ECG App Algorithms Clinical Validation Study

• Sponsor: Apple Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT04247581
• Collaborator: Iqvia Pty Ltd (Industry)
• Enrollment: 546
• Locations: 4
• Arms: 2
• Actual Duration (Months): 2.4
• Patients Per Site: 136.5
• Patients Per Site Per Month: 56.9

Study Details

Study Description

Brief Summary

The purpose of the study is to evaluate the performance of ECG classification algorithms and their ability to classify heart rhythms into multiple categories of rhythms and heart rates

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Device: 1-lead ECG	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 546 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Screening
• Official Title: ECG App Algorithms Clinical Validation Study
• Actual Study Start Date: Jan 7, 2020
• Actual Primary Completion Date: Mar 20, 2020
• Actual Study Completion Date: Mar 20, 2020

Arms and Interventions

Arm	Intervention/Treatment
Other: Cohort 1 This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening	Device: 1-lead ECG; 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.; Other Names: 12- lead ECG Exercise
Other: Cohort 2 This will include subjects with known persistent or permanent AF who are in AF at the time of screening	Device: 1-lead ECG; 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.; Other Names: 12- lead ECG Exercise

Outcome Measures

Primary Outcome Measures

1. Percentage of Trials With Correct Classification of Normal Sinus Rhythm on Simultaneous 12-lead ECG as "Sinus Rhythm" or "High Heart Rate" on a Readable and Classifiable ECG App Strip. [1 Day]

   Specificity of sinus rhythm classification

2. Percentage of Trials With Correct Classification of AF on Simultaneous 12-lead ECG as "AF" on a Readable and Classifiable ECG App Strip. [1 Day]

   Sensitivity of sinus rhythm classification

Secondary Outcome Measures

1. Percentage of Trials With Correct Classification of Normal Sinus Rhythm at Normal Heart Rates as "Sinus Rhythm" on a Readable and Classifiable ECG App Strip [1 Day]

2. Percentage of Trials With Correct Classification of AF at Normal Heart Rates as "AF" on a Readable and Classifiable ECG App Strip [1 Day]

3. Percentage of Trials With Correct Classification of Sinus Tachycardia at High Heart Rates as "High Heart Rate" on a Readable and Classifiable ECG App Strip [1 Day]

4. Percentage of Trials With Correct Classification of AF at High Heart Rates as "AF (High Heart Rate)" on a Readable and Classifiable ECG App Strip [1 Day]

5. Percentage of Trials With Equivalence of the ECG App Waveform to Lead I From a 12-lead ECG as Measured by Acceptable Morphology of PQRST Complexes [1 Day]

   A "pass" rating is given when the waveforms of the ECG tracings generated by the algorithm and the Lead 1 of the 12-Lead ECG appear to overlay to the unaided eye. The morphology of the waveforms will be considered equivalent if at least 80% of the paired waveforms for the first 6 PQRST complexes are given a "pass" rating.

6. Percentage of Trials With Equivalence of the ECG App Waveform to Lead I From a 12-lead ECG as Measured by R-Wave Amplitude Agreement [1 Day]

   A "pass" rating is given when the difference of the R-wave amplitudes (typically the highest peak of one cardiac rhythm cycle) between the ECG tracings generated by the algorithm and the Lead 1 of the 12-Lead ECG is <= 2mm. The R-wave amplitude agreement will be considered equivalent if at least 80% of the largest R-wave amplitudes of the paired waveforms are given a "pass" rating.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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 at time of screening

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).

6. Subjects enrolled into Cohort 1 must have no known medical history of AF and in normal sinus rhythm at the time of screening.

7. Subjects enrolled into Cohort 2 must have a known diagnosis of persistent or permanent AF and be in AF at the time of screening.

Exclusion Criteria:

• Subjects must meet none of the following criteria to be enrolled:

1. Physical disability that precludes safe and adequate testing

2. Physical or medical impairments that preclude exercise testing such as musculoskeletal back pain, arthritis, leg claudication, etc.

3. Mental impairment as determined by the Investigator

4. Pregnant women at the time of the screening visit.

5. Subjects with any Medical History, Physical exam, vital sign or any other study procedure finding/assessment that in the opinion of the investigator could compromise subject safety during study participation or interfere with the study integrity and/or the accurate assessment of the study objectives. This includes patients with known untreated medical conditions that are considered clinically significant by the Investigator, such as but not limited to significant anemia, important electrolyte imbalance and untreated or uncontrolled thyroid disease. Physical exam limitations include but not limited to open wound(s) on the wrist and forearm where the subject will be wearing the watch.

6. Any history of wrist surgery with scarring in the area of the sensor location on the wrist where the subject will be wearing the watch

7. Vital signs measurement, medical history, or physical exam finding that makes the subject inappropriate for participation according to the Investigator.

8. Tattoos or moles in the area of the sensor location on the wrist where the subject will be wearing the watch.

9. Skin conditions on either wrist that would preclude subject from wearing watch on either wrist. Severe symptomatic (or active) overly dry/injured skin, skin disorders, or allergic skin reactions such as eczema, rosacea, impetigo, dermatomyositis or allergic contact dermatitis on wrist and locations where the electrodes will be placed (e.g. chest, forearms, stomach), as determined by the investigator.

10. Known allergy or significant sensitivity to medical adhesives, isopropyl alcohol, or ECG patch

11. Known allergy or sensitivity to fluorocarbon-based synthetic rubber, such as fluoroelastomer bands primarily used in the wrist worn fitness devices.

12. Clinically significant hand tremors as judged by the Investigator.

13. Participation in a previous study that involved a wrist-worn ECG device.

14. Subjects with implanted cardiac devices such as a Pacemaker or an automated Implantable Cardioverter - Defibrillator

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hope Research Institute	Phoenix	Arizona	United States	85018
2	Clinical Research of South Florida	Coral Gables	Florida	United States	33134
3	American Health Network of Indiana LLC	Avon	Indiana	United States	46123
4	Heartland Cardiology	Wichita	Kansas	United States	67226

Sponsors and Collaborators

• Apple Inc.
• Iqvia Pty Ltd

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Dec 5, 2019
• Statistical Analysis Plan - Apr 6, 2020

More Information

Publications

None provided.

• Responsible Party: Apple Inc.
• ClinicalTrials.gov Identifier: NCT04247581
• Other Study ID Numbers: 013
• First Posted: Jan 30, 2020
• Last Update Posted: Sep 28, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Apple Inc.: Cardiovascular diseases; Heart Diseases; Arrhythmia; Cardiac
• Additional relevant MeSH terms: Atrial Fibrillation

Study Results

Participant Flow

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Period Title: Overall Study
STARTED	241	305
COMPLETED	241	293
NOT COMPLETED	0	12

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Total
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	Total of all reporting groups
Overall Participants	241	305	546
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	207 85.9%	80 26.2%	287 52.6%
>=65 years	34 14.1%	225 73.8%	259 47.4%
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	43.1 (15.92)	69.7 (9.35)	58.0 (18.32)
Sex: Female, Male (Count of Participants)
Female	129 53.5%	76 24.9%	205 37.5%
Male	112 46.5%	229 75.1%	341 62.5%
Race/Ethnicity, Customized (Count of Participants)
Ethnicity: Hispanic or Latino	99 41.1%	71 23.3%	170 31.1%
Ethnicity: Not Hispanic or Latino	142 58.9%	234 76.7%	376 68.9%
Race: American Indian or Alaska Native	0 0%	0 0%	0 0%
Race: Asian	13 5.4%	1 0.3%	14 2.6%
Race: Black or African American	35 14.5%	4 1.3%	39 7.1%
Race: Native Hawaiian or Other Pacific Islander	3 1.2%	0 0%	3 0.5%
Race: White	185 76.8%	298 97.7%	483 88.5%
Race: More than one race	2 0.8%	1 0.3%	3 0.5%
Race: Not Reported	3 1.2%	1 0.3%	4 0.7%
Region of Enrollment (participants) [Number]
United States	241 100%	305 100%	546 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Trials With Correct Classification of Normal Sinus Rhythm on Simultaneous 12-lead ECG as "Sinus Rhythm" or "High Heart Rate" on a Readable and Classifiable ECG App Strip.
Description	Specificity of sinus rhythm classification
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	429	10
Number [percentage of trials]	99.3	100

2. Primary Outcome

Title	Percentage of Trials With Correct Classification of AF on Simultaneous 12-lead ECG as "AF" on a Readable and Classifiable ECG App Strip.
Description	Sensitivity of sinus rhythm classification
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	1	480
Number [percentage of trials]	100	98.5

3. Secondary Outcome

Title	Percentage of Trials With Correct Classification of Normal Sinus Rhythm at Normal Heart Rates as "Sinus Rhythm" on a Readable and Classifiable ECG App Strip
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	228	6
Number [percentage of trials]	98.2	100

4. Secondary Outcome

Title	Percentage of Trials With Correct Classification of AF at Normal Heart Rates as "AF" on a Readable and Classifiable ECG App Strip
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	1	274
Number [percentage of trials]	100	98.9

5. Secondary Outcome

Title	Percentage of Trials With Correct Classification of Sinus Tachycardia at High Heart Rates as "High Heart Rate" on a Readable and Classifiable ECG App Strip
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	201	4
Number [percentage of trials]	90.5	100

6. Secondary Outcome

Title	Percentage of Trials With Correct Classification of AF at High Heart Rates as "AF (High Heart Rate)" on a Readable and Classifiable ECG App Strip
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	241	293
Measure Trials	0	206
Number [percentage of trials]	83

7. Secondary Outcome

Title	Percentage of Trials With Equivalence of the ECG App Waveform to Lead I From a 12-lead ECG as Measured by Acceptable Morphology of PQRST Complexes
Description	A "pass" rating is given when the waveforms of the ECG tracings generated by the algorithm and the Lead 1 of the 12-Lead ECG appear to overlay to the unaided eye. The morphology of the waveforms will be considered equivalent if at least 80% of the paired waveforms for the first 6 PQRST complexes are given a "pass" rating.
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	45	48
Measure Trials	84	94
Number [percentage of trials]	100	100

8. Secondary Outcome

Title	Percentage of Trials With Equivalence of the ECG App Waveform to Lead I From a 12-lead ECG as Measured by R-Wave Amplitude Agreement
Description	A "pass" rating is given when the difference of the R-wave amplitudes (typically the highest peak of one cardiac rhythm cycle) between the ECG tracings generated by the algorithm and the Lead 1 of the 12-Lead ECG is <= 2mm. The R-wave amplitude agreement will be considered equivalent if at least 80% of the largest R-wave amplitudes of the paired waveforms are given a "pass" rating.
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Subjects in each cohort include up to 2 trial measurements (at rest; after exercise). Overall number of units represents the number of trials rather than number of subjects.

Arm/Group Title	Cohort 1	Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.	This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
Measure Participants	45	48
Measure Trials	84	94
Number [percentage of trials]	96.4	97.9

Adverse Events

Time Frame	1 Day
Arm/Group Title	Cohort 1		Cohort 2
Arm/Group Description	This will include subjects with no known history of AF and are in normal sinus rhythm at time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.		This will include subjects with known persistent or permanent AF who are in AF at the time of screening 1-lead ECG: 1 lead ECG - All participants will record three single-lead ECGs at rest and three single-lead ECGs after exercise. Intervention Other: Exercise - All participants will undergo three trials of exercise. Other interventions: 12-lead ECG - All participants will simultaneously record 12-lead ECGs during rest and exercise sessions.
All Cause Mortality
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/241 (0%)		0/305 (0%)
Serious Adverse Events
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/241 (0%)		0/305 (0%)
Other (Not Including Serious) Adverse Events
	Cohort 1		Cohort 2
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/241 (0.4%)		0/305 (0%)
Skin and subcutaneous tissue disorders
Contact Dermatitis	1/241 (0.4%)	1	0/305 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.