Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) 3 Trial A Comparison of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention and Coronary Artery Bypass Graft Surgery in Patients With Multivessel Coronary Artery Disease
Phase: NA
Conditions: Coronary Disease, Coronary Stenosis
Sponsor: Stanford University

27Feb2018 
FAME 3 IDE 
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Fractional Flow Reserve versus Angiography for Multivessel Evaluation 
(FAME) 3 Trial 
A Comparison of Fractional Flow Reserve-Guided Percutaneous Coronary Intervention and Coronary 
Artery Bypass Graft Surgery in Patients with Multivessel Coronary Artery Disease  
Protocol 
NCT02100722

27Feb2018 
 
FAME 3 IDE 
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Table of Contents 
1. 
Protocol Summary ................................................................................................................... 4 
2. 
Summary of Investigational Plan Changes .............................................................................. 6 
3. 
Background ............................................................................................................................ 12 
4. 
Objective ................................................................................................................................ 16 
5. 
Population .............................................................................................................................. 16 
Inclusion Criteria ....................................................................................................................... 16 
Exclusion Criteria ...................................................................................................................... 16 
6. 
Design .................................................................................................................................... 17 
Study Enrolment ........................................................................................................................ 17 
Randomization .......................................................................................................................... 18 
Baseline Data............................................................................................................................. 18 
Coronary Artery Bypass Graft Surgery (CABG) ...................................................................... 18 
Fractional Flow Reserve-Guided PCI ....................................................................................... 19 
Medications ............................................................................................................................... 21 
 Ticlopidine should not be used. ............................................................................................... 22 
Follow-up .................................................................................................................................. 22 
Recording of Adverse Events .................................................................................................... 22 
Electrocardiography .................................................................................................................. 23 
Recording of Cardiac Medication ............................................................................................. 23 
Angina Assessment ................................................................................................................... 23 
Blood Sampling ......................................................................................................................... 23 
Resource Utilization .................................................................................................................. 24 
Quality of Life Assessment ....................................................................................................... 24 

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Working Status .......................................................................................................................... 25 
7. 
Reporting of Events ............................................................................................................... 25 
Vigilance Reporting .................................................................................................................. 25 
8. 
Organization .......................................................................................................................... 26 
Sponsor ...................................................................................................................................... 26 
Support ...................................................................................................................................... 26 
Steering Committee ................................................................................................................... 26 
Monitoring ................................................................................................................................. 26 
Investigator responsibilities....................................................................................................... 28 
Clinical Events Committee........................................................................................................ 28 
Data Safety Monitoring Board .................................................................................................. 28 
Study Flowchart ........................................................................................................................ 29 
9. 
Endpoints ............................................................................................................................... 30 
Primary Endpoints ..................................................................................................................... 30 
Key Secondary Endpoint ........................................................................................................... 30 
Other Secondary Endpoints ....................................................................................................... 30 
Pre-specified Subgroup Analyses ............................................................................................. 31 
10. 
Statistics ............................................................................................................................. 32 
11. 
Appendix A. ....................................................................................................................... 35 
Definitions ................................................................................................................................. 35 
12. 
References .......................................................................................................................... 41 
 
 

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1. Protocol Summary 
Title 
A Comparison of Fractional Flow Reserve-Guided Percutaneous Coronary 
Intervention and Coronary Artery Bypass Graft Surgery in Patients with 
Multivessel Coronary Artery Disease: Fractional Flow Reserve versus 
Angiography for Multivessel Evaluation (FAME) 3 Trial. 
Hypothesis 
Fractional flow reserve (FFR)-guided percutaneous coronary intervention 
(PCI) in patients with multivessel coronary artery disease (CAD) will 
result in similar outcomes to coronary artery bypass graft surgery (CABG). 
Objective 
Compare outcomes after FFR-guided PCI to CABG in patients with 
multivessel CAD. 
Design 
The FAME 3 trial is a multicenter, international, randomized, controlled 
noninferiority trial.  All patients with multivessel CAD (not involving the 
left main) will be screened by the site’s Heart Team (including but not 
limited to an interventional cardiologist, cardiac surgeon and research 
coordinator).  If all agree that the patient can be treated either with FFR-
guided PCI or CABG, and all inclusion criteria are met and no exclusion 
criteria are met, then the patient will be randomized. 
Baseline clinical, functional, laboratory and electrocardiographic data will 
be obtained.  Patients will receive treatment within 4 weeks of 
randomization. Patients randomized to CABG will receive state of the art 
therapy at the discretion of the local surgeon with a strong emphasis on 
arterial revascularization.  Patients undergoing PCI will have FFR 
measured with a Abbott coronary pressure wire across all lesions.  If the 
FFR is ≤0.80, then PCI will be performed with the Medtronic Resolute 
Integrity/Onyx drug-eluting stent (DES) as per usual routine.  If the FFR is 
>0.80 then PCI will be deferred.   
Post procedure laboratory tests will be obtained including troponin within 
12-24 hours after the procedure. Resource utilization will be obtained.  All 
patients will receive medical therapy as per published guidelines. 
Patients will follow-up at 1 and 6 months, and 1, 2, 3, and 5 years with an 
evaluation of clinical status, functional status, medications and events.  
Core lab analyses will include formal quantitative coronary angiography 
(QCA) of the baseline angiograms with calculation of the Synergy between 
Percutaneous Coronary Intervention with Taxus and Cardiac Surgery 
(SYNTAX) score and Functional SYNTAX Score. 
Population 
A complete listing of all inclusion and exclusion criteria can be found in 
section 5 of the protocol. 
Duration 
Ten years: 5 years of enrollment and 5 years follow-up from last patient 
enrolled.  
 
Primary Endpoint 
Death, MI, stroke and any repeat revascularization (MACCE) will be 
evaluated at 1 year, where subjects contribute data from time of 
randomization until the occurrence of MACCE or one year follow-up, 

27Feb2018 
 
FAME 3 IDE 
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whichever occurs first.  Subjects who die or are lost to follow up before 1 
year will be censored at their last recorded activity. 
Key Secondary Endpoint 
Death, MI, and stroke will be evaluated at 3 years, where subjects 
contribute data from time of enrollment until the occurrence of one of the 
above events or three year follow-up, whichever occurs first.  Subjects who 
die or are lost to follow up before this time will be censored at their last 
recorded activity. 
Statistics 
The study will use a noninferiority design.  For the primary endpoint, 
assuming 12% of subjects experience MACCE in the CABG arm by 1 year 
post randomization, given a clinically irrelevant hazard ratio of 1.65, a one-
sided 2.5% significance level and 90% power to reject the null hypothesis 
if it is false, the sample size necessary is 645 patients per group (1290 for 
the entire study).  To account for loss to follow-up and subject withdrawal, 
up to 1500 patients will be enrolled from 50 sites.   
Principal Investigators 
William F Fearon, MD (PI), Bernard De Bruyne, MD, PhD (Co-PI) and 
Nico HJ Pijls, MD, PhD (Co-PI) 
Steering Committee 
William F. Fearon, MD, Bernard De Bruyne, MD, PhD, Nico HJ Pijls, 
MD, PhD, Keith Oldroyd, MD, Alan C. Yeung, MD, Joseph Woo, MD, 
Olaf Wendler, MD, Michael Reardon, MD. 
Clinical Events Committee 
Kenneth Mahaffey, MD, (Chair) Stanford University Medical Center 
, MD, Duke University Medical Center 
, MD, Duke University Medical Center 
, MD, Stanford University Medical Center 
Data Safety Monitoring 
Board 
, MD, (Chair) University of California, Irvine 
, MD, New York Presbyterian Hospital/Weill-Cornell 
Medical Center 
, MD, UCLA Medical Center 
Statistical Analysis 
Manisha Desai, PhD, Quantitative Sciences Unit, Stanford University 
Medical Center 
FFR Core Lab 
Stanford University Medical Center 
Angiography Core Lab 
Stanford University Medical Center 
Economic and Quality of 
Life Analyses 
Mark Hlatky, MD, Department of Health Research and Policy 
Stanford University Medical Center 
Clinical Research 
Organization 
genae  
Sponsor(s) 
Investigator Initiated Trial, with Leland Stanford Jr. University as the 
official Sponsor.  
Support 
Study is supported through research grants by Medtronic Corp. and Abbott 
Vascular. 

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2. Summary of Investigational Plan Changes 
 
Version 2.0, 15May2015 
Section 
Change From 
Change To 
Rationale for Change 
1.0 Protocol Summary 
table, Steering Committee 
 
Added Steering 
Committee members Woo 
and Reardon 
Updated to include new 
Steering Committee 
members that agreed to 
participate after initial 
CIP version. 
5.0 Design, subheading 
Follow-up 
after randomization 
after the index procedure 
To harmonize follow up 
schedule across sites. 
Time to procedure from 
randomization could vary 
significantly depending 
on site waiting times.. 
9.0 Appendix A, 
Definitions 
(ii) angiographic 
documented new graft or 
new native coronary 
occlusion 
(ii) angiographic 
documented new graft or 
new major native 
coronary occlusion 
Update definition of 
periprocedural MI to be in 
line with the 3rd 
Definition of 
periprocedural MI. 
 
Version 2.1, 15Jun2016 
Section 
Change From 
Change To 
Rationale for Change 
1.0 Protocol Summary 
table, Duration 
Five years: 2 years of 
enrollment and 3 years 
follow-up. 
Eight years: 5 years of 
enrollment and 5 years 
follow-up from last 
patient enrolled. 
Extend enrolment period 
due to slower than 
expected enrolment rate 
5.0 Design, subheading 
study enrolment 
an enrollment period of 2 
years 
an enrollment period of 
up to 5 years 
Extend enrolment period 
due to slower than 
expected enrolment rate 
 
Version 3.0, 27Feb2018 
Section 
Change From 
Change To 
Rationale for Change 
Table of Contents 
 
 
Fix numbering of sections 
1. Protocol Summary 
table, Design 
Patients undergoing PCI 
will have FFR measured 
with a St. Jude Medical 
coronary pressure wire 
Patients undergoing PCI 
will have FFR measured 
with a Abbott coronary 
pressure wire 
Device manufacturer 
change of name 
1. Protocol Summary 
table, Design 
PCI will be performed 
with the Medtronic 
Resolute Integrity drug-
eluting stent (DES) 
PCI will be performed 
with the Medtronic 
Resolute Integrity/Onyx 
drug-eluting stent (DES) 
The Onyx stent has now 
replaced the Integrity 
stent 
Revision History 
Effective Date 
1.0 
28Feb2014 
2.0 
15May2015 
2.1 
15Jun2016 
3.0 
27Feb2018 

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1. Protocol Summary 
table, Design 
Patients will follow-up at 
1 and 6 months, and 1, 
and 3 years with an 
evaluation of clinical 
status, functional status, 
medications and events.  
Follow up may be 
extended to 5 years, if 
funding allows. 
 
Patients will follow-up at 
1 and 6 months, and 1, 2, 
3, and 5 years with an 
evaluation of clinical 
status, functional status, 
medications and events.  
Correct follow up 
description and remove 
text related to possible 5 
year follow up.  Funds 
now available. 
1. Protocol Summary 
table, Duration 
Eight years: 5 years of 
enrollment and 3 years 
follow-up from last 
patient enrolled.  Note: 5 
year follow up will be 
performed if funding 
allows. 
Ten years: 5 years of 
enrollment and 5 years 
follow-up from last 
patient enrolled. 
Funding for follow-up 
through 5 years post 
procedure available. 
1. Protocol Summary 
table, Statistics 
clinically irrelevant 
hazard ratio of 1.45 
clinically irrelevant 
hazard ratio of 1.65 
See new text in the 
statistical analysis section 
1.0 Protocol Summary 
table, Statistics 
the sample size necessary 
is 712 patients per group 
(1424 for the entire 
study).  To account for 
loss to follow-up, 1500 
patients will be enrolled 
from 50 sites over 2 
years. 
the sample size necessary 
is 645 patients per group 
(1290 for the entire 
study).  To account for 
loss to follow-up and 
subject withdrawal, up to 
1500 patients will be 
enrolled from 50 sites.   
Based on the new non-
inferiority margin and the 
expected event rate in the 
control arm 
1.0 Protocol Summary 
table, Sponsor(s) 
Investigator Initiated Trial 
and supported through 
research grants by 
Medtronic Corp. and St. 
Jude Medical, Inc. 
Investigator Initiated 
Trial, with Leland 
Stanford Jr. University as 
the official Sponsor. 
Clarification of who 
Sponsor is. 
1.0 Protocol Summary 
table, Support 
 
 
Newly added to indicate 
study is supported 
through research grants. 
2. Summary of 
Investigational Plan 
Changes 
 
 
Newly added. 
3. Background 
the Medtronic Resolute 
Integrity stent has been 
shown to be safe and 
effective. Thus, one might 
hypothesize that a 
comparison of PCI with 
the second generation 
Medtronic Resolute 
Integrity stent technology 
the Medtronic Resolute 
Integrity/Onyx stent has 
been shown to be safe and 
effective. Thus, one might 
hypothesize that a 
comparison of PCI with 
the second generation 
Medtronic Resolute 
Integrity/Onyx stent 
technology 
Added for inclusion of 
Onyx stent. 
Multiple sections 
Medtronic Resolute 
Integrity stent 
Medtronic Resolute 
Integrity/Onyx stent, 
Added for inclusion of 
Onyx stent. 
4. Objective 
St. Jude Medical 
Coronary Pressure Wire 
Abbott Coronary Pressure 
Wire 
To account for change in 
name of device 
manufacturer 

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5. Population, exclusion 
criteria 1 
Requirement for other 
cardiac or non-cardiac 
surgical procedure (e.g., 
valve replacement, 
carotid revascularization) 
Requirement for other 
cardiac or non-cardiac 
surgical procedure (e.g., 
valve replacement, carotid 
revascularization), 
however a MAZE 
procedure or pulmonary 
vein ablation is allowed 
 
The MAZE and 
pulmonary vein ablation 
are frequent add-on 
procedures at the time of 
CABG and not felt to 
increase the risk of the 
procedure significantly 
5. Population, exclusion 
criteria 11 
Inability to take dual 
antiplatelet therapy for six 
months 
to take dual antiplatelet 
therapy or anticoagulation 
and single antiplatelet 
therapy for at least six 
months 
Single antiplatelet therapy 
with anticoagulation is 
now an accepted 
treatment after PCI for 
patients requiring 
anticoagulation 
5. Population, exclusion 
criteria 16 
 
More than one major 
epicardial vessel which is 
chronically occluded 
 
Newly added 
6. Design, PCI Strategy 
PCI may be staged if 
necessary, but this is not 
encouraged.  The plan to 
stage the PCI of a 
particular lesion should 
be declared before 
instrumenting the lesion.  
The second portion of the 
PCI procedure should be 
performed within four 
weeks of the first portion. 
 
PCI may be staged if 
necessary, but this is not 
encouraged.  The plan to 
stage the PCI of a 
particular lesion should be 
declared before 
instrumenting the lesion 
and can be contingent 
upon the patient having 
persistent symptoms.  The 
second portion of the PCI 
procedure should be 
performed within four 
weeks of the first portion. 
 
Clarification 
6. Design, Medications 
table 
 
For patients who require 
anticoagulation, single 
antiplatelet therapy is 
acceptable 
Newly added row. 
6. Design, Follow-up 
Patients will be seen and 
evaluated at 1 month (±7 
days), and 1 and 3 years 
(±30 days) after the index 
procedure with the 
specific assessments as 
outlined in the follow-up 
table below.  (5 year 
follow up will be 
performed if funding 
allows). Phone call 
follow-up will occur at 6 
months, 2 years (and 4 
years, if funding allows). 
Patients will be seen and 
evaluated at 1 month (±7 
days), and 1, 3 and 5 
years (±30 days) after the 
index procedure with the 
specific assessments as 
outlined in the follow-up 
table below.  Phone call 
follow-up will occur at 6 
months and 2 years . 
Correction to account for 
changes to follow-up 
schedule with addition of 
5 year follow-up. 
6. Design, Follow-up 
Schedule table 
Follow-Up Schedule 
(including the potential 
for 4 and 5 year) 
Follow-Up Schedule 
Change of table heading 
to account for addition of 
5 year follow-up. 

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6. Design, 
Electrocardiography 
at discharge1, 1 month, 1, 
and 3 years post index 
procedure. 
at discharge, 1 month, 1, 3 
and 5 years post index 
procedure. 
Change to account for 
addition of 5 year follow-
up visit 
6. Design, Blood 
Sampling 
At 1 year and 3 year 
follow-up if assessed 
locally, per standard of 
care 
At 1, 3 and 5 year follow-
up if assessed locally, per 
standard of care 
Change to account for 
addition of 5 year follow-
up visit 
6. Design, Quality of Life 
Assessment 
Data collection will 
include the completion of 
the EQ-5D questionnaire 
prior to the procedure and 
at the different follow-up 
time points as indicated 
inFollow Up Schedule 
(including the potential 
for 4 and 5 year). 
Data collection will 
include the completion of 
the EQ-5D questionnaire 
prior to the procedure and 
at the different follow-up 
time points as indicated in 
the Follow-Up Schedule. 
Change to account for 
addition of 5 year follow-
up visit 
8. Organization, Support 
The study is supported by 
research grants provided 
by Medtronic Corporation 
and St. Jude Medical.  
The study is supported by 
research grants provided 
by Medtronic Corporation 
and Abbott Vascular.  
To account for change in 
name of device 
manufacturer 
8. Organization, Steering 
Committee 
 
 
Added names of 3 
Steering Committee 
members 
Study Flow Chart 
 
 
Correction to account for 
inclusion of 5yr follow 
up. 
10. Statistics 
a hazard ratio of 1.45 or 
less is not clinically 
meaningful. 
a hazard ratio of 1.65 or 
less is not clinically 
meaningful. 
See new text in statistical 
analysis section 
10. Statistics 
All patients will be 
followed for 3 years post-
randomization (5 years if 
funding allows) or until 
they die, whichever 
comes first. 
All patients will be 
followed for 5 years post-
randomization or until 
they die, whichever 
comes first. 
Change to account for 
addition of 5 year follow-
up visit 
10. Statistics, Sample Size 
and Power Considerations 
We anticipate that within 
1 year of follow up the 
PCI arm will have a 12% 
event rate based on the 
18% rate in SYNTAX 
and the decrease in death, 
MI and revascularization 
seen with FFR guidance 
in FAME and with second 
generation drug eluting 
stents, like the Resolute 
Integrity stent. Thus, 
assuming 12% of subjects 
in the CABG arm 
experience MACCE 
(from the SYNTAX study 
and FREEDOM trial), 
given a clinically 
Recently, the EXCEL, 
NOBLE and BEST trials 
have been published. 
These studies demonstrate 
a one year MACCE rate 
which is in the 10% or 
lower range in the CABG 
arm, compared with the 
SYNTAX and 
FREEDOM trials which 
were in the 12% range. In 
addition, in EXCEL, a 
clinically acceptable non-
inferiority margin for 
death, CVA and MI was a 
hazard ratio in the 1.4 
range. Because of the 
lower event rates after 
Include new information 
related to recently 
published Trial results 
and rationale for changes 
in hazard ratio.  
                                                          
 

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FAME 3 IDE 
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irrelevant hazard ratio of 
1.45, a one-sided 2.5% 
significance level and 
90% power to reject the 
null hypothesis if it is 
false, the sample size 
necessary is 712 patients 
per group (1424 for the 
entire study). These 
calculations are based on 
assumptions of uniform 
accrual over time, no loss 
to follow-up, 
exponentially distributed 
death times, and a Wald 
test statistic.  Thus, to 
account for patients lost 
to follow-up we will 
enroll 1500 patients from 
up to 50 medical centers. 
CABG in more recent 
studies and because we 
will also be including 
revascualrzation as part of 
MACCE, we feel a hazard 
ratio of 1.65 is more 
appropriate for defining a 
clinically acceptable non-
inferiority margin. We 
assume a 10% of subjects 
in the CABG arm 
experience MACCE, and 
further that patients in the 
PCI arm will not 
experience a higher rate 
than those in the CABG 
arm. We would deem an 
increase in event rate up 
to and including a 16% 
event rate as not clinically 
inferior. Thus, given a 
clinically irrelevant 
hazard ratio of 1.65, a 
one-sided 2.5% 
significance level and 
90% power to reject the 
null hypothesis if it is 
false, the sample size 
necessary is 645 patients 
per group (1290 for the 
entire study). These 
calculations are based on 
assumptions of uniform 
accrual over time, no loss 
to follow-up, 
exponentially distributed 
death times, and a Wald 
test statistic.  Thus, to 
account for patients lost to 
follow-up and subject 
withdrawal we will enroll 
up to 1500 patients from 
up to 50 medical centers. 
11. Appendix A, 
Definitions 
 
Acute Kidney Injury 
AKI (acute kidney injury) 
is defined as any of the 
following: 
• 
K Increase in SCr 
(Serum 
creatinine) by ≥0.3 
mg/dl (≥26.5 µmol/l) 
within 48 hours;  
• 
or K Increase in SCr 
to≥1.5 times baseline, 
which is known or 
presumed to have 
Newly added definition 

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FAME 3 IDE 
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occurred within the 
prior 7 days;  
• 
or K Urine 
volume ˂0.5 ml/kg/h 
for 6 hours. 
11. Appendix A, 
Definitions 
 
Cross-over 
If, during the first month 
after randomization, a 
patient receives as the 
initial revascularization 
therapy the alternative 
form of revascularization 
than the assigned 
treatment (i.e. 
Randomized to CABG 
but receives PCI), this 
will be defined as a cross-
over and not a repeat 
revascularization event, 
unless the reason for the 
alternative 
revascularization strategy 
is due to a change in the 
patient’s clinical status 
resulting in 
urgent/emergent 
revascularization. 
Newly added definition 
 

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3. Background 
 
Both United States and European guideline statements recommend coronary artery 
bypass graft surgery (CABG) over percutaneous coronary intervention (PCI) for patients with 
multivessel coronary artery disease (MVD), defined as angiographically significant disease 
involving all three major epicardial vessels. 1,2  This recommendation is based primarily on the 
Synergy between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery 
(SYNTAX) study, which randomized 1800 patients with MVD or significant left main coronary 
disease to either PCI or CABG and demonstrated significantly higher rates of the primary 
endpoint, a composite of the major adverse cardiovascular and cerebrovascular events 
(MACCE), death, myocardial infarction (MI), cerebrovascular accident (CVA) and repeat 
revascularization at one year in the PCI arm (17.8 vs. 12.4%, p=0.002).3  This difference was 
driven primarily by a significant difference in the need for repeat revascularization (13.5 vs. 
5.9%, p<0.001), although there was a strong trend towards lower rates of cardiac death (3.7 vs. 
2.1%, p=0.05) and MI (4.8 vs. 3.3%, p=0.11) in the CABG arm.  These events were 
counterbalanced to some degree by a significantly lower rate of CVA in the PCI arm (0.6 vs. 
2.2%, p=0.003).   
The three year follow-up in these patients continued to show a significantly higher rate of 
MACCE in the PCI arm (28.0 vs. 20.2%, p<0.001), as well as a now significantly higher rate of 
cardiac death (6.0 vs. 3.6%, p=0.02) and MI (7.1 vs. 2.6%, p=0.002) in the PCI arm.4  When 
comparing the 1095 patients with MVD not involving the left main coronary, the same 
significant differences were noted in MACCE between the two groups at both one and three 
years (19.2 vs. 11.5%, p<0.001) and (28.8 vs. 18.8%, p<0.001). 
Another development of the SYNTAX trial was the application of the SYNTAX score as a 
method for identifying patients with complex disease, who might benefit more from CABG.  The 
SYNTAX score is an angiography-based scoring system which assigns points to lesions based on 
their features of complexity, such as ostial location, length, morphology, severity and 
involvement of sidebranches.  After dividing the population into tertiles, based on the SYNTAX 
score, the investigators demonstrated that outcomes were significantly improved after CABG 
when compared to PCI in patients falling in the intermediate (SYNTAX score >22 and <33) and 
high (SYNTAX score >33) tertiles.3,4 

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The recently published Future Revascularization Evaluation in Patients with Diabetes Mellitus: 
Optimal Management of Multivessel Disease (FREEDOM) trial adds further support to the 
findings from SYNTAX.5  The FREEDOM trial randomized 1900 diabetic patients to PCI or 
CABG and found a significantly higher rate of the primary endpoint, death, MI or CVA in the 
PCI arm at 5 year follow-up (26.6 vs. 18.7%, p=0.005).  This difference was driven by higher 
rates of death and MI in the PCI arm and higher rates of CVA in the CABG arm. 
Based on these two studies, most patients with multivessel CAD are now routinely referred to 
CABG, particularly if they have an intermediate or high SYNTAX score.  However, the inferior 
results of PCI demonstrated by both SYNTAX and FREEDOM might be explained by the use of 
inferior stent technology, and even more importantly, by the lack of application of fractional 
flow reserve (FFR)-guided PCI.  
Patients undergoing PCI in SYNTAX received the paclitaxel-eluting Taxus stent and patients in 
the FREEDOM trial received predominantly the sirolimus-eluting Cypher stent and the Taxus 
stent.  These stents have now been shown to be inferior to second generation drug-eluting stents, 
which have lower rates of stent thrombosis, target lesion revascularization, and in some cases, 
death or myocardial infarction.6,7,8  Studies directly comparing second generation drug-eluting 
stents to each other have shown no appreciable difference in these endpoints.9,10  In addition, in 
over 1,000 patients with multivessel CAD, the Medtronic Resolute Integrity/Onyx stent has been 
shown to be safe and effective.7,9,10  Thus, one might hypothesize that a comparison of PCI with 
the second generation Medtronic Resolute Integrity/Onyx stent technology to CABG might 
result in lower rates of death, MI and the need for repeat revascularization as compared to what 
was seen with the Taxus stent, and which are more similar to those seen after CABG. 
The second reason outcomes may have been inferior with PCI in SYNTAX and FREEDOM 
relate to the lack of FFR-guided PCI.  FFR is a coronary pressure wire-based index for assessing 
the ischemic potential of a coronary lesion.  It is defined as the mean distal coronary pressure 
divided by the mean proximal coronary pressure during maximal hyperemia.  Numerous studies 
have demonstrated that if the FFR is ≤0.80, then significant ischemia is present and 
revascularization is warranted.  If the FFR is >0.80, then the lesion can be safely treated with 
medication, despite its angiographic appearance, and one can expect an excellent outcome.11 

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The Fractional Flow Reserve versus Angiography for Multivessel Evaluation (FAME) trial, 
randomized 1005 patients with two or three vessel coronary disease and stable symptoms or non 
ST elevation acute coronary syndromes in whom PCI was indicated to either angiography-guided 
PCI or to FFR-guided PCI, in which case FFR was measured across every lesion and PCI was 
performed only if the FFR was ≤ 0.80.12  The one year primary endpoint of death, MI or the need 
for repeat revascularization occurred in significantly fewer patients randomized to the FFR-
guided strategy (13.2 vs. 18.3%, p=0.02).  This was driven by numerical reductions in all three 
components of the primary endpoint: death (1.8 vs. 3.0, p=0.19), MI (5.7 vs. 8.7%, p=0.07) and 
repeat revascularization (6.5 vs. 9.5, p=0.08).  The composite of death and MI was significantly 
reduced by FFR-guided PCI (7.3 vs. 11.1, p=0.04).  
Figure 1 One year outcomes from FAME 1 Trial 
 
 
At two year follow-up, there continued to be a significant reduction in death and MI with FFR-
guided PCI (8.4 vs. 12.9%, p=0.02) and a trend towards a lower rate of death, MI or the need for 
repeat revascularization (17.9 vs. 22.4%, p=0.08).13  The improved outcomes with FFR-guided 
PCI are likely a result of more judicious PCI whereby ischemia-producing lesions are 

27Feb2018 
 
FAME 3 IDE 
15 
 
revascularized and non-ischemia producing ones are treated medically.  In this manner, the 
benefit of PCI can be maximized by relieving ischemia and the risks can be minimized by 
avoiding unnecessary PCI.  
This difference between functional complete revascularization with FFR-guided PCI and 
anatomic complete revascularization with angiography guidance was further demonstrated by a 
substudy from FAME evaluating the so-called Functional SYNTAX Score (FSS).14  In this 
substudy, the SYNTAX score was calculated in the usual fashion in the 497 patients in FAME 
who were randomized to FFR guidance.  The FSS was then calculated in these patients by 
subtracting the points for any lesions incorporated into the SYNTAX score in which the FFR 
was >0.80.  The FSS resulted in reclassification of 32% of patients from a higher risk SYNTAX 
score tertile to a lower risk FSS tertile.  The FSS was a better discriminator of the risk for death 
and MI or death, MI and the need for repeat revascularization as compared to the SYNTAX 
score. 
Figure 2 Comparison of Functional SYNTAX Score and SYNTAX Score in FAME 1 Trial   
 
If one compares the results of the FAME study to the results of SYNTAX (excluding the left 
main subset), the major adverse event rate (excluding stroke) was similar between the 
angiography-guided arm in FAME and the PCI arm in SYNTAX, reflecting the fact that PCI in 
SYNTAX was performed primarily with angiography guidance alone.  On the other hand, the 
FFR-guided arm in FAME had similar event rates to the CABG arm in SYNTAX.  Based on this 

27Feb2018 
 
FAME 3 IDE 
16 
 
comparison and the trials showing improved outcomes with the Medtronic Resolute 
Integrity/Onyx stent, one can hypothesize that a comparison between FFR-guided PCI with the 
Resolute stent and CABG in patients with multivessel coronary disease would be favorable. 
4. Objective 
The primary objective of the FAME 3 Trial is to demonstrate that FFR-guided PCI is noninferior 
to coronary artery bypass graft surgery in patients with multivessel CAD.  If we fail to reject the 
null hypothesis that FFR-guided PCI is worse than CABG, this study will be considered 
negative.  The FAME 3 study is not intending to support a label change for either the Resolute 
Integrity 
Zotarolimus-Eluting Coronary Stent System or the Abbott Coronary Pressure Wire. 
5. Population 
Inclusion Criteria 
1. Age ≥ 21 years with angina and/or evidence of myocardial ischemia 
2. Three vessel CAD, defined as ≥ 50% diameter stenosis by visual estimation in each of the 
three major epicardial vessels or major side branches, but not involving left main 
coronary artery, and amenable to revascularization by both PCI and CABG as determined 
by the Heart Team. Patients with a non-dominant right coronary artery may be included if 
only the left anterior descending artery (LAD) and left circumflex have ≥50% stenosis 
3. Willing and able to provide informed, written consent 
Exclusion Criteria 
1. Requirement for other cardiac or non-cardiac surgical procedure (e.g., valve replacement, 
carotid revascularization), however a maze procedure or pulmonary vein isolation is 
allowed 
2. Cardiogenic shock and/or need for mechanical/pharmacologic hemodynamic support  
3. Recent STEMI (<5 days prior to randomization) 
4. Ongoing Non STEMI with biomarkers (cardiac troponin) still rising 
5. Known left ventricular ejection fraction <30% 

27Feb2018 
 
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6. Life expectancy < 2 years 
7. Requiring renal replacement therapy 
8. Undergoing evaluation for organ transplantation 
9. Participation or planned participation in another clinical trial, except for observational 
registries 
10. Pregnancy 
11. Inability to take dual antiplatelet therapy or anticoagulation and single antiplatelet 
therapy for at least six months 
12. Previous CABG 
13. Left main disease requiring revascularization 
14. Extremely calcified or tortuous vessels precluding FFR measurement 
15. Any target lesion with in-stent drug-eluting stent restenosis 
16. More than one major epicardial vessel which is chronically occluded 
6. Design 
FAME 3 is an investigator-initiated, multicenter, international, randomized, controlled trial 
including up to 50 sites worldwide.  Consecutive patients with multivessel CAD (not involving 
the left main coronary) who meet the inclusion criteria and none of the exclusion criteria outlined 
above will be randomized in a 1:1 fashion to either CABG or FFR-guided PCI.  
Study Enrolment 
With a goal of including 1500 patients from up to 50 sites and an enrollment period of up to 5 
years, each site is expected to include ≥ 2 patients per month.  We anticipate 20-25 US sites will 
enroll 40-50% of patients in the trial.  Consecutive patients will be screened at each participating 
center and those with multivessel CAD, defined as ≥ 50% diameter stenosis in each of the three 
major epicardial vessels, and not involving the left main coronary will be eligible.  After the 
baseline angiogram has been performed, the Heart Team will review the patient’s case to 
determine if all of the inclusion criteria and none of the exclusion criteria are met.  In particular, 
the Heart Team will evaluate whether or not both FFR-guided PCI and CABG are reasonable 
treatment alternatives.  This may involve the calculation of the SYNTAX score or any other 
scores predicting outcomes after CABG or PCI, but these are not mandated.  The SYNTAX 

27Feb2018 
 
FAME 3 IDE 
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score and other scores will be calculated by a core laboratory after patient enrolment.  The study 
will be discussed with the patient, and if the patient provides informed, written consent, then the 
patient will be enrolled.   
Randomization 
Randomization will occur via a web-based system stratified by diabetes status and site.  Once a 
patient has been randomized, treatment should occur within 2 weeks, and no longer than 4 
weeks.  A patient will be considered enrolled once randomization has occurred. 
Baseline Data 
Every patient will undergo baseline assessment as outlined below. 
• Baseline demographics and clinical characteristics will be recorded as outlined in the case 
report form. 
• Medications 
• Laboratory studies including complete blood count, basic metabolic panel, lipid panel 
and glycosylated hemoglobin (HgbA1C); all hospitalized patients will have cardiac 
markers, including troponin checked, and if elevated, repeated 4-12 hours later to 
determine if they are stable or declining 
• Electrocardiogram 
• Quality of life (EQ-5D) assessment 
Coronary Artery Bypass Graft Surgery (CABG) 
CABG will be performed as per clinical routine at each participating center.  FFR assessment of 
lesions to help guide bypass is not mandated, but if performed at the time of the diagnostic 
angiogram, the information can be used by the surgeon.  We expect this will occur in 
approximately ¼ of cases, and in most of these cases we expect the decision to place a bypass 
graft will be based on the FFR result.  Adjunctive pharmacologic therapy during and 
immediately after the CABG should be prescribed as per the clinical routine at each participating 
center.  Recommendations are described in the section Medications.  
Both off-pump and on-pump surgery are acceptable, as long as the surgeon and the site are 
experienced in the particular technique.  An internal mammary graft to the LAD should be 
attempted in all cases, if feasible.  Complete arterial revascularization is strongly recommended, 

27Feb2018 
 
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however, each center should use a conduit strategy with which they are most comfortable.  All 
vessels ≥ 1.5 mm in diameter and with ≥ 50% stenosis should undergo bypass procedure, if 
technically feasible.    
Fractional Flow Reserve-Guided PCI 
Access: 
• PCI can be performed via the radial artery or the femoral artery, as per the site’s usual 
routine. 
Performance of FFR: 
• Only those sites with prior experience measuring FFR will be included in the FAME 3 
trial.  Intracoronary pressure measurements should be obtained with a guiding catheter 
and a St Jude Medical Pressure Wire. For correct use of the pressure guidewire, refer to 
the instructions for use provided by St Jude Medical along with the product. The FFR 
tracings from the first 10 patients at every site will be recorded on the RADIANALYZER 
and reviewed by the FFR core lab at Stanford immediately after each patient is treated.  
The Steering Committee will provide feedback to the Interventional Cardiology site 
Principal Investigator.  We expect measurement of FFR will not be possible in 5% of 
lesions due to technical or anatomic reasons.  These patients in whom FFR of a particular 
lesion was not possible will be included in all analyses based on the intention to treat 
principle. 
• Ensure correct calibration of all equipment, the aortic pressure transducer and the 
pressure guidewire.    
• Before introducing the guidewire into the coronary artery, intracoronary nitroglycerin 
(100-200 micrograms, or its equivalent) should be administered. 
• Before advancing the pressure guidewire sensor past the stenosis, baseline pressure as 
measured by the guide catheter and the pressure guidewire should be equalized, with the 
pressure wire sensor positioned at the tip of the guiding catheter.  At this point, the 
pressure tracing of the guiding catheter and of the pressure guidewire should be equalized 
electronically.   
• The sensor is then advanced across the stenosis.  

27Feb2018 
 
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• Administer hyperemia according to standard practice. It is recommended that hyperemia 
is induced by intravenous adenosine (140 µg/kg/min for at least 2 minutes or until a 
steady state is obtained) via central venous access. If intravenous adenosine cannot be 
given, it is recommended that intracoronary adenosine is given by a bolus injection of at 
least 100 µg and repeated twice.  
• FFR should be recorded once steady state maximal hyperemia has been achieved based 
on examination of the pressure and heart rate tracing and based on symptom development 
in the case of intravenous adenosine.  The lowest Pd/Pa ratio during steady state 
hyperemia in the absence of any artifact or arrhythmia should be recorded as the FFR.   
• Only those lesions with an FFR ≤0.80 should be stented. 
• If the FFR in a vessel is ≤0.80, the operator is not obligated to stent.   For example, if on 
pullback of the wire, diffuse disease is diagnosed without an obvious focal step-up, 
stenting is not mandated.  Or if a small sidebranch of a bifurcation lesion has an FFR 
≤0.80, stenting is not mandated.  In other words, operators should use their good clinical 
judgment and follow their routine practice.   
• In case of serial stenoses, FFR “of the complete vessel” should be ≤0.80 to warrant PCI 
of one of more of these stenoses.  Long stents to cover a segment or multiple shorter 
stents, can be placed at the discretion of the operator.  After treating one stenosis, FFR 
should be remeasured to determine whether the second stenosis warrants therapy. 
• In the case in which the operator decides to revascularize a chronic total occlusion, FFR 
measurement is not mandatory and a default FFR value of 0.50 can be applied. 
• It is strongly advocated to measure the final post DES implantation FFR, to document the 
degree of resolution of the pressure gradient achieved by the revascularization.  A 
pullback should be performed to address the source of any residual gradient and to check 
for drift in the pressure wire.  
• Based on the literature and clinical experience, we expect a <1% complication rate from 
FFR measurement.15 
PCI Strategy: 

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• PCI will be performed solely with the Medtronic Resolute Integrity/Onyx stent.  If the 
Resolute stent cannot be delivered, an alternative current generation drug-eluting stent 
can be substituted, preferably an everolimus eluting stent. 
• Covering the entire diseased portion of the lesion with a single drug-eluting stent is 
recommended. 
• A single cross-over stent strategy for bifurcation lesions is recommended, with 
provisional sidebranch stenting only if < TIMI 2 flow is persistent after kissing balloon 
inflation of the sidebranch. 
• It is not recommended to revascularize a chronic total occlusion (CTO) unless a patient 
has persistent symptoms after the initial PCI, documented ischemia on noninvasive 
testing involving the region subtended by the vessel with the CTO, and visible collaterals 
which fill a vessel >2.5 mm in diameter.  If the operator is considering bringing the 
patient back for revascularization of a CTO, this should be documented in the CRF at the 
time of the baseline procedure.  The operator is not obligated to bring the patient back, 
but this will avoid confusion regarding whether or not the follow-up procedure is 
planned. 
• PCI may be staged if necessary, but this is not encouraged.  The plan to stage the PCI of a 
particular lesion should be declared before instrumenting the lesion and can be contingent 
upon the patient having persistent symptoms.  The second portion of the PCI procedure 
should be performed within four weeks of the first portion. 
 
Medications 
Type of medication 
CABG 
FFR-guided PCI 
Aspirin 80-100 mg once a day for the duration of the study 
Pre- and post-procedure 
High dose statin (e.g., atorvastatin 80 mg) 
≤ 24 hours before the procedure 
Clopidogrel or its equivalent (i.e. prasugrel or ticagrelor)2 
for 6 months (12 months recommended) 
- 
 
Pre-loading with 600 
mg or equivalent 
Bivalirudin for anticoagulation 
- 
 
Recommended 
Beta blockers or amiodarone to prevent atrial fibrillation 
At site’s 
discretion 
 
                                                          
 

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For patients who require anticoagulation, single antiplatelet 
therapy is acceptable 
 
 
1 Ticlopidine should not be used. 
Follow-up 
 
Patients will be seen and evaluated at 1 month (±7 days), and 1, 3 and 5 years (±30 days) 
after the index procedure with the specific assessments as outlined in the follow-up table below.  
. Phone call follow-up will occur at 6 months and 2 years .  One month is defined as 30 days (i.e. 
6 months equals 180 days).  Each year will be defined as 360 days.  During follow-up patients 
will be assessed for any MACCE, angina severity, and quality of life (EQ-5D).    
 
Follow-Up Schedule  
 
Base- 
Line 
12-24 
Hours 
Post 
Proc. 
Dis- 
charge 
1  
month 
(±7 
days) 
6 
month 
(±30 
days) 
1 
year 
(±30 
days) 
2 
years 
(±30 
days) 
3 
years 
(±30 
days) 
5  
years 
(±30 
days) 
 
Hosp. 
Hosp. 
Hosp. 
Visit 
Call 
Visit 
Call 
Visit 
Visit 
Medical 
History 
X 
 
 
 
 
 
 
 
 
QOL (EQ-5D) 
X 
 
 
X 
 
X 
 
X 
X 
Working 
Status 
X 
 
 
X 
X 
X 
X 
X 
X 
ECG 
X 
X1 
X 
X 
 
X 
 
X 
X 
Lab Studies 
X 
X1 
X 
 
 
X 
 
X 
X 
Cardiac 
Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
Resource 
Utilization 
 
 
X 
X 
X 
X 
X 
X 
X 
MACCE 
 
 
X 
X 
X 
X 
X 
X 
X 
1 The 12-24 hour assessment is sufficient in case discharge is within 36 hours post-procedure 
Recording of Adverse Events  
For the purpose of this trial, only MACCE events will be reported. In case a patient does not 
attend the final visit, all efforts should be made to obtain a complete inventory of these events.  

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Electrocardiography  
Twelve lead electrocardiograms (ECGs) are recorded before the procedure (within 24 hours), 1 
day after the procedure (12 to 24 hours post procedure) and at discharge3, 1 month, 1, 3 and 5 
years post index procedure. 
Recording of Cardiac Medication  
Cardiac medications prescribed during the initial hospital stay and at the time of follow-up visits 
must be recorded. Investigators should review all medications carefully at every out-patient 
clinic visit. 
Angina Assessment  
The anginal status of the patient will be assessed according to the Canadian Cardiovascular 
Society (CCS) Classification at all follow-up contacts (calls or visits).  
Blood Sampling  
Baseline blood samples: Pre catheterization analyses, assessed locally, per standard of care 
should include:  
• Total Cholesterol 
• HDL Cholesterol  
• LDL Cholesterol  
• Triglycerides 
• Creatinine 
• Hemoglobin 
• Glycosylated hemoglobin 
Mandatory post PCI or CABG blood sampling will include 12 – 24 hours post index procedure: 
• Troponin (and CK and CK-MB if available) 
• Hemoglobin 
• Creatinine  
                                                          
 

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If elevated, cardiac markers will be measured every 8 hours until they begin to decline.  The 
highest creatinine and the lowest hemoglobin during the hospitalization will be recorded. 
At 1, 3 and 5 year follow-up if assessed locally, per standard of care 
• Total Cholesterol  
• HDL Cholesterol  
• LDL Cholesterol  
• Triglycerides, 
• Creatinine 
• Hemoglobin 
• Glycosylated hemoglobin 
Resource Utilization  
Resource utilization data will be collected for each patient at the time of each follow-up contact.  
Specific data to be collected will include:  
1. 
Resource use concerning the initial procedure  
2. 
Hospital readmissions  
3. 
Major procedures after the initial procedure 
o revascularization procedures (CABG, PCI) 
o diagnostic procedures (angiography, echocardiography, exercise testing, etc.) 
4. 
Medication 
o Anti anginal medication  
o Medication for treatment of other cardiovascular conditions (hypertension, CHF, 
arrhythmia) 
o Antiplatelet agents and anticoagulants  
Quality of Life Assessment  
Data collection will include the completion of the EQ-5D questionnaire prior to the procedure 
and at the different follow-up time points as indicated in the Follow-Up Schedule.  

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Working Status 
In addition to the quality of life assessment prior to treatment allocation and at all planned 
clinical follow-up visits, the patient will be requested to provide information relative to his/her 
working status or any change therein. 
 
 
 
 
 
 
 
7. 
Reporting of Events  
The study will evaluate two different common treatments. For the purpose of this study, only 
endpoint related events and other possible vascular events are reported.  
Trial personnel must report any of the following events within 1 business day of learning of the 
event. 
• Death  
• Myocardial infarction 
• Cerebrovascular event (TIA, CVA) 
• Revascularization (PCI, CABG) 
• Bleeding event  
• Acute renal failure 
• Atrial fibrillation or other arrhythmia 
• Rehospitalization 
The notification is by preference performed via the electronic CRF (eCRF).  Alternatively e-mail 
or phone may be used for immediate notification, however the eCRF must be completed as soon 
as possible. Detailed procedures will be listed in the manual of operations.  Study personnel must 
update any follow-up information in the completed adverse event CRF as the event continues 
and/or resolves.  It is the responsibility of the Site Principal Investigator to inform the 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of the adverse event as 
required by local procedure.  
Vigilance Reporting 
Since commercially available products are used in this study, reporting relative to device 
malfunctions must be reported to the relevant manufacturer according to the procedure as 
defined by the relevant entity.  

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8. 
Organization 
Sponsor 
This is an investigator initiated trial. The Principal Investigators are considered to be the 
sponsors of this study. The Principal Investigators will be supported by the clinical research 
organization, genae, for the financial and logistic aspects of this clinical trial.  
Support 
The study is supported by research grants provided by Medtronic Corporation and Abbott Vascular.  
Steering Committee 
The Steering Committee (SC) is the main decision making committee of the trial and has final 
responsibility for the medical and scientific conduct of the trial. The SC will approve the trial 
protocol and any amendment (if applicable). The SC further will review all reported adverse 
events on a regular basis. The Committee may request that the trial be put on hold or even 
terminated for safety, ethical or other reasons. 
The Committee will be comprised of physician-investigators: 
- 
William F. Fearon, MD, Stanford, CA, USA, Chairperson and Coordinating Clinical 
Investigator (CCI)  
- 
Bernard De Bruyne, MD, PhD, Aalst, BE, Co-CCI   
- 
Nico HJ Pijls, MD, PhD, Eindhoven, NL, Co-CCI 
- 
Keith Oldroyd, MBCHB, MD, Glasgow, UK, Co-CCI 
- 
Michael Reardon, MD, Houston, TX, USA, Co-CCI 
- 
Olaf Wendler, MD, PhD, London, UK, Co-CCI 
- 
Joseph Woo, MD, Stanford, CA, USA, Co-CCI 
- 
Alan C. Yeung, MD, Stanford, CA, USA, Co-CCI 
Monitoring  
Central clinical and statistical monitoring will be the primary monitoring method of FAME 3 
with a commercially available approved device widely used in clinical practice and using 
techniques outlined by FDA.16  The Steering Committee believes this risk-based monitoring 
approach will be effective because the majority of the investigators in FAME 3 are established 
investigators who have worked with the Principal Investigators in other recent large clinical 

27Feb2018 
 
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27 
 
randomized trials (FAME 1 and FAME 2).  Factors for selection of Investigators include their 
experience in clinical research and experience with the sponsor or members of the Steering 
Committee.  The Steering Committee also believes this monitoring approach is appropriate 
because the two treatment strategies being tested are accepted clinical approaches performed 
routinely; the device being tested (the Medtronic Resolute Integrity/Onyx stent) has a robust 
safety record in prior human studies; and because the treatment after the initial procedure will be 
according to routine practice.  All sites will enter data or upload electronic records into a secure 
electronic CRF.  Investigators will receive training from the CRO on the protocol and study 
requirements including data collection and event reporting.  The objective clinical outcomes of 
FAME 3 will undergo central adjudication.  
The electronic CRF will not allow randomization into the study unless all inclusion criteria have 
been met and no exclusion criteria have been met.  The CRF will not allow submission unless all 
of the data elements have been successfully entered.  Drop down selections in the electronic CRF 
will only allow selection of data within a specific expected range for each data point.  This will 
help to eliminate human error in entering data.  All sites will electronically upload the signed 
consent page for each patient enrolled into FAME 3.  A minimum of 10% of the CRFs will be 
randomly selected and monitored to identify inconsistent data, data outliers, and potential 
protocol deviations that may be indicative of systemic or significant errors in data collection and 
reporting at a site.  If this is identified, targeted on-site monitoring will be conducted.  In 
addition, on site monitoring may occur if the number of adverse events, protocol deviations, 
subject withdrawals or missed follow-up visits exceeds a pre-defined threshold.  Root cause 
analysis will be performed as necessary to identify appropriate corrective or preventive actions.  
All adverse events which occur during the study will trigger monitoring which will include 
review of source documents.  Statistical analyses of the entered data will be performed to 
identify unusual trends, such as too little variance in data at a particular site, too many 
withdrawals or screen failures, and delays in reporting.  Regular videoconferences and email 
communication will occur between the CRO and the sites to ensure compliance with the above 
monitoring plan.  In person, biannual investigators’ meetings will further reinforce the 
monitoring plan.  The monitoring results will be documented and communicated to the Steering 
Committee by the CRO on a quarterly basis or more frequently, as necessary.  The Steering 
Committee will provide reports to FDA as requested.   

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Investigator responsibilities 
As this is an investigator Initiated Clinical Trial, it is expected that each involved investigator is 
responsible for obtaining the relevant approvals and to provide the required reporting throughout 
the trial.  
Clinical Events Committee  
The Clinical Events Committee is made up of interventional and non-interventional cardiologists 
and cardiac surgeons who are not participants in the trial. A stroke consultant will be available to 
review neurologic event adjudication as necessary.  The Clinical Events Committee is charged 
with the development of specific criteria used for the adjudication of clinical events and clinical 
endpoints in the trial which are based on protocol.  
The Clinical Events Committee will establish explicit rules outlining the minimum amount of 
data required, and the algorithm followed in order to classify a clinical event. All members of the 
Clinical Events Committee will be blinded to the primary results of the trial. 
The Clinical Events Committee will meet regularly to review and adjudicate all clinical events in 
which the required minimum data is available blinded to treatment group assignment. The 
Committee will also review and rule on all deaths that occur throughout the trial.  
All events will be reviewed by the Steering Committee only. 
Data Safety Monitoring Board 
The Data Safety Monitoring Board (DSMB) will be an independent group of physicians 
including an interventional cardiologist, cardiac surgeon and statistician.  The DSMB, in 
conjunction with the Steering Committee, will develop a charter with specific guidelines 
regarding monitoring the safety of the subjects enrolled in FAME 3.  In brief, this group will 
initially convene quarterly during the first year of enrolment and then every 6 months for the 
remainder of the trial and have complete access to the adverse events in each arm of the trial.  
Based on their clinical judgment, the DSMB can recommend stopping the trial.  The final 
decision regarding stopping enrollment will rest with the Steering Committee.     
 

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Study Flowchart 
All Comers with 3 vessel CAD 
(not involving Left Main) 
 
 
 
Amenable to PCI/CABG per Heart Team 
Meet inclusion criteria 
No exclusion criteria met 
and patient consents 
 
 
                                                    
                                                                        Patient is randomized 
 
 
 
 
 
 
 
 
FFR-Guided PCI with DES 
Stent all lesions with FFR ≤ 0.80 
(n=750) 
Perform CABG based on 
coronary angiogram 
(n=750) 
One Year follow-up for MACCE 
Three Year follow-up for  
Death, MI, CVA 
(1 and 6 months, 2, and 5 years) 

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9. 
Endpoints 
Primary Endpoints 
 
Death, MI, stroke and any repeat revascularization (MACCE) will be evaluated at 1 year 
from the last patient randomized, where subjects contribute data from time of enrollment until 
the occurrence of MACCE or one year follow-up, whichever occurs first.  Subjects who die or 
are lost to follow up before this time will be censored at their last recorded activity. 
Key Secondary Endpoint 
 
Death, MI, and stroke will be evaluated at 3 years from the last patient randomized, 
where subjects contribute data from time of enrollment until the occurrence of MACCE or three 
year follow-up, whichever occurs first.  Subjects who die or are lost to follow up before this time 
will be censored at their last recorded activity.  This secondary endpoint is not a co-primary 
endpoint because we would need to adjust for multiplicity and this would increase our sample 
size. 
Other Secondary Endpoints 
• Comparison of proportion of patients in each arm with MACCE at one year, excluding 
patients lost to follow-up from each arm 
• MACCE rate at each time point besides one year 
• Rate of each individual component of MACCE at each time point 
• Rate of death, MI, and stroke at each time point 
• Rate of death and MI at each time point 
• Rate of cardiac death alone and in combination with other end points 
• Rate of death, MI, stroke and all repeat revascularizations at each time point 
• Stent thrombosis (ARC definition) and graft occlusion at each time point 
• Bleeding complication 
• Significant arrhythmia 
• Development of acute renal failure 
• Length of hospital stay 
• Rehospitalization within 30 days and 1 year of the primary procedure 

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• Usefulness of the STS, logistic Euroscore, SYNTAX score, clinical SYNTAX score, 
ACEF score, Functional SYNTAX score and other scoring systems for predicting 
outcomes 
• Outcomes based on left internal mammary artery use alone versus multiple arterial 
conduits 
• Cost and cost-effectiveness at each time point 
• Health-related quality of life index (EQ-5D) at each time point 
• Functional class at each time point 
• Number of anti-anginal medications at each time point. 
Pre-specified Subgroup Analyses 
These analyses will be performed between the PCI and CABG arms, as well as within each arm, 
as appropriate.   
• Comparison of outcomes by baseline features including diabetes status, sex, age, ejection 
fraction, kidney function, acute coronary syndrome, prior MI, and geographic location 
(within or outside of the United States). 
• Comparison of outcomes by STS, logistic Euroscore, SYNTAX score, clinical SYNTAX 
score, ACEF score and Functional SYNTAX score  
• Comparison of outcomes by revascularization status (i.e., complete or incomplete as 
defined by angiogram)  
• Compare complete arterial revascularization to incomplete arterial revascularization in 
the CABG group 
• Compare on-pump to off-pump CABG results 
• Comparison of outcomes by proximal LAD versus non proximal LAD 
• Comparison of surgical results between patients with FFR measured before CABG and 
angiography-guided CABG 
 
 

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10. 
Statistics 
Null and Alternative Hypotheses to Address Primary Question 
The study makes use of a noninferiority design and assumes that a hazard ratio of 1.65 or less 
is not clinically meaningful.  More specifically, the null hypothesis is that the hazard of MACCE 
for PCI patients is greater than that of CABG patients and the alternative hypothesis is that the 
hazard of MACCE for PCI is not worse (not greater) than that for CABG patients.  Let HR0 be 
the non-inferiority margin – i.e., the maximum ratio of clinical insignificance.  Then the null 
(H0) and alternative (H1) hypotheses can be expressed as: 
 
 
 
Primary Analysis Plan: Statistical Tools and Test Statistic 
The primary analysis will be based on the intention-to-treat (ITT) principle, whereby all 
randomized patients will be included in the analysis and according to the treatment group to 
which they were originally allocated.  Patients will be encouraged to remain in the trial until 
completion of up to 5 years follow-up.  All patients will be followed for 5 years post-
randomization or until they die, whichever comes first.  If a patient refuses further clinical 
follow-up, the follow-up evaluation will be conducted using telephone interviews.  For patients 
who drop out or are lost to follow-up, the reason for dropping out or being lost will be recorded.  
Importantly, for the primary analysis the patient will be censored at the time when the last 
follow-up examination or telephone contact took place if the subject did not experience MACCE, 
allowing the subject to be included in the analysis according to the ITT analysis plan. 
Kaplan-Meier curves will be used to graphically display differences in MACCE by treatment 
arm and by diabetes status.  In addition, we will use survival analytic techniques such as a log-
rank test or, if appropriate, a Cox proportional hazards (PH) model to estimate the difference in 
hazard of MACCE by treatment arm, stratified by center, and with diabetes status included as a 
term in the model.  The test for non-inferiority of fractional flow reserve-guided PCI will be one-
sided and assessed at the 0.025 level of significance.  For example, a Cox PH model for the 
hazard of MACCE can be expressed as: 
 

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for i=1, 2, …, 50 where i indexes the clinical sites involved in the study, PCI represents an 
indicator for whether a subject has been randomized to the PCI arm, DM is an indicator for 
whether the subject has been diagnosed with diabetes at baseline, 
, represents the hazard of 
MACCE, and 
 represents the baseline hazard of MACCE at the ith clinical site.  Our model 
allows the baseline hazard of MACCE to vary by clinical site.  Our interest lies in inference 
about 
, which represents the difference in log-hazard between the treatment arms.  A Wald test 
statistic that is a function of 
can then be used to assess whether the hazard ratio for the 
treatment arms is within the non-inferiority margin.  For this purpose, we will conduct a one-
sided test at the 0.025 level of significance. 
Model Diagnostics: Assessing heterogeneity of hazards across levels of confounders and 
assessing adherence to the proportional hazards assumption 
We will perform a number of tests to confirm that the assumptions in the above model are 
reasonable.  If the number of subjects per site is too small, we will pool smaller sites so that there 
are at least 10 subjects per site.  Then, to confirm that the hazard of MACCE does not vary by 
pooled site, diabetes status and gender, we will include an interaction term between pooled site, 
PCI and diabetes and test whether the corresponding coefficient is greater than zero using a two-
sided Wald test statistic at the 0.15 level of significance.  We will take a similar approach by 
including an interaction term between gender and PCI.  If homogeneity of the hazard by a feature 
is rejected, the corresponding interaction term will be included in the model.  The test statistic 
corresponding to the primary question of interest (i.e., the treatment effect) will be evaluated in 
the presence of the interaction term to describe the overall treatment effect.  We will additionally 
present the hazard ratios by levels of the modifying factor. 
The proportional hazards assumption will be evaluated through graphical techniques 
including plots of transformed survival estimates (i.e., log(-log(survival at time t))) by log-
transformed time and Kaplan-Meier curves by treatment arm. Should the assumption be violated, 
we can relax the assumption through inclusion of an interaction term between treatment arm and 
log-transformed time. 
 
 

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Sample Size and Power Considerations17 
Recently, the EXCEL18, NOBLE19 and BEST20 trials have been published. These studies 
demonstrate a one year MACCE rate which is in the 10% or lower range in the CABG arm, 
compared with the SYNTAX and FREEDOM trials which were in the 12% range. In addition, in 
EXCEL, a clinically acceptable non-inferiority margin for death, CVA and MI was a hazard ratio 
in the 1.4 range. Because of the lower event rates after CABG in more recent studies and because 
we will also be including revascularization as part of MACCE, the Steering Committee feels a 
hazard ratio of 1.65 is more appropriate for defining a clinically acceptable non-inferiority 
margin.  We assume a 10% of subjects in the CABG arm experience MACCE, and further that 
patients in the PCI arm will not experience a higher rate than those in the CABG arm. We would 
deem an increase in event rate up to and including a 16% event rate as not clinically inferior. 
Thus, given a clinically irrelevant hazard ratio of 1.65, a one-sided 2.5% significance level and 
90% power to reject the null hypothesis if it is false, the sample size necessary is 645 patients per 
group (1290 for the entire study). These calculations are based on assumptions of uniform 
accrual over time, no loss to follow-up, exponentially distributed death times, and a Wald test 
statistic.  Thus, to account for patients lost to follow-up and subject withdrawal we will enroll up 
to 1500 patients from up to 50 medical centers.   
Sensitivity Analyses 
Our current approach is to do an intent-to-treat analysis and include all randomized subjects 
in the analysis.   Subjects who are lost to follow-up will be included in the analysis up to the time 
they are censored.  An alternative set of analyses that will serve as sensitivity analyses will be to 
compare the proportion of subjects who experience the primary event at one year of follow-up by 
treatment arm using logistic regression techniques, where subjects who are lost to follow-up are 
excluded from the analysis, or included with an imputed outcome using multiple imputation 
techniques that rely on missing at random and missing not at random techniques.  Auxiliary 
variables to be used in the multiple imputation include all baseline variables such as age, gender, 
site, diabetes status, etc.  This will allow comparisons to our primary analysis.  If results are 
similar across analyses, this will bolster our findings.  If they are different, we will report the 
discrepancy.  The results from our primary analysis, however, will be reported as our final 
analysis. 

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Secondary Analyses 
Secondary analyses will be performed to inform future studies and are therefore considered 
hypothesis-generating.  For example, we will use Cox proportional hazards regression techniques 
to assess whether the differences in hazard of the key secondary outcome of death, MI, and 
stroke (censored at 3 years) is different by treatment arms.  Similarly, we will use these tools to 
investigate whether relationships between outcome and treatment vary by baseline features such 
as age, sex, geographic location, etc.    
11. 
Appendix A. 
Definitions 
Death is defined as all cause death.  Cardiac death is defined as any sudden death, death related 
to acute myocardial infarction, arrhythmia or congestive heart failure, death secondary to a 
cerebrovascular accident, or death directly related to PCI or CABG, even if the ultimate cause of 
death is not clearly a cardiac event (e.g., infection).  Non-cardiac death is any death which is not 
clearly cardiac in etiology. 
Myocardial infarction is defined in two ways, depending on whether or not it is PCI or CABG-
related or a spontaneous event, as recently described in the literature.21  
 
Spontaneous myocardial infarction (>72 hours after PCI or CABG): 
Detection of rise and/or fall of cardiac biomarkers (CK-MB or troponin) with at least one value 
above the 99th percentile of the upper reference limit (URL) together with evidence of 
myocardial ischemia with at least one of the following: 
• Symptoms of ischemia 
• ECG changes indicative of new ischemia [new ST-T changes or new, persistent, non 
rate-related left bundle branch block (LBBB)] 
• Development of pathological Q waves (≥ 0.03 seconds in duration and ≥ 1 mm in 
depth) in ≥ 2 contiguous precordial leads or ≥ 2 adjacent limb leads of the ECG  
• Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 

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PCI or CABG-related MI (<72 hours after PCI or CABG):  
 
Elevation of the cardiac troponin value > 10 x 99th percentile of the URL in patients with a 
normal baseline reference level, or an increase of > 20%, if the baseline values are elevated, but 
are stable or falling.  In addition, at least one of the following:  
(i) 
new pathologic Q waves or new left bundle branch block 
(ii) 
angiographic documented new graft or new major native coronary occlusion 
(iii) 
imaging demonstration of new loss of viable myocardium or new regional wall 
motion abnormalities is required. 
Stroke (cerebrovascular accident or CVA) is the rapid onset of a focal or global neurological 
deficit.  If the duration is <24 hours, the event is deemed a transient ischemic attack (TIA), 
except if an intervention is performed as defined below.  If the duration is ≥24 hours, it is 
deemed a stroke.  Stroke is subdivided as ischemic, hemorrhagic, or undetermined.  Ischemic 
stroke refers to acute symptomatic episode of focal cerebral, spinal, or retinal dysfunction caused 
by an infarction of the central nervous system tissue.  Hemorrhagic stroke is an acute 
symptomatic episode of focal or global cerebral or spinal dysfunction caused by nontraumatic 
intraparenchymal, intraventricular or subarachnoid hemorrhage.  Undetermined stroke is one 
with insufficient information to allow categorization as either of the above two.  
Stroke is diagnosed when the following criteria are met: 
1. Rapid onset of a focal/global neurological deficit with at least one of the following: 
- 
Change in level of consciousness 
- 
Hemiplegia 
- 
Hemiparesis 
- 
Numbness or sensory loss affecting one side of the body 
- 
Dysphagia/aphasia 
- 
Hemianopia 
- 
Amaurosis fugax 
- 
Other new neurological sing(s)/symptom(s) consistent with stroke 

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2. Duration of focal/global neurological deficit is ≥24 hours, or it can be <24 hours if a 
therapeutic intervention is performed, brain imaging clearly documents a new 
hemorrhage or infarct, or the neurological deficit results in death. 
3. Confirmation of the diagnosis by at least one of the following: 
- 
Neurology or neurosurgical specialist 
- 
Brain imaging (CT, MRI, or cerebral vessel angiography) 
- 
Lumbar puncture diagnostic of intracranial hemorrhage 
Urgent revascularization is defined as an unplanned hospitalization for an acute coronary 
syndrome with at least one of the following: electrocardiographic changes, biomarker elevation, 
or new perfusion/wall motion abnormalities to document ischemia and which results in 
revascularization during the hospitalization. 
Repeat revascularization is defined as any unplanned (elective or urgent) revascularization, 
whether PCI or CABG.  Planned staged PCI procedures do not qualify. 
Bleeding is defined as per the Bleeding Academic Research Consortium (BARC).22  Other 
descriptions of bleeding, such as TIMI, will be applied as well. 
 
BARC Bleeding Definitions: 
Type 0: no bleeding 
Type 1: bleeding that is not actionable and does not cause the patient to seek unscheduled 
performance of studies, hospitalization, or treatment by a healthcare professional; may include 
episodes leading to self-discontinuation of medical therapy by the patient without consulting a 
healthcare professional 
Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be expected for 
a clinical circumstance, including bleeding found by imaging alone) that does not fit the criteria 
for type 3, 4, or 5 but does meet at least one of the following criteria: (1) requiring nonsurgical, 
medical intervention by a healthcare professional, (2) leading to hospitalization or increased 
level of care, or (3) prompting evaluation 
Type 3 
 
Type 3a  
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL* (provided hemoglobin drop is related to 
bleed)  
Any transfusion with overt bleeding 
 
Type 3b 
Overt bleeding plus hemoglobin drop ≥5 g/dL* (provided hemoglobin drop is related to bleed) 

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Cardiac tamponade 
Bleeding requiring surgical intervention for control (excluding dental/nasal/skin/hemorrhoid) 
Bleeding requiring intravenous vasoactive agents 
 
Type 3c 
Intracranial hemorrhage (does not include microbleeds or hemorrhagic transformation, does 
include intraspinal) 
Subcategories confirmed by autopsy or imaging or lumbar puncture 
Intraocular bleed compromising vision 
Type 4: CABG-related bleeding 
Perioperative intracranial bleeding within 48 h 
Reoperation after closure of sternotomy for the purpose of controlling bleeding 
Transfusion of ≥5 U whole blood or packed red blood cells within a 48-h period† 
Chest tube output ≥2 L within a 24-h period 
Type 5: fatal bleeding 
 
Type 5a 
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious 
 
Type 5b 
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
Stent thrombosis is defined as per the Academic Research Consortium.23  
ARC Definitions: 
Definite stent thrombosis 
1. Angiographic confirmation of stent thrombosis 
2. The presence of a thrombus that originates in the stent or in the segment 5 mm proximal 
or distal to the stent and presence of at least 1 of the following criteria within a 48-hour 
time window: 
• Acute onset of ischemic symptoms at rest 
• New ischemic ECG changes that suggest acute ischemia 
• Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI) 
• Nonocclusive thrombus 
• Intracoronary thrombus is defined as a (spheric, ovoid, or irregular) noncalcified filling 
defect or lucency surrounded by contrast material (on 3 sides or within a coronary 

27Feb2018 
 
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39 
 
stenosis) seen in multiple projections, or persistence of contrast material within the 
lumen, or a visible embolization of intraluminal material downstream. 
• Occlusive thrombus 
• TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most adjacent proximal side 
branch or main branch (if originates from the side branch). 
• Pathological confirmation of stent thrombosis 
• Evidence of recent thrombus within the stent determined at autopsy or via examination of 
tissue retrieved following thrombectomy. 
 
Probable stent thrombosis 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases:  
• Any unexplained death within the first 30 days  
• Irrespective of the time after the index procedure, any MI that is related to documented 
acute ischemia in the territory of the implanted stent without angiographic confirmation 
of stent thrombosis and in the absence of any other obvious cause 
 
Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of trial follow-up. 
Graft Occlusion is defined based on an ARC-like definition24 
 
Definite graft occlusion 
1. Clinical presentation of acute coronary syndrome with graft occlusion confirmed by 
angiography, multi-slice CT or autopsy 
2. Q-wave MI in the territory of one or more of the treated vessels within the first 30 days 
 
Probably graft occlusion 
1. Any unexplained death within 30 days of CABG 
2. Any MI that is related to documented acute ischemia in the territory of the anastomosed 
graft without angiographic confirmation of graft occlusion 
 
Possible graft occlusion 
1. Any unexplained death beyond 30 days 
Significant Arrhythmia consists of ventricular tachycardia or fibrillation requiring 
cardioversion, atrial fibrillation lasting > 24 hours, or need for a permanent pacemaker. 

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Acute Kidney Injury AKI (acute kidney injury) is defined as any of the following: 
K Increase in SCr (Serum creatinine) by ≥0.3 mg/dl (≥26.5 µmol/l) within 48 hours;  
or K Increase in SCr to≥1.5 times baseline, which is known or presumed to have occurred 
within the prior 7 days;  
or K Urine volume ˂0.5 ml/kg/h for 6 hours. 
 
Rehospitalization is defined as a hospital stay of >36 hours. 
 
Cross-over 
If, during the first month after randomization, a patient receives as the initial revascularization therapy the 
alternative form of revascularization than the assigned treatment (i.e. Randomized to CABG but receives 
PCI), this will be defined as a cross-over and not a repeat revascularization event, unless the reason for 
the alternative revascularization strategy is due to a change in the patient’s clinical status resulting in 
urgent/emergent revascularization. 
 
 
 
 
 

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