DEFINE AFib Atrial Fibrillation - Development of a Predictive Model for Future Health Care Utilization From Measurements Collected From an Implantable Cardiac Monitor.
Conditions: Atrial Fibrillation
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

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Clinical Investigation Plan 
Clinical Investigation Plan/Study Title  
DEFINE AFib Study 
Clinical Investigation Plan Identifier 
MDT20024 
Study Product Name 
Any market-released LINQ device 
Medtronic research application  
Sponsor  
 
Medtronic, Inc.  
8200 Coral Sea Street NE 
Mounds View, MN U.S.A. 55112 
Phone: 1-800-328-2518 
Document Version 
4.0, dated 29JUL2022 
Lead Principal Investigator(s) 
Dr. Jonathan Piccini 
Associate Professor of Medicine 
Duke University 
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 
1. 
Contact Information and Glossary .................................................................................. 6 
1.1 Sponsor Contact Information ............................................................................................ 6 
1.2 Glossary ........................................................................................................................ 6 
2. 
Synopsis ......................................................................................................................... 7 
3. 
Introduction ................................................................................................................. 11 
3.1 Background .................................................................................................................. 11 
3.2 Purpose ....................................................................................................................... 12 
4. 
Objectives and/or Endpoints ........................................................................................ 13 
4.1 Objectives .................................................................................................................... 13 
4.1.1 
Primary Objective(s) ....................................................................................................... 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5. 
Study Design ................................................................................................................ 15 
5.1 Duration ...................................................................................................................... 15 
5.2 Rationale ..................................................................................................................... 16 
5.3 Study Oversight ............................................................................................................ 16 
6. 
Product Description ...................................................................................................... 16 
6.1 General ........................................................................................................................ 16 
6.1.1 
Reveal LINQTM and LINQ IITM ICM System ........................................................................ 16 
6.1.2 
Medtronic Research App ................................................................................................ 19 
6.1.3 
Data Collection from LINQ Devices ................................................................................. 20 
6.2 Manufacturer ................................................................................................................ 20 
6.3 Packaging .................................................................................................................... 20 

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6.4 Intended Population....................................................................................................... 20 
6.5 Product Use .................................................................................................................. 21 
7. 
Study Site Requirements .............................................................................................. 21 
Study Site requirements, including site selection and activation, can be found in each specific DEFINE 
AFib study addendum. .......................................................................................................... 21 
8. 
Selection of Subjects .................................................................................................... 21 
9. 
Study Procedures ......................................................................................................... 21 
9.1 Schedule of Events ........................................................................................................ 21 
*+/-5 days survey administered randomly within each deployment window ................................... 23 
**+/-2 days is to correct for survey transmission issues ............................................................. 23 
9.2 Subject Screening .......................................................................................................... 23 
9.3 Prior and Concomitant Medications/Therapies .................................................................... 24 
9.4 Subject Consent and Enrollment ...................................................................................... 24 
9.5 Randomization and Treatment Assignment ........................................................................ 25 
9.6 Medication Use and Compliance ....................................................................................... 25 
9.7 Survey and Device Data Non-Compliance .......................................................................... 25 
9.8 Assessment of Safety ..................................................................................................... 26 
9.9 Recording Data ............................................................................................................. 26 
9.9.1 
Geofencing and Location Services ................................................................................... 27 
9.9.2 
Patient Surveys ............................................................................................................... 27 
9.9.2.1 Dynamic Surveys ................................................................................................................ 29 
9.9.3 
Healthcare Utilization ..................................................................................................... 30 
9.10 Patient Access to Device Data .......................................................................................... 30 
9.11 Deviation Handling ........................................................................................................ 31 
9.12 Subject Exit, Withdrawal or Discontinuation ....................................................................... 31 
10. 
Risks and Benefits..................................................................................................... 31 
10.1 Potential Risks .............................................................................................................. 31 
10.2 Potential Benefits .......................................................................................................... 32 
10.3 Risk-Benefit Rationale .................................................................................................... 32 
10.4 Risk Determination ........................................................................................................ 32 
11. 
Adverse Events and Device Deficiencies .................................................................... 32 
11.1 Adverse Events ............................................................................................................. 32 

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11.2 Product Complaint Reporting ........................................................................................... 33 
12. 
Data Review Committees .......................................................................................... 33 
13. 
Statistical Design and Methods ................................................................................. 33 
13.1 Statistical Study Design Considerations ............................................................................. 34 
13.2 General Aspects of Analysis ............................................................................................. 35 
13.3 Primary Objective .......................................................................................................... 35 
13.3.1 
Hypothesis...................................................................................................................... 35 
13.3.2 
Determination of Subjects/Data for Analysis................................................................... 36 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
14. 
Ethics ........................................................................................................................ 41 
14.1 Statement(s) of Compliance ............................................................................................ 41 
15. 
Study Administration ................................................................................................ 42 
15.1 Monitoring .................................................................................................................... 42 
15.2 Data Management ......................................................................................................... 42 
15.3 Direct Access to Source Data/Documents .......................................................................... 42 
15.4 Confidentiality ............................................................................................................... 42 
15.5 Liability ........................................................................................................................ 42 
15.6 CIP Amendments........................................................................................................... 43 
15.7 Record Retention ........................................................................................................... 43 
15.7.1 
Investigator Records ....................................................................................................... 43 
15.7.2 
Sponsor Records ............................................................................................................. 43 
15.8 Reporting Requirements ................................................................................................. 43 
15.8.1 
Investigator Reports ....................................................................................................... 43 
15.8.2 
Sponsor Reports ............................................................................................................. 43 

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15.9 Publication and Use of Information ................................................................................... 43 
15.9.1 
Publication Committee ................................................................................................... 43 
15.9.2 
Management of Primary and Ancillary Publications ........................................................ 44 
15.9.3 
Criteria for Determining Authorship................................................................................ 44 
15.9.4 
Transparency .................................................................................................................. 45 
15.10 
Suspension or Early Termination ............................................................................... 45 
16. 
References ................................................................................................................ 45 
17. 
Version History ......................................................................................................... 47 
 

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procedures, medications and lifestyle actions taken and their impact 
on device-detected AF.  Additionally, this study will help Medtronic 
evaluate patients’ interaction with reports generated from health 
data collected by the market-released LINQ ICM. This study will 
improve our understanding of how data from the LINQ family of 
devices can be used to guide the management of AF patients. 
• Product Status 
The study will be conducted using the components of the Medtronic 
Reveal LINQ or LINQ II system which are currently market-released in 
the participating geography (United States).  Future LINQ devices may 
also be used, should a new iteration be released during the study.  
 
This study will also use an iPhone® app built using Apple ResearchKit 
to collect data both (1) via the iPhone® through patient-reported 
health surveys and Bluetooth-enabled devices connected through the 
Apple Health app and (2) data accessed through or stored on the 
phone pertaining to health records, activity, and other lifestyle data. 
This will require an iOS of 13.X or higher.  
 
EHR and claims data will be collected if the patient has connected 
their DEFINE AFib profile to their EHR or claims data through the 
Apple Health app.   
 
The app will also be used to provide patients visibility to select data 
collected by their market-released LINQ (and other future models), 
and to characterize patient preferences for viewing and interacting 
with device data.  The iPhone® app will not directly communicate with 
any component of the Reveal LINQ or LINQ II system. 
Primary Objective 
To evaluate whether summary and episodic measurements collected 
by market-released LINQ ICMs are able to predict increased AF-
related healthcare utilization (HCU) 
Endpoint: Confirmed healthcare visit in the inpatient hospital, 
outpatient hospital, clinic/office, emergency department, or other 
care location (including remote visits) where AF was a reason or 
suspected reason for healthcare interaction 

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Study Design 
DEFINE AFib is a prospective, observational post-market clinical study. 
This study will enroll approximately 5,000 patients in the United 
States who have a Reveal LINQ or LINQ II ICM (or future market-
released LINQ devices) and using an Apple iPhone® with iOS version 
13.X or higher. Health and activity data will be collected from the 
iPhone® directly.  A study application will be used to administer 
health-focused and QoL surveys to patients at variable time points.  
Additionally, patients will be provided a summary of their device-
related data with subsequent patient experience surveys to 
understand how patients respond to and interact with their device 
data. Patients will be followed to either the end of their ICM service 
life or for up to five years.  
Randomization 
As this is an observational study, patients will not be randomized 
Sample Size 
Approximately 5,000 patients (see section 13.1) 
Inclusion/Exclusion Criteria 
Specific Inclusion/Exclusion criteria can be found in the applicable 
Addendum 

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Study Procedures and 
Assessments 
Interested patients will complete a screening questionnaire to 
determine eligibility.  Eligible patients will be invited to undergo an 
DEFINE AFib app-based electronic informed consent.  Following 
consent, the app will guide patients through the completion of their 
research profile, including the enabling of data collection and will 
complete baseline medical history and quality of life surveys. Consent 
documents will be stored in the DEFINE AFib app on the iPhone®. A 
copy of the consent will also be stored on secure Medtronic servers 
for compliance purposes.  
 
Following consent, patients will be asked to review what data they 
are willing to share with the study sponsor. For approved data 
sources, data will be collected through the iPhone® applications on an 
ongoing basis (including but not limited to physical activity and 
electronic medical record information).  Health, medication, 
symptom, and QoL surveys will be administered at variable 
timepoints based on LINQ ICM summary and episodic measurements, 
and the time interval since the last completed survey.  Lastly, patients 
will be provided select data from their LINQ ICM device, with 
subsequent patient experience surveys to understand how patients 
respond to and interact with their device data. Patients will have the 
ability to terminate their participation at any time.   
Safety Assessments 
The collection of adverse events and device deficiencies are not 
required to meet the objective(s) of this study.  
 
3. Introduction 
3.1 Background 
Atrial fibrillation (AF) is the most frequent clinically significant cardiac arrhythmia.1  When diagnosed 
clinically, AF is associated with increased risk for stroke, heart failure (HF), cardiovascular (CV) morbidity 
and mortality.2  It is also a major contributor to the costs of health care.3, 4  The prevalence of AF is 
predicted to rise significantly in the coming years due to the aging of the population and growing 
frequency of other AF risk factors.5, 6  Considering the rising burden and clinical sequalae of AF, 
strategies that enable early detection and appropriate clinical management are needed.   
 

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Insertable cardiac monitors (ICMs) now allow for continuous arrhythmia monitoring for up to four 
years.7  These devices have enabled early detection of AF that can be asymptomatic, infrequent, and/or 
of short duration.8-12  Accordingly, AF detected by ICMs may not be diagnosed through traditional clinical 
assessment.  Studies have demonstrated significantly higher rates of AF detection with ICM versus 
conventional monitoring in patients with a recent cryptogenic stroke11 and in patients undergoing 
catheter ablation for AF.13  Moreover, four recent trials have observed high rates of AF detection (21%-
40% over 12-30 months of follow-up) with ICM monitoring in patients who have risk factors for AF and 
stroke, but no clinical history of AF.8-10, 14  Two of these studies required conventional cardiac monitoring 
at baseline.9, 10  Together these studies demonstrate that continuous monitoring with an ICM can 
identify AF that would not be readily detected through standard clinical assessment.   
Prior studies have demonstrated that device-detected AF is associated with the same clinical outcomes 
as AF diagnosed through standard clinical practice, including stroke, mortality, and heart failure.15-17  
However, AF detected on implantable cardiac devices including ICMs can be transient and short in 
duration.  The amount of device-detected AF required to increase the risk of cardiovascular morbidity 
and mortality is unclear.  Prior studies have observed device-detected AF of different thresholds ranging 
from 6 minutes to 24 hours is associated with an increased risk of stroke.18-22  While stroke risk seems to 
increase with longer durations of device-detected AF, this relationship is not linear,17 and is impacted by 
the presence of other stroke risk factors.23, 24  Even less evidence is available for other adverse 
consequences of AF such as mortality, healthcare utilization and quality of life.  Accordingly, physicians 
are not clear when or how to intervene when AF is detected by ICM monitoring.25, 26  A key requirement 
to advance the management of AF patients is the development of tools that can assess important 
variables such as AF burden or patterns of AF that, alone or in combination with other clinically 
important variables, improve the risk prediction for AF-associated clinical outcomes with greater efficacy 
than current risk stratification modalities. Therefore, the goal of this study is to characterize the 
association between summary and episodic measurements collected by LINQ ICMs and AF-related 
healthcare utilization (HCU) in patients with device-detected AF.  
This information will inform how LINQ may be used to guide the appropriate care of patients with 
device-detected AF. 
3.2 Purpose 
The purpose of this study is to evaluate the association between complex patterns of device-detected 
AF and elevated healthcare utilization, reduced QoL and specific clinical outcomes in patients with a 
market released LINQ ICM.  These data will improve our understanding of how data from the LINQ ICM 
Family can be used to guide the management of patients with AF.  

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5. Study Design 
DEFINE AFib is a prospective, observational, post-market clinical study. This study will enroll 
approximately 5,000 patients (see section 13.1) in the United States who have a Reveal LINQ or LINQ II 
(or any other market-released LINQ device) and using an Apple iPhone®.  
This study will utilize the Reveal LINQ and LINQ II ICM or newer commercial ICM models and a 
Medtronic, Inc. developed research application for the Apple, Inc. iPhone®. The research application will 
allow for the remote enrollment and follow-up of patients by first administering electronic consent, 
providing patients the option to share their data from the Apple Health app, Electronic Health Records 
through the Apple Health app or location data, and deploying scheduled and triggered surveys to collect 
patient reported outcome measures. The market-released LINQ device will collect and report standard 
cardiac parameters through the CareLink network. The purpose of this study is to evaluate whether 
summary and episodic measurements collected by the market-released LINQ ICM are able to predict 
increased AF-related healthcare utilization (HCU) in patients with device-detected AF.  
Interested patients will download Medtronic’s research app (the “study app” or “research app”) and 
complete a brief in-app screening questionnaire to determine eligibility.  Eligible patients will be invited 
to proceed through the app to review and sign an electronic consent document. Should the patient have 
any questions regarding the study, the patient will have access to a phone number that connects them 
with a study help desk. The help desk has been qualified through Medtronic’s Global Security Office and 
Global Privacy Office to handle patient calls and is trained and overseen by Medtronic.  Following 
consent, patients will create a profile, opt in to sharing location, EHR data and other optional 
components of the study, and complete a baseline medical history survey and medication log.  
Following consent, data will be collected directly from the iPhone® on an ongoing basis (see section 9.9).  
Health, medication, and QoL surveys will be administered at baseline and at regularly scheduled 
intervals, while healthcare utilization and symptom surveys will be administered at variable timepoints 
based on market released LINQ ICM summary and episodic measurements and a patient, with 
anonymized location services (if enabled), crossing a predetermined healthcare location geofence.  
Lastly, patients will be provided select data from their LINQ ICM device, with subsequent patient impact 
surveys to understand how patients respond to and interact with their device data. To limit survey 
fatigue in patients with frequent health care utilization or qualifying AF episodes, no triggered survey 
will be deployed within 7 days of a previously deployed survey of the same kind. To limit the opportunity 
for duplicate surveys, each survey will have an expiration that is dependent upon how frequently it is 
issued (Table 4). Patients will have the ability to terminate their participation at any time through the 
study app.   
5.1 Duration 
All patients will be followed for up to 5 years, until study closure, or until their ICM either completes its 
service life or is explanted, upon which time they will no longer be followed.  Study closure may occur 

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when Medtronic requirements have been satisfied per the Clinical Investigation Plan (CIP) and/or 
following a decision by Medtronic or applicable external parties (i.e. institutional review board (IRB) or 
regulatory authority) to discontinue the study.    The estimated total study duration is up to 9 years, 
representing a four-year enrollment period and up to 5 years of follow-up for patients. Follow-up may 
be shortened based upon the interim analysis as outlined in section 13.   
5.2 Rationale 
The DEFINE AFib study is a prospective, observational, post market study to allow for the association 
between device-detected AF and healthcare utilization, physician-guided treatment, and QoL. A up to 5-
year follow-up duration was chosen to accommodate the low event rates expected in this patient 
population.  
A retrospective analysis using existing datasets including Optum electronic health records (EHR) and 
Claims data was considered.  Because these data sources are not specifically intended for research, they 
have numerous limitations including: inaccuracies, upcoding, absence of data provenance, insufficient 
granularity, and incomplete information (e.g. missing information due to receipt of care at different 
locations, changes in coverage, absence of data on medication compliance and QoL, etc.).  Considering 
these limitations, we have chosen to conduct a prospective study.  However, existing data sources have 
been leveraged in a preliminary analysis to inform the present investigation. 
5.3 Study Oversight 
The study will utilize a Steering Committee. The Steering Committee advises on the scientific content of 
the study and provides input for the execution. Members may be study site investigators. The purpose 
of the Steering Committee is to provide unbiased opinions and expertise to the clinical study design and 
process. The Steering Committee will support the execution of the DEFINE AFib study and provide 
guidance, feedback and direction to the study. The Steering Committee is comprised of the members as 
indicated in the DEFINE AF Steering Committee Charter. As membership may change, the current list of 
members can be made available upon request. 
6. Product Description 
6.1 General  
The study will be conducted using market released products/components as described below.  
Instructions for use of the devices used in this study are provided in their respective manuals. 
6.1.1 Reveal LINQTM and LINQ IITM ICM System 
The Reveal LINQTM ICM is a programmable device that continuously monitors a patient’s 
electrocardiogram (ECG) and other physiological parameters. The device records cardiac information in 
response to automatically detected arrhythmias and patient activation.  Patients with an existing Reveal 

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Reveal LINQ Description 
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 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. 
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. 
The Medtronic Programmer and LINQ Mobile Manager (LMM) are used to set up the device to detect 
arrhythmias and allow the user to view, save, or print the information stored by the device.   
The 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.  
The 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.  
Additional information related to the Reveal LINQ ICM, including indications, contraindications, 
warnings, and precautions can be found in the respective clinician manual. 
 
LINQ II Description 
LINQ II ICM: The LINQ IITM ICM is a small, leadless device that is inserted under the skin, in the chest. The 
device uses two electrodes on the body of the device to monitor the patient’s subcutaneous ECG 

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continuously. The device memory can retain ECG details for up to 30 min of symptom marked episodes 
per day. The system provides three options for segmenting the patient activated episode storage: a 10 
min recording (9 min before and 1 min after a symptom mark),  a 15 min recording (14 min before and 1 
min after a symptom mark) or no symptom activated episode storage. 
MyCareLink Heart App: The MyCareLink Heart™ mobile app is an application downloaded onto the 
patient’s smartphone. The patient app paired with a mobile device transfers encrypted medical device 
data between the inserted device and the CareLink Network. The patient interacts with the patient app 
for initial setup, viewing status information, and recording symptoms. The patient app can be enabled to 
record cardiac information in the LINQ IITM ICM while the patient is experiencing symptoms or 
immediately after a symptomatic event. The clinician uses the recorded information to determine if the 
symptoms were associated with a cardiac event. 
MyCareLink Relay Home Communicator: The MyCareLink RelayTM Home Communicator is a stationary 
device that transfers encrypted data from/to the patient’s inserted device and the CareLink Network for 
patients unwilling or unable to use a smartphone/tablet. Data communication is via Bluetooth Low 
Energy (BLE) to the LINQ IITM device and wireless internet to the CareLink Network. 
Patient Assistant: The Patient Assistant is a hand-held, battery-operated device that communicates with 
the LINQ II™ ICM via Bluetooth Low Energy.  The Patient Assistant enables the patient to record cardiac 
information in the LINQ IITM ICM while experiencing symptoms or immediately after a symptomatic 
event. The clinician uses the recorded information to determine if the symptoms were associated with a 
cardiac event. 
LINQ Mobile Manger (LMM) and Patient Connector Head: The Reveal LINQ Mobile Manager (LMM) 
clinician app is an application downloaded onto the clinic’s tablet that communicates with the LINQ IITM 
device using BLE (the tablet downloaded with the clinician app is also referred to as the “LMM” within 
this document). The LMM provides the operator an interface to change device settings (programming), 
interrogate the collected data, and display real-time data such as ECG, telemetered EGM and Marker 
Channel information. The LMM can also be used to assess the system. The LMM uses the 24967 Patient 
Connector head for communication.  
6.1.2 Medtronic Research App 
Medtronic’s research app (or “study app”) will be used for Define AFib to collect iPhone® data (including 
the  iPhone® Health App data, anonymized location services, and EHR/claims data if available), to 
electronically consent the subject in the app, administer patient questionnaires and to display select 
data from their LINQ ICM device directly to the patient.  This app is not intended as a substitute for 
medical diagnosis or treatment. This app was developed by Medtronic using the Apple ResearchKit and 
will be used for other studies in the future.  The research app will be available for download in Apple’s 
App Store.  The name for this app is the Medtronic Discovery App however, may be renamed through 
the course of the study.  All data collected from Medtronic’s research app will be stored in a Medtronic 

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secure, 21 CFR Part 11 compliant databases with controlled access.  The databases have been reviewed 
and approved by Medtronic’s Global Security and Privacy Office. 
6.1.3 Data Collection from LINQ Devices 
The following (but not limited to) data will be collected passively through the CareLink database. All 
device parameters and alerts will be programmed by the physician per standard care, and no changes 
will be mandated for the patient to participate in the study.   Data will be collected on an ongoing basis 
following documented patient consent, and until study termination or patient withdrawal.  Select 
variables will be collected. 
•   AF Episode 
•   AF events reported  
•   Daily Activity Level 
•   HR Variability  
•   AF Episode Duration 
•   Daily AF Burden 
•   History of EGMs  
•   HR in AT/AF  
•   Number of AF Episodes 
•   Baseline Heart Rate  
•   Counters  
•   HR Day 
• Episodes History 
 
 
• HR Night 
Data collection schedule is outlined in section 9. 
6.2 Manufacturer 
The Reveal LINQ and LINQ II ICM systems are manufactured by Medtronic, Inc.  
The Medtronic research app was developed by Medtronic, Inc.  
The Apple iPhone® is manufactured by Apple, Inc.  
6.3 Packaging 
Instructions for use of the devices used in this study are provided within their respective manuals.  None 
of the devices used in this study are investigational and therefore are not labeled with study-specific 
information.  
6.4 Intended Population 
The Reveal LINQ and LINQ II ICMs are indicated for the following: 
 
• 
Patients with clinical syndromes or situations at increased risk of cardiac arrhythmias 
• 
Patients who experience transient symptoms such as dizziness, palpitation, syncope, and chest 
pain that may suggest a cardiac arrhythmia   
See Section 8 for a description in inclusion and criteria.  
Medtronic’s research app is intended for all participants in the DEFINE AFib study.  

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6.5 Product Use 
The Reveal LINQ and LINQ II ICMs will be used in accordance with approved indications and site-specific 
standard of care.  No investigational products are being used in this study. 
The Medtronic’s research app will be available for download in Apple’s App Store.  All data collected 
from the DEFINE AFib Study research app will be stored in a Medtronic secure, 21 CFR Part 11 compliant 
databases with controlled access.    The databases have been reviewed and approved by Medtronic’s 
Global Security and Privacy Office. 
7. Study Site Requirements 
Study Site requirements, including site selection and activation, can be found in each specific DEFINE 
AFib study addendum. 
8. Selection of Subjects 
Selection of subjects, including study population, subject enrollment and inclusion/exclusion criteria can 
be found in each specific DEFINE AFib study addendum. 
9. Study Procedures 
9.1 Schedule of Events 
Clinical data are collected at designated time points throughout the study. The requirements for data 
collection and study procedures by visit are summarized in Table 3 below.  

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or first 
triggered 
event 
days*) (+/-2days**)   
(For triggered surveys, 
including healthcare 
facility geofence and daily 
AF burden from CareLink  
see section 9.9.2 ) 
• HCU survey should always 
be deployed with 
Symptom and Symptom 
Severity Survey 
• Symptom 
and 
Symptom 
Severity 
• MAFSI and 
modified 
EHRA 
symptom 
severity 
• Dynamic 
• Starting 30 
days after 
enrollment 
or first 
triggered 
event 
• Starting 30 days after 
enrollment and then 
monthly (30 days +/- 5 
day*)(+/-2days**)  
(For triggered surveys, 
including healthcare 
facility geofence and daily 
AF burden from CareLink  
see section 9.9.2 ) 
• Symptom and Symptom 
Severity survey should 
always be deployed with 
HCU survey 
• 7 days post 
issuance 
• Medication 
• SMAQ 
• Static 
• Starting 90 
days after 
enrollment 
(+/-2 days**) 
• Starting 90 days after 
enrollment and then every 
3 months (every 90 days 
+/-2days**) 
• 30 days post-
issuance 
• Patient 
App  
• Patient 
impact  
• Static 
• Starting 6 
months after 
enrollment 
(180 days +/-
2 days**),  
• Starting 6 months after 
enrollment and then every 
6 months (every 180 days 
+/-2 days**) 
• 90 days post-
issuance 
*+/-5 days survey administered randomly within each deployment window 
**+/-2 days is to correct for survey transmission issues 
9.2 Subject Screening 
Interested patients will be required to download Medtronic’s research application. Upon first accessing 
the application after downloading, potential subjects will undergo authentication. Potential participants 
will complete the eligibility survey available in the app.  Patients who meet the inclusion criteria based 
on self-report and a device serial number check via the app will be invited to participate in the study and 
directed to a digital consent form within the app for their review and electronic signature.  A phone 
number for the Help Desk will be provided prior to consenting of the subject if the subject has any 
questions regarding their participation in the clinical study.   

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9.3 Prior and Concomitant Medications/Therapies 
There are no requirements or restrictions with respect to prior or concomitant medications.  Patients 
will be asked to record the medications they are taking and will be routinely asked to recall medication 
compliance through regularly deployed surveys throughout the study.  
9.4 Subject Consent and Enrollment 
The informed consent is defined as a legally effective documented confirmation of a patient’s voluntary 
agreement to participate in a particular clinical study after information has been given to the patient 
through the study app on all aspects of the clinical study that are relevant to the patient’s decision to 
participate.  This process includes obtaining an ICF and an Authorization to Use and Disclose Personal 
Health Information that has been approved by an Institutional Review Board and electronically signed 
and dated by the patient.  
Prior to enrolling patients, approval of the CIP, ICF, and all other written study information to be 
provided to the patients must have been approved by a registered IRB.  The document(s) must be 
controlled (i.e. versioned and dated) to ensure it is clear which version(s) were approved.   
The investigator must notify patients of any significant new findings about the study that become 
available during the study which are pertinent to the safety and well-being of the patient, as this could 
impact a patient’s willingness to participate in the study.  If relevant, approval may be requested from 
patients to confirm their continued participation. 
Electronic consent will be obtained prior to subject enrollment and before any study-specific procedures 
are initiated. Consent will be self-administered by the patient via the informed consent process. The 
process of obtaining informed consent must be conducted without using coercion or undue improper 
influence on or inducement of the patient to participate by the study or affiliated personnel.  The 
informed consent process shall not waive or appear to waive patient’s legal rights.  The language used 
shall be as non-technical as possible and must be understandable to the patient. 
The patient must have ample time and opportunity to read and understand the ICF, to inquire about 
details of the study via the study help desk, and to decide whether to participate in the clinical study.  All 
questions about the study should be answered to the satisfaction of the patient. To facilitate patient 
access for questions, patients will have access to the study help desk, which will be equipped to answer 
study-related questions.  A phone number for the Help Desk will be provided prior to consenting of the 
subject to allow the subject the ability to answer any questions regarding their participation in the 
clinical study. 
When the patient decides to participate in the clinical study, the ICF must be electronically signed and 
dated by the subject acknowledging that their participation is voluntary.  

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The ICF and Authorization to Use and Disclose Personal Health Information will be electronic. A copy of 
the signed and dated ICF and Authorization documents will be available within Medtronic’s research app 
for patient reference.  An additional copy of the signed and dated ICF and Authorization will be stored in 
a secure part 11 compliant system, access-controlled Medtronic database and shared with the primary 
investigator upon request. 
The informed consent will be obtained the same day the subject is eligible to begin participating in 
study-related procedures, and therefore consent date and time will be documented in the meta-data 
collected with consent. The study app will allow for the patient to access their consent at any time.  
9.5 Randomization and Treatment Assignment 
There will be no randomization or treatment assignments as this is an observational study. 
9.6 Medication Use and Compliance 
Patients will be asked to log medications at baseline and asked at regular intervals to update their 
medication list if there are any changes throughout the duration of their participation in the DEFINE AFib 
study (Table 4). Patients will store current medications in their research profile and update every 6 
months; medication use and compliance assessed via the SMAQ survey deployed every 3 months. For 
patients with health record access, statistical models will be developed to estimate the proportion of 
days covered by leveraging EHR or claims data and/or patient surveys regarding prescription fills and/or 
refills. All changes in medication use will be marked with time and date via meta-data tracked in 
Medtronic’s research application.  All medication changes will be confirmed.    
9.7 Survey and Device Data Non-Compliance 
Monthly reports will be generated to assess response rates on surveys.  Patients with missing survey 
responses or other incomplete tasks will be sent reminders through the app, via email, and via text 
depending on which communication methods are available and the patient has enabled. A schedule of 
these reminders can be found in Table 5. In the instance that a patient has undergone a prolonged 
period of time without transmitting device data, they will be notified via the app. At 90 days, mortality, 
HCUs,  and specific clinical outcome status will be assessed via EHR or confirmed via study site 
personnel. After 90 days, if confirmed to be alive, they will continue to be monitored but may be 
excluded from statistical analysis.  
Subjects will be reimbursed $25 every 6 months if they complete >75% of surveys.  Subjects will receive 
an electronic gift card to their email. 
Table 5: Notification and Reminder Schedule 
Expiration Schedule 
Reminder Schedule 
7 Day Expiration Schedule 
4 Days post issuance 
14 Day Expiration Schedule 
7 Days post issuance 

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1 Month Expiration Schedule 
10 Days post issuance, then 20 days post issuance if action not 
completed 
3 Month Expiration Schedule 
10 Days post issuance, then 20 days post issuance if action not 
completed 
6 Month Expiration Schedule 
10 Days post issuance, then 20 days post issuance if action not 
completed 
 
9.8 Assessment of Safety 
Because 1) this is an observational study using market approved devices for approved indications and 2) 
there are no study aims evaluating device safety, adverse events will not be collected. Should any new 
risks associated with the study be identified including patient data security, patients will be notified via 
push notifications, in-app messaging, email, and SMS text message, depending on what form of 
communications the patient has opted into. Physicians will be notified of any new risks associated with 
the study.  Continuous monitoring of study risks will be performed using Medtronic’s Global Security 
Office-required security controls which include monitoring procedures/platforms that are capable of 
logging, monitoring, detecting data breaches and app problems.  These procedures are governed by 
Medtronic’ Global Security Office and Cloud Governance teams. Monitoring of study risks will be 
performed using standard monitoring procedures. 
9.9 Recording Data 
The following data will be collected passively through Medtronic’s research app.  Data will be collected 
on an ongoing basis following documented patient consent, and until study termination or patient 
withdrawal. Following consent, patients will create a profile, opt in to sharing location, EHR data and 
other optional components of the study and the patient will have the opportunity to change data 
permissions that determine collectable data throughout the study. If patients consent to sharing their 
EHR data, that patient’s EHR data will be pulled via the Apple Health app.  If EHR access is available, it 
will be used to confirm patient-reported events as described in section 12.  EHR data may also be used 
to compile and analyze variables as outlined in section 13.  
• 
Electronic Health Records  
o Clinical Vitals 
o Diagnoses/Conditions 
o Lab results 
o Medications 
o Medical procedures/clinical actions 
o Patient mortality 

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• 
Health app data (when available, including but not limited to) 
o Step counts to assess activity 
o Nutrition  
o Sleep 
o Vitals 
 
Glucose 
 
Blood pressure 
 
SPO2 
o Body measurements: 
 
Weight 
 
Height 
 
Body mass index 
• 
Location services (when available) 
o Anonymized geofencing triggers 
9.9.1 Geofencing and Location Services 
Use of geofences will only be permissible in patients who have consented and enabled to the use of 
their phone’s location services feature. Geofenced facilities will include 12,000+ hospitals and urgent 
care healthcare facilities in which a patient is likely to seek care. Only anonymized geofence data will be 
collected which cannot be connected back to the patient it originated from. After Consent, Medtronic 
servers will deploy the appropriate surveys under the logic provided in Table 4. 
 
9.9.2 Patient Surveys 
Patient surveys will be administered to assess medical history, QoL, HCU, changes in medical 
management, AF-associated symptoms, and medication use.  Surveys will also be administered to 
evaluate patient preferences for viewing and interacting with device data.  Exact content of the surveys 
may change throughout the study, but any significant content changes will be submitted to IRBs for 
approval.   
Survey deployment logic is outlined in Table 4. 

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• 
QoL Questionnaires 
o The EQ-5D-5L general QoL survey will be distributed via the app at enrollment and then 
every 3 months(90 days +/-2 days)  to assess general quality of life metrics 
o AFEQT, an AF specific QoL survey will be deployed via the app at enrollment and then 
every month (30 days +/-2 days)  to characterize and assess the impact of AF on each 
patient 
• 
Symptom Survey: 
o A symptom survey will be administered to characterize the presence and severity of AF-
related symptoms when a patient crosses a predefined healthcare facility geofence, 
reaches the threshold for a single AF episode or daily AF burden or AF pattern, or; 
o On a routine monthly (30 days +/-5 days) schedule unless a symptom survey has been 
deployed for any reason within the previous 7 days. 
• 
Healthcare Survey 
o A healthcare survey will be deployed to characterize healthcare utilization and 
modifications to patient care (administration of medical interventions/procedures) 
when a patient crosses a predefined healthcare facility geofence, reaches the threshold 
for a single AF episode or daily AF burden or AF pattern, or; 
o On a routine monthly (30 days +/-5 days) schedule unless a symptom survey has been 
deployed for any reason within the previous 7 days. 
• 
Medication compliance 
o Patients will answer the Simplified Medication Adherence Questionnaire (SMAQ) every 
3 months (90 days +/- 2 days) following initial enrollment. 
• 
Medication list 
o Patients will be prompted to input/update their medications upon enrolling in the study 
and every 6 months (180 days +/-2 days) following initial enrollment. 
Surveys will also be administered to evaluate patient preferences for viewing and interacting with device 
data.  Data around app-use will also be collected (time in app, app feature use, number of clicks, etc.). 
 

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In the event that the patient has lost connectivity (no signal or phone powered off) for an extended 
period of time, all non-expired surveys will be received upon first opportunity of connectivity.  
Expiration windows will remain consistent as noted in table 4 regardless of connectivity. 
9.9.2.1 Dynamic Surveys 
 
The HCU and Symptom survey are dynamic in nature.  Patients will be prompted to complete surveys 
through Medtronic’s research app.  Surveys will be triggered at variable times based on the following 
factors: 
• 
Time from enrollment  
• 
Time since last survey – (HCU and Symptom and Symptom Severity surveys) 
• 
ICM device data (triggers HCU and Symptom and Symptom Severity surveys) 
o A single AF episode lasting longer than 1-hour 
o Cumulative daily AF burden of 5% or greater 
o A patient meets the running average/AF pattern threshold as developed by a prior 
internal analysis  
• 
Geofence (triggers HCU and symptom surveys) 
o Patient crosses a geofence threshold and remains within the geofenced area for ≥45 
minutes 
Each patient will receive surveys via one of three methods: 1) Regularly scheduled surveys at specified 
cadences, 2) AF burden or pattern trigger detected via the Reveal LINQ or LINQ II device (or future 
market-released LINQ devices) and transmitted through CareLink, 3) a patient crossing and staying 
within a geofence. Each regularly scheduled deployment window will be +/- 5 days around 30 days from 
previous survey deployment, with the survey administered randomly within each deployment window. 
This method reduces the likelihood that a patient will suspect a survey has been given in response to an 
AF episode they experienced, and helps to avoid any bias associated with the expectation of a survey at 
a particular cadence. Additionally, patients may receive a HCU and symptom survey at pre-specified 
trigger points based on Reveal LINQ or LINQ II (or future market-released LINQ devices) detected AF 
burden or AF patterns, or via the patient being present in a geofenced healthcare facility, within 24-48 
hours of the trigger being activated in order to best associate AF patterns with patient health and 
environmental factors. Patients who trigger any of the AF burden thresholds for HCU or symptom survey 
deployment will, at the first instance, all receive the assigned surveys. Patients will not be notified which 
method triggered a survey. Thereafter, any AF burden trigger will be administered at a rate of 50%, 

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allowing for the testing of bias introduced by triggered survey deployment and reduce patient survey 
burden.   
 
9.9.3 Healthcare Utilization 
Healthcare utilization (HCU) information data will be collected and classified according to the below 
definitions.  
Details on how HCU will be confirmed can be found in each specific DEFINE AFib study addendum. 
Table 6: Healthcare Utilization Definitions 
Healthcare Utilizations 
(HCU) 
All inpatient hospitalizations, outpatient hospital encounters, emergency department visits, 
clinic visits, urgent care visits, rehab center or other care location interactions (including 
remote visits) 
CV-related HCU 
A healthcare utilization relating to the heart and the blood vessels or the circulation (e.g., 
atrial fibrillation, myocardial infarction, stroke, peripheral vascular disease, heart failure). 
AF-related HCU 
HCU related to AF, suspected AF, AF treatment, or complications related to AF (including 
bleeding and drug toxicity as determined by treating clinician.   
HF-related HCU 
A healthcare utilization related to worsening heart failure signs and symptoms  (as 
determined by treating clinicians) such as (but not limited to) hypervolemic and hypovolemic 
status requiring the administration, alteration, adjustment, or augmentation of HF therapy 
(diuretics, inotropes and/or vasodilators etc.) or the utilization of ultrafiltration devices. 
Hospitalization 
A therapeutic inpatient hospitalization (excludes outpatient and emergency room visits) 
lasting greater than or equal to 24 hours. 
Non-hemorrhagic 
stroke 
Rapid onset of a focal or global neurological deficit or other neurological signs/symptoms 
consistent with stroke; whereas focal, global cerebral or spinal dysfunction was NOT caused 
by a non-traumatic intraparenchymal, intraventricular, or subarachnoid hemorrhage, as 
determined by the treating clinician.  
Systemic embolism 
An embolus resulting in clinical and objective evidence of sudden loss of end organ perfusion. 
TIA 
New focal neurological deficit with rapid symptom resolution (usually 1 
– 2 hours), always within 24 hours without tissue injury (based on 
neuroimaging) as determined by the treating clinician.  
 
 
9.10 Patient Access to Device Data 
Select data collected by the market-released LINQ devices will be accessible to patients through 
Medtronic’s research app. Through the app, patients will be able to see and interact with infographic 
screens and charts that show their average daily, weekly or monthly Atrial fibrillation burden. 
Patients will be notified through the app that they should not make any changes in behavior, 
modifications to treatment, or any other actions related to their health without first speaking with their 
physician. Patients will be notified that the Medtronic research app does not communicate with other 

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Medtronic apps and that data shared through the research app is not shared with their physician and 
will not be sent back through the CareLink network. Patients will also be notified how the data they are 
viewing is generated and any reason for delays in their data updates. 
9.11 Deviation Handling 
A study deviation is defined as an event within a study that did not occur according to the Clinical 
Investigation Plan. Due to the nature of this study, deviations will not be collected via the patient or site.  
Patients who do not meet inclusion/exclusion criteria will be excluded from analysis.  Study level 
deviations will be collected as appropriate and submitted to IRBs. 
9.12 Subject Exit, Withdrawal or Discontinuation 
A subject may choose to discontinue participation at any point, and can do so by selecting the 
appropriate option through the study app.  Subjects may also be notified and exited by the sponsor (via 
the study app) if they are inactive, have either stopped responding to surveys or stopped transmitting 
LINQ data for 90 days or greater, or determined to be deceased.  Upon study exit, subject data 
collection will discontinue and data collected up until the time of withdrawal will be utilized for 
statistical analysis unless otherwise specified by the patient and in accordance with data privacy laws. 
Patients who withdraw from the study prior to a minimum 12 month follow up will be replaced to 
ensure appropriate statistical power can be achieved. As this is an observational study in a patient 
population that received their ICM device per standard of care and independently of their participation 
in this study, patients will continue routine care with their physician.  
See specific Addendum for additional details. 
10. Risks and Benefits 
10.1 Potential Risks 
There are no additional risks of having the LINQ device since all patients are indicated to have the LINQ 
device as part of standard of care.   
Medtronic’s research app does not present a potential for serious risk to the health, safety, or welfare of 
a participant, as the app only serves as a method to collect non-invasive study data and present the 
patient’s own device data back to them. 
As there is the potential for a patient to have more than one Medtronic app for their LINQ device, any 
screens that could be confused with another Medtronic app for clinical management of patients (i.e. the 
MyCareLink Heart app), plain language disclaimers with acknowledgement prompts will be present to 
inform the patient that any information reported through Medtronic’s research app will not reach their 
physician, unless otherwise specified. There is no interaction between any other Medtronic app for this 
study.   

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The patient data view does have the potential to share device data that may include false positive AF 
episodes. To minimize this risk, the only AF specific device data patients will have the ability to view is 
their daily AF burden in intervals, and will include notification that the data has not been adjudicated by 
their physician.  There is the possibility of app dysfunction that could delay participants’ ability to enter 
information into the study. Any modifications to the study, including the cessation/re-starting of study 
data collection, or newly detected risks of participating in the study will be communicated to the patient 
via several outreach methods including in app notification and text message, and email, if the patient 
has opted into those notification methods. 
Continuous monitoring of study risks will be performed using Medtronic’s Global Security Office-
required security controls which include monitoring procedures/platforms that are capable of logging, 
monitoring, detecting data breaches and app problems.  These procedures are governed by Medtronic’ 
Global Security Office and Cloud Governance teams. 
10.2 Potential Benefits 
The DEFINE AFib study may not provide direct benefit to the patient, although the patient will have a 
platform to view certain data about their health. Patients will be able to view certain summary views of 
their LINQ or LINQ II (or other approved LINQ family of products) device data, including AF burden (in 
summarized graphs), patient activity, and average heart rates. This may lead to a better understanding 
of their condition.  The information gained from the study could result in improved management of AF 
and help better understand outcomes in different patient populations in the future.  
10.3 Risk-Benefit Rationale 
Medtronic has minimized the possibility of applicable risks and potential sources of bias by providing 
guidelines for subject selection and evaluation. In addition, a documented protocol and standardized 
data collection within the app will be used. Privacy risks have been minimized by the use of Part 11 
compliant systems. 
10.4 Risk Determination 
No investigational devices are being used in this study.  This study is a prospective, observational, post-
market study.  
11. Adverse Events and Device Deficiencies 
11.1 Adverse Events 
The collection of adverse events/device deficiencies are not required to meet the objective(s) of this 
study. The LINQ devices used in the study are market-approved and used within the current indications 
for use as indicated in the product labeling; however, it is the responsibility of the Investigator to abide 
by any adverse event and/or device deficiency reporting requirements stipulated by the site’s IRB. User 

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(Investigator) reporting of events to regulatory authorities related to market approved product may be 
required. Refer to local regulations for reporting requirements. 
11.2 Product Complaint Reporting 
For devices that are market-released, product complaint reporting is applicable. The reporting of 
product complaints is not part of the clinical study. 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-products. 
12. Data Review Committees 
This is a prospective, observational, post-market clinical study.  There are no objectives for this study 
related to safety or efficacy. The collection of adverse events is not required to meet the objective(s) of 
this study. Therefore, data review committees will not be used for this study, however, there are 
reviews and confirmation of certain variables as detailed below. 
Individual AF episodes will be batched and adjudicated throughout the study by an independent 
reviewer that will classify the event as a true-positive or false positive AF episode.  
Healthcare utilization and modification to treatment or management of AF will be reviewed and 
confirmed in subjects with available health records to compare to patient completed surveys.  Specifics 
on how each utilization is confirmed can be found in each DEFINE AFib Study addendum.   
Data from Apple Health App will not be independently adjudicated as there are no reliable means to do 
so within the scope of this study. Patient geofence trigger counts will be reviewed to screen for patients 
who may have reasons for triggering this survey deployment tool due to reasons other than seeking 
medical care (i.e. a patient works in or directly near a hospital, a mislabeled hospital, etc.).  
13. Statistical Design and Methods 
Data analysis will be performed by a Medtronic statistician or designee. 
The cohort will include all enrolled subjects, but non-confirmed events will not contribute to the study’s 
endpoints.  

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A Statistical Analysis Plan will be developed and kept under separate cover and will include a 
comprehensive description of the statistical methods and reports to be included in the final study 
report, as well as a description of how missing, unused, and spurious data will be accounted. 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. 
13.1 Statistical Study Design Considerations 
The DEFINE AFib study is a prospective, observational post-market clinical study intended to leverage 
machine learning to evaluate the association between complex patterns of device-detected AF and 
elevated healthcare utilization, reduced QoL and specific clinical outcomes in patients with a LINQ ICM.  
These data will improve our understanding of how data from the LINQ ICM can be used to guide the 
management of AF patients.  The DEFINE AFib study is not designed to be powered and no specific 
hypotheses will be tested.  However, the sample size was determined with the goal of having an 
adequate number of endpoint events to develop risk prediction models that can have incremental 
clinical benefit beyond what is available as standard of care. 
 A retrospective analysis of the Optum EHR deidentified database (2007-2019), linked to the Medtronic 
CareLink database of insertable cardiac monitoring (ICM) devices, suggests that in a cohort of 5,000 
patients from the intended population of ICM patients, 600 (12%) will have at least one ischemic stroke 
event and 2,350 (47%) will have at least one healthcare utilization in a five-year follow-up period.  Of the 
healthcare utilization events, 1,050 (21%) will be AF-related.  It is expected there will be approximately 
5.2 million follow-up days.  Given the large number of follow-ups, the ratio of events to follow-up days is 
extremely rare.  Traditional classification approaches (CART, random forest) require under/over-
sampling methods and control parameters for adequate convergence.  In our retrospective analysis, we 
defined the target window as the five days prior to an event (thereby over-sampling events by a factor 
of five) and then under-sampled controls to a 1:1 ratio with over-sampled cases to create a balanced 
data set.  Setting a minimum node size of 80 patients and requiring the minimum node size to range 
between 2% and 5% of balanced data, adequately converged to results.  The under-sampling and model 
fitting exercise was repeated 100 times to bootstrap an estimate of variable importance for each 
variable in the model.  Using this methodology for convergence and estimation, we expect a minimum 
of 160 (80/0.05/10) to 400 (80/0.02/10) events are needed for analyzing predictor variable influence 
and 320 to 800 events for creating a prediction algorithm that requires development, test, and 
validation partitions as part of its methodology.  This latter range is sufficient for deep learning 
approaches (e.g., LSTM autoencoder, CNN classification network) for predicting extremely rare events. 
A minimum of 320 to 800 events implies a 5,000 patient cohort is minimally sufficient for algorithm 
development.  This, however, assumes patients enroll immediately after implant and does not consider 
attrition.  Moreover, this retrospective analysis showed that 30% of patients will miss at least 50% of 
their daily CareLink transmissions.  Considering these challenges, it is reasonable to expect as little as 

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50% of our cohort to provide complete data.  In such a scenario, a 5,000 patient cohort would be 
sufficient for modeling health care utilization (1,175 events, 525 AF-related) but would be insufficient for 
modeling ischemic stroke or for modeling outcome events by smaller subgroups. 
A planned interim analysis will be performed in which we will re-assess these assumptions to determine 
if the sample size or follow-up duration of the study needs to be adjusted.  
13.2 General Aspects of Analysis 
Data from all enrolled patients will be summarized, but analysis of each objective will account for the 
completeness of the data in the context of addressing the objective.  In particular, patients contributing 
to objectives that are modeling HCU-based outcomes should have provided a minimal amount of 
information to ensure that HCU data has been made available.  This can be accomplished through the 
completion of monthly and triggered surveys or by sharing EHR information through the study app or via 
sites.  Complete device data should be available for all patients.  Patients should have regularly 
transmitted CareLink data throughout follow-up.  If no device data or limited device data is available 
from a patient, that patient will need to be either excluded from analysis or follow-up will need to be 
limited to the period of time up until device data is not available.  
For patients that enroll at the time of ICM implant, all follow-up data will be analyzed from the time of 
implant if the patient completes all baseline enrollment tasks within 7 days of the ICM implant.  Baseline 
enrollment tasks include enrollment, signing their consent, and completing all baseline survey 
questionnaires (patient profile, medical history, medication history, EQ-5D-5L, AFEQT).  For patients that 
are enrolled more than 7 days after the ICM implant or that complete enrollment tasks more than 7 
days post-implant, follow-up will begin when the patient has completed electronic consent.  
13.3 Primary Objective 
To evaluate whether summary and episodic measurements collected by the market-released LINQ ICMs 
are able to predict increased AF-related healthcare utilization (HCU)  
13.3.1 
Hypothesis 
No formal statistical hypotheses will be tested for this objective.  Rather, the goal will be to determine 
whether a risk prediction model can be developed from device-collected measurements that can has 
adequate sensitivity and specificity to be of use in a clinical setting. 
Analysis Methods 
Various risk prediction models will be developed and compared to each other. The model(s) with best 
predictive power will be selected.  The input data of these models might be composed of values (original 
or derived) collected by LINQ ICMs, and the output of the model will be the risk of patient having a AF-
related HCU in the future. The model may also account for attributes of patients’ medical histories, 
including CHA2DS2-VASc scores, individual components of CHA2DS2-VASc scores and any other medical 

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history information provided by the patient at enrollment.  The predictive value of the model will 
generally be assessed against the predictive power of any clinical tools available at the time of model 
development.  If additional predictive tools become available at the time of model development, those 
tools can be integrated into the development of the model and the value of the model will reflect the 
incremental benefit provided above and beyond the available clinical tools. 
Endpoint: Confirmed healthcare visit in the inpatient hospital, outpatient hospital, clinic/office, 
emergency department, or other care location (including remote visits) where AF was the reason or 
suspected reason for healthcare interaction. 
13.3.2 
Determination of Subjects/Data for Analysis 
All subjects enrolled in the study that have successfully installed the app and consented will be included 
in the primary objective analysis.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

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14. Ethics 
14.1 Statement(s) of Compliance 
The DEFINE AFib study is classified as an prospective, observational, post market study.  
 
 
The principles of the Declaration of Helsinki have been implemented in this study by means of the 
patient informed consent (PIC) consent (also known as the Informed Consent Form), IRB approval, study 
training and clinical trial registration.  
 
In the United States, the study will be conducted in compliance with: 21 CFR 803, 21 CFR Parts 11, 50, 
and 56. Local laws and regulations will be applicable in the countries where the study is conducted. 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 IRB before 
initiating a study, continuing review of an ongoing study by IRBs, and obtaining and documenting the 
freely given informed consent of a subject before initiating the study. 
 
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).  

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15. Study Administration 
15.1 Monitoring 
Monitoring requirements can be found in each specific DEFINE AFib study addendum.  
15.2 Data Management 
Data collected via the study app and will be stored in a secure, part 11 compliant, password-protected 
database which will be backed up routinely.  At the end of the study, the data will be frozen and will be 
retained by Medtronic in accordance with applicable regulations. 
Data will be reviewed using programmed and manual data checks in addition to reports that compile 
relevant data collected from the study app.  Subjects will receive notifications and reminders when their 
study tasks are due.  Study management reports may be generated to monitor data quality and study 
progress.   
Device data from CareLink transmissions will be uploaded to secure servers. Upon receipt, device data 
will be maintained within databases and retrieved for analysis and reporting.   
Changes to the data elements in the electronic system will retain the original data and an audit trail 
(date, time, and originator of the change and reason).  At the end of the study, the data will be frozen 
and will be retained indefinitely by Medtronic. 
15.3 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, IRB review, 
and regulatory inspection(s) by providing direct access to source data/documents. If study site’s 
documents are electronic, these must be made available in their original form (or printouts signed and 
dated with the statement that this is complete and true reproduction of the original source document) if 
requested by the sponsor and/or regulatory authority. Study sites should inform Medtronic upon 
notification of an audit by a regulatory body immediately.  
15.4 Confidentiality 
All records and other information about subjects participating in this study will be treated as 
confidential. This means information about subjects participating in the study will be secured and 
protected from unauthorized access. Data will be key coded prior to use by Medtronic or any designated 
third-parties to reduce any risk of reidentification unless it’s impossible to make it anonymous.  
15.5 Liability 
Medtronic maintains appropriate clinical study liability insurance coverage as required under applicable 
laws and regulations and will comply with applicable local law and custom concerning specific insurance 
coverage. If required, a clinical study insurance statement/certificate will be provided to the IRB/EC. 

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The Publication Committee’s role is to:   
• 
Manage elements addressed in the publication plan as outlined in this section 
• 
Develop the final Publication Plan under a separate cover 
• 
Execute the Publication Plan 
• 
Oversee the publication of primary, secondary, and ancillary study results 
• 
Review and prioritize publication proposals 
• 
Provide input on publication content, and 
• 
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 as 
needed. 
15.9.2 
Management of Primary and Ancillary Publications 
The Publication Committee reviews, prioritizes, and manages all publications including primary and 
ancillary publications.  Primary publications are those that address analyses of the primary objective as 
specified in the Clinical Investigation Plan. An ancillary publication is any publication that does not 
address the primary study objective identified in the Clinical Investigation Plan.  They include 
publications proposed and developed by the Publication Committee, 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 the 
primary results, 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.   
15.9.3 
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. 
Decisions regarding authorship and contributor ship will be made by the Publication Committee. The 
selected authors will be responsible for drafting the publication. All selected authors must fulfill ICMJE 
authorship conditions to be listed as authors. 

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All investigators not listed as co-authors will be acknowledged as the “Define AFib Study Investigators” 
and will be individually listed according to the guidelines of the applicable scientific journal when 
possible. Any other contributors will be acknowledged by name with their specific contribution 
indicated. 
15.9.4 
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 and IRBs/ECs 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 (e.g., financial) of the co-authors of publications according to the 
policies set forth by the corresponding journals and conferences  
• 
Making an individual site’s study data accessible to the corresponding investigator after the 
completion of the study, if requested 
15.10 
Suspension or Early Termination 
Early Suspension or Early termination, including study-wide or Investigator/Site suspension or early 
termination, requirements can be found in each DEFINE AFib Study Addendum. 
16. References 
1.   Chugh SS, Blackshear JL, Shen WK, Hammill SC, Gersh BJ. Epidemiology and natural history of atrial 
fibrillation: clinical implications. J Am Coll Cardiol 2001;37:371-378. 
2. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the management of atrial fibrillation 
developed in collaboration with EACTS. Europace 2016;18:1609-1678. 
3. Kim MH, Johnston SS, Chu BC, Dalal MR, Schulman KL. Estimation of total incremental health care 
costs in patients with atrial fibrillation in the United States. Circ Cardiovasc Qual Outcomes 
2011;4:313-320. 
4. Stewart S, Murphy NF, Walker A, McGuire A, McMurray JJ. Cost of an emerging epidemic: an 
economic analysis of atrial fibrillation in the UK. Heart 2004;90:286-292. 
5. Benjamin EJ, Chen PS, Bild DE, et al. Prevention of atrial fibrillation: report from a National Heart, 
Lung, and Blood Institute workshop. Circulation 2009;119:606-618. 
6. Mairesse GH, Moran P, Van Gelder IC, et al. Screening for atrial fibrillation: a European Heart 
RhythmAssociation (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia 

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Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulaci on Cardıaca y 
Electrofisiologia (SOLAECE). Europace 2017;19:1589-1623. 
7. Lee R, Mittal S. Utility and limitations of long-term monitoring of atrial fibrillation using an 
implantable loop recorder. Heart Rhythm 2018;15:287-295. 
8. Healey JS, Alings M, Ha A, et al. Subclinical Atrial Fibrillation in Older Patients. Circulation 
2017;136:1276-1283. 
9. Nasir JM, Pomeroy W, Marler A, Hann M, Baykaner T, Jones R, Stoll R, Hursey K, Meadows A, Walker 
J, Kindsvater S. Predicting Determinants of Atrial Fibrillation or Flutter for Therapy Elucidation in 
Patients at Risk for Thromboembolic Events (PREDATE AF) Study. Heart Rhythm 2017;14:955-961. 
10. Reiffel JA, Verma A, Kowey PR, Halperin JL, Gersh BJ, Wachter R, Pouliot E, Ziegler PD, Investigators 
RA. Incidence of Previously Undiagnosed Atrial Fibrillation Using Insertable Cardiac Monitors in a 
High-Risk Population: The REVEAL AF Study. JAMA Cardiol 2017;2:1120-1127. 
11. Sanna T, Diener HC, Passman RS, et al. Cryptogenic stroke and underlying atrial fibrillation. N Engl J 
Med 2014;370:2478-2486. 
12. Strickberger AS, Ip J, Saksena S, Curry K, Bahnson TD, Ziegler PD. Relationship between atrial 
tachyarrhythmias and symptoms. Heart Rhythm 2005;2:125–131. 
13. Kapa S, Epstein AE, Callans DJ, et al. Assessing arrhythmia burden after catheter ablation of atrial 
fibrillation using an implantable loop recorder: the ABACUS study. J Cardiovasc Electrophysiol 
2013;24:875-881. 
14. Philippsen TJ, Christensen LS, Hansen MG, Dahl JS, Brandes A. Detection of subclinical atrial 
fibrillation in high-risk patients using insertable cardiac monitor. J Am Coll Cardiol EP 2017;3:1557-
1564. 
15. Piccini JP, Passman R, Turakhia M, Connolly AT, Nabutovsky Y, Varma N. Atrial fibrillation burden, 
progression, and the risk of death: a case-crossover analysis in patients with cardiac implantable 
electronic devices. Europace 2018. 
16. Wong JA, Conen D, Van Gelder IC, et al. Progression of Device-Detected Subclinical Atrial Fibrillation 
and the Risk of Heart Failure. J Am Coll Cardiol 2018;71:2603-2611. 
17. Uittenbogaart SB, Lucassen WAM, van Etten-Jamaludin FS, de Groot JR, van Weert H. Burden of atrial 
high-rate episodes and risk of stroke: a systematic review. Europace 2018;20:1420-1427. 
18. Glotzer TV, Daoud EG, Wyse DG, Singer DE, Ezekowitz MD, Hilker C, Miller C, Qi D, Ziegler PD. The 
relationship between daily atrial tachyarrhythmia burden from implantable device diagnostics and 
stroke risk: the TRENDS study. Circ Arrhythm Electrophysiol 2009;2:474-480. 
19. Glotzer TV, Hellkamp AS, Zimmerman J, et al. Atrial high rate episodes detected by pacemaker 
diagnostics predict death and stroke: report of the Atrial Diagnostics Ancillary Study of the MOde 
Selection Trial (MOST). Circulation 2003;107:1614-1619. 
20. Healey JS, Connolly SJ, Gold MR, et al. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med 
2012;366:120-129. 
21. Capucci A, Santini M, Padeletti L, et al. Monitoredatrial fibrillation duration predicts arterial embolic 
events in patients suffering from bradycardia and atrial fibrillation implanted with antitachycardia 
pacemakers. J Am Coll Cardiol 2005;46:1913-1920. 
22. Van Gelder IC, Healey JS, Crijns H, Wang J, Hohnloser SH, Gold MR, Capucci A, Lau CP, Morillo CA, 
Hobbelt AH, Rienstra M, Connolly SJ. Duration of device-detected subclinical atrial fibrillation and 
occurrence of stroke in ASSERT. Eur Heart J 2017;38:1339-1344. 

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Updated Clinical Study Type to be consistent 
and match regulatory determination 
Created DEFINE AFib Core CIP that is generic 
to all phases 
Clarified the electronic Consenting process 
Added in subject payments 
Clarified Study Level Deviations will be 
collected. 
All specifics to the Site Assisted Model moved 
to an Addendum 
Extended enrollment from 2 years to 3 years 
Updated EHR and Claims Data Source 
Updated 9.10 to reflect what device data 
patients have access to 
Updated Ancillary Objective #6 and #7 
Removed reference to a run in phase since 
that did not occur due to slower than 
anticipated enrollments 
Updated Analysis Methods for clarification 
Updated Determination of Subjects/Data for 
Analysis as specifics will be provided in 
the Statistical Analysis Plan 
Updated Analysis methods for Ancillary 
Objective #1 
 
 
Nancy McClelland, Clinical Study 
Manager, Principal Clinical 
Research Specialist 
4.0 
Administrative changes to clarify survey 
timing 
Combined Table 4 and 6 
Added section 9.9.2.1 to separate out 
Dynamic Scheduled Surveys 
Removed the requirement to have completed 
all enrollment surveys to be included in 
the primary analysis – Section 13.3.2 
Cody Johnson, Senior Clinical 
Research Program Manager 
 
Nancy McClelland, Clinical Study 
Manager, Principal Clinical 
Research Specialist 
 
 
 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
 
 
Cli ni c al I n v e sti g ati o n  Pl a n  A d d e n d u m  
 Sit e  Assist e d  P h as e  
Cli ni c al I n v e sti g ati o n  Pl a n / St u d y  Titl e    D E FI N E  A Fi b  Sit e  Assist e d  P h as e  
A  p art  of t h e  D E FI N E  A Fi b  St u d y  Pl atf or m  
Cli ni c al I n v e sti g ati o n  Pl a n I d e ntifi er   M D T 2 0 0 2 4  
St u d y  Pr o d uct  N a m e   A n y  m ar k et -r el e as e d  LI N Q  d e vi c e 
M e dtr o ni c r es e arc h  a p pli c ati o n  
S p o n s or / L oc al  S p o n s or   M e dtr o ni c, I n c.   
8 2 0 0  C or al  S e a  Str e et  N E  
M o u n ds  Vi e w,  M N  U. S. A.  5 5 1 1 2  
P h o n e:  1 -8 0 0 -3 2 8 -2 5 1 8  
 V ersi o n   2 . 0, 2 9J UL 2 0 2 2  
C o m pris e d  of:  
D E FI N E  A Fi b  v 4 , 2 9J U L 2 0 2 2  
D E FI N E  A Fi b  Sit e  Assist e d  P h as e 
A d d e n d u m 2. 0 ,  2 9J U L 2 0 2 2 
L e a d  Pri n ci p al I n v esti g at or(s)  Dr. J o n at h a n  Pi c ci ni  
Ass o ci at e  Pr of ess or  of  M e di ci n e  
D u k e  U ni v ersit y  
C o nfi d e nti alit y  St at e m e nt  
T h e i nf or m ati o n  c o nt ai n e d i n t his  d o c u m e nt is  c o nfi d e nti al  a n d t h e  pr o pri et ar y  pr o p ert y  of 
M e dtr o ni c.  A n y  distri b uti o n,  c o p yi n g,  or  dis cl os ur e  wit h o ut t h e  pri or  writt e n  a ut h oriz ati o n  of 
M e dtr o ni c is stri ctl y  pr o hi bit e d.  P ers o ns t o  w h o m t h e i nf or m ati o n is  dis cl os e d  m ust  k n o w t h at it is 
c o nfi d e nti al  a n d t h at it  m a y  n ot  b e f urt h er  dis cl os e d  b y t h e m.  
 
 
 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  2  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
T a bl e  of  C o n t e n t s  
T a bl e  of  C o nt e n t s  ..................................................................................................................   2 
1.  
Gl o s s a r y  .........................................................................................................................   3 
2.  
S y n o p si s  .........................................................................................................................   3 
3.  
S t u d y  Sit e  R e q ui r e m e n t s  ................................................................................................   8 
3. 1  I n v e sti g at or/I n v e sti g ati o n  Sit e  S el e cti o n .............................................................................   8 
3. 2  St u d y  Sit e  A cti v ati o n  .......................................................................................................   9 
3. 3  R ol e  of t h e  S p o n s or  R e pr e s e nt ati v e s  ..................................................................................   9 
4.  
S el e cti o n  of  S u bj e ct s  ....................................................................................................  1 0  
4. 1  St u d y  P o p ul ati o n  ...........................................................................................................  1 0  
4. 2  S u bj e ct  E nr oll m e nt  ........................................................................................................  1 0  
4. 3  I ncl u si o n  Crit eri a  ...........................................................................................................  1 0  
• 
P ati e nt s  w h o  h a v e  a  s elf -r e p ort e d  hi st or y  of  A F ..................................................................  1 0  
• 
P ati e nt s  wit h  a  R e v e al  LI N Q  or  LI N Q II I C M  w h o  h a v e r e c ei v e d  a n I C M f or t h e f oll o wi n g  d e vi c e 
l o g g e d i n di c ati o n s,  c at e g ori z e d i nt o t h e f oll o wi n g  di s cr e et  gr o u p s: ............................................... 1 0  
• 
I n di vi d u al  a c c e s s  a n d  a bilit y t o  u s e  a n  A p pl e i P h o n e ®  c o m p ati bl e  wit h  M e dtr o ni c’ s r e s e ar c h  a p p 
(i O S  v.  1 3. X  or  hi g h er) ..........................................................................................................  1 1  
4. 4  E x cl u si o n  Crit eri a  ...........................................................................................................  1 1  
5.  
S t u d y  P r o c e d u r e s  .........................................................................................................  1 1  
5. 1  H e alt h c ar e  Utili z ati o n  C o nfir m ati o n  ...................................................................................  1 1  
5. 2  S u bj e ct  E xit,  Wit h dr a w al  or  Dis c o nti n u ati o n  .......................................................................  1 2  
6.  
S t u d y  A d mi ni st r a ti o n  ....................................................................................................  1 2  
6. 1  M o nit ori n g  ....................................................................................................................  1 2  
6. 2  I n v e sti g at or  R e c or d s ......................................................................................................  1 3  
6. 3  I n v e sti g at or  R e p orts ......................................................................................................  1 4  
6. 4  S p o n s or  R e c or d s  ...........................................................................................................  1 4  
6. 5  S u s p e n si o n  or  E arl y  T er mi n ati o n  ......................................................................................  1 5  
6. 5. 1   
St u d y -wi d e  S us p e nsi o n  or  E arl y  T er mi n ati o n  .................................................................. 1 5  
6. 5. 2   
I n v esti g at or/ Sit e  S us p e nsi o n  or  E arl y  T er mi n ati o n .......................................................... 1 5  
6. 5. 3   
Pr o c e d ur es f or  S us p e nsi o n  or  E arl y  T er mi n ati o n  ............................................................. 1 6  
7.  
V e r si o n  Hi st o r y  .............................................................................................................  1 7  
 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  4  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
Pr o d u ct  N a m e  
R e v e al  LI N Q I ns ert a bl e  C ar di a c  M o nit or  or  n e w er  c o m m er ci al 
m o d el  
M e dtr o ni c r es e arc h  a p pli c ati o n  
S p o n s or   
M e dtr o ni c  C ar di o v as c ul ar  Di a g n osti cs  &  S er vi c es  
L o c al  S p o n s or  
M e dtr o ni c, I n c.  
8 2 0 0  C or al  S e a  Str e et  N E  
M o u n ds  Vi e w,  M N  U. S. A.  5 5 1 1 2  
1- 8 0 0 -3 2 8 -2 5 1 8  
I n di c ati o n  u n d er 
i n v e sti g ati o n  
P ati e nts  will  b e  eli gi bl e t o  p arti ci p at e if t h e y  1)  h a v e  a n  e xisti n g 
m ar k et -r el e as e d  LI N Q I C M; a n d  2)  h a v e r e c ei v e d t h eir  LI N Q I C M 
f or t h e i d e ntifi c ati o n  of  A F (i n cl u d es  cr y pt o g e ni c str o k e,  A F 
m a n a g e m e nt,  A F  a bl ati o n,  p al pit ati o ns,  or s us p e ct e d  A F;  a n d  3)  a 
s elf-r e p ort e d  hist or y  of  A F.   T h es e  c o n diti o ns  will  b e  c o nfir m e d 
pri or t o st u d y  e nr oll m e nt.   
I n v e sti g ati o n  P ur p o s e 
T h e  p ur p os e  of t his st u d y is t o  e v al u at e t h e  ass o ci ati o n  b et w e e n 
c o m pl e x  p att er ns  of  d e vi c e -d et e ct e d  A F  a n d  ot h er s u m m ar y  a n d 
e pis o di c  m e a s ur e m e nts  c oll e ct e d  b y t h e  m ar k et -r el e as e d  LI N Q 
I C M  d e vi c e  a n d  A F-r el at e d  h e alt h c ar e  utiliz ati o n,  q u alit y  of lif e, 
A F -r el at e d s y m pt o ms,  a n d s p e cifi c  cli ni c al  o ut c o m es i n  p ati e nts 
wit h  a  m ar k et -r el e as e d  LI N Q I C M.   T h e  M e dtr o ni c  Dis c o v er y  a p p 
will  b e  us e d t o  c oll e ct  d at a  b ot h ( 1)  vi a t h e i P h o n e ® t hr o u g h 
p ati e nt -r e p ort e d  h e alt h s ur v e ys  a n d  Bl u et o ot h-e n a bl e d  d e vi c es 
c o n n e ct e d t hr o u g h t h e  A p pl e  H e alt h  a p p  a n d ( 2)  d at a  a c c ess e d 
t hr o u g h  or st or e d  o n t h e  p h o n e  p ert ai ni n g t o  h e alt h r e c or ds, 
a cti vit y,  a n d  ot h er lif est yl e  d at a.   S e c o n d aril y, t his st u d y  will 
e x a mi n e  ass o ci ati o ns  b et w e e n  cli ni c al  pr o c e d ur es,  m e di c ati o ns 
a n d lif est yl e  a cti o ns t a k e n  a n d t h eir i m p a ct  o n  d e vi c e -d et e ct e d 
A F.   A d diti o n all y, t his st u d y  will  h el p  M e dtr o ni c  e v al u at e  p ati e nts’ 
i nt er a cti o n  wit h r e ports  g e n er at e d fr o m  h e alt h  d at a  c oll e ct e d  b y 
t h e  m ar k et-r el e as e d  LI N Q I C M.  T his st u d y  will i m pr o v e  o ur 
u n d erst a n di n g  of  h o w  d at a fr o m t h e  LI N Q f a mil y  of  d e vi c es  c a n 
b e  us e d t o  g ui d e t h e  m a n a g e m e nt  of  A F  p ati e nts.  
Pr o d u ct  St at u s  
T h e st u d y  will  b e  c o n d u ct e d  usi n g t h e  c o m p o n e nts  of t h e 
M e dtr o ni c  R e v e al LI N Q  or  LI N Q II s yst e m  w hi c h  ar e  c urr e ntl y 
m ar k et -r el e as e d i n t h e  p arti ci p ati n g  g e o gr a p h y ( U nit e d  St at es).  
F ut ur e  LI N Q  d e vi c es  m a y  als o  b e  us e d, s h o ul d  a  n e w it er ati o n  b e 
r el e as e d  d uri n g t h e st u d y.  
 
T his st u d y  will  als o  us e  a n i P h o n e ®  a p p  b uilt  usi n g  A p pl e 
R es e ar c h Kit t o  c oll e ct  d at a  b ot h ( 1)  vi a t h e i P h o n e ® t hr o u g h 
p ati e nt -r e p ort e d  h e alt h s ur v e ys  a n d  Bl u et o ot h-e n a bl e d  d e vi c es 
c o n n e ct e d t hr o u g h t h e  A p pl e  H e alt h  a p p  a n d ( 2)  d at a  a c c ess e d 
t hr o u g h  or st or e d  o n t he  p h o n e  p ert ai ni n g t o  h e alt h r e c or ds, 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  7  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
s u bs e q u e nt  p ati e nt  e x p eri e n c e s ur v e ys t o  u n d erst a n d  h o w  p ati e nts 
r es p o n d t o  a n d i nt er a ct  wit h t h eir  d e vi c e  d at a.  P ati e nts  will  b e 
f oll o w e d t o  eit h er t h e  e n d of t h eir I C M s er vi c e lif e  or f or  u p t o fi v e 
y e ars.   
R a n d o mi z ati o n  
As t his is  a n  o bs er v ati o n al st u d y,  p ati e nts  will  n ot  b e r a n d o miz e d  
S a m pl e  Si z e  
A p pr o xi m at el y  5, 0 0 0  p ati e nts (s e e s e cti o n  1  of t h e  D E FI N E  A Fi b  C or e 
CI P  v 3. 0 ) 
I n cl u si o n / E x cl u si o n  Crit eri a 
I n cl usi o n  Crit eri a 
•  
P ati e nts  w h o  h a v e  a s elf r e p ort e d  hist or y  of  A F  
•  
P ati e nts  wit h  a  LI N Q I C M  w h o  h a v e r e c ei v e d  a n I C M 
f or t h e f oll o wi n g  d e vi c e- l o g g e d i n di c ati o ns, 
c at e g oriz e d i nt o t h e f oll o wi n g  dis cr e et  gr o u ps:  
o  
Str o k e:  Cr y pt o g e ni c str o k e  i n di c ati o ns 
o  
A F  m a n a g e m e nt:  A F  m a n a g e m e nt  a n d  p ost -
a bl ati o n  m a n a g e m e nt  i n di c ati o ns 
o  
S us p e ct e d  A F:  S us p e ct e d  A F  a n d  
p al pit ati o ns i n di c ati o ns  
•  
I n di vi d u al  A c c ess  a n d  a bilit y t o  us e  a n  A p pl e 
i P h o n e ®  c o m p ati bl e  wit h  M e dtr o ni c’s r es e ar c h 
a p p (i O S  v.  1 3. X  or  hi g h er)  
•  
P ati e nt is  willi n g  a n d  a bl e t o  c o m pl y  wit h t h e  
pr ot o c ol, i n cl u di n g  C ar e Li n k tr a ns missi o ns 
(r e q uir es a d e q u at e  c o n n e cti vit y), r e m ot el y 
a d mi nist er e d i nstr u cti o ns,  a n d r e m ot e s ur v e y 
p arti ci p ati o n  
•  
P ati e nt is  2 2  y e ars  of  a g e  or  ol d er  
•  
L o c at e d i n t h e  U nit e d  St at es,  wit h  C ar e Li n k  m a n a g e d 
t hr o u g h s er v ers l o c at e d i n  U nit e d  St at es ( 5 0 st at es 
or  Distri ct  of  C ol u m bi a)  
•  
V ali d  e m ail  a d dr ess fr o m s elf -r e p ort  at e nr oll m e nt  
•  
P ati e nt  m ust  b e  a bl e t o r e a d  a n d  writ e i n  E n glis h  
E x cl u si o n  Crit eri a  
P ati e nts  wit h  >  2 4  m o nt hs  el a ps e d ti m e fr o m r e c or d e d  LI N Q  d e vi c e 
i m pl a nt  or  >  4 8  m o nt hs  el a ps e d fr o m r e c or d e d  LI N Q II i m pl a nt  d at e 
St u d y  Pr o c e d ur e s  a n d 
A ss e ss m e nt s  
I nt er est e d  p ati e nts  will  c o m pl et e  a s cr e e ni n g  q u esti o n n air e t o 
d et er mi n e  eli gi bilit y.   Eli g i bl e  p ati e nts  will  b e i n vit e d t o  u n d er g o  a n 
D E FI N E  A Fi b  a p p -b as e d  el e ctr o ni c i nf or m e d  c o ns e nt.   F oll o wi n g 
c o ns e nt, t h e  a p p  will  g ui d e  p ati e nts t hr o u g h t h e  c o m pl eti o n  of t h eir 
r es e ar c h  pr ofil e, i n cl u di n g t h e  e n a bli n g  of  d at a  c oll e cti o n  a n d  will 
c o m pl et e  b as eli n e  m e di c al  hist or y  a n d  q u alit y  of lif e  s ur v e ys.  C o ns e nt 
d o c u m e nts  will  b e st or e d i n t h e  D E FI N E  A Fi b  a p p  o n t h e i P h o n e ®.  A 
c o p y  of t h e  c o ns e nt  will  als o  b e st or e d  o n s e c ur e  M e dtr o ni c s er v ers 
f or  c o m pli a n c e  p ur p os es.  

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  8  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
 
F oll o wi n g  c o ns e nt,  p ati e nts  will  b e  as k e d t o r e vi e w  w h at  d at a t h e y 
ar e  willi n g t o s h ar e  wit h t h e st u d y s p o ns or.  F or  a p pr o v e d  d at a 
s o ur c es,  d at a  will  b e  c oll e ct e d t hr o u g h t h e i P h o n e ®  a p pli c ati o ns  o n  a n 
o n g oi n g  b asis (i n cl u di n g  b ut  n ot li mit e d t o  p h ysi c al  a cti vit y  a n d 
el e ctr o ni c  m e di c al r e c or d  i nf or m ati o n).   H e alt h,  m e di c ati o n, 
s y m pt o m,  a n d  Q o L s ur v e ys  will  b e  a d mi nist er e d  at  v ari a bl e 
ti m e p oi nts  b as e d  o n  LI N Q I C M s u m m ar y  a n d  e pis o di c  m e as ur e m e nts, 
a n d t h e ti m e i nt er v al si n c e t h e l ast  c o m pl et e d s ur v e y.  L astl y,  p ati e nts 
will  b e  pr o vi d e d s el e ct  d at a fr o m t h eir  LI N Q I C M  d e vi c e,  wit h 
s u bs e q u e nt  p ati e nt  e x p eri e n c e s ur v e ys t o  u n d erst a n d  h o w  p ati e nts 
r es p o n d t o  a n d i nt er a ct  wit h t h eir  d e vi c e  d at a.  P ati e nts  will  h a v e t h e 
a bilit y t o t er mi n at e t h eir  p arti ci p ati o n  at  a n y ti m e.    
S af et y  A ss e ss m e nt s   
T h e  c ol l e cti o n  of  a d v ers e  e v e nts  a n d  d e vi c e  d efi ci e n ci es  ar e  n ot 
r e q uir e d t o  m e et t h e  o bj e cti v e(s)  of t his st u d y.   
3.  S t u d y  Si t e  R e q ui r e m e n t s  
3. 1   I n v e s ti g a t o r / I n v e s ti g a ti o n  Si t e  S el e c ti o n  
T h e r ol e  of t h e  pri n ci p al i n v esti g at or is t o i m pl e m e nt  a n d  m a n a g e t h e  d a y -t o-d a y  c o n d u ct  of t h e  cli ni c al 
i n v esti g ati o n  as  w ell  as t h e ri g hts, s af et y  a n d  w ell-b ei n g  of t h e s u bj e cts i n v ol v e d i n t h e  cli ni c al 
i n v esti g ati o n.  
T h e  pri n ci p al i n v esti g at or s h all:  
•   B e  q u alifi e d  b y  e d u c ati o n, tr ai ni n g,  a n d  e x p eri e n c e t o  ass u m e r es p o nsi bilit y f or t h e  pr o p er 
c o n d u ct  of t h e  cli ni c al i n v esti g ati o n  
•   Dis cl os e  p ot e nti al  c o nfli cts  of i nt er est, t h at i nt erf er e  wit h t h e  c o n d u ct  of t h e  cli ni c al 
i n v esti g ati o n  or i nt er pr et ati o n  of r es ults 
•   M ai nt ai n t h e I n v esti g ati o n al  Sit e  Fil e (I S F)  at t h e sit e  or f or t h e  e ntir e  n et w or k, if  a p pli c a bl e  
•   B e  a bl e t o  d e m o nstr at e t h at t h e  pr o p os e d i n v esti g ati o n al st u d y sit e:  
•   H as t h e r e q uir e d  n u m b er  of  eli gi bl e s u bj e cts  n e e d e d  wit hi n t h e r e cr uit m e nt  p eri o d  
•   H as sit e  p ers o n n el t h at  c a n  c o nfir m  p ati e nt -r e p ort e d  e v e nts  via  E H R   
•   Dri v e  e nr oll m e nt r ef err als  wit hi n t h eir  n et w or k/sit e  

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  9  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
•   E ns ur e st u d y sit e  p ers o n n el tr ai ni n g is  c o m pl et e d  a n d  d o c u m e nt e d  pri or t o  p arti ci p ati o n i n t his 
st u d y 
3. 2   S t u d y  Si t e  A c ti v a ti o n  
D uri n g t h e  a cti v ati o n  pr o c ess ( pri or t o s u bj e ct  e nr oll m e nt),  M e dtr o ni c  w ill tr ai n st u d y sit e  p ers o n n el  o n 
t h e  cli ni c al i n v esti g ati o n  pl a n, st u d y fl o w,  a p p  o v er vi e w,  a n d r el e v a nt st a n d ar ds  a n d r e g ul ati o ns.  If  n e w 
m e m b ers j oi n t h e st u d y sit e t e a m, t h e y  will r e c ei v e tr ai ni n g  o n t h e  a p pli c a bl e st u d y r e q uir e m e nts 
r el e v a nt t o t h eir r ol e  b ef or e  c o ntri b uti n g t o t h e st u d y.   At  a  mi ni m u m, t h e  pri n ci p al i n v esti g at or  a n d sit e 
p ers o n n el r es p o nsi bl e f or  c o nfir mi n g  p ati e nt -r e p ort e d  e v e nts  at t h e sit e  or  wit hi n t h e  n et w or k  will  b e 
tr ai n e d.   
Pri or t o  p erf or mi n g st u d y r el at e d  a cti viti es,  all r e g ul at or y r e q uir e m e nts s h all  b e f ulfill e d, i n cl u di n g,  b ut 
n ot li mit e d t o t h e f oll o wi n g:   
•   I R B  a p pr o v al ( a n d  v oti n g list,  as r e q uir e d  b y l o c al l a w)  of t h e  c urr e nt  v ersi o n  of t h e  CI P  a n d I C F 
•   F ull y  e x e c ut e d  C T A   
•   D o c u m e nt ati o n  of  d el e g at e d t as ks   
•   D o c u m e nt ati o n  of st u d y tr ai ni n g  
•   D o c u m e nt ati o n  of  c o m pl et e d  P arti ci p ati n g  Sit es  a n d  Cli ni cs  F or m  
•   A d diti o n al r e q uir e m e nts i m p os e d  b y l o c al r e g ul ati o ns  a n d t h e I R B s h all  b e f oll o w e d,  as 
a p pr o pri at e   
I n  a d diti o n,  all  p arti ci p ati n g st u d y sit e st aff  m ust  b e tr ai n e d  o n t h e  c urr e nt  v ersi o n  of t h e  CI P  as  w ell  as 
o n t h e  a p pli c a bl e st u d y r e q uir e m e nts  d e p e n di n g  o n t h eir r ol e  a n d  m ust  b e  d el e g at e d  b y t h e  pri n ci p al 
i n v esti g at or t o  p erf or m st u d y r el at e d  a cti viti es.   
M e dtr o ni c  will  pr o vi d e  e a c h st u d y sit e  wit h  d o c u m e nt ati o n  of st u d y si t e/i n v esti g at or r e a di n ess; t his 
l ett er  m ust  b e r e c ei v e d  pri or t o  p erf or mi n g st u d y r el at e d  a cti viti es. 
3. 3   R ol e  of  t h e  S p o n s o r  R e p r e s e n t a ti v e s  
I n  a d diti o n t o  p erf or mi n g  m o nit ori n g  a n d  a u diti n g,  M e dtr o ni c  p ers o n n el  m a y  pr o vi d e s u p p ort  as 
r e q uir e d f or t h e st u d y  u n d er s u p er visi o n  of t h e  Pri n ci p al I n v esti g at or, i n cl u di n g: 
St u d y tr ai ni n g r el e v a nt  a n d  p erti n e nt t o t h e i n v ol v e m e nt  of  p ers o n n el  c o n d u cti n g  st u d y  a cti viti es  a n d 
i n v esti g at or r es p o nsi biliti es 
P ati e nt  or  p h ysi ci a n  e d u c ati o n, s u p p ort  wit h  a p p  q u esti o ns/r es o ur c es, i n  c o m pli a nc e  wit h I R B  a p pr o v e d 
g ui d eli n es.  

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 0  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
4.  S el e c ti o n  of  S u bj e c t s  
4. 1   S t u d y  P o p ul a ti o n  
T h e  D E FI N E  A Fi b st u d y  will  e nr oll  a p pr o xi m at el y  5, 0 0 0  p ati e nts (s e e s e cti o n  1 3. 1  of t h e  D E FI N E  A Fi b  C or e 
CI P  v 3. 0 ) i n t h e  U nit e d  St at es  w h o  h a v e  a  R e v e al  LI N Q  or  LI N Q II I C M  a n d  a n  A p pl e i P h o n e ®.  P ati e nts 
m ust  h a v e   a  hist or y  of  A F.  
4. 2   S u bj e c t  E n r oll m e n t  
I nstit uti o n al  R e vi e w B o ar d (I R B)  a n d  M e dtr o ni c  a p pr o v al  will  b e  o bt ai n e d f or t his  Cli ni c al I n v esti g ati o n 
Pl a n, t h e i nf or m e d  c o ns e nt f or m (I C F)  a n d  all  ot h er  a p pli c a bl e st u d y  d o c u m e nts  pri or t o  e nr olli n g 
s u bj e cts i n t h e st u d y.  M e dtr o ni c  will  pr o vi d e  e a c h st u d y  c e nt er  wit h  d o c u m e nt ati o n  of st u d y 
c e nt er/i n v esti g at or r e a di n ess; t his l ett er  m ust  b e r e c ei v e d  pri or t o s u bj e ct  e nr oll m e nt.   
P ati e nts  will i niti all y  b e r e cr uit e d t hr o u g h  offi ci al st u d y sit es  a n d  e n g a g e d  h e alt h c ar e  n et w or ks,  aft er t h e 
sit e  or  n et w or k  h as  u n d er g o n e its i niti ati o n.  P ati e nts  m a y  als o  b e r e cr uit e d t hr o u g h  a d diti o n al sit es t h at 
q u alif y  b as e d  o n t h e st u d y s p e cifi c ati o ns.  
W h e n  a  p ati e nt  h as  c o m pl et e d t h e  eli gi bilit y s ur v e y (i n cl u di n g t h e  c o m p o n e nts t o  c al c ul at e  a virt u al 
C H A 2 D S 2 -V A S c s c or e ) a n d  el e ctr o ni c all y si g n e d  a n d  d at e d t h e I C F  vi a t h e st u d y  a p p, t h e  p ati e nt is 
c o nsi d er e d  a s u bj e ct  e nr oll e d i n t h e st u d y.  S u bj e cts  m ust  pr o vi d e i nf or m e d  c o ns e nt  b ef or e  a n y st u d y 
r el at e d  pr o c e d ur es  o c c ur ( d at a  c oll e cti o n).   W hil e  v ul n er a bl e  p o p ul ati o ns  will  n ot  b e t ar g et e d, t h er e is 
n o  e x cl usi o n  of  v ul n er a bl e  p o p ul ati o ns,  ot h er t h a n t h os e t h at  d o  n ot  m e et i n cl usi o n/ e x cl usi o n  crit eri a.   
T h e I C F  a n d  A ut h oriz ati o n t o  Us e  a n d  Dis cl os e  P ers o n al  H e alt h I nf or m ati o n  will  b e  el e ctr o ni c.  A  c o p y  of 
t h e si g n e d  a n d  d at e d I C F  a n d  A ut h oriz ati o n d o c u m e nts  will  b e  a v ail a bl e  wit hi n t h e  D E FI N E  A Fi b 
R es e ar c h  a p p f or  p ati e nt r ef er e n c e.   A n  a d diti o n al  c o p y  of t h e  el e ctr o ni c all y si g n e d  a n d  d at e d I C F  a n d 
A ut h oriz ati o n  will  b e st or e d i n  a s e c ur e  p art  1 1 c o m pli a nt s yst e m,  a cc ess -c o ntr oll e d  M e dtr o ni c  d at a b as e 
a n d s h ar e d  wit h t h e  pri m ar y i n v esti g at or  of t h at sit e  or  n et w or k.  
4. 3   I n cl u si o n  C ri t e ri a  
•   P ati e nts  w h o  h a v e  a s elf -r e p ort e d  hist or y  of  A F 
•   P ati e nts  wit h  a  R e v e al  LI N Q  or  LI N Q II I C M  w h o  h a v e r e c ei v e d  a n I C M f or t h e f oll o wi n g  d e vi c e 
l o g g e d i n di c ati o ns,  c at e g oriz e d i nt o t h e f oll o wi n g  dis cr e et  gr o u ps: 
   
  
o   Str o k e:  Cr y pt o g e ni c str o k e i n di c ati o n  
   
  
o   A F  m a n a g e m e nt:  A F  m a n a g e m e nt  a n d  p ost -a bl ati o n  m a n a g e m e nt i n di c ati o ns  
                            o   S us p e ct e d  A F:  S us p e ct e d  A F  a n d  p al pit ati o ns i n di c ati o ns  

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 1  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
•   I n di vi d u al  a c c ess  a n d  a bilit y t o  us e  a n  A p pl e i P h o n e ® c o m p ati bl e  wit h M e dtr o ni c’s r es e ar c h  a p p 
(i O S  v.  1 3. X  or  hi g h er)  
•      P ati e nt is  willi n g  a n d  a bl e t o  c o m pl y  wit h t h e  pr ot o c ol, i n cl u di n g  C ar e Li n k  tr a ns missi o ns (r e q uir es 
a d e q u at e  c o n n e cti vit y), r e m ot el y  a d mi nist er e d i nstr u cti o ns,  a n d r e m ot e s ur v e y  p arti ci p ati o n  
•      P ati e nt is  2 2  y e ars  of  a g e  or  ol d er   
•      L o c at e d i n t h e  U nit e d  St at es,  wit h  C ar e Li n k  m a n a g e d t hr o u g h s er v ers l o c at e d i n  U nit e d  St at es ( 5 0 
st at es  or  Distri ct  of  C ol u m bi a) 
•      V ali d  e m ail  a d dr ess s elf -r e p ort e d  at  e nr oll m e nt 
•      P ati e nt  m ust  b e  a bl e t o r e a d  a n d  writ e i n  E n glis h   
4. 4   E x cl u si o n  C ri t e ri a  
P ati e nts  wit h  >  2 4  m o nt hs  el a ps e d ti m e fr o m r e c or d e d  LI N Q  d e vi c e i m pl a nt  or  >  4 8  m o nt hs  el a ps e d 
fr o m r e c or d e d  LI N Q II i m pl a nt  d at e. 
5.  S t u d y  P r o c e d u r e s  
5. 1   H e al t h c a r e  U tili z a ti o n  C o nfi r m a ti o n  
H e alt h c ar e  utiliz ati o n  a n d  m o difi c ati o n t o tr e at m e nt  or  m a n a g e m e nt  of  A F  will  b e r e vi e w e d  a n d 
c o nfir m e d  vi a  E H R  b y  h e alt h c ar e sit e  p ers o n n el f or s u bj e cts  wit h  a v ail a bl e  h e alt h r e c or ds t o  c o m p ar e t o 
p ati e nt  c o m pl et e d s ur v e ys.  Tr ai n e d  a n d  D el e g at e d  p ers o n n el  will  b e s e nt  p ati e nt r e p ort e d  o ut c o m es  vi a 
a  p art  1 1  c o m pli a nt s yst e m f or  o nl y t h e s u bj e cts t h at  ar e  p art  of t h eir  c ar e  n et w or k  or  cli ni c  a n d  as k e d t o 
c o nfir m  p ati e nt  H C U r e p orts.   T h er e  will  b e  a st a n d ar diz e d s et  of  q u esti o ns r el at e d t o  e a c h  H C U  a n d/ or 
m e di c ati o n/tr e at m e nt  c h a n g e t h at i n cl u d es  w h et h er  or  n ot t h e  p ati e nt -r e p ort e d  utiliz ati o n/ c h a n g e tr ul y 
o c c urr e d.   T h e r e as o n  a n d s p e cifi c  d et ails f or  e a c h  visit  will  b e r e c or d e d ( as  d et er mi n e d  b y t h e tr e ati n g 
cli ni ci a n i n t h e  E H R). If t h er e  ar e  err ors i n t h e  p ati e nt r e p ort, t h e  d esi g n at e d sit e  p ers o n n el  will  h a v e t h e 
o p p ort u nit y t o r e c or d  a  c orr e cti o n st ati n g t h e tr u e  e v e nts t h at  h a p p e n e d  u p o n  a  p ati e nt’s  visit  t o t h eir 
affili at e d  h e alt h  c ar e f a cilit y.   T his  pr o c ess  will  als o  b e  us e d f or  all  e xits  p erf or m e d  b y t h e s p o ns or,  as 
o utli n e d i n s e cti o n  9  of t h e  D E FI N E  A Fi b  C or e  CI P  v 3. 0 .   Sit e  p ers o n n el  will  b e  as k e d t o  d et er mi n e 
p ati e nt’s  m ort alit y st at us  al o n g  wit h  a n y  H C Us  or  m e di c ati o n/tr e at m e nt  c h a n g es/c ert ai n  cli ni c al 
o ut c o m es si n c e t h e l ast r e p ort e d  e v e nt.  N o n -c o nfir m a bl e  e v e nts  will  b e  n ot e d  as s u c h  a n d  will  n ot 
c o ntri b ut e t o t h e st u d y’s  e n d p oi nts.    
T a bl e  7  H e alt h c ar e  Utiliz ati o n  D efi niti o ns  
H e alt h c ar e 
Utiliz ati o ns ( H C U)  
All i n p ati e nt  h os pit aliz ati o ns,  o ut p ati e nt  h os pit al  e n c o u nt ers,  e m er g e n c y 
d e p art m e nt  visits,  cli ni c  visits,  ur g e nt  c ar e  visits, r e h a b  c e nt er  or  ot h er  c ar e l o c ati o n 
i nt er a cti o ns (i n cl u di n g r e m ot e  visits) 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 2  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
C V -r el at e d  H C U 
A  h e alt h c ar e  utiliz ati o n r el ati n g t o t h e  h e art  a n d t h e  bl o o d  v ess els  or t h e  cir c ul ati o n 
( e. g.,  atri al fi brill ati o n,  m y o c ar di al i nf ar cti o n, str o k e,  p eri p h er al  v asc ul ar  dis e as e, 
h e art f ail ur e).  
A F -r el at e d  H C U 
H C U r el at e d t o  A F, s us p e ct e d  A F,  A F tr e at m e nt,  or  c o m pli c ati o ns r el at e d t o  A F 
(i n cl u di n g  bl e e di n g  a n d  dr u g t o xi cit y  as  d et er mi n e d  b y tr e ati n g  cli ni ci a n.   
H F -r el at e d  H C U 
A  h e alt h c ar e  utiliz ati o n r el at e d t o  w ors e ni n g  h e art f ail ur e si g ns  a n d s y m pt o ms  ( as 
d et er mi n e d  b y tr e ati n g  cli ni ci a ns) s u c h  as ( b ut  n ot li mit e d t o)  h y p er v ol e mi c  a n d 
h y p o v ol e mi c st at us r e q uiri n g t h e  a d mi nistr ati o n,  alt er ati o n,  a dj ust m e nt,  or 
a u g m e nt ati o n  of  H F t h er a p y ( di ur eti cs, i n otr o p es  a n d/ or  v as o dil at ors  et c.)  or t h e 
utiliz ati o n  of  ultr afiltr ati o n  d e vi c es.  
H os pit aliz ati o n  
A t h er a p e uti c i n p ati e nt  h os pit aliz ati o n ( e x cl u d es  o ut p ati e nt  a n d  e m er g e n c y r o o m 
visits) l asti n g  gr e at er t h a n  or  e q u al t o  2 4  h o urs.  
N o n -h e m orr h a gi c 
str o k e 
R a pi d  o ns et  of  a f o c al  or  gl o b al  n e ur ol o gi c al  d efi cit  or  ot h er  n e ur ol o gi c al 
si g ns/s y m pt o ms  c o nsist e nt  wit h str o k e;  w h er e as f o c al,  gl o b al  c er e br al  or s pi n al 
d ysf u n cti o n  w as  N O T c a us e d  b y  a  n o n -tr a u m ati c i ntr a p ar e n c h y m al, i ntr a v e ntri c ul ar, 
or s u b ar a c h n oi d  h e m orr h a g e,  as  d et er mi n e d  b y t h e tr e ati n g cli ni ci a n.   
S yst e mi c  e m b olis m  
A n  e m b ol us r es ulti n g i n  cli ni c al  a n d  o bj e cti v e  e vi d e n c e  of s u d d e n l oss  of  e n d  or g a n 
p erf usi o n.  
TI A  
N e w f o c al  n e ur ol o gi c al  d efi cit  wit h r a pi d s y m pt o m r es ol uti o n ( us u all y  1  
–  2  h o urs),  al w a ys  wit hi n  2 4  h o urs  wit h o ut tiss u e i nj ur y ( b as e d  o n  
n e ur oi m a gi n g)  as  d et er mi n e d  b y t h e tr e ati n g  cli ni ci a n.   
 
5. 2   S u bj e c t  E xi t,  Wi t h d r a w al  o r  Di s c o n ti n u a ti o n  
A n y s u bj e ct  w h o is  e xit e d  b y t h e s p o ns or  will  b e  ass ess e d  b y t h e sit e t o  c o nfir m  m ort alit y st at us  a n d t o 
d o c u m e nt  a n y  H C Us  or  c ert ai n  cli ni c al  o ut c o m es  o bs er v e d si n c e t h e l ast r e p ort e d/ c o nfir m e d  H C U.  If  a 
d e at h is f o u n d  vi a sit e  c o nfir m ati o n  or  E H R, t h e  p ati e nt  will  b e  e xit e d fr o m t h e st u d y.   
6.  S t u d y  A d mi ni s t r a ti o n  
6. 1   M o ni t o ri n g  
It is t h e r es p o nsi bilit y  of  M e dtr o ni c t o  e ns ur e  pr o p er  m o nit ori n g  of t his  cli ni c al st u d y.   Tr ai n e d 
M e dtr o ni c  p ers o n n el  or  d el e g at es  a p p oi nt e d  b y  M e dtr o ni c  m a y  p erf or m st u d y  m o nit ori n g  at t h e st u d y 
c e nt er  or  vi a  r e m ot e  m o nit ori n g i n  or d er t o  e ns ur e t h at t h e st u d y is  c o n d u ct e d i n  a c c or d a n c e  wit h t h e 
CI P, t h e  Cli ni c al  Tri al  A gr e e m e nt,  a n d  a p pli c a bl e r e g ul at or y r e q uir e m e nts.   M e dtr o ni c,  or  d el e g at es, 
m ust t h er ef or e  b e  all o w e d  a c c ess t o t h e s u bj e ct’s  c as e  hist ori es  u p o n r e q u est  as  p er t h e I nf or m e d 
C o ns e nt  F or m  a n d  Cli ni c al  Tri al  A gr e e m e nt.   T h e  Pri n ci p al I n v esti g at or s h o ul d  als o  b e  a v ail a bl e  d uri n g 
o nsit e  m o nit ori n g  visits.  
Fr e q u e n c y  of  m o nit ori n g  visits  m a y  b e  b as e d  u p o n s u bj e ct  e nr oll m e nt,  d ur ati o n  of t h e st u d y, st u d y 
c o m pli a n c e, fi n di n g s fr o m  pr e vi o us  m o nit ori n g  visits  a n d  a n y s us p e ct e d i n c o nsist e n c y i n  d at a t h at 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 3  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
r e q uir es i n v esti g ati o n.   R e g ul at or y  d o c u m e nts  m a y  b e r e vi e w e d f or  e a c h st u d y  c e nt er.  M o nit ori n g f or 
t h e st u d y, i n cl u di n g sit e  q u alifi c ati o n  a n d sit e i niti ati o n  visits, i nt eri m  m o nit ori n g  visits,  a n d  cl os e o ut 
visits  will  b e  d o n e i n  a c c or d a n c e  wit h t h e  D efi n e  A F  m o nit ori n g  pl a n.  
M o nit ori n g  visits  m a y  b e  c o n d u ct e d  p eri o di c all y t o  ass ess  c e nt er st u d y  pr o gr ess, t h e I n v esti g at or’s 
a d h er e n c e t o t h e  CI P, r e g ul at or y  c o m pli a n c e i n cl u di n g  b ut  n ot li mit e d t o I R B  a p pr o v al  a n d r e vi e w  of t h e 
st u d y,  m ai nt e n a n c e  of r e c or ds  a n d r e p orts, r e vi e w  of s u bj e ct i nf or m e d  c o ns e nt f or ms,  a n d r e vi e w  of 
s o ur c e  d o c u m e nts  a g ai nst s u bj e ct  e C R Fs.   M o nit ors  will r e vi e w  c e nt er r e g ul at or y  a n d st u d y  c o m pli a n c e 
b y i d e ntif yi n g fi n di n g s  of  n o n -c o m pli a n c e  a n d  c o m m u ni c ati o n t h os e fi n di n g s  al o n g  wit h 
r e c o m m e n d ati o ns f or  pr e v e nti v e/ c orr e cti v e  a cti o ns t o  c e nt er  p ers o n n el.   M o nit ors  m a y  w or k  wit h st u d y 
p ers o n n el t o  d et er mi n e  a p pr o pri at e  c orr e cti v e  a cti o n r e c o m m e n d ati o ns  a n d t o i d e ntif y tr e n ds  wit hi n 
t h e st u d y  or  at  a  p arti c ul ar  c e nt er.  
T h e I n v esti g at or  will  p er mit st u d y r el at e d  m o nit ori n g,  a u dits, I R B r e vi e w  a n d r e g ul at or y i ns p e cti o ns  b y 
pr o vi di n g  dir e ct  a cc ess t o s o ur c e  d at a  a n d s o ur c e  d o c u m e nts.   
M e dtr o n i c  will r e q u est t h at st u d y  c e nt ers  u pl o a d i d e ntifi e d s u bj e ct  c as e  hist or y fil es  a n d r e g ul at or y 
d o c u m e nts t o  a s e c ur e,  p ass w or d -pr ot e ct e d  w e bsit e  pri or t o r e m ot e  m o nit ori n g  visits.  
6. 2   I n v e s ti g a t o r  R e c o r d s  
T h e i n v esti g at or is r es p o nsi bl e f or t h e  pr e p ar ati o n  a n d  r et e nti o n  of t h e r e c or ds i n cl u di n g,  b ut  n ot li mit e d 
t o t h os e  cit e d  b el o w.  All  of t h e  b el o w r e c or ds,  wit h t h e  e x c e pti o n  of  c o nfir m e d  p ati e nt-s p e cifi c 
i nf or m ati o n, s h o ul d  b e  k e pt i n t h e I n v esti g at or  Sit e  Fil e (i. e., t h e st u d y  bi n d er  pr o vi d e d t o t h e 
i n v esti gat or)  or  S u bj e ct  St u d y  Bi n d er.  T h e f oll o wi n g r e c or ds  ar e s u bj e ct t o i ns p e cti o n  a n d  m ust  b e 
r et ai n e d f or  a  p eri o d  of t w o  y e ars ( or l o n g er  as l o c al l a w  or  h os pit al  a d mi nistr ati o n r e q uir es)  aft er t h e 
d at e  o n  w hi c h t h e i n v esti g ati o n is t er mi n at e d.  M e as ur es s h all  b e t a k e n t o  a v oi d l oss  or  pr e m at ur e 
d estr u cti o n.  
•   All  c orr es p o n d e n c e  b et w e e n t h e I R B, s p o ns or,  m o nit or, r e g ul at or y  a ut h orit y  a n d/ or t h e 
i n v esti g at or t h at  p ert ai ns t o t h e i n v esti g ati o n, i n cl u di n g r e q uir e d r e p orts  
•   All r e c or ds  of  p ati e nt -s p e cifi c  e v e nts’ so ur c e  d o c u m e nt ati o n   
•   All  a p pr o v e d  v ersi o ns  of t h e  CI P  a n d i nf or m e d  c o ns e nt f or m  
•   F ull y  e x e c ut e d  Cli ni c al  Tri al  A gr e e m e nt  
•   St u d y tr ai ni n g r e c or ds f or sit e  p ers o n n el   
•   D o c u m e nt ati o n  of  d el e g at e d t as ks   
•   I R B  a p pr o v al  d o c u m e nt ati o n, i n cl u di n g t h e I R B  c o m p ositi o n  w h er e r e q uir e d  b y l a w,  a n d  writt e n 
i nf or m ati o n t h at t h e i n v esti g at or  or  ot h er st u d y st aff,  w h e n  m e m b er  of t h e I R B,  di d  n ot 
p arti ci p at e i n t h e  a p pr o v al  pr o c ess  
•   R e g ul at or y  a ut h orit y  c orr es p o n d e n c e,  n otifi c ati o n,  a n d  a p pr o v al,  w h er e r e q uir e d  b y  n ati o n al 
l e gislati o n  

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 5  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
•   R e g ul at or y  a ut h orit y  c orr es p o n d e n c e,  n otifi c ati o n  a n d  a p pr o v al  as r e q uir e d  b y  n ati o n al 
l e gisl ati o n 
•   N a m es/ c o nt a ct  a d dr ess es  of  m o nit ors  
•   M o nit ori n g r e p orts  
•   Sit e  q u alifi c ati o n  visit r e p orts ( or  w ai v ers  w h e n  a p pli c a bl e)  
•   St atisti c al  a n al ys es  a n d  u n d erl yi n g s u p p orti n g  d at a  
•   Fi n al r e p ort  of t h e  cli ni c al s t u d y 
•   T h e  Cli ni c al I n v esti g ati o n  Pl a n  a n d st u d y r el at e d r e p orts,  a n d r e visi o ns  
•   S a m pl e  of  d at a  c oll e cti o n s cr e e ns  
•   A n y  ot h er r e c or ds t h at l o c al r e g ul at or y  a g e n ci es r e q uir e t o  b e  m ai nt ai n e d  
6. 5   S u s p e n si o n  o r  E a rl y  T e r mi n a ti o n  
E arl y  T er mi n ati o n is t h e  cl os ur e  of  a  cli ni c al st u d y t h at  o c c urs  pri or t o  m e eti n g  d efi n e d  e n d p oi nts.  T his  
is  p ossi bl e f or t h e  w h ol e st u d y  or  a si n gl e sit e.  S us p e nsi o n is  a t e m p or ar y  p ost p o n e m e nt  of st u d y 
a cti viti es r el at e d t o  e nr oll m e nt  a n d  distri b uti o n  of t h e  pr o d u ct.  T his is  p ossi bl e f or  t h e  w h ol e st u d y  or  a 
si n gl e sit e.  
6. 5. 1   S t u d y - wi d e  S u s p e n si o n  o r  E a rl y  T e r mi n a ti o n  
P ossi bl e r e as o ns f or  c o nsi d eri n g st u d y s us p e nsi o n  or t er mi n ati o n  of t h e st u d y i n cl u d e  b ut  ar e  n ot li mit e d 
t o: 
•    O bs er v e d/s us p e ct e d  p erf or m a n c e  of st u d y  a p p  diff er e nt fr o m t h e  ori gi n al i nt e nt  
•    D e cisi o n  b y  M e dtr o ni c  or r e g ul at or y  b o d y ( w h er e t h e st u d y is  o p er ati n g  u n d er r e g ul at or y 
b o d y  a ut h orit y)  
6. 5. 2   I n v e s ti g a t o r / Si t e  S u s p e n si o n  o r  E a rl y  T e r mi n a ti o n  
P ossi bl e r e as o ns f or  cli ni c al i n v esti g at or  or sit e t er mi n ati o n  or s us p e nsi o n i n cl u d e  b ut  ar e  n ot li mit e d t o:  
•      F ail ur e t o  o bt ai n i niti al I R B  a p pr o v al  or  a n n u al r e n e w al  of t h e st u d y  a p pr o v al  
•      L a c k  of  e nr oll m e nt  
•      N o n c o m pli a n c e t o r e g ul ati o ns  a n d t h e t er ms  of t h e  Cli ni c al  Tri al  A gr e e m e nt ( e. g., f ail ur e t o 
s u b mit  d at a i n  a ti m el y  m a n n er)  
•      I R B s us p e nsi o n  of t h e sit e 

D E F I N E  A Fi b  Si t e  A s si s t e d  P h a s e  Cli ni c al 
I n v e s ti g a ti o n  Pl a n  
 
 
V er si o n:  2 . 0  2 9 J U L 2 0 2 2 
    
P a g e  1 6  of  1 7  
 
M e d t r o ni c 
e d t r o ni c  B u si n e s s  R e s t ri ct e d
B u si n e s s  R e s t ri ct e d  
 
 
C O N FI D E N TI A L    
0 5 6-F 2 7 5,  v C  Cli ni c al I n v e sti g ati o n  Pl a n  T e m pl at e  
•      Fr a u d  or fr a u d ul e nt  mis c o n d u ct is  dis c o v er e d ( as  d efi n e d  b y l o c al l a w  a n d r e g ul ati o ns)  
•      I n v esti g at or r e q u est ( e. g.,  n o l o n g er  a bl e t o s u p p ort t h e st u d y) 
6. 5. 3   P r o c e d u r e s f o r  S u s p e n si o n  o r  E a rl y  T e r mi n a ti o n  
B el o w  pr o c e d ur es  will  a p pl y i n  a d diti o n t o  a n y  ot h er s p e cifi c r e q uir e m e nt  p er l o c al r e g ul ati o ns.  
M e dtr o ni c -i niti at e d  a n d r e g ul at or y  a ut h orit y-i niti at e d 
•    M e dtr o ni c  will  pr o m ptl y i nf or m t h e  cli ni c al i n v esti g at ors  of t h e t er mi n ati o n  or s us p e nsi o n 
a n d t h e r e as o ns  a n d i nf or m t h e r e g ul at or y  a ut h orit y(i es)  w h er e r e q uir e d  
•   I n t h e  c as e  of st u d y t er mi n ati o n  or s us p e nsi o n f or r e as o ns  ot h er t h a n  a t e m p or ar y  E C 
a p pr o v al l a ps e, t h e i n v esti g at or  will  pr o m ptl y i nf or m t h e  E C.  A  d et ail e d  writt e n  e x pl a n ati o n 
of t h e t er m i n ati o n  or s us p e nsi o n  will  b e  pr o vi d e d,  w h er e r e q uir e d  p er r e g ul at or y 
r e q uir e m e nts 
•   I n t h e  c as e  of st u d y t er mi n ati o n,  M e dtr o ni c  will i nf or m t h e s u bj e cts  vi a t h e st u d y  a p p.   
•   I n t h e  c as e  of  a st u d y s us p e nsi o n, s u bj e ct  e nr oll m e nt  m ust st o p  u ntil t h e s us p e nsi o n is lift e d 
b y  M e dtr o ni c.   
•   I n t h e  c as e  of  a st u d y s us p e nsi o n,  e nr oll e d s u bj e cts s h o ul d  c o nti n u e t o  b e f oll o w e d  o ut  of 
c o nsi d er ati o n  of t h eir s af et y, ri g hts,  a n d  w elf ar e  
I n v e sti g at or-i niti at e d 
•    T h e i n v esti g at or  will i m m e di at el y  or  pr o m ptl y i nf or m  M e dtr o ni c  a n d  pr o vi d e  a  d et ail e d 
writt e n  e x pl a n ati o n  of t h e t er mi n ati o n  or s us p e nsi o n ( M e dtr o ni c, i n t ur n,  will  n otif y  aff e ct e d 
p ati e nts  vi a t h e st u d y  a p p)  
•    T h e i n v esti g at or  will  pr o m ptl y i nf or m t h e i nstit uti o n ( w h er e r e q uir e d  p er r e g ul at or y 
r e q uir e m e nts) 
•    T h e i n v esti g at or  will  pr o m ptl y i nf or m t h e  E C,  al o n g  wit h  a  d et ail e d  writ t e n  e x pl a n ati o n  of t h e 
t er mi n ati o n  or s us p e nsi o n ( w h er e r e q uir e d  p er r e g ul at or y r e q uir e m e nts) 
•   I n t h e  c as e  of  a st u d y s us p e nsi o n, s u bj e cts  e nr oll e d s h o ul d  c o nti n u e t o  b e f oll o w e d  o ut  of 
c o nsi d er ati o n  of t h eir s af et y, ri g hts,  a n d  w elf ar e  
I R B-i niti at e d