Evaluation of the Use of Apple Watch Features for Identification of Cardiac Arrhythmias
Phase: NA
Conditions: Atrial Fibrillation, Arrhythmias, Cardiac, Atrial Flutter
Sponsor: Apple Inc.

Protocol 
 
 
Study Official Title: Evaluation of the use of Apple Watch features for 
identification of cardiac arrythmias 
ClinicalTrials.gov Identifier: NCT03769207 
Document Date: November 13, 2018 
 
 

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1 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
Protocol 
Apple Heart Study 1.2 
Evaluation of the use of Apple Watch features for identification of cardiac arrhythmias 
Protocol Version: 
1.14   
Protocol Date:  
November 13, 2018 
Sponsor: 
Apple Inc. 
One Apple Park Way 
Cupertino CA 95014 
United States 
Coordinating Principal Investigators and Study Contacts: 
Marco V. Perez, MD 
Assistant Professor of Medicine 
Stanford University 
300 Pasteur Dr., M/C 5773 
Stanford, CA 94305 
Tel (650) 723-9363 
Fax (650) 725-7568 
E-mail: mvperez@stanford.edu
Minang (Mintu) Turakhia, MD, MAS 
Associate Professor of Medicine 
Stanford University 
1070 Arastradero Rd 
Palo Alto, CA 94304 
Phone: (650) 497-9345 
E-mail: mintu@stanford.edu
In collaboration with Stanford Center for Clinical Research (SCCR), Quantitative 
Sciences Unit (QSU), and Center for Digital Health (CDH). 

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2 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
PROTOCOL APPROVAL PAGE 
STUDY TITLE:  
Apple Heart Study 1.2 
Protocol Version: 
1.14    
Protocol Date:  
November 13, 2018 
This research study will be conducted in the United States, in accordance with applicable parts 
of 21 CFR Parts 50, 54, and 56. 
I, the undersigned, have read and approved this protocol, and agree on its contents. 
_____________________________  _____________________________   _____________ 
[Sponsor Contact] 
 
 
Signature 
 
     
  
    Date 
Apple Inc. 
___________________________ 
_____________________________    _____________ 
_____________________________  _____________________________   _____________ 
[Sponsor Regulatory Approval] 
Signature 
      
 
 
    Date  
Apple Inc. 

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3 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
INVESTIGATORS’ SIGNATURE PAGE 
STUDY TITLE:  
Apple Heart Study 1.2 
Protocol Version: 
1.14  
Protocol Date:  
November 13, 2018  
I have read this Study Protocol and agree to adhere to the requirements of this current version 
of the protocol. 
I have not been restricted from participating in clinical research, nor is any action pending that 
could result in such restriction.  If this occurs, I shall provide immediate notification to the 
Sponsor. 
I, the undersigned, have read and understand the protocol specified above and agree on its 
content.  I agree to perform and conduct the study as described in the protocol and in 
accordance with applicable parts of 21 CFR Parts 50, 54, and 56, and all governing IRB 
requirements. 
Marco Perez 
___________________________ 
_____________________________    _____________ 
Investigator Name 
Signature 
      
 
 
    Date  
Minang [Mintu] Turakhia 
___________________________ 
_____________________________    _____________ 
_____________________________  _____________________________   _____________ 
Investigator Name 
Signature 
 
     
  
    Date 

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4 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
TABLE OF CONTENTS 
PROTOCOL APPROVAL PAGE 
2 
INVESTIGATORS’ SIGNATURE PAGE 
3 
ACRONYMS 
5 
PROTOCOL SYNOPSIS 
6 
1.0 INTRODUCTION 
10 
2.0 STUDY OBJECTIVES 
12 
3.0 OUTCOMES 
13 
4.0 STUDY DESIGN 
14 
5.0 STUDY POPULATION 
16 
6.0 STUDY DEVICES 
18 
7.0 STUDY PROCEDURES 
19 
8.0 ADVERSE EVENTS REPORTING 
29 
9.0 WITHDRAWAL 
32 
10.0 STATISTICAL CONSIDERATIONS 
33 
11.0 TRAINING 
37 
12.0 ETHICAL AND REGULATORY CONSIDERATIONS 
37 
13.0 HUMAN SUBJECTS PROTECTION 
38 
14.0 RECORD KEEPING/REPORTING 
39 
15.0 REFERENCES 
40 

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5 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
ACRONYMS 
AF - Atrial Fibrillation or Atrial Flutter 
AFib - Atrial Fibrillation 
CFR - Code of Federal Regulations 
EAS - ECG Analysis Set 
ECG - Electrocardiography, Electrocardiogram, Electrocardiographic 
Apple Watch ECG app-AFib - Apple Watch ECG app classification of atrial fibrillation 
EMS - Emergency Medical Services 
FAS - Full Analysis Set 
FDA - Food and Drug Administration 
FOG - Fallout Subgroup 
HIPAA - Health Insurance Portability and Accountability Act  
HITRUST - Health Information Trust Alliance 
HR - Heart Rate 
IRN - Irregular Rhythm Notification 
IPNA - Irregular Pulse Notification Algorithm 
IRB - Institutional Review Board 
NAS - Notification Analysis Set 
NOC - Network Operating Center 
OAC - Oral anticoagulation 
OCG - Online Care Group 
PCI - Payment Card Industry 
PPG - Photoplethysmography, Photoplethysmogram 
PPV - Positive Predictive Value 
PRO - Patient Reported Outcomes 
SAP - Statistical Analysis Plan 
SC - Steering Committee 

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6 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
PROTOCOL SYNOPSIS 
 
Study Title 
Apple Heart Study 1.2: evaluation of the use of the Apple Watch for 
identification of cardiac arrhythmias 
Protocol Version 
1.14 
Protocol Date 
November 13, 2018 
Study Design 
Prospective, single arm, experimental, non-significant risk study. 
Inclusion Criteria 
1. Possession of the following at time of eligibility screening, 
ascertained from automatic hardware/software/device pairing 
check: 
I. iPhone (5s or later) with iOS version 12.1.1 or later 
defined as iPhone model/iOS version used to complete 
screening eligibility. 
II. Apple Watch (Series 1-4) with watchOS version 5.1.2 or 
later defined as Apple Watch model/watchOS paired with 
iPhone used to complete screening eligibility. 
2. At least one of the following by self-report before consent: 
I. 
Irregular Rhythm Notification 
II. 
ECG app classification of Atrial Fibrillation 
III. ECG app classification of Inconclusive defined as 
“Inconclusive,” “Heart Rate Over 120,” or “Heart Rate 
Under 50”  
3. Age ≥ 22 years at time of eligibility screening, ascertained from 
self-reported date of birth. 
4. Current resident of the United States at time of eligibility 
screening, defined by self-reported state of residence within the 
50 states of the United States or District of Columbia, and will 
reside in the United States for the length of the study. 
5. Proficient in written and spoken English, defined by self-report 
of comfort reading, writing, and speaking English on iPhone. 
6. Valid phone number associated with iPhone, ascertained from 
self-report. 
7. Valid email address, ascertained from self-report. 

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Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Exclusion Criteria 
1. Shared iCloud account 
2. Shared AppleWatch 

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Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Objectives 
1a. To measure the proportion of participants with an Irregular 
Rhythm Notification (IRN) prior to enrollment who have atrial 
fibrillation or atrial flutter (AF) confirmed by ambulatory 
electrocardiographic (ECG) patch monitoring. 
 
1b. To measure the proportion of participants with an ECG app 
classification of Atrial Fibrillation (ECG app-AFib) prior to 
enrollment who have AF confirmed by ambulatory ECG patch 
monitoring. 
 
2a. To measure the proportion of participants who receive an IRN or 
ECG app-AFib reporting contact with a non-study healthcare 
provider at 15 and 60 days after study enrollment. 
 
2b. To measure the proportion of participants with an ECG app 
classification of inconclusive prior to enrollment who have AF 
confirmed by ambulatory ECG patch monitoring. 
 
2c. To measure the proportion of participants who have AF 
confirmed by ambulatory ECG patch monitoring by age at 
enrollment (< 65 and 65+). 
 

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Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Primary Outcome Atrial fibrillation or atrial flutter of at least 30 seconds duration on 
an ambulatory ECG patch monitor. 
Secondary 
Outcomes 
1. Arrhythmias other than AF on an ambulatory ECG patch monitor 
2. Self-reported contact with healthcare provider 
 
Study Devices 
Irregular Rhythm Notification feature 
ECG app 
Duration of Study 
Participation 
Enrollment will occur over approximately a 6 month-period. Every 
participant will complete baseline questionnaires and wear an 
ambulatory ECG patch for up to 7 days. Every participant will 
receive an app notification to complete a web-based Patient 
Reported Outcomes (PRO) survey 15 and 60 days following 
enrollment. Participation in the study will end after completion of 
the 60 day PRO survey or after 90 days, whichever date is earlier. 
Number of 
Participants  
Approximately 2600 participants will be enrolled 
 
 
 
 
 

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Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
1.1 INTRODUCTION 
 
1.1 Background 
 
Undiagnosed Atrial Fibrillation 
Atrial fibrillation and atrial flutter (AF) affect approximately 6 million people in the US, with 
prevalence expected to rise to 12 million by 2030 (Benjamin 2018). AF is associated with 
higher rates of stroke, heart failure, thromboembolic events, cognitive decline, and death 
(Benjamin 2018).  However, approximately 13% of AF is estimated to be undiagnosed 
(Turakhia 2018). There is a need to identify new strategies to identify these individuals to 
connect them with appropriate treatments to prevent stroke and modify risk factors. 
 
Guidelines for AF Screening 
The USPSTF recently published an “I” recommendation for AF screening in asymptomatic 
individuals, finding that there was insufficient evidence to recommend for or against screening 
for AF (USPSTF 2018, Jonas 2018). Specifically, there was insufficient evidence on whether 
screening for asymptomatic AF improves health outcomes compared to usual care. 
Additionally, potential harms of screening were not well-characterized. 
 
Wearable Health Technology 
Wearable health technologies offer a novel approach for disease screening. Users wear devices 
on a daily basis, and there is an opportunity to screen for AF passively and actively in the 
moment when an individual has symptoms. This approach may be able to identify more 
individuals with AF. Virtual care models may be able to connect these individuals with 
treatment. Additionally, wearable technology may be able to facilitate monitoring of disease 
and management of risk factors (Chen 2018). 
 
Irregular Rhythm Notification (IRN) 
The Irregular Rhythm Notification (IRN) feature is a software-only mobile medical application 
that is intended to be used with the Apple Watch. The feature analyzes pulse rate data to 
identify episodes of irregular heart rhythms suggestive of AFib. Using observable variations in 
PPG signal intensity, changes in blood flow can be measured and beat-to-beat pulse 
measurements can be made. During normal sinus rhythm, there is minimal variation in pulse. 
However, during AF, the beat-to-beat variability increases significantly. Therefore, a PPG 
signal can be used to differentiate between a regular pulse and an irregular pulse that may be 
indicative of AF. 
 
An algorithm has been developed by Apple to identify periods of irregular pulse based on PPG 
signal variation as measured by the Irregular Pulse Notification Algorithm (IPNA). The time 
between PPG signal peaks observed during periods of minimal arm movement are marked as 
intervals between heart beats. A tachogram is a period of time over which heart beat intervals 

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11 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
are measured. The degree of beat-to-beat variability is measured from spot tachograms over the 
course of approximately one minute intervals. An irregular tachogram is flagged when the 
variability, measured using a Poincare plot, crosses a predefined threshold. An IPNA checks 
multiple tachograms over a period of approximately an hour or more. An IRN is then sent to 
the user when a period of an irregular pulse suggestive of AFib has been identified. This 
feature was granted FDA de novo classification on 9/11/2018. 
 
ECG app 
The ECG app is a software-only mobile medical application intended for use with the Apple 
Watch to create, record, store, transfer, and display a single channel ECG similar to a Lead I 
ECG. The ECG app processes electrical signals from two sensors on the Apple Watch - an 
electrode on the back of Apple Watch and an electrode on the digital crown. A user opens the 
ECG app on their Apple Watch, places a finger on the digital crown, and remains still for 30 
seconds to capture an ECG. The ECG app analyzes the waveform to determine the presence of 
atrial fibrillation (AFib) or sinus rhythm on a classifiable waveform. The ECG app waveform 
is stored in the Health App and can be exported as a .pdf. This app was granted FDA de novo 
classification on 9/11/2018. 
 
1.2 Study Rationale 
  
The IRN feature and ECG app will be available to the public as a software update in early 
December 2018. IRN will be available on Apple Watch Series 1-4; ECG app will be available 
on Apple Watch Series 4.  
 
The data collected in this study will provide an understanding of the experience of participating 
users of IRN and ECG app to help inform how mobile medical applications, such as the IRN 
and ECG app may be optimally used to facilitate heart disease screening and treatment. 
Findings may also help to inform the design of future research to determine whether use of 
Apple Watch to facilitate novel approaches to heart disease screening and treatment can 
improve health outcomes. 
 

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12 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
2.0 STUDY OBJECTIVES 
 
2.1 Research Question 
 
The overall objective is to characterize the ability of Apple Watch rhythm analysis software to 
identify AF and facilitate subsequent clinical evaluation among users who contact AppleCare. 
 
2.2 Study Objectives  
 
1a. To measure the proportion of participants with an Irregular Rhythm Notification (IRN) 
prior to enrollment who have atrial fibrillation or atrial flutter (AF) confirmed by ambulatory 
electrocardiographic (ECG) patch monitoring. 
 
1b. To measure the proportion of participants with an ECG app classification of Atrial 
Fibrillation (ECG app-AFib) prior to enrollment who have AF confirmed by ambulatory ECG 
patch monitoring. 
 
2a. To measure the proportion of participants who receive an IRN or ECG app-AFib reporting 
contact with a non-study healthcare provider at 15 and 60 days after study enrollment. 
 
2b. To measure the proportion of participants with an ECG app classification of inconclusive 
prior to enrollment who have AF confirmed by ambulatory ECG patch monitoring. 
 
2c. To measure the proportion of participants who have AF confirmed by ambulatory ECG 
patch monitoring by age at enrollment (< 65 and 65+). 
 
 

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Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
3.0 OUTCOMES 
 
3.1 Primary Outcome 
 
Atrial fibrillation or atrial flutter of at least 30 seconds duration on an ambulatory ECG patch 
monitor. 
  
 
3.2 Secondary Outcomes 
 
1. Arrhythmias other than AF on an ambulatory ECG patch monitor 
2. Self-reported contact with healthcare provider 
 
 
 
 

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14 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
4.0 STUDY DESIGN 
 
4.1 Overall Study Design 
 
Scope 
 
This will be a prospective, single arm, experimental non-significant risk study, conducted with 
the assistance of eligible participants.  
 
Participants calling into AppleCare self-reporting that they have received an IRN or ECG app 
classification of AF or inconclusive (defined as “Inconclusive,” “Heart Rate Over 120,” or 
“Heart Rate Under 50”) will be offered information about participation in the study, and the 
AppleCare representative will offer to e-mail the participants a link to download the Study App 
for more information. If the participant agrees, the participant will be emailed a link to 
download the Study App. Once downloaded, the Study App will provide the information about 
the study and screen for eligibility. If the participant meets the eligibility criteria and wishes to 
enroll in the study, the Study App will initiate the consenting process and provide the consent 
and authorization to sign in the app. Participants who install the Apple Heart Study 1.2 App 
and meet the eligibility criteria proceed to consent and then be enrolled in the study. 
Participants will be required to provide signed informed consent; once enrolled they will 
complete a short questionnaire to collect demographic information, medical history, and health 
status, after which the study period will commence. 
 
Monitoring 
 
After enrollment in the study, participants will be prompted to contact the telemedicine 
technology services company, American Well Corporation (together with the Online Care 
Group, the "Study Telehealth Provider") to conduct Study Telehealth Visit #1 (voice or video). 
During Study Telehealth Visit #1, participants will undergo a virtual medical evaluation which 
will include an abbreviated assessment for symptoms, medical history, and medications. 
Participants with urgent symptoms (chest pain, shortness of breath, fainting/losing 
consciousness) will be directed to an urgent care clinic or emergency room for medical 
evaluation. For participants with non-urgent symptoms, the Study Telehealth Provider will 
order an ambulatory ECG monitor (i.e. an ePatch) from BioTelemetry. Participants will be 
expected to contact the Study Telehealth Provider within 30 days of enrollment. Study 
participants will be reminded to initiate Study Visit #1 with reminders via email and phone 
calls if needed. Participants who call after 30 days will still be able to obtain an ePatch and 
undergo remaining study procedures, but may not be included in all analyses.  
 
The participants will be mailed the ambulatory ECG monitor, which the participant will then 
be requested to wear for up to 7 days. The minimum analyzable time acceptable for primary 

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15 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
analysis is one hour. Participants with the ECG app will be asked to take an ECG app 
recording at least 2 times each day while wearing the ePatch, as well as after receiving an 
irregular rhythm notification. The participant will then mail the ambulatory ECG monitor back 
to BioTelemetry, which will generate a standard technical report that will be read by 
BioTelemetry’s technical readers. The report will be adjudicated by two board-certified 
clinicians, and a final report will be made available to the Study Telehealth Provider by 
BioTelemetry. 
 
A second study visit, Study Visit #2, will occur with the Study Telehealth Provider once the 
ambulatory ECG monitor results are available.  After the final ambulatory ECG monitor report 
is made available to the Study Telehealth Provider, the Study Telehealth Provider will contact 
the participant to prompt them to complete Study Visit #2. During Study Visit #2 (voice or 
video), the ambulatory ECG monitor results will be reviewed. If AF or any other arrhythmias 
have been detected in reviewing the ambulatory ECG monitor data, or if there are other non-
urgent symptoms needing further evaluation, the Study Telehealth Provider will direct the 
participant to their primary health care provider, or other health care provider as deemed 
appropriate by the Study Telehealth Provider.  The report and visit summary will be made 
available to the participant and also to participant’s physician or health care provider, if the 
participant provides his/her physician information and permission to send that physician a copy 
of the report.  For participants who do not have an established primary health care provider, the 
Study Telehealth Provider will encourage and offer advice in establishing a primary care 
provider per standard Study Telehealth Provider protocol. 
 
Patient Reported Outcomes (PROs) 
 
Fifteen and sixty days after enrollment, participants will receive a separate app notification to 
complete the patient reported outcomes (PRO) questionnaires. The participant will be notified 
about the sixty day questionnaire even if the participant does not complete the fifteen day 
questionnaire. These outcomes will include whether or not the participant contacted a primary 
health care provider and what additional treatments or diagnostic tests they underwent. They 
will also be asked questions related to measures of anxiety about testing, experience with the 
IRN feature and ECG app, and health status.  Participants will receive reminders via 
notifications from the app to complete the PROs prior to the due date (within 30 days of 
notification). 
 
 
 
 

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16 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
5.0 STUDY POPULATION 
 
5.1 Inclusion Criteria 
 
1. Possession of the following at time of eligibility screening, ascertained from automatic 
hardware/software/device pairing check: 
I. iPhone (5s or later) with iOS version 12.1.1 or later defined as iPhone model/iOS 
version used to complete screening eligibility. 
II. Apple Watch (Series 1-4) with watchOS version 5.1.2 or later defined as Apple 
Watch model/watchOS paired with iPhone used to complete screening eligibility. 
2. At least one of the following by self-report before consent: 
I. 
Irregular Rhythm Notification 
II. 
ECG app classification of Atrial Fibrillation 
III. ECG app classification of Inconclusive defined as “Inconclusive,” “Heart Rate 
Over 120,” or “Heart Rate Under 50”  
3. Age ≥ 22 years at time of eligibility screening, ascertained from self-reported date of birth. 
4. Current resident of the United States at time of eligibility screening, defined by self-
reported state of residence within the 50 states of the United States or District of 
Columbia, and will reside in the United States for the length of the study. 
5. Proficient in written and spoken English, defined by self-report of comfort reading, 
writing, and speaking English on iPhone. 
6. Valid phone number associated with iPhone, ascertained from self-report. 
7. Valid email address, ascertained from self-report. 
 
 
5.2 Exclusion Criteria 
 
1. Shared iCloud account 
2. Shared AppleWatch 
 
5.3 Recruitment 
Apple Watch Series 1-4 users who telephone AppleCare about the Irregular Rhythm 
Notifications or ECG app and report having received an IRN or ECG app classification of 
atrial fibrillation or inconclusive on repeated measurement will be offered information about 
participation in the study. AppleCare provides technical support for Apple hardware, software, 
and services. For issues related to the IRN feature and ECG app, participants will be routed via 
telephone to an AppleCare advisor who is trained in handling technical questions and any 
medical complaints related to the use of the IRN feature and ECG app. Users who indicate 
interest in the study will be emailed a link to download and install the Study App. The Study 
App will determine study eligibility and enroll the participant in the study. If, 60 days after the 

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17 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
study opens, there is evidence that enrollment rates will not be adequate to meet enrollment 
goals for each subgroup, then alternative recruitment strategies may be employed to help reach 
recruitment goals. 
 
 

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18 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
6.0 STUDY DEVICES 
Device 1 Name: Irregular Rhythm Notification feature 
The Irregular Rhythm Notification Feature is a software-only, FDA-cleared, mobile medical 
application that is intended to be used with the Apple Watch. The feature analyzes pulse rate 
data to identify episodes of irregular heart rhythms suggestive of AFib and provides a 
notification to the user. The feature is intended for over-the-counter (OTC) use. It is not 
intended to provide a notification on every episode of irregular rhythm suggestive of AFib and 
the absence of a notification is not intended to indicate no disease process is present; rather the 
feature is intended to opportunistically surface a notification of possible AFib when sufficient 
data are available for analysis. These data are only captured when the user is still. Along with 
the user’s risk factors, the feature can be used to supplement the decision for AFib screening. 
The feature is not intended to replace traditional methods of diagnosis or treatment.  
Device 2 Name: ECG app 
The ECG app is a software-only, FDA-cleared, mobile medical application intended for use 
with the Apple Watch to create, record, store, transfer, and display a single channel 
electrocardiogram (ECG) similar to a Lead I ECG. The ECG app determines the presence of 
atrial fibrillation (AFib) or sinus rhythm on a classifiable waveform. The ECG app is not 
recommended for users with known arrhythmias other than atrial fibrillation. 
The ECG app is intended for over-the-counter (OTC) use. The ECG data displayed by the ECG 
app is intended for informational use only. The user is not intended to interpret or take clinical 
action based on the device output without consultation of a qualified healthcare professional. 
The ECG waveform is meant to supplement rhythm classification for the purposes of 
discriminating AFib from normal sinus rhythm and not intended to replace traditional methods 
of diagnosis or treatment. 
 

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19 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
7.0 STUDY PROCEDURES 
Time (days) Event 
0 
Study Opens 
60 
Interim check of enrollment 
180 
End Enrollment 
270 
Study Closes (latest date for completion of PRO 
questionnaire) 
270+ 
Analyses 
 
 
Table 1. Study Timeline  
 
7.1 Eligibility Determination and Enrollment 
 
The potential participant will first download the Apple Heart Study 1.2 App. The app will 
automatically ensure compatibility with the iPhone iOS version and Watch version. If 
compatible, the participant will be able to continue forward in the app. An overview of the 
study will be displayed in the app. 
 
The participant will then advance to a screen for study enrollment, where they will confirm 
whether they meet general participation requirements. The participant will be asked questions 
based on study inclusion and exclusion criteria. The app will automatically determine 
eligibility based on the responses provided. If the participant is determined to be eligible, they 
will initiate the consenting process with an in-app consent and authorization form to be read 
and signed if they agree to participate.  
 
Participants will be able to enroll between STUDY START DATE and END OF 
ENROLLMENT (STUDY START DATE + 6 months).   
 
On END OF ENROLLMENT, enrollment will close. The study period will end on END OF 
ENROLLMENT + 60. 
 
A 15-day PRO will become available 15 days after enrollment, no later than END OF 
ENROLLMENT + 15. A 60-day PRO will become available 60 days after enrollment, no later 
than END OF ENROLLMENT + 60.  All PROs will be due by end of study on END OF 
ENROLLMENT + 90. After this date, all monitoring will end, the Study Telehealth Provider 
line will be closed and no further data will be collected. 

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20 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
 
Enrollment may be terminated early if more than 400 participants receiving an IRN and more 
than 400 participants using the ECG app are diagnosed with AF by ECG patch. Enrollment 
will be reviewed at STUDY START DATE + 60 days. If enrollment in each of the study 
subgroups outlined in the objectives appears that it will not achieve a sufficient number of 
subjects to meet study goals, we will enhance recruitment by targeting recruitment strategies to 
the group(s) of participants at risk for failing to meet study goals or extend the duration of 
enrollment. 
 
 
7.2 Enrollment: Consent, Baseline Demographics and Medical History Collection 
 
The Apple Heart Study 1.2 is an app-based research study utilizing the iOS platform. As in 
other mobile-mediated research studies, the informed consent process in the study is conducted 
remotely in a completely self-administered setting with no required physical contact with the 
research team prior to consent and enrollment. 
 
The approach to informed consent for the study has been adapted accordingly to ensure the 
ethical requirement of informedness, i.e. that participants are adequately informed about the 
research before participation, is met.  Potential candidates as well as enrolled participants will 
be able to contact a study hotline (available 24/7 at 1-800-358-2286) anytime and have the 
ability to ask questions and request clarifications at any time prior to or during the study.  This 
hotline will be open from the study start date until study closure.  
 
Participants who successfully pass the eligibility criteria will be directed to a page requesting 
their consent to participate. Participants will be asked to read and sign the study informed 
consent and authorization document within the app if they agree and are willing to participate.  
A copy of the signed study consent and authorization document will be available for review 
and download to the participant via the app.   
 
After consenting to participate, the participant will be directed to complete a questionnaire to 
collect self-reported baseline demographics, medical history, and health status. 
 
A participant will be considered enrolled if the participant has consented and completed 
onboarding questionnaires. 
 
7.3 Procedures for Study Visit #1 
 
7.3.1 Study Telehealth Provider 
American Well (Boston, MA) is a healthcare technology company that developed the 
Telehealth platform being used to support study visits. The American Well technology 
supports mobile-based interactions between participants and providers during the study, in 

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21 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
which both the participant and provider can see and hear each other through American Well’s 
proprietary videoconferencing capabilities. Virtual visits can be conducted using a wireless or 
network connection, meaning a study participant can initiate a visit from anywhere in the 50 
United States of District of Columbia. American Well’s platforms are a SaaS (Software as a 
Service) offering—this means all operational hardware and support software is housed and 
maintained within American Well data centers and is serviced by the American Well Hosting 
Operations department. American Well is a PCI-compliant and is designed to meet HIPAA 
security requirements, HITRUST-certified, federally recognized security platform. 
  
The Online Care Group (OCG) is American Well’s clinical partner.  OCG providers are 
responsible for conducting the study required assessments during study visits.  All OCG 
physicians are licensed, board certified, have 10-15 years of experience in a brick-and-mortar 
practice, and have undergone a vigorous training on American Well’s platform.  Additionally, 
the OCG has an internal credentialing process that meets all standards as dictated by the 
National Committee for Quality Assurance. The OCG’s staff physician-led credentialing 
committee (comprised of a chief medical officer, staff physician, and director of behavioral 
health) reviews and approves all practitioners before they are permitted to practice on the 
American Well System.  
 
Study Telehealth Provider Team, a term used throughout this protocol, relates to physicians 
from the OCG, Quality, Customer Support (Level 1 agents operating the 24-hour hotline and 
Level 2), and the Network Operations Center (NOC) staff who will coordinate visits and 
facilitate the communication of patch report results and clinical summaries to the participant. 
All these groups provide services through American Well platform. 
 
7.3.2 Study Telehealth Provider Visit #1 
 
The Study App will provide a button for the participant to connect with the Study Telehealth 
Provider. The first connection with the Study Telehealth Provider will constitute Study Visit 
#1. 
 
After the participant connects with the Study Telehealth Provider team, they will undergo a 
study visit. The participant will be asked about cardiovascular clinical signs and symptoms. If 
the Study Telehealth Provider concludes that the participant has a medical emergency, the 
Study Telehealth Provider will follow its emergency protocol and either instruct the participant 
and/or a family member, if available, to call emergency medical services (EMS) or will call on 
the participant’s behalf if the participant and/or a family member are unable to contact EMS. 
Participants with a medical emergency will not be prescribed an ePatch.  
 
Once emergency symptoms have been ruled out, the telehealth clinician will perform an 
abbreviated review of medical history and perform a virtual review of physical symptoms. The 
telehealth provider will also confirm which of the following the participant received: Irregular 

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22 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Rhythm Notification, ECG app classification of AF, or ECG app classification of inconclusive. 
If the participant cannot confirm having received any of the above notifications or 
classifications, the Study Telehealth Provider will not prescribe an ePatch. The information 
obtained will assure that the Study Telehealth Provider Data Collection variables [see 7.3.3 
Study Telehealth Provider Data Collection] are obtained.  
 
The visit summary will be made available to the participant and also to participant’s physician 
or health care provider, if the participant provides the Study Telehealth Provider information of 
participant’s physician and permission to send that physician a copy of the report. Any referral 
visits will be conducted outside of the study, at the discretion of the participant, and at the cost 
of the participant. 
 
The Study Telehealth Provider will provide the participant information about the ePatch, 
answer any questions the participant might have, and contact BioTelemetry to initiate the order 
and shipment of the ambulatory ECG monitor (ePatch). 
 
7.3.3 Study Telehealth Provider Data Collection – Visit #1 
 
The following data elements will be collected during the study visit: 
 
1. Demographics 
2. IRN or ECG app results 
3. Past medical history 
4. Medications 
5. Symptoms 
6. Clinical assessment 
7. Complaints or adverse events 
 
 
7.4 Procedures for Ambulatory ECG Patch 
7.4.1 BioTelemetry Flow 
 
1. The Study Telehealth Provider will order the ECG patch from BioTelemetry and 
communicate information necessary for mailing ECG patch and study data 
management to BioTelemetry. 
 
2. If the participant did not have Study Visit #1 within 30 days of enrollment, participant 
will still be able to receive a patch monitor and continue with study procedures 
including PROs, but they will not be included in the primary analyses.    
 
3. BioTelemetry will mail the ambulatory ECG monitor to the participant. 
 

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23 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
4. The participant will wear the ambulatory ECG monitor for up to 7 days and mail the 
monitor back to BioTelemetry. 
 
5. After the ambulatory ECG monitor has been worn by the participant for up to 7 days 
and returned back to BioTelemetry, BioTelemetry will perform data extraction and an 
initial technical read of the ambulatory ECG findings by trained ECG technicians. The 
ECG technician review will determine if the participant has any serious or potentially 
life-threatening abnormality. Although rare, this includes atrial fibrillation with 
sustained rapid ventricular rates, sustained ventricular tachycardia or ventricular 
fibrillation, high-degree heart block, and long pauses. If one of these urgent arrhythmias 
is identified, then the participant will be contacted and directed to local emergency care 
or advised how to seek local emergency care. Best attempt will be made to send the 
ECG report to participant’s emergency care provider. After confirmation that a 
participant’s ambulatory ECG data does not have any of these urgent arrhythmias, the 
ambulatory ECG study will be processed into the adjudication workflow. The 
adjudication workflow is described in a separate charter. 
 
6. The adjudication process will result in generation of a final adjudicated report.  
 
7. Once the adjudicated report is complete, it will be issued to the Study Telehealth 
Provider.  
 
7.4.2 Procedures for ECG patch wear 
 
 
 
 
The BioTelemetry ePatch Monitor will be used for ambulatory ECG monitoring. The battery 
life with a single channel recording is 7 days. The participant will be instructed to wear the 
ePatch for up to 7 days. However, the data collected from a participant will be considered 
adequate for a participant with a minimum analyzable time of 1 hour.  
 
BioTelemetry will send participants, via courier, an ambulatory ECG monitoring kit containing 
one sensor and two adhesive patches. If the adhesive patch is no longer functional, the sensor 

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24 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
can be moved to the backup adhesive patch. At the end of the recording period, the participant 
will be required to mail the monitor back to BioTelemetry using the supplied prepaid mailer. 
 
In the event it is discovered that the participant never received the ePatch due to a shipping 
error or became lost in transit, then BioTelemetry will issue a second ePatch to that participant. 
Any subsequent loss of ePatches will not be replaced. 
 
Approximately 14-20 days after enrollment it is expected that most participants will have 
completed wearing the patch for up to 7 days and will have returned the patch to BioTelemetry 
via a provided tracked USPS mailer.  The ambulatory ECG monitor should be received by 
BioTelemetry within 45 days from enrollment. Those who return patches beyond 45 days after 
enrollment or do not begin wearing their patch within 14 days of patch shipment will be 
included in the fall-out subgroup, however they will still be eligible for a follow-up visit with 
the Study Telehealth Provider. Those who never return the ambulatory ECG monitor will also 
be placed in the fall-out subgroup. 
 
 
7.5 Procedures for Apple Watch wear 
Participants will be asked to wear their Apple Watch as they would with normal use. 
Participants with a Series 4 Apple Watch will be asked to take an ECG at least 2 times each 
day while wearing the ECG patch. In addition, participants will be asked to take an ECG app 
recording after receiving each irregular rhythm notification. 
 
7.6 Procedures for Study Visit #2 
Once the ePatch has been received by BioTelemetry and the final report has been adjudicated, 
BioTelemetry will issue a notification to the Study Telehealth Provider. The participant will be 
notified by way of a secure email that their patch report is ready and will be instructed to 
contact the Study Telehealth Provider for Study Visit #2 through a button in the app. It is 
expected that this visit will occur between 15-45 days after enrollment, depending on timing of 
ambulatory ECG monitor wear, mailing, and interpretation. 
 
The Study Telehealth Provider will review the ambulatory ECG monitoring report with the 
participant and make any necessary recommendations to the participant.  The Study Telehealth 
Provider will then refer participants with AF, any clinically relevant cardiac arrhythmias, or 
any non-urgent symptoms requiring follow up detected on patch monitoring to their primary 
health care provider for further treatment and diagnostic testing. For participants without 
established primary health care providers, the Study Telehealth Provider will offer referral per 
standard Study Telehealth Provider protocols. The ambulatory ECG monitoring report and visit 
summary will be made available to the participant and also to participant’s physician or health 
care provider, if the participant provides the Study Telehealth Provider information of 
participant’s physician and permission to send that physician a copy of the report. Any referral 

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25 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
visits will be conducted outside of the study, at the discretion of the participant, and at the cost 
of the participant. 
 
Symptoms, disposition recommendations, and any adverse events reported will be logged.  
 
7.7 Study Telehealth Provider Additional Visits 
Participants may contact the Study Telehealth Provider through a button in the app outside of 
the scheduled study visits if they have symptoms concerning for arrhythmia that they wish to 
discuss with a provider, or questions/concerns about the study. The Study Telehealth Provider 
will review the participant’s symptoms and refer participants to emergency medical services or 
their primary health care provider. Visits, symptoms, and any adverse events reported will be 
logged. 
 
7.8 PRO Instruments at 15 and 60 days 
 
Participants will be notified by the app to complete the 15 and 60-day PRO questionnaires at 
15 and 60 days following enrollment. The questionnaires will be administered through a web-
based survey, and the participant will have 30 days, up until END OF ENROLLMENT + 90, to 
complete them. Participants will receive reminders via notifications from the app to complete 
the PRO questionnaires. Questions will ask if the participant followed up with the Study 
Telehealth Provider and/or a non-study health care provider, received an AF diagnosis, was 
evaluated in-person by a non-study health care provider, the type of non-study health care 
provider and/or specialists, received additional cardiac testing, received other clinical 
arrhythmia diagnoses, anxiety as a result of participation, health status, and experience with the 
IRN feature and ECG app.  
 

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26 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
7.9 Data to be collected from HealthKit and Apple Watch 
There will be two phases to HealthKit and Apple Watch data collection. Phase 1 will occur 
between the study start date and approximately January 2019. Phase 2 will occur from 
approximately January 2019 and later. Participants in each phase will consent to the specific 
data to be collected in each phase. If a participant begins participation in Phase 1 of the study 
and remains in the study when Phase 2 begins, the participant will be re-consented for Phase 2.  
 
In Phase 1 of the study, no data will be collected from HealthKit or Apple Watch. In Phase 2 of 
the study, this study will collect participant data from the Apple Watch and iPhone, including 
heart rate tachograms, IRNs, and ECG app results. Data will include ECG waveform data from 
the ECG app. Data will be prospectively collected, beginning after consent and continuing until 
the end of study. In addition, we will retrospectively collect IRNs and ECG app classifications 
that were recorded within the 14 days prior to consent. 
 
7.10 Time and Events Schedule  
 
 
 
Evaluation 
 
Screening 
and 
Eligibility 
 
Consent 
and 
Enrollment 
Study Visit 
#1 
Study Visit 
#2 
15- Day 
PRO 
60-Day PRO 
Inclusion/ 
Exclusion 
Criteria 
X 
 
 
 
 
 
Informed 
Consent 
 
X 
 
 
 
 
Demographics/ 
Medical History 
Questionnaire 
 
X 
 
 
 
 
Health status 
 
X 
 
 
 
X 
Experience with 
IRN feature and 
Apple Watch 
ECG app 
 
 
 
 
X 
 
Ambulatory 
ECG Monitor – 
Introduction/Shi
pment 
 
 
X 
 
 
 

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27 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Virtual Review 
of Medical 
History / 
Physical 
Symptoms 
 
 
X 
 
 
 
Ambulatory 
ECG Monitor - 
Results Review 
 
 
 
X 
 
 
Arrhythmia 
Recommendatio
ns for PCP 
referral 
 
 
 
X 
 
 
Survey 
Completion 
 
 
 
 
X 
X 
 
 
 
7.11 Participant Recontact 
For participants who do not complete study procedures on time, study staff may contact the 
participant by email or phone to encourage timely completion of study procedures. 
 

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28 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
7.12 Participants that may be excluded from specific analyses 
 
Participants may be excluded from some analyses for incomplete data or for various other 
reasons. The reasons may include: 
 
1. Failure to contact Study Telehealth Provider within 30 days of enrollment. 
2. Failure to be deemed eligible for ePatch wear due to emergent symptoms, determined at 
Study Visit #1. 
3. Failure to return an ePatch within 45 days of enrollment. 
4. Failure to begin wearing ePatch within 14 days of patch shipment 
5. Failure to verify at Study Visit #1 that the participant had a cohort classification as 
either (1) Irregular Rhythm Notification, or status of (2) Afib or (3) Inconclusive via the 
ECG app (i.e., with at least 1 ECG recorded within the 14 days before study enrollment 
indicating classification of either AFib or Inconclusive, where the latter is defined as 
“Inconclusive,” “Heart Rate Over 120,” or “Heart Rate Under 50”) 
6.  Withdrawal from the study per Section 9.0 
 
 
 
 
 
 
 

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29 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
8.0 ADVERSE EVENTS REPORTING 
 
All suspected adverse events (AEs) will be reported to the Study Safety Monitoring Desk at the 
Stanford Center for Clinical Research (SCCR) by the Study Telehealth Provider Team. The 
Study Safety Monitoring Desk will review all suspected AEs and determine relatedness to the 
device (related to the IRN feature, Apple Watch ECG app, or ePatch) and seriousness. 
 
8.1 Definitions and Classification 
 
Term 
Definition 
Reference 
Adverse 
Event (AE) 
Any untoward medical occurrence, unintended 
disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in 
participants, users or other persons, whether or 
not related to the device. 
ISO 
14155-1 
Serious 
Adverse 
Event (SAE) 
Adverse event that 
a) Led to death, 
b) Led to serious deterioration in the health 
of the participant, that either resulted in 
1) A life-threatening illness or 
injury, or 
2) A permanent impairment of a 
body structure or a body 
function, or 
3) In-patient or prolonged 
hospitalization, or 
4) Medical or surgical intervention 
to prevent life-threatening 
illness or injury or permanent 
impairment to a body structure 
or a body function, 
c) Led to fetal distress, fetal death or a 
congenital abnormality or birth defect 
ISO 
14155-1 
 
 
 
8.2 Adverse Events (AEs) 
 

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30 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
The Study Safety Monitoring Desk is responsible for determining whether the adverse event 
occurred and is related to the IRN feature, ECG app on Apple Watch, ePatch, or associated 
with participation in the study.  
 
Possible AEs include the following: 
 
● Skin rash due to wearing the ambulatory ECG monitor (ePatch); 
● Skin itchiness due to wearing the ambulatory ECG monitor (ePatch); 
● Blister due to wearing the ambulatory ECG monitor (ePatch); 
● Skin rash on wrist due to wearing the Apple Watch;  
● Pressure artifacts on wrist due to wearing the Apple Watch; 
● Signs or symptoms related to use of the IRN feature or ECG app on Apple Watch.  
The common signs and symptoms include stress and anxiety and associated 
symptoms that may include dizziness, depression, palpitations, tremors, sleep 
difficulty, and shortness of breath. 
 
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; 
● Receipt of an IRN;  
● Detection of atrial fibrillation or other irregular heartbeat through the IRN feature or 
ECG App; 
● Detection of atrial fibrillation or other irregular heartbeat through ePatch; 
● Pre-planned procedure(s); 
● Complaint about iPhone or Apple Watch functionality;  
● Failure of the participant to regularly wear the Apple Watch or to wear the ePatch 
● Apple Heart Study 1.2 app, IRN feature, ECG app, and ePatch functionality issues 
that do not allege an adverse event 
 
 
8.3 Serious Adverse Event  
 
If an event is determined by the Study Safety Monitoring Desk to be related to the IRN feature, 
ECG app, or ePatch, the Study Safety Monitoring Desk will further investigate the event for 
classification as a Serious Adverse Event. 
 
 
8.4 Reporting of Suspected Device-Related Serious Adverse Event  
 
8.4.1 Related to IRN feature or Apple Watch ECG App 

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31 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Possible adverse events related to the IRN feature or ECG app will be reported to the 
sponsor within 2 business days of being reviewed by the Study Safety Monitoring 
Desk. The Study Safety Monitoring Desk will conduct further investigation of these 
events and determine seriousness. The investigation of these events will be completed 
and reported to the sponsor within 20 days of initial report to sponsor. 
 
8.4.2 Related to ePatch 
Events confirmed to be Serious Adverse Events and related to the ePatch will be 
reported to the BioTelemetry by the Study Safety Monitoring Desk. 
 
8.5 Reporting of Adverse Events (AEs) to IRB  
 
Adverse events will be promptly reported to the IRB if they meet the definition of an 
Unanticipated Problem (UP), as defined in section 12.1. Timeframes for UP reports are as 
follows: 
1.     Within 10 working days from when the Stanford study team learns of the event 
2.     Within 5 working days from when the Stanford study team learns of the event for 
unexpected deaths or life-threatening experiences related to the research. 
 
 
 
 

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32 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
9.0 WITHDRAWAL 
 
Every participant should be encouraged to remain in the study until they have completed the 
protocol-required follow-up period. If the participant withdraws prematurely from the study, 
the reason for withdrawal should be documented. Possible reasons for premature withdrawal 
may include, but are not limited to the following:  
 
● Withdrawal of consent: participant decides to withdraw from the study for any reason. 
This may be concluded if/when a participant taps the withdraw button within the app or 
asks to be withdrawn. 
● Investigators believe it is in the best interest of the participant to discontinue the study, 
for any reason. 
● It is discovered that participant does not meet inclusion/exclusion criteria 
 
Withdrawal Process: 
 
Participants will have the option to withdraw from the study by tapping a “Withdraw from 
Study” button within the app. This will disable notifications and will result in a cessation of 
data collection.  If a participant calls the Study Telehealth Provider requesting withdrawal from 
the study, the Study Telehealth Provider will instruct the participant how to initiate withdrawal 
on the app. It will not be possible for any party other than the study participant themselves to 
withdraw from the study. In the few cases where the participant has initiated contact with the 
Study Telehealth Provider, and thereafter selects “Withdraw from Study” on the app, they may 
still receive follow-up communication from the Study Telehealth Provider.  In order to stop 
further communication, these participants would need to inform the Study Telehealth Provider 
Team that they wish to be withdrawn.   
 
Once withdrawn, participants would be able to re-enroll only by reinstalling the application, 
but will be considered a new study participant without linkage to their prior data. 
 
The following will be considered lost-to-follow-up: 
 
● Death of the participant 
● Lost/stolen iPhone and/or Apple Watch 
 
 
 

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33 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
10.0 STATISTICAL CONSIDERATIONS  
 
10.1 Analysis Sets 
 
All analyses will be reported for the overall cohort, as well as by cohort status determined at 
enrollment: (1) Irregular Rhythm Notification, and status of (2) Afib or (3) Inconclusive via the 
ECG app (i.e., with at least 1 ECG recorded within the 14 days before study enrollment 
indicating classification of either AFib or Inconclusive, where the latter is defined as 
“Inconclusive,” “Heart Rate Over 120,” or “Heart Rate Under 50”. 
The Full Analysis Set (FAS) will consist of all enrolled participants who complete the 
informed consent process.  This analysis set will be used to summarize subject demographics, 
medical history, adverse events, self-reported health status, diagnosis, and contact with the 
health care provider. 
The ePatch eligible analysis set (EEAS) will consist of those in the FAS deemed eligible to 
receive an ePatch at Study Visit #1.  
The ePatch Analysis Set (EAS) will consist of all those in the EEAS who receive and return an 
ePatch with at least 1 hour of usable data and who do not belong to the Fallout Group.  
The Fallout Subgroup Analysis Set (FOG) will consist of participants meeting the criteria of 
Section 7.10.  Demographic and medical history information will be presented for this analysis 
set. 
 
Objectives 1a, 1b, and 2b and 2c will be conducted using the EAS, whereas Objective 2a will 
be conducted using the EEAS.  The analyses for Objectives 1a, 1b, and 2b and 2c will be 
repeated in the EEAS as a sensitivity analysis using appropriate methods for handling missing 
data. 
 
10.2 Outcomes and Definitions 
 
10.2.1 Primary Outcome 
Atrial fibrillation or atrial flutter of at least 30 seconds duration on an ambulatory ECG patch 
monitor for a participant who received an IRN or Apple Watch ECG app-AFib classification 
prior to enrollment. 
 
10.2.2 Secondary Outcomes 
 
1. Arrhythmias other than AF on an ambulatory ECG patch monitor 
2. Self-reported contact with a non-study healthcare provider 
 
10.3 Statistical Approaches to Outcome Analyses 

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34 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
There are no pre-specified statistical hypotheses in this clinical study.  Descriptive statistics 
and 95% confidence intervals will be presented using available data as detailed below. 
 
10.3.1 Primary Outcome Analyses 
 
Objective 1a Analysis   
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an IRN before enrollment, divided by the number of participants in the EAS who 
received an IRN before enrollment. An exact 95% two-sided confidence interval will also be 
presented.   We will also describe the number of participants who received an IRN before or 
during ECG enrollment with arrhythmias other than atrial fibrillation. 
Objective 1b Analysis. 
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an ECG app-AFib classification before enrollment divided by the number of 
participants in the EAS who received an ECG app-AFib classification before enrollment.  An 
exact 95% two-sided confidence interval will also be presented. We will also describe the 
number of participants who received an ECG app-Fib before enrollment with arrhythmias other 
than atrial fibrillation. 
 
 
10.3.2 Secondary Outcome Analyses 
 
Objective 2a Analysis 
This proportion will be estimated as the ratio of the number of participants who received an 
IRN or ECG app-AFib in the EEAS who reported contact with a non-study healthcare provider 
at 15 (and separately at 60) days after study enrollment divided by the number of participants 
in the EEAS who received an IRN or ECG app-AFib.  An exact 95% two-sided confidence 
interval will also be presented. 
 
Objective 2b Analysis   
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an ECG app-Inconclusive status before enrollment, divided by the number of 
participants in the EAS who received an ECG app-Inconclusive status before enrollment. An 
exact 95% two-sided confidence interval will also be presented.   We will also describe the 

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35 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
number of participants who received an ECG app-Inconclusive status before enrollment with 
arrhythmias other than atrial fibrillation. 
Objective 2c Analysis. 
This proportion will be estimated as the ratio of the number of participants who have atrial 
fibrillation or atrial flutter of at least 30 seconds duration on patch wear who are greater than 
65 years of age at enrollment divided by the number of participants enrolled who are greater 
than 65 years of age at enrollment using the EAS.  An exact 95% two-sided confidence interval 
will also be presented. We will also describe the number of participants who are 65 years of 
age or older at enrollment with arrhythmias other than atrial fibrillation.  
A similar proportion will be presented for those less than 65 years of age at enrollment.  
 
 
10.3.3 Subgroup Analyses 
 
The proportions and 95% confidence intervals for the primary outcomes (study objectives 1a 
and 1b) will be performed separately by age group (<55, 55-64, ≥65), sex, and race/ethnicity, 
cohort status determined at enrollment, and cohort status determined throughout the 
observations period (e.g., received an IRN during patch wear, received an ECG app-
Inconclusive classification during patch wear).  Chi-squared tests will be performed to 
determine if these proportions differ significantly by subgroup. 
 
10.3.4 Additional Analyses 
Subject accountability, baseline demographics and medical history, survey results, and adverse 
events will be summarized using descriptive statistics for the FAS.  Baseline demographics and 
medical history will also be summarized for participants in the FOG. Additional details may be 
found in the SAP. 
Additional analyses may be performed to gain further insight into the relationships between 
receiving notifications or app-based classifications and ePatch data. Importantly, we will 
additionally evaluate use of the IRN feature and behavioral response to notifications as 
captured in the 15 day PRO. Similarly, we will evaluate behavioral response to engaging a 
healthcare provider as captured in the 60 day PRO among those in the FAS by relevant 
participant characteristics.  
Apple may perform additional analyses using participant data to support future product 
development. 
 
 
10.4 Handling of Missing Data 
 

Confidential 
 
This document contains information that is privileged or confidential and may not be disclosed unless such disclosure is 
required by applicable laws and regulations. The information in this document is the property of Apple Inc. and may not 
be reproduced, published, or disclosed to others without written authorization from Apple Inc. 
36 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
Participants who do not respond to the 15 or 60 day PROs, do not have at least an hour of 
analyzable wear time from the ambulatory ECG monitor or do not return a patch within 45 
days will be considered to have missing data. Methods for missing data such as multiple 
imputations will be implemented when performing analyses on the FAS or the EEAS. The 
assumptions of the missing data method will be evaluated in sensitivity analyses.  
 
 
10.5 Sample Size and Power Considerations 
 
This clinical study is not designed to test any pre-specified statistical hypotheses.  Because all 
participants enrolling in this clinical trial will either have received an irregular rhythm 
notification (IRN) or an ECG app-AFib classification, this sample size justification applies to 
Objectives 1a and 1b.  To address our aims, we require 400 IRN participants that are 
exclusively in the IRN group (i.e., who do not enter the study via the ECG app), who are 
deemed eligible for ePatch receipt and who return their ePatches, and 400 participants who 
exclusively enroll via the ECG-app classification of AFib, who are deemed eligible for ePatch 
receipt and who return their ePatches. This sample size provides sufficient precision for our 
purposes, yielding a 95% confidence interval with a width that is no greater than 0.10 when 
addressing the primary objectives. Further, it does not require assessment or unblinding of 
ePatch results on an ongoing basis. If, after enrolling 500 participants, we observe that there is 
50% overlap or greater between participants who enroll through both the IRN and the ECG 
app, we will modify our targeted enrollment with the understanding that the reporting of 
findings will be accompanied with a detailed context of the types of subjects that contribute to 
both the point estimates of interest. Given these considerations, a targeted enrollment of 2600 
participants is suggested. This allows for approximately a 35% attrition rate and a 50% overlap 
between participant types (IRN vs ECG-app). 
 
10.6 Limitations 
Because the study population is enriched for participants with irregular rhythms and 
inconclusive results who call AppleCare in response to receiving an IRN, an ECG 
classification of Atrial Fibrillation, or an ECG classification of Inconclusive, the results of this 
study may not be generalizable to the broader population of Apple Watch users. 
 
 

Confidential 
 
This document contains information that is privileged or confidential and may not be disclosed unless such disclosure is 
required by applicable laws and regulations. The information in this document is the property of Apple Inc. and may not 
be reproduced, published, or disclosed to others without written authorization from Apple Inc. 
37 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
11.1 TRAINING 
 
To ensure accurate, complete, and reliable data, the Stanford study team in conjunction with 
sponsor, will provide instructional material to Study Telehealth Provider, BioTelemetry, ECG 
Adjudicating Clinicians and other study personnel as appropriate. 
 
12.0 ETHICAL AND REGULATORY CONSIDERATIONS 
This study will be conducted in accordance with applicable FDA regulations (21 CFR Parts 11, 
50, 54, 56, 803, and 820, as applicable). 
  
 
 12.1 Institutional Review Board 
  
The protocol must be submitted to the appropriate Institutional Review Board (IRB) and 
written approval must be obtained prior to enrolling any participants. Yearly approvals for the 
continuation of the study must be obtained by the Investigator. 
  
In addition to the IRB reports submitted during the yearly approval process, certain events 
require prompt reporting to the IRB. The timeline and type of events will follow the most 
updated policy of the governing IRB, but in general, those events, as relevant to this protocol, 
include: 
1. Unanticipated Problems Involving Risks to Participants or Others (UPs): Events 
(internal or external, deaths, life-threatening experiences, injuries, or other) occurring 
during the research study, which meet all of the following criteria: 
a. Unexpected in terms of nature, severity, or frequency; and 
b. Related to participation in the research or there is a reasonable possibility or 
likelihood that the event may have been caused by the procedures involved in 
the research; and 
c. Harmful – places research participants or others at a greater risk of harm than 
was previously known or recognized. 
2. New Information that indicates a change to the risks or potential benefit of the research 
in terms or severity or frequency or impacts the participant’s willingness to participate. 
3. Noncompliance with the IRB approved protocol and other applicable policies when the 
event is: 
a. Possibly serious (affects the rights and welfare of participants) 
b. Possibly continuing (a pattern of noncompliance that continues to occur) 
4. Complaint that is unresolved by the research team 
5. Other events or information 
 

Confidential 
 
This document contains information that is privileged or confidential and may not be disclosed unless such disclosure is 
required by applicable laws and regulations. The information in this document is the property of Apple Inc. and may not 
be reproduced, published, or disclosed to others without written authorization from Apple Inc. 
38 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
12.2   Informed Consent and HIPAA Authorization   
 
The Informed Consent will be provided within the study app and will employ ResearchKit 
electronic consent framework for the signature view to obtain signed and dated informed 
consent and HIPAA authorization prior to enrollment. Signed consent forms will be stored on 
an encrypted server which is 21 CFR Part 11 compliant. The protocol and informed consent 
form must be approved by the reviewing IRB prior to commencement of the study. Any 
subsequent revisions to the informed consent form must also receive IRB approval prior to use.  
 
 
12.3 Confidentiality of Participants  
 
Participant confidentiality will be maintained throughout the clinical study in a way that 
ensures the information can always be tracked back to the source data. For this purpose, a 
unique participant identification code (ID number) will be used that allows identification of all 
data reported for each participant. The ID number will be randomly generated. 
 
Participant information collected in this study will comply with the applicable standards for 
protection of privacy of individually identifiable health information. The Sponsor, investigators 
and all study affiliates will make every reasonable effort to protect the confidentiality of the 
participants participating in this study. Participant records may be released to governing 
regulatory authorities, if requested. In all cases, caution will be exercised to assure the data are 
treated confidentially and that the participant’s privacy is protected. 
 
13.0 HUMAN SUBJECTS PROTECTION  
 
13.1 Research participant Selection and Justification of Exclusions  
There will be no exclusion from participation in the study on the basis of ethnicity or race. 
Participants younger than 22 years of age will be excluded from the study, as the target 
population is adults ≥ 22 years. Participants who are not proficient in written English will be 
excluded as this will prohibit informed consent as well as completion of any necessary data 
collection forms. Participants with shared iCloud accounts or Apple Watches will be excluded 
due to inability to confirm participant-level measures and outcomes. 
 
 
13.2 Compensation to participants  
 
There will be no direct monetary remuneration to study participants.  

Confidential 
 
This document contains information that is privileged or confidential and may not be disclosed unless such disclosure is 
required by applicable laws and regulations. The information in this document is the property of Apple Inc. and may not 
be reproduced, published, or disclosed to others without written authorization from Apple Inc. 
39 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
 
14.0 RECORD KEEPING/REPORTING 
 
14.1 Data Collection  
 
The study will create 21 CFR Part 11 compliant data flows for relevant study sources to 21 
CFR Part 11 compliant servers housing information on participant demographics, baseline 
health history, questionnaires, data from the Irregular Rhythm Notification features and ECG 
app, ambulatory ECG monitor results, Adverse Events, and 15- and 60-day PROs. 
 
 
14.2 Study Documentation  
Study documentation includes but is not limited to all consent forms, app screens, app based 
forms, Irregular Rhythm Notification data, ECG app data, PROs, ambulatory ECG monitor 
reports, and regulatory documents (e.g., signed protocol and amendments, IRB correspondence 
and approval, approved and signed participant consent forms, Statement of Investigator form, 
etc.). The investigator will prepare and maintain complete and accurate study documentation in 
compliance with applicable federal, state, and local laws, rules, and regulations. 
 
 
 
 
 
 
 

Confidential 
 
This document contains information that is privileged or confidential and may not be disclosed unless such disclosure is 
required by applicable laws and regulations. The information in this document is the property of Apple Inc. and may not 
be reproduced, published, or disclosed to others without written authorization from Apple Inc. 
40 
Heart Study 1.2 
Protocol Version: 1.14, Date: November 13, 2018 
 
 
 
15.0 REFERENCES  
Benjamin EJ, et al. Heart Disease and Stroke Statistics - 2018 Update. Circulation. 
2018;137:e67–e492. DOI: 10.1161/CIR.0000000000000558  
 
Turakhia MP, Shafrin J, Bognar K, Trocio J, Abdulsattar Y, Wiederkehr D, et al. (2018) 
Estimated prevalence of undiagnosed atrial fibrillation in the United States. PLoS ONE 13(4): 
e0195088. https://doi.org/10.1371/journal. pone.0195088  
US Preventive Services Task Force. Screening for Atrial Fibrillation with Electrocardiography: 
US Preventive Services Task Force Recommendation Statement. JAMA. 2018;320(5):478-484. 
doi:10.1001/jama.2018.10321 
Jonas DE, et al. Screening for Atrial Fibrillation with Electrocardiography: Evidence Report 
and Systematic Review for the US Preventive Services Task Force. JAMA. 2018;320(5):485-
498. doi:10.1001/jama.2018.4190 
Chen LY, et al. Atrial Fibrillation Burden: Moving Beyond Atrial Fibrillation as a Binary 
Entity. Circulation. 2018;137:e623–e644. DOI: 10.1161/CIR.0000000000000568  

Statistical Analysis Plan 
 
 
Study Official Title: Evaluation of the use of Apple Watch features for 
identification of cardiac arrythmias 
ClinicalTrials.gov Identifier: NCT03769207 
Document Date: December 3 2018 
 

 
 
 
 
Statistical Analysis Plan 
 
Study Name 
Apple Heart Study 1.2 
 
Version Number 1.0 
 
Date 
3 December 2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apple Heart Study 1.2 
 
Evaluation of the use of Apple Watch features for 
identification of cardiac arrhythmias 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Statistical Analysis Plan  
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Version 1.0 
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2 
SIGNATURE PAGE 
Approved by: 
_____________________________ 
Manisha Desai, PhD 
Study Biostatistician  
Stanford University 
______________________________ 
Jason Bentley, PhD 
Study Biostatistician  
Stanford University 
__________________12/12/2018____ 
Marco Perez, MD 
Study PI  
Stanford University 
______________________________ 
Mintu Turakhia, MD, MAS 
Study PI  
Stanford University 

Statistical Analysis Plan  
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______________________________ 
Alexis Beatty 
Study Monitor 
Apple Inc. 
12/19/2018

Statistical Analysis Plan  
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TABLE OF CONTENTS 
PAGE 
1. Study Details _____________________________________________________________ 7 
1.1 Study objectives ______________________________________________________________ 7 
1.2 Study design _________________________________________________________________ 7 
1.3 Number of Participants Needed to Address Objectives _____________________________ 9 
2. Endpoints _______________________________________________________________ 11 
2.1 Primary Endpoints ___________________________________________________________ 11 
2.2 Secondary Endpoints _________________________________________________________ 11 
3. Analysis Sets _____________________________________________________________ 11 
4. Analysis Methods _________________________________________________________ 12 
4.1 General Principles ____________________________________________________________ 12 
4.2 Study Population ____________________________________________________________ 12 
4.3 Analysis Methods ____________________________________________________________ 16 
4.5 Definitions __________________________________________________________________ 19 
4.6 Handling of Missing Data _____________________________________________________ 20 
4.7 Potential Limitations and Mitigation Strategies __________________________________ 20 
5. Interim Checks ___________________________________________________________ 22 
 
 
 
 

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LIST OF ABBREVIATIONS  
The following abbreviations and special terms are used in this Statistical Analysis Plan (SAP). 
Abbreviation or special term 
Explanation 
AE 
Adverse Event 
AF 
Atrial Fibrillation and Atrial Flutter 
AFib 
Atrial Fibrillation 
Apple Watch ECG app-AFib 
Apple Watch ECG app classification of atrial fibrillation 
CI 
Confidence Interval   
EAS 
ePatch Analysis Set 
EEAS 
ePatch Eligibility Analysis Set 
ECG 
Electrocardiography, Electrocardiogram, Electrocardiographic 
FAS 
Full Analysis Set 
FOG 
Fallout Subgroup 
IRN 
Irregular Rhythm Notification  
IPNA 
Irregular Pulse Watch Notification Algorithm 
PAC 
Premature Atrial Contractions 
PPG 
Photoplethysmography, Photoplethysmogram 
PRO 
Patient Reported Outcome 
PVC 
Premature Ventricular Contractions 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SV1 
Study Visit 1 
SV2 
Study Visit 2 
 
 

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Revision history 
Revision 
Date 
Section/Page 
Changes Made -- Reasons for the 
Change 
 
 
 
 
 
 
 

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INTRODUCTION 
This statistical analysis plan (SAP) is a comprehensive and detailed description of the 
strategy, rationale and statistical techniques that we will use to evaluate the ability of the 
Apple Watch Irregular Pulse Watch Notification Algorithm (IPNA) feature and 
Electrocardiography (ECG) app to identify atrial fibrillation or atrial flutter (AF) and facilitate 
subsequent clinical evaluation among users who contact AppleCare. 
1. STUDY DETAILS 
1.1 Study objectives 
Objective 1a: To measure the proportion of participants with an Irregular Rhythm 
Notification (IRN) prior to enrollment who have atrial fibrillation or atrial flutter (AF) 
confirmed by ambulatory electrocardiographic (ECG) patch monitoring. 
Objective 1b: To measure the proportion of participants with an ECG app classification of 
Atrial Fibrillation (ECG app-AFib) prior to enrollment who have AF confirmed by 
ambulatory ECG patch monitoring. 
Objective 2a: To measure the proportion of participants who receive an IRN or ECG app-
AFib reporting contact with a non-study healthcare provider at 15 and 60 days after study 
enrollment. 
Objective 2b: To measure the proportion of participants with an ECG app classification of 
inconclusive prior to enrollment who have AF confirmed by ambulatory ECG patch 
monitoring. 
Objective 2c: To measure the proportion of participants who have AF confirmed by 
ambulatory ECG patch monitoring by age at enrollment (< 65 and 65+). 
 
1.2 Study design 
This will be a prospective, single arm, experimental, non-significant risk study conducted with 
the assistance of eligible participants wearing an Apple Watch Series 1-4 with the IRN feature 
or an Apple Watch Series 4 with the ECG app who receive an IRN or an ECG app 
classification of AF or “inconclusive”. 
 
The Irregular Rhythm Notification (IRN) feature is a software-only mobile medical 
application that analyzes pulse rate data to identify episodes of irregular heart rhythms 
suggestive of AFib. Using observable variations in photoplethysmogram (PPG) signal 
intensity, changes in blood flow can be measured and beat-to-beat pulse measurements can be 
made. During normal sinus rhythm, there is minimal variation in pulse. However, during AF, 
the beat-to-beat variability increases significantly. Therefore, a PPG signal can be used to 
differentiate between a regular pulse and an irregular pulse that may be indicative of AF. 

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An algorithm has been developed by Apple to identify periods of irregular pulse based on 
PPG signal variation as measured by the Irregular Pulse Notification Algorithm (IPNA). The 
time between PPG signal peaks observed during periods of minimal arm movement are 
marked as intervals between heart beats. A tachogram is a period of time over which heart 
beat intervals are measured. The degree of beat-to-beat variability is measured from spot 
tachograms over the course of approximately one minute intervals. An irregular tachogram is 
flagged when the variability, measured using a Poincare plot, crosses a predefined threshold. 
An IPNA checks multiple tachograms over a period of approximately an hour or more. An 
IRN is then sent to the user when a period of an irregular pulse suggestive of AFib has been 
identified. 
The ECG app is a software-only mobile medical application intended for use with the Apple 
Watch to create, record, store, transfer, and display a single channel ECG similar to a Lead I 
ECG. The ECG app processes electrical signals from two sensors on the Apple Watch - an 
electrode on the back of Apple Watch and an electrode on the digital crown. A user opens the 
ECG app on their Apple Watch, places a finger on the digital crown, and remains still for 30 
seconds to capture an ECG. The ECG app analyzes the waveform to determine the presence of 
atrial fibrillation (AF) or sinus rhythm on a classifiable waveform. The ECG app waveform is 
stored in the Health App and can be exported as a .pdf. The ECG app provides rhythm 
classifications such as AF, “Inconclusive”, “Heart Rate Over 120”, or “Heart Rate Under 50”. 
The ECG app group classifications; “Inconclusive”, “Heart Rate Over 120”, or “Heart Rate 
Under 50” are all considered inconclusive for the purposes of this study and are considered 
eligible for this study. Both the IRN feature and the ECG app were granted United States Food 
and Drug Administration (FDA) de novo classification on 9/11/2018. 
Participants who call into AppleCare and self-report having received an IRN or ECG app 
classification of AF or inconclusive will be offered information about participation in the 
study. The AppleCare representative will offer to e-mail the participant a link to download the 
Study App for more information. If the participant agrees, the participant will be emailed a 
link to download the Study App. Once downloaded, the Study App will provide the 
information about the study and screen for eligibility. If the participant meets the eligibility 
criteria and wishes to enroll in the study, the Study App will initiate the consenting process 
and provide the consent and authorization to sign in the app. Participants who install the 
Apple Heart Study 1.2 App and meet the eligibility criteria proceed to consent and then enroll 
in the study. Participants will be required to provide signed informed consent; once enrolled 
they will complete a short questionnaire to collect demographic information, medical history, 
and health status, after which the study period will commence. 
 
After enrollment, participants will be prompted to contact the Study Telehealth Provider to 
conduct Study Visit #1 (SV1) via voice or video. During SV1, participants will undergo a 
virtual medical evaluation which will include an abbreviated assessment for symptoms, 
medical history, and medications. Participants with urgent symptoms (chest pain, shortness of 
breath, fainting/losing consciousness) will be directed to an urgent care clinic or emergency 
room for medical evaluation. For participants with non-urgent symptoms, the Study 
Telehealth Provider will order an ambulatory ECG monitor (i.e., an ePatch) from 

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BioTelemetry. Participants will be expected to contact the Study Telehealth Provider within 
30 days of enrollment. Study participants will receive reminders via email and phone calls if 
needed to initiate SV1. Participants who call after 30 days will still be able to obtain an ePatch 
and undergo remaining study procedures, but may not be included in all analyses.  
Participants will be mailed the ePatch, and once received, the participant will be required to 
wear it for up to 7 days. The minimum analyzable time acceptable for primary analysis is one 
hour. Participants with the ECG app will be asked to take an ECG app recording at least twice 
daily while wearing the ePatch, as well as after receiving an irregular rhythm notification. The 
participant will then mail the ambulatory ECG monitor back to BioTelemetry within 45 days 
of enrollment, which will generate a standard technical report that will be read by 
BioTelemetry’s technical readers. The report will be adjudicated by two board-certified 
clinicians, and a final report will be made available to the Study Telehealth Provider by 
BioTelemetry. 
After the final ambulatory ECG monitor report is made available to the Study Telehealth 
Provider, the Study Telehealth Provider will contact the participant to prompt them to 
complete Study Visit #2 (SV2). During SV2 the ePatch results will be reviewed. If AF or any 
other arrhythmias have been detected in reviewing the ambulatory ECG monitor data, or if 
there are other non-urgent symptoms needing further evaluation, the Study Telehealth 
Provider will direct the participant to their primary health care provider, or other health care 
provider as deemed appropriate. The report and visit summary will be made available to the 
participant and also to the participant’s physician or health care provider, if the participant 
provides his/her physician information and permission to send that physician a copy of the 
report. For participants who do not have an established primary health care provider, the 
Study Telehealth Provider will encourage and offer advice in establishing a primary care 
provider per standard Study Telehealth Provider protocol. 
 
1.3 Number of Participants Needed to Address Objectives 
This clinical study is not designed to test any pre-specified statistical hypotheses. Because all 
participants enrolling in this clinical trial will either have received an IRN or an ECG app-
AFib classification, we derived the number of enrolled participants needed to achieve our 
desired precision for addressing Objectives 1a and 1b. 
To obtain a 95% confidence interval (CI) with a width no greater than 0.10 when addressing 
Objective 1a we will require 400 IRN participants that are exclusively in the IRN group (i.e., 
who do not enter the study via the ECG app), who are deemed eligible for ePatch receipt and 
who return their ePatches. Similarly, for Objective 1b to obtain a 95% CI with a width no 
greater than 0.10 we will require 400 participants who exclusively enroll via the ECG-app 
classification of AFib, who are deemed eligible for ePatch receipt and who return their 
ePatches. 
 

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The figure above displays the 95% CI width for the target sample size of 400 (over the range 
of possible AF percents we could observe) and three sample sizes that represent a failure to 
meet the target; n=350 (87.5% of target), n=300 (75% of target) and n=200 (50% of target). 
The height of the lines (the vertical axis) correspond to the CI width. The horizontal axis 
corresponds to the percent AF observed. As noted 400 patches (the blue line) will ensure the 
estimated CIs are no wider than 10%. The lines representing a failure to meet the target 
number of returned ePatches for each group shows at worst the CI could be as wide as 13.9% 
at 50% of the target and a percent with AF of 50%. However, even at 87.5% or even 75% of 
the recruitment target the worst case is a CI width of 11.3% and in both cases a modest 
amount of possible AF percentages will yield a CI with a width < 10%. 
If, after enrolling 500 participants, we observe that there is 50% overlap or greater between 
participants who enroll through both the IRN and the ECG app, we will modify our targeted 
enrollment with the understanding that the reporting of findings will be accompanied with a 
detailed context of the types of subjects that contribute to both estimates addressing 
Objectives 1a and 1b.  
Allowing for an approximate attrition rate of 35% and an overlap of 50% between participant 
types (IRN vs ECG-app) we calculated a minimum target enrollment of 2600 participants. 

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Further, the expected period for completion of study recruitment is approximately 6 months. 
If, 60 days after the study opens, there is evidence that enrollment rates will not be adequate to 
meet enrollment goals for each subgroup, then alternative recruitment strategies will be 
employed to help reach recruitment goals. 
2. ENDPOINTS 
2.1 Primary Endpoints 
The primary endpoint of the study is   
● An indicator for whether atrial fibrillation or atrial flutter of at least 30 seconds duration 
on an ambulatory ECG patch monitor. 
2.2 Secondary Endpoints 
The secondary endpoints are 
● Arrhythmias other than AF on an ambulatory ECG patch monitor. 
● Self-reported contact with healthcare provider. 
3. ANALYSIS SETS 
The Full Analysis Set (FAS) will consist of all enrolled participants who complete the 
informed consent process. This analysis set will be used to summarize subject demographics, 
medical history, adverse events, self-reported health status, diagnosis, and contact with the 
health care provider. 
The ePatch Eligibility Analysis Set (EEAS) will consist of those in the FAS deemed eligible 
to receive an ePatch at Study Visit #1. This analysis set will be used to assess Objective 2a. 
The ePatch Analysis Set (EAS) will consist of all those in the EEAS who receive and return 
an ePatch with at least 1 hour of usable data and who do not belong to the Fallout Subgroup. 
This analysis set will be used to assess Objectives 1a, 1b, and 2b and 2c. We will repeat these 
analyses in the EEAS as a sensitivity analysis using appropriate methods for handling missing 
data. 
The Fallout Subgroup Analysis Set (FOG) will consist of participants who enroll and 
complete the informed consent process but otherwise do not complete the study. Reasons for 
study incompletion include; failure to contact Study Telehealth Provider within 30 days of 
enrollment, being deemed ineligible at Study Visit #1 for ePatch wear due to emergent 
symptoms, ePatch not returned within 45 days of enrollment, failure to start wearing ePatch 
within 14 days of shipment, unable to verify at Study Visit #1 a study eligible IRN or ECG-
app notification, study withdrawal (i.e., withdrawal of consent), or lost to follow-up (i.e., 
death). We will present demographic and medical history information for this analysis set. 

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4. ANALYSIS METHODS 
4.1 General Principles 
Method for Constructing Confidence Intervals 
We will construct confidence intervals using the asymptotic Gaussian approximation. For 
proportions near 1 or 0, a potential drawback of this method is confidence intervals containing 
values outside of the range [0,1]. If we encounter confidence intervals with bounds outside of 
the [0,1] range we will instead construct the confidence intervals using the bias corrected and 
accelerated (BCa) method of creating a bootstrap confidence interval. 
Incomplete Dates 
If only the year of a date is given (YY), then the date shall be set to ‘YY0701’. If only the year 
and month of a date is given (YYMM), then the date shall be set to ‘YYMM15’. 
Descriptive Statistics 
Numerical variables will be summarized using standard summary statistics including the 
number of participants, mean, standard deviation, median, 10th and 90th percentile and range 
(i.e., minimum and maximum) as appropriate. For categorical data, proportions will be 
presented in a frequency table format. 
Multiple Patches per Participant 
In rare instances where a single user ID is associated with data available from more than one 
patch, only data from the final patch will be used in statistical analyses. 
4.2 Study Population 
Participant Disposition 
The number and percent of participants who completed the study, discontinued from the 
study, and reasons for discontinuation from the study will be summarized by age group, 
participant classification (i.e., IRN, ECG App classification of AFib, or ECG App 
classification of inconclusive) and overall, for the FAS (table shown by age for illustrative 
purposes). 
Age group, 
yrs 
Measures 
IRN 
ECG: 
AFib 
ECG: 
inconclusive 
< 55 
N 
Completed the study, n (%) 
Discontinued from study, n (%) 
Reasons for discontinuation 
 
 
 

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55-64 
N 
Completed the study, n (%) 
Discontinued from study, n (%) 
Reasons for discontinuation 
 
 
 
65+ 
N 
Completed the study, n (%) 
Discontinued from study, n (%) 
Reasons for discontinuation 
 
 
 
Overall 
N 
Completed the study, n (%) 
Discontinued from study, n (%) 
Reasons for discontinuation 
 
 
 
 
Participants having protocol deviations will be summarized using the FAS population. 
Age group, yrs 
FAS, N 
Protocol deviations, n (n/N) 
<55 
 
 
55-64 
 
 
65+ 
 
 
Overall 
 
 
 
Demographic and Other Baseline Characteristics 
Demographic and other baseline characteristics will be summarized overall, by age, and by 
participant classification using the EEAS and EAS. No statistical tests will be performed for 
comparison of any baseline measurement by age group. 
All summaries of continuous characteristics will be based on non-missing observations and 
the percent of participants missing values will be reported. For categorical characteristics, 
percents will be calculated out of the total number of participants in the data set (i.e., each 
denominator includes the number of participants with missing/unknown values for the 
variable), where the percentage missing will also be reported. 
 

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Table 2 Summaries of Demographic and Other Characteristics at Baseline.     
Characteristic 
Summarized as  
Categories 
Age 
Categorical and 
Continuous 
<55, 55-64, 65+ years 
Gender 
Categorical    
Female 
Male 
Non-binary 
Race/Ethnicity 
Categorical 
American Indian or Alaska Native 
Asian 
Black or African American 
Hispanic, Latino or Spanish origin 
Middle Eastern or North African 
Native Hawaiian or Other Pacific Islander 
White 
Some other race, ethnicity or origin 
Prefer not to respond 
BMI 
Categorical and 
Continuous  
<30 kg/m2 and ≥30 kg/m2   
Average number of 
cigarettes smoked per 
day 
Categorical 
None 
1-10 
11-20 
21-40 
41 or more 
Rather not say 
Average number of 
alcoholic beverages 
consumed per week 
Categorical 
Less than 1 
1-5 
6-9 
10 or more 
Rather not say 

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Medical History 
Categorical 
High blood pressure or hypertension 
Diabetes mellitus 
Heart attack or myocardial infarction 
Heart failure 
Stroke or transient ischemic attack 
Peripheral arterial disease 
Ever diagnosed you with atrial fibrillation or atrial flutter 
Told by doctor had a 
type of irregular heart 
beat 
Categorical 
Atrial Tachycardia  
Frequent Premature Ventricular Contractions (PVCs) 
Frequent Premature Atrial Contractions (PACs) 
Supraventricular Tachycardia (SVT) 
Ventricular Tachycardia (VT) 
None of the above 
I don’t know 
Currently taking 
medications 
Categorical 
Aspirin 
Warfarin (coumadin) 
Apixaban (Eliquis) 
Dabigatran (Pradaxa) 
Edoxaban (Savaysa) 
Rivaroxaban (Xarelto) 
None of these 
Notification received Categorical 
Irregular rhythm notification 
ECG app on Apple Watch result of “Atrial Fibrillation” 
ECG app on Apple Watch result of “Inconclusive” 
ECG app on Apple Watch result of “Heart Rate over 120” 
ECG app on Apple Watch result of “Heart Rate under 50” 
I’m not sure 
How would you rate 
your physical health 
Categorical 
Excellent 
Very good 
Good 
Fair 
Poor 

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To what extent are 
you able to carry out 
your everyday 
physical activities 
Categorical 
Completely 
Mostly 
Moderately 
A little 
Not at all 
How would you rate 
your mental health 
Categorical 
Excellent 
Very good 
Good 
Fair 
Poor 
How would you rate 
your satisfaction with 
your social activities 
and relationships 
Categorical 
Excellent 
Very good 
Good 
Fair 
Poor 
 
Medications at study visits 1 and 2 
Medications reported during study visit 1 and 2 will be summarized using the EEAS group by 
drug category or generic drug name by age group and overall. We will also describe new 
medications started between SV1 and enrollment and SV2 and SV1. 
Drug Category or Name 
N 
Responding 
SV1 (%) 
N on 
Medication 
SV1 (%)* 
N 
Responding 
SV2 (%) 
N on 
Medication 
SV2 (%)* 
Beta blockers 
 
 
 
 
Calcium channel blockers 
 
 
 
 
Aspirin 
 
 
 
 
Anticoagulants 
 
 
 
 
* Percent calculated as percent of participants who responded to whether they used the 
corresponding drug type. 
 
4.3 Analysis Methods  
Analysis of the Primary Endpoint Addressing Objective 1a and 1b 

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For Objectives 1a and 1b we have designed the study to estimate the proportion of participants 
diagnosed with AF within a 0.10 confidence interval width. 
 
Objective 1a – The proportion of participants with an IRN prior to enrollment who have AF 
confirmed by ambulatory ECG patch monitoring. 
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an IRN before enrollment, divided by the number of participants in the EAS who 
received an IRN before enrollment. An exact 95% two-sided confidence interval will also be 
presented. We will also describe the number of participants who received an IRN before or 
during enrollment with arrhythmias other than atrial fibrillation. 
 
Objective 1b Analysis – The proportion of participants with an ECG app-AFib classification 
prior to enrollment who have AF confirmed by ambulatory ECG patch monitoring. 
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an ECG app-AFib classification before enrollment divided by the number of 
participants in the EAS who received an ECG app-AFib classification before enrollment. An 
exact 95% two-sided confidence interval will also be presented. We will also describe the 
number of participants who received an ECG app-Fib before enrollment with arrhythmias 
other than atrial fibrillation. 
 
Analysis of the Secondary Endpoints Addressing Objectives 2a, 2b and 2c 
Objective 2a Analysis - The proportion of participants with an IRN or ECG app-AFib 
classification reporting contact with a non-study healthcare provider at 15 and 60 days after 
study enrollment. 
This proportion will be estimated as the ratio of the number of participants who received an 
IRN or ECG app-AFib classification in the EEAS who reported contact with a non-study 
healthcare provider at 15 (and separately at 60) days after study enrollment divided by the 
number of participants in the EEAS who received an IRN or ECG app-AFib. An exact 95% 
two-sided confidence interval will also be presented. 
 
 
Objective 2b Analysis   
This proportion will be estimated as the ratio of the number of participants in the EAS who 
have atrial fibrillation or atrial flutter of at least 30 seconds duration on patch wear and 
received an ECG app-Inconclusive status before enrollment, divided by the number of 
participants in the EAS who received an ECG app-Inconclusive status before enrollment. An 
exact 95% two-sided confidence interval will also be presented. We will also describe the 

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number of participants who received an ECG app-Inconclusive status before enrollment with 
arrhythmias other than atrial fibrillation. 
 
Objective 2c Analysis 
This proportion will be estimated as the ratio of the number of participants who have atrial 
fibrillation or atrial flutter of at least 30 seconds duration on patch wear who are greater than 
65 years of age at enrollment divided by the number of participants enrolled who are greater 
than 65 years of age at enrollment using the EAS. An exact 95% two-sided confidence 
interval will also be presented. We will also describe the number of participants who are 65 
years of age or older at enrollment with arrhythmias other than atrial fibrillation. A similar 
proportion will be presented for those less than 65 years of age at enrollment.  
 
Sensitivity and Sub-analyses  
The proportions and 95% confidence intervals for Objectives 1a and 1b will be performed 
separately by age group (<55, 55-64, ≥65), sex, race/ethnicity, cohort status determined at 
enrollment, cohort status determined during patch wear (e.g., received an IRN during patch 
wear, received an ECG app-Inconclusive classification during patch wear) and selected 
medical history conditions (e.g., ever diagnosed you with atrial fibrillation or atrial flutter, or 
ever had a stroke, Transient Ischemic Attack (TIA) or “Mini Stroke”). Chi-squared tests will 
be performed to determine if proportions differ significantly by subgroup. 
Baseline demographics and medical history, survey results, and adverse events will be 
summarized using descriptive statistics for the FAS. Baseline demographics and medical 
history will also be summarized for participants in the FOG. 
Additional analyses may be performed to gain further insight into the relationships between 
receiving notifications or app-based classifications and ePatch data. Importantly, we will 
additionally evaluate use of the IRN and ECG app features and behavioral response to 
notifications as captured in the 15 day PRO. Similarly, we will evaluate behavioral response 
to engaging a healthcare provider as captured in the 60 day PRO by relevant participant 
characteristics. 
To understand the sensitivity of our findings for study objectives utilizing the EAS that 
requires at least 1 hour of useable data from participants in the EEAS, we will vary the 
requirement that participants with less than 1 hour of wear time be considered as missing their 
ECG data. We will also conduct additional sensitivity analyses considering the following 
alternative minimum wear times: 6 hours, 1 day, 2 days, and 5 days. 
Adverse Events 

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A participant will be counted once for a reported AE even if the participant had multiple 
occurrences of that AE. We will summarize the proportion of participants reporting anxiety 
and rash in the EEAS and EAS. All AEs will be collected; however, these AEs are of most 
interest to the study device (anxiety) and are highest risk in the study (rash). 
Adverse Events 
N EEAS 
% EEAS 
N EAS 
% EAS 
Anxiety 
 
 
 
 
Rash 
 
 
 
 
 
The participant incidence of all serious adverse events will be presented for each analysis set 
by age group and overall. 
Age group, yrs 
N SAEs 
N unique participants with 
SAEs 
SAEs/participants with 
SAEs 
< 55 
 
 
 
55-64 
 
 
 
65+ 
 
 
 
Overall 
 
 
 
 
Analysis of Fall-Out Subgroup 
The FOG (a subset of the FAS) will include participants who are enrolled but otherwise do not 
complete the study. Possible reasons are listed in Section 3. We will describe baseline 
characteristics for this group and for those in the FOG that have completed the PRO, we will 
report rates of contact with a non-study healthcare provider. 
 
4.5 Definitions  
 
Irregular Arrhythmias 
AF is defined as irregular QRS complexes with no clearly discernible p-waves lasting 30s or 
more ever during the ECG monitoring. In tertiary analyses, we consider definitions requiring 
longer periods of AF, up to 24 hours. 
Sinus arrhythmia is defined as a beat-to-beat variation lasting at least 120ms with discernible 
sinus p-waves ever during the ECG monitoring. 

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Frequent PACs are defined as p-waves that are observed before the predicted time interval. A 
participant is considered to have frequent PACs if they average 30 or more PACs/hour during 
the ambulatory ECG monitoring.  
Frequent PVCs are defined as wide QRS complexes without preceding p-waves. A participant 
is considered to have frequent PVCs if their (total number of PVCs/total number of 
beats)*100% is ≥ 5% and very frequent PVCs if ≥ 15% during the ambulatory ECG 
monitoring. (See the next subsection for criteria used to indicate presence of PACs and PVCs 
at the tachogram-level.) 
Intermittent heart block is defined as the presence of p-waves that are not followed by a QRS 
complex and are not preceded by a gradually prolonging PR interval. No minimum amount of 
time is required. 
Multifocal atrial tachycardia is defined as an irregular, narrow complex tachycardia with 
discernable preceding p-waves preceding the QRS complex that are of at least two different 
morphologies, lasting at least 30 seconds. 
  
Atrial tachycardia with variable conduction is defined as an irregular narrow complex 
tachycardia with one predominant p-wave morphology lasting at least 30 seconds.  The p-
waves are followed by QRS complexes with varying ratios, from one QRS for every p-wave, 
to one QRS for multiple p-waves. The p-waves are a distinct morphology from typical flutter 
waves. 
 
Notification Concordance 
The ambulatory ECG monitoring will be considered to be concordant with either an IRN or 
ECG app-AFib classification before enrollment if 30 seconds of AF is observed on the 
ambulatory ECG monitor during the period of wear in the study for study participants with at 
least 1 hour of usable ECG monitor data. 
 
4.6 Handling of Missing Data  
 
Participants who do not respond to the 15 or 60 day PROs, do not have at least an hour of 
analyzable wear time from the ambulatory ECG monitor or do not return a patch within 45 
days will be considered to have missing data. We will use methods for missing data such as 
multiple imputation when performing analyses on the FAS or the EEAS. We will further 
evaluate the assumptions of missing data methods in sensitivity analyses. 
 
4.7 Potential Limitations and Mitigation Strategies  
 

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We have identified several potential limitations in our planned analyses and have planned 
various sensitivity analyses and alternate approaches to understand and mitigate the impact of 
these limitations on our findings. The ePatch is not worn at the time of the initial notification 
and we may not detect AF on the subsequent ambulatory ECG monitoring, particularly in 
participants with low burden AF. We additionally expect that some participants will wear their 
ePatch for a period shorter than 7 days. We acknowledge that several factors may contribute 
to an overestimated or underestimated proportion of AF in participants who receive an IRN or 
ECG app-AFib classification. We describe above sensitivity analyses to evaluate the 
sensitivity of estimates to the minimum wear time for inclusion in the analysis (described in 
Section 4.3). 
 
In particular, we anticipate several biases that may impact the estimates for Objectives 1a, 1b, 
2b and 2c.  
 
x Patch Wear Bias: We anticipate that not all participants will wear their patches for the 
full 7 day wear period. We acknowledge that wear periods shorter than 7 days and a 
study design where the ePatch is worn during a period that follows the initial 
notification (and not simultaneously) will likely contribute to an underestimated true 
proportion of AF in participants who receive an IRN or ECG app-AFib classification 
because the AF that triggered the initial notification may not be detected during the 
subsequent ambulatory ECG monitoring. We will evaluate the sensitivity of our 
estimates addressing Objectives 1a, 1b, 2b and 2c to the minimum wear time for 
inclusion in the analysis (described in Section 4.3). 
 
x Missing Data Bias: For some participants, the IRN or ECG app-AFib classification 
will occur but no subsequent analyzable ECG monitoring data will be available (e.g., 
participant requires urgent care, participant doesn’t return patch). Because these 
participants will not provide ambulatory ECG monitoring data, they will not be 
included in analyses to estimate the proportions in Objectives 1a, 1b, 2b and 2c. Their 
exclusion may bias the estimates up or down. Participants who require urgent care are 
presumably more likely to have AF and their exclusion would lead to an 
underestimate. On the other hand, participants who do not return patch may be less 
sick and their exclusion would result in an overestimate of the proportion of 
participants with AF. This bias is an inherent limitation of an observational study. 
 
x Observation Period Bias: It is possible that participants may receive an IRN or ECG 
app-AFib classification but the subsequent ECG monitoring may not be of sufficient 
length to observe AF. 
 
x Classification self-report bias: For the primary analysis patients will be analyzed 
according to their self-reported classification status at enrollment. However, a change 
in data collection in Phase II of the study will allow tachogram data prior to patient 
enrollment to be used to validate the patient self-reported classification. Sub-group 
analysis will be performed using Phase II data where classifications will be validated 

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according to tachogram data and results compared between those who are in 
agreement with those who are not.  
5. INTERIM CHECKS 
Interim checks in this study will be performed to assess study recruitment. 
 
Throughout the course of the study, we will check the number of recruited participants 
according to their cohort designation at enrollment (i.e, IRN, ECG app-AFib classification and 
ECG app-inconclusive classification). Specifically, at 60 days after the study opens, if 
enrollment rates are not adequate to meet enrollment goals for each subgroup for the EAS 
group (i.e. viable ePatch data for assessing the primary study objectives), then alternative 
recruitment strategies may be employed to help reach recruitment goals. Additionally, 
recruitment rates will be assessed by age (<65, 65+ years). 
 
 
 
 
N EAS at 60 
days 
Expected N EAS at 
end of study 
Meeting study 
recruitment goals? 
IRN 
 
 
 
ECG app-AFib classification