DEFINE PCI: Physiologic Assessment of Coronary Stenosis Following PCI
Conditions: Coronary Artery Disease, Coronary Stenosis, Angina, Unstable, Angina, Stable
Sponsor: Volcano Corporation

Philips Volcano 
 
DEFINE-PCI Protocol 
Document Control # D000124064/C 
 
#160101 
 
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Study Protocol 
 
 
 
Physiologic assessment of coronary stenosis following PCI 
 
 
Sponsor:   
Philips Volcano  
3721 Valley Centre Drive, Suite 500  
San Diego, CA  92130  USA  
 
 
Principal 
Investigators(PI):   
Allen Jeremias,  MD, MSC, FACC, FSCAI    
Cardiovascular Research Foundation 
Manesh Patel, MD, FACC, FAHA, FSCAI    
Duke Clinical Research Institute 
Justin Davies, MBBS, MRCP, BSc, PhD       
Imperial College London 
 
 
 
Protocol Version:   
3.0  
 
 
Protocol Date:   
October 26, 2017 
 
 
Protocol Number:   
160101 
 
 
IDE Number:   
Not Applicable  
 
Version History 
Approval Date 
1.0 
December 20, 2016  
2.0 
July 24, 2017 
 
 
This document is confidential and the property of Philips Volcano. No part of it may be 
transmitted, reproduced, published, or used by other persons without prior written 
authorization from the study sponsor. This document may be disclosed to the appropriate 
IECs/IRBs or to duly authorized representatives of the US Food and Drug Administration or 
other regulatory authority under the condition that they maintain confidentiality. 

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PROTOCOL APPROVAL PAGE 
 
Study Title: DEFINE-PCI: Physiologic assessment of coronary stenosis following 
PCI 
 
 
 
Version: 3.0 
 
Date of Issue:  October 16, 2017 
 
 
 
 
I have received a copy of this version of the protocol, have read, understand the protocol, 
and agree the study will be conducted in compliance with the protocol, GCP, the Declaration 
of Helsinki, and the applicable regulatory requirement(s). 
 
 
 
 
______________________________________________  
 
Investigator Name 
 
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Investigator Signature 
 
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Date 
 
 
 
 
 
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Philips Volcano 
 
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Signature 
 
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Table of Contents 
Study Protocol ....................................................................................................................1 
Protocol Approval Page .......................................................................................................2 
STUDY SUMMARY...........................................................................................................5 
Abbreviations .....................................................................................................................10 
INTRODUCTION................................................................................................................11 
Background……………. ...........................................................................................11 
Clinical Experience with Device ..........................................................................12 
Study Rationale .....................................................................................................13 
STUDY OBJECTIVES ..............................................................................................14 
Primary Endpoints ...............................................................................................14 
Secondary Endpoints ...........................................................................................14 
Predictors of delta iFR before and after PCI ......................................................15 
Study Design .....................................................................................................................16 
Overview ...............................................................................................................16 
Methods .................................................................................................................17 
Treatment Arms ...................................................................................................17 
Inclusion Criteria ..................................................................................................17 
Exclusion Criteria .................................................................................................18 
Study Procedures .................................................................................................18 
Baseline………….. ...................................................................................................18 
Index Procedure ...................................................................................................19 
Angiographic Assessment ....................................................................................19 
PCI Procedure……………. .......................................................................................21 
Discontinued Subjects ..........................................................................................24 
Device Malfunctions or Use Errors .....................................................................26 
Reporting Requirements .....................................................................................26 
Protocol Deviations and Waivers ........................................................................27 
Ethical Considerations .....................................................................................................29 
Benefits ..................................................................................................................29 
Mitigation of Risks ................................................................................................30 
Data Handling and Record Keeping ................................................................................30 
Case Report Forms ...............................................................................................31 
Source Documents ................................................................................................31 
Data Queries..........................................................................................................31 
Record Retention ..................................................................................................31 
 

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Monitoring and Oversight ................................................................................................32 
Selection of Investigators ....................................................................................32 
Site Initiation Visits ..............................................................................................32 
Interim Monitoring Visits ....................................................................................33 
Study Close-out Visits ..........................................................................................33 
Direct Access to Source Data / Documents ........................................................33 
Amendments to the Protocol ...............................................................................33 
Device Accountability ..........................................................................................34 
Administrative Responsibilities ......................................................................................34 
Independent Ethics Committee/ Institutional Review Board Information ....34 
Informed Consent and Subject Information .......................................................34 
Investigator Responsibilities ...............................................................................35 
Discontinuation of the Trial by the Sponsor ......................................................36 
Discontinuation of a Site by the Sponsor............................................................36 
Confidentiality ......................................................................................................36 
Publication Policy .............................................................................................................37 
Statistical Analysis Plan and Determination of Sample Size .............................................37 
References .........................................................................................................................40 
Study Sponsor Contacts .......................................................................................42 
Declaration of Helsinki.........................................................................................43 
Draft Informed Consent Form .............................................................................44 
Instructions for Use ..............................................................................................45 
 
 
 
 
 
 
 
  
 
 

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STUDY SUMMARY 
 
Title 
DEFINE-PCI 
Study Chairman 
Gregg Stone (CRF) 
Study PIs 
Allen Jeremias (CRF), Manesh Patel (Duke), Justin Davies (Imperial 
College London) 
Background 
Numerous studies of coronary stenting over the past decade have 
consistently demonstrated that  recurrent episodes of angina within 
the first year post PCI are common, occurring in approximately 20% 
of patients. This may lead to a substantial increase in repeat invasive 
procedures and associated health care costs.  
 
Physiologic assessment of coronary stenoses prior to percutaneous 
coronary intervention (PCI) is superior to coronary angiography alone 
for lesion evaluation, reducing overall major cardiac events as well as 
cost. However, data on post PCI physiology is scarce and thus rarely 
used in clinical practice. Limited clinical data on post PCI Fractional 
Flow Reserve (FFR) and instantaneous wave-free ratio (iFR) indicate 
that a substantial number of patients (up to 20%) have impaired 
coronary physiology at the completion of the procedure despite an 
angiographically successful PCI. It is not known whether an abnormal 
post-PCI FFR or iFR is predictive of recurrent angina and whether the 
routine use of physiological indices of coronary function can predict 
future cardiovascular events. 
 
iFR safely and accurately quantifies stenosis severity in a wide range 
of lesions and may be helpful in assessing post PCI physiology. 
Compared with FFR, it allows rapid assessment of the lesion without 
induction of maximal hyperemia with adenosine. iFR pullback has the 
potential additional advantage of interrogating the entire coronary 
artery to identify culprit lesions with significant pressures gradients.  
Hypothesis 
This is a pilot study designed to assess the relationship between iFR 
pullback and the distribution of coronary atheroma/stenoses as 
assessed by Quantitative Coronary Angiography (QCA) post 
angiographically successful PCI. The hypotheses of this study are: 
1. iFR is impaired in a substantial proportion of patients 
following operator-assessed angiographically successful PCI  
2. Post-PCI iFR detects residual significant CAD that is not 
detected on QCA (defined by >50% stenosis) 
3. Post PCI iFR is predictive of future adverse cardiovascular 
events 
Objectives 
1. Determine the range of post-PCI iFR and the rate of significant 
residual ischemia defined as iFR <0.90 following operator-
assessed angiographically successful PCI 
2. Determine the proportion of cases in which the iFR would 
become non-significant if a focal stenosis demonstrated by iFR 
pullback were treated with PCI. This will be the number or 

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proportion used in the sample size calculation for the planned 
randomized trial. 
3. Determine the relationship between post-PCI iFR pullback and 
QCA with respect to residual stenosis by QCA, residual stenoses 
and device success (i.e. optimal stent implantation). The goal is to 
correlate abnormal iFR measurements to their anatomic reason 
(i.e. device related complications, angiographically undetected 
residual lesions, or diffuse atherosclerotic disease).  
4. Determine the relationship between post-PCI iFR and clinical 
outcomes, such as recurrent angina and MACE.  
5. Establish the relationship between post-PCI iFR and objective 
assessment of quality of life. 
 
Study Design and 
Methods 
DEFINE-PCI is a multi-center, prospective study in up to 25 centers in 
USA and internationally. Consented subjects with CAD who undergo 
physiologic lesion assessment with iFR<0.90 in at least 1 coronary 
artery are eligible for participation. After successful PCI to all culprit 
lesions based on angiographic assessment of the treating physician, a 
blinded post-PCI iFR and iFR pullback will be performed. The 
proportion of patients with impaired post-PCI iFR will be assessed, 
and the number of patients in whom ischemia could theoretically be 
normalized with further PCI determined. Additionally, the association 
between the post-PCI iFR results and cardiovascular events and 
clinical symptoms will be assessed. Follow-up will be at 1, 6 and 12 
months, including administration of quality of life questionnaires. 
Number of subjects 
An exact one sample binominal proportion test will be used for 
analysis of the primary endpoint. Assuming a 10% rate of residual 
>50% stenosis based on QCA versus a conservative 15% rate of 
iFR<0.90 with a two-sided type I error of 0.05, approximately 500 
patients will be required to achieve 90% power.  
 
Primary Endpoint 
Rate of residual ischemia defined as iFR <0.90 after operator-
assessed angiographically successful PCI (residual diameter 
stenosis <50% in any treated lesion in the target vessel) 
Secondary 
Endpoint 
Secondary clinical endpoints (assessed in relation to post PCI 
iFR ([as dichotomous and continuous variable]): 
1. Composite of cardiac death, target vessel myocardial infarction, 
ischemia-driven target vessel revascularization or recurrent 
ischemia at one year (definition below)  
2. Target vessel failure defined as cardiac death, target vessel 
myocardial infarction, ischemia-driven target vessel 
revascularization  
3. Quality of life (assessed by the Seattle Angina Questionnaire) at 
baseline, 30-days, 6 months and 1year 
4. All-cause and cardiac mortality at one year  
5. Target vessel Myocardial infarction at one year  
6. Ischemia-driven target vessel revascularization at one year 

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7. Recurrent ischemia at one-year  
Secondary physiology endpoints: 
8. Correlation between iFR <0.90 and coronary stenosis >50% 
assessed by visual interpretation 
9. Proportion of cases in which the iFR would become non-
significant if a focal stenosis demonstrated by iFR pullback were 
treated with PCI 
10. Differentiation of the cause for impaired iFR (categorized as stent 
related, distant focal stenosis, or diffuse atherosclerosis) 
11. Predictors of delta iFR before and after PCI 
Inclusion Criteria 
1. Subject must be > 18 years old 
2. Subjects presenting with stable angina, silent ischemia or non-ST-
elevation ACS (unstable angina or biomarker positive) 
3. Single vessel CAD with at least 2 separate lesions (≥10 mm apart) 
of ≥40% stenosis or a single long lesion of ≥20mm OR multi-
vessel CAD, defined as at least 2 vessels with ≥40% stenosis  
4. Pre-PCI iFR performed in all vessels intended for PCI 
5. Pre-PCI iFR of <0.90 of at least 1 stenosis 
6. Subjects are able and willing to comply with scheduled visits and 
tests and to provide informed consent. 
Exclusion Criteria 
1. Pregnant or planning to become pregnant for the duration of the 
study 
2. Acute STEMI within the past 7 days 
3. Cardiogenic shock (sustained (>10 min) systolic blood pressure < 
90 mmHg in absence of inotropic support or the presence of an 
intra-aortic balloon pump). 
4. Ionotropic or temporary pacing requirement  
5. Sustained ventricular arrhythmias  
6. Prior CABG  
7. Known ejection fraction ≤30% 
8. Chronic Total Occlusion (CTO) of study vessel 
9. Known moderate to severe mitral or aortic disease. 
10. Any known medical comorbidity resulting in life expectancy < 12 
months. 
11. Participation in any investigational study that has not yet reached 
its primary endpoint. 
12. Known severe renal insufficiency (eGFR <30 ml/min/1.72 m2). 
13. TIMI flow <3 at baseline of study vessel 
14. Intra-coronary thrombus on baseline angiography 
 
Sample size 
considerations 
N=500 patients 
Definition of 
recurrent ischemia 
Recurrent ischemia is defined as ischemia meeting any of the criteria 
below: 1 

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1. Recurrent ischemia with ECG changes: recurrent ischemic 
discomfort 
or equivalent at rest lasting ≥10 min associated with new ST or 
T-wave changes consistent with ischemia (ST elevation ≥0.1 mV or 
dynamic horizontal/down-sloping ST depression ≥0.05 mV or 
T-wave inversions ≥0.2 mV) 
or 
2. Recurrent ischemia leading to hospitalization: recurrent ischemic 
discomfort or equivalent at rest lasting ≥10 min, repeated episodes 
at rest lasting ≥5 min, or an accelerating pattern of ischemic 
discomfort (episodes that are more frequent, severe, longer in 
duration, and/or precipitated by less exertion) prompting 
re-hospitalization and considered to be myocardial ischemia upon 
final diagnosis 
or 
3. Recurrent ischemia prompting revascularization, defined as: 
(a) During the index hospitalization: PCI or CABG prompted by 
recurrent ischemia with ECG changes  
or 
(b) After hospital discharge from index hospitalization: PCI or CABG 
prompted by increase in angina to a higher Canadian Cardiovascular 
Society 
Class, or evidence for ischemia on provocative testing 
or 
4. Worsening angina/ischemia requiring additional medical therapy 
(a) An increase in angina to a higher Canadian Cardiovascular 
Society Class 
and 
(b) Requiring intensification of antianginal therapy with new or 
increasing doses of antianginal medications 
 
 
 
 
 
 
 
 
 
 
 

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Table 1. Schedule of Events 
 
* Baseline and Post Procedure if Lab measurements are performed per local standard-of-care, data 
should be collected in the eCRF.  
If performed as SOC,  At least one biomarker level should be obtained post PCI at 4-8 hrs. Post 
procedure. CK-MB is preferred but Troponin I/T may be drawn if CK-MB not available. Subsequent 
biomarker levels are highly recommended if initial post PCI biomarker is elevated and should be 
followed per local standard of care 
 
** Pregnancy test must be negative within 7 days prior to enrollment 
 
^ If Echo, TTE, Nuclear Scan, MRI or CCTA is performed per routine standard-of-care, data should be 
collected in the eCRF 
 
+ Angiography and iFR tracings archived to DVD and submitted to the core lab 
 
++ If IVUS or OCT are performed as standard of care- images should be archived to DVD and 
submitted to the core lab 
 
 
Baseline 
During 
Procedure 
Post-
procedure 
(prior to 
D/C ) 
30 day 
follow-
up  
6 
month 
follow-
up  
12 
month 
follow-
up  
Physical assessment and 
Patient Interview 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Current antianginal 
Medications 
X 
 
 
X 
X 
X 
Event assessment  
 
 
X 
X 
X 
X 
Lab measurements 
 
 
 
 
 
 
CBC and platelet count* 
X 
 
X 
 
 
 
Troponin or CK-MB* 
X 
 
X 
 
 
 
Complete metabolic panel* 
X 
 
X 
 
 
 
 Pregnancy test (for women   of 
childbearing potential)** 
X 
 
 
 
 
 
Non-invasive testing 
 
 
 
 
 
 
EKG 
X 
 
X 
 
 
 
Echocardiogram ^ 
X 
 
 
 
 
 
Ischemia assessment^ 
(TTE/nuclear/MRI/CCTA) 
X 
 
 
 
 
 
Invasive Testing 
 
 
 
 
 
 
 iFR + 
 
X 
 
 
 
 
 Angiography + 
 
X 
 
 
 
 
IVUS/OCT ++ 
 
X 
 
 
 
 
Quality of Life measurement 
 
 
 
 
 
 
Seattle Angina Questionnaire 
X 
 
 
X 
X 
X 

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ABBREVIATIONS 
AE 
Adverse event 
ADE 
Adverse Device Effect  
CAD 
Coronary artery disease 
CBC 
Complete blood count 
CCTA 
Coronary computed tomography angiography 
CK-MB 
Creatinine kinase – MB isoenzyme 
EKG 
Electrocardiogram 
FDA 
Food and Drug Administration  
FFR 
Fractional Flow Reserve 
GCP 
Good Clinical Practice  
IEC  
Independent Ethics Committee  
iFR 
Instantaneous wave-free ratio 
iFR 
PULLBACK 
iFR Pressure wire pullback 
IRB  
Institutional Review Board  
MACE 
Major adverse cardiac events 
MRI 
Magnetic resonance imaging 
NSTEMI 
Non ST-segment elevation myocardial infarction 
PCI 
Percutaneous coronary intervention 
PHI 
Personal Health Information  
QCA 
Quantitative Coronary Angiography 
 QoL 
Quality of Life 
SAE 
Serious Adverse Event  
SADE 
Serious Adverse Device Effect  
TTE 
Transthoracic echocardiogram 
UADE  
Unanticipated Adverse Device Effect  
 
 

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INTRODUCTION 
Background 
Although myocardial revascularization with percutaneous coronary intervention 
(PCI) has been demonstrated to provide symptomatic benefit in patients with 
myocardial ischemia, numerous studies have demonstrated that up to 20% of 
patients experience recurrent angina in the year following PCI, potentially leading to 
a substantial increase in invasive and/or noninvasive testing, as well as its attendant 
costs. To date, outside of traditional, guideline-recommended antianginal medical 
therapies, there are no techniques that have been demonstrated to reduce the 
likelihood of post-PCI recurrent angina. 2,3,4    
Among patients with stable angina, physiologic assessment of coronary stenoses for 
angiographically indeterminate lesions prior to PCI, typically with fractional flow 
reserve (FFR), has been demonstrated to be a superior strategy and has been shown 
to improve outcomes and reduce costs compared with coronary angiography alone. 
5,6 
However, although routine assessment of intermediate coronary stenoses pre-PCI is 
common, data on FFR assessment post-PCI is sparse and ill-defined.8  Prior studies 
have demonstrated that post-PCI lesion assessment is uncommon, and current expert 
consensus guidelines do not offer specific recommendations regarding its use. In a 
recent retrospective, single-center study of 574 patients (664 lesions), post-PCI FFR 
led to reclassification of about 20% of lesions, requiring additional intervention. 
Additionally, patients with a final FFR > 0.86 had significantly lower rates of major 
adverse cardiac events (MACE) compared with patients with a final FFR ≤ 0.86.7  
These data suggest a potential important role for the routine physiologic assessment 
of coronary arteries post-PCI, especially in situations where PCI may unmask a serial 
lesion or when additional post-stent deployment optimization may be necessary.  
More recently, instantaneous wave-free ratio (iFR) measurement, which provides an 
instantaneous assessment of stenosis severity without the need for prolonged 
assessment or the administration of pharmacotherapies for maximal hyperemia, has 
emerged as a tool to provide rapid lesion assessment. iFR safely and accurately 
quantifies stenosis severity in a wide range of lesions and may be helpful in assessing 
post PCI physiology.9  Compared with FFR, it allows rapid assessment of the lesion 
without induction of maximal hyperemia. iFR pullback has the potential additional 
advantage of interrogating the entire coronary artery to identify culprit lesions with 
significant pressures gradients as well as diffuse atherosclerosis.10 
It is not known the frequency with which an abnormal iFR occurs post PCI, and to 
what extent that it is determined by a missed focal lesion, or extensive diffuse 
atherosclerosis along the length of the vessel.  Additionally, it remains unknown 
whether an abnormal post-PCI iFR is predictive of recurrent angina and whether the 
routine use of physiological indices of coronary function can predict future 
cardiovascular events. This study will assess (a) the frequency of iFR significant 

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physiological lesions post PCI, (b) differentiation between focal and diffuse disease, 
(c) the proportion of cases in physiology that would normalize with additional PCI, 
and (d) the correlation between physiology and clinical outcomes. 
Clinical Experience with Device 
 
1) Comparisons with FFR:  
Since its introduction multiple studies using off-line analysis have assessed the utility 
of iFR against FFR as a reference standard.11 This approach is intrinsically limited by 
the diagnostic efficiency of FFR, which in itself is a surrogate of non-invasive ischemia 
detection tests.13 Overall these studies have shown that iFR can be used to identify 
ischaemia-generating stenoses, as defined with FFR.14 Variations in the diagnostic 
efficiency of iFR appear related to the robustness of the identification algorithm used.  
When calculated using the proprietary Imperial College-Volcano algorithm, which 
among other features uses ECG for identification of the wave-free period within 
diastole, every study has reported a classification match between iFR and FFR of 80-
90%. Recently, a large international analysis demonstrated similar levels of 
agreement with FFR when performed on-line using the commercially available 
console, in real-world catheter laboratory environments. 17 
 
2) Head to head comparisons of iFR and FFR against other diagnostic modalities:  
Direct comparisons with non-invasive ischemia detection tests (single-photon 
emission computed tomography, SPECT) or other physiological non-FFR indices 
(coronary flow reserve (CFR), hyperaemic stenosis resistance index (HSR) 12,14   have 
the advantage of overcoming the limitations of FFR as a comparator, and allow head-
to-head comparison between both techniques. The number of reported direct iFR 
comparisons with these modalities at present is lower than studies using FFR as a 
comparator. 
 
• Comparison with HSR: HSR assesses coronary stenoses according to their 
pressure-flow velocity relationships that form the foundation of all coronary 
physiology. HSR provides a highly stenosis-specific assessment of coronary 
flow limitation.  iFR has been assessed in the CLARIFY study, and in a larger 
independent dataset against hyperaemic stenosis resistance index (HSR). In 
both of these studies, iFR had a diagnostic classification match in excess of 
90% with HSR as the reference standard.  No improvement in diagnostic 
accuracy was seen when adenosine was administered over the entire cardiac 
cycle (FFR) or over the wave-free period (iFR-adeno).   
 
• Comparison with SPECT: iFR has been assessed against nuclear imaging in a 
study reported by Van de Hoef et al 13 This study reported that iFR, FFR, and a 
flow-based resting index, basal stenosis resistance index (BSR), all had similar 
diagnostic power.  Again no improvement was observed following 
administration of adenosine.     
 

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• Comparison with CFR: A recent study by Petraco et al.15 compared the 
classification match between FFR and iFR against CFR. In this multi-center 
invasive study of 216 lesions measuring coronary pressure and flow in 
patients undergoing physiological assessment of the severity of coronary 
artery disease, it suggested that the discordance rates between pressure and 
flow based indices were significantly improved by using iFR as opposed to 
FFR. This improved accuracy was independent of the CFR threshold used (i.e. 
1.7, 2.0 or 2.5), or whether clinical or ischemic cut-points for iFR or FFR were 
used.  
 
• Comparison with PET: Two recent studies have compared PET perfusion 
imaging with hyperaemic and rest invasive physiological measures.  De Waard 
et al. showed no difference between classification of ischemia between iFR and 
FFR against PET as the reference standard.  Classification agreement with PET 
hyperemic MBF was 76% for FFR and 77% for iFR. Hwang et al. also show 
similar findings with overall diagnostic accuracies of FFR and iFR of 69.6%, 
and 73.9% respectively. 12,16 
 
Study Rationale 
 
Although iFR is increasingly used for physiologic assessment of coronary lesions 
prior to PCI, data on post-PCI iFR values is limited, and it is unclear how often 
coronary physiology remains abnormal after PCI, and whether PCI performance 
could be improved by routine use of iFR pullback. This study is designed to assess the 
relationship between iFR pullback and the distribution of coronary stenoses as 
assessed by Quantitative Coronary Angiography (QCA) following angiographically 
successful PCI. The hypotheses of this study are: 
• iFR is impaired in a substantial proportion of patients following operator-
assessed angiographically successful PCI.   
• Post-PCI iFR detects residual significant CAD that is absent on QCA (defined by 
>50% stenosis) 
o This could be due to:-  
 
 The presence of stenosis which are not apparent on angiography 
 The presence of diffuse disease  
 Sub-optimal PCI result  
• Post PCI iFR is predictive of future adverse cardiovascular events 

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STUDY OBJECTIVES 
• Determine the range 
•  of post-PCI iFR and the rate of significant residual ischemia defined as iFR 
<0.90 following operator-assessed angiographically successful PCI 
• Determine the proportion of cases in which the iFR would become non-
significant if a focal stenosis demonstrated by iFR pullback were treated with 
PCI. This will be the used in the sample size calculation for a future 
randomized trial. 
• Determine the relationship between post-PCI iFR pullback and QCA with 
respect to residual stenosis by QCA, residual stenoses and device success (i.e. 
optimal stent implantation). The goal is to correlate abnormal iFR 
measurements to their anatomic reason (i.e. device related complications, 
angiographically undetected residual lesions, or diffuse atherosclerotic 
disease).  
• Determine the relationship between post-PCI iFR and clinical outcomes, such 
as recurrent angina and MACE.  
• Establish the relationship between post-PCI iFR and objective assessment of 
quality of life. 
 
 
STUDY Endpoints 
Primary Endpoints 
 
• Rate of residual ischemia defined as iFR <0.90 after operator-assessed 
angiographically successful PCI (residual diameter stenosis <50% in any treated 
lesion in the target vessel) 
 
Secondary Endpoints 
 
Secondary clinical endpoints (assessed in relation to post PCI iFR ([as 
dichotomous and continuous variable]) : 
• Composite of cardiac death, target vessel myocardial infarction, ischemia-driven 
target vessel revascularization or recurrent ischemia at one year (definition 
below)  
• Target vessel failure defined as cardiac death, target vessel myocardial 
infarction, ischemia-driven target vessel revascularization  

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• Quality of life (assessed by the Seattle Angina Questionnaire) at baseline, 30-
days, 6 months and 1year 
• All-cause and cardiac mortality at one year  
• Target vessel Myocardial infarction at one year  
• Ischemia-driven target vessel revascularization at one year 
• Recurrent ischemia at one-year  
 
Secondary physiology endpoints: 
• Correlation between iFR <0.90 and coronary stenosis >50% assessed by visual 
interpretation 
• Proportion of cases in which the iFR would become non-significant if a focal 
stenosis demonstrated by iFR pullback were treated with PCI 
• Differentiation of the cause for impaired iFR (categorized as stent related, 
distant focal stenosis, or diffuse atherosclerosis) 
• Predictors of delta iFR before and after PCI 
 
Secondary clinical endpoints will be evaluated using iFR in a dichotomous fashion 
with a cut-point of iFR<0.90 as well as iFR as a continuous variable.  
 

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STUDY DESIGN 
Overview 
This is a prospective, single-arm, multi-center, pilot study to assess the relationship 
between iFR  pullback and the distribution of coronary atheroma/stenoses as 
assessed by Quantitative Coronary Angiography (QCA) post angiographically 
successful PCI. 
 
 
Informed Consent
Inclusion- Exclusion 
Criteria
Angiographic Assessment
Pre PCI Physiological 
Assessment
PCI
Blinded post PCI 
Physiological  Assessment
1 month, 6 month and  
12 month follow up

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Methods 
Consented subjects with CAD who undergo physiologic lesion assessment with 
iFR<0.90 in at least 1 coronary artery are eligible for participation. After successful 
PCI to all culprit lesions based on (visual) angiographic assessment of the treating 
physician, a blinded post-PCI iFR pullback will be performed. The proportion of 
patients with impaired post-PCI iFR will be assessed, and the number of patients in 
whom ischemia could theoretically be normalized with further PCI determined. 
Additionally, the association between the post-PCI iFR results and cardiovascular 
events and clinical symptoms will be assessed. Follow-up will be at 1, 6 and 12 
months, including administration of quality of life questionnaires. 
Treatment Arms 
As this is a nonrandomized study, all patients will receive standard of care therapy. 
All patients will undergo iFR prior to PCI in order to provide physiologic assessment 
of each vessel. Following PCI, all patients will undergo blinded iFR pullback in order 
to determine the proportion of patients with impaired post-procedure physiology.  
 
 
Study Population 
 
Number of Subjects 
 
This study will enroll approximately 500 subjects at approximately 25 centers 
globally.  Enrollment is expected to last approximately 1 year. 
 
Subject Enrollment and Length of Participation   
Subjects are considered enrolled in this clinical study when the pre-interventional iFR 
measurement is abnormal (iFR<0.90) and with the intention to perform a PCI of at 
least 1 coronary stenosis. The expected duration of enrollment is approximately 12 
months across all sites with each individual subject’s participation lasting for 12 
months after enrollment. 
 
In the event that a post PCI iFR pullback is unable to be performed, the patient will 
remain in the study and continue to be followed during the follow up period. 
 
 
 
 
 
Inclusion Criteria 
To be eligible for this trial, subjects must meet all of the following criteria: 

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1. 
Subject must be > 18 years old 
2. 
Subjects presenting with stable angina, silent ischemia or non-ST-elevation 
ACS (unstable angina or biomarker positive) 
3. 
Single vessel CAD with at least 2 separate lesions (≥10 mm apart) of ≥40% 
stenosis or a single long lesion of ≥20mm OR multi-vessel CAD, defined as 
at least 2 vessels with ≥40% stenosis  
4. 
Pre-PCI iFR performed in all vessels intended for PCI 
5. 
Pre-PCI iFR of <0.90 of at least 1 stenosis 
6. 
Subjects are willing to comply with scheduled visits and tests and are able 
and willing to provide informed consent. 
 
Exclusion Criteria 
If subjects meet any of the following criteria, he or she may not be enrolled in the 
study: 
1. Pregnant or planning to become pregnant for the duration of the study  
2. Acute STEMI within the past 7 days 
3. Cardiogenic shock (sustained (>10 min) systolic blood pressure < 90 mmHg 
in absence of inotropic support or the presence of an intra-aortic balloon 
pump). 
4. Ionotropic or temporary pacing requirement 
5. Sustained ventricular arrhythmias  
6. Prior CABG  
7. Known ejection fraction ≤ 30% 
8. Chronic Total Occlusion (CTO) of study vessel 
9. Known moderate to severe mitral or aortic disease 
10. Any medical comorbidity resulting in life expectancy <12 months. 
11. Participation in any investigational study that has not yet reached its primary 
endpoint. 
12. Known severe renal insufficiency (eGFR <30 ml/min/1.72 m2). 
13. TIMI flow <3 at baseline of study vessel 
14. Intra-coronary thrombus on baseline angiography 
 
 
 
 
 
 
Study Procedures  
Baseline (up to 30 days prior to index procedure)  
 

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Prior to any study-specific procedures, the subject’s written informed consent will be 
obtained. Basic demographic data will be collected, a targeted history and physical 
examination focused on the study limb. Female subjects of childbearing potential 
must have a negative pregnancy test within 7 days of the index procedure in order to 
participate. If the subject meets all Inclusion Criteria and none of the Exclusion 
Criteria, and provides written informed consent, he/she may be enrolled in the study. 
 
• Informed Consent 
• Medical History 
• Current antianginal medications 
• CBC and platelet count (if performed as SOC) 
• Troponin or CK-MB (If performed as SOC) 
• Complete metabolic panel (if performed as SOC) 
• EKG 
• Echocardiogram  (if performed)  
• Ischemia assessment (if performed) – TTE/nuclear/MRI/CCTA 
• Seattle Angina Questionnaire 
 
 
Pre PCI Procedure 
Subjects are taken to the procedure room and appropriate anesthesia is administered 
per institutional standards.  Assessments: 
• Angiography 
• Baseline iFR of each vessel intended for PCI 
• Drift Check after each vessel assessment 
• UADE assessment 
• IVUS/OCT (if performed as SOC) 
• iFR Pullback should not be performed during pre pci assessment. This is a 
major protocol deviation. 
 
Angiographic Assessment 
• Intracoronary Nitrates 
• Orthogonal views of any potential target vessel in which 1 or more 
stenosis is at least 40% by visual assessment. 
 
 
 
 
 
 
 

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*When pulling the wire back to check for drift, it is a MAJOR protocol deviation to 
perform this under the iFR pullback mode. 
 
 
 

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PCI Procedure 
 
• Create a second case in the Volcano system for the blinded data 
• If Verrata wire is used for the PCI, it must be renormalized prior re-crossing 
the lesion 
• Any coronary guidewire can be used 
• Perform PCI in accordance with the local PCI guideline and protocols 
• IVUS/OCT (if performed as SOC) 
• Visual assessment of final angiographic results documented 
 
 
Post PCI Procedure (Blinded Data) 
 
• If re-inserting Verrata wire, it must be renormalized. 
• Perform Post PCI iFR measurements of each vessel treated 
• Perform Post PCI iFR Pullback measurements of each vessel treated 
• Drift Check should occur after each vessel iFR pullback 
• No additional IVUS/OCT imaging after final iFR measurements 
• No additional treatment after final iFR measurements, unless 
urgent/emergent needs arise. 
 
 
 
 

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Blinding Procedure 
During the post-PCI iFR pullback, and the remainder of the study, these steps should 
be taken when possible to ensure Investigator and other Blinded research staff 
continue to be blinded to the results. 
 
 
Index Procedure Post PCI iFR Pullback 
• Monitors (with integrated systems) will be turned off in the catheter 
laboratory procedure room. With a mobile unit, the screen will be turned away 
from the Investigator. Investigator will perform blinded iFR pullback under 
fluoroscopy. 
• A second case will be created in the Volcano system for the Blinded portion of 
the study. This case will not contain patient identifiers and it will not be 
archived to the hospital archiving system. 
• The blinded data (case #2) will be closed out immediately after the PCI, so the 
operator does not have visibility of the blinded data. 
• Un-blinded catheter laboratory staff and/or research staff will burn the 
blinded data to a DVD, and will then be deleted from the Volcano system once 
confirmation the data is on the disk.  Blinded data will not be documented in 
catheter laboratory procedure notes or patients chart. 
• For sites where the cases are automatically pushed to an archiving system (i.e. 
PACS, Heart lab), it will be necessary to ensure the post-PCI iFR pullback 
(blinded data) does not get archived with the patients procedural images and 
data. 
• The catheter laboratory staff will be educated on the importance of the blinded 
data; to ensure they do not share the information with the Investigators or 
blinded research staff. 
 
Immediately after the index procedure: 
• The un-blinded research staff will secure the blinded data.  There is no written 
blinded data- only the data on the disk. The data will be transferered 
electronically to the core lab and will then be secured in a sealed envelope in 
the subject binder in the research office. . Only to be opened by monitors for 
source document verification, then resealed. 
 
Follow up Phone Calls/Visits 
• A blinded research staff member will be assigned to perform the follow up 
phone calls/visits with the subject. 

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Post Procedure to Discharge 
• CBC and platelet count (if performed as SOC) 
• Troponin or CK-MB: If performed as SOC,  at least one biomarker level should 
be obtained post PCI at 4-8 hrs. Post procedure. CK-MB is preferred but 
Troponin I/T may be drawn if CK-MB not available. Subsequent biomarker 
levels are highly recommended if initial post PCI biomarker is elevated and 
should be followed per local standard of care. 
 
• Complete metabolic panel (if performed as SOC) 
• EKG 
• Event Assessment 
 
Follow Up Procedures 
1 month follow up (day 30 +14 days), 6 month follow up (day 180 +30 days) and 
 
12 month follow up (day 365 +30 days) 
Follow up can be done via telephone conversation. 
• Current Anti-anginal medications 
• Event Assessment 
• Seattle Angina Questionnaire 
 
Note: Event Assessment will be conducted at every encounter (scheduled and 
unscheduled) with the subject to specifically collect possible endpoints for CEC 
adjudication. Specifically, the subject should be asked regarding any cardiac 
hospitalization, myocardial infarction, repeat coronary angiography, repeat PCI, or 
recurrent angina. 
 
Discontinued Subjects  
Subjects have the right to withdraw from this study at any time and for any reason. 
Data that is collected prior to the subject’s withdrawal from the study will be 
analyzed. The Principal Investigator has the right to discontinue a subject’s 
participation in the study in the event of an underlying illness, adverse event, or 
protocol violation. Philips Volcano has the right to discontinue the study at any time. 
A complete final evaluation at the time of the subject's discontinuation should be 
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report form (CRF). Discontinued subjects will not be replaced; i.e., overall study 
enrollment will not exceed 500 subjects.  
 
Adverse Event Reporting  
 
For the purposes of this study, because the Verrata pressure guide wire is 
commercially available, adverse event reporting for this study will be limited to ADEs, 
SADEs, and UADEs (per the below definitions). 
 
 
Definitions  
 
Adverse Event (AE) 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or 
clinical investigation subject administered a pharmaceutical product or medical 
device and which does not necessarily have a causal relationship with this treatment. 
An adverse event (AE) can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product or device, whether or 
not related to the medicinal (investigational) product or device. 
 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is defined as any untoward medical occurrence that: 
• results in death, 
• is life-threatening,  
• requires inpatient hospitalization or prolongation of existing hospitalization,  
• results in persistent or significant disability/incapacity, or  
• results in a congenital anomaly/birth defect.  
 
Important medical events that do not meet the above criteria may still be considered 
an SAE if they seriously jeopardize the subject and require immediate medical or 
surgical intervention to prevent one of the aforementioned outcomes.  
 
Note that adverse events requiring hospitalization are SAEs but elective 
hospitalizations related to non-study-emergent conditions do not constitute SAEs.  
 
Adverse Device Effect (ADE) 
For the purposes of this protocol, an ADE is defined as an adverse event that is related 
to or associated with Veratta pressure wire use, or an adverse event for which a causal 
relationship by iFR cannot be ruled out.  
 
 
Serious Adverse Device Effect (SADE) 

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An SADE is defined as an adverse device effect that has resulted in any of the 
consequences or characteristics of a serious adverse event.  
 
 
 
Unanticipated Adverse Device Effect (UADE)  
An unanticipated adverse device effect (UADE) is defined as any serious adverse 
effect on health or safety or any life-threatening problem or death caused by – or 
associated with – the device, if that effect, problem or death was not previously 
identified in nature, severity, or degree of incidence in the protocol (including 
documents such as the protocol, informed consent form, or other study-related 
documents), or any other unanticipated serious problem associated with the device 
that relates to the rights, safety or welfare of subjects.  
Anticipated potential Adverse Events (per device IFU) are described below in 
Description of Device. 
 
Reporting of Clinical Events 
 
All clinical events observed during the course of this study will be recorded by the 
investigator on the appropriate e-CRF.  All MACE will be evaluated by the CEC after 
review of original study records, ECGs, and angiograms. Additional events may be 
triggered by review of lab data, monitoring, and by CEC review of other events (these 
additional possible events will be referred to as “triggered events”.) 
 
Device Malfunctions or Use Errors  
Device malfunctions or use errors will be recorded and evaluated for possible 
untoward effects on the subject. For the purposes of this study, a device malfunction 
is defined as a failure of the device to perform its intended function when used in 
accordance with the Instructions for Use (IFU). If a VERRATA® PRESSURE GUIDE 
WIRE or any subsequent next generation Philips Volcano pressure wires device 
malfunction results in an adverse experience for the subject, this adverse experience 
should be considered an adverse device effect and recorded on the appropriate CRF. 
A device malfunction by itself should not be reported as ADE unless it leads to the 
new medical condition or worsening of pre-existing condition. If a VERRATA® 
PRESSURE GUIDE WIRE device malfunction occurs in this study, the site should 
follow standard commercial procedures as described in the Precautions section of the 
VERRATA® PRESSURE GUIDE WIRE IFU.  
Reporting Requirements  
The VERRATA ® PRESSURE GUIDE WIRE or any subsequent next generation Philips 
Volcano pressure wires used in this study are cleared by the FDA and CE marked for 
use in coronary vessels. Information related to contraindications, adverse effects, 
warnings, and precautions are included in the device Instructions for Use.  

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For these reasons, adverse event reporting for this study will be limited to ADEs, 
SADEs, and UADEs (per the above definitions). These events will be recorded on the 
corresponding case report forms. Complaints should be reported to the Study Medical 
Monitor and Customer_Inquiry@volcanocorp.com (see below). All serious adverse 
device effects (SADEs) must be reported to Philips Volcano as soon as possible after 
first awareness of the event; every attempt must be made to report such events to 
Philips Volcano within 24 hours of first awareness.  
 
 
Contact information for SADE reporting: 
 
Brad Matsubara, MD  
Study Medical Monitor  
Philips Volcano  
Office:  (858) 720-4045  
Mobile:  (858) 568-8946  
Fax:  (858) 720-0325 
Email:  bmatsubara@volcanocorp.com and Customer_Inquiry@volcanocorp.com  
 
 
Protocol Deviations and Waivers   
A protocol deviation is defined as an event where the clinical Investigator or site 
personnel deviate from the study protocol or study procedures. It is the 
Investigator’s responsibility to ensure that there are no deviations from the protocol 
without prior notification and approval of the Sponsor or Sponsor’s designee and in 
full compliance with all established procedures and conditions of the reviewing 
IRB/IEC.  
The Investigator may deviate from the protocol without prior written approval from 
the Sponsor or Sponsor’s designee in cases of medical emergencies, when the 
deviation is necessary to eliminate an apparent immediate hazard to the subject. In 
that event, the Investigator will notify the Sponsor or Sponsor’s designee 
immediately by phone or electronic communication, notify the reviewing IRB/IEC 
and confirm notification to the Sponsor or designee in writing. Prior deviation 
approval is generally not expected in situations where unforeseen circumstances 
are beyond the Investigator’s control, for example, the subject was not available for 
a scheduled follow-up office visit. These events, although outside the Investigator’s 
control, are still required to be reported on the appropriate protocol deviation form 
in order to ensure that all deviations from the standard subject population are 
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Sponsor’s designee of all deviations, and the reviewing IRB/IEC of all protocol 
deviations as per the IRB/IEC requirements for this study.   
The occurrence of protocol deviations will be monitored by the Sponsor or 
Sponsor’s designee for evaluation of Investigator compliance to the Protocol, Good 
Clinical Practices, and regulatory requirements.  
Gross non-compliance with the protocol at an individual site that may jeopardize the 
outcomes or the integrity of the trial may result in termination of enrollment at such 
non-compliant sites. 
 
Description of the Device  
 
The Verrata pressure guide wire (hereafter referred to as the “pressure guide wire”) 
is a steerable guide wire with a pressure transducer mounted 3 cm proximal to the 
tip. The Verrata guide wire measures pressure when used with the SmartMap, 
ComboMap, s5 Series, and CORE Series of systems. The pressure guide wire has a 
diameter of 0.014” (0.36 mm) and is available in lengths of 185 cm or 300 cm* and 
also in straight or preshaped tips. The pressure guide wire is packaged attached to 
the connector with a torque device to facilitate navigation through the vasculature.  It 
is possible that future iterations of the Verrata wire may be used in the study which 
will offer improved performance and reliability.  
 
CONTRAINDICATIONS: 
This pressure guide wire is not intended for use in crossing a total vessel occlusion. 
 
 
 
Please review IFU attached. 
 
 
 
 
 
 
 
 
 
 

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Ethical Considerations  
This protocol and any amendments will be submitted to a properly constituted Independent 
Ethics Committee (IEC) or Institutional Review Board (IRB), in agreement with local legal 
prescriptions, for formal approval of the study conduct. The decision of the IEC/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.  
Benefits  
 
No direct benefits to the patient are expected.  However, information gained during this 
study may lead to improved treatment workflows for patients with coronary artery disease 
in the future. 
Risks   
The Philips Volcano pressure guide wires used in this study are cleared for commercial use 
by the FDA and CE marked for commercial distribution in Europe for use in the coronary 
vessels as described in this protocol. Information related to contraindications, adverse 
effects, warnings, and precautions are included in the device Instructions for Use.   
 
Risks associated with the use of pressure guide wires in patients with coronary artery 
disease are well understood, and incidence rates are very low. An extensive review of the 
safety of using pressure wires in 14 studies covering 1,284 patients revealed just 2 reports 
of arterial dissection (0.16%) and a single report of device entrapment (0.8%). The largest 
of these studies0F1 (N=648) is that which reported the 2 dissections.  Both were successfully 
managed and represented only 0.3% of the adverse events for this single study.  A widely 
reported event was chest discomfort associated with the administration of adenosine in 
86% of patients.  Notably, the DEFINE PCI protocol will be using the instantaneous free-
wave ration (iFR) which does not require the administration of adenosine. 
 
 
 
 
 
 
 
 
1 Ahmed N, Layland J, Carrick D, et al. Safety of guidewire-based measurement of fractional flow reserve 
and the index of microvascular resistance using intravenous adenosine in patients with acute or recent 
myocardial infarction. International Journal of Cardiology. 2016;202:305-310. 
 

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The single report of device entrapment occurred when a pressure guide wire was extended 
across a mechanical aortic valve1F2 and was not used in the native coronary anatomy.  The 
incidence of pressure guide wire entrapment or breakage in the Volcano complaints record 
is 0.0056% and 0.0048 (less than one chance in more than 17,000-20,000 uses), 
respectively.         
 
Patients deciding to participate in this study are thus expected to bear standard risk 
associated with advancing and pulling back the pressure guide wire through the 
vasculature more times than would be typical in a standard PCI procedure. Site personnel 
are well-practiced in the use of pressure guide wires in the coronary anatomy, and are 
advised to use discretion in repeating a pressure reading in cases where this presents 
elevated patient risk due to any specific anatomical or physiological factor.  Hence, the 
risk associated with the additional pressure wire procedures is considered standard.   
 
Mitigation of Risks  
The study site investigators will be selected for their experience and skill in Coronary 
interventions and familiarity with the use iFR and iFR pullback. Appropriate subjects will be 
selected using clearly defined inclusion/exclusion criteria to ensure that subject treatment 
is consistent with current medical standards and practices.  
Risk – Benefit Analysis 
. In terms of complexity, the Verrata Wire does not have moving or expandable parts, nor is 
any portion of the device implanted within the subject. Finally, the Verrata Wire is cleared 
by the FDA and CE marked for use in coronary arteries, and the device does not emit 
ionizing radiation.  Patient participation is expected to provide insight for better managing 
ischemic coronary artery disease despite not experiencing any direct benefit.  Hence, the 
overall benefits to the body of knowledge for treating coronary artery disease outweighs 
the risk associated with the additional pressure wire steps.    
 
Data Handling and Record Keeping  
 
 
 
 
 
 
 
2 Marmagkiolis K, Cilingiroglu M. Radi pressurewire rupture and embolization to the right common carotid 
artery after crossing a Bjork-Shiley mechanical aortic valve. Journal of Invasive Cardiology. 
2013;25(10):E191-E193. 

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Case Report Forms  
This study will be performed using an electronic data capture (EDC) system. The 
Investigator and study site staff will receive training and support on the use of the EDC 
system. All eCRF data are to be completed by the Investigator, study coordinator, or other 
designated site personnel.  
Source Documents 
Investigators are required to maintain information in the study subject’s medical records to 
corroborate data collected on the eCRF. Shadow charts are not appropriate or adequate for 
source documentation. Source data includes all information, original records of clinical 
findings, observations, or other activities in a clinical trial necessary for the reconstruction 
and evaluation of the trial. Source data are contained in source documents. Examples of 
source documents are:  hospital medical records, clinical and office medical charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 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, print-outs of ECG, CDs/DVDs of angiograms 
and IVUS images, subject files, and records kept at the pharmacy, at the laboratories, and at 
medical-technical departments involved in the clinical study.  
Data Queries  
During the review of source documents and eCRF, any discrepancies will be queried by the 
monitor or its designee and must be resolved by the investigational site staff and 
Investigator in a timely manner. In addition, the monitor or its designee may also generate 
data queries during routine or remote review of the data. These queries will be sent to the 
site and must also be resolved in a timely manner by the Investigator and/or the study site 
staff.  
Record Retention  
All source documents (i.e., laboratory reports, progress notes, medical histories, 
physical and diagnostic findings, fluoroscopic and IVUS images and tracings, 
diagnoses and procedure dates, device disposition records, etc.) that support the 
CRFs of each subject must be retained in the files of the responsible Investigator for 
a minimum of two years following notification by Philips Volcano that all 
investigations of the device have been completed or discontinued.  
If the responsible Investigator retires, relocates, or for other reasons withdraws 
from the responsibility of keeping the study records, custody must be transferred to 

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a person who will accept the responsibility. Philips Volcano must be notified in 
writing of the name and address of the new custodian.   
 
Monitoring and Oversight  
 
This study will be monitored according to the applicable requirements in the US 
Code of Federal Regulations (21 CFR Part 812, 50, 56), the guidelines in the 
International Conference on Harmonization (ICH) Guideline for Good Clinical 
Practice (GCP), the standards in the International Organization for Standardization 
(ISO) 14155:2011, and of the Declaration of Helsinki (2013).  
 
Selection of Investigators  
Study Investigators will be selected for their experience and skill in cardiovascular 
interventions and familiarity with the use of iFR physiology assessment. The 
Sponsor or designee may conduct a site visit to verify the qualifications of each 
Investigator, tour the site facilities, and evaluate the suitability of the site for 
participation in this study.  
Individual Investigators will be evaluated by the Sponsor based on experience with 
the intended procedure, and ability to conduct the study according to the study 
protocol. Prior to enrolling subjects, each potential investigator must submit 
current, signed and dated curriculum vitae. Additional criteria may be applied to site 
and/or Investigator selection including: 
• Adequate patient population to meet requirements of the study  
• Adequate time to be personally involved in the conduct of the study  
• Adequate research staff and resources to support the study  
• Experience conducting clinical trials research  
• Facility must be associated with an IRB/IEC that satisfies all applicable 
regulatory requirements, or be able to use a Central IRB/IEC that satisfies 
these requirements  
 
 
Site Initiation Visits 
Training of appropriate clinical site personnel will be the responsibility of the Sponsor. To 
ensure uniform data collection and protocol compliance, the Sponsor will review the 

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Protocol, techniques for identification of eligible subjects, instructions on data collection, 
and methods for scheduling follow-up visits in the defined follow-up window.  
Interim Monitoring Visits  
Routine monitoring visits will be made to ensure that the Investigator obligations are 
fulfilled and all applicable regulations and guidelines are being followed. These visits will 
ensure that the facilities are acceptable, the protocol is being followed, and the IRB has been 
notified of approved protocol changes as required, complete records are being maintained, 
appropriate and timely reports have been made to Philips Volcano and/or its designees and 
the IRB, and the Investigator is carrying out all agreed activities. 
During monitoring visits, the monitor will perform, at a minimum, a review of source data 
for key variables for all enrolled subjects at each site (including but not limited to, 
inclusion/exclusion criteria, informed consents, endpoints, and safety) from the eCRFs 
compared against each subject’s source documents. All available source documentation for 
monitored subjects will be reviewed for potential adverse device effects. Any discrepancies 
will be noted and resolved.  
Study Close-out Visits  
Upon completion of the study at a site, a close-out visit (remote or on-site) will be 
conducted. The monitor will ensure that the study related files at the investigational site are 
up to date and complete and that any outstanding issues from previous visits have been 
resolved. The monitor will ensure that the clinical trial materials and subject data are 
properly documented and stored for a minimum of two years following study completion. 
The Sponsor or designee will notify each site during the closeout visit of the current data 
storage requirements. Other topics that will be reviewed at this visit include: possibility of 
site audits, publication policy, notifying the IRB/EC of study closure, etc. 
Direct Access to Source Data / Documents  
The Investigator will permit study-related monitoring, audits, and inspections by the 
IEC/IRB, the Sponsor, government regulatory bodies, and 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., pharmacy, diagnostic laboratory, etc.).  
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable compliance and quality assurance offices.  
Amendments to the Protocol  
To alter the protocol, amendments must be written, receive approval from the appropriate 
Sponsor personnel, and receive IRB/IEC approval prior to implementation (if appropriate). 
All amendments will be distributed to all protocol recipients, with appropriate instructions.  

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Device Accountability  
No device will be supplied to sites for this study. 
Administrative Responsibilities  
 
Independent Ethics Committee/ Institutional Review Board Information 
The study will not be initiated before the protocol, informed consent, and any applicable 
subject information forms have been reviewed and received approval/favorable opinion 
from the local or regional Independent Ethics Committee/ Institutional Review Board. 
Should a protocol amendment be made that needs IEC/IRB approval and Authority 
notification/approval, the changes in the protocol will not be instituted until the 
amendment and revised informed consent (if appropriate) have been reviewed and have 
received approval/favorable opinion form the local IEC/IRB.  
The constitution of the IEC/IRB must meet the requirements of the participating 
country/countries. A list of the IEC/IRB members must be provided. The Investigator (for 
EU: The Sponsor) must provide to the regulatory authorities, if applicable, the name and 
address of the IEC/IRB along with a statement from the IEC/IRB that is organized according 
to Good Clinical Practice and the applicable laws and regulations. The IRB/IEC must 
perform all duties outlined by the requirements of the participating country/countries.   
 
Informed Consent and Subject Information 
Prior to participation in the study, written informed consent must be obtained from each 
subject according to the regulatory and legal requirements of the participating site/country. 
Each signature must be dated by each signatory and the informed consent and any 
additional subject information forms retained by the Investigator as part of the trial 
records. A signed copy of the informed consent and any additional subject information must 
be given to each subject.  
The subject must be informed that his/her personal trial-related data will be used by Philips 
Volcano in accordance with the local data protection law. The subject must be informed that 
his/her medical records may be examined by authorized sponsor personnel, quality 
assurance auditors appointed by Philips Volcano, by appropriate IEC/IRB members, and by 
inspectors from regulatory authorities.   
Should a trial protocol amendment be necessary, the subject informed consent form may 
need to be revised to reflect the changes to the protocol. It is the responsibility of the 
Investigator to ensure that an amended consent form is reviewed and he has received 

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approval/favorable opinion from the IRB/IEC, and that it is signed by all subjects 
subsequently entered in the trial, and those currently in the trial affected by the 
amendment.  
 
Investigator Responsibilities 
Participating Investigators are required to accept the following responsibilities according to 
21 CFR Part 812, and the ICH/ISO guidelines:  
• 
Ensure that the investigation is conducted according to the Investigators agreement. 
• 
Protect the rights, safety, and welfare of subjects. 
• 
Obtain informed consent from each subject. 
• 
Retain specific records and issue specific reports. 
• 
Assure that an IEC/IRB is provided information for initial and continuing review of 
the study. 
• 
Ensure that all work and services described within this protocol are conducted in 
accordance with the highest standards of medical practice and Good Clinical 
Practice.   
• 
Ensure that all associated clinical and support staff members conduct the study in 
accordance with the protocol and amendments. 
• 
Ensure that complete and accurate study data is collected and submitted to the 
sponsor. 
• 
Ensure that the study regulatory binder, and study files containing CRFs, consent 
information, source documentation, records of adverse events and their resolution 
and all other relevant subject information are complete and up to date.   
 
The Investigator is responsible for the conduct of the study at the site. Prior to enrollment of 
first patient, the Investigator must read and understand the Protocol and must sign and 
complete the Clinical Trial Agreement. The Clinical Trial Agreement requires agreement to 
all conditions of the Protocol and agreement to conduct the study according to all applicable 
regulations and guidelines.  
Participation as an Investigator in this study implies acceptance of potential inspection by 
government regulatory authorities. The Investigator and/or designee must be available to 
respond to reasonable requests and queries made by authorized regulatory representatives 
during the audit process. The Investigator must provide the Sponsor or designee with 
copies of all correspondence that may affect the review of the current study or their 
qualification as an Investigator in clinical studies conducted by the Sponsor.  
In the event the Investigator is contacted by a regulatory agency (such as the FDA) with 
regard to this study, the Investigator will notify the Sponsor immediately. The Investigator 
will ensure the capability for the inspection of applicable study-related facilities and 
records.  

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Discontinuation of the Trial by the Sponsor 
Philips Volcano reserves the right to discontinue the trial at any time for any of the 
following reasons:   
• 
Failure to meet expected enrollment goals, 
• 
Any effectiveness/safety information that could significantly affect continuation of 
the trial or any other administrative reasons 
 
Discontinuation of a Site by the Sponsor  
Philips Volcano also reserves the option to terminate the participation of a study site at any 
time. Reasons for terminating the participation of a study site include, but are not limited to, 
the following:  
• 
Subject enrollment is unsatisfactory  
• 
Data recording is consistently inaccurate or incomplete  
• 
Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study  
• 
IRB/IEC decides to terminate or suspend approval for the Investigator  
• 
Study center or Investigator violates GCP or the study contract, disrupting the 
appropriate conduct of the trial  
• 
Investigator asks to withdraw from study participation  
 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the 
requirements of the local regulatory authority, as well as applicable US laws and 
regulations.  
Personal Health Information (PHI) will be acquired during the consenting process of the 
subject and from the medical records. This information will be utilized to identify the 
subject and contact the subject for emergencies and follow up appointments. The PHI is part 
of the subject clinic chart, and will be secured in a locked office when not in use. To ensure 
that confidentiality is maintained, subject names will not be used in this evaluation in any 
other way. A unique identifying number will be used. This identification method will be 
consistent for each subject throughout the evaluation.  
In the event that a subject revokes authorization to collect or use Protected Health 
Information (PHI), the Investigator, by regulation, retains the ability to use all information 
collected prior to the revocation of the authorization.   
 

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Publication Policy  
 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts, abstracts, or presentation 
materials to Volcano prior to submission. This allows the Sponsor to protect proprietary 
information and to provide comments based on information from other studies that may 
not yet be available to the Investigator. Any formal publication of the study with the input of 
Volcano personnel exceeding that of conventional monitoring will be considered as a joint 
publication by the Investigator and the appropriate Volcano personnel. Authorship will be 
determined by mutual agreement.   
 
STATISTICAL ANALYSIS PLAN AND DETERMINATION OF SAMPLE 
SIZE                                                                                         
 
Target population  
This analysis focuses on CAD Patients reporting an iFR < 90 in at least one coronary 
artery chosen from 25 US and International centers. 
Data lock determination 
The dataset will lock after all data needed for assessment of primary and secondary 
endpoints are reliably obtained, and any impossible data points are investigated and 
resolved. 
Definition of Endpoints 
This analysis classifies each patient into one of two categories: patients with residual 
ischemia (RI) and patients without. This data is distributed binomially, and the 
primary endpoint measures the proportion of patients with residual ischemia defined 
as iFR <0.90 after successful PCI (p).   
Primary Endpoint Analysis 
The primary endpoint, the proportion of patients with RI defined as iFR <90, is 
computed using maximum likelihood analysis. We compute the maximum likelihood 
estimate as 𝑝𝑝= 𝑁𝑁−1 ∑
𝑦𝑦𝑠𝑠
𝑁𝑁
𝑠𝑠=1
, and Clopper – Pearson 95% confidence intervals. 
The null hypothesis states no difference in the proportion of RI from 10%, or more 
formally,  𝐻𝐻0: 𝑝𝑝−0.10 = 0. The alternative hypothesis concludes any difference in RI 
from 10%, or 𝐻𝐻𝑎𝑎: 𝑝𝑝−0.10 ≠0.  

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Sample size computation 
We assume a 10% rate of RI in the study (?) population which is defined as a residual 
stenosis of >50% on QCA. 
With 500 enrolled patients, type I error held at 5%, and the ability to detect a 
proportion of 15% RI, this study is powered at 90%.   
 Secondary Endpoint analysis  
Kaplan Meier’s product limit estimate computed as 𝑆𝑆(𝑡𝑡) = ∏
൬1 − 
𝑑𝑑𝑗𝑗
𝑛𝑛𝑗𝑗൰
𝑡𝑡𝑗𝑗<𝑡𝑡
 , where we 
partition time into j intervals 𝑡𝑡𝑗𝑗 based on events, will measure time to event endpoints 
(listed as secondary endpoints 1-5). We conclude a significant survival difference 
between any two groups with the logrank test, and hold the expected type I error to 
5%. We correct the type I error of the 5 related survival hypothesis using Benjamini 
and Hochberg’s False Discovery Rate.   
This protocol models Quality of life (secondary endpoint 6) as a mixed linear model,  
𝑄𝑄𝑖𝑖𝑖𝑖𝑖𝑖 ~ Ν൫𝛽𝛽0 +  𝐹𝐹𝑗𝑗ൣ𝛽𝛽1 + 𝑏𝑏1𝑗𝑗𝑇𝑇𝑗𝑗 ൧+ 𝛽𝛽2𝑇𝑇𝑗𝑗, Σ൯, where β’s describe fixed effects, b’s describe 
random effects, Σ describes a compound symmetric covariance matrix, and Ν the 
multivariate Gaussian distribution. We parameterize the covariance matrix with 
Compound symmetry, as opposed to autoregressive, because within time points will 
dominate variability compared to across time points. 
The Kappa statistic will measure agreement between iFR and QCA’s ability to detect 
RI by computing 𝜅𝜅= (𝑝𝑝𝑒𝑒− 𝑝𝑝1)
(1 − 𝑝𝑝1)
൘
, or the difference between empirical 
agreement and chance agreement divided by chance disagreement. 
We estimate the proportion of cases in which the iFR would become non-significant if a 
focal stenosis demonstrated by iFR pullback were treated with PCI (Secondary endpoint 
8) by 
𝑝𝑝= #(Number of non −significant iFR pullbacks)
#(Patients)
൘
 
And assess the significance using a Binomial test. 
The cause for impaired iFR is summarized using proportions, and the χ2 test assess 
the null hypothesis that each cause of impaired iFR occurs at the same rate.  
We use linear regression to associate a set of covariates with the change in post-PCI 
iFR minus pre-PCI iFR. In case of nonlinear associations of covariates with change in 
iFR, we use kernel regression. 
 

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Sensitivity Analysis  
The sensitivity analysis evaluates the primary endpoint a second way, using the 
normal approximation to the binomial distribution. The null hypothesis argues the 
proportion of RI detected with iFR equals 10%. The alternative hypothesis concludes 
the proportion of RI detected by iFR is unequal to 10%. The normal approximation 
tests this hypothesis using the statistic 𝑍𝑍= √𝑛𝑛(𝑝𝑝−0.10)
ඥ𝑝𝑝(1−𝑝𝑝) , and compares this statistic to 
the standard normal distribution. 
Handling Missing data 
Any patients with missing primary or secondary endpoints will be list-wise deleted 
from the above analysis. If unable to recover missing covariates, we will impute 
missing values for covariates if the total amount of missing values is less than 5%. 
This analysis will exclude any covariates with a majority of values missing.  
 

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REFERENCES 
1. David Marrow MD - Evaluation of a Novel Anti-ischemic Agent in Acute Coronary 
Syndromes: Design and Rationale for the Metabolic Efficiency with Ranolazine  
for Less Ischemia in Non–ST-Elevation Acute Coronary Syndromes (MERLIN)-
TIMI 36 TRIAL 
2. Serruys P.W., Unger F., Sousa J.E., et al.  Comparison of Coronary-Artery Bypass 
Surgery and Stenting for the Treatment of Multivessel Disease                                                                
N Engl J Med 2001; 344:1117-1124    
3. Boden W.E., O'Rourke R.A., Teo K.K., et al.,  Optimal Medical Therapy with or 
without PCI for Stable Coronary Disease                                                                              
N Engl J Med 2007; 356:1503-1516 
4. Cohen D.J., Van Hout B., Serruys P.W., et al, Quality of Life after PCI with Drug-
Eluting Stents or Coronary-Artery Bypass Surgery                                                           
N Engl J Med 2011; 364:1016-1026   
5. Tonino P.A.L., De Bruyne B., Pijls N.H.J., et al,  Fractional Flow Reserve versus 
Angiography for Guiding Percutaneous Coronary Intervention                                      
N Engl J Med 2009; 360:213-224 
6. De Bruyne B., Pijls N.H.J., Kalesan B., et al.,  Fractional Flow Reserve–Guided PCI 
versus Medical Therapy in Stable Coronary Disease                                                          
N Engl J Med 2012; 367:991-1001 
7. Agarwal SK, Kasula S, Hacioglu Y, et al., Utilizing Post-Intervention Fractional 
Flow Reserve to Optimize Acute Results and the Relationship to Long-Term 
Outcomes   JACC Cardiovasc Interv. 2016 May 23;9(10):1022-31  
8. Mathias Wolfrum, Gregor Fahrni, Giovanni Luigi de Maria., et al.,   Impact of 
impaired fractional flow reserve after coronary interventions on outcomes: a 
systematic review and meta-analysis                                                                                   
BMC Cardiovascular Disorders 2016 16:177 
9. Sen S, Escaned J, Malik IS, Mikhail GW, Foale., et al., Development and validation 
of a new adenosine-independent index of stenosis severity from coronary wave-
intensity analysis: results of the ADVISE (ADenosine Vasodilator Independent 
Stenosis Evaluation) study                                                                                                
J Am Coll Cardiol. 2012 Apr 10; 59(15):1392-402 
10. Nijjer SS, Sen S, Petraco R, Mayet J, Francis DP, Davies JE., The Instantaneous 
wave-Free Ratio (iFR) pullback: a novel innovation using baseline physiology to 
optimise coronary angioplasty in tandem lesions.                                                  
Cardiovasc Revasc Med. 2015 Apr-May;16(3):167-71    

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11. Allen Jeremias, MD, MSC, Akiko Maehara, MD, Philippe Généreux, MD, et al., 
Multicenter Core Laboratory Comparison of the Instantaneous Wave-Free Ratio 
and Resting Pd/Pa With Fractional Flow Reserve.  The RESOLVE Study                                                
J Am Coll Cardiol. 2014;63(13):1253-1261 
12. Guus de Waard; Ibrahim Danad; Ricardo Petraco da Cunha, et al.; HYPEREMIC 
FFR AND BASELINE IFR HAVE AN EQUIVALENT DIAGNOSTIC ACCURACY WHEN 
COMPARED TO MYOCARDIAL BLOOD FLOW QUANTIFIED BY H215O PET 
PERFUSION IMAGING                                                                                                                   
J Am Coll Cardiol. 2014; 63(12_S) doi: 10.1016/S0735-1097(14)61695-8       
13. Van de Hoef TP, et al. Fractional flow reserve as a surrogate for inducible 
myocardial ischaemia. Nat Rev Cardiol. 2013;10:439-452.      
14.  Sen S, et al. Diagnostic classification of the instantaneous wave-free ratio is 
equivalent to fractional flow reserve and is not improved with adenosine 
administration. Results of CLARIFY (Classification Accuracy of Pressure-Only 
Ratios Against Indices Using Flow Study). J Am Coll Cardiol. 2013;61:1409-1420. 
15.    Petraco R. et al. Circ. Cardiovascular int. 2014 Aug;7(4):492-502)    
16.    Koo EuroPCR 2016, paper under review.    
17.   Petraco R, Al-Lamee R, Gotberg M, Sharp A; et al., Real-time use of 
instantaneous wave-free ratio: results of the ADVISE in-practice: an 
international, multicenter evaluation of instantaneous wave-free ratio in clinical 
practice                                                                                                                                             
Am Heart J. 2014 Nov;168(5):739-48. 
 
 
 
 
 
 
 
 
 
 

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Attachments  
Study Sponsor Contacts  
 
Project  Manager   
Tammy Snow,  RT.R.CV, CCRP  
Project Manager 
tammy.snow@philips.com  
Phone:  +1 (336) 466-0417  
Fax:  +1 (336) 945-0501  
 
 
 
 
Lead CRA- OUS 
Daniëlle Op den Kamp, BSc 
 
Clinical Project Manager 
Danielle.op.den.kamp@philips.com 
 
Phone: +31 (0) 6 27218737 
 
 
 
 
Medical Monitor   
Brad Matsubara, MD  
Sr. Clinical Scientist, Clinical Affairs  
bmatsubara@volcanocorp.com  
Phone:  +1 (858) 720-4045  
 
 
 
 
 
 
 
 
 
 
 
 
 

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Declaration of Helsinki  
The following attachment is a copy of the World Medical Association (WMA) 
Declaration of Helsinki – Ethical Principles for Medical Research Involving Human 
Subjects (last amended:  64th WMA General Assembly, Fortaleza, Brazil, October 
2013)   
[http://www.wma.net/en/30publications/10policies/b3/ accessed 18Dec2013]  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Draft Informed Consent Form  
Attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Instructions for Use  
Attached