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

 
 
 
 
 
 
 
 
 
Electrocardiogram Clinical Validation Study 
 
NCT03492554 
 
15Jun2018 
 

 
 
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Electrocardiogram Clinical Validation Study 
 
Sponsor: 
New Atlantis Research 
Protocol Number 
099-11774 
Version and date: 
 15 June 2018 
Compliance Statement: 
This study will be conducted in accordance 
with the ethical principles that have their 
origin in the Declaration of Helsinki, clinical 
research guidelines established by the U.S. 
Food and Drug Administration (21 CFR Parts 
50, 54, 56, and 812), and ICH GCP 
Guidelines. 
 
 

 
 
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INVESTIGATOR APPROVAL PROTOCOL SIGNATURE PAGE 
 
Protocol: 
099-11774 
Title: 
Electrocardiogram Clinical Validation Study 
 
Amendment: 
 
N/A 
 
 
I confirm that I have read and understood this trial protocol and attached appendices and will 
conduct this study in compliance with the protocol, all statements regarding confidentiality, 
local regulations, International Conference on Harmonization Good Clinical Practice E6 (ICH-
GCP), and U.S. Code of Federal Regulations applicable to clinical studies (21 CFR Parts 50 
(protection of human subjects), 54 (financial disclosure by clinical investigators), 56 (informed 
consent and IRB requirements), 812 (Investigational Device Exemptions).  
With my signature, I agree to: 
(i) Conduct the investigation in accordance with the agreement, the 
investigational plan, applicable provisions of 21 CFR Part 812 and other 
FDA regulations, and conditions of approval imposed by the reviewing IRB 
or FDA;  
(ii) Supervise all testing of the device involving human subjects; and  
(iii) Ensure that the requirements for obtaining informed consent are met. 
 
Reviewed and Approved by: 
 
 
 
 
  
Investigator’s Signature 
 
 
Date 
 
 
 
 
 
Name/Title 
 
 
 

 
 
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SYNOPSIS 
Electrocardiogram Clinical Validation Study 
Overview 
The purpose of this study is two-fold: 
1) To validate a rhythm classification algorithm and its ability to detect and classify heart 
rhythms into one of two categories (sinus rhythm [SR] and atrial fibrillation [AF]) using a 
single Lead I ECG strip.  
2) To validate the software’s ability to generate a Lead 1 electrocardiogram (ECG) that is 
clinically equivalent to a standard 12-lead ECG. 
Study Objectives 
1) The primary objective is to demonstrate that the software under testing (SUT) has 
acceptable sensitivity and specificity;  
2) Secondary objectives are 
a. To demonstrate that the SUT produces a waveform that provides clinically 
equivalent information to the gold standard.  
b. To understand ease of use between three different data collection devices. 
Study Endpoints 
1) Primary endpoints: Sensitivity, specificity 
2) Secondary endpoints: clinically equivalent waveform, ease of use 
Study Hypotheses 
1) The primary hypothesis is that the SUT will have >90% sensitivity and >92% specificity 
in detecting AF on “readable and classifiable” strips generated by a single Lead I ECG. 
2) The secondary hypothesis is that the SUT produces a waveform that provides clinically 
equivalent information to the gold standard. 
 
Subject Population 
Study cohorts and target population 
• Study subjects 
o A minimum of 260 subjects (up to a maximum of 400 subjects) with AF 
§ A population of subjects with a known diagnosis of AF (permanent or 
persistent AF as the likelihood of being in AF during data collection is 
higher) 
o Approximately 300 subjects with SR 
§ A population of subjects with no known diagnosis of AF  

 
 
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• There is no age distribution requirement for the AF population. For subjects with SR, 
there will be at least 25 subjects in each of the 22-30, 31-50, 51-64 categories and at least 
150 subjects in the 65+ category. 
• Men and women should be equally represented between the two study cohorts with a goal 
of having women represent >30% of subjects. 
 
Inclusion criteria 
Subjects must meet all the following inclusion criteria to be enrolled: 
1. Able to read, understand, and provide written informed consent 
2. Willing and able to participate in the study procedures as described in the consent form 
3. Individuals who are 22 years of age and older 
4. Able to communicate effectively with and follow instructions from the study staff 
5. Have a wrist circumference between 130 mm and 245 mm (measured at “band center” on 
the preferred wrist. This location is determined by asking the volunteer to put on a normal 
wrist-watch and marking the skin with a pen/marker to outline the edges of the band.) 
6. For subjects enrolled into the AF population, subjects must have a known diagnosis of 
AF and be in AF at the time of screening. Subjects may have any type of AF including 
paroxysmal, persistent, and permanent AF although persistent and permanent AF are 
preferred as they are more likely to be in AF at the time of screening. 
Exclusion criteria 
Subjects who meet any of the following criteria may not be enrolled: 
1. Physical disability that precludes safe and adequate testing  
2. Mental impairment resulting in limited ability to cooperate  
3. Subjects with a pacemaker or implantable cardioverter-defibrillator (ICD) 
4. Acute myocardial infarction (MI) within 90 days of screening or other cardiovascular 
disease that, in the opinion of the Investigator, increases the risk to the subject or renders 
data uninterpretable (e.g., recent or ongoing unstable angina, significant valvular heart 
disease or heart failure, myocarditis or pericarditis) 
5. Acute pulmonary embolism, pulmonary infarction, or deep vein thrombosis within 
90 days of screening  
6. Stroke or transient ischemic attack within 90 days of screening  
7. Subjects taking rhythm control drugs (e.g., disopyramide, quinidine, flecainide, 
propafenone, amiodarone, dofetilide, dronedarone, sotalol, procainamide, ibutilide, 
moricizine, procainamide). An exception will be made for subjects who are undergoing 
scheduled cardioversion for known AF within 30 days after study participation. These 
study participants will be allowed to participate in the study even when on rhythm control 
drugs. 

 
 
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a. Rate control and anti-coagulants, anti-platelet medications are permitted (e.g., 
metoprolol, atenolol, diltiazem, coumadin, clopidogrel, aspirin) 
8. Symptomatic (or active) allergic skin reactions such as eczema, rosacea, impetigo, 
dermatomyositis or allergic contact dermatitis on both wrists or over electrode attachment 
sites  
9. Known sensitivity to medical adhesives, isopropyl alcohol, watch bands, or 
electrocardiogram (ECG) electrodes including known allergy or sensitivity to 
fluoroelastomer bands primarily used in wrist worn fitness devices 
10. A history of abnormal life-threatening rhythms as determined by the investigator (e.g., 
ventricular tachycardia, ventricular fibrillation, 3rd-degree heart block, resting heart rate < 
50 beats per minute (bpm), resting heart rate >110 bpm) 
11. Significant tremor that prevents subject from being able to hold still 
12. Pregnant women: Women who are pregnant at the time of study participation. 
13. 
 
 
14. 
 
 
 
 
15. For subjects enrolled into the sinus rhythm population, they must not have any diagnosis 
of AF. For example, subjects cannot be enrolled into the sinus rhythm population if they 
have a diagnosis of paroxysmal AF but during screening are in sinus rhythm. 
 
Study Details 
Screening for Participation 
Subjects should be screened based on the above inclusion and exclusion criteria.  
Informed consent will be obtained before any study protocol-directed procedures are performed. 
After the signing of informed consent, the subject’s eligibility based on the inclusion/exclusion 
criteria will be evaluated. 
During screening, the following should be obtained on each subject: 
• Age 
• Gender 
• Race and ethnicity 
• Occupation 
• Diagnosed medical conditions 

 
 
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• Medications 
• Allergies 
• Smoking history 
• Alcohol Use (self reported) 
• Recreational Drug Use (self reported) 
• Brief physical examination 
• Height and weight 
• Body mass index (BMI) 
• Vital signs will be collected after sitting for at least 5 minutes (blood pressure 
with systolic recorded within the range of 80-180 mm Hg and diastolic recorded 
in the range of 40-120 mmHg, heart rate recorded within the range from 50-110 
beats per minute, temperature recorded within range of 35.5-37.5 degrees) 
• Urine pregnancy testing for women of childbearing potential 
• Caffeine intake 
• Exercise habits 
• Dominant hand 
• Wrist circumference (for wrist that device will be worn on) 
• Skin fold thickness (for wrist that device will be worn on) 
• Wrist hairiness (for wrist that device will be worn on) 
• 12-lead ECG will be collected supine after lying for at least 5 minutes 
All volunteers will undergo a 12-lead ECG. The 12-lead ECG will be reviewed live by study 
personnel. AF subjects must be in AF at the time of the 12-lead ECG in order to be assigned to 
the AF population. If subjects are not in AF at the time of the 12-lead screening ECG, they may 
be re-screened for participation at a later date. 
 
If any of the study staff believe the vital signs or screening 12-lead ECG are of poor quality, they 
may repeat the measurements. 
 
Day of participation 
• No special preparation for this visit is required. 
• All subjects may take their normal medications the day of the study. 
• All subjects may eat normally. 
• All subjects will be asked to remove jewelry and any underwire bras during active data 
collection. 
• It is recommended that participants wear t-shirt and shorts during data collection. 
 
Study Procedures 
Data collection device set up: The data collection device consists of two dry electrodes built into 
a smartwatch. It allows for the collection of raw single-lead ECG data that are then processed by 

 
 
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the software under testing (SUT) to produce a Lead-1 ECG as well as a rhythm classification of 
the waveform. 
1. Hand subject a watch and ask subject to place it on his/her preferred wrist. Observe how 
the subject places the watch on their wrist. 
2. Assign a device to each subject and document the device number. 
3. Instruct the subject to choose his/her preferred wrist to wear the data collection device 
(DCD). The DCD can be worn on whichever side the subject prefers unless there is a 
skin condition on one wrist as noted above in the exclusion criteria, in which case, the 
device must be worn on the non-affected wrist. Record the subject’s choice of wrist. If 
the subject does not have a side preference or skin condition on one wrist, the device 
will be placed on the left wrist. 
4. Study staff will place the DCD on the study participant’s wrist (as indicated in 3.) The 
device should be fitted tightly enough that it does not move when the hand/wrist is 
shaken.  
5. Check band tightness for a snug fit and adjust as needed. 
6. Instruct the subject to read the provided instructions on how to record a single-lead 
ECG. The written instructions are: 
a) “It takes 30 seconds to record a measurement. It’s important to keep your arms 
still. Try resting them on a table or your leg. To begin recording rest your finger 
on the knob.” 
b) Practice data will be recorded. 
7. After the first practice run, site study staff will guide subject to appropriate study posture 
and grip (if not achieved independently during the first test run). 
8. Allow subject up to three additional practice runs if more practice runs are needed to 
ensure study posture and grip instruction understanding (fewer than 3 additional practice 
runs are acceptable if study posture and grip are correct and subject is comfortable with 
the positioning), 
9. Record the number of practice runs completed by the subject. First practice run data and 
number of practice runs completed by the subject will be used to determine ease of use. 
 
Data collection: 
10. Instruct subject to remain seated for a 5-minute resting period prior to collecting three 
12-lead ECGs and set the reference system to 40 Hz filter. Use standard placement of all 
12-lead electrodes (with limb lead for Lead 1). 
11. Collect 3 separate complete 12-lead ECGs (review to ensure there is no artifact). Each 
recording will be approximately 30 seconds in duration with a 1-minute rest period 
between each recording (i.e., 1 minute between the end of the previous recording and the 
start of the next recording). Simultaneously, instruct the subject to record 3 separate 
complete single-lead ECGs using the DCD. A total of three complete single-lead ECGs 

 
 
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will be collected for each subject. Each recording will be approximately 30 seconds in 
duration with a 1-minute rest period between each recording (i.e., 1 minute between the 
end of the previous recording and the start of the next recording). Each recording will 
correspond to the time of collection of each 12-lead ECG recording.  
a) Monitor the 12-lead waveform to ensure a good quality recording is obtained. 
b) Monitor the waveform from the Lead 1 ECG from the DCD, between ECG 
recordings, provide feedback to the subject on how to improve the reading. 
12. After data collection, instruct study subjects to rate the ease of use of the DCD on a scale 
of 1-5 (1 being Unable to Use, 2 being Below Average Ease of Use, 3 being Average 
Ease of Use, 4 being Above Average Ease of Use, 5 being Easiest to Use). Record the 
rating in the eCRF. Remove DCD from subject. 
13. Instruct study subjects to apply and simulate a recording with each of the other devices 
 to rate the comfort and ease of use of 
each of these devices on a scale of 1-5 (scale is listed above in #10). Record the ratings.  
Data Processing: 
14. The Sponsor will receive data files from: 
a) The reference device 12-lead ECG files  
b) Raw data DCD files  
15. The Sponsor will check data for Protocol and MOP adherence. 
16. For Part A (described below), the Sponsor will sync Lead 1 of the 12-lead (reference 
strip) to the corresponding SUT’s strip to ensure that the same beats from each subject 
are presented.  
17. The Sponsor will provide a PDF of the full 30-second strip of both the reference strips 
and the SUT’s strips on the standard clinical ECG scale to Cardiac Core Lab (for each of  
Part A, Part B-1, and Part B-2). 
18. Cardiac Core Lab will print the strips for analysis and distribute to appropriate experts 
for review. 
Data Review by Cardiac Core Lab: (refer to Operations Plan/Imaging Charter) 
19. Part A (To address Objective 2a): Analysis of paired sets of strips. 
a) The Sponsor will prepare one paired set of strips from approximately 140 
randomly selected subjects (70 AF, 70 SR) (approximate strips = 280) 
i. 
One set includes a Lead 1 strip from the 12-lead and a paired strip from 
the SUT.  
ii. 
The first reading from data collection will be used for all subjects. 
b) Cardiac Core Lab review: 

 
 
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i. 
Three independent cardiac technicians will review each paired set of 
strips. The strips will be rendered semi-transparent through the use of back 
lighting and overlaid to visually assess for morphological similarity.  
ii. 
One reviewer will identify the first six consecutive distinct readable 
PQRST complexes without artifact that match between the strips for 
evaluation. For example, if the reference strip has an artifact in beats 2 and 
5 but all other beats are good and the strip from the SUT has artifact in 
beats 1 and 6 but all other beats are good, the six consecutive beats to be 
used will begin at beat 7 of both strips. The strip will be excluded if six 
consecutive beats cannot be found. The six PQRST complexes identified 
by the initial reviewer will be used by the 2 other reviewers. 
iii. 
Each reviewer will assign a pass/fail to the strips by visually assessing all 
6 PQRST complexes. A “pass” is given when the morphology of the 
PQRST complexes appears to overlay to the unaided eye. 
iv. 
Measure R amplitude from the isoelectric baseline to the nearest 
millimeter for the first two QRS complexes in both the reference strip and 
SUT strip (reviewers will be blinded to the identity of the reference strip 
and SUT strip). Record these lengths.  
20. Part B-1 (To address Objective 1): Analysis of reference strips. 
a) The first reading from 12-lead ECG data collection will be used for all subjects 
(total strips = ~560). In the event that the planned sample size for analysis is not 
obtained due to a higher than expected amount of data loss, the 2nd and 3rd reading 
from data collection may be used as described in the statistical analysis plan 
(SAP). 
b) A pool of 3 to 9 blinded independent U.S. board-certified cardiologists will 
review each complete 12-lead ECG (reference strip) and provide a diagnosis of 
the rhythm. (i.e. Each reference strip will be reviewed independently 3x)  
c) The diagnosis of the rhythm will fall into one of four categories  
i. 
Sinus rhythm (SR) 
ii. 
AF  
iii. 
Other specific diagnoses should be called out (examples include normal 
sinus with premature ventricular contraction [PVC] (if ≥4 beats in the 
strip), normal sinus with PACS, 2nd degree block, AF with a rate >150 
bpm, supraventricular tachycardia [SVT], etc.) 
iv. 
Unreadable = a diagnosis cannot be made as the strip is not adequate for 
reading. 
21. Part B-2: Analysis of SUT’s strips. 
a) The first reading from the SUT’s Lead I ECG will be used for all subjects (total 
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b) A pool of 2 to 5 blinded independent cardiologists will review each of the SUT’s 
strips (single-lead ECG strip generated by the Sponsor’s system) and provide a 
diagnosis. Diagnoses are listed above under #20c (total strips = ~560) 
22. Part C: Algorithm classification 
a) The Sponsor will generate a rhythm classification (through use of the algorithm) 
for the strips that match those strips analyzed in Part B-1 from the SUT for all 
subjects. (hereon referred to as algorithm classification) (total strips = ~560) 
b) The rhythm classification generated by the algorithm will fall into one of four 
categories:  
v. 
Sinus rhythm (SR) 
vi. 
AF  
vii. 
Unclassifiable = Other specific diagnoses which are not AF or SR 
(examples include normal sinus with premature ventricular contraction 
[PVC] (if ≥4 beats in the strip), normal sinus with PACS, 2nd degree 
block, AF with a rate >150 bpm, supraventricular tachycardia [SVT], etc.) 
viii. 
Unreadable = a classification cannot be made as the strip is not adequate 
for reading. 
c) The Cardiac Core Lab will not review the rhythm classifications. 
 
Required equipment 
Sponsor-provided 
Data collection device (DCD) for single-lead ECG collection  
Hardware to view single-lead ECG waveforms during data collection 
Assortment of other devices for simulation 
a) Commercially available wrist-worn device 
 
b) Commercially available handheld device 
 and 
companion device (tablet/phone/iPod) 
 
Contract Research Organization (CRO)-provided 
• 12-lead ECG monitor: GE Healthcare CardioSoft system. CardioSoft is an FDA-cleared 
ECG device (K031561). 
• Secure Network Attached Storage (NAS) 
Investigational Study Site - provided 
• Space to screen subjects 

 
 
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• Space to conduct testing and regular exam room/office equipment 
• Equipment to record vital signs 
• Appropriate safe and storage area for devices. 
 
 
Statistical Analyses 
Details of planned statistical analyses are included in the body of the protocol (Section 5.3). 

 
 
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TABLE OF CONTENTS 
SYNOPSIS................................................................................................................................. 4 
LIST OF ABBREVIATIONS ................................................................................................. 15 
1. INTRODUCTION .............................................................................................................. 17 
1.1. Background ................................................................................................................. 17 
1.2. Device Description ...................................................................................................... 17 
1.3. Study Rationale ........................................................................................................... 17 
1.4. Risk/Benefit Assessment ............................................................................................. 18 
2. STUDY OBJECTIVES, ENDPOINTS, AND HYPOTHESES ......................................... 19 
2.1. Study Objectives ......................................................................................................... 19 
2.2. Study Endpoints .......................................................................................................... 19 
2.3. Study Hypotheses ........................................................................................................ 19 
3. STUDY DESIGN ................................................................................................................ 20 
3.1. Overview .................................................................................................................... 20 
3.2. Required Equipment.................................................................................................... 20 
3.2.1. Sponsor-provided ............................................................................................ 20 
3.2.2. Contract Research Organization (CRO)-provided ............................................ 21 
3.3. Qualification Criteria for ECG Operators and Independent Cardiologists .................... 21 
3.4. Randomization and Blinding ....................................................................................... 21 
3.5. Duration of Subject Participation................................................................................. 21 
4. STUDY POPULATION ..................................................................................................... 22 
4.1. Number of Subjects and Subject Recruitment .............................................................. 22 
4.2. Study Cohorts and Target Population .......................................................................... 22 
4.3. Inclusion Criteria ........................................................................................................ 22 
4.4. Exclusion Criteria ....................................................................................................... 22 
4.5. Subject Withdrawal and Replacement ......................................................................... 24 
4.6. Subject Follow up ....................................................................................................... 24 
5. STUDY PROCEDURES .................................................................................................... 25 
5.1. Screening .................................................................................................................... 25 
5.2. Day of Participation .................................................................................................... 26 
5.2.1. Study Procedures ............................................................................................. 26 
5.2.1.1. Data Collection Device Set up ................................................................ 26 
5.2.1.2. Data Collection ...................................................................................... 27 
5.2.1.3. Data Processing ...................................................................................... 27 
5.2.1.4. Data Review by Cardiac Core Lab .......................................................... 28 
5.3. Statistical Methodology and Determination of Sample Size ......................................... 30 
5.3.1. Primary Objective/Endpoint ............................................................................ 30 
5.3.2. Secondary Objectives/Endpoints ...................................................................... 30 
6. SAFETY PARAMETERS AND ASSESSMENT .............................................................. 33 
6.1. Adverse Events ........................................................................................................... 33 

 
 
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6.2. Serious Adverse Event ................................................................................................ 33 
6.2.1. AE/SAE Collection ......................................................................................... 33 
6.2.2. SAE Reporting ................................................................................................ 33 
6.3. Intensity of Adverse Events ......................................................................................... 34 
6.4. Causal Relationship Assessment ................................................................................. 34 
6.5. Outcome ..................................................................................................................... 34 
6.6. Safety Plan .................................................................................................................. 35 
7. REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ......... 36 
7.1. Institutional Review Board .......................................................................................... 36 
7.2. Informed Consent ........................................................................................................ 36 
7.3. Ethical Conduct of Study ............................................................................................ 36 
7.4. Confidentiality and Privacy ......................................................................................... 36 
7.5. Data Collection and Management Responsibilities ...................................................... 37 
7.6. Study Monitoring ........................................................................................................ 37 
7.7. Data Quality Assurance and Quality Control ............................................................... 38 
7.8. Use of Information ...................................................................................................... 38 
7.9. Study Termination and Site Closure ............................................................................ 38 
7.10. 
Completion of the Study ....................................................................................... 39 
8. REFERENCES ................................................................................................................... 40 
 
 

 
 
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LIST OF ABBREVIATIONS 
The following abbreviations are used in this study protocol. 
Abbreviations and Definitions of Terms 
Abbreviation or Specialist Term 
Explanation 
AF 
atrial fibrillation 
CRO 
contract research organization 
DCD 
Data Collection Device 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
HCP 
healthcare provider 
HIPAA 
Health Insurance Portability and Accountability Act of 
1996 
ICD 
implantable cardioverter-defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
MI 
myocardial infarction 
Ms 
millisecond(s) 
NAS 
Network Attached Storage 
NSR 
normal sinus rhythm 
PAC 
premature atrial contraction 
PQRST 
A full beat on the ECG including the p wave, QRS 
complex, and T wave. 
PVC 
premature ventricular contraction 

 
 
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Abbreviation or Specialist Term 
Explanation 
QC 
quality control 
R amplitude 
The height of the R wave measured from the baseline 
to the peak of the R wave.  
SUT 
Software under development 
SVT 
supraventricular tachycardia 
US 
United States 

 
 
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1. 
INTRODUCTION 
1.1. 
Background 
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and when left untreated, is a 
leading cause of morbidity and mortality from stroke, heart failure and myocardial infarctioni,ii. 
Data from the Framingham Heart Study indicates that by age 40 years, lifetime risk for 
developing AF is 1 in 4iii. AF is also a growing public health problem with prevalence projected 
to triple between 2010 and 2050, with an estimated 12.1 million diagnosed cases in 2030 in the 
United States (US) aloneiv.  
Early detection and treatment of patients with AF minimizes the risk of sequelae of 
thromboembolism including >60% reduced risk of strokeii,v. However, many affected with AF 
are unaware they have this dysrhythmia due to a number of factors including lack of symptoms, 
or experience only mild symptoms that they do not attribute to a diseaseii. As a result, 
asymptomatic patients are 3 times as likely to have sustained an ischemic stroke prior to 
diagnosis than those with symptomsi,vi. These findings raise concerns and have prompted several 
variations of screening programs to detect patients with asymptomatic AF to prevent an embolic 
eventi,ii. While systematic and opportunistic screening programs have demonstrated increased 
rates of detection when compared to detection during routine clinical practice, such screening 
programs are not yet widely implementedii. Additionally, AF may be paroxysmal (PAF, or 
intermittent AF) and therefore missed by recording a single in-clinic electrocardiogram (ECG). 
This is especially true for those patients with intermittent symptoms. Holter devices are 
commonly used for ambulatory 24-hour ECG monitoring in at-risk patients, but have limited 
sensitivity for the detection of new AFvii. Given that mobile ECG devices permit an on-demand 
assessment by a user, our hypothesis is that the SUT can facilitate identification of AF. 
1.2. 
Device Description 
The data collection device includes electrodes that can be used to obtain heart rate and lead I 
ECG information. A user can use the device to take an ECG measurement by wearing it on their 
wrist while placing the finger of the opposing hand on an accessible electrode of the device.  
The software under testing analyzes the acquired single channel ECG signals and detects the 
presence of AF and SR for each ECG recording. 
1.3. 
Study Rationale 
AF increases the risk of heart failure by 11 per 1000, kidney problems by 6 per 1000, death by 
4 per 1000, stroke by 3 per 1000, and coronary heart disease by 1 per 1000. However, if 
detected, treatment of AF with oral anticoagulation is effective in reducing stroke risk by 
approximately two-thirds and death by almost one-third. Studies have shown that systematic 
screening, where an ECG is taken for all patients, yields a higher rate of AF detection when 
compared to opportunistic screening, where an ECG is taken only if the standard pulse taking 
yields an irregular pulse. Therefore, widespread screening for AF by an easy-to-use device can 
potentially result in improved detection, leading to more effective treatment and improving  

 
 
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health outcomes. The purpose of this study is to aid in the development of a system that reads 
ECG signals and is capable of detecting AF.  
1.4. 
Risk/Benefit Assessment 
No significant risks or permanent side effects are anticipated. However, participants may 
experience temporary discomforts or have risks while or as a result of participating in this study.  
• 
Subjects may experience slight to moderate discomfort associated with attachment and 
removal of adhesive electrodes as well as mild skin irritation from the wristband of the 
data collection device. The risk will be minimized by using medical-grade disposable 
electrodes and both electrodes and wrist bands will be attached to the skin only for the 
limited study duration. Temporary skin irritation may still occur locally at the sites where 
the electrodes are placed or the band is worn, and will not be recorded as an Adverse 
Event.   
 

 
 
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2. 
STUDY OBJECTIVES, ENDPOINTS, AND HYPOTHESES 
2.1. 
Study Objectives 
The objectives of this study are: 
1) The primary objective is to demonstrate that the software under testing (SUT) has 
acceptable sensitivity and specificity.  
2) Secondary objectives are 
a. To demonstrate that the SUT produces a waveform that provides clinically 
equivalent information to the gold standard.  
b. To understand the ease of use between three different data collection devices. 
2.2. 
Study Endpoints 
The endpoints of this study are: 
1) Primary endpoints: Sensitivity, specificity 
2) Secondary endpoints: clinically equivalent waveform, ease of use 
2.3. 
Study Hypotheses 
The hypotheses of this study are: 
1) The primary hypothesis is that the SUT will have >90% sensitivity and >92% specificity 
in detecting AF on “readable and classifiable” strips generated by a single Lead I ECG. 
2) The secondary hypothesis is that the SUT produces a waveform that provides clinically 
equivalent information to the gold standard. 
 

 
 
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3. 
STUDY DESIGN 
3.1. 
Overview 
This is a non-invasive, 2-part, multi-center study. The purpose of this study is two-fold: 
1) To validate a rhythm classification algorithm and its ability to detect and classify heart 
rhythms into one of two categories (SR or AF) using a single Lead I ECG strip.  
2) To demonstrate that the SUT produces a waveform that provides clinically equivalent 
information to the gold standard.  
Eligible subjects will be enrolled and scheduled to attend a single day of participation at the 
clinic (Section 5.2). Subjects will wear the data collection device (DCD) on their wrist and 
record 3 single-lead ECGs using the DCD while the study staff simultaneously records three 12-
lead ECGs.  
In Part A of the study, 3 blinded, independent cardiac technicians will review paired sets of SUT 
strips and Reference strips from a subset of approximately140 randomly selected subjects (70 
SR; 70 AF) in order to address objective 2a (Section 2). The strips will be rendered semi-
transparent through the use of back lighting and overlaid to visually assess for morphological 
similarity. The cardiac technicians will assign a pass/fail to the strips by visually assessing 6 
consecutive readable PQRST complexes.  
In Part B-1 of the study, each 12-lead ECG reference strip will be reviewed 3x by blinded, 
independent U.S. board-certified cardiologists to provide a diagnosis of the rhythm according to 
the categories presented in Section 5.2.1.4, Item 20c.  
In Part B-2 of the study, at least 2, but up to 5 blinded, independent cardiologists will review 
each of the SUT’s strips (single-lead ECG strip generated by the Sponsor’s system) and provide 
a diagnosis of the rhythm according to the categories presented in Section 5.2.1.4, Item 20c. 
In Part C of the study, the Sponsor will generate a rhythm classification through the use of an 
algorithm (hereon referred to as algorithm diagnosis).  
3.2. 
Required Equipment 
All data collection devices and the SUT will be identical in design and function and will be 
returned to the Sponsor at the end of the evaluation.  
3.2.1. 
Sponsor-provided 
The Sponsor will provide the study sites with: 
• Data collection device (DCD) for single-lead ECG collection 
• Hardware to view single-lead ECG waveforms during data collection 
• Assortment of other devices for simulation 
a) Commercially available wrist-worn device 
 
b) Commercially available handheld device 
 and 

 
 
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companion device (tablet/phone/iPod) 
3.2.2. 
Contract Research Organization (CRO)-provided 
The CRO will provide: 
• 12-lead ECG monitor: GE Healthcare CardioSoft System. CardioSoft is a FDA cleared 
ECG device (K031561). 
• Secure Network Attached Storage (NAS) 
Investigational Study Site - provided 
• Space to screen subjects 
• Space to conduct testing and regular exam room/office equipment 
• Equipment to record vital signs 
• Appropriate safe and storage area for devices 
 
3.3. 
Qualification Criteria for ECG Operators and Independent 
Cardiologists 
Only individuals trained by the Sponsor or its designee(s) will be qualified to assume the role of 
an ECG operator or independent cardiology reviewer. ECG operators may include appropriately 
trained technicians, students, nurses, and/or physicians. Cardiac technicians must be Certified 
Cardiographic Technicians. Cardiology reviewers may include physicians experienced in reading 
ECG leads in order to make diagnostic determinations of adult patients. Cardiology reviewers 
must be a licensed medical doctor specialized in cardiology.  
Information regarding the specific training, years of experience, and specialty of each reviewer 
will be collected. 
3.4. 
Randomization and Blinding 
This study is not randomized.  
Cardiac technicians will be blinded in Part A and will not know which strip is the reference vs 
SUT strip. 
U.S. board-certified cardiologists in Part B-1 and board-certified in Part B-2 will be blinded to 
the subject’s past medical history and algorithm classification. 
3.5. 
Duration of Subject Participation 
Subjects will participate in a screening visit and, if eligible, participate in the study at the same 
visit. Participants with AF who are not in AF at the time of screening will be eligible for re-
screening and participation at a later date. 

 
 
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4. 
STUDY POPULATION 
4.1. 
Number of Subjects and Subject Recruitment 
Subject recruitment can be accomplished in any appropriate fashion, within the guidelines of the 
central Institutional Review Board (IRB). 
4.2. 
Study Cohorts and Target Population 
The study will include 2 cohorts:  
• A minimum of 260 subjects (up to a maximum of 400 subjects) with AF 
o 
A population of subjects with a known diagnosis of AF (permanent or 
persistent AF as the likelihood of being in AF during data collection is higher) 
• Approximately 300 subjects with SR 
o 
A population of subjects with no known diagnosis of AF 
• There is no age distribution requirement for the AF population. For subjects with SR, 
there will be at least 25 subjects in each of the 22-30, 31-50, 51-64 categories and at least 
150 subjects in the 65+ category. 
• Men and women should be equally represented between the two study cohorts with a goal 
of having women represent >30% of subjects. 
4.3. 
Inclusion Criteria 
Subjects must meet all the following inclusion criteria to be enrolled: 
1. Able to read, understand, and provide written informed consent 
2. Willing and able to participate in the study procedures as described in the consent form 
3. Individuals who are 22 years of age and older 
4. Able to communicate effectively with and follow instructions from the study staff 
5. Have a wrist circumference between 130 mm and 245 mm (measured at “band center” on 
the preferred wrist. This location is determined by asking the volunteer to put on a normal 
wrist-watch and marking the skin with a pen/marker to outline the edges of the band.) 
6. For subjects enrolled into the AF population, subjects must have a known diagnosis of 
AF and be in AF at the time of screening. Subjects may have any type of AF including 
paroxysmal, persistent, and permanent AF although persistent and permanent AF are 
preferred as they are more likely to be in AF at the time of screening. 
4.4. 
Exclusion Criteria 
Subjects who meet any of the following criteria may not be enrolled: 
1. Physical disability that precludes safe and adequate testing  
2. Mental impairment resulting in limited ability to cooperate  

 
 
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3. Subjects with a pacemaker or implantable cardioverter-defibrillator (ICD) 
4. Acute myocardial infarction (MI) within 90 days of screening or other cardiovascular 
disease that, in the opinion of the Investigator, increases the risk to the subject or renders 
data uninterpretable (e.g., recent or ongoing unstable angina, significant valvular heart 
disease or heart failure, myocarditis or pericarditis)  
5. Acute pulmonary embolism, pulmonary infarction, or deep vein thrombosis within 
90 days of screening  
6. Stroke or transient ischemic attack within 90 days of screening  
7. Subjects taking rhythm control drugs (e.g., disopyramide, quinidine, flecainide, 
propafenone, amiodarone, dofetilide, dronedarone, sotalol, procainamide, ibutilide, 
moricizine, procainamide). An exception will be made for subjects who are undergoing 
scheduled cardioversion for known AF within 30 days after study participation. These 
study participants will be allowed to participate in the study even when on rhythm control 
drugs. 
a. Rate control and anticoagulants, anti-platelet medications are permitted (e.g., 
metoprolol, atenolol, diltiazem, coumadin, clopidogrel, aspirin) 
8. Symptomatic (or active) allergic skin reactions such as eczema, rosacea, impetigo, 
dermatomyositis or allergic contact dermatitis on both wrists or over electrode attachment 
sites including known allergy or sensitivity to fluoroelastomer bands primarily used in 
wrist worn fitness devices  
9. Known sensitivity to medical adhesives, isopropyl alcohol, watch bands, or 
electrocardiogram (ECG) electrodes 
10. A history of abnormal life-threatening rhythms a determined by the investigator (e.g., 
ventricular tachycardia, ventricular fibrillation, 3rd-degree heart block, resting heart rate < 
50 bpm, resting heart rate >110 bpm) 
11. Significant tremor that prevents subject from being able to hold still 
12. Pregnant women: Women who are pregnant at the time of study participation. 
13. 
 
 
14. 
 
 
 
15. For subjects enrolled into the sinus rhythm population, they must not have any diagnosis 
of AF. For example, subjects cannot be enrolled into the sinus rhythm population if they 
have a diagnosis of paroxysmal AF but during screening are in sinus rhythm. 

 
 
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4.5. 
Subject Withdrawal and Replacement 
A consented, enrolled subject may withdraw from the study for any reason. Subjects who 
withdraw prior to participation or who fail to complete study participation will be replaced.  
4.6. 
Subject Follow up 
After completion of study participation, the subject is discharged from the study with no 
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5. 
STUDY PROCEDURES 
5.1. 
Screening 
Informed consent will be obtained before any study protocol-directed procedures are performed. 
After the signing of informed consent, the subject will be evaluated for eligibility according to 
the study inclusion/exclusion criteria (Section 4.3 and Section 4.4).  
During screening, the following should be obtained on each subject 
• 
Age 
• 
Gender 
• 
Race and ethnicity 
• 
Occupation 
• 
Diagnosed medical conditions 
• 
Medications 
• 
Allergies 
• 
Smoking history 
• 
Alcohol Use (self reported) 
• 
Recreational Drug Use (self reported) 
• 
Brief physical exam 
• 
Height and weight 
• 
Body mass index (BMI) 
• 
Vital signs will be collected after sitting for at least 5 minutes (blood pressure with 
systolic recorded within the range of 80-180 mm Hg and diastolic recorded in the 
range of 40-120 mmHg, heart rate recorded within the range from 50-110 beats per 
minute, temperature recorded within range of 35.5-37.5 degrees) 
• 
Urine Pregnancy testing for women of childbearing potential 
• 
Caffeine intake 
• 
Exercise habits 
• 
Dominant hand 
• 
Wrist circumference (for wrist that device will be worn on) 
• 
Skin fold thickness (for wrist that device will be worn on) 
• 
Wrist hairiness (for wrist that device will be worn on) 
• 
12-lead ECG will be collected supine after lying for at least 5 minutes 

 
 
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All volunteers will undergo a 12-lead ECG. The 12-lead ECG will be reviewed live by study 
personnel. AF subjects must be in AF at the time of the 12-lead ECG in order to be assigned to 
the AF population. If subjects are not in AF at the time of the 12-lead screening ECG, they may 
be re-screened for participation at a later date. 
If any of the study staff believe the vital signs or screening 12-lead ECG are of poor quality, they 
may repeat the measurements. 
5.2. 
Day of Participation 
Subjects will report to the clinic for evaluation at their scheduled date and time. No special 
preparation for this visit is required. All subjects may take their normal medications on the 
day of the study and may eat normally the day of participation. Participants will be asked to 
remove jewelry and any underwire bras during active data collection. It is recommended that 
participants wear t-shirt and shorts during data collection. 
5.2.1. 
Study Procedures  
5.2.1.1. 
Data Collection Device Set up 
The following procedures will be performed for each study subject at study participation:  
1. Hand subject a watch (regular wristwatch) and ask subject to place it on his/her preferred 
wrist. Observe how the subject places the watch on their wrist. 
2. Assign a device to each subject and document the device number. 
3. Instruct the subject to choose his/her preferred wrist to wear the data collection device 
(DCD). The DCD can be worn on whichever side the subject prefers unless there is a skin 
condition on one wrist as noted above in the exclusion criteria, in which case, the device 
must be worn on the non-affected wrist. Record the subject’s choice of wrist. If the 
subject does not have a side preference or skin condition on one wrist, the device will be 
placed on the left wrist. 
4. Study staff will place the DCD on the study participant’s wrist (as indicated in 3.). The 
device should be fitted tightly enough that it does not move when the hand/wrist is 
shaken.  
5. Check band tightness for a snug fit and adjust as needed. 
6. Instruct the subject to read the provided instructions on how to record a single-lead ECG. 
The written instructions are: 
a) “It takes 30 seconds to record a measurement. It’s important to keep your arms 
still. Try resting them on a table or your leg. To begin recording rest your finger 
on the knob.” 
b) Practice data will be recorded. 
7. After the first practice run, site study staff will guide subject to appropriate study posture 
and grip (if not achieved independently during the first test run). 

 
 
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8. Allow subject up to three additional practice runs if more practice runs are needed to 
ensure study posture and grip instruction understanding (fewer than 3 additional practice 
runs are acceptable if study posture and grip are correct and subject is comfortable with 
the positioning), 
9. Record the number of practice runs completed by the subject. First practice run data and 
number of practice runs completed by the subject will be used to determine ease of use. 
 
5.2.1.2. 
Data Collection 
10. Instruct subject to remain seated for a 5-minute resting period prior to collecting three 
12-lead ECGs and set the reference system to 40 Hz filter. Use standard placement of all 
12-lead electrodes (with limb lead for Lead 1). 
11. Collect 3 separate complete 12-lead ECGs (review to ensure there is no artifact). Each 
recording will be approximately 30 seconds in duration with a 1-minute rest period 
between each recording (i.e., 1 minute between the end of the previous recording and the 
start of the next recording). Simultaneously, instruct the subject to record 3 separate 
complete single-lead ECGs using the DCD. A total of three complete single-lead ECGs 
will be collected for each subject. Each recording will correspond to the time of 
collection of each 12-lead ECG recording.  
c) Monitor the 12-lead waveform to ensure a good quality recording is obtained. 
d) Monitor the waveform from the Lead 1 ECG from the DCD, between ECG 
recordings, provide feedback to the subject on how to improve the reading. 
12. After data collection, instruct study subjects to rate the ease of use of the DCD on a scale 
of 1-5 (1 being Unable to Use, 2 being Below Average Ease of Use, 3 being Average 
Ease of Use, 4 being Above Average Ease of Use, 5 being Easiest to Use). Record the 
rating in the eCRF. Remove DCD from subject. 
13. Instruct study subjects to apply and simulate a recording with each of the other devices 
 to rate the comfort and ease of use of 
each of these devices on a scale of 1-5 (Scale is listed above under #10). Record the 
ratings.  
5.2.1.3. 
Data Processing 
14. The Sponsor will receive data files from: 
a) The reference device 12-lead ECG files 
b) Raw data DCD files  
15. The Sponsor will check data for Protocol and MOP adherence.  
16. For Part A (described below), the Sponsor will sync Lead 1 of the 12-lead (reference 
strip) to the corresponding SUT’s strip to ensure that the same beats from each subject 
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17. The Sponsor will provide a portable document format (PDF) of the full 30-second strip of 
both the reference strips and the SUT’s strips on the standard clinical ECG scale to 
Cardiac Core Lab (for both Part A, Part B-1, and Part B-2). 
18. Cardiac Core Lab will print the strips for analysis and distribute to appropriate experts for 
review. 
 
5.2.1.4. 
Data Review by Cardiac Core Lab (refer to Operations Plan/ Imaging Charter) 
19. Part A (To address Objective 2a): Analysis of paired sets of strips. 
a) The Sponsor will prepare one paired set of strips from approximately 140 
randomly selected subjects (70 AF, 70 SR) (approximate strips = 280 strips) 
i. 
One set includes a Lead 1 strip from the 12-lead and a paired strip from 
the SUT. 
ii. 
The first reading from data collection will be used for all subjects. 
b) Cardiac Core Lab review: 
i. 
Three blinded, independent cardiac technicians will review each paired set 
of strips. The strips will be rendered semi-transparent through the use of 
back lighting and overlaid to visually assess for morphological similarity.  
ii. 
One reviewer will identify the first six consecutive distinct readable 
PQRST complexes without artifact that match between the strips for 
evaluation. For example, if the reference strip has an artifact in beats 2 and 
5 but all other beats are good and the strip from the SUT has artifact in 
beats 1 and 6 but all other beats are good, the six consecutive beats to be 
used will begin at beat 7 of both strips. The strip will be excluded if six 
consecutive beats cannot be found. The six PQRST complexes identified 
by the initial reviewer will be used by the 2 other reviewers. 
iii. 
Each reviewer will assign a pass/fail to the strips by visually assessing all 
6 PQRST complexes. A “pass” is given when the morphology of the 
PQRST complexes appears to overlay to the unaided eye. 
iv. 
Measure R amplitude from the isoelectric baseline to the nearest 
millimeter for the first two QRS complexes in both the reference strip and 
SUT strip. The reviewers will be blinded to the identity of the reference 
strip and SUT strip. Record these lengths.  
 
20. Part B-1 (To address Objective 1): Analysis of reference strips. 
a) The first reading from 12-lead ECG data collection will be used for all subjects 
(total strips = ~560). In the event that the planned sample size for analysis is not 
obtained due to a higher than expected amount of data loss, the 2nd and 3rd reading 
from data collection may be used as described in the statistical analysis plan 
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b) Three U.S. board-certified cardiologists out of a pool of nine cardiologists will 
review each complete 12-lead ECG (reference strip) and provide a diagnosis of 
the rhythm. (i.e. each reference strip will be reviewed independently 3x)  
c) The diagnosis of the rhythm will fall into one of four categories:  
i. 
Sinus rhythm (SR) 
ii. 
AF  
iii. 
Other specific diagnoses should be called out (examples include normal 
sinus with premature ventricular contraction [PVC] (if ≥4 beats in the 
strip), normal sinus with PACS, 2nd degree block, AF with a rate >150 
bpm, supraventricular tachycardia [SVT], etc.) 
iv. 
Unreadable = a diagnosis cannot be made as the strip is not adequate for 
reading. 
 
21. Part B-2: Analysis of SUT’s strips. 
a) The first reading from the SUT’s Lead I ECG will be used for all subjects (total 
strips = ~560). 
b) Two cardiologists out of a pool of five blinded, independent cardiologists will 
review each of the SUT’s strips (single-lead ECG strip generated by the Sponsor’s 
system) and provide a diagnosis. Diagnoses are listed above (Item #20Error! 
Reference source not found. (total strips = ~560) 
 
22. Part C: Algorithm classification 
a) The Sponsor will generate a rhythm classification (through use of the algorithm) for 
the strips that match those strips analyzed in Part B-1 from the SUT for all subjects. 
(hereon referred to as algorithm classification) (total strips = ~560) 
b) The rhythm classification generated by the algorithm will fall into one of four 
categories:  
i. 
Sinus rhythm (SR) 
ii. 
AF  
iii. 
Unclassifiable = Other specific diagnoses which are not AF or SR 
(examples include normal sinus with premature ventricular contraction 
[PVC] (if ≥4 beats in the strip), normal sinus with PACS, 2nd degree 
block, AF with a rate >150 bpm, supraventricular tachycardia [SVT], etc.) 
iv. 
Unreadable = a classification cannot be made as the strip is not adequate 
for reading. 
c) The Core Cardiology Lab will not review the classifications. 
 

 
 
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STATISTICAL ANALYSIS  
5.3. 
Statistical Methodology and Determination of Sample Size 
5.3.1. 
Primary Objective/Endpoint 
The primary endpoints of this study are the sensitivity in detecting AF and specificity in 
detecting SR on readable/ classifiable strips (i.e., resulting in a diagnosis of AF or SR) generated 
by the single Lead I ECG of the SUT using the 12-lead ECG monitor GE Healthcare CardioSoft 
ECG device (K031561) as the Reference. The primary hypotheses for sensitivity and specificity 
are as follows: 
 
H01: ΠSen = 0.90  
vs.  
HA1: ΠSen > 0.90 
 
H02: ΠSpec = 0.92 
vs.  
HA2: ΠSpec > 0.92 
 
5.3.2. 
Secondary Objectives/Endpoints 
Two hypotheses associated with secondary objective 2a to demonstrate that the SUT produces a 
waveform that provides clinically equivalent information to the gold standard Reference will also 
be tested.   
 
The first hypothesis is aimed at demonstrating that the proportion of subjects with a pass rating 
based on the visual assessment of 6 consecutive readable PQRST complexes is at least 80%.  
The majority result from the pass/fail readings of the three independent cardiac technicians will 
be used for analysis. The hypothesis for this objective can be stated as follows: 
 
H03: Π1 = 0.80 
vs.  
HA3: Π1 > 0.80  
 
where Π1 represents the true population subject success proportion of pass ratings.  
 
The second hypothesis associated with objective 2a is based on the results of the quantitative 
analysis of the R-wave amplitudes as measured by each of three cardiac technicians on the paired 
SUT and Reference strips in Part A.  The majority result from the three technicians (i.e., if at 
least two technicians measure the  difference in amplitudes between the SUT and reference strip 
to be ≤2mm, then the paired strips for a given subject will be deemed ≤2mm) will be used for 
testing the hypothesis that the proportion of paired R-Wave amplitude measurements ≤ 2 mm of 
each other is at least 80% 
 
H04: Π2 = 0.80 
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HA4: Π2 > 0.80  
 
where Π2 represents the true population agreement proportion of paired R-Wave amplitude 
measurements. For each participant, the QRS complex from the 12-lead ECG with the largest R 
amplitude (out of the two QRS complexes with R-wave amplitude measurements will be used for 
purposes of determining the majority result.  
5.3.3 Sample Size 
Under the assumption that the true population sensitivity is 95%, 231 subjects who are diagnosed 
with AF based on the 12-lead ECG reference strip and where the device algorithm classification 
produces a result of AF or SR will provide at least 80% power to reject its null hypothesis, H01, 
using a one-sided type I error of 0.025. Moreover, under the assumption that the true population 
specificity is 96.5%, 226 subjects who are diagnosed with SR based on the 12-lead ECG reference 
strip and where the device algorithm classification produces a result of AF or SR will provide at 
least 80% power to reject its null hypothesis, H02, using a one-sided type I error of 0.025. To 
account for obtaining readable waveforms, a minimum of 260 subjects with a known diagnosis of 
AF and approximately 300 subjects with no known diagnosis of AF will be enrolled.  The sample 
size for AF subjects may be increased if the unreadable/unclassifiable rate is higher than originally 
assumed up to a maximum of 400 enrolled AF subjects. 
 
For the secondary objective hypothesis, H03, under the assumption that the true population 
subject success rate is 90%, 88 subjects will provide at least 80% power to reject its null 
hypothesis using a one-sided type I error of 0.05. To account for obtaining readable waveforms, 
approximately 140 subjects (70 SR; 70 AF) will be randomly selected. 
 
5.3.4  Randomization and Blinding 
This study is not randomized. Cardiac technicians will be blinded in Part A and will not know 
which strip is the Reference vs SUT strip. U.S. board-certified cardiologists in Part B-1 and 
board-certified cardiologist in Part B-2 will be blinded to the subject’s past medical history and 
algorithm classification.  
 
Approximately 140 subjects (70 SR; 70 AF) will be randomly selected to address objective 2a in 
Part A using a systematic sampling approach.  A number between 1 and 4 will be randomly 
selected for the AF cohort and then every 4th consecutively enrolled AF subject will be selected 
at random within each site. Likewise, a number between 1 and 4 will be randomly selected for 
the SR cohort and then every 4th consecutively enrolled SR subject will be selected at random 
within each site. 
 
5.3.5  Significance Level 
The primary hypothesis tests of sensitivity and specificity will use a one-sided significance level 
of 0.025. The hypothesis tests, H03, and H04, associated with the secondary objectives will use a 
one-sided significance level of 0.05.  Multiple comparison corrections will not be used.   
 
5.3.6  Missing Data/Outliers 

 
 
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Rigorous efforts will be made to ensure all subjects are compliant with the protocol.  However, 
some subjects may drop out prematurely or some planned measurements may not be readable or 
obtainable.  The data analyses will be conducted on all readable/classifiable data.  Outliers may be 
removed from the analyses after investigation by the sponsor and biostatistician; any removal of 
data points from the analyses will be documented in the CSR.  No outliers will be removed from 
the analyses of the primary or secondary endpoints. 
 
 
5.3.7  Subgroup Analyses 
In accordance with the FDA Guidance8 on the reporting of age-, race-, and ethnicity-specific 
data, the sensitivity and specificity (primary endpoint) will be reported by the following 
subgroups (data permitting).  Some subgroups may be combined depending on data availability. 
 
• 
Age group (22-30, 31-50, 51-64, and 65+) 
• 
Sex (M/F) 
• 
Race (White; Black or African American; Asian; American Indian or Alaska Native; 
Native Hawaiian or other Pacific Islander) 
• 
Ethnicity (Hispanic or Latino; Not Hispanic or Latino) 
 
5.3.8  Interim Analyses 
There are no interim analyses planned in this study.  There will be a planned interim data transfer 
after enrollment of 50 subjects for study progress monitoring purposes. None of the study 
hypotheses will be tested at this interim data transfer. 
5.3.9 ANALYSIS SETS 
Based on the results of the 12-lead ECG at screening, a minimum of 260 subjects are targeted to 
be enrolled into an AF cohort and approximately 300 subjects are targeted to be enrolled into a 
SR cohort to address objective 1.  Approximately 140 of these subjects (70 SR; 70 AF) will be 
randomly selected to address objective 2a in Part A.  The following analysis sets are defined for 
this study.   
 
All Enrolled Analysis Set: All subjects who sign informed consent and are enrolled into the 
study. This analysis set will be used to summarize subject and ECG measurement accountability, 
demographic and baseline characteristics, safety data, and the ease of use data. 
 
Classifiable Analysis Set: All subjects who have readable/classifiable paired SUT and Reference 
strip from Parts C and B-1, respectively.  This analysis set will be used for analyzing the primary 
endpoints of sensitivity and specificity. 
 
Waveform Assessment Analysis Set: Randomly selected subjects in Part A with paired SUT and 
Reference strips.  If 6 consecutive paired beats for analysis cannot be found in these strips, they 
will be excluded from further analysis.  This analysis set will be used for assessing the quality of 
the clinical waveform associated with secondary objective 2a.  

 
 
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6. 
SAFETY PARAMETERS AND ASSESSMENT 
6.1. 
Adverse Events  
The definition of adverse events are as follows, 
Adverse event - An adverse event is any untoward medical occurrence in a study subject which 
does not necessarily have to have a causal relationship with the study procedures.  
An AE can therefore be any clinically significant sign (including an abnormal laboratory finding, 
for example), symptom, or disease temporally associated with the study procedures, whether or 
not considered related to the study procedures.  
6.2. 
Serious Adverse Event  
A serious adverse event (SAE) is any untoward medical occurrence that:  
• Results in death  
• Is life-threatening (defined as an event in which the subject was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have 
caused death if it were more severe)  
• Requires inpatient hospitalization or causes prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity  
• Is a congenital anomaly/birth defect  
• Is an important medical event that may jeopardize the subject or may require 
intervention [e.g. medical, surgical] to prevent one of the other serious outcomes 
listed in the definition above.  
Unanticipated Adverse Event - Any serious adverse effect on health or safety or any  
Life-threatening problem  or  death  caused  by,  or  associated  with  the  study  treatment,  if 
that effect, problem, or death was not previously identified in nature, severity, or degree  
of incidence in the investigational plan or application, or any other unanticipated serious  
problem associated with a device that relates to the rights, safety, or welfare of the patient. 
 
6.2.1. 
AE/SAE Collection  
All adverse events must be fully recorded throughout the entire study period, whether they are 
considered to be related to the study procedures or not. Signs and symptoms of each AE should 
be described in detail: onset time and date, offset time and date, description of event, severity, 
relationship to study procedures, action taken and outcome. Adverse events will be collected as 
spontaneously reported by the subjects.  
6.2.2. 
SAE Reporting  
SAEs occurring on this study will be reported by the Investigator to the Sponsor and the IRB 
within 24 hours of becoming aware of the event. The Investigator will be requested to complete a 
separate SAE reporting form in addition to the information in the source documentation.   

 
 
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6.3. 
Intensity of Adverse Events  
The intensity of an AE will be categorized as follows:  
• 
Mild:  Events that are easily tolerated with no disruption of normal daily activity 
• 
Moderate:  Events that cause sufficient discomfort to interfere with daily activity 
• 
Severe:  Events that incapacitate and prevent usual activity  
6.4. 
Causal Relationship Assessment  
Causal relationship assessment to study procedures is required for purposes of reporting AEs. To 
promote consistency, the following guidelines should be taken into considerations along with 
good clinical and scientific judgment when determining the relationship of study procedures to 
an AE:  
• 
Definitely Related:  A clinical event, including laboratory test abnormality, occurring in 
a plausible temporal relationship to the study procedures, and which cannot be explained 
by concurrent disease or other drugs or chemicals. 
• 
Possibly Related:  A clinical event, including laboratory test abnormality, with a 
reasonable temporal relationship to the study procedures, but which could also be 
explained by concurrent disease or other drugs or chemicals. 
• 
Unlikely Related:  A clinical event, including laboratory test abnormality, with little or 
no temporal relationship to the study procedures, and which could be explained by 
concurrent disease or other drugs or chemicals. 
• 
Not Related: A clinical event, including laboratory test abnormality, that has no temporal 
relationship to the study procedures. 
Action Taken   
Action taken will be defined as:  
• 
None   
• 
Study procedures interrupted   
• 
Study procedures stopped  
6.5. 
Outcome 
Outcome will be defined as:   
• 
Resolved   
• 
Ongoing or stabilized and followed by private MD   
• 
Lost to follow up  

 
 
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6.6. 
Safety Plan  
The clinical staff is responsible for the ongoing safety and well-being of the subjects while they 
are in the clinical unit. Management of all medical complications arising during the course of the 
research study will be managed by the investigator as deemed appropriate. All incidental 
findings identified during screening will be referred at the investigator’s discretion to the 
appropriate additional care in accordance with current standard of care. This can include removal 
of the study associated devices, as well as other measures as required. Even if the study device is 
removed prior to the specified duration, data may be used if of suitable quality. Replacement of 
the study subject who has had the device removed prematurely will be as deemed appropriate, 
following review of the data.  
 

 
 
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7. 
REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
7.1. 
Institutional Review Board 
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
informed consent, and all other forms of subject- and reviewer-related materials be reviewed by 
an IRB. IRB approval of the protocol, informed consent and subject information and/or 
advertising will be obtained prior to study initiation. Any amendments to the protocol will 
require IRB approval prior to the implementation of any changes to the study design.  
7.2. 
Informed Consent 
All information about the study, including the subject information and the informed consent form 
(ICF), is prepared and used for the protection of the human rights of the subject according to 
International Conference on Harmonisation (ICH) GCP guidelines and the Declaration of 
Helsinki. 
It is the responsibility of the Investigator to obtain signed ICFs from each subject participating in 
this study after adequate explanation of the aims, methods, and objectives of the study and before 
undertaking any study-related procedures. 
The ICF, prepared by the Investigator with the assistance of the Sponsor, must be approved 
along with the study protocol by the IRB and be acceptable to the Sponsor. 
The subject must be provided with the subject information and ICF consistent with the study 
protocol version used and approved by the relevant IRB. The ICF must be in a language fully 
comprehensible to the prospective subject. Subjects (and/or relatives, guardians, or legal 
representatives, if necessary) must be given sufficient time and opportunity to inquire about the 
details of the study and to discuss and decide on their participation in the study with the 
Investigator concerned. The subject and the person explaining about the study and with whom 
they discuss the informed consent will sign and date the ICF. A copy of the signed and dated ICF 
will be retained by the subject and the original will be filed in the Investigator file unless 
otherwise agreed. New information will be provided in written form to the subject. 
7.3. 
Ethical Conduct of Study  
This study will be conducted in accordance with GCP guidelines. Trial documents should be 
retained until at least 2 years after the last approval of marketing application in an ICH region 
and until there are no pending or contemplated-marketing applications in an ICH region. If there 
are no local laws, sites should retain filed for 5 years after completion of the study. Records 
include informed consent, protocols, and electronic case report forms (eCRFs).  
7.4. 
Confidentiality and Privacy 
Subject confidentiality is strictly held in trust by the participating investigators, their staff, and 
the Sponsor and its agents. The study protocol, documentation, data and all other information 
generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the Sponsor. 

 
 
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Compliant with Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
guidelines, only certified copies of subject-anonymized data will be sent from the study site to 
the cardiology reviewers. Under no circumstances, except when legally compelled, will any 
healthcare provider of any enrolled subject be allowed to receive specific outcome data for that 
subject. 
7.5. 
Data Collection and Management Responsibilities  
Data will be collected using eCRFs in a validated system. The Sponsor or designee will supply 
the eCRFs. All eCRFs should be completed by designated, trained personnel, as appropriate. All 
changes or corrections to the eCRF will be documented via a data correction form (query) with 
an audit trail and adequate explanation for the revision is required. eCRFs will be signed and 
dated by the Principal Investigator or designee.  
The lead investigator(s) will permit trial-related monitoring, audits, IRB review and regulatory 
inspections(s), providing access to data documents. Members of the investigational site team and 
their designated authorization(s) will be identified in a log. 
Access to data collection devices and SUT will be controlled and the SUT will be used only in 
the clinical investigation and according to the clinical investigation plan. The investigator or 
authorized designee will keep records documenting the receipt, use and return of the data 
collection devices and SUT. 
7.6. 
Study Monitoring 
On behalf of the Sponsor, a CRO monitor will contact and visit the Investigator(s) at the study 
site(s) before the entry of the first subject and at predetermined appropriate intervals during the 
study until after the last subject has completed. The monitor will also perform a study closure 
visit. 
In accordance with ICH GCP guidelines, the Investigators must ensure provision of sufficient 
time, reasonable space, and adequate qualified personnel for the monitoring visits. The visits are 
for the purpose of verifying adherence to the study protocol and the completeness, consistency, 
and accuracy of data entered on the eCRF and other documents. 
The Investigator will make all source data (i.e., the various study records, the eCRFs, other 
subject records, and other pertinent data) available for the monitor and allow access to them 
throughout the entire study period. Monitoring is done by comparing the relevant site records of 
the subjects with the entries on the eCRF (i.e., source data verification). It is the monitor’s 
responsibility to verify the adherence to the study protocol and the completeness, consistency, 
and accuracy of the data recorded on the eCRFs. 
By agreeing to participate in the study, the Investigator agrees to cooperate with the monitor to 
ensure that any problems detected in the course of the monitoring visits are resolved. Contact 
information for the study monitor is located in the Investigator file. Representatives from the 
Sponsor may also contact and visit the Investigators and monitor data during the study. 

 
 
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7.7. 
Data Quality Assurance and Quality Control  
The Sponsor or designee will provide and maintain a charter that describes the independent 
review and training process for reviewers. This will include, but is not limited to:  
• Project Objective and Overview 
• Acquisition Standards 
• Data Transfer Process 
• Monitoring Plans  
The Sponsor or designee will perform internal quality management of study conduct, and data 
collection, documentation and completion. Quality Control (QC) procedures will be 
implemented beginning with the data entry system and data QC checks that will be run on the 
database will be generated. Any missing data or data anomalies will be communicated to study 
staff for clarification/resolution.  
7.8. 
Use of Information 
All information concerning the SUT and the Sponsor is considered confidential information. The 
information developed during the conduct of this clinical trial is also considered confidential and 
will be used by the Sponsor in connection with the development of the SUT. This information 
may be disclosed as deemed necessary by the Sponsor to allow the use of information derived 
from this clinical study and to ensure complete and thorough analysis. The investigator is 
obligated to provide the Sponsor with complete study results and all data developed in this study.  
 
 
 
 
 
 
This confidential information shall remain the sole property of the Sponsor and shall not be 
disclosed to others without the written consent of the Sponsor and shall not be used except in the 
performance of this study. 
7.9. 
Study Termination and Site Closure 
The Sponsor and the Investigators reserve the right to terminate the study or participation in the 
study, respectively, at any time. Both parties will arrange discontinuation procedures. In 
terminating the study, the Sponsor and the Investigators will assure that adequate consideration is 
given to the protection of the subjects’ interests. 
The Sponsor reserves the right to discontinue the study at any time for medical or administrative 
reasons. When feasible, a 30-day written notification will be given. 

 
 
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The entire study will be stopped if: 
• Evidence has emerged that, in the opinion of the Sponsor or the Investigator(s), 
makes the continuation of the study unnecessary or unethical; 
• The stated objectives of the study are achieved; 
• The development of the SUT is discontinued. 
Regardless of the reason for termination, all data available for subjects at the time of 
discontinuation of follow up must be recorded on the eCRF. All reasons for discontinuation of 
treatment must be documented.  
7.10. 
Completion of the Study 
The investigator(s) agree to provide financial disclosure forms and to complete this study in 
satisfactory compliance with the protocol and all applicable regulatory requirements within the 
timeframe allotted in the financial contract. Delays in the completion and/or reporting of the 
study beyond this time must be mutually agreed upon in writing by both the investigator and the 
Sponsor. 
 
 

 
 
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8. 
REFERENCES 
i Ben Freedman S, Lowres N. Asymptomatic Atrial Fibrillation: The Case for Screening to 
Prevent Stroke. JAMA. 2015 Nov 10;314(18):1911-2. doi: 10.1001/jama.2015.9846. 
 
ii Moran PS1, Teljeur C, Ryan M, Smith SM. Systematic screening for the detection of atrial 
fibrillation. Cochrane Database Syst Rev. 2016 Jun 3;(6):CD009586. doi: 
10.1002/14651858.CD009586.pub3. 
 
iii Lloyd-Jones DM1, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS, D'Agostino 
RB, Massaro JM, Beiser A, Wolf PA, Benjamin EJ. Lifetime risk for development of atrial 
fibrillation: the Framingham Heart Study. Circulation. 2004 Aug 31;110(9):1042-6. Epub 2004 
Aug 16. 
 
iv Colilla S1, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future 
incidence and prevalence of atrial fibrillation in the U.S. adult population. Am J Cardiol. 2013 
Oct 15;112(8):1142-7. doi: 10.1016/j.amjcard.2013.05.063. Epub 2013 Jul 4. 
 
vOmboni S1, Verberk WJ2. Opportunistic screening of atrial fibrillation by automatic blood 
pressure measurement in the community. BMJ Open. 2016 Apr 12;6(4):e010745. doi: 
10.1136/bmjopen-2015-010745. 
 
vi O'Neal WT1, Efird JT2, Judd SE3, McClure LA4, Howard VJ5, Howard G3, Soliman EZ6,7. 
Impact of Awareness and Patterns of Nonhospitalized Atrial Fibrillation on the Risk of 
Mortality: The Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. 
Clin Cardiol. 2016 Feb;39(2):103-10. doi: 10.1002/clc.22501. Epub 2016 Feb 16. 
 
vii Brachmann J1, Morillo CA2, Sanna T2, Di Lazzaro V2, Diener HC2, Bernstein RA2, Rymer 
M2, Ziegler PD2, Liu S2, Passman RS2. Uncovering Atrial Fibrillation Beyond Short-Term 
Monitoring in Cryptogenic Stroke Patients: Three-Year Results From the Cryptogenic Stroke 
and Underlying Atrial Fibrillation Trial. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003333. 
doi: 10.1161/CIRCEP.115.003333.