10.3. 
Reporting of Adverse Events ........................................................................................... 44 
10.3.1. 
Subject Death .................................................................................................................... 45 
10.3.1.1. 
Death Data Collection .................................................................................................... 45 
10.3.1.2. 
Death Classification and Reporting ................................................................................ 47 
10.4. 
Product Complaint Reporting .......................................................................................... 47 
11. 
Data Review Committees .............................................................................................. 48 
11.1. 
Clinical Events Committee (CEC) Review .......................................................................... 48 
12. 
Statistical Design and Methods ..................................................................................... 49 
12.1. 
Primary Objective .......................................................................................................... 49 
i. 
Hypothesis .................................................................................................................................... 50 
ii. 
Endpoint Definition ................................................................................................................... 50 
iii. 
Performance Requirements ...................................................................................................... 50 
iv. 
Rationale for Performance Criteria ........................................................................................... 50 
v. 
Sample Size Determination ....................................................................................................... 51 
vi. 
Analysis Methods ...................................................................................................................... 51 
vii. 
Determination of Patients/Data for Analysis ............................................................................ 51 
12.2. 
Secondary Objective ...................................................................................................... 52 
i. 
Hypothesis .................................................................................................................................... 52 
ii. 
Endpoint Definition ................................................................................................................... 52 
iii. 
Performance Requirements ...................................................................................................... 52 
iv. 
Sample Size Determination ....................................................................................................... 52 
v. 
Analysis Methods ...................................................................................................................... 53 
vi. 
Determination of Patients/Data for Analysis ............................................................................ 53 
13. 
Ethics ............................................................................................................................. 53 
13.1. 
Statement(s) of Compliance ........................................................................................... 53 
14. 
Study Administration ..................................................................................................... 54 

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14.1. 
Monitoring .................................................................................................................... 54 
14.1.1. 
Monitoring Visits ......................................................................................................... 54 
14.2. 
Data Management ......................................................................................................... 54 
14.3. 
Direct Access to Source Data/Documents ......................................................................... 55 
14.4. 
Confidentiality ............................................................................................................... 55 
14.5. 
Liability ......................................................................................................................... 55 
14.6. 
CIP Amendments ........................................................................................................... 55 
14.7. 
Record Retention ........................................................................................................... 56 
14.7.1. 
Investigator Records .......................................................................................................... 56 
14.7.2. 
Investigator Reports .......................................................................................................... 56 
14.7.3. 
Sponsor Records ................................................................................................................ 57 
14.7.4. 
Sponsor Reports ................................................................................................................ 58 
14.8. 
Publication and Use of Information .................................................................................. 58 
14.8.1. 
Publication Committee ...................................................................................................... 58 
14.8.2. 
Management of Primary, Secondary and Ancillary Publications ...................................... 59 
14.8.3. 
Criteria for Determining Authorship ................................................................................. 59 
14.8.4. 
Transparency ..................................................................................................................... 60 
14.9. 
Suspension or Early Termination ..................................................................................... 60 
14.9.1. 
Planned Study Closure ....................................................................................................... 60 
14.9.2. 
Early Termination or Suspension ....................................................................................... 60 
14.9.2.1. 
Study-wide Termination or Suspension ......................................................................... 61 
14.9.2.2. 
Investigator/Site Termination or Suspension ................................................................ 61 
14.9.3. 
Procedures for Termination or Suspension ....................................................................... 61 
14.9.3.1. 
Medtronic-Initiated and Regulatory Authority-Initiated ............................................... 61 
14.9.3.2. 
Investigator-Initiated ..................................................................................................... 62 
14.9.3.3. 
Ethics Committee-Initiated ............................................................................................ 62 
15. 
References ..................................................................................................................... 63 
16. 
Version History .............................................................................................................. 65 
 
 
 

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Listing of Tables 
Table 1: Reveal LINQ System Component Information 
21 
Table 2: Data Collection and Study Procedures 
26 
Table 3: Reveal LINQ ICM Programming 
31 
Table 4: Follow-up Visit / CareLink Transmission Schedule 
32 
Table 5: Recommended Programming Parameters for Medtronic IPG, ICD or CRT Devices 
34 
Table 6: Adverse Event Definitions 
40 
Table 7: Adverse Event Classification Responsibilities 
44 
Table 8: AE Reporting Requirements 
45 
Table 9: Subject Death Classification 
47 
Table 10: Investigator Reports per Medtronic Requirements 
57 
Table 11: Sponsor Reports 
58 
 
 
 

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1. Glossary 
Term 
Definition 
Adverse Event (AE) 
(Adapted from ISO 14155:2011, 3.2) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, 
users or other persons, whether or not related to the investigational 
medical device 
NOTE 1: This definition includes events related to the investigational 
medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
Adverse Device Effect (ADE) 
(ISO 14155:2011, 3.1) 
Adverse event related to the use of an investigational medical device 
NOTE 1: This definition includes adverse events resulting from insufficient 
or inadequate instructions for use, deployment, implantation, installation, 
or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from an error use or 
from intentional misuse of the investigational medical device.  
American Heart Association (AHA) 
A non-profit organization in the United States that fosters appropriate 
cardiac care in an effort to reduce disability and deaths caused by 
cardiovascular disease and stroke. 
Antiplatelet (AP) 
Antiplatelet agents decrease platelet aggregation (clumping together) and 
inhibit thrombus formation. 
Atrial Fibrillation (AF) 
Atrial fibrillation (also called AFib or AF) is a quivering or irregular heartbeat 
(arrhythmia) that can lead to blood clots, stroke, heart failure and other 
heart-related complication.  
Cardiac Death 
A death directly related to the electrical or mechanical dysfunction of the 
heart. 
Cardiac Resynchronization Therapy (CRT) 
CRT is a clinically proven treatment option for some individuals with heart 
failure. A CRT device sends small electrical impulses to both lower 
chambers of the heart to help them beat together in a more synchronized 
pattern. This may improve the heart’s ability to pump blood and oxygen to 
your body.  
Cardiovascular Related 
An adverse event relating to the heart and the blood vessels or the 
circulation. 
CHADS Score 
Clinical prediction rules for estimating the risk of stroke in patients with 
non-rheumatic atrial fibrillation. A high score corresponds to a greater risk 
of stroke, while a low score corresponds to a lower risk of stroke.  
Carotid Endarterectomy (CEA) 
A surgical procedure used to reduce the risk of stroke by correcting stenosis 
in the common carotid artery or internal carotid artery. Endarterectomy is 
the removal of material on the inside of an artery.  
Clinical Event Committee (CEC) 
An independent committee of experts not participating in the clinical study 
that provides adjudication of study specific endpoints and/or events 
utilizing study-specific or consensus definitions available in the field. 
Clinical Investigation Plan (CIP) 
The present document describing the study protocol. 
Complication  
An adverse event that results in death, involves any termination of 
significant device function, or requires invasive intervention. 
Non-invasive: when applied to a diagnostic device or procedure, means one 
that does not by design or intention: 

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Term 
Definition 
• 
Penetrate or pierce the skin or mucous membranes of 
the body, the ocular cavity or the urethra or 
• 
Enter the ear beyond the external auditory canal, the 
nose beyond the nares, the mouth beyond the 
pharynx, the anal canal beyond the rectum, or the 
vagina beyond the cervical os 
For purposes of this part, blood sampling that involves simple venipuncture 
is considered non-invasive, and the use of surplus samples of body fluid or 
tissue that are left over from samples taken for non-investigational 
purposes is also considered non-invasive. 
Coronary Artery Bypass Graft Surgery (CABG) 
Coronary artery bypass surgery, also known as coronary artery bypass graft 
surgery, and colloquially heart bypass or bypass surgery, is a surgical 
procedure to restore normal blood flow to an obstructed coronary artery.  
Cryptogenic Stroke 
A stroke without an obvious explanation (of unknown origin). 
Device Deficiency (DD) 
(ISO 14155:2011, 3.15) 
 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  
NOTE: Device deficiencies include malfunctions, use errors and inadequate 
labeling  
Electronic Case Report Forms (eCRF) 
Forms where the clinical data are collected. eCRF is the electronic version of 
case report forms. 
Ethical Committee / Institutional Review Board 
(EC / IRB) 
Any board, committee, or other group formally designated by an institution 
to review, to approve the initiation of, and to conduct periodic review of, 
biomedical research involving human subjects. The primary purpose of such 
review is to assure the protection of the rights and welfare of the human 
subjects. 
Hospitalization 
A therapeutic inpatient hospitalization (excludes outpatient and emergency 
room visits) lasting greater than or equal to 24 hours. 
Insertable Cardiac Defibrillator (ICD) 
A device implantable inside the body, able to perform cardioversion, 
defibrillation, and pacing of the heart. 
Insertable Cardiac Monitor (ICM) 
An implantable loop recorder, also known as an insertable cardiac monitor, 
is a small device that is implanted just under the skin of the chest for long 
term cardiac monitoring. 
Ischemic Stroke (IS) 
Ischemic stroke occurs as a result of an obstruction within a blood vessel 
supplying blood to the brain. 
Non-cardiac Death 
A death not classified as a cardiac death 
Non-sudden Cardiac Death 
All cardiac deaths that are not classified as sudden deaths, including all 
cardiac deaths of hospitalized subjects on inotropic support. 
Observation 
Any adverse event that is not a complication. 
Note 1: Only system or procedure related AEs will be classified as 
Complication or Observation. 
Oral anticoagulation (OAC) 
Anticoagulant agents prevent or reduce coagulation of blood.  
Remote Data Capture (RDC) 
An interface that allows site users at sites to enter data directly into the 
study database via a web interface. RDC is an example of Electronic Data 
Capture method or EDC. 
Reveal LINQ ICM Procedure Related 
 
An adverse event that occurs that is directly related to the implantation or 
modification of the Reveal LINQ system. 

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Term 
Definition 
Reveal LINQ ICM System Related 
 
An adverse event that results from the presence or performance (intended 
or otherwise) of any component of the system (including: Reveal LINQ ICM, 
Programmer, Patient Assistant, and MyCareLink Patient Monitor). 
Serious Adverse Event (SAE) 
(Adapted from ISO 14155:2011, 3.37) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either 
resulted in 
1. a life-threatening illness or injury, or 
2. a permanent impairment of a body structure or a 
body function, or 
3. in-patient or prolonged hospitalization, or 
4. medical or surgical intervention to prevent life-
threatening illness or injury or permanent 
impairment to a body structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth 
defect 
NOTE 1: Planned hospitalization for a pre-existing condition, or a procedure 
required by the CIP, without serious deterioration in health, is not 
considered a serious adverse event. 
 
Stroke 
 
Hemorrhagic or Ischemic stroke with rapid onset of a focal or global 
neurological deficit or other neurological signs/symptoms consistent with 
stroke. 
Stroke Diagnosis 
Diagnosis will be determined by the site’s neurologist clinical evaluation 
and include clinical signs and symptoms consistent with focal or global 
neurological deficit in addition to one or more of the following: 
• 
Neuroimaging procedure (CT, MR, or cerebral angiogram) 
• 
Lumbar Puncture (i.e. subarachnoid hemorrhage) 
Sudden Cardiac Death (SCD) 
Natural death due to cardiac causes, indicated by abrupt loss of 
consciousness within one hour of the onset of acute symptoms; preexisting 
heart disease may have been known to be present, but the time and mode 
of death are unexpected. If time of onset cannot be determined, SCD will 
alternatively be defined as any unexpected cardiac death occurring out of 
the hospital or in the emergency room as dead on arrival. 
Transient Ischemic Attack (TIA) 
New focal neurological deficit with rapid symptom resolution (usually 1 – 2 
hours), always within 24 hours without tissue injury (based on 
neuroimaging). 
Unavoidable Adverse Event 
An Adverse Event inherent to a surgical procedure that is expected to occur 
in all subjects for a projected duration according to the Investigator’s 
opinion, including, but not limited to:  

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Term 
Definition 
Event Description 
Timeframe 
(hours) from the 
Surgical 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Pocket site / Incisional pain 
72 
Mild to moderate bruising / ecchymosis 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Shoulder pain/discomfort/stiffness related to 
shoulder immobilization during procedure 
72 
Unknown 
There is insufficient or inadequate information to classify the death. 
2. Synopsis 
Title 
Stroke AF 
Clinical Study Type 
Post Market 
Product Name 
Medtronic Reveal LINQ™ System 
Sponsor  
Medtronic, Inc. 
8200 Coral Sea Street NE 
Mounds View, MN  55112 
U.S.A. 
Indication under 
investigation  
The Reveal LINQ system is being used in accordance with the indications for 
the device. 
Investigation Purpose 
The purpose of the Stroke AF study is to compare the incidence of atrial 
fibrillation (AF) through 12 months between continuous cardiac rhythm 
monitoring with the Reveal LINQ™ Insertable Cardiac Monitor (ICM) 
(continuous monitoring arm) and standard of care (SoC) medical treatment 
(control arm) in subjects with a recent ischemic stroke of presumed known 
origin.  
Product Status 
The Stroke AF study will be conducted using the components of the 
Medtronic Reveal LINQ system, as described in the below. 

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Model Number  
Component 
Investigational or 
Market-released 
LNQ11 or other 
commercial model 
Reveal LINQ Insertable Cardiac 
Monitor  
Market- released 
2090 or other 
commercial model 
Medtronic Programmer 
Market- released 
960000 or other 
commercial model 
Patient Assistant  
Market- released 
24950 or other 
commercial model 
MyCareLink Patient Monitor  
Market- released 
Primary Objective 
To compare the incidence rate of AF through 12 months between the 
continuous monitoring arm and the control arm in subjects with a recent 
ischemic stroke of presumed known origin. 
Secondary Objective 
To compare the incidence rates of AF through the duration of study follow-
up between study arms. 
Ancillary Objectives 
1.  
Study Design 
Stroke AF is a prospective, multi-site, randomized, controlled, non-blinded, 
post-market study. The Stroke AF study will compare the incidence rate of AF 
through 12 months between the continuous monitoring arm and the control 
arm in subjects with a recent ischemic stroke of presumed known origin. 
Randomization 
Once enrolled, subjects will be randomized 1:1 (continuous monitoring vs 
control). 
Treatment 
Subjects randomized to the continuous monitoring arm will have a Reveal 
LINQ ICM inserted within 10 days of the qualifying stroke and undergo 
continuous remote monitoring. Subjects randomized to the control arm will 
be followed per site specific standard of care. 
Sample Size 
The study will be conducted at approximately 40 study sites in the United 
States (U.S.). Approximately 496 subjects may be enrolled in the study. It is 
anticipated that it will take approximately 42 months to complete study 
enrollments. Subjects will be followed for 3 years, until end of device life or 
until official study closure, whichever occurs first. 
Inclusion Criteria 
• 
Subject has had an ischemic stroke believed to be due to small vessel 
disease, large vessel cervical or intracranial atherosclerosis within the 
past 10 days 
• 
Subject is willing and able to undergo study requirements and expected 
to be geographically stable during study follow-up 
• 
Subject is 60 years of age or older, or age 50 to 59 years plus a 
documented medical history of at least one of the following additional 
risk factors for stroke: 
o Congestive heart failure 
o Hypertension (Systolic Blood Pressure >140) 
o Diabetes Mellitus 

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o Prior Stroke (>90 days ago, other than study qualifying index event) 
o Vascular disease (e.g. coronary artery disease, heart attack, 
peripheral artery disease and complex aortic plaque) 
Exclusion Criteria 
• 
Subject has had a cryptogenic stroke 
• 
Subject has had a cardioembolic stroke 
• 
Subject has untreated hyperthyroidism 
• 
Subject has had a recent myocardial infarction <1 month of stroke 
• 
Subject has had a recent cardiac surgery (e.g. coronary artery bypass 
surgery (CABG)) <1 month of stroke 
• 
Subject has a mechanical heart valve 
• 
Subject has valvular disease requiring immediate surgical intervention 
• 
Subject has documented prior history of atrial fibrillation or atrial flutter 
• 
Subject has permanent indication for oral anticoagulation  
• 
Subject has permanent contraindication to oral anticoagulation such that 
detection of AF would not change medical management, based on 
enrolling investigators judgment 
• 
Subject is enrolled in a concurrent study that may confound the results 
of this study. Co-enrollment in any concurrent clinical study (including 
registries) requires approval of the study manager or designee. 
• 
Subject’s life expectancy is less than 1 year 
• 
Subject is pregnant 
• 
Subject has or is indicated for implant with a pacemaker, ICD, CRT, or an 
implantable hemodynamic monitor 
• 
Subject with a medical condition that precludes the patient from 
participation in the opinion of the investigator 
Safety Assessments 
All Reveal LINQ ICM system/component-related, Reveal LINQ ICM procedure 
related, cardiovascular related AEs, and all serious adverse events leading to 
death will be collected throughout the study duration, starting at the time of 
signing the consent form. 

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Clinical Procedures 
Study Procedure 
Baseline 
LINQ 
Insertion* 
1, 6 and 12 
Month 
Follow-up 
3, 9 Months 
Remote 
Follow-up* 
Recurring 6 
Month 
Follow-up 
(through 
study exit) 
Unscheduled 
Follow-up 
Stroke/TIA 
Recurrence 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Demographics, Medical History 
X 
 
 
 
 
 
 
Cardiovascular Medications 
X 
 
X 
 
X 
 
 
TOAST1 
X 
 
 
 
 
 
X 
NIH Stroke Scale 
X 
 
 
 
 
 
X 
Modified Rankin Scale 
X 
 
X 
 
 
 
X 
EQ-5D 
X 
 
X 
 
 
 
 
Blood Draw 
X 
(if available) 
 
 
 
 
 
 
System & Procedure Information* 
 
X* 
 
 
 
 
 
Full Reveal LINQ Interrogation or 
CareLink Transmission* 
 
X* 
X* 
X* 
X* 
X* 
(if available) 
X* 
(if available) 
AF Assessment 
 
 
X 
 
X 
X 
X 
Symptom Assessment 
 
 
X 
 
X 
X 
 
Stroke/TIA Assessment 
 
 
X 
 
X 
X 
 
Adverse Events 
 
 
 
 
As they occur 
 
Device Deficiencies 
System Modifications* 
Crossover 
Study Deviations 
Subject Exits 
Death 
1Trial of Org 10172 in Acute Stroke Treatment 
* Subjects with a Reveal LINQ ICM 
 

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3. Introduction 
3.1. Background  
Stroke is a devastating disease. In the United States (U.S.) more than 780,000 people experience a new 
or recurrent stroke each year; approximately 600,000 of these are first attacks and 180,000 are 
recurrent attacks. About 20% of patients die within the first year after having a stroke and another 20% 
are bound to a nursing home for the rest of their life. Furthermore, stroke is the fifth leading cause of 
death in the U.S. (when considered separately from other cardiovascular diseases) and the leading cause 
of serious long-term disability in the U.S. (Dariush Mozaffarian, 2015). 
Of all strokes, 87% are ischemic (Dariush Mozaffarian, 2015), which occur as a result of decreased or 
insufficient blood flow to the brain. Patients with ischemic stroke (IS) are often treated with 
antithrombotic therapy. For most patients with IS, the mainstay of treatment is anti-platelet (AP) 
therapy with aspirin, clopidogrel, or aspirin+extended release dipyridamole. However, patients with IS 
who have been diagnosed with atrial fibrillation (AF) are normally treated with long-term oral 
anticoagulation (OAC), per recommendations within the AHA/ASA 2014 guidelines. OAC is dramatically 
more effective at preventing recurrent IS than AP therapy in patients with AF (Owen, 2009). In contrast, 
for patients without AF (or other rare cardiac sources of embolism), OAC has not been shown more 
effective than AP therapy. Therefore, detection of AF after IS is crucial, as it results in an important 
change in the administration of antithrombotic therapy from AP to OAC, thereby reducing the risk of 
recurrent stroke. 
Episodes of AF are often asymptomatic, which makes detection of AF based on patient’s symptoms 
unreliable (L. M. Christensen, 2014) (S. Adam Strickberger, 2005).  Additionally, due to its episodic 
nature, AF is difficult to detect via intermittent monitoring techniques (Paul D. Ziegler, 2009). While 
AHA/ASA guidelines recommend cardiac monitoring of patients for up to 30 days after stroke, the 
optimum duration of monitoring is not known. It has generally been shown that longer durations of 
cardiac monitoring result in higher rates of AF detection after stroke. The advent of insertable cardiac 
monitors (ICM) allows continuous monitoring to detect infrequent episodes of AF for up to 3 years. 
Longer monitoring periods may be necessary to detect infrequent but clinically important paroxysms of 
AF (William C. Choe, 2015). 
Studies to date suggest that AF is present in ~4-25% of patients with a recent IS of presumed known 
origin, but this has only been examined using short term (up to 3 weeks) or intermittent monitoring. 
Rabinstein et al (2013) compared the rate of detection of AF over a three-week period of cardiac 
monitoring in 66 patients with cryptogenic stroke to an equal number of patients with stroke of known 
origin. Overall, there was no difference in detection rate between cryptogenic stroke and stroke of 
known origin (25% vs 14%, respectively, P=0.12). However, in patients over 65 years, the rates of 
detection were 27% and 25% respectively, whereas in younger patients, more AF was found in those 

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with cryptogenic stroke (21% vs 0%, p=0.03). Similarly, Sposato et al (2012) found that continuous 
cardiac monitoring during hospitalization found newly diagnosed AF in a substantial number of patients 
with non-cryptogenic stroke. Other studies have shown that the presence of atherosclerotic risk factors 
as denoted by the CHADS2 score predicts the risk of newly detected AF after IS, regardless of stroke 
mechanism.  Lastly, Grond et al (2013) found that of a total of 1135 patients enrolled post stroke or TIA, 
unknown AF was detected in 49 patients (4.3% by 72-hour ECG). In summary, these data suggest that AF 
is present in patients with a recent IS of presumed known origin, but this has only been examined using 
short term (up to 3 weeks) or intermittent monitoring. To date, there is yet to be a published study that 
has used an ICM for AF detection specifically in patients with stroke of presumed known origin. 
The occurrence of a first stroke dramatically increases the risk of a second stroke.  About 25% of all IS 
occur in patients who have had a prior IS (recurrent IS) (Ralph L. Sacco, et al., 2006). Recurrent ischemic 
strokes are generally more severe than first strokes, and recurrent strokes are more costly, disabling, 
and fatal. Additionally, recurrent stroke is the most likely major adverse event after a first IS. Therefore, 
in patients with a first stroke, prevention of recurrence (secondary prevention) is the primary goal of 
therapy.  
Secondary prevention of IS rests on determining and addressing the risk factors for future stroke. For 
example, patients with stroke ipsilateral to carotid stenosis are treated with carotid endarterectomy 
(CEA), which has been proven to reduce the risk of recurrence. Although strokes are classified by 
mechanism, definitive identification of the cause of stroke is often difficult, and many patients have 
multiple potential causes or have no clear cause. It is therefore not always possible to tailor stroke 
prevention to the cause of the prior stroke. Rather, preventive therapies are usually directed at 
identifiable causes of future stroke. Importantly, the effectiveness of a preventive therapy does not 
prove that the target of that therapy caused the index stroke. Rather, it proves that the intervention 
addressed a risk factor for future stroke. 
Both persistent AF and paroxysmal AF are potent predictors of first and recurrent stroke. More than 
75,000 cases of stroke per year are attributed to AF (Ralph L. Sacco, et al., 2006). AF is a major risk factor 
in this patient population, and it often goes undetected due to its episodic and asymptomatic nature. 
While guidelines do recommend cardiac monitoring of patients after stroke, the optimum duration of 
monitoring in all patients with stroke is not known. For most patients standard of care appears to 
involve monitoring these patients for 24 hours with a Holter monitor. It has generally been shown that 
longer durations of cardiac monitoring have better rates of detection of AF after stroke. The advent of 
insertable cardiac monitors (ICM) allows detection of infrequent episodes of AF for up to 3 years.  
This clinical study was designed to address known gaps in the clinical evidence related to the incidence 
of AF in patients with an IS. ISs are generally classified according to their presumed cause. However, 
there is a subset of patients who have suffered stroke for which a cause cannot be determined. These 
patients are said to have suffered a cryptogenic stroke, or an embolic stroke of an unknown source 

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(ESUS). The CRYSTAL AF study demonstrated that continuous monitoring via ICM is superior to standard 
of care for detecting AF after cryptogenic stroke. At 6 months, AF had been detected at a rate of 8.9% in 
the ICM group vs 1.4% of patients in the control group. By 12 months, AF had been detected at a rate of 
12.4% in the ICM group vs 2.0% in the control group (Tommaso Sanna, 2014). While the CRYSTAL AF 
data is promising for patients with a cryptogenic stroke, it remains unclear what the long-term rate of AF 
is in the IS patient population with a presumed known origin. Many post IS patients have risk factors for 
AF, regardless of the cause of their stroke. Newly detected episodes of AF were found in 28% of patients 
with previous thromboembolic events in the TRENDS study (Paul D. Ziegler, et al., 2010) and most of 
these episodes would not have been detected by standard intermittent monitoring.  
3.2. Purpose 
Medtronic is sponsoring the Stroke AF study. This is a prospective, multi-site, randomized, controlled, 
non-blinded, post-market study. 
The purpose of the Stroke AF study is to compare the incidence rate of AF through 12 months between 
continuous cardiac rhythm monitoring and standard of care in subjects with a recent IS of presumed 
known origin (the cause of the stroke is not unknown), specifically due to small vessel disease, large 
vessel cervical or intracranial atherosclerosis. Upon enrollment subjects will be randomized 1:1 to 
continuous monitoring arm vs control arm. Subjects randomized to the continuous monitoring arm will 
have a Reveal LINQ™ ICM inserted within 10 days of the index event and undergo continuous 
monitoring. Subjects randomized to the control arm will be followed per site specific standard of care. 
Detection of AF after IS is crucial, as it results in an important change in antithrombotic therapy from AP 
to OAC, thereby reducing the risk of recurrent stroke in these patients.  
This study supports introducing Reveal LINQ ICM into the care pathway in subjects with an ischemic 
stroke of presumed known origin. 
4. Objectives and Endpoints 
4.1. Objectives 
The Stroke AF study will compare the incidence rate of AF through 12 months between continuous 
monitoring and standard of care in subjects with a recent ischemic stroke of presumed known origin. 
Subjects will be randomized 1:1 to the continuous monitoring arm or control arm. 
4.1.1. 
Primary Objective(s) 
To compare the incidence rate of AF through 12 months between the continuous monitoring arm vs 
control arm in subjects with a recent ischemic stroke of presumed known origin. 

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4.1.2. 
Secondary Objective(s)  
To compare the incidence rates of AF through the duration of study follow-up between study arms. 
5. Study Design  
5.1. Study Design 
Stroke AF is a prospective, multi-site, randomized, controlled, non-blinded, post-market study. The 
Stroke AF study will compare the incidence rate of AF through 12 months between the continuous 
monitoring arm and the control arm in subjects with a recent ischemic stroke of presumed known origin. 
Once enrolled, subjects will be randomized 1:1 (continuous monitoring vs control). Subjects randomized 
to the continuous monitoring arm will have a Reveal LINQ ICM inserted within 10 days of the qualifying 
stroke and undergo continuous remote monitoring. Subjects randomized to the control arm will be 
followed per site specific standard of care. 
The study is expected to be conducted at approximately 40 sites located in the United States (U.S.).  
It is estimated that approximately 496 subjects will be enrolled in the study. Assuming 2% attrition from 
enrollment to randomization, approximately 486 subjects will have randomized. A total of 23 first 
documented AF events within 12 months of randomization are required for the study to test the primary 
objective. AF will be defined as an AF event lasting more than 30 seconds and adjudicated by the 
endpoint adjudication committee. The analysis of the primary objective will occur after all enrolled 
subjects have completed 12 months of follow-up. Approximately 248 devices may be used in the study. 
Based on previous studies of this scope and magnitude, it is estimated that sites may identify and enroll 
on average one eligible subject per month. 
To ensure a widespread distribution of data and minimize site bias in study results, the maximum 
number of subjects who may be enrolled at a single site is 50 subjects. Sites that enroll faster than 
others will be allowed to do so in order to maintain an adequate overall study enrollment rate. In 
addition, to ensure a robust dataset is available for subgroup analysis, a maximum of 50% 
(approximately248) subjects with lacunar stroke (i.e., small vessel disease) may be enrolled. Medtronic 
will notify study sites when enrollment of lacunar stroke subjects is no longer allowed, if applicable. 
5.1.1. 
Minimization of Bias 
Selection of subjects, treatment of subjects, and evaluation of study data are potential sources of bias. 
Methods incorporated in the study design to minimize potential bias include (but are not limited to): 
• 
Subjects will be screened to confirm eligibility for enrollment with defined inclusion/exclusion 
criteria prior to enrollment. 

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• 
Subjects will be randomized 1:1 to the continuous monitoring arm vs control arm  
• 
Demographics and medical history will be collected at baseline in order to later assess possible 
characteristics that may influence endpoints.  
• 
To ensure a widespread distribution of data from study sites, no more than 10% of total 
expected enrollments (50 subjects) may come from a single site. 
• 
It is recommended that all patients at an investigational site with a recent ischemic stroke of 
presumed known origin be screened for the study. 
• 
All study site and Medtronic personnel will be trained using standardized training materials. 
• 
Regular monitoring visits will be conducted to verify adherence to the Clinical Investigation Plan 
and source data. 
• 
An independent clinical events committee (CEC) will be utilized to regularly review and 
adjudicate reported adverse events and recurrent stroke/TIAs. 
• 
An independent committee will adjudicate AF episodes. The committee will be comprised of 
individuals experienced with identifying AF will review the device EGM records to ensure AF was 
appropriately identified.  
 
In summary, potential sources of bias that may be encountered in this clinical study have been 
considered and minimized by careful study design. 
 
5.2. Duration 
The enrollment period is expected to start in early 2016 and will take approximately 42 months. Subjects 
will be followed for 3 years, until end of device life or until official study closure, whichever occurs first. 
Therefore, the expected study duration from first enrollment to official study closure (final report) is 
approximately 6.5 years. The duration of individual subject participation will vary based on timing of site 
activation and their enrollment; however, at a minimum, participation of an individual subject will be for 
3 years, until end of device life or until study closure, whichever occurs first. 
5.3. Rationale  
The results of the Stroke AF clinical study will provide evidence that could impact the treatment and 
long-term prognosis for patients classified as having an IS of presumed known origin by demonstrating 
the value of long term monitoring for AF in this patient population. While current guidelines do 
recommend short term (up to 30 days) cardiac monitoring in patients after stroke, evidence generated 
in the Stroke AF study could influence the guidelines with regards to long term (greater than 30 day) 
ICM use post IS. 

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6. Product Description 
6.1. General 
The Stroke AF study will be conducted using the components of the Medtronic Reveal LINQ system.  
 
6.2. Reveal LINQ System 
The Reveal LINQ system consists of 4 main components.  
The Medtronic Reveal LINQ ICM is a programmable device that continuously monitors a patient’s ECG and 
other physiological parameters. The device records cardiac information in response to automatically 
detected arrhythmias and patient activation.  
The device is designed to record the occurrence of an arrhythmia in a patient automatically. Arrhythmias 
may be classified as tachyarrhythmia, brady arrhythmia, pause, atrial tachyarrhythmia, or atrial 
fibrillation. In addition, while experiencing or immediately after a symptomatic event, the patient can 
activate the device to record their cardiac rhythm. 
Reveal LINQ ICM: is a small, leadless device that is inserted under the skin, in the chest. The device uses 
2 electrodes on the body of the device to monitor the patient’s subcutaneous ECG continuously. The 
device memory can store up to 27 min of ECG recordings from automatically detected arrhythmias and 
up to 30 min of ECG recordings from patient-activated episodes. The system provides 3 options for 
segmenting the patient-activated episode storage: up to four 7.5 min recordings, up to three 10 min 
recordings, or up to two 15 min recordings. Arrhythmia detection parameters are set to pending 
automatically, based on patient information entered on the programmer during pre-insertion device 
setup: the patient’s Date of Birth and the clinician’s Reason for Monitoring the patient. Arrhythmia 
detection parameters can also be programmed manually by the clinician. 

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Medtronic Programmer: is used to set up the device to detect arrhythmias. It also allows the user to view, 
save, or print the information stored by the device.  
Patient Assistant: is a hand-held, battery-operated telemetry device that enables the patient to activate 
the recording of cardiac information in the Reveal LINQ ICM while experiencing or immediately after a 
symptomatic event. The clinician uses the recorded information to determine if the symptoms were 
associated with a cardiac event.  
MyCareLink Patient Monitor: is used by patients to gather information automatically from their inserted 
device and communicate the information to their physician. The inserted device communicates wirelessly 
with this monitor which then transmits the information over a cellular telephone connection to the 
Medtronic CareLink Network. This daily wireless audit transmission is scheduled by the clinic and is usually 
set for a time when the patient is asleep. At other times, if requested to do so by their physician or clinic, 
the patient can use their monitor to perform a manual device interrogation to gather information from 
their inserted device and communicate it to their physician. Patient interaction with their monitor includes 
the initial setup procedure, performing physician-requested data gathering, and responding to physician-
specified notifications on the monitor screen. Refer to the literature that is included with the MyCareLink 
Patient Monitor for connection and usage information. 
Additional information related to the Reveal LINQ ICM, including indications, contraindications, warnings 
and precautions can be found in the respective clinician manual. 
 
 
 

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Table 1: Reveal LINQ System Component Information 
Model Number 
Component (Manufacturer) 
Investigational or Market-
released in the United States 
LNQ11 or other 
commercial model 
Reveal LINQ Insertable Cardiac Monitor  
Market- released 
2090 or other 
commercial model 
Medtronic Programmer 
Market- released 
960000 or other 
commercial model 
Patient Assistant  
Market- released 
24950 or other 
commercial model 
MyCareLink Patient Monitor  
Market- released 
 
6.3. Intended Population 
The Reveal LINQ system is being used in accordance with the indications for the device. The Reveal ICM is 
indicated for: 
• 
Individuals with clinical syndromes or situations at increased risk of cardiac arrhythmias. 
• 
Individuals who experience transient symptoms such as dizziness, palpitation, syncope, and chest 
pain that may suggest a cardiac arrhythmia. 
6.4. Packaging 
Labeling and package for all products used in this study will follow the local regulatory requirements. 
Labeling and reference/technical manuals for the Reveal LINQ ICM will be provided under separate cover. 
Labeling for all other market approved system components can be found with each package insert. 
6.5. Equipment 
The following equipment must be available at each site to support study activities: 
• 
Computer with high speed internet and Windows Internet Explorer for data entry (Version 6, 8 
or future compatible version) or other compatible browser 
• 
Medtronic Market Released Programmer 
 
The maintenance and calibration of the equipment used for this study will be assessed by the study site.  
Programmer calibration will not be monitored by the clinical investigation team, but will be maintained 
by Medtronic field representatives as per standard practice. 

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6.6. Product Use 
Instructions for use of the devices used in this study are provided in their respective manuals. 
6.7. Product Training Requirements 
6.7.1. 
Investigator / Investigation Site Selection 
All clinical investigators managing the subject’s condition during the study must be qualified 
practitioners experienced in the diagnosis and medical treatment of subjects with ischemic stroke.  All 
physicians performing the insertion procedure must be experienced and/or trained in the handling of 
insertable cardiac monitoring devices.  
The role of the principal investigator is to implement and manage the day-to-day conduct of the clinical 
investigation as well as ensure data integrity and the rights, safety and well-being of the subjects 
involved in the clinical investigation. 
The principal investigator shall: 
• 
Be qualified by education, training, and experience to assume responsibility for the proper 
conduct of the clinical investigation 
• 
Be experienced in the diagnoses and treatment of stroke patients 
• 
Disclosure of potential conflicts of interest that interfere with the conduct of the clinical 
investigation or interpretation of results 
The principal investigator shall be able to demonstrate that the proposed investigational site: 
• 
Has the required number of eligible subjects needed within the recruitment period 
• 
Has one or more qualified investigators, a qualified investigational site team and adequate 
facilities for the foreseen duration of the clinical investigation 
Site personnel training will be completed prior to participation in this clinical study. 
6.7.2. 
Site Activation  
During the activation process (prior to subject enrollment), Medtronic will train site personnel on the 
clinical investigation plan, relevant standards and regulations, if needed, informed consent, and on data 
collection and reporting tools. If new members join the study site team, they will receive training on the 
applicable clinical study requirements relevant to their role before contributing to the clinical study. 
Prior to performing study related activities, all local regulatory requirements shall be fulfilled, including, 
but not limited to the following:  
• 
Ethics Committee approval of the current version of the CIP and Patient Informed Consent.  

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• 
Fully executed Clinical Trial Agreement (CTA)  
• 
Curriculum Vitae (CV) of investigators and key members of the investigation site team (as 
required by local law)  
• 
Documentation of delegated tasks 
• 
Documentation of study training  
Additional requirements imposed by the Ethics Committee and regulatory authority shall be followed, if 
appropriate. 
In addition, all participating site staff must be trained on the current version of the CIP and must be 
delegated by the principal investigator to perform study related activities.   
Medtronic will provide each study site with documentation of study site/investigator readiness; this 
letter must be received prior to subject enrollment. 
6.8. Product Storage 
The Reveal LINQ ICM is commercially available and will be managed in a manner consistent with other 
market-released product. 
6.9. Product Return 
All explanted devices (devices or leads or activators, etc.) should be returned to Medtronic for analysis 
when permissible by local laws and regulations. To receive a Returned Product Mailer Kit, please contact 
your local Medtronic field personnel.  
7. Selection of Subjects 
7.1. Study Population 
Subjects will be screened to ensure they meet all of the inclusion and none of the exclusion criteria prior 
to study enrollment. 
7.2. Subject Enrollment 
Ethics Committee approval of the Stroke AF Study Clinical Investigation Plan and Informed Consent Form 
must be obtained prior to enrolling patients in the study. Subjects are considered enrolled in the study 
upon signing the informed consent. Informed consent must be obtained prior to performing any study 
related procedures. The subject must be enrolled within 10 days of the qualifying stroke event. 

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7.3. Inclusion Criteria 
Inclusion Criteria 
Rationale  
Subject has had an ischemic stroke believed to be 
due to small vessel disease, large vessel cervical or 
intracranial atherosclerosis within the past 10 
days. 
Study will be evaluated in an already indicated 
patient population where evidence demonstrating 
benefit is needed. 
Subject is willing and able to undergo study 
requirements and expected to be geographically 
stable during study follow-up. 
Ensure ascertainment of data required for clinical 
evaluation. 
Subject is 60 years of age or older, or age 50 to 59 
years plus a documented medical history of at 
least one of the following additional risk factors 
for stroke: 
• 
Congestive heart failure 
• 
Hypertension (Systolic Blood Pressure > 
140) 
• 
Diabetes Mellitus 
• 
Prior Stroke  (>90 days ago, other than 
study qualifying index event) 
• 
Vascular disease (e.g. coronary artery 
disease, heart attack, peripheral artery 
disease and complex aortic plaque) 
Ensure the enrollment of patients who are at 
highest risk. 
 
7.4. Exclusion Criteria 
Exclusion Criteria 
Rationale  
Subject has had a cryptogenic stroke 
This study aims to fill gaps in knowledge around 
the rate of AF in patients with ischemic stroke of 
presumed known origin. Data on the incidence 
rate of AF in these patients already exists. 
Subject has had a cardioembolic stroke 
Patients with known cardioembolic stroke are 
already being treated with OAC. 
Subject has untreated hyperthyroidism 
Avoid possible confounding factors relative to 
patient’s medical condition. 
Subject has had a recent myocardial infarction <1 
month of stroke 
Avoid possible confounding factors relative to 
patient’s medical condition. 
Subject has had a recent cardiac surgery  (e.g. 
coronary artery bypass surgery (CABG)) <1 month 
of stroke 
Avoid possible confounding factors relative to 
patient’s medical condition. 
Subject has a mechanical heart valve 
Avoid possible confounding factors relative to 
patient’s medical condition. 

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Exclusion Criteria 
Rationale  
Subject has valvular disease requiring immediate 
surgical intervention 
Avoid possible confounding factors relative to 
patient’s medical condition. 
Subject has documented prior history of atrial 
fibrillation or atrial flutter 
AF has already been diagnosed in these patients.  
Subject has permanent indication for oral 
anticoagulation  
Generally patients begin an OAC regimen once 
diagnosed with AF, these patients are already on 
OAC. 
Subject has permanent contraindication to oral 
anticoagulation such that detection of AF would 
not change medical management, based on 
enrolling investigators judgment 
The detection of AF would not result in a change 
to the patients’ medical management. 
Subject is enrolled in a concurrent study that may 
confound the results of this study.  Co-enrollment 
in any concurrent clinical study (including 
registries) requires approval of the study manager 
or designee. 
Standard exclusion criteria. 
Subject’s life expectancy is less than 1 year 
Standard exclusion criteria to ensure study cohort 
is expected to survive to the time of endpoint 
evaluation. 
Subject is pregnant 
Standard exclusion criteria. 
Subject has or is indicated for implant with a 
pacemaker, ICD, CRT, or an implantable 
hemodynamic monitor 
Avoid possible confounding factors relative to 
patients’ cardiac condition. 
Subject with a medical condition that precludes 
the patient from participation in the opinion of 
the investigator 
Standard exclusion criteria to apply medical 
discretion in subject selection 
 
8. Study Procedures  
Prior to performing study related procedures, all sites must have Ethics Board/IRB/MEC as well as 
documentation from Medtronic of site readiness. 
8.1. Schedule of Events 
Clinical data will be collected at baseline, 1, 6, and 12 months post-randomization, and at recurring 6 
month intervals after that until study exit. Additionally, subjects randomized to the continuous 
monitoring arm will have data collected at Reveal LINQ ICM insertion, and 3, and 9 months (Remote 
CareLink Transmission).  

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Data collection requirements are summarized in the table below. 
Table 2: Data Collection and Study Procedures 
Study Procedure 
Baseline 
LINQ 
Insertion* 
1, 6 and 12 
Month 
Follow-up 
3, 9 Months 
Remote 
Follow-up* 
Recurring 6 
Month 
Follow-up 
(through 
study exit) 
Unscheduled 
Follow-up 
Stroke/TIA 
Recurrence 
Informed Consent 
X 
 
 
 
 
 
 
Inclusion/Exclusion Assessment 
X 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
Demographics, Medical History 
X 
 
 
 
 
 
 
Cardiovascular Medications 
X 
 
X 
 
X 
 
 
TOAST1 
X 
 
 
 
 
 
X 
NIH Stroke Scale 
X 
 
 
 
 
 
X 
Modified Rankin Scale 
X 
 
X 
 
 
 
X 
EQ-5D 
X 
 
X 
 
 
 
 
Blood Draw 
X 
(if available) 
 
 
 
 
 
 
System & Procedure Information* 
 
X* 
 
 
 
 
 
Full Reveal LINQ Interrogation or 
CareLink Transmission* 
 
X* 
X* 
X* 
X* 
X* 
(if available) 
X* 
(if available) 
AF Assessment 
 
 
X 
 
X 
X 
X 
Symptom Assessment 
 
 
X 
 
X 
X 
 
Stroke/TIA Assessment 
 
 
X 
 
X 
X 
 
Adverse Events 
 
 
 
 
As they occur 
 
Device Deficiencies 
System Modifications* 
Crossover 
Study Deviations 
Subject Exits 
Death 
1Trial of Org 10172 in Acute Stroke Treatment 
* Subjects with a Reveal LINQ ICM only 

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8.2. Subject Consent 
Patient informed consent (PIC) is defined as a legally effective documented confirmation of a subject’s 
(or their legally authorized representative) voluntary agreement to participate in a particular clinical 
study after information has been given to the subject on all aspects of the clinical study that are relevant 
to the subject’s decision to participate. This process includes obtaining a Patient Informed Consent Form 
and an Authorization to Use and Disclose Personal Health Information/Research Authorization/and 
other privacy language as required by law that has been approved by the study site’s Ethics Committee 
and signed and dated by the subject (or their legally authorized representative). A subject may only 
consent after information has been given to the subject on all aspects of the clinical investigation that 
are relevant to the subject’s decision to participate. Informed consent may be given by the legally 
authorized representative only if a subject is unable to make the decision to participate in a clinical 
investigation. In such cases, the subject shall also be informed about the clinical investigation within 
his/her ability to understand. 
Investigators shall consider all subjects who meet eligibility requirements for study participation to avoid 
any bias in the subject population. Prior to enrolling subjects, each site’s Ethics Committee will be 
required to approve the CIP, PIC Form, and any other written study information to be provided to the 
subjects.  The document(s) must be controlled (i.e. versioned and/or dated) to ensure it is clear which 
version(s) were approved by the Ethics Committee.  Any adaptation of the sample Consent Form must 
be reviewed and approved by Medtronic and the Ethics Committee reviewing the application prior to 
enrolling subjects.  
The investigator must notify the subject (or their legally-authorized representative) of any significant 
new findings about the study that become available during the course of the study which are pertinent 
to the safety and well-being of the subject, as this could impact a subject’s willingness to participate in 
the study. If relevant, approval may be requested from subjects to confirm their continued participation. 
Refer to Appendix C for the sample Patient Informed Consent Form(s). 
Prior to initiation of any study-specific procedures, patient informed consent must be obtained from the 
subject (or their legally authorized representative). Likewise, privacy or health information protection 
regulation may require subjects to sign additional forms to authorize sites to submit subject information 
to the study sponsor. The informed consent process must be conducted by the principal investigator or 
an authorized designee, and the Patient Consent Form and Authorization to Use and Disclose Personal 
Health Information/Research Authorization/other privacy language as required by law must be given to 
the subject (or their legally authorized representative) in a language he/she is able to read and 
understand. The process of patient informed consent must be conducted without using coercion or 
undue improper influence on or inducement of the subject to participate by the investigator or other 
site personnel. The informed consent process shall not waive or appear to waive subject’s legal rights. 

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The language used shall be as non-technical as possible and must be understandable to the subject and 
the impartial witness, where applicable.  
The subject must have ample time and opportunity to read and understand the informed consent form, 
to inquire about details of the study, and to decide whether or not to participate in the clinical study. All 
questions about the study should be answered to the satisfaction of the subject. 
When the subject decides to participate in the clinical study, the PIC must be signed and personally 
dated by the subject and investigator or authorized designee, as required by the Patient Consent Form.  
A copy of the Patient Consent Form and the Authorization to Use and Disclose Personal Health 
Information/Research Authorization/other privacy language, signed and dated as required by law, must 
be provided to the subject.  
If the PIC is obtained the same day the subject begins participating in study-related procedures, it must 
be documented in the subject’s case history that consent was obtained prior to participation in any 
study-related procedures. It is best practice for the informed consent process to be documented in the 
subject’s case history, regardless of circumstance. 
In the event the subject cannot read and/or write, witnessed (impartial third party) patient informed 
consent will be allowed, provided detailed documentation of the process is recorded in the subject’s 
case history and the witness signs and dates the patient informed consent. The Consent Form should 
document the method used for communication with the prospective subject and the specific means by 
which the prospective subject communicated agreement to participate in the study.  
The Patient Consent Form and Authorization to Use and Disclose Personal Health Information/Research 
Authorization/other privacy language as required by law must be available for monitoring and auditing. 
Any Medtronic Field personnel who support the Reveal LINQ ICM insertion procedure must be able to 
review the subject’s original signed and dated Consent Form and verify its completeness prior to 
proceeding with the insertion. In the event the Medtronic Field personnel identify patient informed 
consent as being incomplete, the study procedure will not be allowed to occur until the consent of the 
subject can be adequately and appropriately obtained.  
When a patient and the principal investigator or authorized designee, as required have personally 
signed and dated the Consent Form, the patient is considered a subject enrolled in the study.  
The date the subject signed the Consent Form and data protection authorization must be documented 
in the subject’s medical records. 

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8.3. Randomization and Treatment Assignment 
Subjects are eligible for randomization assignment after study enrollment and verification of eligibility 
criteria. Enrollment, randomization and insertion of the Reveal LINQ ICM must occur within 10 days of 
the qualifying stroke event.  
Subjects will be randomized in a 1:1 fashion to the continuous monitoring arm (Reveal LINQ ICM) or 
control arm (standard of care) using the RDC electronic system. Randomization schedules will be created 
by a statistician and randomization assignments will be automatically populated on the Randomization 
e-CRF after subject consent and eligibility verification have been entered in RDC. The randomization 
schedule will be stratified by study site to ensure 1:1 randomization within each study site. 
Once subjects are assigned to a study arm (continuous monitoring or control), they are considered 
randomized.  All randomized subjects should be encouraged to comply with the Stroke AF study 
procedures until study closure and every effort should be made to avoid crossover. Statistical analysis 
will be done on an intention to treat basis unless otherwise specified. Therefore, once a subject is 
assigned to an arm, he/she will remain in this arm and all efforts will be made to provide the optimal 
therapy specified per the assigned treatment arm. In case this is clinically or technically not feasible, the 
intention to treat is assured. A per-protocol analysis cohort will also be defined within the statistical 
analysis plan (SAP) and additional supportive analyses of the objectives may be performed in this cohort.  
8.4. Procedures and Data Collection 
8.4.1. 
Baseline 
The baseline visit can be a standalone visit or can be performed on the same day, but not later than the 
insertion procedure. 
The following information is required to be collected at the baseline visit: 
• 
Informed Consent 
• 
Inclusion/Exclusion Assessment 
• 
Randomization 
• 
Subject Demographics  
• 
Medical History, including but not limited to cardiovascular history, and details about the 
qualifying stroke event (if available) 
• 
Cardiovascular Medications 
• 
TOAST Stroke Classification 
• 
National Institute of Health (NIH) Stroke Scale 
• 
Modified Rankin Scale 
• 
EQ-5D™  
• 
Blood Draw 

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o Five blood tubes (one plasma, three serum and one whole blood) will be collected, 
processed, and sent to the central laboratory for analysis of biomarkers that are 
considered potential predictors of identifying patients who may at high risk for AF.  
• 
One 6 mL tube of blood will be collected and processed for plasma for B-type 
Natriuretic Peptide (BNP) analysis. The residual from the tube will be kept in 
long-term storage for future analysis. 
• 
Two 5 mL tubes of blood will be collected and processed for serum for 
Troponin-I, C-reactive protein (CRP), and thyroid-stimulating hormone (TSH) 
testing. The residuals from these three tubes will be kept in long-term storage 
for future analysis.  
• 
One 5 mL tube of blood will be collected, processed for serum and kept in long-
term storage for future analysis.  
• 
One 4 mL tube of whole blood will be collected for genetic testing such as 
genotyping single nucleotide polymorphisms (SNP). 
o Specifics regarding the acquisition of these specimens, necessary supplies, and shipping 
information, under separate cover, will be provided to all study centers by the central 
laboratory.  
o If a study center does not have the ability to perform the blood draw per the CIP or if 
the patient declines, a study deviation is not required. 
8.4.2. 
Reveal LINQ ICM Insertion 
The insertion procedure must occur within 10 days of the qualifying stroke event and after 
randomization. The insertion will be performed in accordance with the hospital’s standard insertion 
practice and in accordance with the Medtronic Reveal LINQ ICM insertion instructions which are found 
within the Reveal LINQ ICM Clinician manual. The following information is required to be collected at the 
insertion visit: 
• 
System and Procedure Information 
System and procedure details will be collected including, but not limited to procedure date, device 
serial number, location of insertion procedure, location/orientation of inserted device, antibiotic 
use, and closure method.  
• 
Device Programming/Interrogation 
Programming requirements for the Reveal LINQ ICM are outlined in Table 6 below. A full device 
interrogation will be collected after final programming. Programming changes will be allowed only 
when clinically necessary. All deviations from the programming guidelines (regardless of when they 
occur) must be documented on a Study Deviation e-CRF, including the rationale for the deviation.  
 
 

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Table 3: Reveal LINQ ICM Programming 
Parameter 
Required Setting 
Reason for Monitoring 
Cryptogenic Stroke 
AF Detection Sensitivity 
Balanced Sensitivity 
Ectopy Rejection 
Aggressive 
AT/AF Recording Threshold 
All Episodes 
Type of AT/AF Detection 
AF Only 
Wireless Data Priority 
Tachy, Pause, Brady 
Tachy Detection 
ON 
Brady Detection  
ON 
Pause Detection 
ON 
 
The subject will be instructed about the use of the Medtronic MyCareLink Monitor and the Patient 
Assistant. 
If the subject does not have a Reveal LINQ ICM device in the body at the conclusion of the procedure, 
the subject should remain in the study and the follow-up schedule remains unchanged. For these 
patients, CareLink transmissions at 3 and 9 months are not required. 
8.4.3. 
Scheduled Follow-up Visits/CareLink Transmissions 
After receiving notice of randomization assignment, Medtronic will provide the target dates and 
windows for each scheduled visit/CareLink transmission to the site. Should a subject miss a 
visit/transmission or the visit/transmission fall outside the pre-specified window, a study deviation must 
be reported and the original follow-up schedule maintained for subsequent visits/transmissions.  
Data analyses include follow-up visits/CareLink transmissions, regardless of whether the visit occurs 
within the window; therefore, a late visit is preferred over a missed visit. Follow-up visit/CareLink 
transmission windows are listed in the Table 7 below and are based on days post randomization. 
 

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Table 4: Follow-up Visit / CareLink Transmission Schedule 
Study Follow-up 
Visit 
Window 
(Calculated days post randomization) 
Window Start 
 
Target 
 
Window End 
 
1 Month 
23 
30 
37 
3 Month 
(CareLink Transmission)  
76 
91 
106 
6 Month 
168 
183 
198 
9 Month 
(CareLink Transmission) 
259 
274 
289 
12 Month (1 year) 
365 
365 
421 
18 Month  
521 
549 
577 
24 Month (2 year) 
702 
730 
758 
30 Month 
887 
915 
943 
36 Month (3 year) 
1067 
1095 
1123 
8.4.3.1. 
Follow-up Visits 
The following information will be collected at during follow-up visits at 1, 6, and 12 months post-
insertion, and at recurring 6 month intervals after that until study closure: 
• 
Cardiovascular Medications 
• 
Modified Rankin Scale (1, 6 and 12 month only) 
• 
EQ-5D™ (1, 6 and 12 month only) 
• 
Reveal LINQ Interrogation or remote CareLink transmission (subjects with a Reveal LINQ ICM 
only) 
• 
AF Assessment 
• 
Symptom Assessment 
• 
Stroke/TIA Assessment 
 
Data may be collected remotely for subjects unable to return to the clinic for the follow up visit. 
Patients in the control arm should be monitored for cardiac arrhythmias per the study site standard of 
care. Source documentation (e.g. ECG, Holter, etc.) from any additional cardiac arrhythmia diagnostic 
testing or monitoring which detects AF must be sent to Medtronic.  

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8.4.3.2. 
Follow-up Visits / Remote CareLink Transmissions 
Subjects are required to perform a manual CareLink transmission at 3, and 9 months following 
successful Reveal LINQ ICM insertion.  
CareLink transmission data will be automatically transferred to the Medtronic Data Warehouse for 
CareLink. If unavailable, sites may be asked to submit CareLink reports by uploading them to a secure 
server or sending printed versions of the CareLink reports to Medtronic. Printouts only need to be 
provided to Medtronic upon request.  
8.4.4. 
Unscheduled Follow-up Visits 
An unscheduled visit is defined as any unplanned cardiology or neurology visit by the subject to the 
study site. Routine visits or other planned visits are not collected.  
The following information is required to be collected at unscheduled follow-up visits: 
• 
Reveal LINQ Interrogation (if available, subjects with a Reveal LINQ ICM only) 
• 
AF Assessment 
• 
Symptom Assessment 
• 
Stroke/TIA Assessment 
• 
Adverse Event e-CRF (if applicable) 
8.4.5. 
Stroke/TIA Recurrence 
Following the index event, a subject should be monitored for stroke recurrence. If there is a stroke/TIA 
recurrence, the following data is required to be collected: 
• 
Details about the stroke event, such as type, size, and location. 
• 
TOAST stroke classification 
• 
National Institute of Health (NIH) Stroke Scale 
• 
Modified Rankin Scale 
• 
Reveal LINQ Interrogation (if available, subjects with a Reveal LINQ ICM only) 
• 
AF Assessment 
• 
Adverse Event e-CRF 
8.4.6. 
System Modification 
A system modification will be reported in the event the Reveal LINQ ICM requires invasive modification 
(e.g., explant, replacement, repositioning).  
• 
If the modification consists of repositioning or replacement, the follow-up schedule for the 
subject will remain unchanged.  

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• 
If the Reveal LINQ ICM is explanted, the subject should continue participation in this study and a 
crossover e-CRF is required. If the subject receives implant of another Medtronic device (IPG, 
ICD or CRT) reference Table 8 for recommended programming parameters for these devices.  
The other parameters for these devices are to be programmed based on the investigator’s 
opinion. 
Table 5: Recommended Programming Parameters for Medtronic IPG, ICD or CRT Devices 
Parameter 
Recommended Setting 
Atrial preference pacing (APP) 
OFF 
Atrial rate stabilization (ARS) 
OFF 
Post-mode switch overdrive pacing (PMOP) 
OFF 
Atrial Anti-tachycardia pacing (ATP) 
OFF 
AT/AF detection and EGM collection  
Nominal 
 
The following will be collected in the event of a system modification: 
• 
Reason for modification 
• 
System/Procedure Information 
• 
Pre-modification: device interrogation  
• 
Post-modification: device interrogation (if modification includes a Medtronic device) 
 
All explanted product should be returned to Medtronic for analysis when permissible by local laws and 
regulations.  
8.4.7. 
Study Exit 
A study exit e-CRF is required for all subjects except in the case of death.  Prior to exiting a subject from 
the study, it is recommended to follow the subject until all ongoing system and/or procedure related 
AEs are resolved or unresolved with no further actions planned.  Following exit, subjects should 
continue to receive standard medical care.  Upon exiting from the study, no further study data will be 
collected or study visits will occur for the subject.  All data available through the time of the subject’s 
exit will be used for analysis.  
Subjects are urged to remain in the study as long as possible but may be exited from the study for any of 
the following situations: 
• 
Subject lost to follow-up 
• 
Subject did not meet inclusion/exclusion criteria and not randomized 
• 
Subject not randomized 
• 
Subject did not provide consent or data use protection authorization 

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• 
Subject chooses to withdraw (e.g., consent withdrawal, relocation to another geographic 
location)  
• 
Investigator deems withdrawal necessary (e.g., medically justified, inclusion/exclusion criteria 
not met, failure of subject to maintain adequate study compliance)  
• 
Subject with a Reveal LINQ ICM that has reached end of device life (continuous monitoring 
patients only) 
• 
Subject has completed 3 years of follow-up 
• 
Study Closure 
 
The following information is required to be collected at study exit on the study exit e-CRF: 
• 
Date of exit 
• 
Reason for exit  
• 
Reveal LINQ Interrogation (if available, subjects with a Reveal LINQ ICM inserted only) 
• 
AF Assessment (except in the case of lost to follow-up or death) 
• 
Stroke/TIA Assessment (except in the case of lost to follow-up or death) 
 
In the case that the subject is determined to be lost to follow-up, details of a minimum of two attempts 
and the method of attempt (e.g., one letter and one phone record or two letters) to contact the subject 
must be documented. In addition, follow the regulations set forth by the governing Ethics Committee.  
8.5. Assessment of Safety 
Timely, accurate, and complete reporting and analysis of safety information for clinical studies are 
crucial for the protection of subjects. Reporting and analysis of safety data are mandated by regulatory 
authorities worldwide. Medtronic has established procedures in conformity with worldwide regulatory 
requirements to ensure appropriate reporting of safety information. This study is conducted in 
accordance with these procedures and regulations. 
Since the safety reporting requirements and classification systems vary for each regulatory agency, 
requirements from all geographies are taken into account for the collection and reporting of safety 
information. 
8.6. Recording Data 
Data will be collected via electronic Case Report Forms (e-CRFs), Reveal LINQ ICM device interrogation 
files, and Medtronic CareLink transmissions. A web-based application tool, Remote Data Capture (RDC) 
will be used for data entry of e-CRFs. The investigator is responsible for the preparation (review and 
signature) of the e-CRF.  

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8.7. Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the Clinical 
Investigation Plan or the Clinical Trial Agreement. 
Prior approval by Medtronic is expected in situations where the investigator anticipates, contemplates, 
or makes a conscious decision to deviate. Prior approval is not required when a deviation is necessary to 
protect the safety, rights or well-being of a subject in an emergency or in unforeseen situations beyond 
the investigator’s control (e.g. subject failure to attend scheduled follow-up visits, inadvertent loss of 
data due to computer malfunction, inability to perform required procedures due to subject illness). 
For medically justifiable conditions which preempt a subject’s ability to complete a study-required 
procedure, it may be permitted to report only one deviation which will apply to all visits going forward. 
This may also apply for other unforeseen situations (e.g. the subject permanently refuses to complete a 
study required procedure and the data will not contribute to the primary end point analysis). However, 
prior approval from Medtronic is required for such situations.  
All study deviations must be reported on the Study Deviation e-CRF regardless of whether medically 
justifiable (e.g. crossover), pre-approved by Medtronic, an inadvertent occurrence, or taken to protect 
the subject in an emergency. The deviation description must be recorded with an explanation for the 
deviation. In the occurrence of a corrupted device interrogation file, Medtronic may request a deviation 
to document that a readable interrogation file is unavailable. 
In the event the deviation involves a failure to obtain a subject’s consent, or is made to protect the life 
or physical well-being of a subject in an emergency, the deviation must be reported to the Ethics 
Committee as well as Medtronic within five (5) working days. Reporting of all other study deviations 
should comply with Ethics Committee policies and/or local laws and must be reported to Medtronic as 
soon as possible upon the site becoming aware of the deviation. Reporting of deviations must comply 
with Ethics Committee policies, local laws, and/or regulatory agency requirements.  Refer to Investigator 
Reports, Table 12 for geography-specific deviation reporting requirements and timeframes for reporting 
to Medtronic and/or regulatory bodies.  
Medtronic is responsible for analyzing deviations, assessing their significance, and identifying any 
additional corrective and/or preventive actions (e.g. amend the Clinical Investigation Plan, conduct 
additional training, terminate the investigation). Repetitive or serious investigator compliance issues 
may result in initiation of a corrective action plan with the investigator and site, and in some cases, 
necessitate suspending enrollment until the problem is resolved or ultimately terminating the 
investigator's participation in the study. Medtronic will provide site-specific reports to investigators 
summarizing information on deviations that occurred at the investigational site on a periodic basis.  

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8.8. Subject Withdrawal or Discontinuation  
Subjects will be followed until study closure. 
9. Risks and Benefits 
Medtronic follows rigorous Quality Assurance and Control procedures throughout the life of a product, 
from the business analysis phase through development, market release, and post-market surveillance.  
The Stroke AF study system and components are commercially released and used in accordance with 
their approved labeling. The safety and clinical performance of these devices has been demonstrated 
through previous pre-clinical testing and previous clinical studies. There are no incremental risks 
introduced to the subject as a result of participation in the Stroke AF study. Devices should be handled 
in accordance to the Clinical Manual.  
For subjects with a Reveal LINQ ICM inserted, Risks and Risk Mitigations to the subject identified below 
are consistent with those outlined in the device manual. There may be other discomforts and risks 
related to the device system and/or this study that are not foreseen at this time. 
9.1. Potential Risks 
Possible risks associated with the Reveal LINQ ICM include but are not limited to the following: 
• 
Risks associated with a minor surgical procedure  
• 
Slight risk of infection  
• 
Sensitivity to the device 
9.2. Potential Benefits 
The Reveal LINQ ICM may offer no benefit. The potential benefits of having the Reveal LINQ ICM include 
more intensive follow-up treatment and frequent device transmissions and/or continuous monitoring 
enabling more precise detection of AF. This better precision to detect AF may lead to clinicians having 
better data to quantify AF burden. The information gained from this study could result in the improved 
detection and management of atrial fibrillation. Additionally, information collected from this study may 
assist in the design of new product(s)/therapy(ies) and/or instructions for use. The System may not offer 
a direct clinical benefit to study subjects. The information collected from this study may assist in the 
design of new product(s)/therapy(ies) and/or instructions for use.  
9.3. Risk-Benefit Rationale 
The potential risks associated with the Reveal LINQ ICM were identified and have been successfully 
mitigated. Any potential risks associated with this study are further minimized by selecting qualified 
investigators and training study personnel on the Clinical Investigation Plan.  

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In addition, investigators will be actively involved in the insertion and follow-up of the subjects 
implanted with the Reveal LINQ system.  
Risks will be minimized by careful assessment of each subject prior to, during, and after insertion of the 
Reveal LINQ ICM. Prior to insertion, it is recommended subjects undergo a complete cardiac evaluation. 
After insertion, subjects in the Stroke AF clinical study will be followed at regular intervals. At each 
protocol required follow-up, the investigator must interrogate the Reveal LINQ ICM and assess for any 
adverse events.  
• 
Risks associated with a minor surgical procedure  
• 
Slight risk of infection  
• 
Sensitivity to the device 
10. Adverse Events and Device Deficiencies 
All reported Adverse Events (AEs) must be followed until resolved, ongoing without further actions to be 
taken, the subject exits the study or until study closure, whichever occurs first. In the event that a 
subject is exited from the study prior to study closure, all efforts should be made to continue following 
the subject until all ongoing AEs are resolved or they are ongoing without further actions to be taken. 
10.1. Adverse Event Assessment 
10.1.1. 
Adverse Events 
All Reveal LINQ ICM system/component-related, Reveal LINQ ICM procedure related, cardiovascular 
related AEs, and all serious adverse events leading to death will be collected throughout the study 
duration, starting at the time of signing the consent form.  
Reporting of these events to Medtronic will occur on an Adverse Event (AE) e-CRF, including a 
description of AE, date of onset of AE, date of awareness of site, treatment, resolution, assessment of 
both the seriousness and the relatedness to the investigational device. Each AE must be recorded on a 
separate AE Form. Subject deaths are also required to be reported. Refer to Section 10.5 for Subject 
Death collection and reporting requirements. 
Documented pre-existing conditions are not considered AEs unless the nature or severity of the 
condition has worsened. Additionally, detected arrhythmias (including AF) for which no action is taken 
are not reportable AEs. Unavoidable Adverse Events, listed in Table 9 need not be reported unless the 
adverse event worsens or is present outside the stated timeframe post-insertion.  
For AEs that require immediate reporting (see Table 11), initial reporting may be done by phone, fax, or 
on the e-CRF completing as much information as possible, with missing or follow-up information 
provided as soon as it becomes available. The AE e-CRF must be completed as soon as possible.  

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10.1.2. 
Device Deficiencies  
Device deficiency (DD) information will be collected throughout the study and reported to Medtronic. 
Note that device deficiencies that result in an adverse device effect (ADE) to the subject should be 
captured as an Adverse Event only. 
10.1.3. 
Processing Updates and Resolution 
For any changes in status of a previously reported AE (i.e. change in actions taken, change in outcome, 
change in relatedness), information needs to be updated on or added to the original AE e-CRF. All 
reported adverse events must be followed until the adverse event has been resolved, is unresolved with 
no further actions planned, the subject exits the study or until study closure, whichever occurs first.  
In the event that a subject is exited from the study prior to study closure, all efforts should be made to 
continue following the subject until all unresolved procedure or system related adverse events, as 
classified by the investigator, are resolved or they are unresolved with no further actions planned.  
At the time of study exit, all AEs with an outcome of “Unresolved, further actions or treatment planned” 
must be reviewed and an update to the original AE e-CRF must be reported. At a minimum, if there are 
no changes to the description, relatedness, test and procedures or actions taken, the outcome must be 
updated to reflect “Unresolved at time of study closure.” 
10.2. Definitions/Classifications 
10.2.1. 
Adverse Event and Device Deficiency Definitions 
Where the definition indicates “device”, it refers to any device used in the study.  

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Table 6: Adverse Event Definitions 

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General 
Adverse Event (AE) 
(Adapted from ISO 14155:2011, 3.2) 
Any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in 
subjects, users or other persons, whether or not related to the 
investigational medical device 
 
NOTE 1: This definition includes events related to the investigational 
medical device or the comparator. 
 
NOTE 2: This definition includes events related to the procedures 
involved. 
 
Adverse Device Effect (ADE) 
(ISO 14155:2011, 3.1) 
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from 
insufficient or inadequate instructions for use, deployment, 
implantation, installation, or operation, or any malfunction of the 
investigational medical device. 
 
NOTE 2: This definition includes any event resulting from an error use or 
from intentional misuse of the investigational medical device.  
 
Device Deficiency (DD) 
(ISO 14155:2011, 3.15) 
 
Inadequacy of a medical device with respect to its identity, quality, 
durability, reliability, safety or performance.  
 
NOTE: Device deficiencies include malfunctions, use errors and 
inadequate labeling  
 
Relatedness 
Reveal LINQ ICM Procedure Related 
 
An adverse event that occurs that is directly related to the implantation 
or modification of the Reveal LINQ system. 
Reveal LINQ ICM System Related 
 
An adverse event that results from the presence or performance 
(intended or otherwise) of any component of the system (including: 
Reveal LINQ ICM, Programmer, Patient Assistant, and MyCareLink 
Patient Monitor). 
 
Cardiovascular Related 
An adverse event relating to the heart and the blood vessels or the 
circulation. 
Seriousness 

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Complication  
An adverse event that results in death, involves any termination of 
significant device function, or requires invasive intervention. 
 
Non-invasive: when applied to a diagnostic device or procedure, means 
one that does not by design or intention: 
• 
Penetrate or pierce the skin or mucous membranes of the 
body, the ocular cavity or the urethra or 
• 
Enter the ear beyond the external auditory canal, the nose 
beyond the nares, the mouth beyond the pharynx, the anal 
canal beyond the rectum, or the vagina beyond the cervical os 
 
For purposes of this part, blood sampling that involves simple 
venipuncture is considered non-invasive, and the use of surplus samples 
of body fluid or tissue that are left over from samples taken for non-
investigational purposes is also considered non-invasive. 
 
Observation 
Any adverse event that is not a complication. 
 
Note 1: Only system or procedure related AEs will be classified as 
Complication or Observation. 
 
Serious Adverse Event (SAE) 
(Adapted from ISO 14155:2011, 3.37) 
 
Adverse event that 
a) led to death, 
b) led to serious deterioration in the health of the subject, that either 
resulted in 
5. 
a life-threatening illness or injury, or 
6. 
a permanent impairment of a body structure or a body 
function, or 
7. 
in-patient or prolonged hospitalization, or 
8. 
medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body 
structure or a body function, 
c) led to fetal distress, fetal death or a congenital abnormality or birth 
defect 
 
NOTE 1: Planned hospitalization for a pre-existing condition, or a 
procedure required by the CIP, without serious deterioration in health, 
is not considered a serious adverse event. 
 
 
Other 
Hospitalization 
A therapeutic inpatient hospitalization (excludes outpatient and 
emergency room visits) lasting greater than or equal to 24 hours. 
Stroke 
 
Hemorrhagic or Ischemic stroke with rapid onset of a focal or global 
neurological deficit or other neurological signs/symptoms consistent 
with stroke. 
Stroke Diagnosis 
Diagnosis will be determined by the site’s neurologist clinical evaluation 
and include clinical signs and symptoms consistent with focal or global 
neurological deficit in addition to one or more of the following: 
• 
Neuroimaging procedure (CT, MR, or cerebral angiogram) 
• 
Lumbar Puncture (i.e. subarachnoid hemorrhage) 

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Transient Ischemic Attack (TIA) 
New focal neurological deficit with rapid symptom resolution (usually 1 
– 2 hours), always within 24 hours without tissue injury (based on 
neuroimaging). 
Unavoidable Adverse Event 
An Adverse Event inherent to a surgical procedure that is expected to 
occur in all subjects for a projected duration according to the 
Investigator’s opinion, including, but not limited to:  
 
Event Description 
Timeframe 
(hours) from the 
Surgical 
Procedure 
Anesthesia related nausea / vomiting  
24 
Low-grade fever (<100°F or 37.8°C) 
48 
Pocket site / Incisional pain 
72 
Mild to moderate bruising / ecchymosis 
168 
Sleep problems (insomnia) 
72 
Back pain related to laying on table 
72 
Shoulder pain/discomfort/stiffness related to 
shoulder immobilization during procedure 
72 
10.2.2. 
Adverse Events and Deficiency Classification 
All reported AEs and DDs will be reviewed by a Medtronic representative. AEs will be classified according 
to the definitions provided.  
Upon receipt of AEs at Medtronic, a Medtronic representative will review the AE/DD for completeness 
and accuracy and when necessary will request clarification and/or additional information from the 
Investigator. Medtronic will utilize MedDRA, the Medical Dictionary for Regulatory Activities, to assign a 
MedDRA term for each adverse event based on the information provided by the investigator.  
Regulatory reporting of AEs and DDs will be completed according to local regulatory requirements. Refer 
to Table 12 and Table 13 for a list of required investigator and Medtronic reporting requirements and 
timeframes. It is the responsibility of the investigator to abide by any additional AE reporting 
requirements stipulated by the Ethics Committee responsible for oversight of the study. 
For emergency contact regarding a SAE, contact a clinical study representative immediately (refer to the 
study contact list provided in the site’s study documents binder/investigator site file or refer to the 
contact information provided on the title page). 
Adverse Events and Deaths will be classified according to the standard definitions as outlined below:  

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Table 7: Adverse Event Classification Responsibilities 
What is classified?  
Who classifies? 
Classification Parameters 
Relatedness 
 
Investigator 
• 
Procedure Related 
• 
System Related 
Sponsor 
• 
Procedure Related 
• 
System Related 
• 
Cardiovascular Related 
Seriousness 
Investigator 
SAE 
Sponsor 
SAE, Complication or Observation (for all system or procedure 
related adverse events) 
Diagnosis 
Investigator 
Based on presenting signs and symptoms and other supporting 
data 
Sponsor 
MedDRA term assigned based on the data provided by 
Investigator 
Death Classification 
Investigator 
Sudden Cardiac, Non-sudden Cardiac, Non-Cardiac, Unknown 
 
An independent Clinical Events Committee (CEC) will at minimum conduct a medical review of all 
endpoint related events for subjects participating in the study.  Additionally, the CEC will provide an 
adjudication of the death classification for all reported deaths. 
10.3. Reporting of Adverse Events 
Regulatory reporting of AEs/DDs will be completed according to local regulatory requirements. Refer to 
Table of Adverse Event Reporting Requirements for a list of required investigator reporting 
requirements and timeframes, and of required Medtronic reporting requirements and timeframes. 
 
The investigator is required to report all SAEs to Medtronic immediately, and to the Ethics Committee 
per local requirements. Medtronic is also required to report these events to the local regulatory 
authority based on their requirements. It is the responsibility of the investigator to abide by any 
additional AE/DD reporting requirements stipulated by the Ethics Committee responsible for oversight 
of the study. 
For AEs/DDs that require immediate reporting, initial reporting may be done by contacting the study 
sponsor per the sponsor contact information provided in this document.  

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Table 8: AE Reporting Requirements 
Serious Adverse Events (SAEs) 
Investigator submit to: 
Medtronic 
Submit in a timely manner after the investigator first learns of the event. 
EC/IRB/MEC 
Submit to EC/IRB/MEC per local reporting requirement. 
Regulatory 
authorities 
Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
Regulatory 
authorities 
Submit to regulatory authority per local reporting requirement. 
EC/IRB/MEC 
Submit to EC/IRB/MEC per local reporting requirement. 
All other reportable Adverse Events  
(System, Procedure, Cardiovascular-Related) 
Investigator submit to: 
Medtronic 
Submit in a timely manner after the investigator first learns of the event. 
EC/IRB/MEC 
Submit to EC/IRB/MEC per local reporting requirement. 
Regulatory 
authorities 
Submit to regulatory authority per local reporting requirement. 
Sponsor submit to: 
Regulatory 
authorities 
Submit to regulatory authority per local reporting requirement. 
EC/IRB/MEC 
Submit to EC/IRB/MEC per local reporting requirement. 
Device Deficiencies  
Investigator submit to: 
Medtronic 
Submit in a timely manner after the investigator first learns of the event. 
EC/IRB/MEC Submit to EC/IRB/MEC per local reporting requirement. 
Regulatory 
authorities 
Submit to regulatory authority per local reporting requirement. 
 
 
10.3.1. 
Subject Death 
10.3.1.1. Death Data Collection 
All subject deaths must be reported by the investigator to Medtronic using an AE e-CRF as soon as 
possible after the investigator first learns of the death.  The AE leading to death must be reported and 
will document the death as the outcome. 
For subjects with a Reveal LINQ ICM 

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In the event of a subject’s death, the inserted device should be explanted and returned to Medtronic for 
analysis whenever possible. Local laws and procedures must be followed where applicable. 
System Interrogation Data Recommendations: 
• 
After the subject has died but prior to explant, the device shall be interrogated and a full 
summary interrogation (Interrogate All) performed when possible. 
If the device is not interrogated, an explanation must be entered on the AE form. If any system 
component is returned to Medtronic, internal return product reporting systems may be used to 
gather additional information about the returned device/component. 
 
A copy of the death certificate, if available and allowed by state/local law, should be sent to the 
Medtronic clinical study team. When a death occurs in a hospital, a copy of the death summary report 
and all relevant hospital records should be sent to the Medtronic clinical study team, if available. If an 
autopsy is conducted, the autopsy report should also be sent to the Medtronic clinical study team if 
available and allowed by state/local law. When the death occurs at a remote site, it is the investigative 
site’s responsibility to attempt retrieval of information about the death. In summary, the following data 
will be collected: 
• 
Date of death 
• 
Detailed description of death 
• 
Cause of death  
• 
Relatedness to system and/or procedure (subjects with Reveal LINQ inserted) 
• 
Device interrogation (if available, subjects with a Reveal LINQ ICM) 
• 
Death summary/hospital records (if available and allowed by state/local law) 
• 
Autopsy report (if available and allowed by state/local law) 
• 
Death certificate (if available and/or allowed by state/local law) 
 
 

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10.3.1.2. Death Classification and Reporting 
Sufficient information will be required in order to properly classify the subject’s death. The Investigator 
shall classify each subject death per the following definitions: 
Table 9: Subject Death Classification 
Classification 
Definition 
Cardiac Death 
A death directly related to the electrical or mechanical dysfunction of the heart 
Sudden Cardiac Death (SCD) Natural death due to cardiac causes, indicated by abrupt loss of consciousness within 
one hour of the onset of acute symptoms; preexisting heart disease may have been 
known to be present, but the time and mode of death are unexpected. If time of onset 
cannot be determined, SCD will alternatively be defined as any unexpected cardiac 
death occurring out of the hospital or in the emergency room as dead on arrival. 
Non-sudden Cardiac Death 
All cardiac deaths that are not classified as sudden deaths, including all cardiac deaths 
of hospitalized subjects on inotropic support. 
Non-cardiac Death 
A death not classified as a cardiac death 
Unknown 
There is insufficient or inadequate information to classify the death. 
 
The Clinical Events Committee (CEC) will review deaths and provide a final adjudication of the primary 
cause of death and death classification. 
Regulatory reporting of Subject Deaths will be completed according to local regulatory requirements. 
Refer to Table 12 and Table 13 for a list of required investigator and sponsor reporting requirements and 
timeframes. 
10.4. Product Complaint Reporting 
Product complaint reporting is applicable to any Medtronic market released product, regardless of 
subject’s participation in a clinical study.  
All devices used in the study are market-released, product complaint reporting is applicable. This 
includes when an AE is related to a market-released device during the study.  The reporting of product 
complaints is not part of the clinical study and should be done in addition to the AE reporting 
requirements.  Refer to local regulations for reporting requirements. 
Product Complaint: Any written, electronic or oral communication that alleges deficiencies related to 
the identity, quality, durability, reliability, safety, effectiveness or performance of a medical device that 
has been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated with a medical 
device distributed by Medtronic, regardless whether they are related to intended use, misuse or abuse 
of the product. Reporting must be done immediately and via the regular channels for market-released 

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products.  The reporting of product complaints by the clinical study team must be done according to 
local Standard Operating Procedures. 
Medtronic will notify the regulatory authorities (e.g. Competent Authority) as applicable for the 
following incidents immediately upon learning of them: 
• 
Any malfunction or deterioration in the characteristics and/or performance of a device, as well 
as any inadequacy in the labeling or instructions for use which led or might have led to the 
death or serious deterioration in the state of health of a patient, user, or other person. 
• 
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
• 
A serious deterioration in the state of heath includes: 
o Life-threatening illness or injury 
o Permanent impairment of a body function or permanent damage to a body structure 
o In-patient or prolonged hospitalization 
o Medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure or a body function 
o Fetal distress, fetal death or a congenital abnormality or birth defect 
11. Data Review Committees  
The Stroke AF study will utilize a Steering Committee for study design and oversite, a CEC for the 
assessment of Adverse Events and recurrent stroke/TIA data, an Endpoint Adjudication Committee (the 
CEC may serve as the EAC) for an independent review of endpoint (AF) and a Publication Committee to 
manage study publications. 
Committee membership rosters will be maintained at Medtronic and will be made available upon 
request 
11.1. Clinical Events Committee (CEC) Review 
At regular intervals, an independent Clinical Events Committee (CEC) will at minimum conduct a medical 
review (adjudicate) of reported arrhythmias including AF episodes/events as well as reported 
strokes/TIAs and deaths for subjects participating in the study.  
The CEC will consist of a minimum of three (3) non-Medtronic employed physicians that are not 
participating investigators for the study, including a CEC chairperson. At least three CEC members must 
adjudicate, at a minimum, all deaths and endpoint related events.  All other AEs may be adjudicated by 
at least one physician member of the CEC.  
Medtronic personnel may facilitate and participate in a CEC meeting but will be non-voting members. 

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For adverse events and deaths reviewed by the CEC, Medtronic will provide the CEC with the 
Investigator’s description and classification. The CEC is responsible for reviewing the Investigator’s 
assessment and supportive documentation (when available), reviewing applicable definitions, and 
determining final classifications for all adjudication parameters. Additionally, the CEC will provide an 
adjudication of the death classification for all reported deaths including primary cause of death. 
If the CEC disagrees with the investigator’s classification of the event, the rationale will be provided to 
the investigator. If the investigator agrees with the CEC’s adjudication, the case report form 
documenting the AE will be updated accordingly. 
If the investigator does not agree with the CEC’s adjudication classification, both determinations will be 
provided within the final report; however the CEC’s adjudication will be used for data analysis. The 
disagreement will also be included in reporting to ethic committees and regulatory authorities, if 
required. 
12. Statistical Design and Methods 
Medtronic employees or designees will perform all statistical analyses. Additionally, a separate 
Statistical Analysis Plan (SAP) will be developed to further describe statistical methods, pre-specified 
data handling rules, and pre-specified analyses that will be included in study reports. Any change to the 
data analysis methods described in the CIP will require an amendment only if it changes a principal 
feature of the CIP. Any other change to the data analysis methods described in the CIP, and the 
justification for making the change, will be described in the clinical study report. Additional exploratory 
analyses of the data may be conducted as deemed appropriate. Missing data will not contribute to the 
objectives unless specified otherwise within the analysis methods. 
The study has been powered for the primary objective (see sample size determination for the primary 
objective below), to be evaluated after 12 months of follow-up have been completed. The primary 
objective data and applicable ancillary objective data will be provided in a 12 month report. Secondary 
objective data, and remaining ancillary objective data will be provided in a final report. Ancillary objects 
are considered exploratory. There will be no correction for multiple testing. Intent-to-treat principles 
will be used for analyzing each of objectives unless otherwise specified. 
12.1. Primary Objective 
The primary objective is to compare the incidence rate of AF through 12 months between the 
continuous monitoring arm vs control arm in subjects with a recent ischemic stroke of presumed known 
origin.  

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i. Hypothesis 
H0:   hC(t) = hT(t) for t ≤ 12 months 
• HA:   hC(t) ≠ hT(t) for t ≤ 12 months 
• 
where hT(t) and hC(t) are the hazard functions of first detected and adjudicated AF at time 
t for subjects with and without the Reveal LINQ diagnostics for AF, respectively. 
ii. 
Endpoint Definition 
AF will be defined as an AF event lasting more than 30 seconds. The first AF episode detected 
and adjudicated by the endpoint adjudication committee will be used for this analysis.  
iii. 
Performance Requirements 
The null hypothesis will be rejected if the two-sided log-rank test p-value is less than 0.05.  
iv. 
Rationale for Performance Criteria 
The exact rate of AF is unknown in this population. Data from the CRYSTAL AF study and 
Rabinstein et al (2013) has been used to estimate the 12 month incidence rate of AF in 
patients with an ischemic stroke of presumed known origin.  
The incidence rate of AF through 12-months was 12.4% in the continuous monitoring arm in 
the CRYSTAL AF study which was conducted in patients with a cryptogenic stroke.  
 
Rabinstein et al (2013) used prolonged ambulatory cardiac monitoring to assess the incidence 
rate of paroxysmal AF through 3 weeks in patients with a cryptogenic stroke and patient with a 
stroke of presumed known cause. The incidence rate of paroxysmal AF through 3-weeks was 
25% in the patients with a cryptogenic stroke and 14% in patients with an ischemic stroke of 
presumed known origin. 
 
The above incidence rates were used to estimate the 12 month incidence rate of AF in patients 
with ischemic stroke of presumed known origin. We expect the AF incidence rate to be lower 
in patients with an ischemic stroke of presumed known origin when compared to the 
incidence rate in patients with a cryptogenic stroke. Consequently, an AF incidence rate of 8% 
through 12 months is expected in our continuous monitoring arm. An AF incidence rate of 2% 
through 12 months is expected our control arm.  This is the same rate observed in the control 
arm for the CRYSTAL AF study. Although we expect the AF incidence rate to be lower in 
patients with an ischemic stroke of presumed known origin, we also expect that present 
standard of care treatment includes more rhythm monitoring then it did during the time of the 
CRYSTAL AF study. 
 
The objective of the study is to compare the incidence rate of AF through 12 months between 
the continuous monitoring arm vs control arm in subjects with a recent ischemic stroke of 
presumed known origin.  

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v. 
Sample Size Determination 
• 
A total of 23 events are required to demonstrate that the hazard rates are different 
between the two arms. Approximately 496 subjects will be enrolled. Assuming 2% attrition 
from enrollment to randomization, approximately 486 subjects will randomized. Subjects will 
be followed for 3 years, until end of device life or until official study closure, whichever occurs 
first. Withdrawn subjects will not be replaced. 
 
• 
The assumptions used for the calculations were: 
• 
Two-sided log-rank test 
• 
Alpha = 0.05 
• 
85% power 
• 
Annual Attrition rate = 10% 
• 
Annual Crossover rate = 5% 
• 
Follow-up Time = 1 year 
• 
Event-free one-year survival rate of 92% in the continuous monitoring arm 
• 
Event-free one-year survival rate of 98% in the control arm (hazard ratio of 4.13) 
The procedure “Logrank tests (Lakatos) using proportion surviving” in PASS 2008 was used to 
calculate the number of events required to test this objective. 
vi. 
 Analysis Methods 
Arrhythmic episodes recorded by the subject’s inserted/implanted device or from external 
monitoring will be adjudicated by the adjudication committee to determine if they meet the 
primary endpoint definition. Only first detected and adjudicated AF episodes within 12-months 
(365 days) will be included for analysis. Each subject’s time to first detected and adjudicated 
AF will be defined as the time from randomization date to the date of first documented AF (i.e. 
the date of event per Reveal LINQ ICM, ECG, etc) to meet the primary endpoint definition, and 
Kaplan-Meier curves will be generated for each randomization arm. Subjects who have not 
experienced an AF endpoint through 12 months will be censored at: 
• 
their point of last contact, usable Reveal  LINQ ICM interrogation or CareLink 
transmission if they occur before 12 months, whichever is later or  
• 
12 months if their point of last contact, usable Reveal  LINQ ICM interrogation or 
CareLink transmission go beyond 12 months.  
A two-sided log-rank test will be performed to compare the rates between arms. 
In addition to the analysis on the full population, subgroup analysis for subjects with small 
vessel disease stroke and large vessel cervical or intracranial atherosclerosis stroke will be 
presented.  
vii. 
Determination of Patients/Data for Analysis  
• 
All randomized subjects will be included in the analysis.   

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12.2. Secondary Objective 
To compare the incidence rates of AF through the duration of study follow-up between study arms 
i. Hypothesis 
H0:   hC(t) = hT(t) for t > 0 months 
• HA:   hC(t) ≠ hT(t) for t > 0 months 
• 
where hT(t) and hC(t) are the hazard functions of first detected and adjudicated AF at time 
t for subjects with and without the Reveal LINQ diagnostics for AF, respectively. 
ii. Endpoint Definition 
Adjudicated AF event as described in section 13.1.ii. 
iii. Performance Requirements 
This secondary objective will be tested in a hierarchical fashion. This means that if the primary 
objective is met, then this secondary objective will be tested.  
The null hypothesis will be rejected if the two-sided log-rank test p-value is less than 0.05. 
iv. Sample Size Determination 
• 
A two-sided log-rank test with the assumptions below achieves 100% power to test the 
secondary objective.  
 
• 
The assumptions used for the calculations were: 
o Two-sided log-rank test 
o Alpha = 0.05 
o Annual Attrition rate = 10% 
o Annual Crossover rate = 5% 
o Accrual Time = 2 years 
o Follow-up Time = 3 years 
o Event-free survival rate of 80% in the continuous monitoring arm 
o Event-free survival rate of 97% in the control arm (hazard ratio of 7.33) 
o Number of subjects randomized = 486 
The procedure “Logrank tests (Lakatos) using proportion surviving” in PASS 2008 was used to 
calculate the power to test this objective. 

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v. Analysis Methods 
Arrhythmic episodes as described in section 13.1 will be used for this objective. However, only 
first detected and adjudicated AF episodes through the duration of the study follow-up will be 
included for analysis. 
 
Each subject’s time to first detected and adjudicated AF will be defined as in section 13.1, and 
Kaplan-Meier curves will be generated for each randomization arm. Subjects who have not 
experienced an AF endpoint through the duration of the study follow-up will be censored at 
their point of last contact, usable Reveal LINQ ICM interrogation or CareLink transmission, 
whichever is later. A two-sided log-rank test will be performed to compare the rates between 
arms. 
 
In addition to the analysis on the full population, subgroup analysis for subjects with small 
vessel disease stroke and large vessel cervical or intracranial atherosclerosis stroke will be 
presented.  
vi. Determination of Patients/Data for Analysis  
All randomized subjects will be included in the analysis. 
13. Ethics 
13.1. Statement(s) of Compliance  
This study will be conducted in compliance with international ethical and scientific quality standards, 
known as good clinical practice (GCP). GCP includes review and approval by an independent Ethics 
Board/IRB/MEC before initiating a study, continuing review of an ongoing study by an Ethics Boards and 
obtaining and documenting the freely given informed consent of a subject before initiating the study. 
The principles of the Declaration of Helsinki have been implemented through the patient informed 
consent (IC) process, Ethics Board/IRB/MEC approval, study training, clinical trial registration, preclinical 
testing, risk-benefit assessment and publication policy. 
This study will be conducted in compliance with 21 CFR Parts 11, 50 and 56. 
The study will be publicly registered prior to first enrollment in accordance with the 2007 Food and Drug 
Administration Amendments Act (FDAAA) and Declaration of Helsinki on http://clinicaltrials.gov (PL 110-
85, Section 810(a)). 
Approval of the CIP is required from the following groups prior to any study procedures at a study site:  
• 
Medtronic  
• 
An independent medical ethics committee or institutional review board. 
 

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14. Study Administration 
14.1. Monitoring  
It is the responsibility of Medtronic to ensure proper monitoring of this clinical study.  Trained 
Medtronic personnel or delegates appointed by Medtronic may perform study monitoring at the study 
site in order to ensure that the study is conducted in accordance with the CIP, the Clinical Trial 
Agreement, and applicable regulatory and local requirements. Medtronic, or delegates, must therefore 
be allowed access to the subjects’ case histories (clinic and hospital records, and other source 
data/documentation) upon request as per the Subject Informed Consent, Research Authorization 
(where applicable) and Clinical Trial Agreement.  The principal investigator should also be available 
during monitoring visits.   
14.1.1. 
Monitoring Visits 
Frequency of monitoring visits may be based upon subject enrollment, duration of the study, study 
compliance, number of adverse events, number of deviations, findings from previous monitoring visits 
and any suspected inconsistency in data that requires investigation. Regulatory documents may be 
reviewed at each study site. Monitoring for the study, including site qualification visits, site initiation 
visits, interim monitoring visits, and closeout visits, will be done in accordance to the study-specific 
monitoring plan. Monitoring will be planned either at the study site, via telephone, or electronically to 
assure compliance with the study protocol. Site activation, periodic visits and study closure visits will 
occur either on-site, via email or via telephone. 
Monitoring visits may be conducted periodically to assess site study progress, the investigator’s 
adherence to the CIP, regulatory compliance including but not limited to IRB/Ethics Committee approval 
and review of the study, maintenance of records and reports, and review of source documents against 
subject e-CRFs. Monitors review site regulatory and study compliance by identifying findings of non-
compliance and communicating those findings along with recommendations for preventative/corrective 
actions to site personnel.  Monitors may work with study personnel to determine appropriate corrective 
action recommendations and to identify trends within the study or at a particular site.  
14.2. Data Management 
Data will be collected using an electronic data management system for clinical studies.  e-CRF data will 
be stored in a secure, password-protected database which will be backed up nightly.  Data will be 
reviewed using programmed and manual data checks.  Data queries will be made available to sites for 
resolution.  Study management reports may be generated to assess data quality and study progress.  At 
the end of the study, the data will be frozen and will be retained indefinitely by Medtronic. 

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All records and other information about subjects participating in this study will be treated as 
confidential. Data will be transferred and processed by Medtronic or a third party designated by 
Medtronic in a key coded form, unless it’s impossible to make it anonymous, for instance, where the 
patient’s name cannot be removed from the data carrier, such as fluoroscopy images.     
Procedures in the CIP require source documentation.  Source documentation will be maintained at the 
site. Source documents, which may include worksheets, patient medical records, programmer printouts, 
and interrogation files, must be created and maintained by the investigational site team.  
The data reported on the e-CRFs shall be derived from source documents and be consistent with these 
source documents, and any discrepancies shall be explained in writing.  
Device data from Reveal LINQ ICM interrogations and CareLink transmissions will be uploaded to secure 
servers.  Save-to-media data collected at office visits will be sent to Medtronic.  Upon receipt, device 
data will be maintained with databases and retrieved for analysis and reporting. 
14.3. Direct Access to Source Data/Documents  
The sponsor or a regulatory authority may audit or inspect the study site to evaluate the conduct of the 
study. The clinical investigator(s)/institution(s) shall allow study related monitoring, audits, Ethics Board 
review and regulatory inspection by providing direct access to source data/documents. 
14.4. Confidentiality 
All records and other information about subjects participating in this study will be treated as 
confidential. The identity of a subject will never be disclosed in the event that study data are published. 
14.5. Liability 
Warranty information is provided in the product packaging for the Reveal LINQ ICM and additional 
copies are available upon request.  
14.6. CIP Amendments 
Approval of the CIP is required from the following groups prior to any study procedures at a study site:  
• 
Medtronic  
• 
An independent medical ethics committee or institutional review board. 
 
Similarly, approval of subsequent revisions to the CIP is required at each study site from the above-
mentioned groups prior to implementation of the revised CIP at that site. 

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14.7. Record Retention 
14.7.1. 
Investigator Records 
The investigator is responsible for the preparation and retention of the records cited below. All of the 
below records, with the exception of case history records and case report forms, should be kept in the 
Investigator Site File (i.e., the study binder provided to the investigator) or Subject Study Binder. E-CRFs 
must be maintained and signed electronically within the electronic data capture system during the 
study. The following records are subject to inspection and must be retained for a period of two years (or 
longer as local law or hospital administration requires) after the date on which the investigation is 
terminated. 
• 
All correspondence between the IRB/MEC, sponsor, monitor, and the investigator that pertains 
to the investigation, including required reports.  
• 
Subject’s case history records, including:  
o Signed and dated informed consent form personally signed by subject 
o Observations of adverse events/adverse device effects/device deficiencies 
o Medical history 
o Insertion and follow-up data 
o Documentation of the dates and rationale for any deviation from the protocol 
• 
List of investigation sites 
• 
All approved versions of the CIP, and PIC.  
• 
Signed and dated Clinical Trial Agreement.  
• 
Current curriculum vitae of principal investigators.  
• 
Documentation of delegated tasks.  
• 
IRB/MEC approval documentation. Written information that the investigator or other study 
staff, when member of the IRB/MEC, did not participate in the approval process. Approval 
documentation must include the Ethics Board composition, where required per local law.   
• 
Study training records for site staff.  
• 
Final Study Report including the statistical analysis.  
 
 
14.7.2. 
Investigator Reports 
The investigator is responsible for the preparation (review and signature) and submission to the sponsor 
of all case report forms, adverse events and adverse device effects (reported per the country-specific 
collection requirements), device deficiencies, deaths, and any deviations from the clinical investigation 
plan.  If any action is taken by an IRB/MEC with respect to this clinical study, copies of all pertinent 

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documentation must be forwarded to Medtronic in a timely manner. Reports are subject to inspection 
and to the retention requirements as described above for investigator records.  
Safety data investigator reporting requirements are listed in Section 10 of the Adverse Event section. 
The investigator shall prepare and submit in a complete, accurate and timely manner the reports listed 
in this section. 
 
Table 10: Investigator Reports per Medtronic Requirements 
Report  
Submit to 
Description/Constraints 
Withdrawal of IRB/MEC 
approval 
Sponsor and Relevant 
Authorities 
The investigator must report a withdrawal of approval by the 
reviewing IRB/MEC of the investigator’s part of the investigation 
within 5 working days. 
Study Deviations  
Sponsor and 
IRB/MEC 
Any deviation from the clinical investigational plan shall be 
recorded together with the explanation of the deviation. 
Notice of deviations from the CIP to protect the life or physical 
well-being of a subject in an emergency shall be given as soon as 
possible, but no later than 5 working days after the emergency 
occurred.  Except in such emergency, prior approval is required 
for changes in the plan or deviations.  
Final Report 
IRBs/MECs and  
Relevant Authorities 
This report must be submitted within 3 months of study 
completion or termination. 
14.7.3. 
Sponsor Records 
Medtronic shall maintain the following accurate, complete, and current records: 
• 
All correspondence which pertains to the investigation 
• 
Signed Investigator Trial Agreements and current curriculum vitae of principal investigator and 
delegated task list 
• 
All approved informed consent templates, and other information provided to the subjects and 
advertisements, including translations 
• 
Copies of all IRB/MEC approval letters and relevant IRB/MEC correspondence and IRB/MEC 
voting list/roster/letter of assurance 
• 
Names of the institutions in which the clinical study will be conducted 
• 
Names/contact addresses of monitors 
• 
Statistical analyses and underlying supporting data 
• 
Final report of the clinical study 
• 
The Clinical Investigation Plan 
• 
Study training records for site personnel and Medtronic personnel involved in the study 
• 
Any other records that local regulatory agencies require to be maintained.  

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14.7.4. 
Sponsor Reports 
Medtronic shall prepare and submit the following complete, accurate, and timely reports listed in the 
table below.  In addition to the reports listed below, Medtronic shall, upon request of reviewing 
IRB/MEC, regulatory agency or FDA, provide accurate, complete and current information about any 
aspect of the investigation. Safety data Medtronic reporting requirements are listed in Section 10 of the 
Adverse Event section. 
Table 11: Sponsor Reports 
Report  
Submit to 
Description/Constraints 
Premature termination 
or suspension of the 
clinical investigation 
Investigators 
IRB/MEC 
Relevant authorities 
Head of the Institution 
Provide prompt notification of termination or suspension and 
reason(s).  
Final report 
Investigators, 
IRB/MEC,  
 
A final report will be submitted to the investigators, and 
IRBs/MECs within six months after completion or termination of 
this study.   
Study deviation  
Investigators 
Site specific study deviations will be submitted to investigators 
periodically.   
 
Medtronic records and reports will be maintained in a password-protected document management 
system, and paper documents (where applicable) will be stored in stored in secured file cabinets at 
Medtronic during the course of this study.  
After closure of the study Medtronic will archive records and reports indefinitely. 
14.8. Publication and Use of Information 
Publications from the Stroke AF study will be handled according to Cardiac Rhythm Heart Failure 
Standard Operating Procedures and as indicated in the Clinical Trial Agreement. 
14.8.1. 
Publication Committee 
Medtronic may form the Stroke AF Publication Committee from study investigators.  Medtronic 
personnel may serve as members of the committee.  This committee will manage study publications 
with the goal of publishing findings from the data.  The Publication Committee will develop the final 
Publication Plan as a separate document.   
The Publication Committee’s role is to: 1) manage elements addressed in the publication plan as 
outlined in this appendix, 2) develop the final Publication Plan under separate cover, 3) execute the 
Publication Plan, 4) oversee the publication of primary and ancillary study results, 5) review and 
prioritize publication proposals, 6) provide input on publication content, and 7) determine authorship.  

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In addition, the committee will apply and reinforce the authorship guidelines set forth in the Publication 
Plan.   
Membership in the Publication Committee does not guarantee authorship.  The committee will meet at 
regular intervals, as needed. 
14.8.2. 
Management of Primary, Secondary and Ancillary Publications 
The Publication Committee reviews, prioritizes, and manages all publications including primary, 
secondary and ancillary publications.  Primary and secondary publications are those that address 
analyses of any or all primary objectives or secondary objectives, respectively, as specified in the Clinical 
Investigation Plan.  
An ancillary publication is any publication that does not address the study objectives identified in the 
Clinical Investigation Plan.  They include publications proposed and developed by other Medtronic 
departments or entities, clinicians participating in this clinical study, and clinicians not participating in 
this clinical study.  The committee will work with Medtronic to ensure that requests do not present 
conflicts with other proposals, are not duplicative, and to determine which ancillary publication 
proposals, if any, will be supported.   
The committee may decide that no publications, including abstracts, will be published prior to the end of 
the study or with individual site data.  Requests for publications on study objectives utilizing subset data 
(e.g., regional) will be evaluated for scientific validity and the ability of Medtronic to provide resources.   
14.8.3. 
Criteria for Determining Authorship 
Publications will adhere to authorship criteria defined by the International Committee of Medical 
Journal Editors (ICMJE, Uniform requirements for manuscripts submitted to biomedical journals, 
www.icmje.org).  Individual authorship criteria defined by the target journal or conference will be 
followed when it differs from ICMJE criteria. 
Authors, including Medtronic personnel, must at a minimum meet all of the conditions below: 
• 
Substantial contribution to conception and design, or acquisition of data, or analysis and 
interpretation of data 
• 
Drafting the article or revising it critically for important intellectual content 
• 
Final approval of the version to be published 
Decisions regarding authorship and contributor-ship will be made by the committee. The selected 
authors will be responsible for drafting the publication. All selected authors must fulfill the authorship 
conditions stated above to be listed as authors, and all contributors who fulfill the conditions must be 
listed as authors. 

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All investigators not listed as co-authors will be acknowledged as the “Medtronic Stroke AF Clinical Study 
Investigators” and will be individually listed according to the guidelines of the applicable scientific 
journal when possible and affiliation. Any other contributors will be acknowledged by name with their 
specific contribution indicated. 
14.8.4. 
Transparency 
Transparency of study results will be maintained by the following means: 
• 
a final report, describing the results of all objectives and analysis, will be distributed to all 
investigators, MECs and Competent Authorities of participating countries when required by local 
law 
• 
registering and posting the study results on ClinicalTrials.gov based on the posting rules 
stipulated  
• 
submitting for publication the primary study results after the study ends  
• 
disclosing conflicts of interest of the co-authors of publications according to the policies set 
forth by the corresponding journals and conferences  
• 
making an individual sites study data accessible to the corresponding investigator after the 
completion of the study, if requested 
14.9. Suspension or Early Termination 
14.9.1. 
Planned Study Closure 
Study Closure is a process initiated by distribution of a study closure letter. Study closure is defined as 
closure of a clinical study that occurs when Medtronic and/or regulatory requirements have been 
satisfied per the Clinical Investigation Plan and/or by a decision by Medtronic or regulatory authority), 
whichever occurs first. The study closure process is complete upon distribution of the Final Report or 
after final payments, whichever occurs last. Ongoing Ethics Committee oversight is required until the 
overall study closure process is complete. Refer to section 7.14 for additional information regarding 
study exit procedures. 
14.9.2. 
Early Termination or Suspension 
Early Termination of the Study is the closure of a clinical study that occurs prior to meeting defined 
endpoints. This is possible for the whole study or a single site. Study Suspension is a temporary 
postponement of study activities related to enrollment and distribution of the product. This is possible 
for the whole study or a single site. 

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14.9.2.1. Study-wide Termination or Suspension 
Possible reasons for considering study suspension or termination of the study include but are not limited 
to: 
• 
Adverse events associated with the system or product under investigation which might 
endanger the safety or welfare of the subject 
• 
Observed/suspected performance different from the product’s design intent 
• 
Decision by Medtronic or regulatory body (where the study is operating under regulatory body 
authority)  
• 
Technical issues during the manufacturing process 
14.9.2.2. Investigator/Site Termination or Suspension 
Possible reasons for clinical investigator or site termination or suspension include but are not limited to: 
• 
Failure to obtain initial Ethics Committee approval or annual renewal of the study 
• 
Persistent non-compliance to the clinical investigation (e.g. failure to adhere to 
inclusion/exclusion criteria, failure to follow subjects per scheduled follow-ups)  
• 
Lack of enrollment 
• 
Noncompliance to regulations and the terms of the Clinical Trial Agreement (e.g. failure to 
submit data in a timely manner, failure to follow-up on data queries and monitoring findings in a 
timely manner, etc.)  
• 
Ethics Committee suspension of the site 
• 
Fraud or fraudulent misconduct is discovered (as defined by local law and regulations)  
• 
Investigator request (e.g. no longer able to support the study)  
14.9.3. 
Procedures for Termination or Suspension 
14.9.3.1. Medtronic-Initiated and Regulatory Authority-Initiated 
• 
Medtronic will promptly inform the clinical investigators of the termination or suspension and 
the reasons and inform the regulatory authority(ies) where required 
• 
In the case of study termination or suspension for reasons other than a temporary 
MEC/IRB/Head of Medical Institution approval lapse, the investigator will promptly inform the 
MEC/IRB/Head of Medical Institution  
• 
In the case of study termination, the investigator must inform the subjects and may inform the 
personal physician of the subjects to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subject enrollment must stop until the suspension is lifted by 
Medtronic 
• 
In the case of a study suspension, enrolled subjects should continue to be followed out of 
consideration of their safety, rights and welfare 

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14.9.3.2. Investigator-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension 
• 
The investigator will promptly inform the institution (where required per regulatory 
requirements)  
• 
The investigator will promptly inform the MEC/IRB/Head of Medical Institution 
• 
The investigator will promptly inform the subjects and/or the personal physician of the subjects 
to ensure appropriate care and follow-up is provided 
• 
In the case of a study suspension, subjects enrolled should continue to be followed out of 
consideration of their safety, rights and welfare 
14.9.3.3. Ethics Committee-Initiated 
• 
The investigator will inform Medtronic and provide a detailed written explanation of the 
termination or suspension within 5 business days 
• 
Subject enrollment must stop until the suspension is lifted 
• 
Subjects already enrolled should continue to be followed in accordance with MEC/IRB/Head of 
Medical Institution policy or its determination that an overriding safety concern or ethical issue 
is involved 
• 
The investigator will inform his/her institution (where required per local requirements)  
• 
The investigator will promptly inform the subjects, or legally-authorized designees or guardians 
and/or the personal physician of the subjects, with the rationale for the study termination or 
suspension 
 
 

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15. References 
Alejandro A. Rabinstein, M. J. (2013). Paroxysmal Atrial Fibrillation in Cryptogenic Stroke:A Case–Control 
Study. Journal of Stroke and Cerbrovascular Disease, 1-7. 
Dariush Mozaffarian, E. J.-P. (2015). Heart Disease and Stroke Statistics—2015 Update: A Report From 
the American Heart Association . Circulation, 29-322. 
L. M. Christensen, D. W. (2014). Paroxysmal atrial fibrillation occurs often in cryptogenic. European 
Journal of Neurology, 884-889. 
Luciano A. Sposato, M. M. (2012). Newly Diagnosed Atrial Fibrillation after Acute Ischemic Stroke and 
Transient Ischemic Attack: Importance of Immediate and Prolonged Continuous Cardiac 
Monitoring. Journal of Stroke and Cerebrovascular Diseases, 210-216. 
Owen, A. (2009). Antithrombotic treatment for the primary prevention of stroke in patients with non 
valvular atrial fibrillation: A reappraisal of the evidence and network meta analysis. International 
Journal of Cardiology, 1-6. 
Paul D. Ziegler, M., Taya V. Glotzer, M., Emile G. Daoud, M., D. George Wyse, M. P., Daniel E. Singer, M., 
Michael D. Ezekowitz, M. P., et al. (2010). Incidence of Newly Detected Atrial Arrhythmias via 
Implantable Devices in Patients With a History of Thromboembolic Events. Stroke, Journal of the 
American Heart Association, 256-260. 
Paul D. Ziegler, T. V. (2009). Incidence of Newly Detected Atrial Arrhythmias via Implantable Devices in 
Patients With a History of Thromboembolic Events. Stroke: Journal of the American Heart 
Association, 256-260. 
Ralph L. Sacco, M. M., Robert Adams, M. F., Greg Albers, M., Mark J. Alberts, M. F., Oscar Benavente, M., 
Karen Furie, M. M., et al. (2006). Guidelines for Prevention of Stroke in Patients With Ischemic 
Stroke or Transient Ischemic Attack. Stroke, 577-617. 
S. Adam Strickberger, M. J. (2005). Relationship between atrial tachyarrhythmias and symptoms. Heart 
Rhythm Society, 125-131. 
Tommaso Sanna, M. H.-C. (2014). Cryptogenic Stroke and Underlying Atrial Fibrillation. The new england 
journal of medicine, 2478-2486. 
William C. Choe, M. R.-C. (2015). A Comparison of Atrial Fibrillation Monitoring Strategies after 
Cryptogenic Stroke. The American Journal of Cardiology. 
 
 
 

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16. Version History 
Version 
Summary of Changes 
Author(s)/Title 
1.0 
• 
Not Applicable, New Document’ 
Jennifer Heim, 
Principal Clinical 
Research Specialist 
2.0 
• 
Table 1. Taryn Randall now monitoring contact at Medtronic. 
Rationale: Accuracy 
Jennifer Heim, 
Principal Clinical 
Research Specialist 
• 
Table 2. Clarified that there will be a CRO to manage blood 
samples. Rationale: Updated study design includes long term 
blood sample storage which will need to be managed by a CRO 
which is TBD. 
• 
Section 1 (Synopsis). Updated to reflect changes in study 
design which include: randomization (SoC vs LINQ), blood 
draw, additional study sites (was 30 now 40) and larger sample 
size (was 250, now 496). Study patients to be followed for 3 
years, until end of device life or study closure, whichever 
comes first. Rationale: Medtronic business decision to make the 
study more robust. 
• 
Section 2 (Introduction). Study purpose and description 
updated to include randomized design, larger sample size(sites 
and patients) and longer study duration. Rationale: Medtronic 
business decision to make the study more robust. 
• 
Section 6 (Methodology). Study objectives updated based on 
changes in study design (randomization). Rationale: Medtronic 
business decision to make the study more robust. 
• 
Section 7 (Study Procedures). Added randomization, blood 
draw, and cross over to study procedure table and updated 
visit descriptions as applicable. Added clarity around data 
collection only applicable to one study arm. Randomization 
section (7.8) added. Rationale: Medtronic business decision to 
make the study more robust. 
• 
Section 9 (Study Deviations). Added crossover as an example 
of a study deviation. Rationale: Clarity. 
• 
Section 13 (Statistical Methods and Data Analysis). Section 
updated to reflect revised study design and objectives. 
Rationale: Changes to study design. 
• 
Appendix I. Clarified that the CEC could serve as the EAC if 
desired. Rationale: To allow flexibility in study management. 
3.0 
• 
Glossary added, and document format updated. Rationale: 
Align with current document template. 
Christine Greening, 
Senior Principal 
Clinical Research 
Specialist 
• 
Removed contact information. Rationale: Contact information is 
maintained under separate cover. 
• 
Study Description and Statistical Methods and Data Analysis: 
Removed stopping rule for enrollment based on number of AF 
events. Rationale: Robust study with adequate data for analysis 
of all objectives. 

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• 
Duration: Enrollment updated from 20 to 42 months and study 
from 4.5 to 6.5 years. Rationale: Estimate updated per 
observed enrollment rate. 
• 
Informed Consent: Updated best practice documentation to 
should document the informed consent process in the source 
documentation. Rationale: Clarity. 
• 
Study Procedures related to blood draw: Added “or if the 
patient declines”. Rationale: Clarity. 
• 
Study Procedures related to Reveal LINQ ICM removed 
requirements for continuous monitoring arm only. Rationale: 
Allow for consistency in data collection for subjects with an 
ICM. 
• 
Follow-up Visit Procedure: Removed “in-clinic”. Data may be 
collected remotely for subjects unable to return to the clinic for 
the follow up visit. Rationale: Reduce patient burden of 
attending in-clinic as all data may be captured remotely. 
• 
System Modification Procedure: Removed “continuous 
monitoring arm only”. Rationale: Device modification should be 
reported for any subject with an ICM. 
• 
Data Review Committee: Steering Committee referenced in 
committee section. Removed contact details. Rationale: Clarity 
as contact details for all committees noted to be maintained 
separately. 
• 
Data Review Committee: Clinic Clinical Events Committee (CEC) 
review. “All” removed regarding reported arrhythmias. 
Rationale: Consistency with adjudication of time to first event. 
• 
Statistical Methods and Data Analysis. Add endpoint AF related 
hospitalization. Rationale: Business decision for additional 
analysis. 
• 
Statistical Methods and Data Analysis. CareLink transmission 
may be used for censoring. Rationale: Clarity. 
• 
Confidentiality: Added statement that all records and other 
information about subjects participating in this study will be 
treated as confidential. The identity of a subject will never be 
disclosed in the event that study data are published. Rationale: 
Clarity. 
4.0 
• 
Study Design: Updated the maximum of 200 subjects with 
lacunar stroke to a maximum of 50% (approximately 248) 
subjects. Rationale: Allow equal characterization of ischemic 
population. 
• 
Procedure table and follow up:  Updated device data to include 
either interrogation or transmissions. Rationale: Include either 
mode of device data collection for patients completing visits in-
clinic or remotely, consistency with text as updated in CIP 
revision 3.0. 
Christine Greening, 
Senior Principal 
Clinical Research 
Specialist