The Value of Fractional Flow Reserve Derived From Coronary CTA and in the Triage of Low to Intermediate Risk Chest Pain Patients: Design: Single Center Prospective Clinical Trial; Target Disease: Coronary Artery Disease
Conditions: Angina, Stable Chest Pain
Sponsor: Northwell Health

 
Protocol Design Template © 2009  
 
 
 
 The Value of Fractional Flow Reserve Derived from Coronary CT Angiography and in the 
Triage of Low to Intermediate Risk Chest Pain Patients:  Design:  Single Center Prospective 
Clinical Trial; Target Disease:  Coronary Artery Disease. 
 
 
PI:  Michael Poon, M.D. 
Department Name:  Non-Invasive Cardiology 
Facility Name: Lenox Hill Hospital 
Address: 100 East 77th Street, 2 East, New York, NY 10075 
Phone: Number 212-434-6119 
Fax Number: 212-434-3189 
E-mail Address: mpoon1@northwell.edu 
Funding Sponsor: 
Primary Funding Institution: Northwell Health Foundation:  
Lenox Hill.  Funded by:  Charitable Contribution for CT-
FFR study to be supervised by Dr. Michael Poon. 
Address:  Northwell Health 
Phone Number: 646-766-7131 
Study Product: 
Device Name –   Coronary Tomographic Fractional Flow 
Reserve; HeartFlow CT-FFR 
Protocol Number: 
n/a 
IND/IDE  Number: 
n/a 
Performance Site(s): 
Lenox Hill Hospital, New York, NY 
 
 
 
 
 
 
 
Date: 
12/22/16 
Amended: 
8/26/2017  3.21.2019 
 
 
 
CONFIDENTIAL 
 
This document is confidential and the property of the North Shore-LIJ Health System.  No 
part of it may be transmitted, reproduced, published, or used by other persons without 
prior written authorization from the study sponsor. 

 
 
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CONFIDENTIAL 
 
Table of Contents 
STUDY SUMMARY ................................................................................................................................................... 1 
1 
PREVIOUS STUDY HISTORY ....................................................................................................................... 2 
2 
BRIEF SUMMARY OF RESEARCH .............................................................................................................. 2 
3 
INTRODUCTION .............................................................................................................................................. 2 
3.1 
BACKGROUND .................................................................................................................................................. 3 
3.2 
INVESTIGATIONAL AGENT................................................................................................................................ 3 
3.3 
PRECLINICAL DATA ......................................................................................................................................... 4 
3.4 
CLINICAL DATA TO DATE ................................................................................................................................ 4 
3.5 
DOSE RATIONALE AND RISK/BENEFITS ............................................................................................................ 4 
4 
STUDY OBJECTIVES ...................................................................................................................................... 4 
5 
RESOURCES AVAILABLE TO CONDUCT THE HUMAN RESEARCH ................................................ 5 
6 
STUDY DESIGN ................................................................................................................................................ 5 
6.1 
GENERAL DESIGN ............................................................................................................................................ 5 
6.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................................... 6 
6.3 
SECONDARY STUDY ENDPOINTS ...................................................................................................................... 7 
6.4 
PRIMARY SAFETY ENDPOINTS .......................................................................................................................... 7 
7 
SUBJECT SELECTION AND WITHDRAWAL............................................................................................ 7 
7.1 
INCLUSION CRITERIA ....................................................................................................................................... 7 
7.2 
EXCLUSION CRITERIA ...................................................................................................................................... 8 
7.3 
VULNERABLE POPULATIONS ............................................................................................................................ 8 
7.4 
SUBJECT RECRUITMENT AND SCREENING ........................................................................................................ 9 
7.5 
CONSENT PROCESS .......................................................................................................................................... 9 
7.6 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................... 10 
7.6.1 
When and How to Withdraw Subjects .................................................................................................. 10 
7.6.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 11 
8 
STUDY DRUG/DEVICE ................................................................................................................................. 11 
8.1 
DESCRIPTION ................................................................................................................................................. 11 
8.2 
TREATMENT REGIMEN ................................................................................................................................... 11 
8.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................................... 11 
8.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG/IMPLANTATION OF STUDY DEVICE .......................... 12 
8.5 
SUBJECT COMPLIANCE MONITORING ............................................................................................................. 12 
8.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................................ 12 
8.7 
PACKAGING.................................................................................................................................................... 13 
8.8 
BLINDING OF STUDY DRUG/DEVICE .............................................................................................................. 13 
8.9 
RECEIVING, STORAGE, DISPENSING AND RETURN .......................................................................................... 13 
8.9.1 
Receipt of Drug Supplies/Device ......................................................................................................... 13 
8.9.2 
Storage ................................................................................................................................................. 13 
8.9.3 
Dispensing of Study Drug/Device ........................................................................................................ 13 
8.9.4 
Return or Destruction of Study Drug/Device ....................................................................................... 13 
9 
STUDY PROCEDURES .................................................................................................................................. 13 
9.1 
VISIT 1 ........................................................................................................................................................... 15 
9.2 
VISIT 2 ........................................................................................................................................................... 15 
9.3 
ETC. ................................................................................................................................................................ 16 
10 
RISKS TO SUBJECTS .................................................................................................................................... 16 
11 
POTENTIAL BENEFIT TO SUBJECTS ...................................................................................................... 17 
12 
RESEARCH RELATED HARM/INJURY .................................................................................................... 17 

 
 
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CONFIDENTIAL 
 
13 
PROVISIONS TO PROTECT PRIVACY INTERESTS OF SUBJECTS .................................................. 18 
14 
STATISTICAL PLAN ..................................................................................................................................... 18 
14.1 
SAMPLE SIZE DETERMINATION ................................................................................................................. 18 
14.2 
STATISTICAL METHODS............................................................................................................................. 18 
14.3 
SUBJECT POPULATION(S) FOR ANALYSIS .................................................................................................. 20 
15 
SAFETY AND ADVERSE EVENTS ............................................................................................................. 20 
15.1 
DEFINITIONS .............................................................................................................................................. 20 
15.2 
RECORDING OF ADVERSE EVENTS............................................................................................................. 21 
15.3 
REPORTING OF SERIOUS ADVERSE EVENTS ............................................................................................... 22 
15.3.1 
Study Sponsor Notification by Investigator ..................................................................................... 22 
15.3.2 
EC/IRB Notification by Investigator ............................................................................................... 22 
15.3.3 
FDA Notification by Sponsor ............................................................ Error! Bookmark not defined. 
15.4 
UNBLINDING PROCEDURES........................................................................................................................ 22 
15.5 
STOPPING RULES ....................................................................................................................................... 22 
15.6 
MEDICAL MONITORING ............................................................................................................................. 22 
15.7 
DATA AND SAFETY MONITORING .............................................................................................................. 23 
15.7.1 
Data and Safety Monitoring Plan ................................................................................................... 23 
15.7.2 
Internal Data and Safety Monitoring Board ..................................... Error! Bookmark not defined. 
15.7.3 
Independent Data and Safety Monitoring Board .............................. Error! Bookmark not defined. 
16 
DATA HANDLING AND RECORD KEEPING .......................................................................................... 24 
16.1 
CONFIDENTIALITY ..................................................................................................................................... 24 
16.2 
SOURCE DOCUMENTS ................................................................................................................................ 24 
16.3 
CASE REPORT FORMS ................................................................................................................................ 24 
16.4 
RECORDS RETENTION ................................................................................................................................ 24 
17 
STUDY MONITORING, AUDITING, AND INSPECTING ....................................................................... 24 
17.1 
STUDY MONITORING PLAN ....................................................................................................................... 24 
17.2 
AUDITING AND INSPECTING ....................................................................................................................... 25 
18 
ETHICAL CONSIDERATIONS .................................................................................................................... 25 
19 
STUDY FINANCES ......................................................................................................................................... 25 
19.1 
FUNDING SOURCE ..................................................................................................................................... 25 
19.2 
CONFLICT OF INTEREST ............................................................................................................................. 25 
19.3 
SUBJECT STIPENDS OR PAYMENTS ...................................................... ERROR! BOOKMARK NOT DEFINED. 
20 
PUBLICATION PLAN .................................................................................................................................... 26 
21 
REFERENCES .................................................................................. ERROR! BOOKMARK NOT DEFINED. 
22 
ATTACHMENTS ............................................................................................................................................ 27 
 

 
 
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List of Abbreviations 
 
Fractional Flow Reserve:  FFR 
Coronary Computed Tomographic Angiography:  CCTA 
Computed Tomographic Fractional Flow Reserve:  CT-FFR 
Percutaneous Coronary Intervention:  PCI 
Cardiac Catheterization: Cardiac Cath 
Coronary Artery Bypass Graft:  CABG  
Stress Myocardial Perfusion Imaging:  Stress MPI 
Invasive Coronary Angiography: ICA 
Body Mass Index: BMI 
Electrocardiogram:  EKG  
Estimated Glomerular Filtration Rate: eGFR 
Portable document format:  pdf

 
 
Page 1 of 31 
Study Summary 
Title 
The Value of Fractional Flow Reserve Derived from Coronary CT 
Angiography and in the Triage of Low to Intermediate Risk Chest Pain 
Patients 
Short Title 
Value of FFR 
Protocol Number 
n/a 
Phase 
n/a – single phased study. 
Methodology 
Prospective clinical trail 
Study Duration 
15 months 
Study Center(s) 
Single center 
Objectives 
The purpose of this study is to evaluate the incremental benefit of 
Fractional Flow Reserve (FFR) derived from Coronary Computed 
Tomographic Angiography (CCTA) (CT-FFR) compared to CCTA with 
or without stress testing, using invasive FFR as the gold standard for 
patients with obstructive disease (> 30% stenosis).  This study will also 
assess the capability of CT-FFR to enhance performance on both 
negative and positive predictive value for less experienced readers by 
providing feedback based on CT-FFR evaluation 
Number of Subjects 
Number of subjects projected for the entire study 572 
Diagnosis and Main 
Inclusion Criteria 
Chest Pain and stable angina patients with suspicion of coronary 
artery disease 
Study Product, Dose, 
Route, Regimen 
n/a.  The study will assess the capability of measuring fractional flow 
reserve noninvasively utilizing computers and information provided by 
routine CCTA studies.  
Duration of 
administration 
  n/a 
Reference therapy 
The standard reference will be invasive FFR. 
Statistical 
Methodology 
Defining an event as performance of ICA when no intervention is 
necessary, we expect to compare event rates for patients treated with 
CCTA and FFR-CT, using t-tests and a multivariate, risk adjusted 90 
day hazard model with 95% confidence interval.  Our null hypothesis 
is that outcomes will not vary regardless of which testing is used to 
assess obstructive disease.  Our alternative hypothesis is that 
evaluation with FFR-CT as oppose to CTTA alone will reduce the 
event rate.   
We will assess the comparability of the  CCTA readers’ readings and 
compare them to the CT-FFR results and the noninvasive FFR results. 
 

 
 
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1 Previous Study History 
Has this study ever been reviewed and rejected/disapproved by another IRB prior to 
submission to this IRB? 
 
X
 No  
 Yes   if yes, please explain:  
 
2 Brief Summary of Research 
 
Coronary Computed Tomography Angiogram (CCTA) is a non-invasive imaging modality 
that has high sensitivity and negative predictive value for the detection of coronary artery 
disease (CAD). The main limitations of CCTA are its poor specificity and positive predictive 
value, as well as its inherent lack of physiologically relevant data on hemodynamic 
significance of coronary stenosis, a data that is provided either by non-invasive stress tests 
such as myocardial perfusion imaging (MPI) or invasively by measurement of the Fractional 
Flow Reserve (FFR). Recent advances in computational fluid dynamic techniques applied to 
standard CCTA are now emerging as powerful tools for virtual measurement of FFR from 
CCTA imaging (CT-FFR). These techniques correlate well with invasively measured FFR [1-
4]. The primary purpose of this study is to evaluate the incremental benefit CT-FFR as 
compared to CCTA in triaging chest pain patients in outpatient settings who are found to have 
obstructive CAD upon CCTA (> 30% stenosis). Invasive FFR and short term clinical 
outcomes (90 days) will be correlated with each diagnostic modality in order to evaluate 
positive and negative predictive value of each when used incrementally with CCTA. 
 
Patients will undergo a CCTA, as part of routine care.  If the patient consents to participate in 
the study and is found to have coronary stenosis of 30% to 100%, based on the cardiologist’s 
reading, the CCTA study will be sent to HeartFlow, a vendor that will provide a computerized 
FFR reading, based on the CCTA study.  If the noninvasive FFR diagnosis indicates 
obstructive disease, the patient will undergo cardiac catheterization with invasive FFR. 
 
As CCTA utilization increases, the need to train additional imaging specialists will increase.  
This study will assess the capability of FFR-CT to enhance performance on both negative and 
positive predictive value for less experienced readers by providing feedback based on CT-FFR 
evaluation.  CCTA readers will be grouped in two categories:  those with more than 10 years 
reading experience and those with less than 10 years reading experience.  Each CCTA will be 
read by a less experienced and a more experienced reader.  Results from each reader will be 
correlated with each other and with the CT-FFR and invasive FFR results.   
 
3 Introduction 
 
This document is a protocol for a human research study. This study is to be conducted 
according to US and international standards of Good Clinical Practice (FDA Title 21 part 312 

 
 
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and International Conference on Harmonization guidelines), applicable government 
regulations and Institutional research policies and procedures. 
 
3.1 Background 
 
Coronary Computed Tomography Angiogram (CCTA) is a non-invasive imaging modality that 
has high sensitivity and negative predictive value for the detection of coronary artery disease 
(CAD). The main limitations of CCTA are its poor specificity and positive predictive value, as 
well as its inherent lack of physiologically relevant data on hemodynamic significance of 
coronary stenosis, a data that is provided either by non-invasive stress tests such as 
myocardial perfusion imaging (MPI) or invasively by measurement of the Fractional Flow 
Reserve (FFR). Recent advances in computational fluid dynamic techniques applied to 
standard CCTA are now emerging as powerful tools for virtual measurement of FFR from 
CCTA imaging (FFR-CT). These techniques correlate well with invasively measured FFR [1-
4]. The primary purpose of this study is to evaluate the incremental benefit FFR-CT as 
compared to CCTA in triaging chest pain patients in outpatient settings who are found to have 
obstructive CAD upon CCTA (> 30% stenosis). Invasive FFR and short term clinical 
outcomes (90 days) will be evaluated for each diagnostic modality in order to evaluate 
positive and negative predictive value of each when used incrementally with CCTA. 
 
3.2 Investigational Agent 
 
CCTA is increasingly becoming a preferred non-invasive imaging modality because of its high 
sensitivity and negative predictive value for the detection of CAD.  It has been shown to be a 
robust imaging modality for evaluation of chest pain, and is associated with decreased 
unnecessary hospital admission, length of stay, major adverse cardiovascular event rates, 
recidivism rates, and downstream resource utilization compared to standard evaluation [5].  
While findings so far are highly suggestive of CCTA’s significance as a gatekeeper for ICA by 
ruling out obstructive CAD, fewer than half of obstructive stenosis identified by CCTA are 
ischemia-causing, signifying its poor positive predictive value and inherent lack of 
physiological information [6-8]. Consequently, utilization of CCTA has not entirely averted 
need for downstream testing for functional assessment of CCTA-detected obstructive lesions 
either by stress testing or ICA.  Recently a major treatment modality, associated with the use 
of CCTA, has become available that offers promise for improving positive predictive value and 
physiological relevant hemodynamic data.  Advances in computational fluid dynamic 
techniques applied to standard CCTA are now emerging as a powerful tool for virtual 
measurement of FFR from CCTA imaging (CT-FFR). This techniques correlate well with 
invasively measured FFR [1-4].  CT-FFR is not an investigational agent, having been 
approved by FDA in November, 2014.  However, more work is necessary to delineate the 
patient population that could derive maximal benefit from this new technology. 
 

 
 
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3.3 Preclinical Data 
 
While few publications regarding the use of CT-FFR specifically address the cost of 
diagnostic work-up for obstructive disease, it is clear that the cost structure resulting from 
changes in diagnostic testing will also change.  Deferral or avoidance of cardiac 
catheterization and nuclear stress testing will likely yield significant reductions in the cost of 
the diagnostic testing.   
 
3.4 Clinical Data to Date 
 
From 1/1/2009 to 3/31/2015 our team introduced and operated a CCTA Chest Pain triage 
program for low to intermediate risk patients at Stony Brook University Hospital ED and non-
emergency outpatient services, the only tertiary care hospital in Suffolk County.  
Concurrently, we established a registry to monitor patient outcomes for all patients receiving 
CCTA at Stony Brook Medicine.  Our registry contained nearly 15,000 patient CCTA 
procedures.  Our major registry study established the effectiveness of CCTA as an imaging 
modality for evaluating ED chest pain in a cost efficient manner with a false negative rate less 
than 1% [5].  However, our registry reflects the poorer positive predictive values documented 
by other industry studies [6-8].   
 
False positive workup results in the necessity of performing cardiac catheterization on 
patients at risk for obstructive disease based on assessment with current standard of care 
(combined screening with CCTA and stress MPI).  Reduction in the rate of false positive 
testing would lead to reduction in risk from invasive procedures and radiation exposure to 
patients and reduced cost to the health care system.    
 
Several medical institutions currently use HeartFlow CT-FFR as standard of care for 
evaluating obstructive disease.  Generally, the standard of care at these institutions is to refer 
patients who are 30 to 100 percent obstructed by CCTA and who have reduction of flow <= to 
0.8 that is deemed to be medical significant by the attending cardiologist to Invasive FFR.  
HeartFlow has reported to us confidentially that this routine use of CT-FFR has resulted in a 
54% reduction in false positive rate as compare to use of CCTA alone.   
 
3.5 Dose Rationale and Risk/Benefits 
n/a  This is not a pharmaceutical study. 
 
4 Study Objectives 
 
The purpose of this study is to evaluate the incremental benefit of Fractional Flow Reserve 
derived from CCTA (FFR-CT) compared invasive FFR as the gold standard for patients with 
obstructive disease (> 30%  stenosis).  This study will also assess the capability of CT-FFR to 

 
 
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enhance performance on both negative and positive predictive value for less experienced 
readers by providing feedback based on CT-FFR evaluation.   
 
5 Resources Available to Conduct the Human Research 
 
The primary data collection for the study will be generated from stable chest pain and angina 
patients receiving routine CCTA as part of their workup.  Patients will be offered the 
opportunity to participate in clinical trial.  Lenox Hill hospital routinely provides more than 
1,000 CCTA scans annually to this patient population. Therefore, out target of 572 cases 
should be achievable. Our noninvasive cardiology imaging team, including 6 attending 
cardiologists, and 2 cardiology fellows, and a cardiac imaging fellow will participate in the 
study.  In addition, we will employ a study coordinator, an IT specialist who works in 
cardiology, our lead CCTA technician, and a PhD with training in statistics and economics.  
All team members attend weekly research group meetings to plan and monitor the study, 
including duties of team members and study process and flow. 
 
6 Study Design 
6.1 General Design 
This will be a prospective clinical trial designed to evaluate the incremental benefit of virtual 
FFR measured from CCTA, compared to invasive FFR and CCTA for the detection of flow-
limiting coronary stenosis, as defined by invasive FFR <=0.8 and vessel diameter of >=2mm.  
 
572 consecutive patients who present to Lenox Hill Hospital Outpatient Clinics for CCTA due 
to chest pain or stable angina over a ten month period and meeting the study inclusion criteria 
are eligible for the study (Figure 1). Our team will employ CCTA-appropriateness criteria to 
ensure proper selection of patients, derived from the Appropriate Use Criteria for Cardiac 
Computed Tomography published in 2010 and jointly authored by multiple societies including 
ACCF, SCCT, and ACR [10]. FFR-CT measurements will be performed by a core laboratory 
in a blinded fashion. All eligible patients will undergo 64-slice or greater multi detector CCTA 
and CT-FFR measurements. The severity of the stenosis will be determined on site by level III 
CCTA readers. Patients with obstructive lesions of (30% to 100% stenosis) will receive Stress-
MPI, per SOC protocol, and CT-FFR.  Patients with positive Stress-MPI and CCTA (50% - 
70%) or positive CCTA (71% to 100%) will undergo ICA with invasive FFR measurement in 
accordance to accepted guidelines and established practice standard. Those patients with 
invasively measured FFR<=0.8 and with vessel diameter of >= 2mm, or those who require 
revascularizations based on invasively estimated stenosis severity will be considered to have 
flow-limiting obstructive CAD, while the rest will be considered to have non-flow limiting 
obstructive CAD (if also >50% stenosis on ICA). If stenosis severity turns out to be < 50% 
after ICA (the gold standard), we will conclude that these patients have non-obstructive CAD. 
(Figure 1). Patients with 30% to 49% obstructive disease, according to CCTA, will be referred 
to optimal follow up care only.   Any in this group who have positive CT-FFR will return for 

 
 
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ICA with invasive FFR measurement, and follow the protocol for those with 50% to 100% 
obstruction. 
 
Figure 1: 
 
 Stable chest pain patients referred for outpatient CCTA 
 
 
In order to assess the primary endpoint of comparison of event rates for patients treated with 
CCTA and FFR-CT, we will perform a retrospective chart review of Invasive Coronary 
Angiograms performed at Lenox Hill Hospital from 2014 to 2018. We will specifically review 
Cardiac Catheterization reports to screen patients and record data for cases where the 
indication for Catheterization was (1) Positive stress test and/or (2) Positive CCTA.  
Based on the catheterization report we will determine whether the patient had obstructive 
coronary artery disease with/without flow limitation, in the same manner and following the 
same definitions as those used to categorize level of obstruction in subjects enrolled in the 
prospective cohort of the study. 
This data will be used as comparison/control group to assess trends and rates of invasive 
coronary catheterization when no intervention is necessary, in cases where CCTA and/or 
stress test without CT-FFR was used to determine the need for cardiac catheterization. Only 
the minimum amount of data required for a robust comparison of event rates will be collected. 
 
6.2 Primary Study Endpoints 
 
Defining an event as performance of ICA when no intervention is necessary, we expect to 
compare event rates for patients treated with CCTA and FFR-CT, using t-tests and a 
multivariate, risk adjusted 90 day hazard model with 95% confidence interval.  Our null 
hypothesis is that outcomes will not vary regardless of which testing is used to assess 

 
 
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obstructive disease.  Our alternative hypothesis is that evaluation with FFR-CT as oppose to 
CTTA will change the event rate.  We will also correlate noninvasive and invasive FFR 
studies. 
 
 
 
6.3 Secondary Study Endpoints 
 
We will assess inter-observer reliability  of the two reader cohorts’ (> 10 years experience 
and less than 10 years experience) readings for CCTA and  CT-FFR..  We will also assess the 
nondiagnostic rate for CT-FFR exams as compared to independent quality ratings of CCTA 
scans by the scan reader.  Scans will be rated as excellent, good, adequate, or non-diagnostic.  
Non-diagnostic exams will not be sent to CT-FFR.  For those sent to CT-FFR we will compare 
the percentage of non-diagnostic exams to the percentage of non-diagnostic for CT-FFR, and 
we will also correlate exam results by level of obstruction.   
 
6.4 Primary Safety Endpoints 
 
The study design evaluates the potential to substitute non-invasive for invasive FFR.  Safety 
endpoints of the study include:  1. Evaluating the diagnostic accuracy of non-invasive FFR.  If 
the end result demonstrates that the procedure is less accurate than invasive FFR, patients 
receiving this procedure, as an alternative to the current standard will be at greater risk.  2.  
Patients who undergo invasive procedures experience increased risk of infection or other 
comorbidities or complications, as compared to those who do not undergo invasive 
procedures.  Therefore, if the noninvasive protocol results are not significantly different than 
the invasive results, patient safety might potentially be increased by using the noninvasive 
technology.  3.  Noninvasive technology has the potential to reduce radiation exposure by 
reducing the number of invasive angiography and Stress MPI procedures necessary to 
complete patient evaluation.  This increases patient safety relative to the adverse effects of 
radiation exposure.  
 
 
 
7 Subject Selection and Withdrawal 
7.1 Inclusion Criteria 
 
1.  Patients must be capable of giving informed consent. 
2. Patients must be able to cooperate with technician performing the procedure. 
3. Patients must have BMI <= 50. 
4. Patients must have  non-STEMI EKG without acute changes 

 
 
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5. Patients must present to Lenox Hill Ambulatory CCTA Clinic with medically 
necessary appointment for CCTA for the purpose of evaluation coronary 
stenosis for the provisional diagnoses of chest pain or angina or angina 
equivalent. 
6. Patient must be able to take nitroglycerin and beta blockers.   
 
7.2 Exclusion Criteria 
Create a numbered list of criteria that would exclude a subject from study enrollment.  If 
appropriate, should generally include that subjects cannot be homeless persons, or have active 
drug/alcohol dependence or abuse history.  If exposure to certain medications or treatments at 
screening is prohibited, that must be noted in the exclusion criteria—if these are also prohibited 
concomitant medications during the study period that should be noted here as well.   
 
7. Patient must not have a history of coronary stenting or coronary artery bypass 
graft. 
8. Patients must not have severe or end stage renal disease as diagnosed as eGFR 
< 50. 
9. Patients must not have a BMI > 50. 
10. Patients must not have active asthma requiring bronchodilator  therapy. 
11. Must not have any allergies to contrast. 
 
 
7.3 Vulnerable Populations 
Indicate whether you will target any of these vulnerable populations.  
  Children or viable neonate  
  Cognitively impaired  
  Pregnant Women, Fetuses or neonates of uncertain viability or nonviable  
  Prisoners  
  NSLIJ Employees, residents, fellows, etc 
  poor/uninsured 
  Students 
  Minorities 
  Elderly 
  Healthy Controls 
 
If any of these populations are included in the study, describe additional safeguards that will be 
used to protect their rights and welfare. 
 
None of these vulnerable populations are targets of this study. 
 
 

 
 
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7.4 Subject Recruitment and Screening 
 
Patients scheduled to present or presenting to the Lenox Hill Ambulatory Care CCTA Clinic 
for evaluation of coronary stenosis with the provisional diagnosis of chest pain of angina will 
be offered the opportunity to participate in this clinical trial.  If possible, patients will be 
contacted in advance of the visit by the study coordinator and educated on the study.  All 
eligible patients will receive education about the study and offered the opportunity to 
participate upon arrival to the clinic.   
 
The study coordinator, cardiology fellow, or cardiologist will take the patient’s medical history 
as it relates coronary stenting, CABG and other cardiac risk factors (including smoking, family 
history of heart disease, hyperlipidemia, diabetes, hypertension.)  Routine preparation for 
CCTA with be conducted by clinic staff.  As part of this activity patient height and weight will 
be obtained, and a blood draw for Serum Creatinine to calculate patient eGFR will be taken.   
 
In order to assess the primary endpoint of comparison of event rates for patients treated with 
CCTA and FFR-CT, we will perform a retrospective chart review of Invasive Coronary 
Angiograms performed at Lenox Hill Hospital from 2014 to 2018. We will specifically review 
Cardiac Catheterization reports to screen patients and record data for cases where the 
indication for Catheterization was (1) Positive stress test and/or (2) Positive CCTA.  
Based on the catheterization report we will determine whether the patient had obstructive 
coronary artery disease with/without flow limitation, in the same manner and following the 
same definitions as those used to categorize level of obstruction in subjects enrolled in the 
prospective cohort of the study. 
 
 
7.5 Consent Process 
 
The study cardiology fellow or cardiologist will obtain the informed consent from the patient 
in the Lenox Hill Ambulatory CCTA Clinic.  An attempt at outreach will be made for 
scheduled patients to apprise them of the fact that a study is being conducted.  Consent will be 
obtained on the days of the study.  Before consent is obtained, the cardiologist or cardiology 
fellow will review the major activities of the study with the patient, provide an opportunity for 
the patient to ask questions, and ask the patient to sign the consent.  The patient will receive a 
copy of the informed consent form (attached), explaining the procedure. Signed informed 
consent forms will be maintained by the Study Coordinator. 
 
We would like to request a waiver of consent and HIPAA Authorization for the retrospective 
chart review portion of the study. There will be no intervention, testing, or contact with 
subjects included in this portion. Only the minimum amount of data required for a robust 
comparison of event rates will be collected. The retrospective portion of the study meets the 
criteria for a complete waiver of consent 1) The research involved no more than minimal risk 
as it simply involves the collection and analysis of previously collected health information of 
patients who underwent CCTA and invasive cardiac catheterization.  2) The wavier will not 
adversely affect the rights or welfare of participants because, given that the research would 

 
 
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not impact the participant’s current or future care; 3) the study could not be practicably 
conducted without the waiver given the large sample size and the fact that the participants 
were never or are no longer patients of the PI. It is also possible that the subjects are now 
deceased or no longer part of the Northwell system. 4) The outcome of the chart review will 
not impact the future care of participants so no additional information will be provided to 
them. The study will protect the identifiers by storing information in REDCap. 
 
PHI (date of procedure and participant name) is required for the conduct of the retrospective 
portion of the study as the researchers will need to access the charts of individuals who meet 
study criteria in order to collect the test results of interest. 
 
 
 
 
 
No study participants under the age of 18 will be recruited. 
 
 
 
 
Cognitively impaired subjects will not be recruited, due to the need for the subjects to be 
capable of following the technologist’s instructions during the CCTA exam. 
 
If the study will enroll non-English speaking subjects: 
 
The study does not target non English speaking populations.  However, we will utilize 
Northwell approved short forms combine with HIPAA authorization forms translated in the 
appropriate language as necessary to ensure that the subject can provide appropriate consent. 
 
7.6 Early Withdrawal of Subjects 
7.6.1 When and How to Withdraw Subjects 
Subjects may withdraw from the study for any reason at their request.  Subjects who cannot or 
will not cooperate with the CCTA technologists instructions will be withdrawn from the study, 
because we will not be able to perform a CCTA.  For some subjects, FFR results may not be 
available due to poor quality of CCTA scan.  In this case, the subject will remain in the study, 
following standard of care, but no FFR reading will be available.   If at any time a patient 
experiences an adverse reaction to medical care, the procedure will be ended and the patient 
will be withdrawn from the procedural part of the study.  Wherever possible, when patients 
withdraw from the procedure part of the study (the CCTA) we will make every effort to 
conduct study follow-up. 
 

 
 
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7.6.2 Data Collection and Follow-up for Withdrawn Subjects 
 
We will make every effort to conduct study follow up for all subjects, regardless of their ability 
to receive CCTA and CT-FFR.  The study coordinator will make a minimum of 5 attempts to 
follow up with the subjects by telephone.  If this does not work, he will try to contact the 
patients 3 times by email, if patient contact information is available, and once by U.S. postal 
service certified mail.  The team will also check records for follow up at Lenox Hill Hospital 
and will review death registries to ascertain whether the patient is still alive.   
 
8 Study Drug/Device  
8.1 Description 
 
The agent in this study is the computer program that provides the CT-FFR interpretation of 
flow.  This is not an investigational agent, having been approved by the IRB in November 
2014.  The results will allow the physician to visualize flow through the coronary arteries and 
measure the level of obstructive disease.  The physician will dictate a report based on his/her 
interpretation of the images.  The report and a portable document format (pdf) file of a major 
view of the coronaries will be maintained as part of the patient’s medical record. 
 
8.2 Treatment Regimen 
 
The CCTA data will be collected as part of the standard of care delivered for patients 
undergoing CCTA with contrast.   
 
8.3 Method for Assigning Subjects to Treatment Groups 
 
This is not a randomized study.  Treatment assignments will follow the clinical protocol. 
 
Once the CCTA results are interpreted by the physician, the physician will order CT-FFR 
exams for patients whose level of stenosis by CCTA standards is 30% to 100%.   
 
If CT-FFR is positive patients will be referred for Cardiac Catheterization and invasive FFR.   
 
If CT-FFR is negative, and level of obstruction is 30 to 49% by CCTA standards, patients will 
be referred to optimal medical care.   
 
If CT-FFR is negative and level of obstruction is 50% to 70% by CCTA standards, patient will 
be referred for stress MPI.  If stress MPI is positive patients will be referred for Cardiac Cath 
and invasive FFR.  If stress MPI is negative, patients will be referred to optimal medical care. 
 

 
 
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If the patient has had a stress MPI within one year of the CCTA exam and the CCTA exam 
result is 50% to 70% obstructive, the physician will rely on the prior stress testing result, 
rather than repeating the stress test. If the stress testing results was negative, the patient will 
be referred to optimal medical care.  If, in the investigator’s opinion, the results indicate that 
the patient is at increased risk of obstructive disease, when considered with the CCTA 
findings, the patient  will be referred to Cardiac Cath and Invasive FFR.  
 
If CT-FFR is negative and level of obstruction is 70% to 100% by CCTA standard, patient will 
be referred to Cardiac Cath and Invasive FFR. 
 
8.4 Preparation and Administration of Study Drug/Implantation of 
Study Device 
 
The device in this study is the computer program that provides the CT-FFR interpretation of 
flow.  The results will allow the physician to visualize flow through the coronary arteries and 
measure the level of obstructive disease.  The physician will dictate a report based on his/her 
interpretation of the images.  The report and a pdf of a major view of the coronaries will be 
maintained as part of the patient’s medical record. 
 
The use of the devise requires no variance from the routine standard of care for CCTA.  The 
CCTA results will be sent to HeartFlow for CT-FFR analysis if the physician finds that the 
patient has 30% to 100% obstructive disease based on CCTA standards. 
 
8.5 Subject Compliance Monitoring 
 
Study treatment regimen requires that the patient follow physicians’ recommendations 
concerning follow-up care as described above.  The study coordinator will monitor the 
patients to determine whether the patient follows the recommended treatment plan.  If not, a 
study cardiologist will contact the patient and encourage compliance with the treatment plan.    
 
8.6 Prior and Concomitant Therapy 
 
Prior and concomitant medical therapy will be collected and documented at the time of patient 
referral to Lenox Hill Hospital Ambulatory Care CCTA Clinic as part of the medical history.  
The coordinator will also contact the patient 90 to 120 days after the CCTA exam and 
interview the patient on follow up care, including any additional medical interventions.  
Specifically, the coordinator will maintain a record of patients’ documented cardiac risk 
history and track cardiac interventions for obstructive disease, including PCI and CABG 
during the study. 
 

 
 
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8.7 Packaging 
 
n/a 
 
8.8 Blinding of Study Drug/Device 
 
This is not a blinded study, in terms of patient randomization into study cohorts.  However, 
when patients are referred for CT-FFR, no information regarding the CCTA results will be 
provided to HeartFlow (the provider of CT-FFR services.) When Cardiologists interpret 
CCTA and Stress-MPI results, no information regarding CT-FFR results will be available to 
them for review. 
 
8.9 Receiving, Storage, Dispensing and Return 
8.9.1 Receipt of Drug Supplies/Device 
 
The device will not be obtained.  The CCTA imaging results will be sent to the HeartFlow 
computer for interpretation.  Cardiologists participating in the study will have access to 
FFR images and results, and make their final recommendations based on these images. 
 
8.9.2 Storage 
n/a 
 
8.9.3 Dispensing of Study Drug/Device 
 
n/a 
 
8.9.4 Return or Destruction of Study Drug/Device 
 
:   
 
At the completion of the study, there will be a final reconciliation of subjects who 
received FFR and those who did not, and related follow up testing and interventions.  
This reconciliation will be logged on a reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented.  
 
9 Study Procedures 
 

 
 
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Figure 1 and Appendix 1 describe this information. 
 
 
Patients scheduled for an outpatient CCTA to evaluate stable chest pain or angina and meet 
the study criteria will be asked to participate in the study.  All study patients will receive a 
CCTA as part of standard of care.   
 
A physician Cardiologist will interpret the CCTA as per current operating protocol.  If the 
Cardiologist diagnoses stenosis in the range of 30% to 100%, the CCTA scan will be uploaded 
to Heart Flow for noninvasive FFR, via HIPAA compliant cloud-based technology reviewed 
and approved by the Northwell security team.   
 
The Noninvasive CT-FFR is considered to be a research procedure at Northwell (though FDA 
approved) and is not part of the standard of care currently offered at Northwell.  However, 
some institutions do use noninvasive CT-FFR as part of their standard of care. According to 
HeartFlow representatives, these include William Beaumont Hospital (Detroit), Sanger Heart 
and Vascular (Charlotte), Weill Cornell Medical College (New York), St Pauls Hospital 
(Vancouver) Cedars Saini (Los Angeles), Baylor Plano (Dallas), Sutter PAMF (SF Bay Area), 
Baylor St Lukes (Houston), Loyola Medical College (Chicago), Duke University (Durham), 
University Hospitals (Cleveland), and Minneapolis Heart Institute (Minneapolis).  
Considering this, and the preliminary results of which we are aware, we believe that CT-FFR 
should be considered a minimal risk procedure. 
 
Once the data has been analyzed by HeartFlow, the physician will receive a notification from 
HeartFlow that will allow for the physician to sign on to the HeartFlow server and analyze the 
flow of all vessels on an interactive program.  The physician will interpret the HeartFlow 
results and the study coordinator will download the best quality phase on a PDF to be stored 
with the study report on RIS System.  The physician will dictate an addendum to the CCTA 
scan discussing the CT-FFR findings.      
 
Patients who have borderline obstructive disease (50% to 70% stenosis) who have negative 
CT-FFR will be referred for Stress MPI to confirm, unless the patient has had stress testing 
within a year of the CCTA.  This is an accepted practice as part of the standard of care at 
Lenox Hill Hospital.  If the stress test is negative, the patient will be referred to his/her 
physician for follow-up.  If the stress test is positive, the patient will be referred to Invasive 
Coronary Angiography for Invasive FFR and diagnostic cardiac catheterization.  If the patient 
has had a history of negative stress testing within a year of the CCTA, then the patient will be 
referred to his/her physician for follow-up.  It the patient’s prior stress test had findings that, 
in the investigator’s opinion, increase the patient’s risk of obstructive disease when viewed 
with the CCTA findings, the patient will be referred to Invasive Coronary Angiography for 
diagnostic cardiac catheterization and Invasive FFR. This is an accepted practice as part of 
the standard of care at Lenox Hill Hospital.*   
 
Patients who have borderline obstructive disease (50% to 70% stenosis) who have positive 
FFR will be referred for Invasive Coronary Angiography for Invasive FFR and diagnostic 

 
 
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cardiac catheterization.  This is an accepted practice as part of the standard of care at Lenox 
Hill Hospital. *   
 
Patients with 71% or greater stenosis will be referred for Invasive Coronary Angiography for 
Invasive FFR and diagnostic cardiac catheterization.  This is an accepted practice as part of 
the standard of care at Lenox Hill Hospital. 
 
*In current standard of care practice at Lenox Hill Hospital, for borderline obstructive 
coronary disease, the decisions as to whether to proceed with stress testing or refer to 
invasive coronary angiography is left to the medical discretion of the attending 
cardiologist. 
 
Invasive Coronary Angiography and Invasive FFR are considered to be the gold standard 
procedures for evaluation of obstructive coronary artery disease.  Patients deemed to be at 
high risk for obstructive disease based on CCTA or Stress testing are referred for invasive 
testing to determine whether cardiac intervention consisting of Percutaneous Coronary 
Intervention or Coronary Artery Bypass Graft is necessary.   
 
     
In order to assess the primary endpoint of comparison of event rates for patients treated with 
CCTA and FFR-CT, we will perform a retrospective chart review of Invasive Coronary 
Angiograms performed at Lenox Hill Hospital from 2014 to 2018. We will specifically review 
Cardiac Catheterization reports to screen patients and record data for cases where the 
indication for Catheterization was (1) Positive stress test and/or (2) Positive CCTA.  
Based on the catheterization report we will determine whether the patient had obstructive 
coronary artery disease with/without flow limitation, in the same manner and following the 
same definitions as those used to categorize level of obstruction in subjects enrolled in the 
prospective cohort of the study. 
This data will be used as comparison/control group to assess trends and rates of invasive 
coronary catheterization when no intervention is necessary, in cases where CCTA and/or 
stress test without CT-FFR was used to determine the need for cardiac catheterization. Only 
the minimum amount of data required for a robust comparison of event rates including the 
following identifiers -name, date of procedure and age will be collected. 
 
9.1 Visit 1 
1. 
Visit 1 is an ambulatory visit to Lenox Hill Outpatient CCTA Clinic.  Consent for 
study participation will be collected and routine CCTA will be administered. 
 
9.2 Visit 2 
 
If CCTA shows < 30% obstruction, visit 2 will be a referral for optimal follow-up cardiac care. 
If CCTA shows 30 to 49% obstructive disease and CT-FFR is negative, visit 2 will be a 
referral for optimal follow-up care. 

 
 
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If CCTA shows 50% to 70% obstructive disease and CT-FFR is negative, visit 2 will be a 
referral for Stress MPI testing.  
 If stress testing has been performed in the past year, then the results of those test will be 
considered, and new stress testing will not be performed. 
If prior stress test was negative, visit 2 will be a referral for optima follow-up cardiac care. 
If the investigator assessed that the prior stress test results increase the risk of acute obstructive 
cardiac disease for the patient, Visit 2 will be a referral to cardiac catheterization and invasive 
FFR. 
If CCTA shows >= 70% obstructive disease visit 2 will be referral to cardiac catheterization 
and invasive FFR. 
If CT-FFR is positive, visit 2 will be a referral to cardiac catheterization and invasive FFR. 
 
9.3 etc. 
Visit 3:  
If patient receives a stress MPI, and it is negative, visit 3 will be referral to optimal follow-up 
care. 
If patient receives a stress MPI, and it is positive, visit 3 will be to cardiac cath and invasive 
FFR. 
 
If patient undergoes a cardiac cath and invasive FFR at visit 2, visit 3 will be a referral to 
optimal follow-up care. 
 
Visit 4:  If patient receives a cardiac cath with invasive FFR at visit 3, visit 4 will be to optimal 
follow-up care. 
 
10 Risks to Subjects 
  
The risks to subjects in this study are minimal, compared to the risks faced by the population 
of patients receiving standard of care for potential coronary artery disease and stable chest 
pain or angina at Lenox Hill Hospital.  Most patients will receive the standard of care 
currently in place, but will have an additional test run (CT-FFR).  This test does not require 
any additional activity of the patient beyond completion of the CCTA with contrast (Standard 
of Care).  This test will be used to assess whether improvements in the standard of care can be 
made for future patients. 
A small percentage of patients, those who have positive CT-FFR, but 30 to 49% obstructive 
disease by CCTA standard will undergo an additional invasive exam.  This exam may identify 
obstructive disease.  If so, the patient will benefit.  If not, the patient will undergo an invasive 
procedure unnecessarily.  We believe that very few patients, if any, will fall into this category. 
 
Patients who undergo Invasive FFR and Diagnostic Cardiac Catheterization will face 
increased risk, as compared to standard of care.  According to the NIH National Heart Lung 
and Blood Institute, this procedure is very common, and rarely causes serious problems.  [22]  
However, complications can include bleeding, infection and pain at the catheter insertion site.  
On rare occasions the catheter can scrape or poke a hole in a blood vessel during insertion 

 
 
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causing damage to the blood vessel.  Patients may also experience an allergic reaction to the 
dye that is used during the procedure.  Less common reactions include arrhythmias, or 
irregular heart beats; kidney damage caused by the dye that is used during the procedure; 
blood clots that can trigger stroke or heart attack or other serious problems; low blood 
pressure; or a buildup of fluid in the sac that surrounds the heart.  This may cause the heart 
not to beat properly. [22] 
 
The anticipated benefit of this study is to identify a more accurate means of diagnosing 
coronary artery disease without invasive procedures and with less exposure to radiation.  The 
use of CT-FFR should address the weakness of CCTA – its lack of specificity.  CT-FFR is 
expected to increase the test’s positive predictive value.  We believe that the use of this 
technology can make significant reductions in the use of diagnostic cardiac catheterization 
without intervention and in the use of stress MPI to validate uncertain findings when CCTA is 
used as a first test.   
 
 
11 Potential Benefit to Subjects 
 
A small percentage of patients, those who have positive CT-FFR, but 30 to 49% obstructive 
disease by CCTA standards will undergo an additional invasive exam.  This exam may 
identify obstructive disease.  If so, the patient will benefit from treatment of obstructive 
disease.  If not, the patient will undergo an invasive procedure unnecessarily.  We believe that 
very few patients, if any, will fall into this category. 
 
The anticipated benefit of this study is to identify a more accurate means of diagnosing 
coronary artery disease without invasive procedures and with less exposure to radiation in the 
future.  The use of CT-FFR should address the weakness of CCTA – its lack of specificity.  
CT-FFR is expected to increase the test’s positive predictive value.  We believe that the use of 
this technology can make significant reductions in the use of diagnostic cardiac cath without 
intervention and in the use of stress MPI to validate uncertain findings when CCTA is used as 
a first test.   
 
12 Research Related Harm/Injury 
 
The only possible research related injury we can identify would be an adverse reaction to a 
cardiac cath procedure that a patient might not have otherwise undergone, if not participating 
in the study.  We expect few if any of these procedures.  Standard treatments for adverse 
reaction to cardiac cath would apply if such an event occurs.  Patients will be informed of this 
risk at the time of obtaining informed consent.  The consent states that the patient would be 
financially liable if such an event were to occur. 
 

 
 
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13 Provisions to Protect Privacy Interests of Subjects 
 
We have described above the method of recruitment.  Because the recruitment will be added to 
the process of care for patients already scheduled for a diagnostic workup, we do not believe 
there is a risk for invasion of privacy.  When contacting patients by telephone, we will not 
disclose the purpose of our call, except to the patient, and leave the message specifically for 
the subject who we need to contact.  All email or certified mail communications will be 
addressed explicitly to the subject.  We will obtain permission to contact the subject as part of 
the informed consent process. 
 
14 Statistical Plan 
14.1 Sample Size Determination 
 
Based on data from Stony Brook and confidential data HeartFlow reported from providers 
who have been using CT-FFR in a similar manner as we propose for this study,   we estimated 
that about 60% of stable chest pain patients who had CCTA were diagnosed with coronary 
stenosis of 30% to 90% and received CT-FFR. Of these patients, about 35% had an ICA test, 
and 14% of those had a negative ICA test result (i.e. the false-positive rate of CTTA+CT-FFR 
was 14%). A sample of 121 patients who received ICA will yield 80% statistical power of 
detecting a 60% reduction in the false-positive rate (from 14% to 6%), based on a two-sided 
one sample Chi-square test with 0.05 significance level. Assuming a similar prevalence of 
flow-limiting obstructive CAD and assuming that similar proportions of stable chest pain 
patients who had CCTA will receive CCT-FFR and then ICA, 576 stable chest pain patients 
who had CCTA need to be complete the clinical trial.  In order to target 576 subjects 
completing the trial, we estimate that number of patients, it will be necessary to  594, because 
18 patients who enrolled were screen failures.  
 
 
14.2 Statistical Methods 
 
 
Statistical Aims 
1. 
To determine the sensitivity, specificity, positive predictive value (PPV) and negative 
predictive value (NPV) of the CCTA test (with or without stress MPI, as specified in Figure 1) 
+ CT-FFR evaluation to identify chest pain patients with flow-limiting obstructive CAD. The 
ICA test will be used as gold standard. 
2. 
To determine inter-observer reliability of CCTA and CCTA+CT-FFR test readings 
between an experienced and a non-experienced reader, and compare the results between 
CCTA and CCTA+CT-FFR; to determine the intra-observer reliability of CCTA and CCTA-
FFR reading, for both the experienced and non-experienced reader, and for each reader 
compare the results between CCTA and CCTA+CT-FFR. 

 
 
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3. 
To identify factors of return visit within 90 days in patients who had no ICA test or a 
negative ICA test result. 
 
Outcome Variables 
• 
CCTA+CT-FFR test status (Positive/Negative). The test is deemed positive if ICA is 
required and negative if ICA is not required (see Figure 1). 
• 
ICA (gold standard) test status (Positive / Negative). ICA is deemed positive if 
FFR<0.8 and vessel diameter >=2mm or if the patient requires revascularizations based on 
invasively estimated stenosis severity. It is deemed negative otherwise. 
• 
Return visit within 90 days (Y/N). Return visit is defined as patients who return for 
unplanned cardiac care, including emergency room visits, emergency hospital admissions, 
urgent percutaneous coronary intervention, coronary artery bypass graft, or acute myocardial 
infarction. Descriptive statistics (n, mean, median, standard deviation, IQR, frequencies and 
percentages) will be used to describe the demographic and clinical characteristics of the 
whole sample. 
 
For Aim 1, sensitivity, specificity, PPV, and NPV will be computed using the ICA result as the 
‘true’ flow-limiting obstructive CAD status and the CTTA+CT-FFR test result as the ‘test’ 
status. Exact binomial 95% confidence intervals will be computed. 
 
For Aim 2, inter- and intra-observer reliability for the CTTA and CTTA+CT-FFR tests will be 
assessed using Cohen’s Kappa coefficient. Dependent Kappa coefficients will be compared 
using a method developed by Donner et al . 
 
For Aim 3, a survival analysis regression model will be carried out to determine which risk 
factors are associated with “time-to-return visit”.  Proposed factors will include age, sex, 
race, diabetes, hyperlipidemia, hypertension, active smoking and smoking history, family 
history of premature heart disease, obesity, and the number of cardiac risk factors present. In 
addition we will consider adding whether the admission was surgical or medical, and the MS 
or AP DRG case weight as a measure of severity.     
 
Statistical Methods 
Descriptive statistics (n, mean, median, standard deviation, IQR, frequencies and percentages) 
will be used to describe the demographic and clinical characteristics of the whole sample. 
 
For Aim 1, sensitivity, specificity, PPV, and NPV will be computed using the ICA result as the 
‘true’ flow-limiting obstructive CAD status and the CTTA+CT-FFR test result as the ‘test’ 
status. Exact binomial 95% confidence intervals will be computed. 
 
For Aim 2, inter- and intra-observer reliability for the CTTA and CTTA+CT-FFR tests will be 
assessed using Cohen’s Kappa coefficient. Dependent Kappa coefficients will be compared 
using a method developed by Donner et al . 
 
For Aim 3, a survival analysis regression model will be carried out to determine which risk 
factors are associated with “time-to-return visit”.  Proposed factors will include age, sex, 
race, diabetes, hyperlipidemia, hypertension, active smoking and smoking history, family 

 
 
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history of premature heart disease, obesity, and the number of cardiac risk factors present. In 
addition we will consider adding whether the admission was surgical or medical, and the MS 
or AP DRG case weight as a measure of severity.     
 
14.3 Subject Population(s) for Analysis 
 
This is not a randomized trial.  Data for all subjects who enroll in the study will be subject to 
analysis, with appropriate adjustments for those who were unable to finish any part of the 
study. 
 
15 Safety and Adverse Events 
15.1 Definitions 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens 
in severity during the course of the study, as a result of study activities.  Intercurrent illnesses 
or injuries will be regarded as adverse events.  Abnormal results of diagnostic procedures are 
considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE 
that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are 
clearly of major clinical significance.   They may jeopardize the subject, and may require 
intervention to prevent one of the other serious outcomes noted above.  For example, drug 
overdose or abuse, a seizure that did not result in in-patient hospitalization, or intensive 
treatment of bronchospasm in an emergency department would typically be considered 
serious.  
 
All adverse events that do not meet any of the criteria for serious will be regarded as non-
serious adverse events.  
Adverse Event Reporting Period 

 
 
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The study period during which adverse events must be reported will be defined as the 
period from the initiation of any study procedures to the end of the study treatment follow-
up.  For this study, the study treatment follow-up is defined as 90 days following the last 
administration of study treatment.  
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  Preexisting 
conditions will be recorded as an adverse event if the errors in diagnosis cause less than 
optimal treatment decisions. 
General Physical Examination Findings 
At screening, any clinically significant abnormality will be recorded as a preexisting 
condition.  At the end of the study, any new clinically significant findings/abnormalities 
that were not diagnosed through the study protocol will meet the definition of an adverse 
event and will also be recorded and documented as an adverse event.  
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are 
resolved, the subject is lost to follow-up, or the adverse event is otherwise explained.     
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization will be 
documented and reported as a serious adverse event.  Any condition responsible for surgery 
will be documented as an adverse event if the condition meets the criteria for and adverse 
event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery will be 
reported as an adverse event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical 
procedures for a preexisting condition.  Surgery will not be reported as an outcome 
of an adverse event if the purpose of the surgery was elective or diagnostic and the 
outcome was uneventful. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the 
study, unless it is the result of inaccurate diagnostic information provided in the 
study. 
15.2 Recording of Adverse Events 
 At the follow-up contact with the subject, the study coordinator will seek information on adverse 
events by specific questioning and, as appropriate, by referral to a study coordinator for  
examination.  Information on all adverse events should be recorded immediately in the source 
document, and also in the appropriate adverse event module of the case report form (CRF).  All 
clearly related signs, symptoms, and abnormal diagnostic procedures results should recorded in 
the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period will  be recorded.  The clinical course of 
each event should be followed until resolution, stabilization, or until it has been determined that 
the study treatment or participation is not the cause.  Serious adverse events that are still ongoing 
at the end of the study period will be followed up to determine the final outcome.  Any serious 

 
 
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adverse event that occurs after the study period and is considered to be possibly related to the 
study treatment or study participation will be recorded and reported immediately. 
15.3 Reporting of Serious Adverse Events 
15.3.1 
Study Sponsor Notification by Investigator 
 
 
This is an investigator initiated trail funded by a charitable contribution from a 
grateful patient.  There is no study sponsor outside of Northwell Health. 
 
15.3.2 
EC/IRB Notification by Investigator 
Reports of all serious adverse events (including follow-up information) will be submitted 
to the EC/IRB according to their policies.  Copies of each report and documentation of 
EC/IRB notification and receipt will be kept in the Clinical Investigator’s binder. 
15.4 Unblinding Procedures 
 
This is not a blinded clinical trial.  Blinding in this study will not affect patient outcome, and, 
therefore, no unblinding is necessary.  Cardiologists will interpret CCTA scans without access 
to FFR results.  This is standard of care, and the interpretation will be necessary to determine 
which cases should be sent for FFR.  The FFR is a computerized procedure.  At the time the 
procedure is run, the computer operator will not know the exact level of obstruction 
documented by the cardiologist.  This information is irrelevant to the operations of the 
computerized procedure and will not change the outcome of the CT-FFR test or the follow up 
patient care. 
 
 
15.5 Stopping Rules  
 
This study is low risk to patients, because essentially, it requires the use of protocols that are 
currently in place and represent standard of care.  There may be a few instances in which a 
Cardiac Catheterization might be recommended for a patient who would not have received 
one if not a study participant.  If the patient’s cardiologist documents concern regarding 
patient safety if a Cardiac Catheterization were to be performed, the procedure will be 
discontinued.  
 
15.6  Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  
This safety monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and safety-monitoring 

 
 
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plan (see section 17 Auditing, Monitoring and Inspecting).  Medical monitoring will include a 
regular assessment of the number and type of serious adverse events. 
15.7  Data and Safety Monitoring  
Only one of the following three sections needs to be included in the protocol. 
15.7.1 
Data and Safety Monitoring Plan 
Michael Kim, M.D. will conduct data safety monitoring for the study.   
 
His role as Director of the Cardiac Catheterization program at lenox Hill Hospital makes him  
the most appropriate person to review the study safety, because he   will have the most 
complete information on the cardiovascular condition of the patient, and the patients response 
to invasive ICA,  the primary study activity that has potential to  influence patient safety.  
 
The expected types of events that will be monitored include major adverse cardiac events 
resulting from any Cardiac Catheterization, Percutaneous Coronary Intervention, or 
Coronary Artery Bypass Graft in a patient who, if not enrolled in the study, would not have 
received Cardiac Cath or invasive treatments. In addition, the monitor will review any 
medical complications for these subjects. The study coordinator will refer all patients who 
received Cardiac Cath, who would not have otherwise have received it if not part of the study.  
The monitor will review whether adverse events were the result of the study activity or related 
to procedures provided as part of standard of care, and whether safety policies and 
procedures were followed within one week of the all referrals.  The monitor will present any 
recommendations for changes to the study resulting from the review to the study PI. 
 
The monitor will conduct reviews as near as possible to the time the event was identified and 
always within a month of the identification of the event. 
 
We do not expect to need to alter or interrupt the study design, because of the very low risk 
nature of the study.  However, any unexpected safety events related to the study design will be 
carefully reviewed by the Safety Monitor and the study PI and reported to the IRB and 
Hospital quality assurance.  If improvement in patient safety can be made by changing the 
design, immediate consideration will be given to the prospective change. 
 
There are no issues with toxicity in this study. 
 
If the study should be temporarily suspended, we will report this to the IRB, Clinical 
trials.gov, and to HeartFlow.   
 
   
 
 
 
 
 

 
 
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16 Data Handling and Record Keeping 
16.1 Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  
Those regulations require a signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information 
 The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization.  For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect at least vital status (i.e. that the subject is alive) at 
the end of their scheduled study period. 
16.2 Source Documents 
  Source data is all information, original records of clinical findings, observations, or other 
activities in the clinical trial necessary for the reconstruction and evaluation of the trial.  Source 
data are contained in source documents   Examples of these original documents, and data records 
include: hospital records, clinical and office charts, CCTA and FFR results, notes, memoranda,  
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the 
laboratories, and at medico-technical departments involved in the clinical trial. 
16.3 Case Report Forms 
  The study case report form (CRF) is the primary data collection instrument for the study.  All 
data requested on the CRF must be recorded.  All missing data must be explained.  If a space on 
the CRF is left blank because the procedure was not done or the question was not asked, the study 
coordinator will indicate this by writing “N/D”.  If the item is not applicable to the individual case, 
the study coordinator will indicate this by writing write “N/A”.  All entries will be maintained on 
RedCap, this includes the retrospective study as well.  
16.4 Records Retention 
 
The investigator will be responsible  to retain study essential documents for at least 2 years after 
the last publication of initial findings.   
17 Study Monitoring, Auditing, and Inspecting 
17.1 Study Monitoring Plan 
 This is a private study.  No external monitor has been assigned. 

 
 
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Auditing and Inspecting: 
The investigator will permit study-related monitoring, audits, and inspections by the EC/IRB, 
government regulatory bodies, and University compliance and quality assurance groups of all 
study related documents (e.g. source documents, regulatory documents, data collection 
instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g.  diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 
18 Ethical Considerations 
This study is to be conducted according to US and international standards of Good Clinical 
Practice (FDA Title 21 part 312 and International Conference on Harmonization guidelines), 
applicable government regulations and Institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted independent 
Ethics Committee (EC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct.  The decision of the EC/IRB concerning 
the conduct of the study will be made in writing to the investigator and a copy of this decision 
will be provided to the sponsor before commencement of this study.  The investigator should 
provide a list of EC/IRB members and their affiliate to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this 
study.  See Attachment _2__ for a copy of the Subject Informed Consent Form.  This consent 
form will be submitted with the protocol for review and approval by the EC/IRB for the study.  
The formal consent of a subject, using the EC/IRB-approved consent form, must be obtained 
before that subject is submitted to any study procedure.  This consent form must be signed by the 
subject or legally acceptable surrogate, and the investigator-designated research professional 
obtaining the consent.  
 
19 Study Finances 
19.1 Funding Source 
 
This study will be financed through a charitable contribution supporting the research of 
Michael Poon, M.D. on the use of CT-FFR. 
 
19.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or 
financial gain greater than the minimum allowable by their institution, etc.) must have the 

 
 
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conflict reviewed by a properly constituted Conflict of Interest Committee with a Committee-
sanctioned conflict management plan that has been reviewed and approved by the study sponsor 
prior to participation in this study.  All North Shore-LIJ Health System investigators will follow 
the University conflict of interest policy. 
 
 
 
20 Publication Plan 
: 
 
Neither the complete nor any part of the results of the study carried out under this protocol, will 
be published or passed on to any third party without the consent of the Principal Investigator.   
 
 
References Cited 
1.  Koo, B.K., et al., Diagnosis of ischemia-causing coronary stenosis by noninvasive fractional 
flow reserve computed from coronary computed tomographic angiograms. Results from the 
prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenosis Obtained 
via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol, 2011. 58(19): p. 1989-97. 
2.  Min, J.K., et al., Diagnostic accuracy of fractional flow reserve from anatomic CT 
angiography. JAMA, 2012. 308(12): p. 1237-45. 
3.  Norgaard, B.L., 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 Using CT Angiography: Next Steps). J Am Coll 
Cardiol, 2014. 63(12): p. 1145-55. 
4.  Ko, B.S., et al., Computed tomography stress myocardial perfusion imaging in patients 
considered for revascularization: a comparison with fractional flow reserve. Eur Heart J, 2012. 
33(1): p. 67-77. 
5.  Niska, R., F. Bhuiya, and J. Xu, National Hospital Ambulatory Medical Care Survey: 2007 
emergency department summary. Natl Health Stat Report, 2010(26): p. 1-31. 
6.  Poon, M., et al., Associations between routine coronary computed tomographic angiography 
and reduced unnecessary hospital admissions, length of stay, recidivism rates, and invasive 
coronary angiography in the emergency department triage of chest pain. J Am Coll Cardiol, 
2013. 62(6): p. 543-52. 
7.  Budoff, M.J., et al., Diagnostic performance of 64-multidetector row coronary computed 
tomographic angiography for evaluation of coronary artery stenosis in individuals without 
known coronary artery disease: results from the prospective multicenter ACCURACY 
(Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing 
Invasive Coronary Angiography) trial. J Am Coll Cardiol, 2008. 52(21): p. 1724-32. 
8.  Meijboom, W.B., et al., Diagnostic accuracy of 64-slice computed tomography coronary 
angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol, 2008. 52(25): p. 
2135-44. 
9.  Miller, J.M., et al., Diagnostic performance of coronary angiography by 64-row CT. N Engl J 
Med, 2008. 359(22): p. 2324-36. 

 
 
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10.  Taylor, A.J., et al., ACCF/SCCT/ACR/AHA/ASE/ASNC/NASCI/SCAI/SCMR 2010 
appropriate use criteria for cardiac computed tomography. A report of the American College of 
Cardiology Foundation Appropriate Use Criteria Task Force, the Society of Cardiovascular 
Computed Tomography, the American College of Radiology, the American Heart Association, 
the American Society of Echocardiography, the American Society of Nuclear Cardiology, the 
North American Society for Cardiovascular Imaging, the Society for Cardiovascular 
Angiography and Interventions, and the Society for Cardiovascular Magnetic Resonance. J Am 
Coll Cardiol, 2010. 56(22): p. 1864-94. 
11.  NIH National heart, Lung and Blood Institute, What are the risks of cardiac catheterization.  
https://www.nhlbi.nih.gov/health/health-topics/topics/cath/risks, accessed on 11/8/2016. 
21 Attachments 
This section should contain all pertinent documents associated with the management of the 
study.  The following list examples of potential attachments: 
 Attachment 1:  Study Flow Chart 
 Attachment 2:  Sample Consent Form 
