The REVEALPLAQUE Study: A pRospEctiVe, multicEnter Study to AnaLyze PLAQUE Using CCTA
Conditions: Coronary Artery Disease (CAD) (E.G., Angina, Myocardial Infarction, and Atherosclerotic Heart Disease (ASHD))
Sponsor: HeartFlow, Inc.

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The REVEALPLAQUE Study:  A pRospEctiVe, multicEnter study to AnaLyze PLAQUE using  
CCTA 
 
 
 
 
Study Objective 
Current clinically available methods to quantify coronary artery plaque 
noninvasively from CCTA data are largely manual and as a result, have 
limited utility, reproducibility, accuracy, and precision. An automated 
deep learning based artificial intelligence method for segmenting the 
vessel wall and atherosclerotic plaque from CCTA data has been 
developed. This study will evaluate the level of agreement between this 
noninvasive CCTA-based quantification and characterization of coronary 
atherosclerosis and invasive IVUS.       
 
Study Design 
Patients who have a stenosis in at least one major epicardial vessel 
confirmed by CCTA and who are scheduled to undergo clinically 
indicated IVUS-guided invasive evaluation and/or treatment will be 
eligible for enrollment. Enrolling sites will have FFRCT analysis 
incorporated when indicated into their standard evaluation of CCTA 
scans. Data collected will include CCTA and FFRCT images, full 
angiographic images, IVUS images, and if obtained, any other imaging 
or physiologic data including OCT, FFR, any NHPR (e.g., dPR, RFR, iFR, 
etc.), and pre- and post-stent implantation invasive data. All non-invasive 
and invasive data collected will be obtained as clinical practice consistent 
with standard clinical care.  
 
Principal 
Investigator(s) 
Thomas Stuckey, MD 
Cone Health 
USA 
 
Jagat Narula, MD, PhD 
Mt. Sinai  
USA 
 
Gaku Nakazawa, MD, PhD 
Kindai University 
Japan 
 
Sponsor 
HeartFlow, Inc. 
1400 Seaport Blvd., Building B 
Redwood City, CA 94063 
 
Campbell Rogers, MD 
Chief Medical Officer 
 
 
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Protocol Signature Page 
 
I have read and understood the protocol and agree that it contains all the ethical, legal, and scientific 
information necessary to conduct this study. I will personally conduct the study as described. I will 
provide copies of the protocol to all assigned physicians, nurses, and other professional personnel who 
will be involved per the delegation of authority log, and I will be responsible for their compliance and 
adherence to the study protocol. I am aware that this protocol must be approved by the Institutional 
Review Board or Ethics Committee. I agree to adhere strictly to the attached protocol. I agree that 
clinical data entered on case report forms by me and my staff will be supplied to HeartFlow and may be 
utilized by HeartFlow in various ways, such as for submission to governmental regulatory authorities 
and/or in combination with clinical data gathered from other research sites, whenever applicable. I 
agree to allow HeartFlow monitors and auditors and their designees full access to all medical records at 
the research facility for subjects screened or randomized in the study. I agree to provide all subjects 
with informed consent forms and will ensure adequate informed consent is obtained, as required by 
government regulations and International Conference on Harmonization guidelines. 
 
 
 
 
   Site Name 
 
 
 
 
       Site Number 
 
 
 
 
   Site Co-Principal Investigator (print name) 
 
 
  
   Site Co-Principal Investigator (signature)  
   Date 
 
 
 
 
   Site Co-Principal Investigator (print name) 
 
 
  
   Site Co-Principal Investigator (signature)  
   Date 
 
 
 
 
 
 
 
 
 
Protocol reviewed and approved by sponsor: 
 
 
 
   Campbell Rogers, MD; HeartFlow, Inc., CMO 
    Date 
 
 
 
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TABLE OF CONTENTS  
STANDARD ABBREVIATIONS                                                                                                               6                   
STUDY SYNOPSIS 
7 
I.   BACKGROUND AND RATIONALE 
9 
II. STUDY OBJECTIVE 
9 
III. STUDY ENDPOINTS 
10 
III. A. Primary Endpoint 
10 
IV. STUDY DESIGN 
10 
IV. A. 
Location and Number of Subjects 
11 
IV. B. 
Patient Population 
11 
IV. C. 
 General Inclusion and Exclusion Criteria 
11 
V. STUDY WORKFLOW 
11 
V. A. Study/Site Selection 
11 
V. B. Subject Selection 
12 
V. C. Screening Period 
12 
V. D. Enrollment 
12 
V. E. Follow up 
13 
VI. STUDY DURATION 
13 
VI. A. Rules for Subject Withdrawal 
13 
VI. B. Screen Failures 
13 
VI. C. Rules for Terminating the Study 
13 
VII. SAFETY ASSESSMENT 
13 
VIII. RATIONALE AND ETHICAL CONSIDERATIONS 
14 
IX. STATISTICAL CONSIDERATIONS 
14 
IX. A.  General Considerations 
14 
IX. B.  Subject Characteristics 
14 
IX. C.  Endpoint Analysis 
14 
IX. D.  Sample Size 
15 
IX. E. Analysis Populations 
15 
X. DATA HANDLING AND QUALITY ASSURANCE 
15 
X. A. Completing and Signing Case Report Forms 
15 
X. B. Clinical Data Management 
15 
X. C. Archiving of Data 
15 
XI. SPECIAL REQUIREMENTS AND PROCEDURES 
16 
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XI. A. Institutional Review 
16 
XI. B. Guidelines for Obtaining Subject Informed Consent 
16 
XI. C. Site Initiation/Training 
16 
XI. D. Study Monitoring and Audit 
16 
XI. E.  Clinical Events Committee 
16 
XI. F.  IVUS Core Lab 
16 
XI. G.  HeartFlow Technology / Data Team 
16 
XII. FINAL REPORT 
16 
XIII. REFERENCES 
17 
 
 
 
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STANDARD ABBREVIATIONS 
 
CAD 
coronary artery disease 
CCTA 
coronary computed tomographic angiography 
dPR 
diastolic pressure ratio 
EDC 
electronic data capture 
eCRF 
electronic case report form 
FFR 
fractional flow reserve 
FFRCT 
non-invasive technique using CCTA to determine FFR 
ICA 
invasive coronary angiography 
ICF 
informed consent form 
IFR 
instantaneous wave free ratio 
IVUS 
intravascular ultrasound  
LoA 
level of agreement 
MACE 
major adverse cardiovascular event 
MI 
myocardial infarction 
NHPR 
non-hyperemic flow reserve 
NI 
non-invasive 
OCT 
optical coherence tomography 
PCI 
percutaneous coronary intervention 
RRF 
resting full cycle ratio 
 
 
 
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STUDY SYNOPSIS 
Protocol Title 
A pRospEctiVe, multicEnter study to AnaLyze PLAQUE using 
CCTA 
Subjects and Study 
Centers 
Approximately 250 subjects across approximately 15 sites in the US and 
Japan. 
 
Planned Study Duration 
The duration of this study will be approximately 24 months: 
● 
3 - 9 months for study start-up (Site qualification, IRB approval, 
and site initiation)  
● 
12 months for enrollment 
● 
3 months for query resolution and database lock 
 
Primary Study Objective This study will evaluate the level of agreement between noninvasive 
CCTA-based quantification and characterization of coronary 
atherosclerosis and invasive IVUS     . 
       
Secondary 
Study 
Objectives 
The secondary objectives of this study are to: 
      
1) Compare total plaque volumes per-patient and per lesion as well 
as comparing different plaque type volumes to the IVUS reference 
standard and assess reproducibility of quantitative plaque 
measurements compared to the reference standard.  
 
2) Perform exploratory analyses on plaque in previously stented 
vessels (protocol to allow up to 20% (50 patients) with one or two 
stented vessels vessels in this category. This can also include 
plaque proximal or distal to the stented vessel.  
 
Hypotheses 
The primary hypothesis of the study is that a deep-learning based 
automated method for segmenting coronary atherosclerotic plaques can 
quantify total plaque volume from CCTA with an acceptable level of 
agreement with IVUS measurements. The secondary hypothesis of the 
study is that CCTA-derived coronary models can accurately assess 
percent plaque burden as well as calcified, low attenuation, and fibrous 
plaque volumes with an acceptable level of agreement and repeatability 
compared to IVUS.        
 
Population 
Clinically stable patients with known CAD who have a CCTA showing 
stenosis in at least one major epicardial vessel of stentable/graftable 
diameter and in whom clinically-indicated IVUS is planned. 
 
Study Design and 
Methods 
This is a prospective, multi-center study. All patients who have a 
stenosis in at least one major epicardial vessel confirmed by CCTA, who 
have undergone FFRCT analysis, and who are scheduled to undergo 
clinically indicated IVUS-guided invasive evaluation and/or treatment will 
be eligible for enrollment. Enrolling sites will have FFRCT analysis 
incorporated when indicated into their standard evaluation of CCTA 
scans.  Data collected will include CCTA and FFRCT, full angiographic, 
and IVUS images, and if obtained, any other imaging or physiologic data 
including OCT, FFR, any NHPR (e.g., dPR, RFR, iFR, etc.), and pre- 
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and post-stent implantation invasive data.  All non-invasive and invasive 
data collected will be obtained as clinical practice consistent with 
standard clinical care. 
 
All details about cardiovascular testing and treatment (planned and 
actual) will be recorded at baseline. There will be no study required visits 
after the baseline invasive procedure.  
 
Primary Endpoint 
The primary endpoint is to assess the level of agreement between total 
plaque volume of a deep-learning based automated method for 
segmenting coronary atherosclerotic plaques, compared to IVUS, on a 
per-IVUS-pullback level.  
 
Secondary 
Endpoints 
Key secondary endpoints are: 
 
Per pullback: 
● 
Total plaque volume 
● 
Percent Plaque burden  
● 
Calcified plaque volume 
● 
Low attenuation plaque volume 
● 
Fibrous plaque volume 
● 
Segment involvement score (SIS) 
● 
Adverse plaque characteristics (APC) 
Per lesion: 
● 
Total plaque volume 
● 
Percent plaque burden  
● 
Calcified plaque volume 
● 
Low attenuation plaque volume 
● 
Fibrous plaque volume 
● 
Minimum lumen area (MLA) 
● 
Percentage area stenosis (%AS) 
● 
Positive remodeling index   
Per lesion/pullback: 
● 
Reproducibility of all metrics above when quantified from 
different CCTA series 
● 
Reproducibility of all metrics above when processing the same 
series twice (analyst and process variation) 
● 
Exploratory analysis of necrotic core volume 
 
 
 
Inclusion 
Criteria 
Inclusion criteria (all must be present): 
 
1. Age ≥18 years 
2. Clinically stable patient with known CAD  
3. CCTA showing stenosis in at least one major epicardial vessel of 
stentable/graftable diameter, in whom clinically indicated IVUS is 
planned within 45 days of the CCTA and FFRCT available  
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4. FFRCT successfully processed 
5. Willing to comply with all aspects of the protocol  
6. Agrees to be included in the study and able to provide written 
informed consent.  
 
 
Exclusion criteria (all must be absent): 
 
1. CCTA showing no stenosis  
2. Uninterpretable CCTA by HeartFlow assessment, in which image 
quality prevents FFRCT from being processed.  
3. Acute chest pain 
4. CABG prior to CCTA acquisition 
5. Prior history of PCI for 3 or more vessels  
6. MI less than 30 days prior to CCTA or between CCTA and ICA. 
7. Suspicion of acute coronary syndrome (acute myocardial infarction or 
unstable angina) 
8. Known complex congenital heart disease 
9. Tachycardia or significant arrhythmia  
10. Subject requires an emergent procedure 
11. Evidence of ongoing or active clinical instability, including acute chest 
pain (sudden onset), cardiogenic shock, unstable blood pressure with 
systolic blood pressure <90 mmHg, and severe congestive heart failure 
(NYHA III or IV) or acute pulmonary edema 
12. Any active, serious, life-threatening disease with a life expectancy of 
less than 2 months 
13. Currently enrolled in another study utilizing FFRCT or in an 
investigational trial that involves a non-approved cardiac drug or device 
14. Persons under the protection of justice, guardianship, or curatorship 
 
Study Follow-Up 
There will be no study required visits after the baseline cath. 
 
Clinical 
Research 
Organization 
Peachtree BioResearch Solutions 
4985 Lower Roswell Road 
Marietta, GA 30068 
 
Sponsor 
HeartFlow, Inc. 
1400 B Seaport Blvd 
Redwood City, CA 94063 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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I.   BACKGROUND AND RATIONALE 
HeartFlow, Inc. (‘HeartFlow’) provides a non-invasive method to determine the hemodynamic significance 
of CAD (FFRCT) from subject specific CCTA data using computational fluid dynamics under rest and 
simulated maximal coronary hyperemic conditions (Taylor 2013). Results from four prospective trials 
suggest that FFRCT accurately predicts the hemodynamic significance of coronary lesions when 
compared to invasively measured FFR (Koo 2011, Min 2012, Nørgaard 2014, Driessen 2018). FFRCT is 
available in Japan, in many European countries (CE mark 2011), in Canada, and in the U.S. (De Novo 
510K clearance 2014).  
One of the next key areas of interest in non-invasive disease identification is confirming whether a deep-
learning based automated method for segmenting coronary atherosclerotic plaques can identify coronary 
atherosclerotic plaque location, quantity, and type. Recent studies have shown the importance of 
understanding plaque burden including non-calcified plaque and especially low attenuation plaque to 
better identify patients at risk of myocardial infarction (Thomsen 2016). A deep-learning based automated 
method for segmenting coronary atherosclerotic plaques which can quantify total plaque volume from 
CCTA has been designed and tested and now requires prospectively collected invasive imaging data to 
assess performance as compared to intravascular ultrasound imaging (IVUS), a gold standard in plaque 
quantification (Voros 2011, Fischer 2013).  
In the REVEALPLAQUE study, all patients who have a stenosis confirmed by CCTA, have had FFRCT 
completed, and are scheduled to undergo IVUS will be eligible for enrollment. Enrolling sites will have 
FFRCT analysis incorporated when indicated into their standard evaluation of CCTA scans. All sites will 
provide demographic and medical history of enrolled subjects, CCTA and FFR images, full angiographic 
images, IVUS images, and if obtained, any other imaging or physiologic data including OCT, FFRCT, any 
NHPR (e.g., dPR, RFR, iFR, etc.), and pre- and post-stent implantation invasive data. All non-invasive 
and invasive data collected will be obtained as clinical practice consistent with standard clinical care. 
Data may be used to train deep learning artificial intelligence algorithms for image segmentation and 
physiological modeling, to improve current and future products.    
 
II. STUDY OBJECTIVE 
Primary Objective: 
Current clinically available software packages to quantify coronary artery plaque noninvasively from 
CCTA data are largely manual and as a result, have limited reproducibility, accuracy, and precision. An 
automated deep-learning based artificial intelligence method for segmenting the vessel wall and 
atherosclerotic plaque from CCTA data has been developed. This study will evaluate the level of 
agreement between noninvasive CCTA-based quantification and characterization of coronary 
atherosclerosis and invasive IVUS.  
 
Secondary Objectives: 
The secondary objectives of this study are to: 
1. Compare total plaque volumes per-patient and per lesion as well as comparing different 
plaque type volumes to the IVUS reference standard and assess reproducibility of quantitative 
plaque measurements compared to the reference standard.  
2. Perform exploratory analyses on plaque in previously stented vessels (protocol to allow up to 
20% (50 patients) with one or two stented vessels in this category). This can also include 
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plaque proximal or distal to the stented vessel.  
 
III. STUDY ENDPOINTS  
III. A. Primary Endpoint 
The primary endpoint is to assess the level of agreement between total plaque volume of a deep-
learning based automated method for segmenting coronary atherosclerotic plaques, compared to 
IVUS, on a per-IVUS-pullback level.  
 
III. B. Secondary Endpoints 
Key secondary endpoints are: 
Per pullback: 
● 
Total plaque volume 
● 
Percent plaque burden  
● 
Calcified plaque volume 
● 
Low attenuation plaque volume 
● 
Fibrous plaque volume 
● 
Segment involvement score (SIS) 
● 
Adverse plaque characteristics (APC) 
Per lesion: 
● 
Total plaque volume 
● 
Percent Plaque burden  
● 
Calcified plaque volume 
● 
Low attenuation plaque volume 
● 
Fibrous plaque volume 
● 
Minimum lumen area (MLA) 
● 
Percentage area stenosis (%AS) 
● 
Positive remodeling index   
Per lesion/pullback: 
● 
Reproducibility of all metrics above when quantified from different CCTA series 
● 
Reproducibility of all metrics above when processing the same series twice (analyst and 
process variation) 
● 
Exploratory analysis of necrotic core volume 
 
IV. STUDY DESIGN  
The REVEALPLAQUE study is a prospective, multi-center study designed to evaluate a deep-learning 
based automated method for segmenting coronary atherosclerotic plaques. All patients who have a 
stenosis confirmed by CCTA and FFRCT available and who are scheduled to undergo IVUS will be eligible 
for enrollment. Enrolling sites will have FFRCT analysis incorporated when indicated into their standard 
evaluation of CCTA scans. All sites will provide CCTA and FFRCT images, full angiographic images, IVUS 
images, and if obtained, any other imaging or physiologic data including OCT, FFR, any NHPR (e.g., 
dPR, RFR, iFR, etc.), and pre- and post-stent implantation invasive data. All non-invasive and invasive 
data collected will be obtained as clinical practice consistent with standard clinical care. 
All details about cardiovascular testing and treatment (planned and actual) will be recorded at baseline. 
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IV. A. Location and Number of Subjects  
Approximately 250 subjects will be enrolled from approximately 15 experienced clinical research sites in 
the US and Japan.  
IV. B. Patient Population 
Clinically stable patients with known CAD who have a CCTA showing stenosis in at least one major 
epicardial vessel of stentable/graftable diameter and FFRCT available, and in whom clinically indicated 
IVUS is planned within 45 days of CCTA will be prospectively enrolled.   
IV. C.  General Inclusion and Exclusion Criteria  
Inclusion Criteria (all must be present): 
 
1. Age ≥18 years 
2. Clinically stable patient with known CAD  
3. CCTA showing stenosis in at least one major epicardial vessel of stentable/graftable diameter, 
in whom clinically indicated IVUS is planned within 45 days of the CCTA  
4. CCTA meets eligibility criteria for FFRCT as defined in the IFU 
5. Willing to comply with all aspects of the protocol, including adherence to follow up visits  
6. Agrees to be included in the study and able to provide written informed consent  
Exclusion Criteria (all must be absent): 
1. CCTA showing no stenosis  
2. Uninterpretable CCTA by HeartFlow assessment, in which image quality prevents FFRCT from 
being processed.  
3. Acute chest pain 
4. CABG prior to CCTA acquisition 
5. Prior history of PCI for 3 or more vessels  
6. MI less than 30 days prior to CCTA or between CCTA and ICA. 
7. Suspicion of acute coronary syndrome (acute myocardial infarction or unstable angina) 
8. Known complex congenital heart disease 
9. Tachycardia or significant arrhythmia  
10. Subject requires an emergent procedure 
11. Evidence of ongoing or active clinical instability, including acute chest pain (sudden onset), 
cardiogenic shock, unstable blood pressure with systolic blood pressure <90 mmHg, and severe 
congestive heart failure (NYHA III or IV) or acute pulmonary edema 
12. Any active, serious, life-threatening disease with a life expectancy of less than 2 months 
13. Currently enrolled in another study utilizing FFRCT or in an investigational trial that involves a 
non-approved cardiac drug or device 
14. Persons under the protection of justice, guardianship, or curatorship 
 
V. STUDY WORKFLOW  
The workflow for the REVEALPLAQUE study is described in the following sections. 
V. A. Study/Site Selection 
HeartFlow will identify and qualify the clinical research sites for the REVEALPLAQUE study. Participating 
sites will be screened for: 
● CCTA acquisition practices conforming to SCCT guidelines  
● Invasive Coronary Angiography (ICA) and other invasive data collection following best practices 
● High quality IVUS data collection experience and ability to use automatic pullback for IVUS 
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● Adequate resources and past clinical research experience  
V. B. Subject Selection 
Institutional Review Board (IRB) approval will be obtained at all participating sites prior to screening 
subjects. All subjects who meet all inclusion criteria and do not meet any exclusion criteria, and are 
able and willing to participate, are candidates for the REVEALPLAQUE study. All subjects providing 
written informed consent and meeting all selection criteria will be enrolled into the REVEALPLAQUE 
study.  
V. C. Screening Period 
1. All subjects must fulfill all study inclusion criteria and no study exclusion criteria. 
2. Each subject will undergo the following assessments to be documented in the appropriate 
electronic case report form (eCRF) upon enrollment:  
a. Collection of demographic information  
b. A summary of the subject’s relevant medical history and cardiovascular risk factors 
c. Information about the subject’s CCTA and FFRCT results 
d. Results and images from non-invasive/invasive tests performed during 90 days prior to 
enrollment 
V. D. Enrollment 
All subjects must provide written informed consent prior to enrollment. A notation will be made in the 
subject’s medical chart, if required by the institution, and in the study records that he/she is participating 
in the study, has had his/her questions answered, has read, signed, and dated the Informed Consent 
Form (ICF), and been given a copy of the ICF.  
All subjects who meet eligibility requirements will be asked to participate. Subjects will be considered 
enrolled in the study after the following criteria have been met:  
1. Informed consent form has been signed and subject has been provided a copy.  
2. All inclusion criteria and no exclusion criteria have been met. 
Subjects included in the study will have anatomic and physiological data obtained as standard clinical 
care during ICA recorded. A guide advising how to obtain IVUS measurements will be provided to sites 
during site protocol training; in summary the below mentioned data will be collected. A maximum of 20% 
of enrolled subjects may have at least one vessel with prior stent implantation. 
ICA procedure: 
1. The subject’s vital signs (blood pressure and heart rate) will be recorded prior to ICA 
procedure.   
2. Medications (adenosine and nitrates) taken within 24 hours of ICA will be recorded.  
3. Angiography is advised to be performed according to the study guides provided during site 
protocol training.  
4. The data from IVUS (mandatory), FFR measurements (as deemed necessary), and OCT (as 
deemed necessary) by the physician will be collected. 
5. All angiographic images will be collected.  
6. IVUS data for non-targeted lesions that are standard clinical care will be collected.  
7. Radiation exposure will be documented. 
8. Total procedural volume of iodinated contrast will be recorded 
9. Fluoroscopy duration will be documented. 
10. Diagnostic and therapeutic procedures and equipment used, including catheters, balloons, 
wires, and stents, and vessels treated will be documented. 
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11. Procedural complications will be documented (e.g., dissection from catheter or wire, reaction 
to medication, side branch occlusion, slow/no flow)       
 
 
 
 
V. E. Follow up 
No follow up with the subjects will be done as a part of this study. 
 
VI. STUDY DURATION 
The anticipated enrollment duration of the REVEALPLAQUE study will be approximately 12 months. No 
subject follow up is planned for this study. 
VI. A. Rules for Subject Withdrawal 
Each subject is free to withdraw from the study at any time. No additional data will be collected after a 
subject informs the Investigator that they want to withdraw.  Withdrawn subjects will be considered screen 
failures if the collected data does not allow for adequate selection criteria assessment. 
VI. B. Screen Failures 
Subjects who sign consent will be deemed a screen failure if: 
● Automatic pullback for IVUS catheter was not used during the procedure 
● Prior to IVUS, the vessel was predilated (medications OK) 
     No data beyond reason for screen failure will be collected. 
VI. C. Rules for Terminating the Study 
There are no formal termination criteria for this study. The sponsor reserves the right to terminate the 
REVEALPLAQUE study at any time. Investigators have the responsibility to comply with all applicable 
regulatory guidelines and regulations. Specific reasons which may cause the sponsor, IRB, or local 
regulatory authorities to terminate a center include, but are not limited to:  
1) Failure of the investigator to comply with investigator agreement, protocol, guidelines, and/or 
regulations.  
2) Serious protocol violations. 
3) Submission of knowingly false information from the research facility to the sponsor, clinical 
monitor, or other party involved in the study.  
 
VII. SAFETY ASSESSMENT 
Subjects will undergo a clinically indicated ICA and invasive physiological measurements, which do not 
require additional radiation, extra contrast, or additional procedure time for this study/protocol. All 
procedures performed will be per standard clinical care and with adherence to revascularization 
guidelines and data obtained will be documented. Therefore, there will be no additional clinical risks for 
subjects who participate. Procedural complications will be documented (i.e., dissection from catheter or 
wire, reaction to medication). 
 
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VIII. RATIONALE AND ETHICAL CONSIDERATIONS  
This prospective, multi-center study is being conducted to expand existing datasets to improve the 
performance of FFRCT and support development of future products. 
The potential risks to subjects participating in this study include potential breach of confidentiality. Data 
transmitted to HeartFlow will not contain any PHI identifiers and will be coded with a unique identifier for 
each subject.  All applicable study data will be transferred to HeartFlow and core laboratories in a secure 
manner and in accordance with all applicable regulations. 
Anticipated benefits  
There are no specific benefits to subjects participating in the study. There may be some benefit to other 
patients who undergo management in the future based on deep-learning based automated methods for 
segmenting coronary atherosclerotic plaques. 
Anticipated risks  
The REVEALPLAQUE study is a prospective study which collects data from clinically indicated CCTA 
imaging and ICA procedures. These procedures will have been planned as part of routine clinical practice; 
therefore, no additional clinical risks are related to participating in the study. Procedural complications 
will be documented that are related to IVUS or FFR (e.g.,. dissection from catheter or wire, reaction to 
medication). 
 
IX. STATISTICAL CONSIDERATIONS 
IX. A.  General Considerations 
Descriptive statistical methods will be used to summarize the data from this study, with confidence 
intervals and hypothesis testing performed for the primary and other selected efficacy endpoints. 
Unless stated otherwise, the term “descriptive statistics” refers to number of events (n), mean, median, 
standard deviation (SD), standard error, minimum, maximum, and coefficient of variation (CV) for 
continuous data and frequencies and percentages for categorical data.  
All data collected during the study will be included in data listings.  
Unless specified otherwise, all statistical testing will be two-sided and will be performed using an overall 
significance (alpha) level of 0.05.  
All statistical analyses will be conducted with the SAS® System, version 9.1.3 or higher. 
A statistical analysis plan (SAP) will describe the methods of data collection, validation, analysis, and 
reporting. The sections below provide a brief overview of statistical consideration for the study. 
IX. B.  Subject Characteristics  
Subject accountability will be described, including number of subjects enrolled, number of subjects 
included in the analysis, and reasons for any subjects discontinued from the study or not included in the 
analysis. Demographic information will be summarized using descriptive statistics. Sex and medical 
histories will be summarized by counts and percentages.   
IX. C.  Endpoint Analysis 
The primary endpoint is to assess the level of agreement between total plaque volume of a deep-learning 
based automated method for segmenting coronary atherosclerotic plaques, compared to IVUS, on a per-
IVUS-pullback level.  
Bland Altman plots will be constructed. If the deep-learning based automated method CCTA 
measurements fall with the limits of agreement (LoA) estimated from the IVUS measurements, the 
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measures will be assumed to agree. Additionally, Pearson’s correlation and paired t-test will be 
constructed to further describe the relationship between IVUS measurements and deep-learning based 
automated method for segmenting coronary atherosclerotic plaques from CCTA. 
All secondary endpoints which are continuous (e.g., per lesion total plaque volume, per lesion calcium 
volume, per lesion low attenuation volume, per lesion non-calcified plaque volume, segment 
involvement score) will be similarly compared using a Bland Altman plot, Pearson’s correlation and 
paired t-tests. Reproducibility will be estimated with Intra Class correlation (ICC).  
IX. D.  Sample Size  
Approximately 250 subjects may be enrolled into this study. 
From published data (Conte 2019), the maximum allowable difference between the measurements is 
36 mm3.  Assuming a standard deviation of 12 mm3, a sample size of 223 patients achieves 90% power 
to detect agreement when the mean is 8, confidence level of the (LoA) is 0.950 and the confidence 
level of the confidence intervals about the LoA is 0.950. 
IX. E. Analysis Populations  
All subjects who meet the study criteria, sign the written informed consent, and are enrolled in the study, 
and provide paired assessments of CCTA and IVUS measurements will be included in the analysis set.  
 
X. DATA HANDLING AND QUALITY ASSURANCE  
X. A. Completing and Signing Case Report Forms  
This study will utilize eCRFs for the collection of all data. Data changes and corrections for any errors 
should be corrected within the eCRF. The audit trail will record all changes made, the date and time of 
the correction, the person making the change, and a reason for the change. The appropriate electronic 
signature will be provided by the investigator as indicated. 
X. B. Clinical Data Management  
The sponsor or designee will be responsible for the processing and quality control of the data. The 
handling of data, including data quality control, will comply with all applicable regulatory guidelines.  
The training of clinical site personnel in eCRF completion will be the responsibility of the sponsor or 
designee. To ensure uniform data collection, Case Report Form Guidelines will be created to assist with 
eCRF completion. All site staff including investigators and research coordinators will undergo site 
initiation training to become thoroughly familiar with the protocol, case report forms, and with methods of 
data verification. 
X. C. Archiving of Data  
All study data collected at the investigator site and sponsor site will be archived in accordance with local 
guidelines and regulations.  
Clinical sites will be asked to retain the data for 5 years following completion of the study. If local country 
guidelines require longer data storage, data will be kept according to that country’s guidelines.  
All data obtained through this protocol will be securely handled and stored by the research site and by 
Heartflow, Inc., its designee, and/or other research entities that are listed in this protocol. Trained 
investigational site staff will keep a record of what data is electronically transferred and to whom. All data 
that is transferred to HeartFlow will be anonymized. 
 
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XI. SPECIAL REQUIREMENTS AND PROCEDURES  
XI. A. Institutional Review  
Before starting this study, the protocol approved by the sponsor will be submitted to the regulatory 
bodies/local health authorities, as required, in accordance with local regulations and to the IRB. The study 
will not start before the IRB gives written approval or a favorable opinion in accordance with all applicable 
regulatory bodies/local health authorities. 
No changes from the final approved protocol will be initiated without the IRB’s prior written approval or 
favorable opinion except when necessary to eliminate immediate hazards to the subjects or when the 
change involves only logistics or administration. The sponsor will authorize any protocol amendments, if 
necessary. Significant protocol amendments should be submitted to the IRB without delay.  
XI. B. Guidelines for Obtaining Subject Informed Consent  
Written informed consent approved by HeartFlow and the IRB will be obtained from each subject, or their 
legal guardian as required according to section V.B. Subject Selection.  
XI. C. Site Initiation/Training  
Prior to sites enrolling subjects, the sponsor or its designee will contact the investigator and research 
coordinator for the site initiation visit.  This visit will include the protocol review the data requirements for 
the study, including eCRF completion instructions, PI responsibilities, and to ensure all other applicable 
regulatory documents and trainings are completed.  
XI. D. Study Monitoring and Audit  
Edit checks will be included in the study database to ensure that out of range values are checked prior 
to inclusion in the dataset. If unusual outliers are found in any of the individual study populations, an audit 
plan may be developed at that time.  
XI. E.  Clinical Events Committee 
There will not be a Clinical Events Committee for this study. 
XI. F.  IVUS Core Lab 
There will be an IVUS core lab responsible for annotating the angio images, IVUS images, and HeartFlow 
provided Paraview models according to predefined study workflows. These workflows will be the joint 
responsibility of HeartFlow and the core lab and will be approved by both parties prior to implementing 
any study case reviews. All imaging data and annotations will be housed in a centralized EDC database.  
XI. G.  HeartFlow Technology / Data Team  
The HeartFlow technology / data team will be responsible for exporting the coronary models for all 
enrolled subjects via Paraview and uploading them into the EDC system for the core lab.  
Following the core lab analysis and blinded to the core lab results, the technology/data team will have 
access to the x,y,z coordinates from the annotated Paraview models and will use those to determine 
the plaque volume from the deep-learning based automated method for segmenting coronary 
atherosclerotic plaques from CCTA. Further details will be included in the study manuals separate from 
the main protocol. 
 
XII. FINAL REPORT 
Following conclusion of the study, a final report from HeartFlow or it’s designee and may be distributed 
to all investigators. This final report will include all enrolled, eligible subjects. 
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XIII. REFERENCES  
 
Taylor CA et al. Computational fluid dynamics applied to cardiac CT for noninvasive quantification of 
fractional flow reserve. J Am Coll Cardiol. 2013 https://doi.org/10.1016/j.jacc.2012.11.083 
 
Thomsen C et al. Characteristics of high-risk coronary plaques identified by computed tomographic 
angiography and associated prognosis: a systematic review and meta-analysis. Eur Heart J. 2016 
http://doi.org/doi: 10.1093/ehjci/jev325 
 
Veros S et al. Coronary Atherosclerosis Imaging by Coronary CT Angiography: Current Status, 
Correlation with Intravascular Interrogation and Meta-Analysis J Am Coll Cardiol-CV Imaging 2011 
http://doi.org/10.1016/j.jcmg.2011.03.006 
 
Koo B et al. Diagnosis of Ischemia-Causing Coronary Stenoses by Noninvasive Fractional Flow 
Reserve Computed from Coronary Computed Tomographic Angiograms: Results From the Prospective 
Multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive 
Fractional Flow Reserve) Study. J Am Coll Cardiol 2011 http://doi.org/10.1016/j.jacc.2011.06.066 
 
Min J et al. Diagnostic Accuracy of Fractional Flow Reserve From Anatomic CT Angiography. JAMA 
2012 http://doi.org/10.1001/2012.jama.11274 
 
Norgaard BL et al. Diagnostic Performance of Noninvasive Fractional Flow Reserve Derived From 
Coronary Computed Tomography Angiography in Suspected Coronary Artery Disease The NXT Trial 
(Analysis of Coronary Blood Flow. J Am Coll Cardiol 2014. https://doi.org/10.1016/j.jacc.2013.11.043 
 
Conte E et al. Plaque quantification by coronary computed tomography angiography using intravascular 
ultrasound as a reference standard: a comparison between standard and last generation computed 
tomography scanners. Eur Heart J 2019 https://doi.org/10.1093/ehjci/jez089 
 
Fischer C et al. Coronary CT angiography versus intravascular ultrasound for estimation of coronary 
stenosis and atherosclerotic plaque burden: a meta-analysis. J Cardiovasc CT 2013 
https://doi.org/10.1016/j.jcct.2013.08.006 
 
 
 
 
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