Electrocardiogram Clinical Validation Study

• Sponsor: Apple Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03492554
• Collaborator: Iqvia Pty Ltd (Industry)
• Enrollment: 602
• Locations: 5
• Arms: 2
• Actual Duration (Months): 2.1
• Patients Per Site: 120.4
• Patients Per Site Per Month: 58.2

Study Details

Study Description

Brief Summary

The purpose of the study is to confirm the software's ability to create a Lead-1 electrocardiogram (ECG) that is clinically equivalent to a reference device. Also, to confirm a rhythm classification algorithm and its ability to detect and classify heart rhythms into two categories (Sinus Rhythm or Atrial Fibrillation) using a single Lead ECG.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation	Other: 1-Lead ECG; Device: 12-Lead ECG	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 602 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Electrocardiogram Clinical Validation Study
• Actual Study Start Date: Mar 12, 2018
• Actual Primary Completion Date: May 14, 2018
• Actual Study Completion Date: May 14, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Atrial fibrillation (AF) Patient with a known history of AF who are in AF at the time of study screening.	Other: 1-Lead ECG; All participants will record three single-lead ECGs; Device: 12-Lead ECG; All participants will simultaneously record three 12-lead ECGs
Other: Normal Sinus Rhythm (SR) Patient with no known diagnosis of AF or other arrhythmia	Other: 1-Lead ECG; All participants will record three single-lead ECGs; Device: 12-Lead ECG; All participants will simultaneously record three 12-lead ECGs

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Software's Rhythm Classification of SR in Agreement to a Physician's Interpretation of a Gold Standard 12-lead ECG [1 Day]

   Specificity of rhythm classification

2. Number of Participants With Software's Rhythm Classification of AF in Agreement to a Physician's Interpretation of a Gold Standard 12-lead ECG [1 Day]

   Sensitivity of rhythm classification

Secondary Outcome Measures

1. Number of Participants With Software's Ability to Produce a Clinically Equivalent Waveform in Agreement to a Gold Standard Lead 1 Reference [1 Day]

   Number of ECGs that pass a visual overlay

2. Number of Participants With Software's Ability to Produce a Clinically Equivalent Waveform in Agreement to a Gold Standard Lead 1 Reference [1 Day]

   Difference in R-wave amplitudes between the software and gold standard reference

3. Ease of Use [1 Day]

   Average ease of use on a 1 (Unable to Use) to 5 (Easiest to Use) scale

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Individuals who are 22 years of age and older

• Able to read, understand, and provide written informed consent

• Willing and able to participate in the study procedures as described in the consent

• Have a wrist circumference that fits within the band

• Able to communicate effectively with and follow instructions from the study staff

• For subjects enrolled into the AF population, subjects must have a known diagnosis of AF and be in AF at the time of screening

Exclusion Criteria:

• Physical disability that precludes safe and adequate testing

• Mental impairment resulting in limited ability to cooperate

• Subjects with a pacemaker or implantable cardioverter-defibrillator (ICD)

• 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

• Acute pulmonary embolism, pulmonary infarction, or deep vein thrombosis within 90 days of screening

• Stroke or transient ischemic attack within 90 days of screening

• Subjects taking rhythm control drugs

• Symptomatic (or active) allergic skin reactions such as eczema, rosacea, impetigo, dermatomyositis or allergic contact dermatitis on both wrists or over electrode attachment sites

• 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

• A history of abnormal life-threatening rhythms as determined by the investigator

• Significant tremor that prevents subject from being able to hold still

• Pregnant women: Women who are pregnant at the time of study participation

• For subjects enrolled into the sinus rhythm population, they must not have any diagnosis of AF

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	QPS	Miami	Florida	United States	33143
2	BioClinicia- Orlando	Orlando	Florida	United States	32806
3	BioClinica- The Villages	The Villages	Florida	United States	32162
4	IQVIA	Overland Park	Kansas	United States	66211
5	Health East	Saint Paul	Minnesota	United States	55102

Sponsors and Collaborators

• Apple Inc.
• Iqvia Pty Ltd

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 15, 2018

More Information

Publications

None provided.

• Responsible Party: Apple Inc.
• ClinicalTrials.gov Identifier: NCT03492554
• Other Study ID Numbers: 099-11774
• First Posted: Apr 10, 2018
• Last Update Posted: Dec 3, 2020
• Last Verified: Nov 1, 2020

• 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.: Yes
• Additional relevant MeSH terms: Atrial Fibrillation

Study Results

Participant Flow

Arm/Group Title	Atrial Fibrillation (AF)	Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Period Title: Overall Study
STARTED	301	301
COMPLETED	301	287
NOT COMPLETED	0	14

Baseline Characteristics

Arm/Group Title	Atrial Fibrillation (AF)	Normal Sinus Rhythm (SR)	Total
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Total of all reporting groups
Overall Participants	301	287	588
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	73.8 (8.62)	59.5 (17.73)	66.9 (15.47)
Sex: Female, Male (Count of Participants)
Female	92 30.6%	159 55.4%	251 42.7%
Male	209 69.4%	128 44.6%	337 57.3%
Race/Ethnicity, Customized (Count of Participants)
Ethnicity : Hispanic or Latino	19 6.3%	57 19.9%	76 12.9%
Ethnicity : Not Hispanic or Latino	282 93.7%	230 80.1%	512 87.1%
Race: American Indian or Alaska Native	2 0.7%	0 0%	2 0.3%
Race: Asian	1 0.3%	2 0.7%	3 0.5%
Race: Black or African American	8 2.7%	46 16%	54 9.2%
Race: Native Hawaiian or Other Pacific Islanders	0 0%	1 0.3%	1 0.2%
Race: White	292 97%	236 82.2%	528 89.8%
Race: Not Reported	0 0%	3 1%	3 0.5%
Region of Enrollment (Count of Participants)
United States	301 100%	287 100%	588 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Software's Rhythm Classification of SR in Agreement to a Physician's Interpretation of a Gold Standard 12-lead ECG
Description	Specificity of rhythm classification
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Classifiable Analysis Set: All subjects who had readable/classifiable paired Software and Reference strips were used. This analysis set was used for analyzing the primary endpoints of sensitivity and specificity.

Arm/Group Title	Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Measure Participants	239
Count of Participants [Participants]	238 79.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Sinus Rhythm (SR)
	Comments	H0: Specificity = 92% H1: Specificity > 92 Under the assumption that the true population specificity is 96.5%, 226 subjects who were diagnosed with SR based on the 12-lead ECG reference strip and where the device algorithm classification produced a result of AF or SR was calculated to provide at least 80% power to reject its null hypothesis, using a one-sided type I error of 0.025. To obtain readable waveforms approximately 300 subjects with no known diagnosis of AF were enrolled.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	1 sided exact binomial test
	Comments

2. Primary Outcome

Title	Number of Participants With Software's Rhythm Classification of AF in Agreement to a Physician's Interpretation of a Gold Standard 12-lead ECG
Description	Sensitivity of rhythm classification
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Classifiable Analysis Set: All subjects who had readable/classifiable paired Software and Reference strips were used. This analysis set was used for analyzing the primary endpoints of sensitivity and specificity.

Arm/Group Title	Atrial Fibrillation (AF)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Measure Participants	240
Count of Participants [Participants]	236 78.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Sinus Rhythm (SR)
	Comments	H0: Sensitivity = 90% H1: Sensitivity > 90% Under the assumption that the true population sensitivity is 95%, 231 subjects who were diagnosed with AF based on the 12-lead ECG reference strip and where the device algorithm classification produced a result of AF or SR was calculated to provide at least 80% power to reject the null hypothesis, using a one-sided type I error of 0.025. To obtain readable waveforms, a minimum of 260 subjects with a known diagnosis of AF were enrolled.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	1 sided exact binomial test
	Comments

3. Secondary Outcome

Title	Number of Participants With Software's Ability to Produce a Clinically Equivalent Waveform in Agreement to a Gold Standard Lead 1 Reference
Description	Number of ECGs that pass a visual overlay
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Waveform Assessment Analysis Set: Paired Software and Reference strips collected from subjects were randomly selected. If 6 consecutive paired beats for analysis cannot be found in these strips, they were excluded from further analysis. This analysis set was used for assessing the quality of the clinical waveform.

Arm/Group Title	Atrial Fibrillation (AF)	Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Measure Participants	61	65
Count of Participants [Participants]	60 19.9%	65 22.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Sinus Rhythm (SR), Normal Sinus Rhythm (SR)
	Comments	H0: agreement proportion of visual display= 0.8 H1: agreement proportion of visual display> 0.8 Under the assumption that the true population agreement proportion of visual display was 90%, 88 subjects would provide at least 80% power to reject the 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) were randomly selected.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	1 sided exact binomial
	Comments

4. Secondary Outcome

Title	Number of Participants With Software's Ability to Produce a Clinically Equivalent Waveform in Agreement to a Gold Standard Lead 1 Reference
Description	Difference in R-wave amplitudes between the software and gold standard reference
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

Waveform Assessment Analysis Set: Paired Software and Reference strips collected from subjects were randomly selected. If 6 consecutive paired beats for analysis cannot be found in these strips, they were excluded from further analysis. This analysis set was used for assessing the quality of the clinical waveform.

Arm/Group Title	Atrial Fibrillation (AF)	Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Measure Participants	61	65
Count of Participants [Participants]	58 19.3%	65 22.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Normal Sinus Rhythm (SR), Normal Sinus Rhythm (SR)
	Comments	H0: agreement proportion of R wave amplitude = 0.8 H1: agreement proportion of R wave amplitude > 0.8 Under the assumption that the true population agreement proportion of R wave amplitude was 90%, 88 subjects would provide at least 80% power to reject the 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) were randomly selected.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	1 sided exact binomial
	Comments

5. Secondary Outcome

Title	Ease of Use
Description	Average ease of use on a 1 (Unable to Use) to 5 (Easiest to Use) scale
Time Frame	1 Day

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Atrial Fibrillation (AF)	Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs	Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
Measure Participants	301	287
1 = Unable to Use	2 0.7%	1 0.3%
2 = Below Average Ease of Use	4 1.3%	2 0.7%
3 = Average Ease of Use	14 4.7%	16 5.6%
4 = Above Average Ease of Use	41 13.6%	29 10.1%
5 = Easiest to Use	240 79.7%	239 83.3%

Adverse Events

Time Frame	1 Day
Adverse Event Reporting Description	Adverse Event, Serious Adverse Event or Mortality were assessed/monitored.
Arm/Group Title	Atrial Fibrillation (AF)		Normal Sinus Rhythm (SR)
Arm/Group Description	Patient with a known history of AF who is in AF at the time of study screening. 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs		Patient with no known diagnosis of AF or other arrhythmia 1-Lead ECG: All participants will record three single-lead ECGs 12-Lead ECG: All participants will simultaneously record three 12-lead ECGs
All Cause Mortality
	Atrial Fibrillation (AF)		Normal Sinus Rhythm (SR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/301 (0%)		0/301 (0%)
Serious Adverse Events
	Atrial Fibrillation (AF)		Normal Sinus Rhythm (SR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/301 (0%)		0/301 (0%)
Other (Not Including Serious) Adverse Events
	Atrial Fibrillation (AF)		Normal Sinus Rhythm (SR)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/301 (0%)		0/301 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.