Assessing Diagnostic Value of Non-invasive FFRCT in Coronary CarE (ADVANCE)
Conditions: Coronary Artery Disease
Sponsor: HeartFlow, Inc.

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Title: 
The HeartFlow ADVANCE Registry: Assessing Diagnostic Value of Non- 
invasive FFRCT in Coronary CarE 
 
Registry Objective The objective of the HeartFlow ADVANCE Registry is to evaluate utility, 
clinical outcomes, and resource utilization of FFRCT-guided evaluation in 
clinically stable, symptomatic patients with coronary artery disease 
(CAD), in order to further inform patients, health care providers, and 
other stakeholders about which technologies are most effective and 
efficient in the diagnosis and management of CAD. 
 
Registry Design 
 
 
 
 
Principal Investigators 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
HeartFlow, Inc. 
 
 
 
 
 
Data Analysis 
HeartFlow, Inc. or designee 
 
Monitoring 
 
 
Clinical Events Committee (CEC) 
& Endpoint Review Committee 

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TABLE OF CONTENTS 
I. BACKGROUND AND RATIONALE .................................................................................................. 4 
II. FFRCT............................................................................................................................................................................................................................................. 4 
III. REGISTRY OBJECTIVE ................................................................................................................... 5 
IV. REGISTRY ENDPOINTS .................................................................................................................. 5 
IV. A. Primary Endpoints ..................................................................................................................... 5 
IV. B. Secondary Endpoints ................................................................................................................ 5 
V. REGISTRY DESIGN .......................................................................................................................... 6 
V. A. 
Location .................................................................................................................................. 6 
V. B. 
Number of Subjects and Patient Population ............................................................................ 6 
V. C. 
Subject Selection .................................................................................................................... 6 
V. D. 
General Inclusion & Exclusion Criteria ................................................................................... 6 
VI. REGISTRY WORKFLOW ................................................................................................................. 6 
VI. A. Screening Period ...................................................................................................................... 7 
VI. B. Enrollment ................................................................................................................................. 7 
VI. C. FFRCT ............................................................................................................................................................................................................................. 7 
VI. D. Summary of Registry Requirements .......................................................................................... 8 
VI. E. Treatment Recommendations ................................................................................................... 8 
VI. F. Documentation of Actual Treatment ........................................................................................... 8 
VI. G. Follow-up Visits ........................................................................................................................ 9 
VI. H. Invasive Catheterization without Obstructive Disease ................................................................ 9 
VII. REGISTRY DURATION ................................................................................................................... 9 
VII. A. Rules for Subject Withdrawal ................................................................................................... 9 
VII. B. Rules for terminating the registry ............................................................................................ 10 
VIII. Safety Assessments and Recording Reportable Events .......................................................... 10 
IX. RATIONALE AND ETHICAL CONSIDERATIONS ......................................................................... 10 
X. STATISTICAL CONSIDERATIONS ................................................................................................. 11 
X. A. General Considerations ........................................................................................................... 11 
X. B. Subject Characteristics ............................................................................................................ 11 
X. C. Endpoint Analysis ................................................................................................................... 11 
X. D. Analysis Populations ................................................................................................................ 12 
X. E. Procedures for Reporting Deviations from Original Statistical Plan ........................................... 12 
XI. DATA HANDLING AND QUALITY ASSURANCE .......................................................................... 12 
XI. A. Completing and Signing Case Report Forms ........................................................................... 12 
XI. B. Clinical Data Management ...................................................................................................... 12 

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XI. C. Archiving of Data ..................................................................................................................... 12 
XIII. SPECIAL REQUIREMENTS AND PROCEDURES ....................................................................... 13 
XIII. A. Institutional Review ................................................................................................................ 13 
XIII. B. Guidelines for Obtaining Subject Informed Consent ............................................................... 13 
XIII. C. Site Initiation/Training............................................................................................................. 13 
XIII. D. Registry Monitoring ................................................................................................................ 13 
XIII. E. Registry Close Out ................................................................................................................ 13 
XIII. F. Executive Steering Committee .............................................................................................. 13 
XIII. G. Clinical Events Committee (CEC) .......................................................................................... 14 
XIII. H. Endpoint Review Committee .................................................................................................. 14 
XIV. FINAL REPORT ............................................................................................................................ 14 
Appendix 1 - REGISTRY DEFINITIONS .............................................................................................. 15 
Appendix 2 – REFERENCES .............................................................................................................. 17 
Appendix 3 – PROTOCOL SIGNATURE PAGE, ADVANCE Registry ................................................ 19 

ADVANCE Registry Clinical Protocol 
CONFIDENTIAL 
 
 
I. BACKGROUND AND RATIONALE 
 
II. FFRCT 
 
III. REGISTRY OBJECTIVE 
 
The objective of the HeartFlow ADVANCE Registry is to evaluate utility, clinical outcomes, and 
resource utilization of FFRCT-guided evaluation in clinically stable, symptomatic patients with CAD in 
order to further inform patients, health care providers, and other stakeholders about which technologies 
are most effective and efficient in the diagnosis and management of CAD. 
 
SPECIFIC OBJECTIVES: 
 
1. To determine if the availability of FFRCT, in addition to coronary anatomy from the cCTA, will 
lead to a significant change in the coronary management plan. 
 
2. To assess the real world outcomes of utilizing FFRCT to guide invasive management and/or 
medical treatment. 
 
3. To assess resource utilization, following standard practice for diagnostic and treatment 
pathways incorporating FFRCT as the preferred CAD diagnostic test. 
 
4. To provide society including patients, health care providers, and other stakeholders with 
information about which diagnostic technologies are most effective and efficient in managing 
patients with CAD. 
 
IV. REGISTRY ENDPOINTS 
 
IV. A. Primary Endpoints 
 
The primary endpoint of the ADVANCE Registry is the reclassification rate between the coronary 
management plan based on the review of the cCTA compared to the management plan based on 
FFRCT when obtained, as assessed by an independent review committee. 
 
IV. B. Secondary Endpoints 
 
The secondary endpoints of the ADVANCE Registry include the following: 
 
a. Rate of reclassification between Investigator management plan based on cCTA alone 
compared to actual clinical management within 90 days. 
b. Rate of invasive catheterization without obstructive disease at 90 days. 
c. Percent of patients undergoing revascularization within 90 days for whom functional data are 
available prior to revascularization. 
d. Major Adverse Coronary Event (MACE) rates at 90 days, 180 days, 1 year, and 3 years. 
MACE is defined as the composite rate of all cause death, non-fatal myocardial infarction (MI) 
and unplanned hospitalization for acute coronary syndrome (ACS) leading to urgent 
revascularization. 

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e. Individual components of MACE (all cause death, non-fatal MI, unplanned hospitalization for 
ACS leading to urgent revascularization) at 90 days, 180 days, 1 year, and 3 years. 
f. 
Estimated cumulative medical radiation exposure at 1 year. 
g. Resource utilization composite at 90 days, 180 days, 1 year, and 3 years: 
a) 
Invasive diagnostic and therapeutic coronary procedures 
b) 
Treatment of MACE events 
c) 
Noninvasive cardiac testing 
 
 
 
 
V. C. Subject Selection 
 
All clinically stable, symptomatic patients diagnosed with CAD by cCTA, that meet eligibility criteria, and 
are able and willing to participate are candidates for the ADVANCE Registry. Those patients that meet 
all inclusion/exclusion criteria and who sign the EC/IRB approved informed consent will be enrolled in 
the registry. FFRCT shall be used in accordance with the current Instructions for Use document. 
 
V. D. 
General Inclusion & Exclusion Criteria 
Inclusion Criteria: 
1. Provide written informed consent 
2. Clinically stable, symptomatic patients who undergo cCTA and are diagnosed with CAD and 
meet eligibility criteria for FFRCT. 
Exclusion Criteria: 
1. cCTA showing no CAD 
2. Uninterpretable cCTA by site assessment, in which severe artifacts prevent angiographic 
evaluation 
3. Any active, serious, life-threatening disease with a life expectancy of less than 1 year 
4. Inability to comply with follow-up requirements 
 
VI. H. Invasive Catheterization without Obstructive Disease 
 
Invasive catheterization without obstructive disease will be measured by either site read coronary 
angiogram showing no stenosis of ≥ 50% or no invasively-measured FFR ≤ 0.80 in a segment distal to 
a stenosis. 
 
 
VII. A. Rules for Subject Withdrawal 
 
Each subject is free to withdraw from the registry at any time. Investigator(s) also have the right to 
withdraw subjects from the registry in the event of illness, death or serious injury, other reasons 
concerning the health or wellbeing of the subject, or in the case of lack of cooperation. Should a subject 
decide to withdraw or should the investigator(s) decide to withdraw the subject, all efforts will be made to 
complete and report the observations up to the time of withdrawal as thoroughly as possible. A complete 
final evaluation at the time of the subject’s withdrawal should be made and an explanation given as to 
why the subject is withdrawing or being withdrawn from the registry. All data collected up to the point of 

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withdrawal will remain in the study database and will be included in the analysis. 
 
The reason for withdrawal must be noted in the eCRFs. 
 
VII. B. Rules for terminating the registry 
 
There are no formal termination criteria for this registry. The sponsor reserves the right to terminate the 
registry at any time. Investigators have the responsibility to comply with all applicable regulatory 
guidelines and regulations. The sponsor, the Institutional Review Board/Ethics Committee, or the 
FDA/local regulatory authorities may terminate a center for the following (but not limited to) reasons: 
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 registry. 
 
VIII. Safety Assessments and Recording Reportable Events 
 
For the purposes of this registry, once HeartFlow becomes aware of an alleged complaint, HeartFlow will 
report per FDA Medical Device Reporting requirements, or local regulatory requirements. Such reportable 
events will include any MACE-related death or serious injury related to an FFRCT result where the 
investigator alleges that the FFRCT result is incorrect. 
 
Additionally, for the purposes of this registry, it will be required to record all MACE in the eCRFs. MACE 
is defined as the composite rate of: 
• 
all cause death 
• 
non-fatal myocardial infarction 
• 
unplanned hospitalization for acute coronary syndrome leading to urgent revascularization 
Please refer to section XIII.L, Clinical Events Committee (CEC), for further details. 
 
IX. RATIONALE AND ETHICAL CONSIDERATIONS 
 
This on-label, post-market, multi-center, prospective registry will enable evaluation of utility, clinical 
outcomes, and resource utilization following FFRCT-guided treatment in clinically stable, symptomatic 
patients with CAD diagnosed by cCTA. 
 
The potential risks to subjects participating in the HeartFlow ADVANCE Registry are solely and directly 
related to the performance of the registry procedures. 

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Anticipated risks 
 
FFRCT utilizing cCTA data, is a commercially available technology in the locations where the registry will 
be conducted, and will be used in the manner in which the product has been authorized for marketing 
and within the authorized intended use and subject population. FFRCT analysis will be performed using 
the required cCTA data-set for these subjects. The FFRCT analysis does not require additional imaging 
or image acquisition protocols, therefore is not expected to present any additional clinical risks to subjects. 
 
 
 
X. STATISTICAL CONSIDERATIONS 
 
X. A. General Considerations 
 
Tabulations of summary statistics, graphical presentations, and statistical analyses will be performed 
® 
using SAS software or an equivalent. Data obtained from clinical records and entered into the eCRF 
database will be provided in separate data listings showing individual subject values. The Steering 
Committee will work on the planning and reporting of statistical analyses by preparing a fully defined 
statistical analysis plan. 
 
X. B. Subject Characteristics 
 
Subject accountability will be described, including number of subjects enrolled, the number 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. Gender will be summarized by 
counts and percentages. Medical histories will be summarized by counts and percentages. 
 
X. C. Endpoint Analysis 
 
X. C. 1. Analysis of Primary Endpoint 
 
The primary endpoint is the reclassification rate between the coronary management plan based on the 
review of the cCTA alone compared to the management based on FFRCT when obtained, as assessed 
by an independent review committee. 
 
X. C. 2. Analysis of Secondary Endpoints 
 
Descriptive statistics for the secondary endpoints will be provided. Rates of MACE and each 
component of MACE, at each follow-up (90 days, 180 days, 1 year, and 3 years) post-procedure and 
annually thereafter) will be estimated.

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X. D. Analysis Populations 
 
Intent-to-Diagnosis (ITD): All patients who meet the registry criteria, sign the written informed consent, 
and are enrolled in the registry, will be counted in the ITD set, which will be the primary analysis set. 
Per-Protocol (PP): The ITD sample excluding patients who are “deregistered” or do not meet certain 
key entry criteria. 
 
X. E. Procedures for Reporting Deviations from Original Statistical Plan 
 
A formal statistical analysis plan encompassing all primary, secondary, and pre-specified analyses will 
be developed with input from the Steering Committee prior to locking the database. Any deviations from 
the statistical analysis (outlined in this protocol,) will be described, with reasons for the deviations listed, 
in the final study report. 
 
XI. DATA HANDLING AND QUALITY ASSURANCE 
 
XI. A. Completing and Signing Case Report Forms 
This registry will utilize eCRFs for the collection of all data. Required data will be recorded on the 
appropriate electronic eCRF at the time of or as soon as possible after the subject visit. 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. 
 
XI. 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, a Case Report Form Guide will be created to assist with 
eCRF completion. All clinical site research coordinators will undergo site initiation training to become 
thoroughly familiar with the protocol, case report forms, and with methods of data verification. 
 
XI. C. Archiving of Data 
All registry 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 2 years following 
completion of the registry. 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. These 
details are also described in the informed consent form and explained to each subject appropriately. 
 
XIII. SPECIAL REQUIREMENTS AND PROCEDURES 
XIII. A. Institutional Review 
Before starting this registry, 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 EC/IRB. The 
registry will not start before the EC/IRB gives written approval or a favorable opinion in accordance with 
all applicable regulatory bodies/local health authorities. 

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No changes from the final approved protocol will be initiated without the EC/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 EC/IRB without delay. 
 
XIII. B. Guidelines for Obtaining Subject Informed Consent 
Written informed consent approved by HeartFlow and the IRB/EC will be obtained from each subject or 
their legal guardian. 
 
XIII. C. Site Initiation/Training 
Prior to enrolling in the registry, the sponsor or its designee will contact the Investigator and Research 
Coordinator to discuss the protocol and review the data requirements of the registry, including eCRF 
completion instructions. 
 
XIII. D. Registry Monitoring 
A monitoring plan will be created at the outset of the registry and will describe the minimum monitoring 
standard to be applied, which may include a combination of on-site and remote monitoring activities. 
 
XIII. E. Registry Close Out 
Upon completion of the registry (when all subjects enrolled have completed the follow-up contacts and 
the eCRFs and queries have been completed), the sponsor and/or its designees will notify the site that 
the registry is complete and a closeout visit (on site or virtual) will be performed. All unused study 
materials will be returned to the sponsor and/or appropriately discarded as per instruction by the 
sponsor and/or its designee. 

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XIII. G. Clinical Events Committee (CEC) 
The Clinical Events Committee (CEC) will adjudicate clinical events that occur during the conduct of the 
registry to make the determination as to whether particular individual events meet the protocol-specified 
endpoints. The events that will be adjudicated in this registry include the following: 
 
• 
Death 
• 
Non-fatal myocardial infarction 
• 
Unplanned hospitalization for ACS leading to urgent revascularization 
 
The eCRF captures some of the data critical to the event adjudication. However, there will still be a 
need for supporting documentation from the sites in order to render an adjudicated result. The eCRF 
data and supporting documentation are completely anonymized by each site and identified only with the 
subject ID. 
Events will be adjudicated by the CEC according to pre-specified criteria. The CEC adjudicated data 
will be used in the analyses unless otherwise stated. 
 
XIII. H. Endpoint Review Committee 
An Endpoint Review Committee, consisting of independent physicians not participating in the 
diagnosing, planning, or treatment of subjects in the registry will be used to adjudicate the primary 
endpoint. The Committee will document the treatment management plan following review of the cCTA 
and again, following review of the enrolling FFRCT for all patients in whom cCTAs and FFRCTs are 
available. 
 
XIV. FINAL REPORT 
 
Following conclusion of the registry, a final report shall be written by HeartFlow or its designee and 
distributed to all investigators. This final report shall account for all enrolled subjects.  
 
 

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Appendix 1 - REGISTRY DEFINITIONS 
Appendix 2 – REFERENCES 
 
Appendix 3 – PROTOCOL SIGNATURE PAGE, ADVANCE Registry 
 
 
SPONSOR APPROVAL 
This protocol has been reviewed and is approved by HeartFlow. 
 
 
 
. 
Date 
 
HeartFlow, Inc. 
 
 
 
 
SITE APPROVAL 
Site Number:  
 
 
Site Name:  
 
 
 
 
I have read and understood the HeartFlow Registry Protocol titled “The HeartFlow ADVANCE Registry: 
Assessing Diagnostic Value of Non-invasive FFRCT in Coronary CarE” and agree to follow the 
procedures and requirements. 
 
 
 
 
Print Name 
Signature 
Date 

1 
 
Statistical Analysis Plan for Heartflow ADVANCE Registry 
 
 
 
By signing this document, I am confirming that I have reviewed and approve the analysis plan 
referenced above. 
 
 
 
 
Principal Investigator 
 
 
 
 
Signature 
Date (mm/dd/yyyy) 
 
 
 
 
Principal Investigator 
 
 
 
 
Signature 
Date (mm/dd/yyyy) 
 
 
 
 
Heartflow 
 
 
 
 
Signature 
Date (mm/dd/yyyy) 

2 
 
Statistical Analysis Plan: Heartflow ADVANCE Registry 
I. 
Study Overview 
cCTA is a non-invasive test used to diagnose the severity of coronary artery disease. 
FFRCT is a non-invasive test that can be added to cCTA. This study seeks to describe the 
findings of each test and describe how adding FFRCT would change the management 
plan indicated by cCTA. The study also seeks to describe subject outcomes, radiation 
exposure, and additional cardiac testing needs for subjects by whether they were 
planned for medication only, PCI, or CABG. 
 
II. 
Study Objectives 
A. Summarize baseline demographics and subject characteristics overall and by 
whether FFRCT results were available 
B. Summarize the extent of disease in each vessel measured by cCTA and FFRCT 
C. Summarize the changes in coronary therapeutic management strategy before 
and after considering both cCTA and FFRCT and report the proportion of intended 
strategies that were changed. 
D. Compare invasive catheterization (ICA) and revascularization rates between 
enrollment and the 90 day assessment based on the findings from cCTA and 
FFRCT 
E. Determine whether major adverse coronary event rates during follow-up differ 
according to treatment plan and testing findings 
F. Summarize the estimated cumulative radiation exposure 
G. Determine whether the time to first cardiovascular test during follow-up differs 
according to management strategy 
 
 
IV. 
General Methodology 
Most of the analyses will be descriptive. Unless noted otherwise, categorical variables 
will be presented as number and percentage and continuous variables will be presented 
as median (25th, 75th percentile). Kaplan-Meier methods will be used to report event 
rates that occur during follow-up. The key objectives that will involve statistical testing 
are the relationships between having an invasive procedure or revascularization and the 
findings from cCTA and FFRCT. 

3 
 
V. 
Subject Accountability and Characteristics 
 
VI. 
Sample Size Determination 
 
 
VII. 
Definitions 
 
VIII. 
Endpoint Analyses 
A. Primary Endpoint: The proportion of coronary management plans that were 
changed when core lab FFRCT coronary anatomy findings were added to the core 
lab cCTA findings 
 
 
B. Secondary Endpoints 
i. Secondary Endpoint 1: The proportion of coronary management plans 
that were changed when site reported lab FFRCT coronary anatomy 
findings were added to the site reported lab cCTA findings 
ii. Secondary Endpoint 2: Vessel level findings from cCTA and FFRCT 
 
iii. Secondary Endpoint 3: Invasive catheterization and revascularization 
rates 90 days post enrollment 
iv. Secondary Endpoint 4: Major adverse coronary event (MACE) rates 
during follow-up 
 
v. Secondary Endpoint 5: Estimated cumulative radiation exposure 
vi. Secondary Endpoint 6: Cardiovascular testing rates during follow-up 
vii. Secondary Endpoint 7: Result from first post-baseline ICA 
 
 
IX. 
Safety Analyses 
Not applicable 
 
XI. 
Changes from the Study Protocol Reflected in this Analysis Plan 
None