Atrial Fibrillation Algorithms Clinical Validation Study
Phase: NA
Conditions: Atrial Fibrillation
Sponsor: Apple Inc.

Atrial Fibrillation Algorithms Clinical Validation Study 
099-25141, 09 April 2021 
NCT04699812

 
 
 
 
 
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 Atrial Fibrillation Algorithms Clinical Validation Study 
 
Sponsor: 
Apple Inc. 
Protocol Number 
099-25141 
Version and date: 
 – 09 April 2021 
Compliance Statement: 
This study will be conducted in accordance 
with this protocol, ICH GCP Guidelines, and 
the applicable regulatory requirements (21 
CFR Parts 50, 54, 56, and 812). The conduct 
of the study will be approved by the 
appropriate Institutional Review Board (IRB) 
of the respective Investigational site. Safety 
assessments (adverse events) for this study 
will be conducted in accordance with ISO 
14155-1 (2011).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 

 
 
 
 
 
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INVESTIGATOR APPROVAL PROTOCOL SIGNATURE PAGE 
 
Protocol: 
099-25141 
Title: 
 Atrial Fibrillation Algorithm Clinical Validation Study 
 
Amendment: 
 
NA 
 
 
I confirm that I have read and understood this study protocol and attached appendices and will 
conduct this study in compliance with the protocol, all statements regarding confidentiality, 
local regulations, International Council for Harmonization Good Clinical Practice E6 (ICH-
GCP), and United States (US) Code of Federal Regulations (CFR) applicable to clinical studies 
(21 CFR Parts 50 [protection of human subjects], 54 [financial disclosure by clinical 
investigators], 56 [informed consent and Institutional Review Board (IRB) requirements], 812 
[Investigational Device Exemptions]).  
With my signature, I agree to: 
(i) Conduct the investigation in accordance with the investigator’s agreement with CRO, the 
investigational plan, applicable provisions of 21 CFR Part 812 and other Food and Drug 
Administration (FDA) regulations, and conditions of approval imposed by the reviewing IRB or 
FDA;  
(ii) Supervise all testing of the device involving human subjects; and  
(iii) Ensure that the requirements for obtaining informed consent are met. 
 
Reviewed and Approved by: 
 
 
  
 
 
 
 
 
 
 

 
 
 
 
 
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SYNOPSIS 
Study Title 
 Atrial Fibrillation Algorithm Clinical Validation Study 
Protocol Version 
 
Protocol Date 
09 April 2021 
Study Design 
Prospective, multi-center, non-significant risk study 
Key Inclusion 
Criteria 
All cohorts:  
• Age 22 or older 
• Able to read and understand a written informed consent form 
(ICF) 
• Willing and able to participate in the study procedures 
• Able to communicate effectively with and follow instructions 
from the study staff 
• Must meet additional binning based on demographics 
• Able to wear the wrist device for duration of study participation 
Cohort 1: No known history of atrial fibrillation (AF)  
Cohort 2 (Aggressor Rhythm Cohort): No known history of atrial 
fibrillation (AF) and active diagnosis of at least one of the following: 
• Frequent premature atrial contractions (PACs) 
• Frequent premature ventricular contractions (PVCs) 
• Supraventricular tachycardia (SVT)  
• Non-sustained ventricular tachycardia (NSVT) 
Cohort 3 (Non-permanent AF cohort): Known diagnosis of 
paroxysmal, persistent, or chronic AF at time of screening (confirmed 
by electronic medical record (EMR) or self-report) 
Cohort 4: Subjects with known diagnosis of permanent AF at time of 
screening (confirmed by EMR or self-report) 
Key Exclusion 
Criteria 
All cohorts:  
• Physical disability that precludes safe and adequate testing  
• Mental impairment resulting in limited ability to cooperate  

 
 
 
 
 
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• Known uncontrolled medical conditions, such as (but not 
limited to) significant anemia, important electrolyte imbalance 
and untreated or uncontrolled thyroid disease 
• Open wound(s) on the wrist and/or forearm 
• Tattoos, large moles, or scars on the wrist at the wrist device 
location 
• Medical history, or physical assessment finding that makes the 
subject inappropriate for participation according to the 
Investigator 
• Skin conditions on either wrist that would preclude subject 
from wearing a wristband on either wrist 
• Known allergy or significant sensitivity to medical adhesives, 
isopropyl alcohol, or electrocardiogram (ECG) patch 
• Participation in a previous study that used a wrist-worn sensor 
device with a simultaneous ECG reference patch 
• Subjects with implanted cardiac devices such as a Pacemaker 
or an automated Implantable Cardioverter - Defibrillator  
Study Objective 
The objective of this study is to collect data to evaluate the 
performance of the investigational Irregular Rhythm Notification 
Feature (IRNF) 2.0 and Atrial Fibrillation Burden Feature (AFBF) 1.0 
algorithms. 
Endpoints  
Primary Endpoints: 
IRNF: 
• Sensitivity of the irregular rhythm notification for the 
identification of persons with AF by 13-day ambulatory ECG, 
with AF defined as at least 30 seconds of AF by ambulatory 
ECG. 
• Specificity of the lack of irregular rhythm notification for the 
identification of persons without AF by 13-day ambulatory 
ECG, with AF defined as at least 30 seconds of AF by 
ambulatory ECG 
 
 
 
 
 

 
 
 
 
 
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AFBF: 
• Weekly AF burden estimate defined as the percentage of time a 
subject is in Atrial Fibrillation during wrist device wear over 
the prior 7 consecutive days 
Secondary Endpoints: 
IRNF: 
• Notification-level positive predictive value (PPV) with AF by 
ambulatory ECG at the time of any tachogram comprising the 
notification.  
• Tachogram-level performance (Sensitivity, Specificity, false 
positive rate (FPR), PPV, negative predictive value (NPV)) for 
tachograms comprising alerts. 
• Tachogram-level performance (Sensitivity, Specificity, FPR, 
PPV, NPV) for all generated tachograms. 
AFBF: 
• Sensitivity, specificity, positive predictive value, and negative 
predictive value of tachograms for the identification of AF by 
ambulatory ECG  
• Day-specific AF burden estimate defined as the percentage of 
time a subject is in Atrial Fibrillation during a specific day of the 
week  
• Four-hour segment-specific AF burden estimate defined as the 
percentage of time a subject is in Atrial Fibrillation during a 
specific four-hour segment of a day  
Test Device 
Investigational Irregular Rhythm Notification Feature (IRNF) 2.0 and 
Atrial Fibrillation Burden Feature (AFBF) 1.0 algorithms 
Study App 
Investigational Study App  
Reference Device 
Cardea SOLO Wireless ECG Patch (K123217) 
Study Procedures 
Screening will include the following: 
• A brief physical assessment, performed either virtually, or in 
person following Sponsor approval 
The following information will also be collected at screening: age, 
gender, race and ethnicity, occupation, diagnosed medical conditions, 
medications, allergies, visual assessment of general appearance and 
skin, body measurements and assessments (height, weight, BMI), 

 
 
 
 
 
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assessment of tattoos, moles, scars on wrist (both), and skin tone 
assessment on Fitzpatrick scale. 
Day 1:  
• This visit can be done remotely, or in person following Sponsor 
approval. This visit should be no more than 14 days after 
screening 
• Two (2) wrist devices of the same series and configuration will 
be assigned to each subject (one for daytime wear and one for 
wear during sleep) at random from the set of wrist device 
series/configurations included in this study. Two iPhones will 
also be assigned to each subject. 
• The single-lead ambulatory ECG patch will be affixed to the 
subject’s upper torso per manufacturer’s instructions and using 
standard procedures. 
• Skin tone assessment on the Fitzpatrick scale will be confirmed. 
Day 5 (+ 2 days):  
• This visit can be done remotely, or in person following Sponsor 
approval 
• Study staff will be in contact with the subject to execute 
replacing the subject’s ECG patch. 
• The ECG patch will be returned to study staff for download 
Day 13 (± 2 days), or end of 2nd ECG patch wear period, if less than 13 
± 2 days: 
• This visit can be done remotely, or in person following Sponsor 
approval 
• Subjects will be asked to report any study procedure-related 
adverse events (AEs) that occurred during the previous period 
of up to 13 days (± 2 days), or during the ECG patch wear 
periods if less than 13 ± 2 days.  
• The subject’s ECG patch will be removed. The ECG patch data 
will be returned to the study staff for processing and 
adjudication. 
The investigational Irregular Rhythm Notification Feature (IRNF) 2.0 
and Atrial Fibrillation Burden Feature (AFBF) 1.0 algorithms (test 
devices) will be run post-hoc on the sensor dataset to generate 
tachograms and notification. The performance of each test device will 
be determined based upon adjudication of concurrent data from the 
reference device. 

 
 
 
 
 
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Duration of Study 
Participation 
• Up to 13 ± 2 days, or until the end of the 2nd ECG patch wear 
period, if less than 13 ± 2 days 
Total Number of 
Study Subjects 
Enrolled  
• A total of n=235 to 627 subjects across the following 4 cohorts 
are targeted for enrollment in this study as follows:  
• n=78  (Cohort 1: No Known Diagnosis of AF)  
• n=67-85  (Cohort 2: Aggressor Rhythm Cohort) 
• n=54-394 (Cohort 3: Non-permanent cohort, Paroxysmal, 
Persistent or Chronic AF) 
• 
n=36-70 (Cohort 4: Permanent AF) 
Additionally, there will be a sub-study of approximately 40 participants 
prior to the pivotal study starting, which would bring the total sample 
size to 667. The sub-study participants are a separate cohort and will 
not be included in any of the endpoint analyses for the pivotal study 
(see section 3.1 Study Design - Overview). 

 
 
 
 
 
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TABLE OF CONTENTS 
SYNOPSIS 4 
TABLE OF CONTENTS .................................................................................................................9 
LIST OF TABLES .........................................................................................................................11 
LIST OF ABBREVIATIONS ........................................................................................................12 
1. 
INTRODUCTION ......................................................................................................14 
1.1. 
Background .................................................................................................................14 
1.2. 
Device Description .....................................................................................................15 
1.3. 
Study Rationale ...........................................................................................................15 
1.4. 
Risk/Benefit Assessment ............................................................................................15 
2. 
STUDY OBJECTIVES, ENDPOINTS, AND HYPOTHESES .................................16 
2.1. 
Study Objective ..........................................................................................................16 
2.2. 
Study Endpoints ..........................................................................................................16 
3. 
STUDY DESIGN .......................................................................................................19 
3.1. 
Overview .....................................................................................................................19 
3.2. 
Required Equipment ...................................................................................................20 
3.2.1. 
Sponsor-Provided .......................................................................................................20 
3.2.2. 
Contract Research Organization (CRO)-Provided .....................................................20 
3.2.3. 
Storage and Handling Procedure ................................................................................20 
3.2.4. 
Accountability .............................................................................................................20 
3.2.5. 
Investigational Study Site-Provided ...........................................................................20 
3.3. 
Qualification Criteria for US Board-Certified Cardiologists ......................................20 
3.4. 
Randomization and Blinding ......................................................................................20 
3.5. 
Duration of Subject Participation ...............................................................................21 
4. 
STUDY POPULATION .............................................................................................22 
4.1. 
Subject Recruitment ....................................................................................................22 
4.2. 
Study Cohorts and Target Population .........................................................................22 
4.3. 
Inclusion Criteria ........................................................................................................23 
4.4. 
Exclusion Criteria .......................................................................................................24 
4.5. 
Subject Discontinuation ..............................................................................................25 
4.6. 
Subject Follow-up .......................................................................................................25 
5. 
STUDY PROCEDURES ............................................................................................26 

 
 
 
 
 
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5.1. 
Screening ....................................................................................................................27 
5.2. 
Study Day 1 ................................................................................................................27 
5.2.1. 
Data Collection Study Equipment Set up ...................................................................27 
5.3. 
Study Days 1-13 .........................................................................................................28 
5.4. 
Study Day 5 ................................................................................................................28 
5.5. 
End of Study Visit ......................................................................................................28 
5.5.1.1. 
Study Procedures ........................................................................................................28 
5.5.1.2. 
Wrist Device Data Processing ....................................................................................29 
5.5.2. 
Adjudication of ECG Data ..........................................................................................29 
5.5.2.1. 
ECG Patch ..................................................................................................................29 
6. 
STATISTICAL ANALYSIS ......................................................................................32 
6.1. 
Dataset Generation ......................................................................................................32 
6.2. 
Statistical Methodology ..............................................................................................32 
6.2.1. 
Randomization Methodology .....................................................................................32 
6.2.2. 
Primary Endpoint Analysis .........................................................................................33 
6.2.3. 
Secondary Endpoint Analyses ....................................................................................36 
6.2.4. 
Safety Analyses ..........................................................................................................39 
6.2.5. 
Additional Analyses ....................................................................................................39 
6.3. 
Sample Size Determination ........................................................................................41 
6.4. 
Significance Level ......................................................................................................43 
6.5. 
Missing Data ...............................................................................................................44 
6.6. 
Subgroup Analyses .....................................................................................................44 
6.7. 
Interim Analyses .........................................................................................................44 
6.8. 
Analysis Sets ...............................................................................................................44 
7. 
SAFETY PARAMETERS AND ASSESSMENT ......................................................46 
7.1. 
Adverse Events ...........................................................................................................46 
7.1.1. 
AE/SAE Collection .....................................................................................................46 
7.1.2. 
SAE Reporting ............................................................................................................47 
7.1.3. 
Reporting of all other Study Adverse Events .............................................................47 
7.2. 
Safety Plan ..................................................................................................................47 
7.3. 
Overview of study suspension and termination criteria .............................................48 
8. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................49 

 
 
 
 
 
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8.1. 
Institutional Review Board .........................................................................................49 
8.2. 
Informed Consent .......................................................................................................49 
8.3. 
Record Keeping ..........................................................................................................50 
8.4. 
Confidentiality and Privacy ........................................................................................50 
8.5. 
Protocol Adherence ....................................................................................................50 
8.6. 
Collection and Management Responsibilities ............................................................50 
8.7. 
Study Monitoring ........................................................................................................50 
8.8. 
Data Quality Assurance and Quality Control .............................................................51 
8.9. 
Use of Information ......................................................................................................51 
8.10. 
Study Record Retention ..............................................................................................52 
8.11. 
Study Termination and Site Closure ...........................................................................52 
8.12. 
Completion of the Study .............................................................................................52 
9. 
REFERENCES ...........................................................................................................53 
 
LIST OF TABLES 
Table 1: 
 Targeted Number of Enrolled Subjects Per Cohort ...................................................23 
Table 2: 
Cohort 3 and 4 Minimum AF Burden Targets ............................................................23 
Table 3: 
Schedule of Events .....................................................................................................26 
Table 4: 
Diagnosis of ≥1 AF Episode Present on ECG Patch ..................................................34 
Table 5: 
No AF Episodes Present on ECG Patch .....................................................................34 
Table 6: 
Cross-Classification Table of Tachogram Results and Adjudicated 
Cardiologist Diagnoses from ECG Strips ...................................................................37 
Table 7: 
Sample Sizes for AF Cohorts of Subjects Required for IRNF Evaluation .................42 
Table 8: 
Sample Sizes for Subjects without AF Required for IRNF Evaluation ......................42 
Table 9: 
Sample Sizes for Aggressor Subjects without AF Required for IRNF 
Evaluation ...................................................................................................................43 
 

 
 
 
 
 
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LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviation  
Explanation 
ADE 
Adverse device effect 
AE 
Adverse event 
AF 
Atrial fibrillation  
AFB 
Atrial fibrillation burden 
AFBF 
Atrial fibrillation burden feature 
AFL 
Atrial flutter 
AV 
Atrioventricular 
AVNRT 
Atrioventricular nodal reentry tachycardia 
AVRT 
Atrioventricular reciprocating tachycardia) 
BMI 
Body mass index 
CFR 
Code of Federal Regulations 
CIED 
Cardiovascular implantable electronic device 
CRO 
Contract research organization 
EAS 
ECG Patch Analysis Set 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
EMR 
Electronic medical record 
FAS 
Full analysis set 
FDA 
U.S. Food and Drug Administration 
FPR 
False positive rate 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization 
IRB 
Institutional Review Board 
IRNF 
Irregular rhythm notification feature 

 
 
 
 
 
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Abbreviation  
Explanation 
ISO 
International Organization for Standardization 
LOA 
Limits of Agreement 
mm 
millimeter 
N or n 
number 
N/A 
Not applicable 
NAS 
Notification Analysis Set 
NPV 
Negative predictive value 
NSR 
Normal sinus rhythm 
NSVT 
Non-sustained ventricular tachycardia 
PAC 
Premature atrial contraction 
PAF 
Paroxysmal atrial fibrillation 
PPAS 
Per-protocol analysis set 
PPG 
Photoplethysmography 
PPV 
Positive predictive value 
QC 
Quality control 
SADE 
Serious adverse device effect 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SR 
Sinus rhythm 
SVT 
Supraventricular tachycardia 
UADE 
Unexpected adverse device effect 
US 
United States 

 
 
 
 
 
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1. 
INTRODUCTION 
1.1. 
Background 
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and when left untreated, is a 
leading cause of morbidity and mortality from stroke, heart failure and myocardial infarction 
(Ben Freedman, 2015; Moran, 2016). Data from the Framingham Heart Study indicates that by 
age 40 years, lifetime risk for developing AF is 1 in 4 (Lloyd-Jones, 2004). AF is also a growing 
public health problem with prevalence projected to triple between 2010 and 2050, with an 
estimated 12.1 million diagnosed cases in 2030 in the United States (US) alone (Colilla, 2013). 
Early detection and treatment of patients with AF minimizes the risk of sequelae of 
thromboembolism including >60% reduced risk of stroke (Moran, 2016; Omboni, 2016). 
However, many affected with AF are unaware they have this dysrhythmia due to a number of 
factors including lack of symptoms, or experience only mild symptoms that they do not attribute 
to a disease (Moran, 2016). As a result, asymptomatic patients are 3 times as likely to have 
sustained an ischemic stroke prior to diagnosis than those with symptoms (Ben Freedman, 2015; 
O'Neal, 2016). These findings raise concerns and have prompted several variations of screening 
programs to detect patients with asymptomatic AF to prevent an embolic event (Ben Freedman, 
2015; Moran, 2016). While systematic and opportunistic screening programs have demonstrated 
increased rates of detection when compared to detection during routine clinical practice, such 
screening programs are not yet widely implemented (Moran, 2016). Additionally, AF may be 
paroxysmal (PAF or intermittent AF) and therefore missed by recording a single in-clinic 
electrocardiogram (ECG). This is especially true for those patients with intermittent symptoms. 
Holter devices are commonly used for ambulatory 24-hour ECG monitoring in at-risk patients, 
but have limited sensitivity for the detection of new AF (Brachmann, 2016).  
Once diagnosed with AF, the condition of AF can affect individual patients with different 
degrees of burden. AF burden itself can be defined as the percentage time a person is in AF 
during a specified time period. AF burden has been traditionally estimated through monitoring 
devices such as Holter devices, implantable loop recorders, or implantable pacemakers and 
defibrillators. AF burden, moreover, is a strong area of focus in medical research on its impact 
on outcomes and management. One recent study (Go, 2018) identified 3-fold higher risk of 
stroke in patients with the highest burden compared to those with low burden. For non-stroke 
outcomes, AF burden has been a focus of research interest as a potential predictor of other events 
such as heart failure, mortality, and other cardiac-related outcomes (Chen, 2018). 
Although established guidelines do not currently utilize AF burden alone to drive clinical 
decision making, for many patients, AF burden can have a negative impact on daily life due to 
symptoms and impact on their cardiovascular health. Indeed, quality of life is of great 
importance in patients with AF and often a primary goal in optimization of their health after 
prioritizing stroke prevention. Patients can have a wide range of symptoms while in AF, from 
palpitations, tiredness, low energy, and other manifestations to complete absence of symptoms. 
For those patients with symptoms, the degree of AF burden can be correlated with their quantity 
of symptoms, and therefore have great impact on their quality of life. A number of clinical 
interventions are utilized to manage AF and its symptoms, including rate control medications, 
antiarrhythmics, and nonpharmacologic strategies such as catheter ablation.  Outside of clinical 

 
 
 
 
 
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interventions, recent data suggests that patients can pursue lifestyle modifications such as weight 
loss, exercise, improved sleep, and stress management to manage AF burden; as an example, 
recent guidelines by the AHA/ACC/HRS now recommend, as a Class I indication, lifestyle 
interventions for overweight persons with AF (January, 2019).  
Recent guidelines and professional society consensus documents highlight the importance of 
enhancing patient knowledge of AF (January, 2019; Lane, 2015). Given that mobile devices 
permit ways to frequently monitor patients in an outpatient setting, our hypothesis is that use of 
the test device can facilitate both the identification of AF in the undiagnosed users as well as 
provide valuable information regarding AF burden estimates for users with known diagnosis of 
AF. 
1.2. 
Device Description 
The Investigational Irregular Rhythm Notification Feature (IRNF) 2.0 and Atrial Fibrillation 
Burden Feature (AFBF) 1.0 algorithms are software-based medical devices.  
The IRNF 2.0 algorithm analyzes background data opportunistically collected by the integrated 
optical sensors on a compatible Apple Watch (wrist device) to identify and notify users of 
irregular rhythm suggestive with AF.   
The AFBF 1.0 algorithm also analyzes background data opportunistically collected by the 
integrated optical sensors on a compatible Apple Watch (wrist device) and estimates the 
proportion of time a user is in an AF rhythm as compared to other rhythms; these results can be 
displayed and accessed by the user on a compatible iPhone. 
1.3. 
Study Rationale 
This clinical study is being conducted to evaluate the performances of investigational Irregular 
Rhythm Notification Feature (IRNF) 2.0 and Atrial Fibrillation Feature Burden (AFBF) 1.0 
algorithms (test devices). 
1.4. 
Risk/Benefit Assessment 
There may be risks or discomforts associated with participating in this study. No significant risks 
or permanent side effects are anticipated. Precautions will be taken to minimize risks; however, 
there may be risks that are not yet known about. Subjects will be encouraged to talk to study staff 
if they experience any injuries, side effects, or discomfort while or as a result of participating in 
this study.  
• Subjects may experience slight to moderate discomfort associated with attachment 
and removal of adhesive electrodes used for ECG patches. The risk will be minimized 
by using medical-grade disposable electrodes and by leaving them attached to the 
skin only for the limited study duration. Even with these precautions, temporary skin 
irritation may still occur.  
• Subjects may experience rash from the ambulatory ECG monitor or from the wrist 
device band. 
• Subjects may experience slight to moderate discomfort associated with wearing the 
wrist device, such as pressure related muscle tenderness.  

 
 
 
 
 
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2. 
STUDY OBJECTIVES, ENDPOINTS, AND HYPOTHESES 
2.1. 
Study Objective 
The objective of this study is to collect data to evaluate the performance of the investigational 
Irregular Rhythm Notification Feature (IRNF) 2.0 and Atrial Fibrillation Burden Feature (AFBF) 
1.0 algorithms. 
2.2. 
Study Endpoints 
Primary Endpoints: 
IRNF: 
• Sensitivity of the irregular rhythm notification for the identification of persons with AF 
by 13-day ambulatory ECG, with AF defined as at least 30 seconds of AF by ambulatory 
ECG. 
• Specificity of the lack of irregular rhythm notification for the identification of persons 
without AF by 13-day ambulatory ECG, with AF defined as at least 30 seconds of AF by 
ambulatory ECG. 
AFBF: 
• Weekly AF burden estimate, defined as the percentage of time a subject is in Atrial 
Fibrillation during wrist device wear over the prior 7 consecutive days 
Secondary Endpoints: 
IRNF: 
• Notification-level positive predictive value (PPV) with AF by ambulatory ECG at the 
time of any tachogram comprising the notification.  
• Tachogram-level performance (Sensitivity, Specificity, false positive rate (FPR), PPV, 
negative predictive value (NPV)) for tachograms comprising alerts. 
• Tachogram-level performance (Sensitivity, Specificity, FPR, PPV, NPV) for all 
generated tachograms. 
AFBF: 
• Sensitivity, specificity, positive predictive value, and negative predictive value of 
tachograms for the identification of AF by ambulatory ECG. 
• Day-specific AF burden estimate  defined as the percentage of time a subject is in Atrial 
Fibrillation during a specific day of the week. 
• Four-hour segment-specific AF burden estimate  defined as the percentage of time a 
subject is in Atrial Fibrillation during a specific four-hour segment of a day.  
 

 
 
 
 
 
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Study Hypotheses 
IRNF: 
The primary endpoint hypothesis associated with the IRNF is: 
 
 
 
 
 
 Data from subjects in Cohorts 1, 3, and 4 will be used to test this 
hypothesis. 
The secondary endpoint hypothesis associated with the IRNF compares the tachogram-level false 
positive rate (FPR) of the test device to that of the predicate device to determine if the test device 
algorithm FPR is non-inferior 
) to that of the predicate device using all tachograms 
generated only from subjects in Cohort 2 (Aggressor Rhythm Cohort). 
 
 
 
 
 
 
  
 
 
 
AFBF: 
The primary endpoint hypothesis associated with the AFBF is: 
 
 
 
 
 
The secondary endpoint hypotheses associated with the day-specific and four-hour segment-
specific endpoints are listed below, respectively:  
 
  

 
 
 
 
 
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  Additional 
information on the simulation methodology is contained in Section 6.2.3 and the SAP. 
 

 
 
 
 
 
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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a prospective, non-significant risk study. The study protocol will undergo review and 
approval by an Institutional Review Board (IRB) prior to recruitment or enrollment of study 
subjects.  
Written, informed consent will be obtained from all subjects before any protocol-directed 
procedures are performed. All potential subjects will participate in a screening visit, and if 
eligibility is confirmed, subjects may begin study participation.  
Subjects will be given two separate wrist devices for use in the study – one wrist device will be 
worn during waking hours, the other wrist device will be worn overnight such that the subject is 
not wearing multiple wrist devices at one time. Subjects will wear a wrist device simultaneously 
with a single-lead ambulatory ECG patch for up to 13 days (± 2 days), or until the end of the 2nd 
ECG patch wear period, if less than 13 ± 2 days, during regular daily life to enable the collection 
of a single sensor dataset for each subject. The 1st ECG patch will be replaced after 5 days (+2 
days). The wrist device will collect accelerometer data continuously  and photoplethysmography 
(PPG) data when the user is still during their daily life use. The study duration will be for up to 
13 days (± 2 days). The ECG patch will be returned and assessed for presentation of AF and 
other arrhythmias. 
The study will target enrollment of subjects with varying diagnoses of AF, normal sinus rhythm, 
and other rhythms with a goal to generate a dataset with AF burdens that span from 0% to 100%. 
Target recruitment bins of AF burden for subjects in Cohorts 3 and 4 will be monitored during 
the study using only data collected from the ambulatory ECG patch to ensure minimum data 
collection in each; study enrollment of Cohort 3 and 4 subjects will continue until minimum 
enrollment targets of low AF burden and high AF burden are achieved (as defined in 
Section 4.2). Because of anticipated discrepancies between self-reported type of AF and the 
amount of AF burden measured via ECG patch, for purposes of analysis, the final Cohort 
assignment will be determined based on the AF burden measured via ECG patch.   
The investigational Irregular Rhythm Notification Feature (IRNF) 2.0 and Atrial Fibrillation 
Burden Feature (AFBF) 1.0 algorithms (test device) will be run post-hoc on the sensor dataset to 
generate tachograms and notifications. The performance of each test device will be determined 
based upon adjudication of concurrent data from the reference device. 
A sub-study cohort of approximately 40 subjects will be enrolled prior to the start of the clinical 
validation (i.e., pivotal) study. These subjects will follow the same study procedures outlined in 
this protocol.  However, no data from this cohort will contribute towards the performance 
evaluation of the test device algorithms.  This sub-study is primarily intended to provide 
assurance that all of the data collection, evaluation, and data transfer tools are performing as 
intended prior to the start of the clinical validation study.  Subject accountability, demographic, 
and safety data will be summarized and reported for this cohort.     

 
Version 5.0 
 
 
 
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3.2. 
Required Equipment 
3.2.1. 
Sponsor-Provided 
The Sponsor will provide the study sites with sufficient wrist devices, iPhones, and ECG patches 
to complete the study. Subjects will be instructed to return all equipment to the CRO at the end 
of the study. Site staff will use accountability log for traceability to sponsor provided devices, 
equipment.  
3.2.2. 
Contract Research Organization (CRO)-Provided 
The CRO will provide the necessary supplies for return of study equipment following subject 
use. 
No specific packaging of the study equipment is required, as this study is non-interventional and 
will temporarily dispense study equipment to subjects. 
3.2.3. 
Storage and Handling Procedure 
All study equipment, including reference devices, will be stored in normal room 
temperature/humidity/pressure conditions with no exposure to direct sunlight or heat source 
throughout the study. The storage area should be secure with restricted access. 
3.2.4. 
Accountability 
Wrist device and reference device ID numbers used for each subject will be recorded in the 
source documents. All study equipment (excluding equipment listed in 3.2.5 below) will be 
returned to the CRO at the end of the study. 
3.2.5. 
Investigational Study Site-Provided 
The Investigational study site will provide the following: 
• Space and technology available to screen and enroll subjects via telehealth visit and/or in 
person visits following Sponsor approval. 
3.3. 
Qualification Criteria for US Board-Certified Cardiologists 
Reviewers of 1-lead ECG data must be US board-certified medical doctors specialized in 
cardiology. 
Curriculum vitae and medical license will be collected for each US board-certified medical 
doctor specialized in cardiology. 
3.4. 
Randomization and Blinding 
Subjects in this study will not be randomized to any treatment regimens but will be randomly 
assigned a specific wrist device series/configuration (
 
) by enrollment cohort using a 1:1 randomization ratio.  
US board-certified cardiologists will be blinded to the subjects’ past medical history, IRNF 
notifications, and AF burden results from the AFBF algorithm during the assessment and 

 
 
 
 
 
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adjudication of ECG patch data. Adjudication of ECG strips corresponding to tachograms will 
also be performed blinded to all other ECG patch data and adjudications. Adjudicators will be 
instructed to review ECGs independently and separately of each other and not to confer about 
diagnoses. 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
3.5. 
Duration of Subject Participation 
Subjects will participate in a screening visit and, if eligible, will participate in the study for up to 
13 days (± 2 days). 

 
 
 
 
 
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4. 
STUDY POPULATION 
4.1. 
Subject Recruitment 
Subject recruitment will abide by the guidelines of the IRB and the investigational site(s). 
Recruitment will continue until enrollment requirements are met, including reaching the targeted 
number of subjects completing the study procedures with adequate data collection.  A subject 
will be considered enrolled if he/she has signed a consent form and participant has passed all 
screening criteria. 
Investigators will keep a record, i.e. subjects screening log, of subjects who are entered into the 
study. Each subject must meet all the inclusion criteria and none of the exclusion criteria for this 
study at the time of screening and study participation. The Sponsor must approve any changes to 
the target distribution of subjects in writing prior to enrollment. 
4.2. 
Study Cohorts and Target Population 
The study will include 4 cohorts of subjects:  
• Cohort 1 will include subjects with no known history of AF* 
• Cohort 2 (Aggressor Rhythm Cohort) will include subjects with no known history of 
AF*, but with history of frequent premature atrial contractions (PACs), frequent 
premature ventricular contractions (PVCs), supraventricular tachycardia (SVT), or non-
sustained ventricular tachycardia (NSVT) 
• Cohort 3 (non-permanent AF) will include subjects with known history of paroxysmal, 
persistent, or chronic AF* 
• Cohort 4 (permanent AF) will include subjects with permanent AF. 
* History of AF encompasses the 2 years prior to participation in study screening procedures. 
For all cohorts, the following age, gender, and race/ethnicity enrollment targets will be adhered 
to during subject recruitment: 
• A minimum of 10% of subjects will be enrolled the age category of <55 and a minimum 
of 20% in of the age categories of 55 to 64, and ≥65 years.  
• At least 40% of subjects in Cohort 1 will be female and at least 40% male. At least 20% 
of subjects in each of Cohorts 3 and 4 will be female and at least 20% will be male. 
• At least 10% of subjects in Cohort 1 will be non-Caucasian. In Cohorts 3 and 4 as a 
combined group, at least 10% of subjects will be non-Caucasian.  
The incidence of AF is known to increase with age, male gender, and White race (Benjamin, 
2019). These recruitment targets are also consistent with the subject population observed in the 
Apple Heart Study, which is representative of the intended use population (Turakhia, 2019).  
Table 1 identifies the estimated number of subjects targeted for enrollment. A minimum of 
subjects will be enrolled in Cohort 2. 

 
 
 
 
 
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Table 1: 
 Targeted Number of Enrolled Subjects Per Cohort 
Cohort 1 (NSR) 
Cohort 2 (Aggressor 
Rhythm Cohort) 
Cohort 3 (non-
permanent AF) 
Cohort 4 (permanent 
AF) 
 
 
  
 
Abbreviations: NSR = normal sinus rhythm 
While subjects will be recruited based upon known inclusion/exclusion criteria including history 
of arrhythmia, there is uncertainty on whether the presentation of that rhythm will present and 
occur during study based on the natural temporal variability of heart rhythms.  Thus, study 
enrollment will continue until minimum targets based on rhythm presentation during study is 
achieved across all cohorts; enrollment may cease after minimum targets are achieved.   
Enrollment for Cohort 1 will continue until the target number of enrolled subjects are achieved 
as in Table 1. 
Enrollment for Cohort 2 will continue until minimum numbers of subject enrolled complete the 
study with presentation of aggressor rhythms as determined by ECG patch are reached, as 
specified in Table 2A.  
Enrollment in Cohorts 3 and 4 will continue during the study until minimum targets of burdens 
are achieved as in Table 3B.  Atrial fibrillation burden for each subject in the self-reported 
enrollment Cohorts 3 and 4 will be determined from the ambulatory ECG Patch reference device 
after subjects complete and/or terminate from the study. A final AF cohort assignment will be 
determined based on this adjudicated AF burden measurement. Enrollment for Cohort 4 will 
continue until minimum numbers with ≥95% AF burden as determined by ECG patch are 
reached.  
Table 3B identifies the minimum number of subjects in Cohorts 3 and 4 required to exhibit the 
level of AF burden as determined by ECG patch after the subject completes and/or terminates 
from the study: 
Table 2A: 
Cohort 2 Minimum Aggressor Rhythm Targets 
Presence of Aggressor Rhythm on ECG Patch 
 
 
Table 3B: 
Cohort 3 and 4 Minimum AF Burden Targets 
Total AF burden >0% 
to <95% 
AF burden >0% to 
33% 
AF burden >33% to 
<95% 
AF burden ≥95% to 
100% 
 
 
 
 
4.3. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be enrolled: 
1. Able to read, understand, and provide written informed consent 

 
 
 
 
 
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2. Willing and able to participate in the study procedures as described in the consent form 
3. Be 22 years of age and older 
4. Able to communicate effectively with and follow instructions from the study staff 
5. Able to wear the wrist device for duration of study participation 
6. For Cohort 1, have no known medical history of AF  
7. For Cohort 2, have no known medical history of AF and active diagnosis of at least one 
of the following arrhythmias within the past 2 years: 
a. Frequent PACs, defined as at least 1% of total beats of atrial ectopic beats by 24-48 
hour Holter, ambulatory ECG monitor, or implantable loop recorder) OR evidence of 
such by 12-lead ECG. 
b. Frequent PVCs, defined as at least 1% of total beats of ventricular ectopic beats by 
24-48 hour Holter, ambulatory ECG monitor, or implantable loop recorder OR 
evidence of such by 12-lead ECG. 
c. SVT, which will include atrial tachycardia, atrioventricular nodal re-entrant 
tachycardia, atrioventricular re-entrant tachycardia by 12-lead ECG or 24-48 hour 
Holter, ambulatory ECG monitor, or implantable loop recorder,  
d. NSVT, defined as three or more consecutive ventricular beats at a rate of at least 100 
beats per minute and lasting no more than 30 seconds, by 12-lead ECG or 24-48 hour 
Holter, ambulatory ECG monitor, or implantable loop recorder 
8. For Cohorts 3 and 4, have a known diagnosis of AF at the time of screening (confirmed 
by electronic medical record (EMR) or self-report) and have had a recent episode of AF, 
or confirmed AF on ECG, in the past 12 months 
9. For Cohort 4, have a known diagnosis of permanent AF at the time of screening 
(confirmed by EMR or self-report) and have had a recent episode of AF, or confirmed AF 
on ECG, in the past 12 months 
10. Meet additional binning based on demographics. 
4.4. 
Exclusion Criteria 
Subjects who meet any of the following criteria may not be enrolled: 
1. Physical disability that precludes safe and adequate testing  
2. Mental impairment resulting in limited ability to cooperate  
3. Known uncontrolled medical conditions, such as (but not limited to) significant anemia, 
important electrolyte imbalance and untreated or uncontrolled thyroid disease 
4. Open wound(s) on the wrist and/or forearm 
5. Tattoos, large moles, or scars on the wrist at the wrist device location 
6. Skin conditions on either wrist that would preclude subject from wearing a wristband on 
either wrist 

 
 
 
 
 
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7. Known allergy or sensitivity to medical adhesives, isopropyl alcohol, wristbands, or ECG 
patch 
8. Medical history or physical assessment finding that makes the subject inappropriate for 
participation according to investigator(s)  
9. Participation in a previous study that used a wrist-worn sensor device with a 
simultaneous ECG reference patch 
10. Implantable cardiac devices such as a Pacemaker or Implantable Cardioverter 
Defibrillator 
11. Clinically significant hand tremors, as judged by the investigator 
12. Acute illness including COVID and other respiratory illnesses 
13. Subjects with known history of AF on rhythm control medications with history of 
complete AF rhythm control (i.e history of zero AF burden) will be excluded from 
Cohorts 3 and 4 
Subjects enrolled into Cohort 2 can be on rate control medications.  
4.5. 
Subject Discontinuation  
Subject participation in the study is voluntary and the subject has the right to withdraw at any 
time. Subjects also may be withdrawn from the study without their consent.  
Reasons for possible subject discontinuation may include:  
• Adverse event 
• Death 
• Protocol deviation 
• Withdrawal of consent 
• Investigator discretion 
• Termination of the study 
• Device malfunction 
• Lost to follow-up 
• Other  
Sites will notify Sponsor of the reason(s) for subject discontinuation. Site investigators must also 
report this to their respective IRBs, as defined per their IRB procedures.  
4.6. 
Subject Follow-up 
A follow-up visit will be conducted at Study Day 13 (± 2 days), or after the conclusion of the 2nd 
ECG patch wear period, if less than 13 ± 2 days, during which the subject will return the wrist 
devices and ECG patch to the site. Following the completion of procedures at this visit, the 
subject’s participation in the study will be concluded.

 
 
 
 
 
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5. 
STUDY PROCEDURES 
Table 4 outlines the procedures to be conducted and the information to be collected during the 
study. 
Table 4: 
Schedule of Events 
Study Procedure 
Screening 
Study 
Day 1 
Visit 
Study Day 
5 (+2 days) 
Visit 
End of 
Study 
Visit*  
Informed Consent 
X 
 
 
 
I/E Criteria Assessment 
X 
 
 
 
Medical History including allergies 
X 
 
 
 
Demographic information (age, gender, 
race/ethnicity, occupation) 
X 
 
 
 
Medications 
X 
 
 
 
Physical examination (will include at a 
minimum visual inspection of general 
appearance and skin) 
X 
 
 
 
Body Measurements and Assessments 
(anthropometrics) (height, weight, BMI; 
may be self-reported) 
X 
 
 
 
Wrist/Hand Assessment (tattoos, moles, 
scars, skin tone assessment on Fitzpatrick 
scale)**  
X 
X 
 
 
Distribution of 2 wrist study devices to 
subject 
 
X 
 
 
Application of ECG patch to subject’s 
upper torso 
 
X 
 
 
Replacement of ECG patch  
 
 
X 
 
Collection of 2 wrist study devices from 
subject 
 
 
 
X 
Removal of ECG patch from subject  
 
 
 
X 
Collection of all AEs encountered during 
the study 
 
X 
X 
X 
* End of study visit is on Day 13 (± 2 days), or after the conclusion of the 2nd ECG patch wear period, if less than 
13 ± 2 days. 
**Skin tone assessment on Fitzpatrick scale confirmed on Study Day Visit 1. 

 
 
 
 
 
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5.1. 
Screening 
Informed consent will be obtained before any study protocol-directed procedures are performed. 
After the signing of informed consent, the subject will be evaluated for eligibility according to 
the study inclusion/exclusion criteria (Section 4.3 and Section 4.4). This visit will be conducted 
remotely; in-person, on-site visits can occur only if approved by Sponsor. 
During screening, the following should be obtained on each subject: 
• 
Age 
• 
Gender 
• 
Race and ethnicity 
• 
Diagnosed medical conditions 
• 
Medications 
• 
Allergies 
• 
Occupation 
• 
Visual assessment of general appearance and skin 
• 
Body measurements and assessments (height, weight, BMI)* 
• 
Skin tone assessment on Fitzpatrick scale 
• 
Assessment of tattoos, moles, scars on wrist (both) 
*Body measurements may be self-reported if the screening visit is conducted virtually. 
5.2. 
Study Day 1 
Subjects will report for the Day 1 visit at their scheduled date and time, which may be the same 
day as the screening visit if conducted in-person, on-site, but in no case more than 14 days after 
the screening visit. No special preparation for this visit is required. If eligibility is confirmed 
after completion of all screening procedures, subjects may begin study participation following 
the screening. This visit will be conducted remotely; in-person, on-site visits can occur only after 
Sponsor approval. 
All subjects may take their normal medications on the day of the study and may eat normally 
prior to this visit.  
Skin tone assessment on the Fitzpatrick scale will be confirmed at this visit. 
5.2.1. 
Data Collection Study Equipment Set up 
The following procedures will be performed for each study subject at study participation:  
Two wrist devices of the same series/configuration will be assigned to each subject for the study. 
The first wrist device will be worn during the day for daytime data collection. The second wrist 
device will be worn during the night for nighttime data collection during sleep. The wrist devices 
are to be charged while not being worn.  

 
 
 
 
 
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1. Instruct the subject to choose his/her preferred wrist to wear the wrist device. The wrist 
device can be worn on whichever side the subject prefers unless there is a skin condition 
on one wrist as noted above in the exclusion criteria, in which case, the wrist device must 
be worn on the non-affected wrist. Record the chosen wrist. If the subject does not have a 
side preference or skin condition on one wrist, the wrist device will be placed on the left 
wrist. 
2. The subject will be asked to put the wrist device on his/her wrist (as indicated in 1). The 
wrist device should be fitted tightly enough that it does not move when the hand/wrist is 
shaken.  
3. Ask user to adjust band tightness for a snug fit and adjust as needed. 
An ECG patch will be self-applied to the upper torso of the subject on Day 1 and Day 5 (+2 
days) of the study. Self-application of ECG patch may be performed with aid of instructions via 
televideo. If the visit is occurring on site, the study staff may assist with the patch placement. 
5.3. 
 Study Days 1-13 
Subjects will continue to wear the wrist devices and patch as directed during normal daily 
activities for up to 13 (± 2) days.  This includes pressing a button on the patch to confirm that the 
patch is still working properly.  Follow up calls or telehealth video calls may be made to the 
subject as needed throughout the home use period. Subjects will be advised to not swim or do 
activities that will cause excessive sweating. 
5.4. 
Study Day 5 
Subjects will remove the 1st ambulatory ECG patch on study Day 5 (+2 days). A 2nd ECG patch 
will be self-applied to the subject. If the visit is occurring on site, the study staff may assist with 
the patch placement. The 1st patch will be returned to study staff.  This visit will be conducted 
remotely; in person on-site visits can occur only after Sponsor approval. 
5.5. 
End of Study Visit 
Thirteen days (±2 days) after the initial study visit, or after the conclusion of the 2nd ECG patch 
wear period, if less than 13 ± 2 days, subjects will have a follow-up visit to be exited from the 
study. Wrist devices, study phones and the second ECG patch will be returned to the CRO. 
Following the completion of procedures at this visit, the subject’s participation in the study will 
be concluded. This visit will be conducted remotely; in-person, on-site visits can occur only after 
Sponsor approval. 
5.5.1.1. 
Study Procedures 
The following study procedures will be performed at this visit/contact: 
1. Subjects will be asked to report any study procedure-related adverse events (AEs) that 
occurred during the previous 13 days (±2 days), or during the ECG patch wear periods if 
less than 13 ± 2 days.  
2. The subject’s second ECG patch will be returned to staff. ECG patch data will be 
downloaded by study staff for processing and adjudication (Section 5.5.2).  

 
 
 
 
 
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5.5.1.2. 
Wrist Device Data Processing 
Wrist device, including accelerometer data and PPG signals, will be uploaded by the subject at 
home. 
Procedures for data analysis based on the data collected via the wrist device are described in 
Section 6.1.  
5.5.2. 
Adjudication of ECG Data 
5.5.2.1. 
ECG Patch 
IRNF 
ECG Patch Diagnosis (Primary Endpoint) 
ECG patch data will be reviewed and adjudicated by the
 Each ECG patch will 
be reviewed by a cardiac technician. The cardiac technician will review each ECG recording in 
its entiret
 
 
 
The cardiac technician will be instructed to review ECG patches independently and 
separately of each other and not to confer about diagnoses. All cardiac technicians will be 
blinded to subject cohort and IRNF notifications.
 
 
  After the cardiac 
technician has completed their assessment of an ECG patch, the following procedure will be 
followed by US Board-Certified Cardiologists:  
a) Each of the cardiac technician’s ECG patch assessments will be reviewed by a 
Cardiologist who did not perform the initial assessment. (“Over-reader”). At no time may an 
over-reader who performed the initial assessment of the ECG patch, over-read their own 
assessment. 
b
 
 
 
c) If the over-reader determines the cardiac technician’s assessments are consistent, they will 
approve the results and electronically sign the case without changes.  
d) If the over-reader determines the cardiac technician’s assessments require amendment, the 
over-reader will make the required changes and approve the results and electronically sign 
the case. All changes will be automatically tracked in a 21CFR11 compliant audit trail.  
e) After the over-reader has completed their over-read, the results will be quality controlled 
 
ECG Strip Diagnosis (Secondary Endpoints) 

 
 
 
 
 
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ECG strips will be identified from the ECG patch for the period of time corresponding to each 
tachogram that was selected for analysis. 
 
 
 
 
 
ll adjudicators will be blinded to cohort and 
IRNF notifications. 
 
 
AFBF  
ECG AF Burden Measurement (Primary Endpoint) 
ECG patch data will be reviewed and adjudicated by the 
 Each ECG patch will 
be reviewed by a cardiac technician. The cardiac technician will review each ECG recording in 
its entirety
 
 
 
The cardiac technician will be instructed to review ECG patches independently and separately of 
each other and not to confer about diagnoses. All cardiac technicians will be blinded to cohort 
and IRNF notifications. After the cardiac technician has completed their assessment of an ECG 
patch, the following procedure will be followed by US Board-Certified Cardiologists:  
a) Each of the cardiac technician’s ECG patch assessments will be reviewed by a 
Cardiologist who did not perform the initial assessment. (“Over-reader”). At no time may an 
over-reader who performed the initial assessment of the ECG patch, over-read their own 
assessment. 
 
 
 
c) If the over-reader determines the cardiac technician’s assessments are consistent, they will 
approve the results and electronically sign the case without changes.  
d) If the over-reader determines the cardiac technician’s assessments require amendment, the 
over-reader will make the required changes and approve the results and electronically sign 
the case. All changes will be automatically tracked in a 21CFR11 compliant audit trail.  
 
   
ECG Strip Diagnosis (Secondary Endpoint) 
ECG strips will be identified from the ECG patch for the period of time corresponding to each 
tachogram that was selected for analysis.
 
Strips will be reviewed by 2 independent US 

 
 
 
 
 
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Board Certified Cardiologist adjudicators for a strip diagnosis (Section 5.5.2.1.1). If there are any 
differences in adjudication decisions, the strip in question will be sent to a third adjudicator for 
final decision. Adjudicators will be instructed to review ECGs independently and separately of 
each other and not to confer about diagnoses. All adjudicators will be blinded to cohort and 
AFBF information.
 
 
5.5.2.1.1. Rhythm Diagnoses 
The diagnosis of the rhythm will fall into one of five categories: 
1. Sinus Rhythm  
2. Atrial Fibrillation (AF) 
3. Atrial Flutter (AFL) 
4. Other irregular rhythms (examples include sinus rhythm with frequent PACs, sinus 
rhythm with frequent PVCs, SVT, VT/VF) 
5. Unreadable as defined that a diagnosis cannot be made as the strip is not adequate for 
reading 
The diagnosis will be made via the following logic flow (in sequential order):  
1. If the ECG strip contains at least 10 seconds of continuous atrial fibrillation, then it will be 
classified as “Atrial fibrillation.”  Any atrial fibrillation with PACs or PVCs will be classified 
as “Atrial fibrillation”, with the note of PACs or PVCs be added to the comments section. 
2. Otherwise, if 6 or more of the sub-strips cannot be interpreted (e.g. due to noise or artifacts), 
then the strip will be classified as “Unreadable.”  
3. Otherwise, if the ECG strip contains a non-AF arrhythmia, then it will be classified as “Other 
arrhythmia”. This includes:  
• Supraventricular Tachycardia (includes atrial tachycardia, AVNRT, AVRT) 
• Sinus rhythm with PACs 
• Sinus rhythm with PVCs 
• Sinus rhythm with junctional beats 
• Sinus arrhythmia  
• Ventricular tachycardia (sustained or nonsustained) 
• Heart Block (includes 2nd or 3rd degree HB) 
4. Otherwise, the ECG will be classified as “Sinus rhythm” 
 

 
 
 
 
 
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6. 
STATISTICAL ANALYSIS  
6.1. 
Dataset Generation 
Subjects will wear wrist devices with specially configured study software to enable the collection 
of a single sensor dataset for each subject. The subjects’ sensor datasets will be used as the 
common source of data for this study to which the algorithms will be applied in a post-hoc 
fashion. 
For evaluation of the IRNF, the algorithm software will collect accelerometer data continuously 
and PPG data when the user is still, which is when it would be possible for a tachogram for either 
the predicate or test algorithms to be collected. The platform and device algorithms for the test 
and predicate devices will be run on the sensor dataset to generate tachograms and notifications. 
The performance of the test device will be compared to the performance of the predicate device 
according to the pre-specified analyses as outlined below. 
For the AFBF, the platform algorithm will be applied to reflect the tachogram sampling strategy 
that will be implemented in the final, finished product. The algorithm parameters associated with 
minimum requirements to produce the 7-day AF burden measurement will be finalized prior to 
database lock. The AFBF algorithm will be run on the subjects’ sensor datasets to estimate the 7-
day average AF burden and identify AF episodes. Additionally, the algorithm will be applied to 
the set of tachograms generated via the IRNF 2.0 algorithm and compared to the corresponding 
ECG strips adjudicated by US Board Certified Cardiologists. The AFBF analyses will be 
performed on all subjects in Cohorts 3 and 4. 
6.2. 
Statistical Methodology  
For all of the IRNF statistical analyses, atrial fibrillation (AF) and atrial flutter (AFL) will be 
treated as a single category of “AF”.  For all of the AFBF statistical analyses, atrial fibrillation 
(AF) will be considered its own unique category (i.e., atrial flutter will not be included as part of 
the detection of AF episodes).  
6.2.1. 
Randomization Methodology 
A summary of the randomization methodology applied in this study is outlined below.  
Additional details may be found in the study Statistical Analysis Plan (SAP). 
Wrist Device Assignments 
Subjects will be randomly assigned to wear two wrist devices 
 
 from the same series/configuration. A pre-determined block randomization schedule will 
be generated for each enrollment cohort and subjects will be assigned sequentially to either a 
 
 
IRNF 
 
 
 
 
 

 
 
 
 
 
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To assess overall tachogram performance, a least burdensome approach will also be used
 
 
 
 
 
 
 
 
 
 
 
 
 
AFBF 
 
 
 
 
 
 
 
 
 
 
 
6.2.2. 
Primary Endpoint Analysis 
IRNF 
Two separate tables will be generated for subject-level data cross-classified by the test device 
and the predicate device results as presented below for the data collected on all subjects in 
Cohorts 1 and 3, and 4.  One table will be diagnosis of at least one AF episode of at least 30 
seconds present on the ECG patch (Table 5) to assess sensitivity and the other table will be no 
AF episodes present on ECG patch (Table 6) to assess specificity per the ECG patch diagnosis 
definition presented in Section 5.5.2.1. AF will be defined as any AF of at least 30 seconds 
duration by ambulatory ECG patch report. A concordant notification is defined as ≥ 30 seconds 
of AF present on ECG patch as determined by AF onsets/offsets + cardiac technician overread 
during the time period defined by the first and last tachograms comprising the alert. A discordant 

 
 
 
 
 
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notification is defined as a notification that is not concordant. Each subject can be represented 
once and in only one of the cells of the tables below. 
Table 5: 
Diagnosis of ≥1 AF Episode Present on ECG Patch 
 
 
 
Test Device (IRN 2.0) 
Predicate Device (IRN 1.0) 
≥1 Notification 
No 
Notifications 
≥1 Concordant 
All Discordant 
-------- 
≥1 Notification 
≥1 Concordant 
a 
b 
c 
 
All Discordant 
d 
e 
f 
No Notifications 
-------- 
g 
h 
i 
By defining N1 as the sum of all subjects in Table 5 above, the sensitivity of the test device will 
be estimated as (a+b+c)/N1 and the sensitivity of the predicate device will be estimated as 
(a+d+g)/N1. 
Table 6: 
No AF Episodes Present on ECG Patch 
 
 
 
Test Device (IRN 2.0) 
Predicate Device (IRN 1.0) 
≥1 Notification 
No 
Notifications 
≥1 Concordant 
All Discordant 
-------- 
≥1 Notification 
≥1 Concordant 
------ 
------ 
------ 
 
All Discordant 
------ 
r 
s 
No Notifications 
-------- 
------ 
t 
u 
By defining N2 as the sum of all subjects in Table 6 above, the specificity of the test and 
predicate devices will be estimated as (t+u)/N2 and (s+u)/N2, respectively. 
Usable wrist device data that aligns with and corresponds to the time interval during which the 
ECG patch is worn will be used for this analysis. 
 
  
Only subjects in Cohorts 1, 3, and 4 will be included in the primary endpoint analysis. 
 
 
 
 
   

 
Version 5.0 
 
 
 
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AFBF 
A single weekly AF burden estimate will be recorded for both the test device and the ambulatory 
ECG Patch reference method for all subjects contributing usable data in Cohorts 3 and 4. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The primary endpoint hypothesis associated with the AFBF algorithm is: 
 
 
 
 
 
 
 
 
 
 
a
 
 

 
 
 
 
 
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 The results will also be graphically displayed on a Bland-Altman Plot.  
6.2.3. 
Secondary Endpoint Analyses 
IRNF 
The notification-level PPV of AF by ambulatory ECG at the time of any tachogram comprising 
the notification will be estimated for both the test and predicate device algorithms. The 
notification-level PPV is defined as the proportion of notifications where at least one of the ECG 
strip results associated with the spot tachograms that comprise the notification exhibits AF of at 
least 10 seconds per the ECG strip diagnosis definition presented in Section 5.5.2.1. 
Notification-Level PPV = (# of notifications with an adjudicated ECG strip diagnosis of AF of at 
least 10 seconds for any tachogram comprising the notification) / (# of alert notifications) 
For subjects who exhibit a high level (≥ 95%) AF burden, it is expected that a large (100 to 200) 
number of notifications will be generated in total for both the IRN 1.0 and 2.0 algorithms 
resulting in >1,000 tachograms per subject in Cohort 4. For these subjects who are permanently 
in AF, a least burdensome approach will be followed where for all notifications generated from 
subjects in Cohorts 1 and 3 and randomly selected notifications from subjects in Cohort 4 will be 
included in this analysis. A corresponding adjudicated ECG strip diagnosis will be determined 
for all tachograms comprising these notifications.  
Because the set of notifications may differ between the test and predicate device algorithms and 
because multiple notifications may be associated with some subjects, a bootstrap approach will 
be implemented to obtain 95% two-sided confidence intervals separately for each algorithm’s 
notification-level PPV. The bootstrap sampling will randomly select subjects who have 
analyzable data with replacement rather than individual data points to account for any correlation 
structure that might exist within subjects so that confidence limits are corrected for within-
subject correlation. 
Two tachogram-level analysis results
 
associated with the secondary endpoints 

 
 
 
 
 
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of tachogram performance will be reported separately for each device algorithm using 
tachograms generated by subjects in Cohorts 1, 3, and 4. Separate contingency tables cross-
classifying the adjudicated cardiologist diagnoses from ECG strips with the binary classification 
of tachogram results for test and predicate devices will be presented as outlined in Table 7 
below.  
Table 7: 
Cross-Classification Table of Tachogram Results and Adjudicated 
Cardiologist Diagnoses from ECG Strips 
 
Adjudicated Cardiologist Diagnosis 
Tachogram     
Result 
SR 
AF 
Atrial 
Flutter 
Other 
Irregular 
Rhythm 
Uninterpretable 
Total 
Irregular 
n11 
n12 
n13 
n14 
n15 
nTI 
Not AF 
n21 
n22 
n23 
n24 
n25 
nTN 
Total 
nSR 
nAF 
nAFL 
nOA 
nU 
N 
Abbreviations: SR = sinus rhythm; AF=atrial fibrillation; AFL=atrial flutter 
Tachogram performance for the test and predicate devices will be estimated separately as 
outlined below because the set of tachograms will differ by device. Two-sided 95% bootstrap 
confidence intervals will be constructed for each performance metric by randomly selecting 
subjects who have analyzable data with replacement to account for any within subject correlation 
of multiple tachograms associated with each subject.  
Tachogram Sensitivity = (n12+n13)/(nAF+nAFL) 
Tachogram Specificity = n21/nSR 
Tachogram False Positive Rate = (n11+n14)/(nSR+nOA) 
Tachogram PPV = (n12+n13)/(nTI-n15) 
Tachogram NPV = n21/(nTN-n25) 
The ECG strips corresponding to all tachograms which comprise each notification for subjects in 
Cohorts 1, 3 and 4 from the test and predicate device algorithms will be adjudicated and included 
in the analysis of this secondary endpoint.  
 
 
 
 
 

 
 
 
 
 
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AFBF 
A tachogram-level analysis associated with the secondary endpoint of tachogram performance 
for the AFBF will be reported by cross-classifying the binary classification of tachogram results 
with the adjudicated cardiologist classifications from ECG strips where the SR and Other 
Abnormal Rhythm adjudications are combined into a single category. 
 
 
Using the notation of Table 7, tachogram performance will be estimated as outlined below from 
the randomly selected tachograms for all subjects in Cohorts 3 and 4. Two-sided 95% bootstrap 
confidence intervals will be constructed for each performance metric to account for potential 
within subject correlation of the multiple tachograms associated with each subject.  
• Tachogram Sensitivity = n12/nAF  
• Tachogram Specificity = (n21+n23+n24)/(nSR+nAFL+nOA)  
• Tachogram PPV = n12/(nTI-n15) 
• Tachogram NPV = (n21+n23+n24)/(nTN-n25)  
Although the set of tachograms for the AFBF device algorithm will differ from the set of 
tachograms generated from the test IRNF device algorithm,
 
 
The same tachogram performance analysis of 
the AFBF device algorithm will be performed as specified above. 
The analysis of the day-specific AF burden estimate will be performed to demonstrate that the 
algorithm provides accurate estimates of AF burden regardless of the set of days included in the 
analysis using a Monte Carlo simulation based approach.  In this approach and at each iteration 
of the simulation, days will be selected at random (and without replacement) for each subject 
from the set of days where reference and test device data is available.  An AFB measurement 
will be determined from the test device across the selected days as will the reference AFB 
measurement for each subject. 
 
 

 
 
 
 
 
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6.2.4. 
Safety Analyses 
All adverse events (AEs) will be recorded throughout the entire study period, whether they are 
considered to be related to the study procedures or not. Signs and symptoms of each AE will be 
described in detail: date of event, description of event, severity, relationship to study procedures, 
action taken and outcome. AEs will be collected as spontaneously reported by the subjects. 
AEs will be coded using MedDRA (latest version). The number of any AEs and the number and 
percentage of subjects reporting each type of adverse event will be presented by Preferred Term. 
Multiple occurrences of the same event reported by the same subject will be counted only once.   
AE summaries (number of events and incidence) will be presented for all AEs, including the 
following: 
• Serious adverse events (SAEs) 
• Study procedure related AEs 
• Severe AEs, which are AEs that are rated as Severe in intensity  
 
Study procedure related AEs will include those events classified as possibly or definitely related 
to the study procedure.  
6.2.5. 
Additional Analyses  
Subject accountability, device accountability, medical history, medication, demographic and 
baseline characteristics will be summarized by final cohort assignment for the reporting of 
results for the subjects included in the evaluation of the IRNF and AFBF devices. The final 
cohort assignments for subjects who self-report at the time of screening in Cohorts 1, 3, and 4 
will be determined based on their final adjudicated reference ECG results of AF burden as 
follows: 
• Cohort 1: Adjudicated AF Burden via reference ECG of 0% 
• Cohort 3: Adjudicated AF Burden via reference ECG of >0% to <95% 
• Cohort 4: Adjudicated AF Burden via reference ECG of > 95% 
The final cohort assignment of subjects who self-report at the time of screening in Cohort 2 will 
remain Cohort 2.  If an adjudicated AF Burden measurement cannot be determined for a subject, 
the final cohort designation will be the same as the self-reported cohort at the time of screening. 
The rationale for reporting the results by final cohort designation is to most closely align the 
reporting of results based on the presentation or absence of AF during the study monitoring 
period regardless of prior diagnosis.    
Additional efficacy analyses are described below. 
IRNF 

 
 
 
 
 
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The performance at the person- and notification-level for AF and other arrhythmias (treated as a 
single combined category) by ambulatory ECG will be analyzed similarly to the corresponding 
primary and secondary endpoint analyses outlined above for the adjudicated diagnoses of only AF 
using all available data for subjects in Cohorts 1, 3, and 4. These additional analyses are distinct 
from the primary and secondary endpoint analyses in that the AF and other arrhythmia categories 
of diagnoses presented in Section 5.5.2.1 will be combined into a single category for purposes of 
analysis. In particular, the following performance parameters will be estimated and presented 
along with their associated 95% confidence intervals.  
1. Sensitivity of the IRNF for the identification of persons for AF or other arrhythmias by 
up to 13-day (±2 days) ambulatory ECG, defined as at least 10 seconds of AF or other 
arrhythmia by ambulatory ECG  
2. Specificity of the lack of IRNF for the identification of persons without AF or other 
arrhythmias by up to (±2 days) 13-day ambulatory ECG, defined as at least 10 seconds of 
AF or other arrhythmia by ambulatory ECG  
3. Notification-level PPV with AF and other arrhythmias by ambulatory ECG at the time of 
any tachogram comprising the notification  
The false positive rate at the person-level for all subjects in Cohort 2 (Aggressor Rhythm Cohort) 
will also be reported. Using the notation of Table 6, the FPR for the test and predicate devices 
will be estimated as (r+s)/N2 and (r+t)/N2, respectively. Two-sided exact binomial confidence 
intervals associated with the FPRs will also be reported. 
The following conditional probabilities computed using the randomly selected tachograms 
generated from subjects in Cohorts 1, 3, and 4 will be reported separately for the test and 
predicate devices along with their associated 95% two-sided bootstrap confidence intervals:  
• 
Pr(Device = Irregular | Reference = Other Irregular Rhythm);  
• 
Pr(Device = Not AF | Reference = Other Irregular Rhythm);  
• 
Pr(Device = Irregular | Reference = Uninterpretable);  
• 
Pr(Device = Not AF | Reference = Uninterpretable);  
• 
Pr(Reference = Other Irregular Rhythm | Device = Irregular);  
• 
Pr(Reference = Other Irregular Rhythm | Device = Not AF);  
• 
Pr(Reference = Uninterpretable | Device = Irregular);  
• 
Pr(Reference = Uninterpretable | Device = Not AF).  
Contingency tables comparing the binary classification of randomly selected tachograms from 
the test and predicate devices will also be presented for each of the adjudicated cardiologist sub-
category classifications of Other Abnormal Rhythm diagnoses presented in Section 5.5.2.1. 
Contingency tables comparing the test and predicate device classifications (notification vs. no 
notifications at the subject-level) with each of the adjudicated cardiologist classifications of 
diagnoses presented in Section 5.5.2.1 including all sub-categories of the Other arrythmia 
category will also be presented. 
AFBF 

 
 
 
 
 
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A histogram will be produced for the paired differences in the weekly AFB average 
measurements. Boxplots of the weekly AFBF device measurements for ECG Patch categories of 
0%, >0% to 33%, >33% to < 95%, ≥95% will also be displayed. 
The paired differences in the weekly AFB average measurements between the AFBF device and 
ambulatory ECG patch and corresponding two-sided 95% confidence intervals for the average 
paired difference will be presented for each of the following ranges of ambulatory ECG patch 
AFB categories:  
• 0% 
• >0% to 33%  
• >33% to < 95%  
• ≥95%  
The false negative rate will be estimated as the number of subjects with a weekly AFBF device 
measurements = 0% and a paired ECG patch AFB measurement > 0% divided by the number of 
subjects with a paired ECG patch AFB measurement > 0%.  A two-sided 95% exact binomial 
confidence interval for the false negative rate will also be reported.    
A modified Bland-Altman analysis will be performed using only reference AF burden 
measurements which are strictly between 0% and 100%. In the analysis, the x-axis will be the 
reference burden and the y-axis will be the paired differences between the test device and 
reference method.  Estimated limits of agreement and mean bias with associated 95% confidence 
interval) will be reported.  No hypotheses will be tested in this analysis. 
Medications (verbatim terms) will also be tabulated and reported. 
6.3. 
Sample Size Determination 
IRNF 
The approach for sample size determination associated with the IRNF primary endpoint follows 
that of Zhou et al for the comparison of sensitivity and specificity of paired subject-level data 
arising from the test and predicate IRNF devices (Zhou 2002). Performance estimates used for 
the sample size calculations are based on internal engineering data. 
 
 
 
  
 
 
 

 
 
 
 
 
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Table 8: 
Sample Sizes for AF Cohorts of Subjects Required for IRNF Evaluation 
Cohort 
Required for 
80% Power 
Targeted for Enrollment to 
Observe AF Rhythm 
Presentation 
Permanent AF (Cohort 4) 
 
 
Non-Permanent AF (Cohort 3) 
 
 
Total for AF Cohorts 
 
 
 
 
  
 
 
 
 
  
Table 9: 
Sample Sizes for Subjects without AF Required for IRNF Evaluation  
Cohort 
Required for 80% 
Power 
After Correction for Attrition  
No Known Diagnosis of AF 
 
 
Additionally, to assess the secondary endpoint hypothesis H02 of the study, an aggressor cohort 
of subjects with no known history of AF but with a known history of other arrhythmias which 
may resemble the irregularity of AF (i.e., frequent premature atrial contractions (PACs), frequent 
premature ventricular contractions (PVCs), supraventricular tachycardia (SVT), or non-sustained 
ventricular tachycardia (NSVT)) will be enrolled.
 
 
 
 
 
 

 
 
 
 
 
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Table 10: 
Sample Sizes for Aggressor Subjects without AF Required for IRNF 
Evaluation 
Cohort 
Required for 80% Power 
After Correction for Attrition and 
Rhythm Presentation  
Aggressor Rhythms 
 
 
AFBF 
The approach for sample size determination follows the approach of Lu et al (Lu, 2016). The power 
associated with the primary endpoint hypothesis can be estimated as  
 
where F(x) is the cumulative density function of the standard normal distribution, () is the 
expected average difference in AF burden measurements between the device and reference 
method, d is the maximum allowable difference, za/2 is the cumulative 100(α/2)% percentile of 
the standard normal distribution, and seLOA is the standard error of the lower or upper Limit of 
Agreement defined as seLOA = SD*sqrt[1/n + (1.96^2)/(2*(n-1)] where SD is the standard 
deviation of the paired AFB differences. 
 
 
 
 
 
  
To summarize, a total 
 subjects will be enrolled into the study according to the 
cohorts below: 
• n
 (Cohort 1: No Known Diagnosis of AF) 
• n
 
(Cohort 2: Aggressor Rhythm Cohort) 
• n
 (Cohort 3: Non-Permanent AF) 
• n
 (Cohort 4: Permanent AF) 
   
6.4. 
Significance Level   
The primary non-inferiority hypotheses test of sensitivity and specificity and the secondary 
endpoint non-inferiority comparison of false positive rates for the IRNF will use a one-sided 

 
 
 
 
 
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significance level of 0.025.  If non-inferiority is demonstrated, a test of superiority will be 
performed using the same significance level.   
All AFBF analyses will use a two-sided significance level of 0.05.   
6.5. 
Missing Data 
Rigorous efforts will be made to ensure all subjects are compliant with the protocol. However, 
some subjects may drop out prematurely or some planned measurements may not be readable or 
interpretable. The data analyses will be conducted on all readable and interpretable data.  
Additional details defining readable and interpretable data may be found in the study Statistical 
Analysis Plan (SAP). 
6.6. 
Subgroup Analyses 
In accordance with the FDA Guidance on the reporting of age-, race-, and ethnicity-specific data, 
the primary endpoints for both IRNF and AFBF devices will be reported by the following 
subgroups (data permitting). Some subgroups may be combined depending on data availability. 
• Age group (<55; ≥55 to <65; ≥65 years) 
• Sex (Male; Female) 
• Race (White; Black or African American; Asian; American Indian or Alaska Native; 
Native Hawaiian or other Pacific Islander) 
• Ethnicity (Hispanic or Latino; Not Hispanic or Latino) 
• Wrist device series/configuration 
 
• Fitzpatrick Scale 
6.7. 
Interim Analyses 
There are no interim analyses planned in this study. 
6.8. 
Analysis Sets 
Full Analysis Set (FAS):  All subjects who sign an informed consent and are enrolled into the 
study. This analysis set will be used to summarize subject and device accountability, 
demographic and baseline characteristics, and safety data. The data for this analysis set will be 
presented overall and separately for each of the final cohort designations.  
ECG Patch Analysis Set (EAS):
 
This analysis set will be used to 
analyze the IRNF primary endpoint and additional subject-level sensitivity/specificity analyses. 
ECG Patch Burden Analysis Set (EABS): All subjects in enrollment cohorts 3 and 4 with paired 
usable Watch and ECG patch data which provides for a weekly AF burden average 
measurement.  This analysis set will be used to analyze the AFBF primary endpoint data. 

 
 
 
 
 
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Notification Analysis Set (NAS): All subjects with a IRNF 1.0 or IRNF 2.0 notification who 
have simultaneous, analyzable ECG patch data at the time of the notification. This analysis set 
will be used to analyze the secondary endpoint and additional notification-level endpoints. 
Tachogram Analysis Set (TAS): All subjects with at least one tachogram paired with a readable 
ECG strip diagnosis. This analysis set will be used to analyze the secondary endpoint and 
additional tachogram-level endpoints for the IRNF and AFBF algorithms. 
Sub-Study Analysis Set: All subjects who sign an informed consent and are enrolled into the 
sub-study which precedes the clinical validation study. This analysis set will be used to 
summarize subject accountability, demographic characteristics, and adverse event information.  
 

 
 
 
 
 
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7. 
SAFETY PARAMETERS AND ASSESSMENT 
7.1. 
Adverse Events  
The definition of adverse events are as follows: 
Term 
Definition 
Reference 
Adverse 
Event (AE) 
Any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in 
subjects, users or other persons, whether or not 
related to the study procedures. 
ISO 14155: 
2011 
Serious 
Adverse 
Event (SAE) 
Adverse event that 
1. Led to death, 
2. Led to serious deterioration in the health of the 
subject, that either resulted in: 
a. A life-threatening illness or injury, or 
b. A permanent impairment of a body 
structure or a body function, or 
c. In-patient or prolonged hospitalization, or 
d. Medical or surgical intervention to prevent 
life-threatening illness or injury or 
permanent impairment to a body structure 
or a body function 
3. Led to fetal distress, fetal death or a congenital 
abnormality or birth defect 
ISO 14155: 
2011 
The Severity of an AE will be categorized as follows: 
Mild 
Mild events are those that are tolerated with no disruption of 
normal daily activity 
Moderate 
Moderate events are those that cause sufficient discomfort to 
interfere with daily activity 
Severe 
Severe events are those that incapacitate and prevent usual 
activity x 
7.1.1. 
AE/SAE Collection  
Any abnormal laboratory findings, abnormal safety assessments, or anticipated day-to-day 
fluctuations which are associated with a pre-existing disease or condition, are not considered an 
adverse event unless judged by the investigator to be worsening or more severe than expected. 
All adverse events must be fully recorded throughout the entire study period, whether they are 
considered to be related to the study procedures or not. Adverse events will be collected as 
spontaneously reported by the subjects.  

 
 
 
 
 
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Adverse events should be followed until they are resolved or stabilized (returns to baseline for a 
pre-existing condition) and followed by a private MD, or the subject is lost to follow-up. In the 
event of a subject not returning to the clinical unit, the outcome of this event will be recorded as 
lost at follow up. 
Possible AEs include the following: 
● Skin rash on wrist due to wearing the wrist device;  
● Pressure artifacts on wrist due to wearing the wrist-sensor device; 
The following occurrences are not to be regarded as AEs: 
● Underlying (pre-existing) symptoms or diseases, unless there is an increase in severity 
or frequency during the course of the investigation; 
● Detection of atrial fibrillation or other irregular heartbeat; 
● Complaint about wrist device functionality. 
7.1.2. 
SAE Reporting  
The site investigator should report all SAEs to the Sponsor as soon as possible but no later than 
24 hours of becoming aware of the event. The site investigator should also report the SAEs to 
their IRB as soon as possible and according to their IRB reporting requirements, but in no event 
later than 10 working days after the investigator becomes aware of the event. On the date the Site 
staff became aware that the event met the SAE definition set out in this protocol, the investigator 
will be requested to complete an AE/ SAE reporting form in the database, in addition to the 
information on the source documentation. The investigator will conduct further investigation of 
these events regarding determination of event as a serious adverse event and determination of 
relatedness of the event to the study. The investigation of these events will be completed and 
reported to the Sponsor within 15 days of initial report to Sponsor. 
7.1.3. 
Reporting of all other Study Adverse Events 
Possible adverse events (non-serious) related to the study will be reported to the Sponsor within 
14 business days of being reviewed by the investigator. The investigator will conduct further 
investigation of these events regarding determination of event as a serious adverse event and 
determination of relatedness of the event to the study. The investigation of these events will be 
completed and reported to the Sponsor within 30 days of initial report to the Sponsor. 
7.2. 
Safety Plan  
The clinical staff is responsible for the ongoing safety and well-being of the subjects during 
study participation. Management of all medical complications arising during the course of the 
research study will be managed by the investigator as deemed appropriate. A medical monitor 
will be available for consultation related to subject safety and adverse events. All incidental 
findings identified during screening will be referred at the investigator’s discretion to the 
appropriate additional care in accordance with current standard of care. This can include removal 
of the study-associated devices, as well as other measures as required. Even if a study-associated 
device is removed prior to the specified duration, data may be used if of suitable quality.  

 
 
 
 
 
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7.3. 
Overview of study suspension and termination criteria 
The research study will be completed as planned unless one or more of the following criteria are 
satisfied that require temporary suspension or early termination of the study: 
• New information regarding the safety or performance of the study becomes available in 
such a way that the research study is deemed unsafe or ineffective; 
• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety; 
• Failure to meet expected enrollment goals; 
• Administrative reasons. 
 
 

 
 
 
 
 
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8. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
8.1. 
Institutional Review Board 
IRB approval for the protocol, ICF, and any subject-facing materials will be obtained by the site 
investigator at each Investigational site prior to study commencement. The IRB approval letter 
must be received at the investigational site prior to starting the study, and a copy must be 
provided to the Sponsor. No changes will be made to the Protocol, ICF, or subject-facing 
materials without appropriate approvals, including the IRB’s and the Sponsor’s approval.  
Until study completion, the site investigator will inform/advise his/her IRB of the study progress, 
per their IRB requirements. Further, any amendments to the protocol, ICF, and/or subject-facing 
materials will be submitted to and approved in writing by the IRB prior to implementation. 
The submitted documents will include but are not limited to: 
a. The final protocol 
b. IRB application forms 
c. ICF 
The study will not begin unless the IRB gives a favorable opinion of the study. 
8.2. 
Informed Consent 
All information about the study, including information about the subjects, and the ICF, is 
prepared and used for the protection of the human rights of the subject according to International 
Council for Harmonisation (ICH) GCP guidelines and the Declaration of Helsinki. 
It is the responsibility of the investigator to obtain signed ICFs from each subject participating in 
this study after adequate explanation of the aims, methods, and objectives of the study and before 
undertaking any study-related procedures. 
The ICF, prepared by the investigator with the assistance of the Sponsor, must be approved along 
with the study protocol by the IRB and be acceptable to the Sponsor. 
The ICF must provide subjects with information about the nature, significance, implications, 
potential risks, and basic procedures of participation in the study, consistent and in accordance 
with the study protocol version approved by the relevant IRB. The ICF must be written in a 
language fully comprehensible to the prospective subject. Subjects must be given sufficient time 
and opportunity to inquire about the details of the study and to discuss and decide on their 
participation in the study with the investigator concerned. The subject and the study staff 
explaining the study and with whom the subject discusses the informed consent will sign and 
date the ICF; this can be done remotely by using the remote consenting capabilities in the 
electronic system. A copy of the signed and dated ICF will be retained by the subject and the 
original will be filed in the investigator file unless otherwise agreed. New information will be 
provided in written form to the subject. 

 
 
 
 
 
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8.3. 
Record Keeping 
This study will be conducted in accordance with GCP guidelines. Study documents should be 
retained until at least 2 years after the last approval of marketing application in an ICH region 
and until there are no pending or contemplated-marketing applications in an ICH region. If there 
are no local laws, sites should retain files for 5 years after completion of the study. Records 
include informed consent, protocols, and electronic case report forms (eCRFs).  
8.4. 
Confidentiality and Privacy 
Subject privacy will be protected by the participating investigators, their staff, and the Sponsor 
and its agents. The study protocol, documentation, data, and all other information collected or 
generated in the study will be held in strict confidence. No information concerning the study or 
the data will be released to any unauthorized third party without prior written approval of the 
Sponsor. Compliant with Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
guidelines as applicable, only certified copies of coded data will be sent from the study site to the 
cardiology reviewers. Under no circumstances, except when legally required or permitted by 
applicable law, will any healthcare provider of any enrolled subject be allowed to receive 
specific outcome data for that subject directly from the study team for that subject. 
8.5. 
Protocol Adherence 
The protocol must be read thoroughly in its entirety and instructions followed exactly. Any 
deviations should be agreed on by Sponsor and the investigator and reported to IRB as per their 
reporting guidelines, with the appropriate written and approved protocol amendments made to 
reflect the agreed upon changes. Where the deviation occurs for the well-being of the subject, the 
Sponsor must be informed of the action taken. Actions taken for the well-being of a subject may 
occur before the Sponsor is notified. 
8.6. 
Collection and Management Responsibilities  
Data will be collected using eCRFs in a validated system. The Sponsor or designee will supply 
the eCRFs. All eCRFs should be completed by designated, trained personnel, as appropriate. All 
changes or corrections to the eCRF will be documented via a data correction form (query) with 
an audit trail and adequate explanation for the revision is required. eCRFs will be signed and 
dated by the Principal Investigator or his/her designee.  
The investigator(s) will permit trial-related monitoring, audits, IRB review and regulatory 
inspections(s), providing access to data documents. Members of the investigational site team and 
their designated authorization(s) will be identified in a log. 
Access to data collection devices will be controlled and the devices will be used only in the 
clinical investigation and according to the clinical investigation plan. The investigator or 
authorized designee will keep records documenting the receipt, use, and return of the study-
related data collection devices. 
8.7. 
Study Monitoring 
On behalf of the Sponsor, a CRO monitor will contact and visit the investigator(s) at the study 
site(s) before the entry of the first subject and at predetermined appropriate intervals during the 

 
 
 
 
 
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study until after the last subject has completed the study. The monitor will also perform a study 
closure visit. 
Prior to starting the study, the investigator understands and accepts the obligation to conduct the 
study according to the Protocol and applicable regulations, and has signed the investigator 
agreement.  In accordance with ICH GCP guidelines, the investigators must ensure provision of 
sufficient time, reasonable space, and adequate qualified personnel for the monitoring visits. The 
visits are for the purpose of verifying adherence to the study protocol, including the safety and 
well-being of subjects, and the completeness, consistency, and accuracy of data entered on the 
eCRF and other documents. 
The investigator will make all source data (i.e., the various study records, ICFs, eCRFs, other 
subject records, and other pertinent data) available for the monitor and allow access to them 
throughout the entire study period. Monitoring is done by comparing the relevant site records of 
the subjects with the entries on the eCRF (i.e., source data verification). It is the monitor’s 
responsibility to verify the adherence to the study protocol and the completeness, consistency, 
and accuracy of the data recorded on the eCRFs. 
By agreeing to participate in the study, the investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved in a 
reasonable period of time. Contact information for the study monitor is located in the 
investigator file. Representatives from the Sponsor may also contact and visit the investigators 
and monitor data during the study. 
8.8. 
Data Quality Assurance and Quality Control  
The Sponsor or designee will perform internal quality management of study conduct, and data 
collection, documentation and completion. Quality Control (QC) procedures will be 
implemented beginning with the data entry system and data QC checks that will be run on the 
database will be generated. Any missing data or data anomalies will be communicated to study 
staff for clarification/resolution.  
8.9. 
Use of Information 
All information concerning the study-associated devices, equipment, and the Sponsor is 
considered confidential information. The information developed during the conduct of this 
clinical study is also considered confidential and will be used by the Sponsor in connection with 
the development of the test device as described in this protocol. This information may be 
disclosed as deemed necessary by the Sponsor to allow the use of information derived from this 
clinical study and to ensure complete and thorough analysis. The investigator is obligated to 
provide the Sponsor with complete study results and all data developed in this study.  
Independent analyses and/or publication of these data by the investigator(s) or any member of 
their staff are not permitted without the prior written consent of the Sponsor. Written permission 
to the investigator will be contingent on the Sponsor’s review of the statistical analysis and/or 
manuscript, and will provide for nondisclosure of the Sponsor’s confidential or proprietary 
information. In all cases, the parties agree to submit all manuscripts or abstracts to all other 
parties at least 30 days prior to submission. This will enable all parties to protect proprietary 

 
 
 
 
 
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information and to provide comments based on information that may not yet be available to other 
parties. 
This confidential information shall remain the sole property of the Sponsor and shall not be 
disclosed to others without the written consent of the Sponsor and shall not be used except in the 
performance of this study. 
8.10. 
Study Record Retention 
All data collected or derived from this research study will remain the property of the Sponsor.  
Any and all correspondence relating to this research study, for example with the Sponsor or the 
IRB, should be kept in the appropriate file folders at the CRO. Records of research study 
subjects’ source documents which pertain to the research study must be kept on file at the CRO.   
Records must be maintained according to ICH GCP guidelines and according to what is stated in 
section 8.3. 
8.11. 
Study Termination and Site Closure 
The Sponsor and the investigators reserve the right to terminate the study or participation in the 
study, respectively, at any time. Both parties will arrange discontinuation procedures. In 
terminating the study, the Sponsor and the investigators will assure that adequate consideration is 
given to the protection of the subjects’ interests. 
The Sponsor reserves the right to discontinue the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 
The entire study will be stopped if: 
• Evidence has emerged that, in the opinion of the Sponsor or the investigator(s), makes the 
continuation of the study unnecessary or unethical; 
• The stated objectives of the study are achieved; 
• The development of the test device is discontinued. 
Regardless of the reason for termination, all data available for subjects at the time of 
discontinuation of follow up must be recorded on the eCRF. All reasons for discontinuation of 
treatment must be documented.  
8.12. 
Completion of the Study 
The investigator(s) agree to provide financial disclosure forms and to complete this study in 
satisfactory compliance with the protocol and all applicable regulatory requirements within the 
timeframe allotted in the financial contract. Delays in the completion and/or reporting of the 
study beyond this time must be mutually agreed upon in writing by both the investigator and the 
Sponsor. 

 
 
 
 
 
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9. 
REFERENCES 
Ben Freedman S, Lowres N. Asymptomatic Atrial Fibrillation: The Case for Screening to 
Prevent Stroke. JAMA. 2015;314(18):1911-2. doi: 10.1001/jama.2015.9846. 
Benjamin EJ, Muntner P, Alonso A, Bittencourt MS, Callaway CW, Carson AP, et al. On behalf 
of the American Heart Association Council on Epidemiology and Prevention Statistics 
Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics 2019. 
Circulation. 2019;139:00–00. DOI: 10.1161/CIR.0000000000000659. 
Bonett DG and Price RM (2012) Adjusted Wald Confidence Interval for a Difference of 
Binomial Proportions Based on Paired Data.  Journal of Educational and Behavioral Statistics 
Vol. 37. No. 4. pp. 479-488. 
Brachmann J, Morillo CA, Sanna T, Di Lazzaro V, Diener HC, Bernstein RA, Rymer M, Ziegler 
PD, Liu S, Passman RS. Uncovering Atrial Fibrillation Beyond Short-Term Monitoring in 
Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke and Underlying 
Atrial Fibrillation Trial. Circ Arrhythm Electrophysiol. 2016;9(1):e003333. doi: 
10.1161/CIRCEP.115.003333. 
Chen LY, Chung MK, Allen LA, et al. Atrial fibrillation burden: moving beyond atrial 
fibrillation as a binary entity: a scientific statement from the American Heart Association. 
Circulation. 2018;137(20): e623-e644. 
Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future 
incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J 
Cardiol. 2013;112(8):1142-7. doi: 10.1016/j.amjcard.2013.05.063. Epub 2013 Jul 4. 
Go AS, Reynolds K, Yang J, et al. Association of burden of atrial fibrillation with risk of 
ischemic stroke in adults with paroxysmal atrial fibrillation: the KP-RHYTHM study. JAMA 
Cardiology. 2018;3(7): 601-608. 
January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS focused update of the 2014 
AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the 
American College of Cardiology/American Heart Association Task Force on Clinical Practice 
Guidelines and the Heart Rhythm Society. Journal of the American College of Cardiology. 2019: 
74(1): 104-132. 
Lane DA, Barker RV, Lip GYH. Best practice for atrial fibrillation patient education. Current 
pharmaceutical design. 2015;21(5): 533-543. 
Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino RB, Massaro 
JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial fibrillation: the 
Framingham Heart Study. Circulation. 2004;110(9):1042-6. Epub 2004 Aug 16. 
Lu M-J, Zhong W-H, Liu Y-X, Miao H-Z, Li Y-C, H-M, 2016. Sample Size for Assessing 
Agreement between Two Methods of Measurement by Bland-Altman Method. Int J Biostat. 
2016 Nov 1;12(2). doi: 10.1515/ijb-2015-0039. 
Moran PS, Teljeur C, Ryan M, Smith SM. Systematic screening for the detection of atrial 
fibrillation. Cochrane Database Syst Rev. 2016 Jun 3;(6):CD009586. doi: 
10.1002/14651858.CD009586.pub3. 

 
 
 
 
 
09 April 2021 
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Page 54 
Omboni S, Verberk WJ. Opportunistic screening of atrial fibrillation by automatic blood pressure 
measurement in the community. BMJ Open. 2016;6(4):e010745. doi: 10.1136/bmjopen-2015-
010745. 
O'Neal WT, Efird JT, Judd SE, McClure LA, Howard VJ, Howard G, Soliman EZ. Impact of 
Awareness and Patterns of Nonhospitalized Atrial Fibrillation on the Risk of Mortality: The 
Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Clin 
Cardiol. 2016;39(2):103-10. doi: 10.1002/clc.22501. Epub 2016 Feb 16. 
Turakhia MP, Desai M, Hedlin H, Rajmane A, Talati N, Ferris T, et al. Rationale and design of a 
large-scale, app-based study to identify cardiac arrhythmias using a smartwatch: The Apple 
Heart Study. Am Heart J. 2019;207:66-75 ISSN 0002-8703. 
https://doi.org/10.1016/j.ahj.2018.09.002. 
Zhou XH, Obuchowski NA, McClish DK (2002). Statistical Methods in Diagnostic Medicine.  
Wiley & Sons. pp. 216 – 218.