Clinical trial NCT03557385
Conditions: Percutaneous Coronary Intervention
Keywords: Fractional Flow Reserve
Sponsor: Duke University
Start date: 2019-01-17; Completion date: 2023-04-04
Enrollment: 201 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to compare FFR measurements done with adenosine to FFR measurements done with contrast, where the contrast is injected using the ACIST CVi automated contrast injector.

The ACCELERATION study will support a safer approach to FFR for patients by potentially reducing toxic drug exposure (adenosine). The 2 main objectives of the study are:

1. Perform a methods comparison between cFFR and the reference standard aFFR, where cFFR is performed using an automated injector with a standardized volume and rate of delivery of contrast with known osmolality.
2. Evaluate the association between final post-PCI FFR and long-term clinical outcomes. The long-term clinical outcomes will include TVR and composite MACE (death, MI, and TVR) at 30 days and 1 year.

Detailed description:

Arms: arm 1: All subjects will receive Fractional Flow Reserve Measurements with both adenosine (aFFR) and contrast (Iopamidol) (cFFR) using the Navvus® Catheter and CVi® Contrast Delivery System
Interventions: intervention 1: Iopamidol intervention 2: adenosine intervention 3: Navvus® Catheter intervention 4: CVi® Contrast Delivery System
Intervention descriptions: intervention 1: aFFR measurement with drug: Iopamidol (ISOVUE®-370). Subjects will receive an injector-based intracoronary bolus of contrast

* Rate of 4 mL/sec, volume of 10 cc (left coronary system)
* Rate of 3 mL/sec, volume of 6 cc (right coronary system). intervention 2: FFR measurement with drug: adenosine. Intravenous adenosine will be administered at a rate of 140 μg/kg of body weight per minute x 2 minutes intervention 3: the NAVVUS RXi microcatheter will be used with a workhorse wire of the operator's choosing intervention 4: The CVi® Contrast Delivery System will be used to deliver the contrast medium

Protocol documents:
Prot_SAP_000.pdf: 
Duke Clinical Research Institute 
This document is a confidential communication of the Duke Clinical Research Institute 
(DCRI). Acceptance of the document constitutes agreement by the recipient that the 
contents will not be disclosed to any unauthorized personnel, without the prior written 
authorization of the DCRI. In the event of actual or suspected breach of this agreement, 
the DCRI will be promptly notified. 
PROTOCOL 
Adenosine Contrast CorrELations in Evaluating RevAscularizaTION 
The ACCELERATION Study 
Date: March 23rd, 2022 
Version: 5.0 
Principal Investigator: 
Rajesh V. Swaminathan, MD, FACC, FSCAI 
Duke University Medical Center 
Durham, NC 27705  USA 
Study Chair: 
Mitchell W. Krucoff, MD 
Duke University Medical Center 
Durham, NC 27705  USA 
Sponsor: 
Rajesh V. Swaminathan, MD, FACC, FSCAI 
Duke Clinical Research Institute 
2400 Pratt Street 
Durham, NC 27705  USA  
Partners: 
ACIST Medical Systems 
Eden Prairie, Minnesota  
NCT03557385


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STATEMENT OF COMPLIANCE 
 
This trial will be conducted in compliance with the protocol, International Conference on 
Harmonisation (ICH) guideline E6: Good Clinical Practice (GCP): Consolidated Guideline, 
and the applicable regulatory requirements from the United States Code of Federal 
Regulations (CFR), including 45 CFR 46 (human subjects protection, incorporating 
Subpart D Additional Protections for Children Involved as Subjects in Research), 21 CFR 
312 (Investigational New Drug [IND]), 21 CFR 50 (Protection of Human Subjects, 
incorporating Subpart D Additional Safeguards for Children in Clinical Investigations), 21 
CFR 11 (electronic records and signatures), 21 CFR 54 (financial disclosure), and 21 
CFR 56 (institutional review board [IRB]). 
 
All individuals responsible for the design and/or conduct of this study have completed 
human subjects’ protection training and are qualified to be conducting this research. 
 
 


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SITE PRINCIPAL INVESTAGATOR STATEMENT 
 
I have read the protocol, including all appendices and the investigator brochure or product 
label, and I agree that it contains all necessary details for my staff and me to conduct this 
study as described. I personally will oversee the conduct of this study as outlined herein 
and will make a reasonable effort to complete the study within the time designated. I agree 
to make all reasonable efforts to adhere to the attached protocol. I understand and am 
aware of my responsibilities as an investigator as described in the applicable GCP 
regulations. 
I will provide all study personnel under my supervision with copies of the protocol and 
access to all information provided by the sponsor or its representative. I will discuss this 
material with them to ensure that they are fully informed about the efficacy and safety 
parameters and the conduct of the study in general. I am aware that, before beginning 
this study, the institutional review board responsible for such matters must approve this 
protocol in the clinical facility where it will be conducted. 
I agree to provide all subjects with informed consent, as required by government 
regulations and the ICH guidelines. I further agree to report to the sponsor or its 
representative any adverse events in accordance with the terms of this protocol and the 
U.S. Code of Federal Regulations, Title 21, part 312. 
 
 
 
 
 
Principal Investigator name (print) 
 
 
 
 
 
 
Signature 
 
Date 
 
 


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STUDY PRINCIPAL INVESTIGATOR SIGNATURE 
 
 
Study Title:  
 
Adenosine Contrast CorrELations in Evaluating 
RevAscularizaTION (The ACCELERATION Study) 
Version:  
 
5.0 
Date of Issue: 
March 23rd, 2022 
 
 
I have read and approve this protocol and agree on its content. 
 
 
 
 
Rajesh V. Swaminathan, MD, FACC, FSCAI 
 
Sponsor: 
Duke Clinical Research Institute 
 
Date 


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PROTOCOL VERSION AND AMENDMENT TRACKING 
 
Version Number/Amendment 
Approval Date 
Protocol: Version 1.0 
February 6, 2018 
Protocol: Version 2.0 
June 5, 2018 
Protocol: Version 3.0 
July 25, 2018 
Protocol: Version 4.0 
August 18, 2020 
Protocol: Version 5.0 
 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title 
Adenosine Contrast CorrELations in Evaluating 
RevAscularizaTION (The ACCELERATION Study) 
Main Criteria for Inclusion 
Patients > 18 years old. All subjects who are clinically stable and 
undergoing non-emergent cardiac catheterization for appropriate 
indications.  Diagnostic angiogram reveals at least one moderate (40-
70%) stenosis by angiographic assessment. 
Study Objectives 
To evaluate the NAVVUS fractional flow reserve (FFR) device, as 
follows:  
• 
Determine the accuracy and correlation of contrast FFR 
(cFFR) using the ACIST CVi automated contrast injector to the 
current gold-standard adenosine FFR (aFFR) 
• 
Evaluate the association of post-percutaneous coronary 
intervention (PCI) FFR to long-term clinical outcomes (death, 
myocardial infarction [MI], target vessel revascularization 
[TVR]) with up to 1-year follow-up 
Study Design 
The ACCELERATION study is an investigator-initiated, multicenter, 
prospective, single-arm trial evaluating the method of delivery of 
contrast for FFR with use of the NAVVUS RXi microcatheter FFR 
system and the CVi automated contrast injector in patients with 
intermediate lesion coronary artery disease.  Up to 200 subjects 
undergoing non-emergent PCI from approximately 5 centers will be 
enrolled.   
After 
NAVVUS 
FFR-guided 
PCI 
(with 
contrast 
and 
aFFR 
measurements), subjects will be contacted for follow-up at 30 days and 
1 year by the enrolling site. Primary endpoint results will be reported 
after all subjects have completed the 30­day clinical follow-up. 
Treatment Regimen 
Patients with intermediate lesions meeting the clinical and angiographic 
inclusion/exclusion criteria will be enrolled. NAVVUS FFR will then be 
performed with contrast and aFFR.  Contrast for cFFR will be injected 
via the ACIST CVi contrast injector with standardized settings, and 
adenosine for aFFR will be delivered systemically via intravenous 
infusion.  If PCI is performed, a final post-PCI contrast and aFFR will be 
obtained. 
Duration of Subject Study 
Participation 
Sites will see patients for their standard-of-care follow-up visit 
approximately 30 days after their procedure. Patients will be contacted 
at 1 year to collect data for the secondary endpoint analysis.  
Number of Patients 
Up to 200 subjects 
Number of Sites 
Approximately 5 centers are planned in the US. 


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Objective/Endpoints for 
Evaluating the ACIST 
NAVVUS FFR microcatheter 
and ACIST contrast power 
injector.  
 
Primary Objective/Endpoint:  
(1) Perform a methods comparison between cFFR and the reference 
standard aFFR, where cFFR is performed using an automated injector 
with a standardized volume and rate of delivery of contrast with known 
osmolality. 
Secondary Objective/Endpoint: 
(1) Evaluate the association between final post-PCI FFR and long-term 
clinical outcomes. The long-term clinical outcomes will include TVR and 
composite major adverse cardiac events (death, MI, and TVR) at index 
hospitalization (prior to discharge), 30 days and 1 year.  
Statistical Analysis  
Sample Size/ 
Power Considerations 
 
Up to 200 patients with intermediate lesions (see statistical analysis 
plan in protocol for details) 
 


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TABLE OF CONTENTS 
 
Statement of Compliance ......................................................................................2 
Site Principal Investagator Statement ...................................................................3 
Study Principal Investigator Signature...................................................................4 
Protocol Version and Amendment Tracking ..........................................................5 
Protocol Synopsis..................................................................................................6 
Table of Contents ..................................................................................................8 
List of Tables ....................................................................................................... 10 
List of Figures ...................................................................................................... 10 
Abbreviations ...................................................................................................... 11 
1. Introduction and Background ........................................................................ 13 
2. Objectives ..................................................................................................... 16 
3. Study Design ................................................................................................ 17 
3.1 Overview of Study ............................................................................ 17 
3.2 Procedural Steps ............................................................................. 18 
3.2.1 Angiographic Confirmation Eligibility ................................... 18 
3.2.2 Procedural Planning ............................................................ 18 
3.2.3 Documentation .................................................................... 20 
3.3 Endpoints ......................................................................................... 20 
3.3.1 Primary Endpoint ................................................................. 20 
3.3.2 Secondary Endpoints .......................................................... 20 
4. Selection and Withdraw of Patients .............................................................. 21 
4.1 Clinical Inclusion Criteria .................................................................. 21 
4.2 Clinical Exclusion Criteria................................................................. 21 
4.3 Angiographic Inclusion/Exclusion Criteria ........................................ 21 
4.4 Withdrawal of Patients ..................................................................... 22 
5. Known and Potential Risks ........................................................................... 23 
6. Study Procedures ......................................................................................... 25 
6.1 Screening Procedures ..................................................................... 25 
6.2 Informed Consent ............................................................................ 25 
6.3 Enrollment ........................................................................................ 25 
6.4 Screen Failures ................................................................................ 25 
6.5 Post-procedure Follow-up ................................................................ 26 
6.6 Schedule of Events .......................................................................... 26 


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7. Data Caputure .............................................................................................. 28 
8. Subject Safety and Adverse Events .............................................................. 29 
8.1 Device Failures, Device Malfunctions, and User Error ..................... 29 
9. STATISTICAL ANALYSIS AND DETERMINATION OF SAMPLE SIZE ....... 30 
9.1 Intent-to-Treat Population ................................................................ 30 
9.2 Per-Protocol Evaluable Population .................................................. 30 
9.3 Primary Endpoint Analysis ............................................................... 30 
9.3.1 Quantitative Method Comparison Between Contrast Fractional 
Flow Reserves and Adenosine Fractional Flow Reserves .. 30 
9.3.2 Qualitative Method Comparison Between Contrast Fractional 
Flow Reserves and Adenosine Fractional Flow Reserves .. 31 
9.4 Secondary Endpoint Analysis .......................................................... 32 
9.4.1 Assessment of the Relationship Between Post-Percutaneous 
Coronary Intervention Fractional Flow Reserves and Long-
Term Clinical Outcomes ...................................................... 32 
9.4.2 Additional Endpoints ........................................................... 33 
9.4.3 Missing Data ....................................................................... 33 
9.5 Estimated Duration of the Study ...................................................... 33 
10. Study Ethical Considerations ........................................................................ 33 
10.1 Confidentiality of Patients................................................................. 33 
11. Administrative Procedures ............................................................................ 34 
11.1 Duke Clinical Research Institute Coordinating Center Responsibilities
 ......................................................................................................... 34 
11.1.1 Investigator Training ............................................................ 34 
11.2 Investigator’s Responsibilities .......................................................... 34 
11.2.1 Reporting and Recording of Study Data .............................. 34 
11.2.2 Source Documentation ........................................................ 34 
11.2.3 Records Retention .............................................................. 35 
12. Steering Committee, Data and Safety Monitoring Committee, and Adjudication 
Committee ................................................................................................ 36 
12.1 Steering Committee ......................................................................... 36 
12.2 Fractional Flow Reserve Core Lab ................................................... 36 
13. Policy for Publication and Presentation of Data ............................................ 37 
14. References ................................................................................................... 38 
 


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LIST OF TABLES 
Table 1 
Schedule of Assessments ................................................................... 27 
 
LIST OF FIGURES 
Figure 1. Study Design and Treatment Schema ................................................ 17 
Figure 2: Sample Size by AUC by various ratio of negative to positive .............. 32 
 


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ABBREVIATIONS 
ACT 
activated clotting time  
ADE 
adverse device effect 
AE 
adverse event 
aFFR 
adenosine fractional flow reserves 
AUC 
area under the curve 
CAD 
coronary artery disease 
cFFR 
contrast fractional flow reserve 
DCRI 
Duke Clinical Research Institute 
dPR 
diastolic pressure ratio 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration (US) 
FFR 
fractional flow reserve 
HR 
hazard ratio 
ICF 
informed consent form 
iFR 
instantaneous wave free ratio 
IFU 
instructions for use 
IRB 
institutional review board 
ITT 
intent to treat 
IV 
Intravenous 
LAR 
legally authorized representative 
MACE major adverse cardiac events 
MI 
myocardial infarction 
NCDR National Cardiovascular Data Registry 
OMT 
optimal medical therapy 
Pd/Pa 
intracoronary distal pressure/aortic pressure 
PCI 
percutaneous coronary intervention 


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ROC 
receiver operating characteristics 
RR 
relative risk 
SAE 
serious adverse event 
SD 
standard deviation 
TVR 
target vessel revascularization 
UADE 
unanticipated adverse device effect 
 
 


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1. 
INTRODUCTION AND BACKGROUND 
Fractional flow reserve (FFR) has emerged as an effective invasive means of 
assessing the physiologic significance of an epicardial coronary stenosis. The test 
complements the visual assessment of a stenotic lesion based solely on anatomic 
features during angiography. The addition of FFR to the diagnostic armamentarium of 
interventional cardiologists has significantly impacted best practice recommendations for 
how and when to treat coronary lesions with percutaneous coronary intervention (PCI), 
selecting only ischemic lesions supplying viable myocardium. This disruptive technology 
received widespread utilization after multiple, large randomized controlled trials 
demonstrated superior patient outcomes with FFR-guided PCI compared with standard 
angiography-guided PCI. 
The initial FAME trial was a randomized, prospective trial of 1,005 patients with 
stable, multivessel coronary artery disease (CAD) of >50% angiographic stenosis who 
were assigned to an angiography vs FFR-guided strategy in selecting lesions amenable 
to PCI. The primary endpoint of major adverse cardiac events (MACE) (including death, 
myocardial infarction (MI), repeat revascularization) occurred in 91 patients (18.3%) in 
the angiography group and in 67 patients (13.2%) in the FFR-guided group (relative risk 
[RR] 0.72, 95% CI 0.54-0.96, p=0.02). The utilization of FFR significantly reduced the 
total number of stents placed (2.7 vs 1.9), total length of stents (51.9 mm vs 37.9 mm), 
cost of materials ($6,007 vs $5,332), and hospital length of stay (3.7 days vs 
3.4 days) (1). 
FAME 2 built on the evidence from FAME and included an optimal medical therapy 
(OMT) arm. In this trial, 888 multivessel CAD patients with at least 1 FFR positive lesion 
were randomized to FFR-guided PCI with drug-eluting stents plus OMT or OMT alone. 
The primary endpoint was a composite of death, MI, hospitalization, or urgent 
revascularization. The study was prematurely halted after interim analysis revealed a 
statistically significant decrease in unplanned hospitalization leading to urgent 
revascularization in the FFR-PCI arm (1.6% vs 11.1%, hazard ratio [HR] 0.13, 95% CI 
0.06-0.30, p<0.001). This drove a significant reduction in the primary endpoint for FFR-
guided PCI plus OMT as compared to OMT alone (4.3% vs 12.7%, HR 0.32, 95% CI 
0.19–0.53, p<.001] (2). 
Based on FAME and other supporting data, FFR was incorporated into the 2011 
American College of Cardiology/American Heart Association/Society for Cardiac 
Angiography and Interventions guidelines for PCI. The adjunctive device received a class 
IIa indication for assessment of angiographic intermediate coronary lesions to guide 
revascularization decisions in patients with stable ischemic heart disease (3). Fractional 
flow reserve is also an integral component of the multi-society–supported Appropriate 
Use Criteria for coronary revascularization (4-6). 
As FFR utilization increases in clinical practice, various methods for inducing 
hyperemia have emerged. These methods are primarily designed to circumvent inherent 
risks associated with the use of adenosine, as well as decrease time and improve 
workflow in the catheterization laboratory, without compromising accuracy. Some 
challenges with traditional systemic intravenous (IV) adenosine administration for FFR 
measurement are: 1) heart block; 2) other undesirable patient side effects, including chest 


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pain, bronchospasm, and shortness of breath; 3) relative contraindications in patients with 
obstructive lung disease or recent caffeine use; 4) added time to prepare and infuse 
adenosine; and 5) associated costs. Intracoronary adenosine push is still associated with 
similar risks and limits the operator from assessing diffuse or tandem lesions given the 
shorter time frame of peak hyperemia. Alternative strategies include a measurement of 
resting physiologic gradients (distal pressure/aortic pressure [Pd/Pa], diastolic pressure 
ratio [dPR], and instantaneous wave free ratio (iFR). iFR assesses the gradient during a 
short period in diastole when resistance across the coronary vasculature is stable (the 
“wave free” period). During this time, coronary flow and pressure are proportional and the 
trans-lesion gradient approximates flow and lesion severity. iFR correlation to traditional 
hyperemia-induced FFR is moderate, yet strengthened by data that support conversion 
to FFR only in a pre-defined “yellow zone” (i.e., 0.86 to 0.93). Lesions with values in the 
“green zone” and “red zone” can be safely deferred or intervened, respectively, without 
the need for adenosine fractional flow reserves (aFFR). iFR with set protocols based on 
these zones received US Food and  Drug Administration (FDA) clearance in 2014.  
Measurement of dPR is not proprietary and can be acquired during real-time resting 
gradient assessment or via post-procedure analysis of the resting gradient waveforms.  
dPR has been shown to be numerically equivalent to iFR regardless of the time period 
acquired within the diastolic period (7). 
An emerging adenosine-free alternative is contrast-induced FFR (cFFR). 
Conventional non-ionic radiographic contrast medium has been shown to induce 
submaximal reactive hyperemia and Pd/Pa ratio measured post-contrast injection has 
been reported to approximate traditional FFR values (8). A prospective study with 80 
patients and 104 intermediate lesions found a strong correlation between cFFR and aFFR 
(r=0.94, p<0.001). Receiver operating characteristics (ROC) curve analysis showed an 
excellent accuracy of a cFFR cut-off of ≤0.83 in predicting an FFR value ≤0.80 (area 
under the curve [AUC] 0.97, 95% CI 0.91-0.99, specificity 96.1, sensitivity 85.7). No cFFR 
value ≥0.88 corresponded to an FFR value ≤0.80. These data suggest that cFFR ≤0.83 
is significant, ≥0.88 is non-significant, and borderline values in between should be further 
assessed with aFFR for inducement of maximal hyperemia (8). 
A recent international study of 763 patients sought to compare the diagnostic 
performance of aFFR with the spectrum of alternative FFR modalities, including Pd/Pa, 
iFR, and cFFR (9). Pd/Pa and iFR had equivalent performances against FFR ≤0.80 with 
~80% accuracy. cFFR improved this accuracy to 86%. A significant limitation of this study 
was the lack of a standardized protocol for the type, volume, and rate of intracoronary 
contrast injection. These considerations were left to the operator’s discretion, including 
the use of either manual (manifold) injection or an automated injector system, and the 
choice of contrast agents with different osmolalities. Standardizing these contrast and 
injection parameters could further improve the diagnostic accuracy of cFFR (9). This 
hypothesis forms the basis for the current proposed study. 
While pre-PCI FFR is now an established modality, there remains limited data on 
whether immediate, post-PCI FFR might have an important long-term clinical impact. A 
recent systematic review and meta-analysis included 59 studies evaluating the 
relationship between post-PCI FFR and clinical outcomes up to 30 months. In general, 
higher post-PCI FFR values were associated with reduced rates of repeat interventions 


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and MACE. A post-PCI FFR ≥0.90 was associated with a 57% RR reduction of repeat 
PCI and a 30% RR reduction of MACE (10). In a multicenter registry of 750 patients, post-
PCI FFR was the most significant independent predictor of clinical events (11). Death, MI, 
and target vessel revascularization (TVR) at 6 months were stratified by categories of 
immediate post-PCI FFR values and found to be 4.9% (post-FFR >0.95), 6.2% (post-FFR 
0.90-0.95), and 20.3% (post-FFR <0.90). In the minority of patients with a post-FFR 
<0.80, the event rate was exceedingly high at 29.5%.  The proposed study will add to the 
growing body of literature supporting use of post-PCI in routine clinical practice, 
particularly as the field moves towards adenosine-free FFR acquisition techniques. 


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2. 
OBJECTIVES 
The ACCELERATION study will support a safer approach to FFR for patients by 
potentially reducing toxic drug exposure (adenosine) if cFFR with standardized injection 
settings is observed to have a strong correlation to traditional FFR. In addition, 
ACCELERATION will utilize the novel NAVVUS RXi microcatheter FFR technology in 
intermediate lesions, which will promote optimal vessel access with a workhorse wire of 
the operator’s choosing during pre- and post-PCI FFR measurements. The 2 main 
objectives of the study are: 
1. Perform a methods comparison between cFFR and the reference standard 
aFFR, where cFFR is performed using an automated injector with a standardized 
volume and rate of delivery of contrast with known osmolality. 
2. Evaluate the association between final post-PCI FFR and long-term clinical 
outcomes. The long-term clinical outcomes will include TVR and composite 
MACE (death, MI, and TVR) at 30 days and 1 year. 
 
 
 


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3. 
STUDY DESIGN 
3.1 
Overview of Study 
The ACCELERATION study is an investigator-initiated, multicenter, prospective, 
single-arm trial evaluating optimal acquisition techniques of FFR using the NAVVUS RXi 
microcatheter FFR system in patients with intermediate lesion CAD. The study will 
determine the accuracy and correlation of cFFR (using the ACIST CVi automated contrast 
injector) to the current gold-standard aFFR, and evaluate the association of post-PCI FFR 
to long-term clinical outcomes including TVR and MACE with 1-year follow-up.  
Figure 1 depicts the study flow diagram with clinical and angiographic screening 
criteria. The enrollment cap is controlled at 200 subjects between 5 centers. 
Figure 1. 
Study Design and Treatment Schema 
aFFR, adenosine fractional flow reserve; CHF, congestive heart failure; COPD, chronic obstructive pulmonary 
disease; CVi, ACIST automated contrast injector; dPR, diastolic pressure ratio; FFR, fractional flow reserve; 
NSTEMI, non–ST-elevation myocardial  infarction; PCI, percutaneous coronary intervention; SA, stable angina; UA, 
unstable angina 
 


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3.2 
Procedural Steps 
3.2.1 Angiographic Confirmation Eligibility  
Patients will be enrolled in the study following angiographic confirmation of a target 
vessel with an intermediate coronary lesion(s) that meet the inclusion and exclusion 
criteria.  Serial stenosis or diffuse disease can be included if the operator would normally 
assess these lesions with FFR and plan for PCI if positive.  1 vessel per patient can be 
enrolled in the study. 
3.2.2 Procedural Planning 
Operators should use FFR per their usual practice and follow standard of care per 
clinical guidelines and appropriate use criteria.  The protocol calls for a recording of 
resting Pd/Pa, dPR (in real-time or post-procedure waveform analysis), contrast FFR, and 
adenosine FFR every time a physiologic assessment is made.  The protocol also requires 
the same measurements immediately post-PCI.  Below are specific procedural details to 
ensure uniformity across sites.  Any deviations should be recorded. 
1. Access site, guide catheter (minimum 6F), 0.014” coronary workhorse wire, and 
antiplatelet/anticoagulant strategy will be at the discretion of the operator.  
2. Systemic anticoagulation confirmation will be achieved by activated clotting time 
(ACT) measurement prior to coronary wire exiting the guide catheter. 
3. After wiring the lesion, administer 1-200 micrograms of intracoronary nitroglycerin 
and chase with saline to clear the guide catheter. Await return of baseline blood 
pressure prior to hemodynamic measurement  
4. Resting Pd/Pa, dPR, contrast FFR, and adenosine FFR will be obtained for each 
physiologic assessment based on the following procedural steps: 
a. Equalization 
i.  NAVVUS RXi FFR microcatheter will be advanced until guide exit 
and equalized.  
ii. Equalization step will be performed each time the NAVVUS FFR 
catheter is used during the protocol and should equal 1.0. 
b. Resting Pd/Pa and dPR 
i. The Rxi FFR microcatheter will be advanced 1-2cm just distal to the 
lesion of interest.  Position microcatheter based on reference still 
images from diagnostic angiogram. Ensure the guide is cleared with 
saline if contrast is needed to position the catheter. 
ii. An initial period of 20 seconds to provide stable assessment of 
resting physiology will be performed 
iii. Resting gradient will be documented.  dPR can be documented at 
same time (if available) or can be documented post-procedure after 
waveform analysis.   


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c. Contrast Injection FFR (cFFR) 
i. Injector-based intracoronary bolus of contrast with the ACIST 
automated injector will deliver contrast medium: Iopamidol 
(ISOVUE®-370), 
a 
low-osmolality 
contrast 
medium 
at 
796 mOsmol/kg water 
ii. Settings:  
• Rate of 4 mL/sec, volume of 10 cc (left coronary system) 
• Rate of 3 mL/sec, volume of 6 cc (right coronary system). 
iii. Any deviation from these settings due to operator judgment will be 
documented. 
iv. Inject contrast to fill guide catheter and wait for return of baseline 
hemodynamics. 
v. Press record on ACIST FFR console and then inject contrast at 
standard settings above for cFFR. Within the first minute of contrast 
injection, the nadir cFFR value will be logged.  
vi. The recorded tracings will be captured and saved for an independent 
FFR core lab review. 
d. Adenosine FFR (aFFR) 
i. Return of baseline hemodynamics  
ii. Intravenous adenosine administered at a rate of 140 μg/kg of body 
weight per minute x 2 minutes will then be performed and the aFFR 
value logged.  
iii. If the aFFR is >0.80, then no PCI is performed and this final FFR 
value will be logged for correlation to long-term outcomes. 
iv. If the aFFR is ≤0.80, then PCI according to standard techniques will 
be performed.  Post-PCI, the NAVVUS FFR microcatheter will be 
used to measure resting Pd/Pa, dPR, contrast FFR, and adenosine 
FFR in the same manner as above with values recorded. 
v. The recorded tracings will be captured and saved for an independent 
FFR core lab review. 
5. Drift 
a. Drift check will be performed at least once during each procedure and 
ideally after each use/measurement of the NAVVUS FFR microcatheter 
b. Clinically significant drift will be defined as > ±0.03 (12).  
c. The presence of any significant drift (yes/no) will be recorded. If there is 
clinically significant drift, the FFR measurements will be repeated after 
repositioning of the guide catheter and re-equalization. 


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3.2.3 Documentation  
Data including baseline clinical and procedural characteristics with all FFR values 
(pre- and post-PCI resting, dPR, contrast, and adenosine) will be entered into the 
electronic case report form (eCRF) and used to analyze the primary and secondary study 
endpoints.  These data will be stored in the IBM Clinical Data platform mirroring the NCDR 
dataset. 
The post-PCI (final) aFFR will be used for correlation to 1-year clinical outcomes 
of death, MI, and TVR. These clinical endpoints will be recorded during the index 
hospitalization (prior to discharge), 30-day visit (at the routine follow-up appointment or 
telephone call if this appointment is missed), and at 1 year by telephone. See post-
procedure follow-up section for details on data acquisition and definitions. 
3.3 
Endpoints 
3.3.1 Primary Endpoint 
The primary endpoint of the study is the accuracy and correlation of cFFR in 
comparison to aFFR, where cFFR is performed using the ACIST CVi automated contrast 
injector with a standardized volume and rate of delivery of contrast with known osmolality. 
3.3.2 Secondary Endpoints 
The secondary endpoint is the association between the final post-PCI aFFR and 
long-term clinical outcomes. The long-term clinical outcomes will include TVR and 
composite MACE (death, MI, and TVR) during the index hospitalization, 30 days, and 
1 year. 
 
 


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4. 
SELECTION AND WITHDRAW OF PATIENTS 
Up to 200 patients > 18 years of age who are eligible for non-emergent PCI will be 
enrolled.  
4.1 
Clinical Inclusion Criteria 
To be eligible for enrollment, subjects must meet all the following criteria: 
1. Have the capacity to understand and sign an informed consent or have a legally 
authorized representative (LAR) that can understand and sign an informed 
consent prior to initial arteriotomy access 
2. Age > 18 years of age at the time of signing the informed consent 
3. Clinically stable and undergoing non-emergent cardiac catheterization for 
appropriate indications 
4. Willing to be contacted by telephone at 30 days (if no standard of care visit) and 
at 1 year with chart review for events.  
4.2 
Clinical Exclusion Criteria 
If a subject meets any of the following criteria, he or she will not be consented: 
1. Any condition associated with a life expectancy of less than 1 year 
2. Participation in another clinical study using an investigational agent or device 
within the past 3 months 
3. Ejection fraction ≤ 35% 
4. Creatinine ≥ 2 
5. Severe valvular heart disease 
6. Decompensated acute diastolic or systolic heart failure  
7. Bronchospastic chronic obstructive pulmonary disease or other intolerance to 
adenosine 
4.3 
Angiographic Inclusion/Exclusion Criteria 
After the diagnostic angiography, patients having an intermediate lesion(s) 
meeting the following angiographic criteria will be enrolled: 
Inclusion: 
Target vessel with an intermediate lesion of 40-70% stenosis by angiographic 
assessment (a visual estimation by the operator).  Serial lesions, diffuse disease, or ostial 
lesions (“all-comer” lesions) are acceptable if the operator would normally perform FFR 
and proceed with PCI (or other revascularization) if positive. 
Exclusion: 
1. ST-segment elevation myocardial infarction culprit lesion or lesions with any 
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2. Lesions with severe calcification 
3. Lesions in a target vessel supplied by a patent graft 
4.4 
Withdrawal of Patients 
Patients may voluntarily withdraw for any reason without penalty or loss of benefits 
to which they are entitled.  
If a patient withdraws from the study at any time either at his or her request or at 
the investigator’s discretion, the reasons for withdrawal must be recorded on the relevant 
page of the patient’s eCRF. Patients who withdraw from the study prematurely should 
undergo all end-of-study assessments, if possible. Study site personnel should make 
every effort to prevent losing patients to follow-up.  
 
 
 


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5. 
KNOWN AND POTENTIAL RISKS 
The risks of FFR assessment in stable CAD are well described in large-scale 
randomized controlled trials (1, 2). These risks are generally considered to be low and 
acceptable, even in the setting of multivessel disease (1, 2), acute coronary syndromes 
(13, 14), and serial lesions (15). Based on low risk, high value in characterizing lesion 
significance, and improving clinical outcomes, FFR has been incorporated into multi-
society supported Guidelines and Appropriate Use Criteria for coronary revascularization 
(3-6). 
The goal of this study is to compare two different methods of acquiring FFR – 
contrast FFR to the gold-standard adenosine FFR.  Contrast FFR is potentially a safer 
approach to FFR.  Contrast FFR has been previously studied and compared with aFFR; 
however, there has been variability in the type, volume, and rate of contrast injected to 
induce vessel hyperemia with a manual (manifold) injection setup. Standardizing the 
injection with the ACIST CVi automated contrast injector may mitigate the variability for 
induction of hyperemia and provide a more robust comparator to systemic adenosine. 
The risk of contrast-induced nephropathy in contrast FFR is expected to be neutral 
compared with aFFR, since approximately the same amount of contrast would be injected 
during cFFR for hyperemia induction as would be delivered during the wiring and 
verification of wire position steps for traditional pressure wire FFR with adenosine. To 
mitigate risk, only patients without renal insufficiency will be enrolled. Furthermore, use 
of the ACIST automated injector is known to be associated with a significant reduction in 
the total volume of contrast media used and in the net amount of contrast delivered to 
patients when compared with traditional methods of manual (manifold) contrast injection 
(16). This pattern held true across varying types of procedures—97.4%, 53.8%, and 
57.3% more contrast media was used during manual injection compared with the ACIST 
automated contrast injector for diagnostic, diagnostic with PCI, and PCI alone 
procedures, respectively (16). 
This protocol will use the FDA-cleared NAVVUS RXi microcatheter for FFR 
assessment, which comes with several advantages that would render the assessment 
and management of all-comer intermediate lesions safer and with greater success, even 
in tortuous vessels. For example, the operator can choose any standard workhorse 
coronary guidewire for initial wiring. In addition, the unique design of the fiber-optic 
pressure sensor near the tip of a monorail microcatheter allows for ease of traversing 
forward and backwards over the standard 0.014” coronary guidewire without losing wire 
position. In the CONTRACT study evaluating over 200 patients randomized to either 
NAVVUS (n=87) or pressure wire (n=141), the NAVVUS catheter had a high lesion 
crossing success rate (96.9%) and was safe (17). There were no differences between the 
2 groups with respect to contrast or radiation dose. 
In the current study, there is the possibility of requiring multiple FFR recordings per 
vessel. Each run will include a repeat dose of systemic adenosine (risk of known patient 
side effects from adenosine), contrast (risk of contrast-induced nephropathy), time on 
anticoagulation (risk of bleeding), and radiation exposure (risk of skin injury).  We will 
mitigate these risks by including patients with no contraindications to adenosine, normal 
baseline renal function, careful monitoring of ACT while on procedural anticoagulation, 
and safe radiation practices, such as using radiation filters and changing camera 


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angulation. We do not anticipate any additional safety concerns, as multiple FFR 
acquisitions per patient has already been shown to be safe in the setting of multivessel 
disease. In fact, in the initial FAME trial of multivessel disease, the number of indicated 
lesions undergoing FFR assessment with systemic IV adenosine was 2.8, yet this arm 
was found to have improved clinical outcomes compared with the angiography-guided 
PCI arm (1).  Multiple studies have also demonstrated the value of measuring post-PCI 
FFR in clinical practice, as there is strong correlation to long-term outcomes (10, 11). 
Our study sites will only include centers that currently use the ACIST contrast 
injector and NAVVUS FFR microcatheter in routine clinical practice. Familiarity with these 
devices will assist in mitigating risk. Furthermore, most operators in our study perform 
diagnostic and coronary interventions via radial access, a method known to reduce 
bleeding risk, which will mitigate the risks of procedural anticoagulation. 
As with any clinical investigation, study records that identify subjects will be kept 
confidential as required by law. Information systems used to maintain study records will 
comply with federal privacy regulations and safeguards for privacy, security, and 
authorized access. Informed consent will be obtained. Subjects will be assigned a unique 
code number to identify their records for other study-related activities. 
As part of the study, sites will report the results of study-related tests and images 
to the DCRI. These would include cardiac catheterization reports and FFR tracings for 
review by an independent FFR core lab. Risks will be further minimized by appropriate 
review by the individual site IRBs. 
 
 
 


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6. 
STUDY PROCEDURES 
Medical questions regarding subject eligibility, procedures, or patient care should 
be directed to the study principal investigator, who can be reached as follows:  
Dr. Rajesh V. Swaminathan at 919-684-1284 during US Eastern Time business 
hours, or 919-684-8111 after US Eastern Time business hours. 
6.1 
Screening Procedures 
Potentially eligible subjects will be screened upon confirmation of non-emergent 
PCI. Study personnel will assess each subject against study inclusion and exclusion 
criteria, and the investigator will determine the subject’s eligibility for participation.  
6.2 
Informed Consent 
Each site will submit the study protocol, informed consent form (ICF), and other 
study documents to their ethics committee IRB for approval. A copy of the signed and 
dated IRB approval for each enrolling center will be stored at the Data Coordinating 
Center (DCRI). Any amendments to the protocol, other than minor administrative 
changes, must be approved by the site’s IRB before the changes are implemented at the 
site. 
The informed consent process will be documented in the subject’s medical record 
or comparable source document. 
Consent will be obtained from the subject or their LAR prior to arterial access and, 
if the subject is consenting, prior to the administration of any medications that might affect 
patient cognition. 
6.3 
Enrollment  
Once a subject has met all clinical inclusion/exclusion criteria and provided 
informed consent, the subject will be eligible for study enrollment. Study staff is 
encouraged to appropriately identify candidates consistent with study objectives.  
After the diagnostic angiogram, subjects who meet angiographic criteria of any 
intermediate lesion(s) as defined by the protocol will be enrolled. 
6.4 
Screen Failures 
All subjects who are consented but not enrolled due to angiographic inclusion and 
exclusion criteria will be logged in the eCRF as a screen failure.  


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6.5 
Post-procedure Follow-up 
Subjects will be seen for their standard post-procedure visit (approximately 30 
days post-procedure). Additional follow-up will be completed at 1 year via telephone call. 
Subjects will be asked to report indications for any hospitalizations, cardiac 
catheterization procedures, and/or coronary interventions since the index enrollment 
procedure. Subjects will be asked specifically about clinical events including MI and 
revascularization with further stents. Source documents will be collected and reviewed to 
verify clinical endpoints. 
6.6 
Schedule of Events 
The schedule of study assessments and procedures is provided in Table 1: 


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Table 1 
Schedule of Assessments 
 
Screening 
and Pre-
enrollment 
Enrollment 
/Procedure  
Post-
procedure 
30 (± 7) 
Days 
1 Year       
(± 30 Days) 
Inclusion/exclusion 
criteria - enrollment 
X 
 
 
 
 
Informed consent and 
patient contact form 
details 
X 
 
 
 
 
Medical history 
X 
 
 
X 
X 
Physical assessment, 
vital signs (standard 
of care) 
Xa, 
 
 
X 
 
Concomitant 
medications 
Xa 
 
 
X 
X 
Diagnostic angiogram 
X 
 
 
 
 
Coagulation labs 
 
Xb 
 
 
 
Perform resting, dPR, 
contrast, and 
adenosine FFR 
 
X 
 
 
 
Perform post-PCI 
FFR if applicable 
 
X 
 
 
 
Collection of specified 
CV endpoints (death, 
MI, TVR) 
 
 
Xc 
Xc 
Xc 
FFR, fractional flow reserves; dPR, diastolic Pressure Ratio; PCI, percutaneous coronary 
intervention; MI, myocardial infarction; TVR, target vessel revascularization 
a Within 7 days or immediately before enrollment . 
b confirm anticoagulation prior to coronary wire exiting the guide catheter 
c All serious adverse events related to the NAVVUS Rxi FFR microcatheter system. Specified 
cardiovascular endpoint events data collection will be reported on the eCRF endpoint pages only 
 
 


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7. 
DATA CAPUTURE 
An electronic data capture (EDC) system will be used for this study (IBM Clinical 
Data/eCOS). All users will be trained on the technical features of the EDC as well as the 
content of the eCRF by qualified personnel prior to gaining access to the EDC. A user 
ID/password will be granted after training. This ID is not to be shared amongst the study 
staff. All users must have a unique account to enter or review data. The eCRF should be 
filled out by the site 3 days after each visit. It is not expected that the eCRF will serve as 
source for any data collected in this study. If there is a reason for a site to do so, it must 
be approved by and documented in the site files.  
Prior to the database being locked, the investigator or designee will review, 
approve, and sign/date each completed eCRF. This signature serves as attestation of the 
investigator’s responsibility for ensuring that all data entered into the eCRF are complete, 
accurate, and authentic. 
 


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8. 
SUBJECT SAFETY AND ADVERSE EVENTS 
Subject safety from pre-procedure evaluation through discharge is the 
responsibility of the treating physician.  The procedural aspects should follow published 
guidelines for appropriate use criteria.  Post-discharge follow-up visits are part of routine 
standard of care.   
All devices used in this study are FDA-cleared and will be used according to current 
instructions for use (IFU).  A device has failed or malfunctioned if it is used in accordance 
with the IFU but does not perform according to the IFU.  Because all devices used in this 
study are marketed and being used from hospital supply, any device failures or 
malfunctions will be reported to the device manufacturer per local policy. 
In addition, the inability to position the NAVVUS Rxi microcatheter at the desired 
location (~1-2 cm beyond the target lesion) will be considered an event of interest. This 
device failure rate will be recorded in the eCRF but will not be mandated for reporting to 
the device manufacturer, as it is not considered a serious adverse event. 
8.1 
Device Failures, Device Malfunctions, and User Error 
In the case of a device failure or malfunction related to the investigation that does 
not constitute a UADE, the manufacturer should be notified and the device returned to 
the manufacturing company, if possible. Since these are approved devices, device 
failures, malfunctions, and user errors will be reported to the appropriate company and 
FDA per local site policy. 
Contact ACIST Medical Customer Service to arrange for a return of the involved 
hardware and to report the device failure or malfunction. 
ACIST Customer Support 
Phone: 888-670-7701 
FAX: 952-256-4524 
Email: customer.support@acistmedical.com  


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9. 
STATISTICAL ANALYSIS AND DETERMINATION OF SAMPLE SIZE 
9.1 
Intent-to-Treat Population 
The intent-to-treat (ITT) population is consented patients that meet the clinical 
inclusion/exclusion criteria will be screened in the catheterization laboratory to determine 
whether they meet the angiographic inclusion/exclusion criteria. Those that meet the 
angiographic inclusion/exclusion criteria will be officially enrolled in the study and 
considered part of the intent-to-treat population. 
9.2 
Per-Protocol Evaluable Population  
The per-protocol population is patients in the ITT population that have successfully 
completed both FFR methods on at least 1 target lesion.  
9.3 
Primary Endpoint Analysis  
9.3.1 Quantitative Method Comparison Between Contrast Fractional Flow 
Reserves and Adenosine Fractional Flow Reserves  
Contrast FFR and aFFR will be quantitatively compared using the procedure 
described in CLSI EP09-A3 Measurement Procedure Comparison And Bias Estimate 
Using Patient Samples Approved Guideline (18). A summary of this comparison is 
described below. 
The measurements from the 2 methods will be plotted against each other. The 
aFFR will be plotted on the x-axis, and the cFFR will be plotted on the y-axis. The plot will 
be examined for highly influential points and heterogeneity of variance along the range of 
measurement values. In addition, several types of difference plots similar to the Bland-
Altman plot will be used to examine whether: 
• the size of the variance changes with changing measurement value 
• the bias changes with changing measurement value 
• the coefficient of variation changes with changing measurement value 
Based on the above information, the appropriate model will be applied to describe 
the relationship of aFFR measured values to their corresponding cFFR values.  
Assuming: 
• sample size of 208 pairs (see the next section) of FFR measurements 
• linear model will be applied in quantitative method comparison 
• width of the 2­sided 95% CI for the slope is expected to be ± 0.06 
• width of the 2­sided 95% CI for the bias is expected to be within ± 0.06 


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9.3.2 Qualitative Method Comparison Between Contrast Fractional Flow 
Reserves and Adenosine Fractional Flow Reserves  
The qualitative method comparison consists assessing the agreement as to which 
lesion is flow limiting. If a lesion has an adenosine FFR measurement ≤ the cutoff value 
of 0.8, then the lesion is considered flow limiting. Using the model developed above, the 
contrast FFR measurement that corresponds to adenosine FFR measurement value of 
0.8 will be used as the cutoff value for determining whether a lesion is flow limiting for 
contrast FFR.  The expected cutoff value for the contrast FFR is 0.83.   
The 2 methods will be compared qualitatively using the AUC under the ROC curve.  
The analysis will incorporate the following: 
1. 
The contrast FFR will be the new diagnostic compared to the adenosine 
FFR as the reference standard. 
2. 
The hypotheses will be designed to demonstrate that that AUC for these 
two methods is greater than 0.8.   
The null and alternative hypotheses are as follows: 
H0: ROC AUC ≤ 0.8 
HA: ROC AUC > 0.8 
Two hundred and eight pairs of measurements are needed assuming an AUC of 
0.9, the ratio of negatives to positives is 1.06, the ratio of the standard deviation of the 
negatives to the SD of the positives is 1, a 2-sided alpha of 0.05 and a power of 0.9.  
Figure 2 shows how the sample size changes with varying assumptions of AUC and ratio 
of negatives to positives.   


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Figure 2: Sample Size by AUC by various ratio of negative to positive  
Contrast FFR compared to Adenosine FFR 
 
The number of pairs of FFR measurements will be tracked and enrollment will be 
stopped once the requisite number of pairs of FFR measurements have been reached.   
9.4 
Secondary Endpoint Analysis 
9.4.1 Assessment of the Relationship Between Post-Percutaneous Coronary 
Intervention Fractional Flow Reserves and Long-Term Clinical Outcomes 
A logistic model will be developed that assesses whether there is a relationship 
between final PCI FFR (resting, dPR, cFFR, aFFR) and long-term outcomes (death, MI, 
TVR). The model will include the known covariates for predicting revascularization 
outcomes: stent length, vessel diameter, diabetes, history of cardiovascular disease, and 
multi-vessel disease. 
N vs AUC1 by R
AUC0=0.80 Alpha=0.050 Power=0.90 2-Sided Z Test
AUC1
N
0.90
0.91
0.92
0.93
0.94
0.95
50
100
150
200
250
R
0.75
0.90
1.06
1.20
1.35


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9.4.2 Additional Endpoints  
Descriptive statistics will be provided for any additional endpoints. For binary 
measures, the rate and Clopper-Pearson 95% CI will be provided. For continuous 
endpoints, the mean, median, SD, and the interquartile range will be provided. For time 
to event measures, the Kaplan-Meier product limit estimate and 95% CI will be provided 
for each year of follow-up. 
9.4.3 Missing Data  
If the missing data for the per-protocol population are less than 10%, no attempt 
will be made to impute the missing data. However, a tipping analysis will be performed as 
a sensitivity analysis. If the missing data are greater than 10%, based on the type of 
missing data (missing at random, not missing at random, missing completely at random, 
etc.), the appropriate multiple imputation method will be employed as a sensitivity analysis 
to assess the impact of the missing data on the primary endpoint. 
9.5 
Estimated Duration of the Study 
The estimated enrollment duration is approximately 1 year.  It is estimated that the 
study involvement for all sites will extend approximately 1 year after the last entered 
subject’s procedure.  
10. 
STUDY ETHICAL CONSIDERATIONS 
10.1 
Confidentiality of Patients 
Patient confidentiality will be maintained throughout the clinical study in a way that 
ensures the information can always be tracked back to the source data. For this purpose, 
a unique patient identification code will be used that allows identification of all data 
reported for each study patient. 
Patient information collected in this study will comply with the standards for 
protection of privacy of individually identifiable health information as promulgated in the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA). All records will be 
kept confidential, and the patient’s name will not be released at any time. Patient records 
will not be released to anyone other than sponsor or its designees, and responsible 
regulatory authorities, when requested.   
 
 


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11. 
ADMINISTRATIVE PROCEDURES 
11.1 
Duke Clinical Research Institute Coordinating Center Responsibilities 
11.1.1 Investigator Training 
All Investigators and their study personnel will receive training regarding the study 
procedures. This training will take place prior to enrollment of the first patient at each 
study center. Any new personnel joining the study after initiation will receive the same 
training prior to participation. 
Questions around eCRF completion or study procedures should be directed to the 
site’s clinical research associate.   
11.2 
Investigator’s Responsibilities 
11.2.1 Reporting and Recording of Study Data 
It is the investigator’s responsibility to ensure the accuracy, completeness, and 
timeliness of the data reported on the patient’s eCRF. Source documentation supporting 
the eCRF data should indicate the patient’s participation in the study and should 
document the dates and details of study procedures and patient’s clinical status from 
informed consent though the 1 year contact. 
11.2.2 Source Documentation 
The investigator must maintain adequate and accurate source documents upon 
which case reports for each patient are based. They are to be separate and distinct from 
eCRFs. 
These records should include detailed notes on: 
− The medical history prior to participation in the study 
− The basic identifying information, such as demographics, that link the patient’s 
source documents with the eCRF 
− The results of all diagnostic tests performed, diagnoses made, therapy provided, 
and any other data on the condition of the patient 
− The patient’s exposure to study treatment 
− The patient’s exposure to any concomitant therapy (including date and quantity 
dispensed) 
− All relevant observations and data on the condition of the patient throughout the 
study 


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− The oral and written communication with the patient regarding the study treatment 
(including the risks and benefits of the study) 
− The date of informed consent recorded in the source documentation 
11.2.3 Records Retention 
The investigator must inform, and receive approval from, the Sponsor prior to the 
destruction of any documents, if documents are to be transferred to a different facility or 
transferred to a different owner. 
The investigator shall maintain the records required for this investigation for a 
period of 6 years after the date on which the investigation is terminated or completed. 


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12. 
STEERING COMMITTEE, DATA AND SAFETY MONITORING COMMITTEE, 
AND ADJUDICATION COMMITTEE 
12.1 
Steering Committee 
The Steering Committee for this study will supervise the conduct, administration, 
and course of the clinical trial. They will provide scientific and clinical oversight and will 
meet periodically to monitor subject enrollment and overall study progress. This 
committee will also be responsible for reviewing the final results, determining the methods 
of presentation and publication, and selection of secondary projects and publications. The 
steering committee for this study will include the study chair, principal investigator, up to 
2 additional clinicians experienced in FFR clinical trials, a DCRI statistician, and a 
member from the ACIST team. 
12.2 
Fractional Flow Reserve Core Lab 
This purpose of the core lab will be to review the quality and validity of each FFR 
tracing obtained from all subjects enrolled in the study as well as derive the dPR via 
waveform analysis. The core lab will consist of 1 physician knowledgeable in FFR 
physiology and the catheter techniques employed for proper FFR acquisition and 1 
engineer from the ACIST team with specific knowledge about FFR acquisition and data 
analysis from the NAVVUS Rxi FFR system. These 2 members will perform an 
independent, blinded review of all FFR tracings and will make a recommendation for 
exclusion if any of the following criteria are noted: ventricularization of aortic waveform, 
change in dampening/distortion of aortic waveform, or significant signal drift. 
Discrepancies in recommendations will be resolved by joint review of the 2 members of 
the tracing in question. 


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13. 
POLICY FOR PUBLICATION AND PRESENTATION OF DATA 
The sponsor will encourage the scientific publication of data from clinical research 
trials. However, investigators may not present or publish partial or complete study results 
individually. The principal investigators and the partners may propose appropriate 
scientific manuscripts or abstracts from the study data. Any manuscript or abstract 
proposed by the investigators must be reviewed and approved in writing by the Steering 
Committee before submission for publication. 


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14. 
REFERENCES  
1. 
Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, et al. 
Fractional flow reserve versus angiography for guiding percutaneous coronary 
intervention. The New England journal of medicine. 2009;360(3):213-24. 
2. 
De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, et al. 
Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. 
The New England journal of medicine. 2012;367(11):991-1001. 
3. 
Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 
ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive 
summary: a report of the American College of Cardiology Foundation/American Heart 
Association Task Force on Practice Guidelines and the Society for Cardiovascular 
Angiography and Interventions. Circulation. 2011;124(23):2574-609. 
4. 
Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. 
ACCF/SCAI/STS/AATS/AHA/ASNC 2009 Appropriateness Criteria for Coronary 
Revascularization: a report by the American College of Cardiology Foundation 
Appropriateness Criteria Task Force, Society for Cardiovascular Angiography and 
Interventions, Society of Thoracic Surgeons, American Association for Thoracic 
Surgery, American Heart Association, and the American Society of Nuclear Cardiology 
Endorsed by the American Society of Echocardiography, the Heart Failure Society of 
America, and the Society of Cardiovascular Computed Tomography. Journal of the 
American College of Cardiology. 2009;53(6):530-53. 
5. 
Patel MR, Dehmer GJ, Hirshfeld JW, Smith PK, Spertus JA. 
ACCF/SCAI/STS/AATS/AHA/ASNC/HFSA/SCCT 2012 Appropriate use criteria for 
coronary revascularization focused update: a report of the American College of 
Cardiology Foundation Appropriate Use Criteria Task Force, Society for Cardiovascular 
Angiography and Interventions, Society of Thoracic Surgeons, American Association for 
Thoracic Surgery, American Heart Association, American Society of Nuclear 
Cardiology, and the Society of Cardiovascular Computed Tomography. Journal of the 
American College of Cardiology. 2012;59(9):857-81. 
6. 
Patel MR, Calhoon JH, Dehmer GJ, Grantham JA, Maddox TM, Maron DJ, et al. 
ACC/AATS/AHA/ASE/ASNC/SCAI/SCCT/STS 2016 Appropriate Use Criteria for 
Coronary Revascularization in Patients With Acute Coronary Syndromes: A Report of 
the American College of Cardiology Appropriate Use Criteria Task Force, American 
Association for Thoracic Surgery, American Heart Association, American Society of 
Echocardiography, American Society of Nuclear Cardiology, Society for Cardiovascular 
Angiography and Interventions, Society of Cardiovascular Computed Tomography, and 
the Society of Thoracic Surgeons. Journal of the American College of Cardiology. 
2017;69(5):570-91. 


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7. 
Veer MV, Pijls NH, Hennigan B, Watkins S, Ali ZA, De Bruyne B, et al.  
Comparison of Different Diastolic Resting Indexes to iFR: Are They All Equal? J Am Coll 
Cardiol 2017;70:3088-96. 
8. 
Leone AM, Scalone G, De Maria GL, Tagliaferro F, Gardi A, Clemente F, et al. 
Efficacy of contrast medium induced Pd/Pa ratio in predicting functional significance of 
intermediate coronary artery stenosis assessed by fractional flow reserve: insights from 
the RINASCI study. EuroIntervention : journal of EuroPCR in collaboration with the 
Working Group on Interventional Cardiology of the European Society of Cardiology. 
2015;11(4):421-7. 
9. 
Johnson NP, Jeremias A, Zimmermann FM, Adjedj J, Witt N, Hennigan B, et al. 
Continuum of vasodilator stress from rest to contrast medium to adenosine hyperemia 
for fractional flow reserve assessment. JACC: Cardiovascular Interventions. 
2016;9(8):757-67. 
10. 
Rimac G, Fearon WF, De Bruyne B, Ikeno F, Matsuo H, Piroth Z, et al. Clinical 
value of post-percutaneous coronary intervention fractional flow reserve value: A 
systematic review and meta-analysis. American heart journal. 2017;183:1-9. 
11. 
Pijls NH, Klauss V, Siebert U, Powers E, Takazawa K, Fearon WF, et al. 
Coronary pressure measurement after stenting predicts adverse events at follow-up: a 
multicenter registry. Circulation. 2002;105(25):2950-4. 
12. 
Menon M, Jaffe W, Webster M, for the ACCESS-NZ Investigators. Poster: FFR 
measurement using a new ultra-thin catheter based system.  EuroPCR; 21-24 May 
2013; Paris, France 2013. 
13. 
Gotberg M, Christiansen EH, Gudmundsdottir IJ, Sandhall L, Danielewicz M, 
Jakobsen L, et al. Instantaneous Wave-free Ratio versus Fractional Flow Reserve to 
Guide PCI. The New England journal of medicine. 2017;376(19):1813-23. 
14. 
Davies JE, Sen S, Dehbi HM, Al-Lamee R, Petraco R, Nijjer SS, et al. Use of the 
Instantaneous Wave-free Ratio or Fractional Flow Reserve in PCI. The New England 
journal of medicine. 2017;376(19):1824-34. 
15. 
Kim H-L, Koo B-K, Nam C-W, Doh J-H, Kim J-H, Yang H-M, et al. Clinical and 
physiological outcomes of fractional flow reserve-guided percutaneous coronary 
intervention in patients with serial stenoses within one coronary artery. JACC: 
Cardiovascular Interventions. 2012;5(10):1013-8. 
16. 
Anne G, Gruberg L, Huber A, Nikolsky E, Grenadier E, Boulus M, et al. 
Traditional versus automated injection contrast system in diagnostic and percutaneous 


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coronary interventional procedures: comparison of the contrast volume delivered. The 
Journal of invasive cardiology. 2004;16(7):360-2. 
17. 
Masdjedi K, Van Mieghem NM, Diletti R, van Geuns RJ, de Jaegere P, Regar E, 
et al. Navvus FFR to reduce CONTRAst, Cost and radiaTion (CONTRACT); insights 
from a single-centre clinical and economical evaluation with the RXi Rapid-Exchange 
FFR device. International journal of cardiology. 2017;233:80-4. 
18. 
Budd J, Durham A, Gwise T, Iriarte B, Kallner A, Linnet K, et al. Measurement 
procedure comparison and bias estimation using patient samples: approved guideline. 
Clinical Laboratory Standards Institute. 2013;33:1-79.