OPtical Coherence Tomography (OCT) Guided Coronary Stent IMplantation Compared to Angiography: a Multicenter Randomized TriaL in PCI
Phase: NA
Conditions: Coronary Artery Disease, Coronary Stenosis, Atherosclerosis, STEMI, STEMI - ST Elevation Myocardial Infarction, NSTEMI - Non-ST Segment Elevation Myocardial Infarction (MI)
Sponsor: Abbott Medical Devices

 
Clinical Investigation Plan Cover Page 
 
 
 
This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used without the 
express written consent of Abbott. 
87173 CIP Posting Cover Page Ver C 
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Page 1 of 1 
 
NCT Number: 03507777 
ILUMIEN IV:  OPTIMAL PCI 
OPtical Coherence Tomography (OCT) Guided Coronary Stent IMplantation Compared to 
Angiography: a Multicenter Randomized TriaL in PCI 
 
 
Date: 6-OCT-2022 
 
 
Sponsor  
 
 
Abbott 
        
 
 
 
 
      
  
 
 
 
        
 
 
 
 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 1 of 114 
 
 
ILUMIEN IV: OPTIMAL PCI 
CLINICAL INVESTIGATION PLAN 
 
 
OPtical Coherence Tomography (OCT) Guided Coronary Stent 
IMplantation Compared to Angiography: a Multicenter Randomized TriaL 
in PCI 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 3 of 114 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements applicable in 
conducting this clinical investigation. 
 
 
Principal Investigator 
 
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Signature: 
Date: 
 
 
Principal Investigator 
 
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Signature: 
Date: 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 4 of 114 
 
 
 
Chairman 
 
SIGNATURE PAGE 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements applicable in 
conducting this clinical investigation.  
 
 
Chairman 
 
Printed name:  
 
Signature: 
Date: 
 
 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 5 of 114 
 
 
STUDY SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
I have read and agree to adhere to the clinical investigation plan and all regulatory requirements applicable in 
conducting this clinical investigation. 
 
 
Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 6 of 114 
 
 
Table of Contents 
 
1 
Synopsis ..................................................................................................................................................... 10 
1.1 
Objective ............................................................................................................................................ 10 
1.2 
Hypothesis ......................................................................................................................................... 10 
1.3 
Devices Used .................................................................................................................................... 10 
1.4 
Indications for Use ............................................................................................................................. 11 
1.5 
Design ............................................................................................................................................... 12 
1.6 
Endpoints ........................................................................................................................................... 12 
1.6.1 
Primary Endpoints ......................................................................................................................... 12 
1.6.2 
Major Secondary Endpoint ............................................................................................................ 12 
1.6.3 
Non-Powered Secondary Endpoints ............................................................................................. 13 
1.7 
Study Population ............................................................................................................................... 18 
1.8 
Inclusion/Exclusion Criteria ............................................................................................................... 18 
1.8.1 
Inclusion Criteria (all must be present) .......................................................................................... 18 
1.8.2 
Exclusion Criteria (none may be present) ..................................................................................... 20 
1.9 
Enrollment ......................................................................................................................................... 23 
1.10 
Study Assessments ........................................................................................................................... 23 
1.11 
Study leadership ................................................................................................................................ 26 
1.12 
Study Flow Chart ............................................................................................................................... 27 
2 
Introduction................................................................................................................................................. 27 
3 
Background and Justification for Clinical Investigation .............................................................................. 28 
4 
Study Devices ............................................................................................................................................ 29 
4.1 
Identification and Description of Study Devices ................................................................................ 29 
4.1.1 
Identification .................................................................................................................................. 29 
4.1.2 
Device Description and Intended Purpose .................................................................................... 30 
4.1.3 
Device Handling and Storage ........................................................................................................ 31 
4.2 
Device Accountability ........................................................................................................................ 31 
5 
Clinical Investigation Design ...................................................................................................................... 31 
5.1 
Clinical Investigation Design ............................................................................................................. 31 
5.1.1 
Blinding .......................................................................................................................................... 32 
5.2 
Objectives .......................................................................................................................................... 32 
5.2.1 
Primary Objective .......................................................................................................................... 32 
5.3 
Endpoints ........................................................................................................................................... 32 
5.3.1 
Primary Endpoints ......................................................................................................................... 33 
5.3.2 
Major Secondary Endpoint ............................................................................................................ 33 

 
  
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5.3.3 
Non-Powered Secondary Endpoints ............................................................................................. 33 
5.4 
Study Population ............................................................................................................................... 38 
5.4.1 
Inclusion Criteria (all must be present) .......................................................................................... 39 
5.4.2 
Exclusion Criteria (none may be present) ..................................................................................... 41 
5.4.3 
Enrollment of Medicare Beneficiaries ............................................................................................ 44 
6 
Procedures ................................................................................................................................................. 44 
6.1 
Overview ............................................................................................................................................ 44 
6.2 
Informed Consent Process ................................................................................................................ 45 
6.3 
Screening .......................................................................................................................................... 47 
6.4 
Point of Enrollment ............................................................................................................................ 47 
6.5 
Scheduled Procedures ...................................................................................................................... 48 
6.5.1 
Baseline ......................................................................................................................................... 48 
6.5.2 
Randomization ............................................................................................................................... 49 
6.5.3 
PCI Procedure ............................................................................................................................... 50 
6.5.4 
Post procedure .............................................................................................................................. 70 
6.5.5 
Scheduled Follow-ups ................................................................................................................... 70 
6.6 
Patient Reported Outcome (PRO) Measures .................................................................................... 71 
6.7 
Unscheduled Visits ............................................................................................................................ 71 
6.8 
Schedule of Events............................................................................................................................ 72 
6.9 
Health Care Economic Data Collection ............................................................................................. 73 
6.10 
Description of Activities Performed by Sponsor Representatives ..................................................... 73 
6.11 
Subject Study Completion ................................................................................................................. 73 
6.12 
Subject Withdrawal ............................................................................................................................ 73 
6.13 
Study Committees ............................................................................................................................. 74 
6.13.1 
Steering Committee (SC) .......................................................................................................... 74 
6.13.2 
Publication Committee (PC) ...................................................................................................... 74 
6.13.3 
Data Safety Monitoring Board (DSMB) ..................................................................................... 74 
6.13.4 
Clinical Events Committee (CEC) ............................................................................................. 74 
7 
Statistical Considerations ........................................................................................................................... 75 
7.1 
Endpoints ........................................................................................................................................... 75 
7.1.1 
Primary Endpoint of MSA and Hypothesis .................................................................................... 75 
7.1.2 
Primary Endpoint of TVF and Hypothesis ..................................................................................... 75 
7.1.3 
Major Secondary Endpoint of TVF Excluding Periprocedural MI and Hypothesis ........................ 76 
7.2 
Justification of Clinical Investigation Design ..................................................................................... 77 
7.3 
Overall Sample Size .......................................................................................................................... 78 

 
  
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7.4 
Timing of Primary Endpoint Analysis ................................................................................................. 78 
7.5 
Success Criteria ................................................................................................................................ 78 
7.6 
Interim Analysis ................................................................................................................................. 78 
7.7 
Multiplicity Adjustment ....................................................................................................................... 78 
7.8 
Sensitivity Analyses ........................................................................................................................... 78 
7.9 
Statistical Criteria for Termination ..................................................................................................... 78 
7.10 
Deviations from Statistical Plan ......................................................................................................... 79 
8 
Risks and Benefits ..................................................................................................................................... 79 
8.1 
Risks Associated with the Study Devices ......................................................................................... 79 
8.1.1 
Residual Risks Associated with Study Devices ............................................................................ 80 
8.2 
Risk Control Measures ...................................................................................................................... 80 
8.3 
Possible interactions with concomitant treatments ........................................................................... 80 
8.4 
Anticipated Benefits ........................................................................................................................... 80 
8.5 
Risk-to-Benefit Rationale ................................................................................................................... 81 
8.6 
History of Device Modifications or Recall .......................................................................................... 81 
9 
Requirements for Investigator Records and Reports ................................................................................. 81 
9.1 
Deviations from CIP........................................................................................................................... 81 
10 
Adverse Events ..................................................................................................................................... 81 
10.1 
Definitions .......................................................................................................................................... 82 
10.1.1 
Adverse Event ........................................................................................................................... 82 
10.1.2 
Serious Adverse Event .............................................................................................................. 82 
10.1.3 
Adverse Device Effect (ADE) .................................................................................................... 82 
10.1.4 
Device Deficiency/Device Malfunction ...................................................................................... 83 
10.1.5 
Unanticipated (Serious) Adverse Device Effect ........................................................................ 83 
10.2 
Safety Reporting ................................................................................................................................ 83 
10.2.1 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC .......................... 84 
10.2.2 
Device Deficiency/Device Malfunction Reporting ...................................................................... 84 
10.2.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor ........................... 85 
10.3 
Safety Monitoring by Data Safety Monitoring Board (DSMB) ........................................................... 85 
10.4 
Source records .................................................................................................................................. 85 
10.5 
Records Retention ............................................................................................................................. 85 
11 
Clinical Data Handling ........................................................................................................................... 85 
11.1 
Protection of Personally Identifiable Information ............................................................................... 85 
11.2 
Data Management Plan ..................................................................................................................... 86 
11.3 
Document and Data Control .............................................................................................................. 86 

 
  
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11.3.1 
Traceability of Documents and Data ......................................................................................... 86 
11.3.2 
Recording Data .......................................................................................................................... 86 
12 
Monitoring .............................................................................................................................................. 86 
13 
Compliance Statement .......................................................................................................................... 87 
13.1 
Statement of Compliance .................................................................................................................. 87 
13.2 
Quality Assurance Audits and Regulatory Inspections ..................................................................... 87 
13.3 
Repeated and Serious Non-Compliance ........................................................................................... 88 
14 
Suspension or Premature Termination of the Clinical Investigation ..................................................... 88 
15 
Ethical Consideration ............................................................................................................................ 89 
15.1 
Institutional Review Board/Medical Ethics Committee Review and Approval ................................... 89 
16 
Clinical Investigation Conclusion ........................................................................................................... 89 
17 
Publication Policy .................................................................................................................................. 89 
18 
Reporting Results on ClinicalTrials.gov Website .................................................................................. 90 
Appendix A: CIP Revisions ............................................................................................................................... 91 
Appendix B: Definitions ..................................................................................................................................... 99 
Appendix C: Labels ......................................................................................................................................... 107 
Appendix D: Case Report Form ...................................................................................................................... 108 
Appendix E: Informed Consent Form .............................................................................................................. 109 
Appendix F: Pre-specified Powered Analysis of XIENCE in the In-Stent Restenosis (ISR) Population ......... 110 
Appendix G: References ................................................................................................................................. 113 
 
 
 

 
  
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• 
 
 
 
 
 
 
 
1.4 
Indications for Use 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
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1.5 
Design 
This is a prospective, single-blind clinical investigation randomizing subjects to OCT-guided coronary stent 
implantation vs. angiography-guided coronary stent implantation in a 1:1 ratio. The clinical investigation will 
be conducted at approximately 125 centers in North America (US and Canada), Europe, Middle East and 
Asia-Pacific.  Up to 3656 randomized subjects and approximately 375 roll-in subjects will be enrolled in the 
clinical investigation. No site may enroll more than 15% of the total randomized subjects. Subjects 
participating in this clinical investigation will be followed for 2 years. 
 
  
 
The clinical investigation has been designed to involve as little pain, discomfort, fear, and any other 
foreseeable risk as possible for subjects. Refer to the Risks and Benefits section of this clinical investigation 
plan for details. 
 
1.6 
Endpoints 
There are two powered primary endpoints, one powered major secondary endpoint and multiple descriptive 
non-powered secondary endpoints in this clinical investigation.  Definitions of endpoints can be found in 
Appendix B.   
1.6.1 
Primary Endpoints 
1. Imaging Outcome (powered): Minimal stent area (MSA), continuous measure 
Final Post-PCI MSA (per target lesion basis) assessed by OCT in each randomized arm, 
measured at an independent OCT core laboratory blinded to imaging modality assignment. 
2. Clinical outcome (powered): Target vessel failure (TVF)  
Time-to-first event rate of the composite outcome of cardiac death, target vessel myocardial 
infarction (TV-MI) (per primary protocol definition [see Appendix B]), or ischemia-driven target 
vessel revascularization (ID-TVR), assessed at 2 years.  
1.6.2 
Major Secondary Endpoint 
1) Target vessel failure (TVF) excluding periprocedural MI.  
Time-to-first event rate of the composite outcome of cardiac death, target vessel-related 
spontaneous myocardial infarction, or ischemia-driven target vessel revascularization (ID-
TVR), assessed at 2 years.  

 
  
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1.6.3 
Non-Powered Secondary Endpoints 
Procedural outcomes, additional procedural and clinical endpoints, patient reported 
outcomes (PRO) and cost-effectiveness measures listed below 
Procedural outcomes 
OCT-defined (OCT core laboratory assessed). Subjects in the angiography-guided arm will 
undergo a post-PCI OCT run, blinded to the operator. Assessed per target lesion. 
1) Stent expansion. Stent expansion is defined by the MSA achieved in the proximal and distal 
stented segments relative to their respective reference lumen areas. The stent length is 
divided into 2 equal segments (proximal and distal) except for lesions containing a 
bifurcation (visually estimated side branch ≥2.5 mm). When there is a bifurcation present, 
rather than splitting the stent into two halves, the division occurs at the proximal most side 
branch.  
• 
Acceptable stent expansion (categorical variable): The MSA of the proximal segment is 
≥90% of the proximal reference lumen area and the MSA of the distal segment is ≥90% 
of the distal reference lumen area. 
 
• 
Unacceptable stent expansion (categorical variable): The MSA of the proximal segment 
is <90% of the proximal reference lumen area, and/or the MSA of the distal segment is 
<90% of the distal reference lumen area. 
In case either segment (proximal or distal) of the stent meets criteria for unacceptable stent 
expansion, the stent is considered to have unacceptable stent expansion. Both segments of 
the stent must meet acceptable stent expansion criteria to be considered acceptable.  
In case a respective reference segment cannot be measured the determination will be made 
with only one of the two reference (proximal or distal) segments. 
Note: If acceptable stent expansion (by operator assessment) is not achieved in either the 
distal or proximal segments of the stent in the OCT-guided arm according to the Post-PCI 
OCT, further post-stent expansion with higher pressures and/or larger balloons must be 
performed per protocol if the POST-PCI OCT EEL measurements now suggest a larger 
balloon be used.  See Section 6.5.3.7 for more details.  
• 
Post-PCI stent expansion (%) (continuous variable): The MSA divided by the average of 
proximal and distal reference lumen areas x 100. 
2) Mean stent expansion (%) (continuous variable): The mean stent area (stent 
volume/analysed stent length) divided by the average of proximal and distal reference 
lumen areas x 100. 
3) Intra-stent plaque protrusion and thrombus 
Defined as a mass attached to the luminal surface or floating within the lumen, meeting the following 
criteria: Protrusion/thrombus is defined as any intraluminal mass protruding at least 0.2 mm within 
the luminal edge of a stent strut, and will be further classified as Major and Minor: 

 
  
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• 
Major: Protrusion area/Stent area at site of tissue protrusion ≥10% and the minimal 
intrastent flow area (MSA – protrusion area) is unacceptable (<90% of respective 
proximal or distal reference area 
• 
Minor: Protrusion area/Stent area at site of tissue protrusion is <10%, or is ≥10% but the 
minimal intraluminal flow area (MSA – protrusion area) is acceptable (≥90% of respective 
proximal or distal reference area 
Note: It is recommended that if protrusion is detected by operator assessment in the OCT-
guided arm during the procedure and meets the criteria for major protrusion, then thrombus 
aspiration, further high-pressure balloon inflation and/or an additional stent be considered. 
4) Untreated reference segment disease 
Defined as focal disease with untreated MLA <4.5 mm2 within 5 mm from the proximal and/or distal 
stent edges.  
Sub-classified by the amount of untreated lipid plaque, divided into 3 grades: 
i. 
Low (≤90° of lipid arc) 
ii. 
Medium (>90°-<180° of lipid arc)  
iii. 
High (≥180° of lipid arc) 
Note: If untreated reference segment disease with an MLA <4.5 mm2 is detected by operator 
assessment in either the proximal reference (inflow disease) or distal reference (outflow 
disease) segment lumen in the OCT-guided arm, an additional stent must be placed to treat 
it, unless there are anatomic reasons that the disease should not be covered (e.g. diffuse 
distal disease or significant vessel tapering, etc.) (Figures 1a-b).  
5) Edge dissections 
Edge dissections will be tabulated as: 
i. 
Major (%): ≥60 degrees of the circumference of the vessel at site of dissection and ≥3 
mm in length 
ii. 
Minor (%): any visible edge dissection <60 degrees of the circumference of the vessel or 
<3 mm in length 
Edge dissections will be further classified as: 
i. 
Intimal (limited to the intima layer, i.e. not extending beyond the internal elastic lamina)  
ii. 
Medial (extending into the media layer) 
iii. 
Adventitial (extending through the external elastic membrane/lamina) 
Note: If a major edge dissection is detected by operator assessment in the OCT-guided arm, 
it is recommended that an additional stent be placed to cover the dissected segment, 
particularly if the site of dissection is at the distal stent edge. 
6) Stent Malapposition 

 
  
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Defined as frequency (%) of incompletely apposed stent struts (defined as stent struts clearly 
separated from the vessel wall (lumen border/plaque surface) without any tissue behind the struts 
with a distance from the adjacent intima of ≥0.2 mm and not associated with any side branch). 
Malapposition will be further classified as: 
• 
Major: if associated with unacceptable stent expansion (as defined above) 
• 
Minor: if associated with acceptable stent expansion (as defined above)  
Note: If malapposition is detected by operator assessment during the procedure in the OCT-
guided arm and meets the criteria for major malapposition (i.e. malapposition associated with 
unacceptable stent expansion), further stent expansion must be performed. The degree of 
stent underexpansion (acceptable or unacceptable) should guide the intervention rather than 
amount of malapposition.  
Stent Malapposition will be tabulated as: 
i. 
Major (%) 
ii. 
Minor (%)  
iii. 
All (Major and Minor) (%) 
7) Border detection (angiography arm post-PCI only, blinded to investigator) 
The visibility of the vessel external elastic lamina (EEL) border by OCT will be evaluated at both 
reference sites (proximal and distal) and the MSA, after intervention and then classified into 3 
grades: 
i. 
Good: ≥75% (270°) of visible circumference 
ii. 
Moderate: ≥50% (180°) - <75% (270°) of visible circumference 
iii. 
Poor:  <50% (180°) of visible circumference 
8) Intra-stent lumen area (intra-stent flow area)  
Defined as stent area minus any protrusion as defined above in secondary endpoint 3). 
9) Effective lumen area (total flow area) 
Defined as intra-stent lumen area plus any area of malapposition between the stent and the vessel 
wall (lumen border/plaque border). 
Additional Procedural and Clinical Endpoints 
10) Angiographic Endpoints (QCA). (Angiographic core laboratory assessed). Assessed per 
target lesion. 
i. 
Final (post-PCI) minimal lumen diameter 
ii. 
Final (post-PCI) percent diameter stenosis 
iii. 
Acute lumen gain post-intervention 
iv. 
Maximum device size (stent or post-dilatation balloon)/reference vessel diameter ratio 
v. 
Post-PCI target vessel TIMI flow rate 

 
  
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vi. 
Angiographic complications – worst (anytime during the procedure) and final (post PCI 
and all imaging) – Angiographic dissection ≥ NHLBI type B, perforations (Ellis 
classification), intra-procedural thrombotic events (including slow-flow, no-reflow, side 
branch closure, distal embolization, and intra-procedural stent thrombosis, as per the 
standard angiographic core laboratory definitions  
11) Device Usage Endpoints (site reported; assessed per subject): 
i. 
Total stent length 
ii. 
Total number of stents 
iii. 
Maximal stent size 
iv. 
Post dilatation (yes/no) 
v. 
Total number of post-dilatation balloons 
vi. 
Maximal post-dilatation balloon size 
vii. 
Maximal device size (stent or post-dilatation balloon) 
viii. 
Maximum inflation pressure (atm.; stent or post-dilatation balloon) 
12) Procedure time (first wire insertion to guide catheter removal), fluoroscopy time, radiation 
exposure 
13) Contrast use; contrast induced nephropathy (defined as serum creatinine rise >25% or 
absolute increase >0.5 mg/dL (44.2µmol/L)); need for renal replacement therapy 
14) Procedural success (must be present in all treated lesions and vessels): 
Defined as A) angiographic core laboratory-assessed final (post-PCI) lesion angiographic 
diameter stenosis <30% and target vessel TIMI III flow without any of the angiographic 
complications listed in 10(vi) above; plus B) the absence of site-assessed prolonged ST-
segment elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or 
cardioversion or hypotension/heart failure requiring mechanical or intravenous hemodynamic 
support or intubation, or procedural death. 
15) Procedural complications 
Defined as A) angiographic core laboratory-assessed complications listed in 10(vi) above 
occurring anytime during the procedure; or B) site-assessed prolonged ST-segment 
elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or 
cardioversion or hypotension/heart failure requiring mechanical or intravenous hemodynamic 
support or intubation, or procedural death. 
16) OCT performance success (site reported) (OCT arm only): 
OCT imaging performed both pre- and post-PCI  
17) OCT imaging-related procedural complications (CEC adjudicated) 
Any procedural complications (e.g. angiographic dissection, perforation, thrombus, acute closure, 
etc.) requiring any active intervention (e.g. prolonged balloon inflations, additional stent implantation, 
pericardiocentesis, intubation, hemodynamic support or pressors, defibrillation or cardioversion) or 
death adjudicated by the CEC as definitely or likely attributable to the physical performance of OCT-
imaging (e.g. passing the catheter through the vasculature or stent, or injecting contrast to clear the 

 
  
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blood for imaging). For this definition, adverse events that arise due to changes in PCI strategy as 
the result of OCT findings are NOT considered OCT imaging-related procedural complications. 
18) Additional interventions on the basis of the pre-PCI or post-stent OCT-imaging run that 
would not have been performed based on angiographic guidance alone (site reported; 
assessed per subject; OCT Arm Only): 
i. 
Use of larger balloon 
ii. 
Use of higher inflation pressures 
iii. 
Use of additional balloons 
iv. 
Use of additional stent(s) 
v. 
Performance of atherectomy 
vi. 
Other interventions 
Reason(s) for additional interventions will be documented by the site (e.g. more calcium than 
anticipated, greater stent under-expansion than appreciated angiographically, greater malapposition 
than appreciated angiographically, greater tissue protrusion or thrombus burden than appreciated 
angiographically, more severe edge dissection than appreciated angiographically, residual reference 
segment disease not appreciated angiographically, other) 
Clinical outcomes at 30 days, 1 year and 2 years (unless otherwise noted) 
19) Target lesion failure (TLF; cardiac death, TV-MI or ischemia-driven target lesion 
revascularization (ID-TLR) 
20) All-cause mortality  
21) Cardiac and non-cardiac mortality 
22) All MI  
23) TV-MI, non-TV-MI and indeterminate vessel MI 
24) Periprocedural MI and non-periprocedural MI 
25) All revascularization 
26) ID-revascularization and non-ID-revascularization 
27) ID-TVR, ID-TLR, ID-non-TLR TVR, and ID-non-TVR 
28) Definite, probable and definite/probable stent thrombosis (ARC-2 definition) 
29) Relationship between immediate post-procedure OCT parameters (e.g. MSA, procedural 
success, malapposition, dissection, protrusion, etc.) and 2-year endpoint rates (e.g. TVF, 
TLF, all-cause mortality, cardiac death, TV-MI, all MI, ID-TLR, ID-TVR, and stent 
thrombosis)  
30) TVF excluding periprocedural MI (i.e. the composite of cardiac death, target vessel-related 
spontaneous MI, or ID-TVR) (at 30 days and 1 year) 

 
  
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In addition, the following outcomes using the SCAI definition of peri-procedural MI3 will be reported as 
sensitivity analyses at 30 days, 1 year and 2 years: 
31) TV-MISCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol definition) 
32) Periprocedural MISCAI (by SCAI definition)  
33) All MISCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol definition) 
34) TVFSCAI; the composite of cardiac death, TV-MISCAI or ID-TVR 
Patient Reported Outcomes (PRO) 
 
Patient Reported Outcome questionnaires will be incorporated into this study to provide a 
complementary evaluation of the effectiveness of OCT-guided stent implantation. The following 
instruments will be administered during this study in hospital (required at baseline, optional post-
procedure), and at 30 day, 12 month and 24 month follow-up:  
• 
EuroQoL 5D (EQ-5D-5L) survey to assess overall health status  
 
Cost-effectiveness 
 
Cost per quality adjusted life year (QALY) and TVF event prevented by OCT-guidance to be 
determined using standardized methods4.  
 
1.7 
Study Population 
The intended population for this clinical investigation is patients over the age of 18 years that are either high 
clinical-risk or have high angiographic-risk lesion characteristics undergoing stent implantation for coronary 
artery disease. 
1.8 
Inclusion/Exclusion Criteria 
1.8.1 
Inclusion Criteria (all must be present) 
1. Subject must be at least 18 years of age. 
2. Subject must have evidence of myocardial ischemia (e.g., stable angina, silent ischemia (ischemia 
in the absence of chest pain or other anginal equivalents), unstable angina, or acute myocardial 
infarction) suitable for elective PCI.   
3. Patients undergoing planned XIENCE stent implantation during a clinically indicated PCI 
procedure meeting one or more of the following criteria: 
 
 
3 Moussa ID et al. Consideration of a New Definition of Clinically Relevant Myocardial Infarction After Coronary Revascularization:  An 
Expert Consensus Document From the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013 
October 22; 62(17): 1563–1570. 
4 Eisenberg J. Clinical economics: A guide to the economic analysis of clinical practices. JAMA 1989; 262:2879-86. 

 
  
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A) High clinical-risk, defined as; 
i. 
Medication-treated diabetes mellitus, AND/OR 
B) High angiographic-risk lesion(s), with at least one target lesion in each target vessel planned 
for randomization meeting at least one of the following criteria; 
i. 
Target lesion is the culprit lesion responsible for either: 
• 
NSTEMI, defined as a clinical syndrome consistent with an acute coronary 
syndrome and a minimum troponin of 1 ng/dL (may or may not have 
returned to normal), OR 
• 
STEMI >24 hours from the onset of ischemic symptoms 
ii. 
long or multiple lesions (defined as intended total stent length in any single 
target vessel ≥28 mm),  
Note:  For a long target lesion, this would permit treatment by a single long 
stent or overlapping stents.  
Note:  For up to two target lesions located in a single target vessel and 
treated with non-overlapping stents, they may be located in a continuous 
vessel or split up between a main vessel and a side branch.  
iii. 
bifurcation intended to be treated with 2 planned stents (i.e. in both the main 
branch and side branch), and where the planned side branch stent is ≥ 2.5 mm 
in diameter by angiographic visual estimation.  
iv. 
angiographic severe calcification (defined as angiographically visible 
calcification on both sides of the vessel wall in the absence of cardiac motion), 
v. 
chronic total occlusion (CTO) (enrolment and randomization in this case 
performed only after successful antegrade wire escalation crossing and pre-
dilatation) 
vi. 
in-stent restenosis of diffuse or multi-focal pattern.  Lesion must be at or within 
the existing stent margin(s) and have angiographically visually-assessed DS 
≥70% or DS ≥50% with non-invasive or invasive evidence of ischemia 
4. All target lesions (those lesions to be randomized) must have a visually estimated or quantitatively 
assessed %DS of either ≥70%, or 50% plus one or more of the following: an abnormal functional 
test (e.g. fractional flow reserve, stress test) signifying ischemia in the distribution of the target 
lesion(s) or biomarker positive ACS with plaque disruption or thrombus.  
Note:  For purposes of study eligibility, a minimum troponin of 1 ng/dL at the time of 
screening will be considered biomarker positive. 
5. All target lesions must be planned for treatment with only ≥2.5 mm and ≤3.5 mm stents and post-
dilatation balloons based on pre-PCI angiographic visual estimation.    
6. No more than 2 target lesions requiring PCI are present in any single vessel., and no more than 2 
target vessels are allowed. Thus, up to 4 randomized target lesions per patient in a maximum of 2 
target vessels are allowed, including branches. The intended target lesions will be declared just prior 
to randomization.  

 
  
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Note: A lesion is defined as any segment(s) of the coronary tree, no matter how long, which 
is planned to be covered with one contiguous length of stent, whether single or overlapped.  
A bifurcation counts as a single lesion even if the side branch is planned to be treated. 
Note:  All lesions in a randomized target vessel that are intended to be treated by PCI are 
designated as target lesions, and at least one target lesion in each randomized target vessel 
must meet angiographic high-risk inclusion criteria summarized above in 3B). The only 
exception is for patients who qualify for the trial on the basis of medication-treated diabetes, 
in which case no target lesion is required to meet angiographic high-risk inclusion criteria. 
7. All target lesions intended to be treated by PCI in the target vessel are amenable to OCT-guided 
PCI (i.e. no lesion-specific angiographic exclusion criteria are present – see Section 5.4.2 below).  
Example: If a qualifying angiographic high-risk lesion is in the proximal LAD, and there is a 
second target lesion in the distal LAD which is a focal lesion not otherwise meeting high-risk 
criteria, both the proximal LAD and distal LAD lesions must be amenable to OCT (e.g. no 
excessive tortuosity or calcification precluding delivering the OCT catheter), and each lesion 
must undergo OCT-guided stenting. Otherwise the vessel should be excluded from 
randomization. 
8. Subject must provide written Informed Consent prior to any study related procedure. 
1.8.2 
Exclusion Criteria (none may be present) 
Clinical exclusion criteria:  
1. STEMI ≤24 hours from the onset of ischemic symptoms 
2. Creatinine clearance ≤30 ml/min/1.73 m2 (as calculated by MDRD formula for estimated GFR)5 
and not on dialysis. Note: chronic dialysis dependent patients are eligible for enrolment regardless 
of creatinine clearance. 
3. Hypotension, shock or need for mechanical support or intravenous vasopressors at the time the 
patient would be undergoing the index procedure. 
4. CHF (Killip class ≥2 or NYHA class ≥3) 
5. LVEF ≤30% by the most recent imaging test within 3 months prior to procedure.  If no LVEF test 
result within 3 months is available, it must be assessed by echocardiography, multiple gated 
acquisition (MUGA), magnetic resonance imaging (MRI), ventriculography (LV gram) or other 
method.   
6. Unstable ventricular arrhythmias 
7. Inability to take DAPT (both aspirin and a P2Y12 inhibitor) for at least 12 months in the patient 
presenting with an ACS, or at least 6 months in the patient presenting with stable CAD, unless the 
 
 
5 Estimated GFR (ml/min/ 1.73 m2) = 175 x [SerumCreatinine (umol/L) x 0.0113]-1.154 x Age (years)-0.203  (x 0.742 if female) 

 
  
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patient is also taking chronic oral anticoagulation in which case a shorter duration of DAPT may be 
prescribed per local standard of care. 
8. Planned major cardiac or non-cardiac surgery within 24 months after the index procedure 
Note: Major surgery is any invasive operative procedure in which an extensive resection is 
performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered.  
Note: Minor surgery is an operation on the superficial structures of the body or a 
manipulative procedure that does not involve a serious risk.  Planned minor surgery is not 
excluded. 
9. Prior PCI within the target vessel within 12 months  
Note:  Prior PCI within the target vessel within 12 months is allowed for in-stent restenosis 
(target lesion is the prior PCI site) if no more than one layer of previously implanted stent is 
present.   
Note:  In-stent restenosis involving two or more layers of stent implanted at any time prior to 
index procedure (i.e. an earlier episode of in-stent restenosis previously treated with a 
second stent) is excluded. 
10. Any planned PCI within the target vessel(s) within 24 months after the study procedure, other 
than a planned staged intervention in a second randomized target vessel.   
Note: Planned staged interventions must be noted at the time of randomization, and the 
decision to stage may be modified within 24 hours of completion of the index PCI. See Section 
6.5.3.8 for more details of multi lesion and vessel treatment. 
Note: PCI in non-target vessels is permitted >48 hours after the index procedure. 
11. Any prior PCI in a non-target vessel within 24 hours before the study procedure, or within 
previous 30 days if unsuccessful or complicated.   
Note: Patients requiring non-target vessel PCI may be enrolled and the non-target vessel(s) 
may be treated in the same index procedure as the randomized lesions (in all cases prior to 
randomization), as long as treatment of the lesion(s) in the non-target vessel is successful and 
uncomplicated. 
Successful and uncomplicated definition for non-target vessel treatment during the index 
procedure: Angiographic diameter stenosis <10% for all treated non-target lesions, with TIMI III 
flow in this vessel, without final dissection ≥ NHLBI type B, perforation anytime during the 
procedure, prolonged chest pain (>5 minutes) or prolonged ST-segment elevation or depression 
(>5 minutes), or cardiac arrest or need for defibrillation or cardioversion or hypotension/heart 
failure requiring mechanical or intravenous hemodynamic support or intubation). 
12. Subject has known hypersensitivity or contraindication to any of the study drugs (including all 
P2Y12 inhibitors, one or more components of the study devices, including everolimus, cobalt, 
chromium, nickel, platinum, tungsten, acrylic and fluoropolymers, or radiocontrast dye that cannot be 
adequately pre-medicated.  

 
  
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13. Subject has received a solid organ transplant which is functioning or is active on a waiting list for 
any solid organ transplants with expected transplantation within 24 months. 
14. Subject is receiving immunosuppressant therapy or has known immunosuppressive or severe 
autoimmune disease that requires chronic immunosuppressive therapy (e.g., human 
immunodeficiency virus, systemic lupus erythematosus, etc.). Note: corticosteroids are not included 
as immunosuppressant therapy. 
15. Subject has previously received or is scheduled to receive radiotherapy to a coronary artery 
(vascular brachytherapy), or the chest/mediastinum. 
16. Subject has a platelet count <100,000 cells/mm3 or >700,000 cells/mm3.  
17. Subject has a documented or suspected hepatic disorder as defined as cirrhosis or Child-Pugh ≥ 
Class B. 
18. Subject has a history of bleeding diathesis or coagulopathy, or has had a significant gastro-
intestinal or significant urinary bleed within the past six months. 
19. Subject has had a cerebrovascular accident or transient ischemic neurological attack (TIA) within 
the past six months, or any prior intracranial bleed, or any permanent neurologic defect, or any 
known intracranial pathology (e.g., aneurysm, arteriovenous malformation, etc.). 
20. Subject has extensive peripheral vascular disease that precludes safe 6 French sheath insertion. 
Note: femoral arterial disease does not exclude the patient if radial access may be used. 
21. Subject has life expectancy <2 years for any non-cardiac cause. 
22. Subject is currently participating in another investigational drug or device clinical study that has 
not yet completed its primary endpoint6.  
23. Pregnant or nursing subjects and those who plan pregnancy in the period up to 2 years following 
index procedure. Female subjects of child-bearing potential must have a negative pregnancy test 
done within 7 days prior to the index procedure per site standard test.  
 
24. Presence of other anatomic or comorbid conditions, or other medical, social, or psychological 
conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical 
investigation or to comply with follow-up requirements, or impact the scientific soundness of the 
clinical investigation results. 
Angiographic exclusion criteria  
1. Syntax score ≥33 as evaluated in Section 6.5.1, unless a formal meeting of the Heart Team, 
including a cardiac surgeon, concludes that PCI is appropriate. 
 
 
6 This includes clinical trials of medications and invasive procedures. Questionnaire-based studies, or other 
studies (regardless of study design) that are non-invasive and do not require medication are allowed.  A 
subject who is taking part in the long-term follow-up phase of a trial, who has completed all medications and 
invasive procedures per protocol requirements, may continue to participate in that trial. 

 
  
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2. Planned use of any stent <2.5 mm in a target vessel based on visual estimation (note: a smaller 
stent may be used in a bail-out scenario – e.g. to treat a distal dissection – but its use cannot be 
planned prior to enrolment) 
3. Planned use of a stent or post-dilatation balloon ≥3.75 mm for the target lesion (see inclusion 
criteria #5 for the one exception to this exclusion criterion) 
4. Severe vessel tortuosity or calcification in a target vessel such that it is unlikely that the OCT 
catheter can be delivered (note: severe vessel calcification is allowed if it is expected that the OCT 
catheter can be delivered at baseline or after vessel preparation with balloon pre-dilatation or 
atherectomy) 
5. The target vessel has a lesion with DS  50% that is not planned for treatment at the time of index 
procedure.  
6. The target lesion is in the left main coronary artery  
7. The target lesion is in a bypass graft conduit. Note: A native coronary artery may be randomized if 
a prior bypass graft conduit to the vessel is totally occluded, but not if it is patent. 
8. The target lesion is an ostial RCA stenosis  
9. The target lesion is a stent thrombosis 
10. Planned use of any stent other than Xience in a target lesion 
1.9 
Enrollment 
Subjects are considered enrolled in ILUMIEN IV after signing the Informed Consent. Subjects are considered 
randomized in the trial after the randomization system has been contacted and a study arm (OCT or 
angiography guidance) has been assigned. Enrolled subjects not randomized in the trial will be considered 
screen failures and will not be followed.  
1.10 Study Assessments 
Baseline/Pre-Randomization Visit: 
All baseline tests will be done within 30 days prior to the index procedure, unless otherwise specified by the 
protocol. 
• 
Demographics: include subject’s age, sex, ethnicity and race 
• 
Cardiovascular history (most recent values closest to baseline visit) 
• 
Medical history: indicate subject’s risk factors, relevant co-morbidities, previous cardiac procedures 
• 
Medication (only chronic medication): indicate the drug category the subject is currently taking on a 
long-term basis, i.e. no short-term medication 
• 
Physical examination: include subject’s height, weight (measurements taken during visit) 
• 
Pregnancy test (negative pregnancy test is required for any female of childbearing potential) 
• 
Serum hemoglobin and creatinine measured within 1 week prior to PCI  
• 
Troponin and/or CK-MB within 48 hours prior to PCI. If abnormal must be repeated either 8-16 hours 
after the last measurement or drawn from the sheath at the time of the procedure so a curve may be 
established for peri-procedural MI adjudication.  Use of high sensitivity troponin is not recommended. 

 
  
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Note: patients with stable CAD may have the biomarker drawn from the sheath prior to any 
intervention, and the result does not need to be available prior to treatment. 
• 
12-lead ECG  
• 
CHF assessment (by Killip class or NYHA class) 
• 
LVEF assessment (if no LVEF test result conducted within 3 months is available).  Assessment can 
be by echocardiography, multiple gated acquisition (MUGA), magnetic resonance imaging (MRI), 
ventriculography (LV gram) or other method. 
• 
Syntax score for patients with moderately complex 2-vessel disease or any 3-vessel disease.  Use 
the online calculator to determine Syntax score I (http://www.syntaxscore.com). For patients with 
single vessel disease or simple 2-vessel disease, no calculation is required – record “< 33” for Syntax 
score.  
• 
Patient Reported Outcome questionnaire (EQ-5D-5L) 
• 
Patients must receive at least 150 mg of oral non-enteric coated aspirin within 12 hours prior to PCI, 
regardless of prior aspirin use.  Intravenous aspirin administration is allowed in geographies where it 
is standard of care. 
• 
Patients shall receive an appropriate loading dose of an ADP antagonist (clopidogrel, prasugrel or 
ticagrelor) as per standard of care, preferably within 12 hours prior to, but in all cases no later than 2 
hours after PCI.  Loading dose of ADP antagonist is not required for subjects receiving chronic 
treatment of ADP antagonist.  
The following considerations apply to subjects having staged procedures, which are described in Section 
6.5.3.8: 
• 
The protocol required pre-procedure serum creatinine, cardiac enzyme and 12-lead ECG 
assessments must be repeated for the staged procedure as done for the original index procedure. 
• 
Pre-procedure administration regimen of aspirin and P2Y12 receptor inhibitor (dosage requirements 
and timing) must be repeated prior to the staged procedure as done for the original index procedure. 
If the subject has not been discharged between the index and staged procedures, and has received 
daily aspirin while in hospital, no aspirin reloading is required.  
 
Procedure Visit: 
• 
After the patient meets all inclusion/exclusion criteria in the cardiac catheterization laboratory, the 
patient is randomized 
• 
PCI is performed according to randomization, with the patient blinded to assignment 
• 
Blinded OCT is performed in the angiography arm at the end of the procedure  
• 
Adverse event assessment 
 
Post-Procedure: 
• 
Troponin level and/or a CK-MB level (CK-MB preferred) drawn at 6-10 hours post PCI. The same 
biomarkers as those drawn at baseline should be assessed post-PCI. 
o 
If the results are abnormal (>upper limits of normal), regardless of clinical significance, or if 
any procedural complications developed (temporary or sustained TIMI flow <III (visually 
assessed) in any vessel, or dissection ≥ NHLBI type B, or perforation, or prolonged ST-
segment elevation or depression (>5 minutes), or cardiac arrest or need for defibrillation or 
cardioversion or hypotension /heart failure requiring mechanical or intravenous 

 
  
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hemodynamic support or intubation), a second post-PCI troponin level and/or CK-MB level 
must be drawn at 6-10 hours after the first post-PCI biomarker draw or at discharge. 
o 
In the event of high sensitivity troponin use (which is not recommended), an elevation of <7X 
ULN in the first (6-10 hr) post-PCI blood draw will not require an additional level, unless any 
procedural complications developed. 
• 
Creatinine level drawn the calendar day after PCI or before discharge, whichever is earlier.  
o 
If the subject develops contrast induced nephropathy (defined as an increase in serum 
creatinine ≥25% or an absolute increase of ≥0.5mg/dl (44.2µmol/L)), regardless of clinical 
significance, it is recommended that serial creatinine levels be drawn daily until the peak is 
reached and the creatinine is decreasing.  
• 
Serum hemoglobin drawn the calendar day after PCI or before discharge, whichever is earlier. 
o 
If the subject develops overt bleeding, or the hemoglobin level has fallen more than 3 g/dL 
(30 g/L) in the absence of overt bleeding, serial hemoglobin levels must be drawn at least 
daily until a nadir is reached or the hemoglobin level has stabilized. 
• 
At least one 12-lead ECG must be performed within 24 hours post PCI in all subjects 
• 
Adverse event assessment 
Aspirin must be continued indefinitely. DAPT must be continued for at least 6 months in patients with stable 
CAD and for at least 12 months in patients who presented with acute coronary syndrome unless the patient is 
also taking chronic oral anticoagulation in which case a shorter duration of DAPT may be prescribed per local 
standard of care. Post-procedural medication use should not vary according to randomization assignment.  
 
The following considerations apply to subjects having staged procedures:   
• 
The protocol required post-procedure serum creatinine, cardiac enzyme and 12-lead ECG 
assessments must be repeated for the staged procedure as done for the original index procedure.  
• 
The follow-up regimen of aspirin and P2Y12 receptor inhibitor (dosage requirements and timing) 
must be maintained following the staged procedure as done for the original index procedure.  
• 
The follow-up period is considered as having begun upon completion of the original index procedure.   
 
Follow-up Visits (30 days, 1 year, 2 years and unplanned): 
• 
Adverse event assessment, medications, laboratory tests and 12-lead ECGs (if performed) will be 
collected  
• 
Patient Reported Outcome questionnaires (EQ-5D-5L) administered to subject 
 
 

 
  
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1.11 Study leadership 
Sponsor  
 
 
Abbott  
 
Co-Principal 
 
 
 
Investigator                             
  
 
 
 
 
Co-Principal  
 
 
 
Investigator                             
 
 
 
 
Chairman  
 
 
 
                             
 
  
 
  
 
 
 
 

 
  
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1.12 Study Flow Chart 
 
 
  
 
 
 
 
 
2 
Introduction 
 
This document is a clinical investigation plan (CIP) for the ILUMIEN IV clinical investigation. The objective of 
this clinical investigation is to demonstrate the superiority of an Optical Coherence Tomography (OCT)-
guided stent implantation strategy compared to an angiography-guided stent implantation strategy in 
achieving larger post-PCI lumen dimensions and improving clinical cardiovascular outcomes in patients with 
high-risk clinical characteristics and/or with high-risk angiographic lesions.  In addition, embedded within the 
ILUMIEN IV protocol is a separate pre-specified powered analysis of XIENCE to be conducted in randomized 
ILUMIEN IV subjects with in-stent restenosis (ISR).  The objective of the analysis is to demonstrate the safety 
and effectiveness of XIENCE in the treatment of ISR lesions.  This is described in further detail in Appendix 
F.  This clinical investigation is sponsored by Abbott. 
 

 
  
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4.1.2 
Device Description and Intended Purpose 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
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4.1.3 
 Device Handling and Storage 
Sponsor requires all study devices be stored according to the labeling and Instructions for Use. 
4.2 
Device Accountability 
ILUMIEN IV is an investigation using market released medical devices and device accountability is not 
required.  
5 
Clinical Investigation Design 
5.1 
Clinical Investigation Design 
This is a prospective, single-blind clinical investigation randomizing subjects to OCT-guided coronary stent 
implantation vs. angiography-guided coronary stent implantation in a 1:1 ratio. The clinical investigation will 
be conducted at approximately 125 centers in North America (US and Canada), Europe, Middle East and 
Asia-Pacific.  Up to 3656 subjects will be enrolled in the clinical investigation. No site may enroll more than 
15% of the total subjects. 
 
There are two powered primary endpoints of the study. The primary imaging endpoint is the acute post-
procedural MSA (per target lesion basis) by OCT-guided-PCI compared to angiography-guided PCI. The 
MSA is an appropriate primary endpoint as it is the most consistent and strongest parameter to predict 
clinical outcomes.10-18 In the present study, after 1600 randomized subjects are enrolled with procedure 
completed, the primary endpoint of MSA will be tested to compare OCT-guided and angiography-guided 
arms. If significantly larger MSA in OCT-guided arm is demonstrated, the trial will continue enrolling subjects. 
Otherwise the trial may be terminated for futility at the discretion of the sponsor.  
 
The primary clinical endpoint is target vessel failure (TVF), the time-to-first event rate of the composite 
outcome of cardiac death, target vessel myocardial infarction (TV-MI) (per primary protocol definition [see 
Appendix B]), or ischemia-driven target vessel revascularization (ID-TVR), assessed at 2 years.  
 
Due to its high resolution and ability to support an optimal strategy planning for complex PCI as well as 
accurately optimize and identify suboptimal results of stent implantation, it is hypothesized that OCT-guided 
PCI will be superior to angiography-guided PCI for both the achieved MSA and rates of TVF. For the greatest 
benefit to be achieved, OCT will be performed in the present study according to a slightly modified version of 
the algorithm used in ILUMIEN III:OPTIMIZE PCI.19 
 
All subjects participating in this clinical investigation will be followed for 2 years. 
 
 
 

 
  
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5.1.1 
Blinding  
This is a prospective, randomized, single-blind clinical investigation. Subjects will be blinded to their treatment 
assignment and the study site personnel will be trained not to disclose the treatment assignment to the 
subject. In addition to standard procedural sedation, headphones will be worn by the patient during the 
procedure to reduce the possibility of unblinding. Patients who refuse to wear headphones may not be 
randomized into the study. Additionally, blinded site personnel, not present at the index procedure, will 
conduct the clinical follow-up and they will be provided with a standard follow-up interview in order to reduce 
bias and maintain subject blinding. Subject blinding must be maintained until the completion of the trial.  
 
The physician performing the procedure will not be blinded to the assigned treatment. Thus, if clinical follow-
up with a study physician is deemed necessary at the protocol required follow-up time points, a different 
physician (or designee) than the one who implanted the device(s) must conduct the follow-up clinical visits in 
order to maintain subject blinding. Similarly, follow-up visits with research personnel must be conducted by 
different persons than those who were unblinded during the index hospitalization. Site personnel will be 
adequately trained such that the physician (or designee) conducting the clinical follow-up is adequately 
blinded to the treatment received by the subject. For unscheduled visits, subjects may see the physician who 
performed the procedure. The treating physician should prevent unblinding of the subject when they conduct 
any non-protocol related visits. In addition, any records to which the patient may have direct access should 
not refer to details of intravascular imaging or use other revealing language, to maintain the blind. The only 
exception to these requirements is if the hospital billing department does not allow this practice. Sites will be 
provided with a blinding guidance document that will instruct the sites on how to maintain blinding at the 
clinical sites.  
 
The Clinical Events Committee (CEC) may not be blinded to the randomization assignment in all patients. 
The angiographic core laboratories may not be blinded to treatment strategy in all patients. The Data Safety 
Monitoring Board (DSMB) will be blinded to the subject’s randomization. Independent statisticians will 
generate blinded tables for review by the DSMB. The DSMB may request unblinded data if a safety signal is 
observed.  
 
Sponsor personnel that will be unblinded will be the independent biostatisticians involved in generating and 
verifying the randomization code, key Clinical Science and Operations, Clinical Safety Monitors, Site 
Monitors, Clinical Data Management, Electronic Database Programmer, Inventory Management staff, and 
Clinical Information System (IS) personnel working on the trial. Restricted access of blinded personnel to the 
clinical database will be maintained until unblinding of the study for analysis of the primary clinical outcome at 
2 years, described below in Section 5.3.1.  
5.2 
Objectives 
5.2.1 
Primary Objective 
The objective of this clinical investigation is to demonstrate the superiority of an Optical Coherence 
Tomography (OCT)-guided stent implantation strategy compared to an angiography-guided stent implantation 
strategy in achieving larger post-PCI lumen dimensions and improving clinical cardiovascular outcomes in 
patients with high-risk clinical characteristics and/or with high-risk angiographic lesions.  
5.3 
Endpoints 
There are two powered primary endpoints, one powered major secondary endpoint and multiple descriptive 
non-powered secondary endpoints in this clinical investigation. Both primary endpoints must be positive for 
the investigation to be considered positive. 

 
  
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5.3.1 
Primary Endpoints 
1. Imaging Outcome (powered): Minimal stent area (MSA), continuous measure 
Final Post-PCI MSA (per target lesion basis) assessed by OCT in each randomized arm, 
measured at an independent OCT core laboratory blinded to imaging modality assignment. 
2. Clinical outcome (powered): Target vessel failure (TVF)  
Time-to-first event rate of the composite outcome of cardiac death, target vessel myocardial 
infarction (TV-MI) (per primary protocol definition [see Appendix B]), or ischemia-driven target 
vessel revascularization (ID-TVR), assessed at 2 years.  
5.3.2 
Major Secondary Endpoint 
1) Target vessel failure (TVF) excluding periprocedural MI.  
Time-to-first event rate of the composite outcome of cardiac death, target vessel-
related spontaneous myocardial infarction, or ischemia-driven target vessel 
revascularization (ID-TVR), assessed at 2 years.   
5.3.3 
Non-Powered Secondary Endpoints 
Procedural outcomes, additional procedural and clinical endpoints, patient reported 
outcomes (PRO) and cost-effectiveness measures listed below 
Procedural outcomes 
OCT-defined (OCT core laboratory assessed). Subjects in the angiography-guided arm will 
undergo a post-PCI OCT run, blinded to the operator. Assessed per target lesion. 
1) Stent expansion. Stent expansion is defined by the MSA achieved in the proximal and distal 
stented segments relative to their respective reference lumen areas. The stent length is 
divided into 2 equal segments (proximal and distal) except for lesions containing a bifurcation 
(visually estimated side branch ≥2.5 mm). When there is a bifurcation present, rather than 
splitting the stent into two halves, the division occurs at the proximal most side branch.  
• 
Acceptable stent expansion (categorical variable): The MSA of the proximal segment is 
≥90% of the proximal reference lumen area and the MSA of the distal segment is ≥90% 
of the distal reference lumen area. 
 
• 
Unacceptable stent expansion (categorical variable): The MSA of the proximal segment 
is <90% of the proximal reference lumen area, and/or the MSA of the distal segment is 
<90% of the distal reference lumen area. 
In case either segment (proximal or distal) of the stent meets criteria for unacceptable stent 
expansion, the stent is considered to have unacceptable stent expansion. Both segments of 
the stent must meet acceptable stent expansion criteria to be considered acceptable.  
In case a respective reference segment cannot be measured the determination will be made 
with only one of the two reference (proximal or distal) segments. 

 
  
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Note: If acceptable stent expansion (by operator assessment) is not achieved in either the 
distal or proximal segments of the stent in the OCT-guided arm according to the Post-PCI 
OCT, further post-stent expansion with higher pressures and/or larger balloons must be 
performed per protocol if the POST-PCI OCT EEL measurements now suggest a larger 
balloon be used.  See Section 6.5.3.7 for more details.  
• 
Post-PCI stent expansion (%) (continuous variable): The MSA divided by the average of 
proximal and distal reference lumen areas x 100. 
2) Mean stent expansion (%) (continuous variable): The mean stent area (stent volume/analysed 
stent length) divided by the average of proximal and distal reference lumen areas x 100. 
3) Intra-stent plaque protrusion and thrombus 
Defined as a mass attached to the luminal surface or floating within the lumen, meeting the following 
criteria: Protrusion/thrombus is defined as any intraluminal mass protruding at least 0.2 mm within 
the luminal edge of a stent strut, and will be further classified as Major and Minor: 
• 
Major: Protrusion area/Stent area at site of tissue protrusion ≥10% and the minimal 
intrastent flow area (MSA – protrusion area) is unacceptable (<90% of respective 
proximal or distal reference area 
• 
Minor: Protrusion area/Stent area at site of tissue protrusion is <10%, or is ≥10% but the 
minimal intraluminal flow area (MSA – protrusion area) is acceptable (≥90% of respective 
proximal or distal reference area 
Note: It is recommended that if protrusion is detected by operator assessment in the OCT-
guided arm during the procedure and meets the criteria for major protrusion, then thrombus 
aspiration, further high-pressure balloon inflation and/or an additional stent be considered. 
4) Untreated reference segment disease 
Defined as focal disease with untreated MLA <4.5 mm2 within 5 mm from the proximal and/or distal 
stent edges.  
Sub-classified by the amount of untreated lipid plaque, divided into 3 grades: 
i. 
Low (≤90° of lipid arc) 
ii. 
Medium (>90°-<180° of lipid arc)  
iii. 
High (≥180° of lipid arc) 
Note: If untreated reference segment disease with an MLA <4.5 mm2 is detected by operator 
assessment in either the proximal reference (inflow disease) or distal reference (outflow 
disease) segment lumen in the OCT-guided arm, an additional stent must be placed to treat 
it, unless there are anatomic reasons that the disease should not be covered (e.g. diffuse 
distal disease or significant vessel tapering, etc.) (Figures 1a-b).  
5) Edge dissections 
Edge dissections will be tabulated as: 
i. 
Major (%): ≥60 degrees of the circumference of the vessel at site of dissection and ≥3 
mm in length 

 
  
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ii. 
Minor (%): any visible edge dissection <60 degrees of the circumference of the vessel or 
<3 mm in length 
Edge dissections will be further classified as: 
i. 
Intimal (limited to the intima layer, i.e. not extending beyond the internal elastic lamina)  
ii. 
Medial (extending into the media layer) 
iii. 
Adventitial (extending through the external elastic membrane/lamina) 
Note: If a major edge dissection is detected by operator assessment in the OCT-guided arm, 
it is recommended that an additional stent be placed to cover the dissected segment, 
particularly if the site of dissection is at the distal stent edge. 
6) Stent Malapposition 
Defined as frequency (%) of incompletely apposed stent struts (defined as stent struts clearly 
separated from the vessel wall (lumen border/plaque surface) without any tissue behind the struts 
with a distance from the adjacent intima of ≥0.2 mm and not associated with any side branch). 
Malapposition will be further classified as: 
• 
Major: if associated with unacceptable stent expansion (as defined above) 
• 
Minor: if associated with acceptable stent expansion (as defined above)  
Note: If malapposition is detected by operator assessment during the procedure in the OCT-
guided arm and meets the criteria for major malapposition (i.e. malapposition associated with 
unacceptable stent expansion), further stent expansion must be performed. The degree of 
stent underexpansion (acceptable or unacceptable) should guide the intervention rather than 
amount of malapposition.  
Stent Malapposition will be tabulated as: 
i. 
Major (%) 
ii. 
Minor (%)  
iii. 
All (Major and Minor) (%) 
7) Border detection (angiography arm post-PCI only, blinded to investigator) 
The visibility of the vessel external elastic lamina (EEL) border by OCT will be evaluated at both 
reference sites (proximal and distal) and the MSA, after intervention and then classified into 3 
grades: 
i. 
Good: ≥75% (270°) of visible circumference 
ii. 
Moderate: ≥50% (180°) - <75% (270°) of visible circumference 
iii. 
Poor:  <50% (180°) of visible circumference 
8) Intra-stent lumen area (intra-stent flow area)  
Defined as stent area minus any protrusion as defined above in secondary endpoint 3) (Intra-stent 
plaque protrusion and thrombus).  

 
  
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9) Effective lumen area (total flow area) 
Defined as intra-stent lumen area plus any area of malapposition between the stent and the vessel 
wall (lumen border/plaque border). 
Additional Procedural and Clinical Endpoints 
10) Angiographic Endpoints (QCA). (Angiographic core laboratory assessed). Assessed per target 
lesion. 
i. 
Final (post-PCI) minimal lumen diameter 
ii. 
Final (post-PCI) percent diameter stenosis 
iii. 
Acute lumen gain post-intervention 
iv. 
Maximum device size (stent or post-dilatation balloon)/reference vessel diameter ratio 
v. 
Post-PCI target vessel TIMI flow rate 
vi. 
Angiographic complications – worst (anytime during the procedure) and final (post PCI and 
all imaging) - Angiographic dissection ≥ NHLBI type B, perforations (Ellis classification), 
intra-procedural thrombotic events (including slow-flow, no-reflow, side branch closure, 
distal embolization, and intra-procedural stent thrombosis, as per the standard angiographic 
core laboratory definitions  
11) Device Usage Endpoints (site reported; assessed per subject): 
i. 
Total stent length 
ii. 
Total number of stents 
iii. 
Maximal stent size 
iv. 
Post dilatation (yes/no) 
v. 
Total number of post-dilatation balloons 
vi. 
Maximal post-dilatation balloon size 
vii. 
Maximal device size (stent or post-dilatation balloon) 
viii. 
Maximum inflation pressure (atm.; stent or post-dilatation balloon) 
12) Procedure time (first wire insertion to guide catheter removal), fluoroscopy time, radiation 
exposure 
13) Contrast use; contrast induced nephropathy (defined as serum creatinine rise >25% or absolute 
increase >0.5 mg/dL (44.2µmol/L)); need for renal replacement therapy 
14) Procedural success (must be present in all treated lesions and vessels): 
Defined as A) angiographic core laboratory-assessed final (post-PCI) lesion angiographic 
diameter stenosis <30% and target vessel TIMI III flow without any of the angiographic 
complications listed in 10(vi) above; plus B) the absence of site-assessed prolonged ST-
segment elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or 
cardioversion or hypotension/heart failure requiring mechanical or intravenous hemodynamic 
support or intubation, or procedural death. 
15) Procedural complications 
Defined as A) angiographic core laboratory-assessed complications listed in 10(vi) above 
occurring anytime during the procedure; or B) site-assessed prolonged ST-segment 

 
  
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elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or 
cardioversion or hypotension/heart failure requiring mechanical or intravenous hemodynamic 
support or intubation, or procedural death. 
16) OCT performance success (site reported) (OCT arm only): 
OCT imaging performed both pre- and post-PCI  
17) OCT imaging-related procedural complications (CEC adjudicated) 
Any procedural complications (e.g. angiographic dissection, perforation, thrombus, acute closure, 
etc.) requiring any active intervention (e.g. prolonged balloon inflations, additional stent implantation, 
pericardiocentesis, intubation, hemodynamic support or pressors, defibrillation or cardioversion) or 
death adjudicated by the CEC as definitely or likely attributable to the physical performance of OCT-
imaging (e.g. passing the catheter through the vasculature or stent, or injecting contrast to clear the 
blood for imaging). For this definition, adverse events that arise due to changes in PCI strategy as 
the result of OCT findings are NOT considered OCT imaging-related procedural complications. 
18) Additional interventions on the basis of the pre-PCI or post-stent OCT-imaging run that would not 
have been performed based on angiographic guidance alone (site reported; assessed per 
subject; OCT Arm Only): 
i. 
Use of larger balloon 
ii. 
Use of higher inflation pressures 
iii. 
Use of additional balloons 
iv. 
Use of additional stent(s) 
v. 
Performance of atherectomy 
vi. 
Other interventions 
Reason(s) for additional interventions will be documented by the site (e.g. more calcium than 
anticipated, greater stent under-expansion than appreciated angiographically, greater malapposition 
than appreciated angiographically, greater tissue protrusion or thrombus burden than appreciated 
angiographically, more severe edge dissection than appreciated angiographically, residual reference 
segment disease not appreciated angiographically, other) 
Clinical outcomes at 30 days, 1 year and 2 years (unless otherwise noted) 
19) Target lesion failure (TLF; cardiac death, TV-MI or ischemia-driven target lesion revascularization 
(ID-TLR) 
20) All-cause mortality  
21) Cardiac and non-cardiac mortality 
22) All MI  
23) TV-MI, non-TV-MI and indeterminate vessel MI 
24) Periprocedural MI and non-periprocedural MI  
25) All revascularization 

 
  
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26) ID-revascularization and non-ID-revascularization 
27) ID-TVR, ID-TLR, ID-non-TLR TVR, and ID-non-TVR 
28) Definite, probable and definite/probable stent thrombosis (ARC definition) 
29) Relationship between immediate post-procedure OCT parameters (e.g. MSA, procedural 
success, malapposition, dissection, protrusion, etc.) and 2-year endpoint rates (e.g. TVF, TLF, 
all-cause mortality, cardiac death, TV-MI, all MI, , ID-TLR, ID-TVR, and stent thrombosis) 
30) TVF excluding periprocedural MI (i.e. the composite of cardiac death, target vessel-related 
spontaneous MI, or ID-TVR) (at 30 days and 1 year) 
In addition, the following outcomes using the SCAI definition of periprocedural MI9 will be reported as 
sensitivity analyses at 30 days, 1 year and 2 years: 
31) TV-MISCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol definition) 
32) Periprocedural MISCAI (by SCAI definition)  
33) All MISCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol definition)  
34) TVFSCAI; the composite of cardiac death, TV-MISCAI or ID-TVR 
Patient Reported Outcomes (PRO) 
 
Patient Reported Outcome questionnaires will be incorporated into this study to provide a 
complementary evaluation of the effectiveness of OCT-guided stent implantation. The following 
instruments will be administered during this study in hospital (required at baseline, optional post-
procedure), and at 30 day, 12 month and 24 month follow-up:  
• 
EuroQoL 5D (EQ-5D-5L) survey to assess overall health status  
 
Cost-effectiveness 
 
Cost per quality adjusted life year (QALY) and TVF event prevented by OCT-guidance to be 
determined using standardized methods10.  
 
5.4 
Study Population 
The intended population for this clinical investigation is patients over the age of 18 years that are either high 
clinical-risk or have high angiographic-risk lesion characteristics undergoing stent implantation for coronary 
artery disease.  
 
Assessment for general eligibility criteria is based on medical records of the site and interview with a 
candidate patient. If some of the clinical and laboratory tests are not included in site standard tests, they must 
 
 
9 Moussa ID et al. Consideration of a New Definition of Clinically Relevant Myocardial Infarction After Coronary Revascularization:  An 
Expert Consensus Document From the Society for Cardiovascular Angiography and Interventions (SCAI). J Am Coll Cardiol. 2013 
October 22; 62(17): 1563–1570. 
10 Eisenberg J. Clinical economics: A guide to the economic analysis of clinical practices. JAMA 1989; 262:2879-86. 

 
  
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be done but after written informed consent is obtained. Patients must meet ALL of the inclusion criteria to be 
considered for the clinical investigation. If ANY of the exclusion criteria are met, the patient is excluded from 
the clinical investigation and cannot be enrolled.  
 
5.4.1 
Inclusion Criteria (all must be present) 
1. Subject must be at least 18 years of age. 
2. Subject must have evidence of myocardial ischemia (e.g., stable angina, silent ischemia (ischemia 
in the absence of chest pain or other anginal equivalents), unstable angina, or acute myocardial 
infarction) suitable for elective PCI.   
3. Patients undergoing planned XIENCE stent implantation during a clinically indicated PCI 
procedure meeting one or more of the following criteria: 
A) High clinical-risk, defined as; 
i. 
Medication-treated diabetes mellitus, AND/OR 
B) High angiographic-risk lesion(s), with at least one target lesion in each target vessel planned 
for randomization meeting at least one of the following criteria; 
i. 
Target lesion is the culprit lesion responsible for either: 
• 
NSTEMI, defined as a clinical syndrome consistent with an acute coronary 
syndrome and a minimum troponin of 1 ng/dL (may or may not have 
returned to normal), OR 
• 
STEMI >24 hours from the onset of ischemic symptoms 
ii. 
long or multiple lesions (defined as intended total stent length in any single 
target vessel ≥28 mm),  
Note:  For a long target lesion, this would permit treatment by a single long 
stent or overlapping stents.  
Note:  For up to two target lesions located in a single target vessel and 
treated with non-overlapping stents, they may be located in a continuous 
vessel or split up between a main vessel and a side branch.  
iii. 
bifurcation intended to be treated with 2 planned stents (i.e. in both the main 
branch and side branch), and where the planned side branch stent is ≥ 2.5 mm 
in diameter by angiographic visual estimation.  
iv. 
angiographic severe calcification (defined as angiographically visible 
calcification on both sides of the vessel wall in the absence of cardiac motion), 
v. 
chronic total occlusion (CTO) (enrolment and randomization in this case 
performed only after successful antegrade wire escalation crossing and pre-
dilatation) 
vi. 
in-stent restenosis of diffuse or multi-focal pattern.  Lesion must be at or within 
the existing stent margin(s) and have angiographically visually-assessed DS 
≥70% or DS ≥50% with non-invasive or invasive evidence of ischemia 

 
  
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4. All target lesions (those lesions to be randomized) must have a visually estimated or quantitatively 
assessed %DS of either ≥70%, or 50% plus one or more of the following: an abnormal functional 
test (e.g. fractional flow reserve, stress test) signifying ischemia in the distribution of the target 
lesion(s) or biomarker positive ACS with plaque disruption or thrombus.  
Note:  For purposes of study eligibility, a minimum troponin of 1 ng/dL at the time of 
screening will be considered biomarker positive. 
5. All target lesions must be planned for treatment with only ≥2.5 mm and ≤3.5 mm stents and post-
dilatation balloons based on pre-PCI angiographic visual estimation..    
6. No more than 2 target lesions requiring PCI are present in any single vessel., and no more than 2 
target vessels are allowed. Thus, up to 4 randomized target lesions per patient in a maximum of 2 
target vessels are allowed, including branches. The intended target lesions will be declared just prior 
to randomization.  
Note: A lesion is defined as any segment(s) of the coronary tree, no matter how long, which 
is planned to be covered with one contiguous length of stent, whether single or overlapped.  
A bifurcation counts as a single lesion even if the side branch is planned to be treated. 
Note:  All lesions in a randomized target vessel that are intended to be treated by PCI are 
designated as target lesions, and at least one target lesion in each randomized target vessel 
must meet angiographic high-risk inclusion criteria summarized above in 3B). The only 
exception is for patients who qualify for the trial on the basis of medication-treated diabetes, 
in which case no target lesion is required to meet angiographic high-risk inclusion criteria. 
7. All target lesions intended to be treated by PCI in the target vessel are amenable to OCT-guided 
PCI (i.e. no lesion-specific angiographic exclusion criteria are present – see Section 5.4.2 below).  
Example: If a qualifying angiographic high-risk lesion is in the proximal LAD, and there is a 
second target lesion in the distal LAD which is a focal lesion not otherwise meeting high-risk 
criteria, both the proximal LAD and distal LAD lesions must be amenable to OCT (e.g. no 
excessive tortuosity or calcification precluding delivering the OCT catheter), and each lesion 
must undergo OCT-guided stenting. Otherwise the vessel should be excluded from 
randomization. 
8. Subject must provide written Informed Consent prior to any study related procedure. 
 
 

 
  
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5.4.2 
Exclusion Criteria (none may be present) 
Clinical exclusion criteria:  
1. STEMI ≤24 hours from the onset of ischemic symptoms 
2. Creatinine clearance ≤30 ml/min/1.73 m2 (as calculated by MDRD formula for estimated GFR)11 
and not on dialysis. Note: chronic dialysis dependent patients are eligible for enrolment regardless 
of creatinine clearance. 
3. Hypotension, shock or need for mechanical support or intravenous vasopressors at the time the 
patient would be undergoing the index procedure.  
4. CHF (Killip class ≥2 or NYHA class ≥3) 
5. LVEF ≤30% by the most recent imaging test within 3 months prior to procedure.  If no LVEF test 
result within 3 months is available, it must be assessed by echocardiography, multiple gated 
acquisition (MUGA), magnetic resonance imaging (MRI), ventriculography (LV gram) or other 
method.   
6. Unstable ventricular arrhythmias 
7. Inability to take DAPT (both aspirin and a P2Y12 inhibitor) for at least 12 months in the patient 
presenting with an ACS, or at least 6 months in the patient presenting with stable CAD, unless the 
patient is also taking chronic oral anticoagulation in which case a shorter duration of DAPT may be 
prescribed per local standard of care. 
8. Planned major cardiac or non-cardiac surgery within 24 months after the index procedure 
Note: Major surgery is any invasive operative procedure in which an extensive resection is 
performed, e.g. a body cavity is entered, organs are removed, or normal anatomy is altered.  
Note: Minor surgery is an operation on the superficial structures of the body or a 
manipulative procedure that does not involve a serious risk.  Planned minor surgery is not 
excluded. 
9. Prior PCI within the target vessel within 12 months  
Note:  Prior PCI within the target vessel within 12 months is allowed for in-stent restenosis 
(target lesion is the prior PCI site) if no more than one layer of previously implanted stent is 
present.   
Note:  In-stent restenosis involving two or more layers of stent implanted at any time prior to 
index procedure (i.e. an earlier episode of in-stent restenosis previously treated with a 
second stent) is excluded. 
 
 
11 Estimated GFR (ml/min/ 1.73 m2) = 175 x [SerumCreatinine (umol/L) x 0.0113]-1.154 x Age (years)-0.203  (x 0.742 if female) 

 
  
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10. Any planned PCI within the target vessel(s) within 24 months after the study procedure, other 
than a planned staged intervention in a second randomized target vessel.   
Note: Planned staged interventions must be noted at the time of randomization, and the 
decision to stage may be modified within 24 hours of completion of the index PCI. See Section 
6.5.3.8 for more details of multi lesion and vessel treatment. 
Note: PCI in non-target vessels is permitted >48 hours after the index procedure. 
11. Any prior PCI in a non-target vessel within 24 hours before the study procedure, or within 
previous 30 days if unsuccessful or complicated.   
Note: Patients requiring non-target vessel PCI may be enrolled and the non-target vessel(s) 
may be treated in the same index procedure as the randomized lesions (in all cases prior to 
randomization), as long as treatment of the lesion(s) in the non-target vessel is successful and 
uncomplicated. 
Successful and uncomplicated definition for non-target vessel treatment during the index 
procedure: Angiographic diameter stenosis <10% for all treated non-target lesions, with TIMI III 
flow in this vessel, without final dissection ≥ NHLBI type B, perforation anytime during the 
procedure, prolonged chest pain (>5 minutes) or prolonged ST-segment elevation or depression 
(>5 minutes), or cardiac arrest or need for defibrillation or cardioversion or hypotension/heart 
failure requiring mechanical or intravenous hemodynamic support or intubation). 
12. Subject has known hypersensitivity or contraindication to any of the study drugs (including all 
P2Y12 inhibitors, one or more components of the study devices, including everolimus, cobalt, 
chromium, nickel, platinum, tungsten, acrylic and fluoropolymers, or radiocontrast dye that cannot be 
adequately pre-medicated.  
13. Subject has received a solid organ transplant which is functioning or is active on a waiting list for 
any solid organ transplants with expected transplantation within 24 months. 
 
14. Subject is receiving immunosuppressant therapy or has known immunosuppressive or severe 
autoimmune disease that requires chronic immunosuppressive therapy (e.g., human 
immunodeficiency virus, systemic lupus erythematosus, etc.). Note: corticosteroids are not included 
as immunosuppressant therapy. 
15. Subject has previously received or is scheduled to receive radiotherapy to a coronary artery 
(vascular brachytherapy), or the chest/mediastinum. 
16. Subject has a platelet count <100,000 cells/mm3 or >700,000 cells/mm3.  
17. Subject has a documented or suspected hepatic disorder as defined as cirrhosis or Child-Pugh ≥ 
Class B. 
18. Subject has a history of bleeding diathesis or coagulopathy, or has had a significant gastro-
intestinal or significant urinary bleed within the past six months. 

 
  
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19. Subject has had a cerebrovascular accident or transient ischemic neurological attack (TIA) within 
the past six months, or any prior intracranial bleed, or any permanent neurologic defect, or any 
known intracranial pathology (e.g., aneurysm, arteriovenous malformation, etc.). 
20. Subject has extensive peripheral vascular disease that precludes safe 6 French sheath insertion. 
Note: femoral arterial disease does not exclude the patient if radial access may be used. 
21. Subject has life expectancy <2 years for any non-cardiac cause. 
22. Subject is currently participating in another investigational drug or device clinical study that has 
not yet completed its primary endpoint12.  
23. Pregnant or nursing subjects and those who plan pregnancy in the period up to 2 years following 
index procedure. Female subjects of child-bearing potential must have a negative pregnancy test 
done within 7 days prior to the index procedure per site standard test.  
 
24. Presence of other anatomic or comorbid conditions, or other medical, social, or psychological 
conditions that, in the investigator’s opinion, could limit the subject’s ability to participate in the clinical 
investigation or to comply with follow-up requirements, or impact the scientific soundness of the 
clinical investigation results. 
 
Angiographic exclusion criteria  
1. Syntax score ≥33 as evaluated in Section 6.5.1, unless a formal meeting of the Heart Team, 
including a cardiac surgeon, concludes that PCI is appropriate. 
2. Planned use of any stent <2.5 mm in a randomized vessel based on visual estimation (note: a 
smaller stent may be used in a bail-out scenario – e.g. to treat a distal dissection – but its use 
cannot be planned prior to enrolment) 
3. Planned use of a stent or post-dilatation balloon ≥3.75 mm for the randomized target lesion (see 
inclusion criteria #5 for the one exception to this exclusion criterion) 
4. Severe vessel tortuosity or calcification in a randomized target vessel such that it is unlikely that 
the OCT catheter can be delivered (note: severe vessel calcification is allowed if it is expected that 
the OCT catheter can be delivered at baseline or after vessel preparation with balloon pre-dilatation 
or atherectomy) 
5. The target vessel has a lesion with DS  50% that is not planned for treatment at the time of index 
procedure 
6. The randomized target lesion is in the left main coronary artery  
 
 
12 This includes clinical trials of medications and invasive procedures. Questionnaire-based studies, or other 
studies (regardless of study design) that are non-invasive and do not require medication are allowed.  A 
subject who is taking part in the long-term follow-up phase of a trial, who has completed all medications and 
invasive procedures per protocol requirements, may continue to participate in that trial. 

 
  
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7. The randomized target lesion is in a bypass graft conduit. Note: A native coronary artery may be 
randomized if a prior bypass graft conduit to the vessel is totally occluded, but not if it is patent. 
8. The randomized target lesion is an ostial RCA stenosis  
9. The randomized target lesion is a stent thrombosis 
10. Planned use of any stent other than Xience in a randomized target lesion 
 
5.4.3 
Enrollment of Medicare Beneficiaries 
This clinical trial will enroll appropriate Medicare beneficiaries that qualify based on the inclusion and 
exclusion criteria set forth in the trial. This IDE clinical trial adheres to all standards of Medicare coverage 
requirements set forth by the IDE and clinical trial coverage policies of the Center for Medicare and Medicare 
Services (CMS). Section 8, Risks and Benefits, describes how all enrolled subjects, including Medicare 
beneficiaries, may be affected by this investigation.   
Subjects enrolled in the clinical trial are expected to be consistent with the Medicare population based on 
demographic characteristics and cardiovascular risk factors; therefore, the clinical trial results are expected to 
be generalizable to the Medicare population. 
 
6 
Procedures  
6.1 
Overview  
Operator experience and performance in the randomized trial.  
Operators participating in this study will be those who have performed at least 50 lifetime OCT-guided stent 
procedures.   
As described in Section 6.4, each operator will perform up to 3 roll-in subjects prior to randomization. Roll-in 
patients must meet all inclusion and exclusion criteria as randomized patients. The procedural results, 
angiograms and OCT technique and data for each roll-in case will be reviewed by the OCT core laboratory 
director. When it is agreed that the operator has full understanding of the OCT-guidance protocol, the roll-in 
requirement for that operator will stop and randomization may proceed. If after 3 roll-in cases the operator is 
still not complying with the OCT-guidance protocol, that operator will not be permitted to randomize within the 
trial.  
 
For all patients, each clinical site should transmit the angiographic and OCT images to the core laboratories 
within 48 hours of the case being completed.  
 
For patients randomized to OCT-guidance, the OCT core laboratory director will review each case to 
determine whether the protocol for OCT-stent guidance was followed, including but not limited to:  
• 
Was the protocol followed to obtain an acceptable MSA?  
• 
Were any major inaccuracies in dimensional or other OCT measurements present? 
• 
Did the operator act appropriately on the final OCT?  
• 
Were any other major protocol violations detected?  
 

 
  
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For patients randomized to angiography-guidance, the OCT core laboratory director will review each case to 
determine that no additional interventions were performed after the blinded OCT imaging (which would 
represent a protocol violation), and that the quality of this blinded OCT run was acceptable.  
 
The OCT core laboratory director may consult the trial Principal Investigator, and/or contact the sites for 
additional data if necessary to make these assessments. The OCT core laboratory director will send a 
screening report back to the sites within 72 hours of receipt of the images detailing if any major or minor 
protocol violations were present. If any major protocol violations were present, the operator may be put on 
“clinical hold” and asked not to randomize further until further training has been performed. If an operator has 
3 such major protocol violations, he/she may be asked to withdraw from the study (although all randomized 
patients will remain in the study by intention to treat). 
 
Patients undergoing coronary angiography in whom possible or definite PCI with intent to implant a stent will 
be asked to participate in the study. Patient demographics and a medical history are required for all patients. 
All patients must have a baseline 12-lead ECG prior to angiography, and a baseline troponin and/or CK-MB 
level within 48 hours prior to PCI – this may be drawn from the vascular sheath prior to PCI in patients with 
stable coronary artery disease. Patients also must have a baseline serum creatinine and hemoglobin 
measured within 1 week prior to PCI. Location of vascular access (whether radial or femoral) is per local site 
discretion, as is sheath size, although at least a 6F sheath must be used. After the informed consent for the 
study is signed by the patient, angiography will be performed. At least 100 µg of IC nitroglycerin or 
appropriate dosage of IC isosorbide dinitrate must be administered prior to angiography. All patients must be 
pre-treated with at least 150 mg of oral non-enteric coated aspirin within 12 hours prior to PCI regardless of 
prior aspirin use. Intravenous aspirin administration is allowed in geographies where it is standard of care. All 
patients should receive a loading dose of an ADP antagonist (clopidogrel, prasugrel or ticagrelor) as per 
standard of care, preferably within 12 hours prior to, but in all cases no later than 2 hours post PCI. Loading 
dose of ADP antagonist is not required for subjects receiving chronic treatment of ADP antagonist.  
 
Following angiography (and successful and uncomplicated treatment of any non-target vessel lesions, if 
present), eligible patients will be randomized in a 1:1 ratio to OCT-guided stent implantation or angiography-
guided stent implantation. An exception is if a randomized target lesion will be a CTO, in which case 
randomization is performed only following successful crossing and pre-dilatation, such that the lesion is 
confirmed as amenable to OCT guidance. If the CTO is not successfully crossed and dilated, the patient may 
not be randomized). Among the OCT-guided group, coronary stenting will be performed according to the 
OCT-sizing and optimization algorithm, while in the angiography-guided PCI group, coronary stenting will be 
performed as per local standard of care. All patients must have a post-PCI 12-lead ECG and measurement of 
at least 1 cardiac biomarker level as described below.  
 
Follow up visits will be scheduled at 1, 12 and 24 months.  
6.2 
Informed Consent Process 
The Principal Investigator or his/her authorized designee will conduct the Informed Consent Process, as 
required by applicable regulations and the center’s Institutional Review Board (IRB) / Ethics Committee (EC). 
This process will include a verbal discussion with the subject on all aspects of the clinical investigation that 
are relevant to the subject’s decision to participate, such as details of clinical investigation procedures, 
anticipated benefits, and potential risks of clinical investigation participation. Subjects must be informed about 
their right to withdraw from the clinical investigation at any time and for any reason without sanction, penalty 
or loss of benefits to which the subject is otherwise entitled. Withdrawal from the clinical investigation will not 
jeopardize their future medical care or relationship with the investigator.  
 

 
  
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During the discussion, the Principal Investigator or his/her authorized designee will avoid any improper 
influence on the subject and will respect subject’s legal rights. Financial incentives will not be given to the 
subject. Subjects may be compensated for time and travel directly related to the participation in the clinical 
investigation.  The subject shall be provided with the informed consent form written in a language that is 
understandable to the subject and has been approved by the center’s IRB/EC. The subject shall have 
adequate time to review, ask questions and consider participation.  The Principal Investigator or his/her 
authorized designee will make efforts to ensure that the subject understands the information provided.  
 
If the subject agrees to participate, the Informed Consent form must be signed and dated by the subject and 
by the person obtaining the consent, prior to any clinical trial/investigation-specific procedures. The signed 
original will be filed in the subject’s hospital or research charts, and a copy will be provided to the subject. 
 
The Principal Investigator or his/her authorized designee will document the informed consent process in the 
subject’s hospital and/or research charts. The date of signature will be entered on an applicable Case Report 
Form (CRF). 
 
In addition, an authorization for use and disclosure of the subject’s protected health information, in 
accordance with the Health Insurance Portability and Accountability Act (HIPAA), must be obtained from the 
subject if enrolled at a US investigational site.  
For Live cases at congresses the patients need to sign a specific Live Case ICF, approved by the IRB. The 
investigator must notify Abbott Vascular prior to performing a Live Case.  FDA approval is also required for a 
live case conducted in US. 
Failure to obtain informed consent from a subject prior to any study related procedure or collection of study 
related data must be reported to Sponsor within 5 working days and to the reviewing center’s IRB/EC 
according to the IRB’s/ EC’s reporting requirements. 
 
If, during the clinical investigation, new information becomes available that can significantly affect a subject's 
future health and medical care, the Principal Investigator or his/her authorized designee will provide this 
information to the subject. If relevant, the subject will be asked to confirm their continuing informed consent in 
writing. 
 
No vulnerable populations will be recruited for this clinical investigation. Vulnerable patients are defined as 
patients whose willingness to volunteer in a clinical investigation could be unduly influenced by the 
expectation, whether justified or not, of benefits associated with participation or of retaliatory response from 
senior members of a hierarchy in case of refusal to participate. Incapacitated individuals, defined as persons 
who are mentally ill, mentally handicapped, or individuals without legal authority, are excluded from the study 
population. Individuals under the age of 18 or age of legal consent are excluded from the study population.  
Additionally, pregnant or breastfeeding women are excluded from the study population. 
 
Individuals unable to read or write may be enrolled in this clinical investigation. Informed consent will be 
obtained through a supervised oral process. An independent witness will be present throughout the Informed 
Consent process. The written Informed Consent form and any other information will be read aloud and 
explained to the prospective subject and he/she will sign and personally date the Informed Consent form. The 
witness will also sign and personally date the Informed Consent form attesting that the information was 
accurately explained and that informed consent was freely given.  
 

 
  
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6.3 
Screening 
Potential patients presenting at the investigational sites will be fully informed about the clinical investigation, 
following the established Informed Consent process (described above). Once a dated and signed Informed 
Consent Form is obtained, the screening procedures may begin.  
 
The following assessments are performed as part of the screening process: 
1) Clinical indication for angiography with potential for PCI 
2) Inclusion and exclusion criteria 
 
 
In case the subject does not meet all inclusion criteria or meets any of the exclusion criteria, the subject is 
considered a screen failure.  Records of patients who are screened will be maintained and submitted to the 
sponsor on a screening log upon request.  The Principal Investigator or the delegated study personnel will 
record the screen failure in the hospital records and on a screening log as required. 
6.4 
Point of Enrollment 
Subjects are considered enrolled in ILUMIEN IV after signing the Informed Consent. Subjects are considered 
randomized in the trial after the randomization system has been contacted and a study arm (OCT or 
angiography) has been assigned. Enrolled subjects not randomized or not included as a roll-in subject in the 
trial will be considered screen failures and will not be followed. 
 
Study participants will be classified as: 
 
Screen Failure 
A subject who provides a signed Informed Consent form but fails to meet the eligibility criteria (i.e. does not 
meet all inclusion or in whom any exclusion criterion is present) and/or does not achieve randomization or is 
not included as a roll-in subject. Screen Failure subjects will not be part of the analysis cohort and will not be 
followed but recorded on screening log.  
 
Roll-in Subject 
Defined as a non-randomized subject who provides a signed Informed Consent Form, meets all eligibility 
criteria and undergoes an OCT-guided stent implant procedure using the study methodology. Procedural 
clinical and safety data will be collected for these patients with follow-up through discharge from the index 
procedure. Post-discharge assessment of cardiac biomarkers or creatinine are not required for roll-in subjects. 
Each operator will be allowed up to 3 roll-in subjects. The procedural results, angiograms and OCT technique 
and data for each roll-in case will be reviewed by the OCT core laboratory director. When it is agreed that the 
operator has full understanding of the OCT-guidance protocol, the roll-in requirement for that operator will have 
been completed and randomization may proceed. If after 3 roll-in cases the operator is still not complying with 
the OCT-guidance protocol, that operator will not be permitted to randomize within the trial. The roll-in phase 
may be waived for operators who participated in ILUMIEN III in whom expertise with the OCT guidance protocol 
was already demonstrated.  Roll-in subjects will not be included in the analysis group for assessment of the 
primary imaging and clinical endpoints.     
 
Randomized Subject 
Defined as a subject who provides a signed Informed Consent Form and undergoes randomization.  These 
subjects will constitute the primary analysis cohort. 

 
  
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6.5 
Scheduled Procedures 
The site Principal Investigator is responsible for ensuring all clinical investigation data is collected as required 
per CIP scheduled procedures. 
6.5.1 
Baseline 
All baseline tests will be done within 30 days prior to the index procedure, unless otherwise specified by the 
protocol. 
• 
Demographics: include subject’s age, sex, ethnicity and race 
• 
Cardiovascular history (most recent values closest to baseline visit) 
• 
Medical history: indicate subject’s risk factors, relevant co-morbidities, previous cardiac procedures 
• 
Medication (only chronic medication): indicate the drug category the subject is currently taking on a 
long-term basis, i.e. no short-term medication 
• 
Physical examination: include subject’s height, weight (measurements taken during visit) 
• 
Pregnancy test (negative pregnancy test is required for any female of childbearing potential) 
• 
Serum creatinine and hemoglobin measured within 1 week prior to PCI  
• 
Troponin and/or CK-MB within 48 hours prior to PCI. If abnormal must be repeated either 8-16 hours 
after the last measurement, or drawn from the sheath at the time of the procedure so a curve may be 
established for peri-procedural MI adjudication.  Use of high sensitivity troponin is not recommended.  
Note: patients with stable CAD may have the biomarker drawn from the sheath prior to any 
intervention, and the result does not need to be available prior to treatment. 
• 
12-lead ECG  
• 
CHF assessment (by Killip class or NYHA class) 
• 
LVEF assessment (if no LVEF test result within 3 months is available).  Assessment can be by 
echocardiography, multiple gated acquisition (MUGA), magnetic resonance imaging (MRI), 
ventriculography (LV gram) or other method. 
• 
Syntax score for patients with moderately complex 2-vessel disease or any 3-vessel disease.  Use 
the online calculator to determine Syntax score I (http://www.syntaxscore.com). For patients with 
single vessel disease or simple 2-vessel disease, no calculation is required – record “< 33” for Syntax 
score.  
• 
Patient Reported Outcome questionnaire (EQ-5D-5L) 
• 
Patients must receive at least 150 mg of oral non-enteric coated aspirin within 12 hours prior to PCI, 
regardless of prior aspirin use.  Intravenous aspirin administration is allowed in geographies where it 
is standard of care.  
• 
Patients shall receive an appropriate loading dose of an ADP antagonist (clopidogrel, prasugrel or 
ticagrelor) as per standard of care, preferably within 12 hours prior to, but in all cases no later than 2 
hours after PCI.  Loading dose of ADP antagonist is not required for subjects receiving chronic 
treatment of ADP antagonist.  
 
The following considerations apply to subjects having staged procedures, which are described in Section 
6.5.3.8:  
• 
The protocol required pre-procedure serum creatinine, cardiac enzyme and 12-lead ECG 
assessments must be repeated for the staged procedure as done for the original index procedure. 
• 
Pre-procedure administration regimen of aspirin and P2Y12 receptor inhibitor (dosage requirements 
and timing) must be repeated prior to the staged procedure as done for the original index procedure. 
If the subject has not been discharged between the index and staged procedures, and has received 
daily aspirin while in hospital, no aspirin reloading is required.  

 
  
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6.5.2 
Randomization 
Target lesions will be identified based on coronary angiography (plus use of physiological assessment of 
coronary artery disease as appropriate) for eligibility for PCI. If all inclusion criteria are present and no 
exclusion criteria are present for at least one target lesion, the patient may be randomized. Randomization 
should be performed immediately following angiography, or after successful and uncomplicated PCI of one or 
more lesions in a non-randomized non-target vessel. Randomization is performed before wire crossing or PCI 
on any lesion in a target vessel is performed with a few exceptions.  The lesion may be crossed with a 
pressure wire to determine its physiological significance and for randomized CTO lesions, for which 
randomization will occur after successful antegrade wire crossing and successful pre-dilatation with 
confirmation that the culprit lesion is amenable to OCT-guidance. If the CTO is not successfully crossed with 
antegrade wire escalation techniques and non successfully pre-dilated, or if complications occur during the 
CTO recanalization procedure, the patient may not be randomized.  
 
Randomization will be stratified by medication-treated diabetes, presentation with a biomarker positive ACS 
(NSTEMI or recent STEMI), and site. Randomization allocation will be through an electronic randomization 
system. A cap of 10% will be implemented for in-stent restenosis in the overall population (see Section 5.4.1, 
Inclusion Criteria #3.B.vi).  Prior to randomization the site will declare to the electronic randomization system 
the stratification variables. Designation of planned staging may be modified within 24 hours after the 
procedure if necessary (see Section 6.5.3.8 for more details). The intent to stage will be used by the CEC in 
determining whether subsequent revascularization procedures are unplanned, thus meeting the criteria for 
endpoint events. However, even planned staged interventions may be included as an endpoint event if done 
urgently and sooner than planned for active ischemia.   
 
Note: Each target vessel may contain up to two target lesions, and there may be up to 2 randomized target 
vessels (i.e. up to 4 target lesions). All lesions in target vessels must be determined by the operator to be 
amenable to OCT-guided PCI, although only one of the lesions must have high-risk angiographic 
characteristics.  
 
Exception: PCI target lesions are not required to meet high-risk angiographic criteria if the patient 
qualifies for randomization on the basis of medication-treated diabetes.  
 
Note: Planned treatment of more than 2 target lesions per target vessel is not allowed.  In cases where 
treatment of a target lesion reveals unexpected additional lesion(s) in the target vessel, the investigator may 
treat the unplanned lesions.  Unplanned lesions will not be part of the analysis of the primary endpoint of 
post-PCI MSA but will be included in the analysis of the primary clinical TVF endpoint.  Unplanned lesions in 
the angiography arm should be treated per angiographic standard of care, without intravascular imaging.  
Unplanned lesion(s) in the OCT arm should be treated per the OCT algorithm if possible.    
 
Additional procedures in target vessel:  Subsequent treatment in the target vessel is allowed in 
circumstances where the operator deems the index procedure to be incomplete and requiring planned 
continuation in a separate procedure to achieve a successful result.  Under these circumstances, the index 
procedure may be completed on a subsequent day, and the continuation of treatment must be per the original 
assigned strategy.  The subsequent procedure if completed without complication should not be reported as 
an AE or considered as a revascularization.  
 

 
  
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6.5.3 
PCI Procedure 
Following is a description of the image acquisition and treatment steps to be used during the index 
procedure.  All angiographic and OCT data will be stored digitally for subsequent analysis and these images 
must be sent to the CRF Core Laboratory for analysis.  
6.5.3.1 
Pre-PCI imaging  
 
At least 100 µg of IC nitroglycerin or appropriate dosage of IC isosorbide dinitrate should be administered 
prior to diagnostic angiography for both arms of the study, unless precluded by low blood pressure. 
Anticoagulation for imaging and PCI must be achieved with either unfractionated heparin, bivalirudin or 
enoxaparin, with or without glycoprotein IIb/IIIa inhibitors, according to local standard of care, prior to 
insertion of any guidewire for imaging or PCI in a coronary artery.  
 
For subjects in the OCT arm, imaging is recommended to be performed using the motorized pullback device 
at 75 mm pullback, 5 frames per mm over 2.1 secs for OCT. If possible, the imaging run should start at least 
1 cm distal to the angiographic extent of the lesion and continue until the end of image acquisition for OCT. If 
the imaging catheter will not cross the lesion prior to stenting, vessel preparation (balloon pre-dilatation – 
standard, cutting or scoring balloon, or atherectomy), with or without a guide extension catheter, may be used 
to facilitate OCT imaging catheter passage prior to stenting. The necessity for lesion preparation prior to OCT 
imaging will be collected on the case report form. In all cases, however, OCT imaging should be performed, if 
at all possible, prior to stent implantation in the OCT arm. In the event the OCT catheter cannot pass despite 
adequate lesion preparation facilitated with a guide catheter extension, the investigator should perform the 
intervention as per local standard of care and follow the OCT guided algorithm following stent placement. In 
the event that the OCT catheter cannot pass even after stent placement, treatment should be per local 
standard of care.  
 
If available, the OPTIS Integrated system angiographic co-registration function should be utilized. If OCT 
angiography co-registration is not available, during the OCT pullback, a cine angiogram must be acquired 
and the OCT pullback then co-registered with the angiogram by visual estimation.  
 
Planned usage of ≥2.5 mm and ≤3.5 mm stents and post-dilatation balloons is required based on pre-PCI 
angiographic visual estimation.  After assessment of pre-dilatation and/or stent implantation result, usage of 
post-dilatation balloons outside of this diameter range is allowed per investigator judgment.  This instruction 
applies to both OCT-guided and angiography-guided arms.  
 
Note: Intravascular ultrasound must not be used in the target vessel in either the OCT-guided or 
angiography-guided arm except in bailout only for an emergent, life-threatening condition such as acute 
closure without obvious cause.  
6.5.3.2 
Randomization to angiography-guided stenting 
 
If the patient is randomized to angiography-guided stent implantation, stenting will be performed and 
optimized with angiography guidance according to local standard practice.  Quantitative coronary 
angiography (QCA) is not required. At the end of the stent procedure, at the time the operator would be 
otherwise removing the guidewire and taking final completion angiography, a blinded OCT must be 
performed for submission to the core laboratory. This blinded OCT run is for study purposes only – the 
operator may not view the OCT results, and may not make additional treatment decisions on the basis of this 
OCT image acquisition. To do so will be considered a major protocol violation.  
 

 
  
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The operator may obtain feedback from a member of the team, such as a technician, nurse, study 
coordinator etc. as to whether the final blinded OCT run was technically adequate, with good lumen 
clearance, capturing at least 10 mm distal and 10 mm proximal to the stented segment. At least 100 µg of IC 
nitroglycerin or appropriate dosage of IC isosorbide dinitrate should be administered for each target vessel 
treated prior to the final angiographic and OCT images, unless precluded by low blood pressure. Following 
the blinded OCT run, a final test coronary contrast injection or recorded cine angiogram may be taken to 
insure vessel patency without complication. In the event the index procedure in the angiography guided arm 
becomes prolonged and a second procedure is needed to complete stent implantation, the blinded OCT run 
may be performed in the second procedure when the operator deems that target vessel treatment is 
complete.  No other intravascular imaging may be performed, and no additional treatment decisions may be 
made on the basis of the OCT image acquisition.  
 
6.5.3.3 
Randomization to OCT-guided stenting 
 
If the patient randomizes to OCT-guided stent implantation, stenting will be performed with OCT-guidance 
according to a slightly modified version of the ILUMIEN III:OPTIMIZE PCI algorithm,19 as described below 
(Figures 1a-b, 2 – 5). The procedure for OCT-guided stent implantation can be found in the flowchart in 
Figure 1a, and details for post-implant stent optimization can be found in the flowchart in Figure 1b. OCT is 
required pre- and post-stent implantation for patients randomized to OCT-guided stent implantation. The one 
exception is that in the case of a 2-stent bifurcation lesion: pre-stent OCT imaging is required in both main 
and side branches, but post-stent OCT imaging is required in the main branch only. Post-stent OCT imaging 
in the side branch is recommended but not required. For the evaluation of stent expansion in the side branch 
of 2-stent bifurcation lesions, MSA in the side branch will be compared to the side branch distal reference (i.e. 
division of the stented segment in side branch into halves is not required).  For any bifurcation, within a 
lesion, where the side branch is visually estimated to be ≥2.5mm, the branch must be protected with a guide 
wire during PCI to prevent abrupt closure, irrespective of whether it is planned for provisional or 2-stent 
strategy. 
 
Following completion of stenting in the target vessel (of one or two target lesions), when the angiographic 
appearance is considered optimal and all interventional equipment would be otherwise removed, a post-PCI 
OCT run is performed as depicted in Figure 6.  If additional PCI is required and performed based on the 
findings of the post-PCI OCT acquisition (to optimize the result based on the OCT findings per the modified 
OPTIMIZE PCI algorithm19), an additional OCT run must be performed to record the impact of the OCT-
guided optimization. Instructions for the management of suboptimal deployment characteristics of 
underexpansion, major malapposition, dissections and untreated reference segment disease is detailed in 
Section 6.5.3.7.  In the event the index procedure in the OCT arm becomes prolonged and a second 
procedure is needed to complete stent implantation, the post-PCI OCT run may be performed in the second 
procedure when the operator deems that target vessel treatment is complete.    
 
At least 100 µg of IC nitroglycerin or appropriate dosage of IC isosorbide dinitrate must be administered for 
each target vessel treated prior to the final angiographic and OCT image acquisition, unless precluded by low 
blood pressure.  
 
OCT images should be acquired using a 75 mm pullback over 2.1 seconds accruing 5 frames per mm. For 
standard pullback using power injectors (recommended) such as the ACIST or Medrad device, the 
recommended contrast injection volume is 14 ml at an injection rate of 4 ml/s in the left coronary artery and 
12 ml at an injection rate of 3 ml/s in the right coronary artery. For large vessels, excessive tortuosity or 
lesions in the distal 3rd of the culprit vessel, 4 ml/sec for 4 seconds and thus 16 mL of contrast is 
recommended. For operators using manual injection, the recommended contrast injection volume is 14 ml in 

 
  
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the left coronary artery and 12 ml in the right coronary artery. Performing cine angiography in the desired 
angiographic view(s) during OCT pullback to maximize utility of delivered contrast is mandatory.  
6.5.3.4 
Selection of the Stent Diameter by OCT 
Stent diameter will be determined by measuring the distal reference EEL to EEL diameter, if visible by OCT 
(which was the case in 77% of distal reference segments in ILUMIEN III:OPTIMIZE PCI 19) (Figure 1a). The 
stent diameter must be chosen using the EEL to EEL diameter(s) at the distal reference, rounded down to the 
next stent size. For example, if the distal reference EEL measures 3.2 mm x 3.1 mm, the mean EEL is 3.15 
mm, and thus a 3.0 mm stent diameter should be chosen.  
Note: In the case where the EEL is equal to an existing stent size, the stent chosen should be equal 
to the EEL measurement.  No rounding down is required.  
 
As described in Figure 1a, if the distal reference EEL cannot be identified, the stent diameter should be 
chosen using the mean lumen diameter at the distal reference, rounded up to the next stent size.  For 
example, if the distal reference lumen measures 2.5 mm x 2.6 mm, the mean lumen diameter is 2.55 mm, 
and thus a 2.75 mm stent diameter should be chosen.  If the distal reference EEL can be identified, it must be 
used instead of mean lumen diameter to choose the stent diameter.   
 
Note: In the case where the lumen diameter is equal to an existing stent size, the stent chosen should 
 
still be the next larger stent size.  Rounding up is always required.   
 
In cases where the luminal border cannot be adequately visualized by OCT, the reference sites and stent size 
(length and diameter) will be determined by angiography – such occurrences will be collected in the case report 
form and should be very infrequent.  
 
If a XIENCE stent of the appropriate diameter is commercially available but not in stock at the study site, a 
XIENCE stent diameter must be used that will adequately expand with post-dilatation to the intended 
dimensions; usually this will be the next smallest diameter.  If that XIENCE diameter size is also not available, 
a competitive DES of the appropriate diameter must be used and a protocol deviation must be recorded.  
 
The procedure for post-implant stent optimization per EEL diameter and per lumen diameter is shown in Figure 
1b.  Examples of EEL and lumen based measurements are shown in Figures 2 and 3. Note, the EEL need 
not be contiguous for the purposes of choosing stent diameter. If there is sufficient EEL present on either side 
of the vessel to allow measurement through the middle of the vessel (Figure 2C and C’), the EEL can and 
should be preferentially used to choose stent diameter.  
 
Planned use of only ≥2.5 mm and ≤3.5 mm stents and post-dilatation balloons based on pre-PCI angiographic 
visual estimation is required. If after pre-PCI OCT assessment it is determined from the procedure described 
above that stents and/or balloons larger (or smaller) than this diameter range should be used, this is acceptable 
and the proper diameter stents and/or post-dilatation balloons must be used per OCT protocol guidance. Note 
that in long tapering lesions, the use of large balloons should be limited to that portion of the stent where the 
EEL diameter measurements are at least as large as the stent or balloon diameter.  
 
There must be an intent to stent (planned stent implantation) of all target lesions for trial eligibility.  However, if 
OCT assessment of a target lesion with in-stent restenosis (ISR) shows that the predominant mechanism of 
the ISR is underexpansion (not neointimal hyperplasia), then balloon only treatment without additional stent is 
allowed.  
 

 
  
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6.5.3.5 
Assessment of the Target Lesion Length by OCT 
The proximal and distal reference segments are initially identified by angiography, and then confirmed by 
performing pre-procedural OCT pullback across the target segment (Figure 1a). In cases in which a severe 
stenosis would interfere with distal clearance of blood, or if the lumen border at both (proximal and distal) 
reference segments cannot be detected by OCT, vessel preparation is strongly recommended with balloon 
dilatation or other modalities (e.g. cutting balloon, atherectomy, thrombectomy, etc.) deemed necessary by 
the operator, followed by OCT.  
 
When the lumen borders at both reference segments can be measured, the reference sites will be decided by 
the position with the largest lumen using the OCT Lumen Profile software, where sufficient external elastic 
lamina is visible to allow measurement of stent diameter, typically several mm away from the angiographic 
lesion shoulders. If sufficient EEL cannot be visualized at the initially chosen reference cross-section, the 
reference cross-section is adjusted ±5 mm to identify a cross-section where the EEL is visible sufficient to 
allow stent diameter measurement. The stent length will be determined by measuring from the distal to the 
proximal reference site using the OCT Lumen Profile software. A XIENCE stent of appropriate length should 
be selected to be implanted in these reference segments if possible. See example in Figure 4.  If a XIENCE 
stent of the appropriate length is commercially available but not in stock at the study site, a competitive DES 
of the appropriate length must be used and a protocol deviation must be recorded. Overlapping XIENCE 
stents must only be used for planned treatment of long lesions where a XIENCE stent of appropriate length is 
not commercially available.  
 
 

 
  
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Figure 1a. Procedure for OCT-guided stent implantation.  Vessel diameter must be assessed by the EEL-
EEL diameter at the reference segment unless the EEL cannot be identified there.  

 
  
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Figure 1b. Procedure for post-implant stent optimization per EEL diameter and per lumen diameter  

 
  
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Figure 2. EEL measurement for determination of stent diameter. Stent diameter should be determined by measuring the distal reference mean-EEL diameter, if visible by OCT, 
rounded down to the nearest available Xience stent diameter. A-A’) The distal reference EEL measures 3.02 mm x 2.86 mm; the mean EEL is 2.94 mm, and thus a 2.75 mm diameter 
Xience stent should be chosen. B-B’) If only a single EEL measurement is possible, this measurement should be used for determination of stent diameter. In this case the distal reference 
EEL measures 3.80 mm. Thus a 3.50 mm diameter Xience stent should be chosen. C-C’) The distal reference EEL measures 3.88 mm. Note, a single EEL measurement is possible 
despite non-contiguous EEL measures. This measurement should be used for determination of stent diameter. Thus a 3.50 mm diameter Xience stent should be chosen. D-D’) The distal 
reference EEL can only be measured on a single side of the vessel, precluding the use of the EEL for measurement of stent diameter. The mean lumen diameter, upsized to the closest 
stent size, should be used to determine stent diameter. In this case the lumen diameter was 2.98 mm x 2.61 mm; the mean lumen reference diameter was 2.80 mm, and thus a 3.00 mm 
Xience stent should be chosen. 

 
  
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Figure 3. OCT-guided stent sizing.  
When the vessel diameter can be determined by EEL reference segment measurements, the mean EEL to 
EEL diameter should be used to determine stent diameter. Example A) Two measurements of vessel 
diameter from EEL to EEL are shown using the measurement function. 3.72 mm (white text) and 3.78 mm 
(blue text) corresponding to the white and blue measurement lines on the OCT cross-section. Per protocol 
the mean of these two measurements ((3.72+3.78)/2 = 3.75 mm) is rounded down to the nearest stent size, 
and therefore a 3.5 mm diameter stent is chosen. The distance from distal to proximal reference (red box) is 
28 mm, and thus a 3.5 x 28 mm Xience stent is chosen.  
When the vessel diameter cannot be determined by measurement to the EEL, the mean lumen diameter 
should be used to determine stent diameter. Example B) The EEL is only visible in a single quadrant of the 
OCT cross-section (white arrows). Automated measures identify the mean reference lumen diameter as 3.34 

 
  
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mm.  Per protocol the mean lumen diameter is rounded up to the nearest stent size, and therefore a 3.5 mm 
diameter stent is chosen. The distance from distal to proximal reference (red box) is 28.6 mm, and thus a 3.5 
x 28mm Xience stent is chosen.  
 
6.5.3.6 
Stent Implantation and Initial Optimization 
Stent implantation should be guided by angiographic co-registration, if available. Positioning stents at the 
intended segments can be confirmed with angiographic co-registration to improve the accuracy of stent 
placement and reduce geographic miss (Figure 5).    
 
After initial stent deployment and angiographic optimization procedures (including post-dilatation and/or 
additional stents as necessary), if the visually assessed residual angiographic diameter stenosis is >0%, 
OCT-guided PCI optimization based on the pre-PCI OCT run should be performed to achieve this 
angiographic target. Post dilatation should be performed in the angiographic segment with visually assessed 
diameter stenosis >0% using non-compliant balloons at ≥18 atmospheres with diameter no larger than the 
closest pre-PCI OCT mean reference vessel EEL (if the EEL is visible) (Figures 1b and 3), or if the EEL was 
not measurable, up to 0.5 mm larger than the closest pre-PCI OCT mean reference lumen diameter (Figures 
1b and 3).  
 
Important:  Caution should be exercised in the post-dilatation of long stented segments (≥28mm) in cases 
where the stent is located in a tapering vessel and/or where the stent covers multiple side branches.  Caution 
should also be exercised in the post-dilatation of lesions with severe calcification (especially calcific 
protruding nodule) or vessel angulation.  If there is underexpansion in one or more locations within the 
stented segment, post-dilatation should be limited to the underexpanded location(s) using a short focal 
balloon(s) (6 – 8 mm in length) having diameter that is appropriately matched to vessel size at that location. 
 
6.5.3.7 
Post-Stent Implantation OCT 
If after initial stent deployment, (including post-dilatation and/or additional stents as necessary), the visually 
assessed residual angiographic diameter stenosis is ≤0%, or pre-PCI OCT guided optimization has already 
been performed (as described in section 6.5.3.6) OCT should be performed to determine whether acceptable 
stent expansion is present (defined as MSA of the proximal segment ≥90% of the proximal reference lumen 
area and MSA of the distal segment ≥90% of the distal reference lumen area) (Figures 1b, 4-6). If the OCT 
catheter will not cross the lesion after stenting, additional post-dilatation is recommended to facilitate catheter 
passage. If based on the post-PCI OCT run acceptable stent expansion is not present, regardless of whether 
or not accompanied by major malapposition, post dilatation must be performed in the segment(s) with 
underexpansion using non-compliant balloons at ≥18 atmospheres with the balloon diameter no larger than 
the closest post-PCI OCT reference vessel EEL to EEL diameter (if the EEL is visible) (Figure 1b), or up to 
0.5 mm larger than the closest post-PCI OCT mean reference lumen diameter (if the EEL is not measurable) 
(Figure 1b).  In the event of balloon-only treatment of ISR lesions (where stent underexpansion is the primary 
mechanism for ISR), acceptable stent expansion may be defined as minimal lumen area (MLA) of the 
proximal segment ≥90% of the proximal reference lumen area and MLA of the distal segment ≥90% of the 
distal reference lumen area.  
 
After post-dilatation, OCT should be repeated to determine whether acceptable stent expansion has been 
achieved (Figure 4-6).  If underexpansion is revealed in the proximal and/or distal segments, at least one 
round of further stent optimization with higher inflation pressures and/or larger balloons is required.  However, 

 
  
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the diameter of the non-compliant post dilatation balloon chosen should not be larger than the post-PCI OCT 
determined mean reference vessel diameter (EEL) (Figure 1b), or no more than 0.5 mm larger than the 
mean reference segment lumen nearest to the dilatation site (if the EEL cannot be measured) (Figure 1b).  In 
situations where the reference EEL is very large ( 4.5 mm), the operator is asked to consider using the OCT 
automated mean reference segment lumen rounded up no more than 0.5 mm to select post-dilation balloon.  
While it is recommended that further PCI attempts be made until the protocol-defined optimal stent expansion 
is achieved, it is up to the operator to decide the number and degree of further interventions, at all times 
taking into account patient safety. 
 
If major malapposition (i.e. malapposition associated with unacceptable stent expansion) is detected by 
operator assessment during the procedure in the OCT-guided arm, further stent expansion must be 
performed. The degree of stent underexpansion (acceptable or unacceptable) should guide the intervention 
rather than amount of malapposition. 
 
If a long stent (≥28mm), was required to cover the lesion such that the proximal and distal reference lumen 
dimensions were different by ≥ 0.5 mm, then multiple non-compliant balloons of different diameters should be 
chosen for proximal and distal inflation to achieve optimal stent expansion in each stent segment with 
underexpansion. If the underexpansion is located in the midsegment of a long stent (≥28mm), post-dilatation 
within the middle segment should be performed with a balloon sized to the average of the proximal and distal 
reference measurements.  
 
For PCI optimization, whenever EEL-EEL measurement is possible, this measurement should be used rather 
than luminal measurements to optimize the respective segment (proximal or distal) of the stent with 
underexpansion. For example, if two opposing segments of EEL can be measured to choose stent diameter 
at the distal reference but not the proximal reference, and both are under-expanded post PCI, the distal 
segment of the stent should be treated using EEL-guided optimization (Figure 1b) and the proximal segment 
of the stent should be treated using lumen-guided optimization (Figure 1b). 
 
Following OCT-guided stent expansion optimization, the proximal and distal reference segments, defined as 
5mm from the edges of the stent, are examined for inflow/outflow disease (Figure 6).  If both the proximal 
and distal reference segments have an MLA ≥4.5 mm2, no further treatment is necessary. If there is untreated 
reference segment disease defined as focal MLA< 4.5 mm2 in either proximal or distal reference segments 
following the additional OCT run, an additional DES must be placed unless anatomically prohibitive (e.g. 
biological vessel tapering, distal diffuse disease, absence of landing zone, etc.). If there is a major edge 
dissection, defined as ≥60 degrees of the circumference of the vessel at site of dissection and ≥3 mm in 
length, it is recommended that additional DES be placed to correct the abnormality unless anatomically 
prohibitive (e.g. biological vessel tapering, distal diffuse disease, absence of landing zone, etc.).  
 
Following OCT-guided stent edge and reference segment optimization, the procedure should be complete 
and a final OCT run must be performed. If any other additional PCI is performed on the study lesion after 
OCT-guided stent edge and reference segment optimization, a final OCT run must be performed.  
 
If after OCT optimization, additional intervention is deemed necessary by the investigator, they are free to do 
so. but an additional OCT pullback with associated algorithmic assessment must always follow each round of 
optimization.  
 

 
  
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No further intervention may be performed following the final OCT, although coronary contrast injection 
or recorded cine angiogram may be taken to insure vessel patency without complication after wire and 
catheter removal.  
 
An example of the OCT guided protocol is shown in Figures 4-6.   
 
Figure 4. Pre-PCI OCT with proximal and distal reference images.  
A) OCT at baseline confirmed that the locations of the distal (blue) and proximal (red) reference segments as 
suggested by angiography were appropriate, being minimally diseased.  B) The lesion length was determined 
by OCT to be 28 mm (white bar). OCT cross-sectional images were scrolled from the edges of the lesion on 
either side to identify vessel segments with minimal disease and clearly identifiable EEL, resulting in the 
choice of a 34 mm long stent.  C) At the proximal reference segment approximately 180 degrees of EEL is 
visualized, allowing a single measurement of EEL for stent sizing through the middle of the vessel. The 
measured EEL diameter of the proximal segment (B, white line) was 4.02mm. A mean EEL diameter could 
not be calculated as only one EEL measurement could be made.  D) At the distal reference segment 360 
degrees of EEL are visualized, allowing multiple measurements of EEL for stent sizing. The measured EEL 
diameters of the distal reference segment were (B, white line) 3.00 mm and (C, blue line) 3.05 mm resulting 
in a mean EEL diameter of 3.03mm. The smallest mean EEL diameter from both distal and proximal 
reference segments was 3.03mm (distal reference) and per protocol this was rounded down to the nearest 
0.25mm and thus a 3.0 mm diameter by 34 mm long stent was chosen. 
 

 
  
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Figure 5. Angiographic co-registration guided stent implantation.  
A) OPTIS OCT angiographic co-registration is activated, allowing visualization of the proximal reference (red 
marker in Figure 5A, and panel C in Figure 4) and distal reference (blue marker in Figure 5A and panel D in 
Figure 4), and used as a reference screen to guide stent placement. 
B) Stent implantation location on real time fluoroscopy is based upon the OPTIS OCT angiographic co-
registration reference screen. 

 
  
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Figure 6 (previous page). Post PCI OCT with assessment of stent expansion. 
Following baseline OCT for stent selection, pre-dilatation with a 2.5 mm diameter x 15 mm compliant balloon 
at 12-14 atm was performed. Following this a 3.0mm diameter x 34 mm drug-eluting stent was implanted at 
12 atm. A) Angiography revealed 0% residual diameter stenosis and per protocol OCT was repeated. Per 
protocol the stent length was divided in half and criteria for MSA assessed in each half. B) In the proximal 
half of the stented segment, C) automated measures measured an MSA of 7.01mm2 and a proximal 
reference lumen area of 5.75mm2  (blue and yellow box) equating to a residual AS of 0.0% ([[1-(7.01/5.75)] 
x100] = -21.9% area stenosis) confirming criteria for optimal MSA were met. D) In the distal half of the 
stented segment, E) automated measures measured an MSA of 4.88mm2 (yellow box) and a distal reference 
lumen area of 5.99mm2  (blue box) and thus stent expansion was unacceptable ([1-(4.88/5.99)] x100] = 
18.5% area stenosis). Post-dilation was performed with a 3.0mm diameter x 15mm long non-compliant 
balloon focused to the area of underexpansion at > 20 atmospheres. F) Following post-dilation in the distal 
half of the stented segment, G) automated measures measured an MSA of 6.20mm2 and a distal reference 
lumen area of 5.98mm2  (blue and yellow box) and thus stent expansion was optimal ([1-(6.20/5.98)] x100] = -
3.6% area stenosis). OCT imaging post-stent demonstrated no major dissection, malapposition or 
tissue/thrombus prolapse.  
 
 
When there is a bifurcation (visually estimated side branch ≥2.5mm) within the lesion, rather than divide the 
stented segments into halves, the stent is divided at the midpoint of the bifurcation into proximal and distal 
segments. This facilitates measurement favoring native vessel biology and promotes the use of the proximal 
optimization technique (Figure 7). In situations where there is more than one ≥2.5 mm side branch 
bifurcation, the division into proximal and distal segment will be at the proximal most side branch.  
 

 
  
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Figure 7. Post-PCI OCT in a long lesion with a non-target lesion bifurcation (provisional)   
A) Angiography revealed 0% residual diameter stenosis, and thus per protocol OCT was repeated.  
B and C) Per protocol the stented segment was divided at the bifurcation, facilitated by 3-D 
bifurcation mode highlighting bifurcations ≥1.5mm (red dot in automated measures), and criteria for 
MSA assessed in each segment.  In the proximal segment, automated measures found an MSA of 
5.82 mm2 (green text) and a proximal reference lumen area of 7.36 mm2  (blue text) equating to a 
residual area stenosis (AS) of 20.9% ([[1-(5.82/7.36)] x100] = 20.9%), confirming criteria for MSA 
were not met and that post-dilation and proximal optimization technique need be performed.   
D and E) In the distal stented segment, automated measures found an MSA of 5.19 mm2 (yellow 
text) and a distal reference lumen area of 5.44 mm2 (blue text), and thus stent expansion was 
acceptable ([1-(5.19/5.44)] x100] = 4.6% area stenosis, or 95.4% stent expansion).  
 
 
In situations where there are multiple branches (≥1.5 mm – marked in the bifurcation automated measures 
feature of the OCT software) within close succession (e.g. septal-diagonal-septal), the operator must take 
care to not overlap the proximal optimization balloon across multiple branches. Rather, short focal balloons 
(6-8mm) should be used, ensuring that the proximal optimization balloon does not cross the largest branch. If 

 
  
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the distance to the carina from the proximal reference is shorter than the available length proximal post-
dilation balloon, the reference segment should be shifted to just distal to the 1st side branch, similar to the 
strategy used for stents that land across side branches. For optimization within long segments where there 
are multiple branches, the diameter of the short focal balloon(s) should be selected to match the reference 
vessel size within that segment. The appropriate reference segment therefore must be contained within the 
segment bounded by side branches. Recognition of this fact may thus require post-dilatation with several 
short non-compliant balloons of different diameters to accommodate the presence of multiple side branches. 
If following stent implantation in this scenario, there is insufficient length proximal to the first major side 
branch to perform proximal optimization technique, the reference diameter should be measured just distal to 
the 1st major side branch and this diameter used for post dilation balloon selection (Figure 8). 
 
Large diameter balloons ≥4.5 mm need not be used for post-dilatation if the operator is concerned about the 
possibility of severe vessel dissection or perforation, even if acceptable expansion has not been achieved 
with balloon of appropriate diameter and inflation pressure.  
 
 
Figure 8. OCT-guided PCI in the presence of multiple side branches. 
Following stent implantation, there is proximal underexpansion in this example.  Per protocol, the proximal 
segment of the stent should be post-dilated with a balloon sized to the proximal reference EEL, if visible, and 

 
  
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downsized to the nearest balloon diameter or the mean lumen diameter, upsized up to 0.5 mm if the EEL is 
not visible. However, in this example the length from the proximal reference (A) to the diagonal branch (B) is 
shorter than any commercially available balloon. Thus, if the proximal reference (A) EEL measurement (3.91 
mm) rounded down to the nearest balloon diameter (3.75 mm) were used even with the shortest available 
balloon length (6 mm) it would overlap and cross the bifurcation and be oversized. Instead, the correct 
approach in this example is to shift the proximal reference to (B) proximal reference’ (see diagram), just distal 
to the 1st major side branch. At that location the EEL measurement is 3.43 mm, and per protocol rounded 
down, would lead to a 3.25 mm non-compliant balloon for proximal post-dilation. 
 
 
6.5.3.8 
Multivessel PCI 
Patients requiring single or multi-vessel PCI may be enrolled in this trial, including either double or triple 
vessel disease.  Up to 2 target vessels may be randomized.  Refer to treatment rules below for cases with a 
second randomized target vessel. Up to 2 non-target vessels may also be treated, but only one non-target 
vessel may be treated during the index procedure. In the case of triple vessel disease, at least one non-target 
vessel must be treated outside the index procedure.  Refer to treatment rules below for non-target vessels.  
 
No more than 2 vessels may be treated during the index procedure.  The possible combinations of treated 
vessels during the index procedure are as follows: 
 
1. One vessel disease treatment: 1 target vessel randomized (with 1 or 2 target lesions, all of which must 
amenable to undergo OCT-guided stenting) 
2. Two vessel disease treatment:  
i) 2 target vessels randomized (each with 1 or 2 target lesions, all of which must amenable for 
undergo OCT-guided stenting) 
ii) 1 non-randomized non-target vessel treated (with no restriction on the number or type of lesions, 
but all must be treated successfully and without complication), followed by 1 target vessel 
randomized (with 1 or 2 target lesions, all of which must be amenable to undergo OCT-guided 
stenting) 
 
Non-target vessels: Non-randomized lesions requiring PCI in up to 2 non-target vessels may be treated 
either: 
a) >30 days prior to the study procedure (in 1 or 2 non-target vessels) if the procedure was unsuccessful or 
complicated; or  
b) >24 hours prior to the study procedure (in 1 or 2 non-target vessels) if the procedure was successful and 
uncomplicated (defined as a final lesion angiographic diameter stenosis <30% for all treated non-target 
lesions, with TIMI III flow in these vessels, without perforation, cardiac arrest or need for defibrillation or 
cardioversion or hypotension/heart failure requiring mechanical or intravenous hemodynamic support or 
intubation, and with no post-procedure biomarker elevation >normal; or  
c) during the study procedure (only 1 non-target vessel allowed), in which case all non-target vessel lesions 
must be treated prior to randomization and such treatment must have been successful and uncomplicated 
(defined more stringently as angiographic diameter stenosis <10% for all treated non-target lesions, with TIMI 
III flow in this vessel, without final dissection ≥ NHLBI type B, perforation anytime during the procedure, 
prolonged chest pain (>5 minutes) or prolonged ST-segment elevation or depression (>5 minutes), or cardiac 
arrest or need for defibrillation or cardioversion or hypotension/heart failure requiring mechanical or 
intravenous hemodynamic support or intubation); or  

 
  
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d) >48 hours after the index study procedure (in 1 or 2 non-target vessels).  
 
There is no restriction on the number and type of non-target lesions that can be treated in a non-target 
vessel.  PCI in non-target vessels may or may not be guided by OCT (or other intravascular imaging) 
according to operator preference.  XIENCE use is optional to treat non-target vessels; operators may use 
XIENCE or other DES at their discretion.  
 
A second randomized target vessel: Lesions requiring PCI in a 2nd target vessel (randomized lesions) may 
be treated during the index procedure (as long as no non-target vessels were treated during the same 
procedure) or staged >24 hours after the index procedure. However, all staged randomized procedures must 
be completed within 2 months (preferably 1 month) after the study procedure. The intent to stage such 
lesions should be declared at the time of randomization, but the decision to stage a randomized vessel which 
was not originally planned for staging may be modified in the case report form within 24 hours of the 
procedure to reflect changes in procedural strategy that may arise from the index PCI (e.g. treatment of the 
first vessel took longer than expected, or was complicated). The original treatment assignment must be used 
to guide all staged procedures. All staged procedures must be performed in a second target vessel – i.e. 
staged procedures cannot occur in a second lesion in the first target vessel treated during the index 
procedure. In no case, however, may a target vessel be randomized which was not declared as intended for 
study randomization prior to randomization.  Note that for staged procedures, the assessments of troponin 
and/or CK-MB and a 12-lead ECG must be repeated within 8-16 hours prior to the staged procedure. If 
troponin and/or CK-MB readings are abnormal, they must be assessed either 8-16 hours after the last 
measurement or drawn from the sheath at the time of the procedure so a curve may be established for peri-
procedural MI adjudication. Note: patients with stable CAD may have the biomarker drawn from the sheath 
prior to any intervention, and the result does not need to be available prior to treatment. 
 
Example: A stable CAD patient has a significant mid-RCA lesion and a mid-LAD-D1 bifurcation lesion (the 
latter representing a qualifying target lesion). If the mid-RCA lesion is a non-target lesion (i.e. not declared 
as a target lesion at the time of randomization), it may be treated a) >30 days prior to the procedure in all 
cases, or b) >24 hours prior to the procedure if its treatment was successful and uncomplicated; or c) 
during the procedure but prior to randomization and treatment of the LAD target vessel (if treatment of the 
RCA lesion is angiographically successful and uncomplicated – if not, randomization of the LAD lesion 
MAY NOT take place during the same procedure [but may still occur >30 days later if desired); or d) >48 
hours after treatment of the randomized LAD lesion. If the mid-RCA lesion is also declared as a target 
lesion in a second target vessel at the time of randomization (meeting criteria either because it has 
qualifying angiographic high-risk characteristics, or if the patient has diabetes), it may be treated after 
randomization either a) during the index procedure in which the LAD is treated (either before or after LAD 
treatment), or b) >24 hours after the procedure, in which case its treatment as a planned staged procedure 
is noted in the case report form either before or within 24 hours after LAD treatment.  
 
If a patient has 2 vessels that require treatment during the index procedure and both meet eligibility criteria 
and qualify as target vessels, at investigator discretion it is permitted to designate one vessel as non-target 
and the other vessel as target.  However, it is encouraged to randomize all qualifying target vessels unless 
investigator judgment dictates otherwise.  
 
If a patient has 3 vessels where all meet eligibility criteria and would qualify as target vessels – since no more 
than 2 target vessels may be randomized, it is permitted to designate one of the 3 eligible vessels as non-
target.  However, it is encouraged to randomize 2 qualifying target vessels unless investigator judgment 
dictates otherwise.   

 
  
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Multivessel disease treatment flow diagrams depicting the permitted combinations of target and non-target 
lesions are summarized below in Figures 9-10 for 2-vessel disease and Figures 11-12 for 3-vessel disease.  
 
Figure 9. 2-Vessel Disease Treatment:  2 Target Vessels.  
 
 
 
Figure 10. 2-Vessel Disease Treatment:  1 Target Vessel / 1 Non-Target Vessel.  

 
  
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Figure 11. 3-Vessel Disease Treatment:  1 Target Vessel / 2 Non-Target Vessels.  
 
 
 
 
Figure 12. 3-Vessel Disease Treatment:  2 Target Vessels / 1 Non-Target Vessel.  

 
  
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6.5.4 
Post procedure 
All patients must have either a troponin level and/or a CKMB level (CK-MB preferred) drawn at 6-10 hours 
post PCI. The same biomarkers as those drawn at baseline should be assessed post-PCI. If the results are 
abnormal (>upper limits of normal), regardless of clinical significance, or if any procedural complications 
developed (temporary or sustained TIMI flow <III (visually assessed) in any vessel, or dissection ≥ NHLBI 
type B, or perforation, or prolonged ST-segment elevation or depression (>5 minutes), or cardiac arrest or 
need for defibrillation or cardioversion or hypotension /heart failure requiring mechanical or intravenous 
hemodynamic support or intubation), a second post-PCI troponin level and/or CK-MB level must be drawn at 
6-10 hours after the first post-PCI biomarker draw or at discharge.  In the event of high sensitivity troponin 
use (which is not recommended), an elevation of <7X ULN in the first (6-10 hr) post-PCI blood draw will not 
require an additional level, unless any procedural complications developed.  
 
At least one 12-lead ECG must be performed within 24 hours post PCI in all patients.  
 
A serum creatinine level must be drawn the calendar day after PCI or before discharge, whichever is earlier. 
If the subject develops contrast induced nephropathy (defined as an increase in serum creatinine ≥25% or an 
absolute increase of ≥0.5mg/dl (44.2µmol/L)), regardless of clinical significance, it is recommended that serial 
creatinine levels be drawn daily until the peak is reached and the creatinine is decreasing. 
 
A serum hemoglobin must also be drawn the calendar day after PCI or before discharge, whichever is earlier. 
If the subject develops overt bleeding, or the hemoglobin level has fallen more than 3 g/dL (30 g/L) in the 
absence of overt bleeding, serial hemoglobin levels must be drawn at least daily until a nadir is reached or 
the hemoglobin level has stabilized. 
 
The following considerations apply to subjects having staged procedures:   
• 
The protocol required post-procedure serum creatinine, cardiac enzyme and 12-lead ECG 
assessments must be repeated for the staged procedure as done for the original index procedure.  
• 
The follow-up regimen of aspirin and P2Y12 receptor inhibitor (dosage requirements and timing) 
must be maintained following the staged procedure as done for the original index procedure.  
• 
The follow-up period is considered as having begun upon completion of the original index procedure.   
 
The timing and method of vascular sheath removal, as well as timing of ambulation, use of post-procedural 
medications and discharge is per standard of care. Aspirin must be continued indefinitely. DAPT must be 
continued for at least 6 months in patients with stable CAD and for at least 12 months in patients who 
presented with acute coronary syndrome unless the patient is also taking chronic oral anticoagulation in 
which case a shorter duration of DAPT may be prescribed per local standard of care. Post-procedural 
medication use should not vary according to randomization assignment.  
 
6.5.5 
Scheduled Follow-ups 
All patients enrolled in the study will be followed with clinic visit or phone calls at 30 (±7) days, 1 year (±30 
days) and 2 years (±30 days) by the authorized study personnel at the study site.  
• 
30-day Follow-Up 
Telephone or clinic visit follow-up at 30 days (± 7 days) including: 

 
  
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• 
Adverse events, medications, laboratory tests and 12-lead ECGs (if performed)   
• 
12 Month Follow-Up 
Telephone or clinic visit follow-up at 12 months (± 30 days) including: 
• 
Adverse events, medications, laboratory tests and 12-lead ECGs (if performed)  
• 
24 Month Follow-Up 
Telephone or clinic visit follow-up at 24 months (± 30 days) including: 
• 
Adverse events, medications, laboratory tests and 12-lead ECGs (if performed)  
6.6 
Patient Reported Outcome (PRO) Measures 
The Study Coordinator or designee will administer patient-reported outcome questionnaires. It is important 
the subject understands the meaning of all words and instructions in the questionnaires. The subject should 
be instructed to ask any questions about the questionnaires if further explanation is needed. Once the 
questionnaires are completed, the Study Coordinator or designee will review for completeness to verify that 
all questions have been answered according to the directions provided.  
 
The following PRO measures will be collected according to the study requirements. 
 
• 
EuroQoL 5D (EQ-5D-5L) to assess Overall Health Status in hospital (required at baseline, optional 
post-procedure), and at 30 day, 12 month and 24 month follow-up   
 
6.7 
Unscheduled Visits 
Any patient, who develops cardiac symptoms or a major adverse cardiac event during the follow-up period 
should be evaluated by the investigator by telephone contact or clinic visit as deemed appropriate.  
 
Requisite data are listed: 
• 
Adverse events, medications, laboratory tests and 12-lead ECGs (if performed) 
 
For any occurrence during follow-up of an ADE/SAE or potential TVF or MACE event, detailed records of that 
event, including but not limited to hospitalization records (admission record, discharge summary, 
catheterization and operative reports, and other supporting data as required) must be collected and sent to 
the Sponsor. Any follow-up angiograms and OCT imaging studies must be sent to the core laboratory for 
analysis. 
 
For all randomized patients returning to the enrolling institution during the follow-up period with a cardiac 
event that requires cardiac catheterization, OCT imaging should be conducted at the time of the 
catheterization in the target vessel coronary distributions (both in the OCT-guided and angiography-guided 
patients).  A three-vessel angiogram should also be performed. These studies must be submitted to the core 
laboratory for analysis. These additional steps should never unduly jeopardize patient safety. If a patient 
develops any TVF or MACE event, or requires repeat hospitalization or repeat angiography following the 
index catheterization, these events must be documented in the eCRF. Copies of charts, lab values, 
examinations and a copy of the angiogram and all diagnostic procedures performed (e.g. OCT) must be 
submitted to the Sponsor.  
 

 
  
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6.9 
Health Care Economic Data Collection 
Data on cardiovascular-specific resource utilization and will be collected prospectively for the index 
hospitalization and the full follow-up period using standardized case report forms. Procedural costs will be 
assessed using a resource-based approach to convert standard measures such as procedural duration and 
device utilization (e.g., stents, balloons, guidewires, etc.) into costs. Other hospital costs will be assessed 
using an “event-driven” approach in which specific complications and outcomes are assigned standard costs 
based on external data. Additional costs will be assigned for follow-up hospitalizations and repeat 
revascularization procedures, emergency room visits, outpatient diagnostic testing, and cardiovascular 
medications. In each case, costs will be assessed from the perspective of the U.S. healthcare system.  
 
Cost and quality of life data will be used to perform a cost-effectiveness analysis from the perspective of the 
U.S. healthcare system. 
6.10 
Description of Activities Performed by Sponsor Representatives 
The Sponsor is responsible for selecting qualified investigators, obtaining a signed investigators’ agreement, 
and providing them with the information needed to conduct the investigation properly, ensuring the protection 
of human patients enrolled in the study, and identifying and distributing significant new information relevant to 
the investigation to the investigators. The Sponsor will evaluate circumstances where an investigator deviates 
from the CIP, and will retain the right to remove either the investigator or the investigational site from the study. 
 
Trained Sponsor personnel will provide technical expertise and technical guidance on the use of the OPTIS 
system and Dragonfly Catheter, including training and proctored case coverage, as appropriate. 
 
While Sponsor representatives may perform these activities, the Principal Investigator remains responsible 
for ensuring all clinical investigation data is collected as required per CIP. 
6.11 
Subject Study Completion 
Subject participation in the clinical investigation will conclude upon completion of the 24-month visit. Upon 
completion of subject participation in the clinical investigation, the subject will return to standard of care. 
6.12 
Subject Withdrawal 
Subjects must be informed about their right to withdraw from the clinical investigation at any time and for any 
reason without sanction, penalty or loss of benefits to which the subject is otherwise entitled. Withdrawal from 
the clinical investigation will not jeopardize their future medical care or relationship with the investigator. 
Subjects will be requested to specify the reason for the request to withdraw. The investigator must make all 
reasonable efforts to retain the subject in the clinical investigation until completion of the clinical investigation. 
 
In case of subject withdrawal, the site should make attempts to schedule the subject for a final study visit. At 
this final study visit, the subject will undergo the following assessments: 
• 
Adverse events, medications, laboratory tests and 12-lead ECGs (if performed)  
 
A subject will be considered ‘Lost to Follow-up’ after 2 consecutive missed visits and a minimum of two 
unsuccessful phone calls from investigational site personnel to the subject or contact to schedule the next 
follow-up visit. These two phone calls must be documented in the subject records. If the subject is deemed 
lost to follow-up a letter must be sent to the subject’s last known address or to the subject’s general 

 
  
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practitioner (GP) or family physician and a copy of the letter must be maintained in the subject’s hospital 
records. 
6.13 
Study Committees 
6.13.1 
Steering Committee (SC) 
A Steering Committee will advise the Sponsor on key aspects related to the development, execution, analysis 
and reporting, and overall conduct of the clinical investigation. A Steering Committee charter will define 
membership of the committee and outline the purpose, roles, responsibilities, and general rules of operation 
for the Steering Committee. This charter is maintained by the Sponsor and sets forth the procedures for the 
implementation of the Steering Committee. 
6.13.2 
Publication Committee (PC) 
A Publication Committee shall be established to oversee study publications. Publication Committee 
membership may include members of the Steering Committee, investigators, representative(s) of Abbott and 
statisticians. The Publication Committee will be responsible for identifying, selecting and approving 
publication proposals and determining authorship according to a Publication Plan.  A Publication Committee 
charter will define membership of the committee and outline the roles and responsibilities of the committee, 
as well as rules to define authorship. 
6.13.3 
Data Safety Monitoring Board (DSMB) 
An independent DSMB will review on a regular basis accumulating data from the clinical investigation and will 
advise the Sponsor regarding the continuing safety of subjects and those yet to be recruited, as well as the 
continuing validity and scientific merit of the clinical investigation. DSMB members will not be investigators in 
the clinical investigation. At any time during the investigation, the DSMB may offer opinions or provide formal 
recommendations concerning aspects of the study that impact subject safety (e.g. safety-related protocol 
changes or input regarding study-related adverse event rates). 
 
All events associated with the baseline imaging and or stenting procedure will be reported to the Data and 
Safety Monitoring Board (DSMB) and reviewed on a regular basis. The DSMB may request additional 
information as needed. Based on safety data, the DSMB may recommend to the Sponsor and Steering 
Committee to stop or otherwise modify the study. The Sponsor will make the final decision after weighing the 
recommendation of the DSMB whether the study should then be stopped, modified or continued without 
change. The DSMB procedures will be described in the DSMB Charter. 
 
The primary function, responsibilities and membership of the DSMB will be described in detail in a DSMB 
charter. 
6.13.4 
Clinical Events Committee (CEC) 
An Independent Clinical Events Committee (CEC) will be established and will be comprised of interventional 
and/or non-interventional cardiologists who are not participants in the study and are independent from the 
study. The CEC will review death, MI, stent thrombosis, repeat revascularizations, and intra-procedural 
complications (to determine their relationship to the imaging catheter).  The CEC will also adjudicate the 
coronavirus disease 2019 (COVID-19) relatedness of a clinical endpoint event.  The Committee procedures 
will be specified in the CEC charter.  

 
  
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7 
Statistical Considerations 
The following section describes the statistical methods for the clinical investigation and justification of the 
design. Additional details on statistical analyses, including sensitivity analyses, poolability analyses, subgroup 
analyses and analysis of descriptive endpoints are maintained in a separate Statistical Analysis Plan (SAP).  
7.1 
Endpoints 
7.1.1 
Primary Endpoint of MSA and Hypothesis 
The primary endpoint of MSA is Post-PCI MSA measured by OCT in each randomized arm, as measured at 
the Cardiovascular Research Foundation OCT Core laboratory, which is blinded to imaging modality 
assignment. 
 
Let M(OCT) be the mean MSA in OCT-guided arm, while M(Angio) is mean MSA in angiography-guided arm.  
The following hypothesis will be tested: 
H0: M(Angio) - M(OCT) ≥ 0 
H1: M(Angio) - M(OCT) < 0 
The null hypothesis will be tested at the one-sided 2.5% significance level 
 
 
 
7.1.1.1 
Analysis Methodology  
 
  
 
 
 
 
  
 
7.1.1.2 
Sample Size Determination 
 
 
 
 
 
 
a sample size of 1600 randomized subjects will provide at least 95% power to demonstrate 
superiority of treatment.   
 
7.1.1.3 
Analysis Population 
The primary endpoint of MSA will be tested in all randomized subjects in whom one or more stents were 
implanted at a target lesion.  Subjects who were randomized but in whom a stent was not implanted at a target 
lesion will be excluded.  
 
 
7.1.2 
Primary Endpoint of TVF and Hypothesis 
The co-primary effectiveness endpoint is the rate of target vessel failure (the composite of cardiac death, target 
vessel MI (per primary protocol definition [see Appendix B]) and ischemia-driven target vessel 

 
  
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revascularization) at 2 years. For patients with multiple target vessels, TVF in either or both target vessels 
constitutes an endpoint event. 
 
The following hypothesis will be tested for the analysis on TVF. 
H0: H(OCT) / H(Angio) ≥ 1 
H1: H(OCT) / H(Angio) < 1 
where H(OCT) and H(Angio) are hazard function for the OCT-guided arm and angiography-guided arm.  The 
null hypothesis will be tested at the one-sided 2.5% significance level. 
 
  
 
  
 
 
 
 
 
 
 
7.1.2.1 
Analysis Methodology  
 
 
 
 
  
 
 
  
 
7.1.2.2 
Sample Size Determination 
 will provide 90% power at a one-sided significance level of 0.025, which is 
associated with approximately 2490 subjects. If an interim analysis indicates a sample size increase, the 
enrollment can be adjusted up to a total of 3656 subjects.  
7.1.2.3 
Analysis Population 
The primary endpoint of TVF will be tested in all randomized subjects by intention-to-treat; subjects will be 
analyzed according to their randomized group regardless of the device attempted or implanted.  
7.1.3 
Major Secondary Endpoint of TVF Excluding Periprocedural MI and Hypothesis 
The major powered secondary endpoint is the rate of target vessel failure excluding periprocedural MI (the 
composite of cardiac death, target vessel-related spontaneous MI or ischemia-driven target vessel 
revascularization).  For patients with multiple target vessels, TVF excluding periprocedural MI in either or both 
target vessels constitutes an endpoint event.  
 
The following hypothesis will be tested for the analysis on TVF excluding periprocedural MI. 
H0: H(OCT) / H(Angio) ≥ 1 
H1: H(OCT) / H(Angio) < 1 
where H(OCT) and H(Angio) are hazard function for the OCT-guided arm and angiography-guided arm.  The 
null hypothesis will be tested at the one-sided 2.5% significance level. 
 

 
  
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7.3 
Overall Sample Size 
The sample size required for evaluation of the first primary endpoint of MSA is 1600 randomized subjects, 
while the sample size for the primary endpoint 
(approximately 2490 subjects). If an 
interim analysis suggests a sample size increase, up to a maximum of 3656 subjects will be randomized.  
7.4 
Timing of Primary Endpoint Analysis 
There will be two analyses planned in the trial. The interim analysis of MSA will be conducted when 1600 
randomized subjects are enrolled with procedures completed. If the superiority in the OCT-guided arm is 
demonstrated, the second analysis of TVF will be implemented when the pre-specified number of adjudicated 
TVF events are reached.  
7.5 
Success Criteria 
The trial has two primary endpoints for MSA and TVF to compare the effectiveness of the OCT-guided PCI 
against the angiography-guided PCI.  Both primary endpoints must be met in order to claim the study 
success.  
7.6 
Interim Analysis 
 
 
 
  
 
 
  
7.7 
Multiplicity Adjustment 
 
  
7.8 
Sensitivity Analyses  
 
  
 
As referenced in Section 5.3.3, the impact of the SCAI definition of periprocedural MI will be reported as 
sensitivity analyses at 30 days, 1 year and 2 years for the endpoints TV-MISCAI, Periprocedural MISCAI, All 
MISCAI and TVFSCAI.  
 
Sensitivity analyses for the primary and major secondary endpoints will be performed by removing the impact 
of COVID-19 if applicable. Details are provided in the SAP.   
7.9 
Statistical Criteria for Termination 
 
   

 
  
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7.10 
Deviations from Statistical Plan 
If any deviations from the original statistical plan occur, such deviations will be documented in the clinical 
study report or statistical report containing the analysis results. 
8 
Risks and Benefits 
The risk analysis included an objective review of published and available unpublished medical and scientific 
data. The sections below provide an overview of residual risks identified in the risk management report and 
anticipated benefits of the medical device. The risks associated with the Dragonfly Imaging Catheter can be 
found in the Instructions for Use.  
8.1 
Risks Associated with the Study Devices 
The risks involved in vascular imaging include those associated with all catheterization procedures. The 
following complications may occur as a consequence of intravascular imaging and may necessitate additional 
medical treatment including surgical intervention.   
 
• 
Allergic reaction to the contrast media or drug administered for the procedure 
• 
Bleeding 
• 
Arterial dissection, injury, or perforation 
• 
Abnormal heart rhythm or arrhythmias 
• 
Unstable angina 
• 
Coronary artery spasm 
• 
Thrombus formation, abrupt closure, or total occlusion 
• 
Embolism 
• 
Myocardial ischemia 
• 
Acute myocardial infarction  
• 
Repeat revascularization 
• 
Renal insufficiency or failure from contrast media use 
• 
Death 
• 
Potential Adverse events: 
o 
Catheter access site reactions: sterile inflammation or granuloma 
o 
Tissue necrosis 
 
In the St. Jude Medical prospective multi-center study, under a significant risk IDE application, one (1/59, 1.7%) 
subject had a serious adverse event which was judged by the DSMB to be related to the procedure but not the 
device. No subjects died during the clinical study. One (1/59, 1.7%) subject had a device-related adverse events 
which was sinus bradycardia although this event was not determined to be serious. In the ILUMIEN 
III:OPTIMIZE PCI study, procedural major adverse events were not different between intracoronary imaging 
(OCT and IVUS) and angiography guidance.19 The use of OCT requires additional contrast media which may 
potentially increase the risk of acute kidney injury, but there were no occurrences of acute renal failure ILUMIEN 
III study.19 Since the devices are currently on the market, the risk profile is known and the risk/benefit ratio is 
reasonable for this study.  
 
Observed and potential adverse events occurring with the XIENCE family of stents are listed in the IFUs.  
The incidence of these adverse events is comparable to other PCI devices. There may be risks related to the 
device that are unknown at present.  
 

 
  
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8.1.1 
Residual Risks Associated with Study Devices 
Possible adverse events associated with the introduction of an imaging catheter are: dissection, thrombosis, 
distal embolization, abrupt closure of the vessel, rupture, bleeding, coronary artery spasm, myocardial 
ischemia or infarction, unstable angina and cardiac arrhythmias.  
Possible adverse events associated with additional use of contrast media or drugs administered during the 
procedure: allergic reaction, renal insufficiency or failure. Other potential adverse events associated with the 
catheter insertion site are sterile reactions, inflammation, granuloma-formation or tissue necrosis.      
 
The XIENCE Risk Assessment Report utilizes the Failure Modes and Effects Analysis (FMEA) tool to 
systematically identify potential hazards associated with the process, design, components, and use of the 
XIENCE product family. Based upon preclinical, clinical, bench data, and commercial post-production data, 
all residual risks are appropriate and acceptable.   
8.2 
Risk Control Measures 
 
Every possible effort will be taken to minimize the risks, including: 
• 
Careful selection of experienced Investigators for the clinical investigation  
• 
Adequate monitoring for clinical investigation sites 
• 
Conducting the clinical investigation in accordance with the CIP, all applicable laws and regulations 
and any conditions of approval imposed by the appropriate IRB/EC or applicable regulatory 
authorities where the clinical investigation is performed 
• 
Preparation of the Dragonfly Imaging Catheter device and performance of the ILUMIEN OPTIS, 
OPTIS Integrated, and OPTIS Mobile systems will be in accordance with the device IFUs 
• 
Training of Investigators both on the CIP and the OPTIMIZE PCI algorithm.  
• 
Futility analysis will be conducted to limit exposure of subjects to an ineffective procedure 
 
All events associated with the baseline imaging and or stenting procedure will be reported to the 
Data and Safety Monitoring Board (DSMB) and reviewed on a regular basis. The DSMB may 
request additional information as needed. Based on safety data, the DSMB may recommend to the 
Steering Committee to stop or otherwise modify the study. The Steering Committee will make the 
final decision after weighing the recommendation of the DSMB whether the study should then be 
stopped, modified or continued without change. The DSMB procedures will be described in the 
DSMB Charter. 
8.3 
Possible interactions with concomitant treatments 
No interaction with concomitant treatment is anticipated.  
8.4 
Anticipated Benefits 
Additional imaging with OCT may benefit patients enrolled in the study. The knowledge of vessel diameter 
and lesion characteristics will help to choose the correct stent size and to optimize implantation which in turn 
can reduce stent thrombosis and prevent in-stent restenosis. Also, in the OCT arm, post stenting imaging 
allows to detect and treat sub optimal results, such as edge dissections, tissue protrusion, malapposition or 
under-expansion. Stent optimization may lead to better clinical outcome.   

 
  
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8.5 
Risk-to-Benefit Rationale 
The excellent safety profile of XIENCE family of stents has been well demonstrated.  Comprehensive 
analysis of product level clinical data, including clinical trial, post-marketing, and literature data, confirms that 
any undesirable risks identified are outweighed by the clinical benefits of XIENCE.  Stent optimization with 
OCT use may lead to better clinical outcome.  All procedures required by the protocol are conducted 
according to current clinical practice, and participation in this trial carries no additional risk to the patient.  
Since the devices are currently on the market and considering the risk profile described above and the 
potential benefits, the risk/benefit ratio is reasonable for this study.  
8.6 
History of Device Modifications or Recall 
There have been no modifications or recall in relation to safety and clinical performance of the devices to be 
used in this study.  
 
9 
Requirements for Investigator Records and Reports 
9.1 
Deviations from CIP 
The Investigator should not deviate from the CIP for any reason except in cases of medical emergencies 
when the deviation is necessary to protect the rights, safety and well-being of the subject or eliminate an 
apparent immediate hazard to the subject. In that event, the Investigator will notify Sponsor immediately by 
phone or in writing.  
 
No waivers for CIP deviations will be granted by the Sponsor.  All deviations must be reported to the Sponsor 
using the Deviation CRF. The occurrence of CIP deviations will be monitored by the Sponsor for evaluation of 
investigator compliance to the CIP and regulatory requirements and dealt with according to written 
procedures. Investigators will inform their IRB/EC or equivalent committee of all CIP deviations in accordance 
with their specific IRB/EC or equivalent committee reporting policies and procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or company 
representative will attempt to secure compliance by one or more of the following (and not limited to):  
• 
Visiting the investigator and/or delegate 
• 
Telephoning the investigator and/or delegate 
• 
Corresponding with the investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the CIP or any other conditions of the clinical 
investigation may result in further escalation in accordance with the Sponsor’s written procedures, including 
securing compliance or, at its sole discretion, Sponsor may terminate the investigator's participation in the 
clinical investigation.   
 
10 
Adverse Events 
To comply with worldwide standards and guidelines on clinical trial adverse event reporting, Abbott Vascular 
has developed uniform and worldwide applicable standard definitions and reporting timelines to be used and 
adhered to by the investigators.  

 
  
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10.1 
Definitions 
10.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or untoward 
clinical signs (including abnormal laboratory findings) in subjects, users or other persons, whether or not 
related to the medical device.  
 
Note 1: This definition includes events related to the medical device or the comparator. 
Note 2: This definition includes events related to the procedures involved. 
Note 3: For users or other persons, this definition is restricted to events related to medical devices. 
 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medical device, whether or not related to the 
medical device.  
 
10.1.2 
Serious Adverse Event 
If the AE meets any of the criteria below, it is regarded as a serious adverse event (SAE).  
a) Led to a death, 
b) Led to a serious deterioration in health that either: 
1) Resulted in a life-threatening illness or injury, or 
2) Resulted in a permanent impairment of a body structure or a body function, or 
3) Required in-patient hospitalization or prolongation of existing hospitalization, or 
4) Resulted in medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
5) Resulted in chronic disease 
c) Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note 1: This includes device deficiencies that might have led to a serious adverse event if a) suitable action 
had not been taken or b) intervention had not been made or c) if circumstances had been less fortunate. 
These are handled under the SAE reporting system. 
Note 2: A planned hospitalization for pre-existing condition, or a procedure required by the CIP without a 
serious deterioration in health, is not considered to be an SAE. 
 
10.1.3 
Adverse Device Effect (ADE) 
An adverse event related to the use of an investigational medical device.  
 
This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
 
This definition includes any event resulting from the use error or from intentional misuse of the investigational 
medical device. 
 

 
  
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10.1.4 
Device Deficiency/Device Malfunction 
Device deficiency (DD) is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance, such as malfunction, misuse or use error and inadequate 
labeling. This includes the failure of the device to meet its performance specifications or otherwise perform as 
intended.  
 
Note: Performance specifications include all claims made in the labeling of the device. 
 
A device malfunction (DM) is the failure of a device to meet its performance specifications or otherwise 
perform as intended, when used in accordance with the instructions for use or the trial protocol.  
 
10.1.5 
Unanticipated (Serious) Adverse Device Effect 
Unanticipated (serious) adverse device effect [U(S)ADE] refers to any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the study plan or 
application (including a supplementary plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or welfare of subjects. 
 
10.2 
Safety Reporting 
Safety surveillance and reporting starts as soon as the patient is randomized (or included as a roll-in subject) 
in the clinical investigation. Safety surveillance and reporting will continue until the last follow-up visit has 
been performed, the subject is deceased, the subject concludes participation in the clinical investigation or 
the subject withdraws from the clinical investigation.  
 
Adverse event data will be collected throughout the time period defined above and will be reported to the 
Sponsor on a CRF. Additional information with regard to an adverse event should be updated within the 
appropriate CRF.  
 
For the purposes of this investigation the following adverse events will be reported: 
▪ 
All serious adverse events 
▪ 
All device and procedure-related adverse events 
▪ 
Unanticipated (serious) adverse device effects 
 
In addition, the following adverse events regardless of seriousness or relatedness will be collected: 
▪ 
Myocardial infarction 
▪ 
Revascularization 
▪ 
Stent thrombosis 
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be reported. 
Non-cardiac related abnormal laboratory values will not be considered AEs unless:  
▪ 
the investigator determined that the value is clinically significant,  
▪ 
the abnormal lab value required intervention, or  
▪ 
the abnormal lab value required subject withdrawal from the clinical investigation. 
 
The investigator should report all SAEs to the Sponsor as soon as possible but no later than outlined below.  

 
  
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Clinical Site 
Reporting timelines 
All Sites 
SAEs must be reported to the Sponsor no later than 3 calendar days from the day 
the site personnel became aware of the event or as per the investigative site’s local 
requirements, if the requirement is more stringent than those outlined above. 
 
The date the site staff became aware the event met the criteria of an SAE must be recorded in the source 
document.  The Investigator will further report the SAE to the local IRB/EC according to the institution’s 
IRB/EC reporting requirements.   
 
An offline form will be made available to allow the investigator to report SAEs in the event the entry cannot be 
made in the EDC. This does not replace the EDC reporting system. All information must still be entered in the 
EDC system as soon as feasible. 
 
Additional information may be requested by the Sponsor in order to support the reporting of AEs to regulatory 
authorities. The investigator must notify the IRB/EC, if appropriate, in accordance with national and local laws 
and regulations, of the AEs reported to the Sponsor.  
 
10.2.1 
Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC 
Abbott Vascular requires the Investigator to report any USADE to the sponsor within 3 calendar days of the 
investigator’s knowledge of the event, unless local requirements are more stringent, and to the EC per EC 
requirements.  
10.2.2 
Device Deficiency/Device Malfunction Reporting  
 
All device deficiencies/malfunctions should be reported within the EDC System on the appropriate eCRF 
form. A fax form will be made available to allow the investigator to report device deficiencies/malfunctions in 
the event that the entry cannot be made in the EDC. This does not replace the EDC reporting system. All 
information must still be entered in the EDC system as soon as feasible.  
In case a device deficiency/malfunction occurred before the patient ID has been assigned, the device 
deficiency should be reported to the Sponsor via the fax form. 
The investigator should report all DDs/DMs to the Sponsor as soon as possible but no later than outlined 
below:  
Trial sites 
Reporting timelines 
All Sites 
DDs/DMs must be reported no later than 3 calendar days from the day the 
trial personnel became aware of the event or as per the trial site’s local 
requirements, if the requirement is more stringent than those outlined. 
The device, if not implanted or not remaining in the subject, should be returned to Abbott Vascular.   
Device deficiencies/malfunctions should be reported to the EC per the trial site’s local requirements.  
 

 
  
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10.2.3 
Adverse Event Reporting to Country Regulatory Authorities by the Sponsor  
The Sponsor or designee will report the SAEs and DDs/product experiences (PEs) to the country regulatory 
authority, per local requirements.  
 
10.3 
Safety Monitoring by Data Safety Monitoring Board (DSMB) 
The DSMB will serve in an advisory role to Abbott Vascular to ensure safety by reviewing cumulative data 
from the clinical trial at prescribed intervals for the purpose of safeguarding the interests of trial participants.  
The DSMB may consider a recommendation for modifications or termination of the trial based on any 
perceived safety concerns regardless of statistical significance. The recommendations of the DSMB are not 
binding, and all final decisions related to trial modifications rest with Abbott Vascular.  
10.4 
Source records 
Source documents will be created and maintained by the investigational site team throughout the clinical 
investigation. The data reported on the CRFs will be derived from, and be consistent with, these source 
documents, and any discrepancies will be explained in writing. 
10.5 
Records Retention 
The Sponsor and the Principal Investigators will maintain the clinical investigation documents as required. 
Measures will be taken to prevent accidental or premature destruction of these documents. The Principal 
Investigator or the Sponsor may transfer custody of records to another person/party and document the 
transfer at the investigational site or the Sponsor’s facility, as appropriate. 
 
The Investigator must obtain permission from Sponsor in writing before destroying or transferring control of 
any clinical investigation records.  
 
All original source documents must be stored for the maximum time required by the regulations at the 
hospital, research institute, or practice in question. If original source documents can no longer be maintained 
at the site, the investigator will notify the Sponsor.  
11 
Clinical Data Handling 
The Sponsor will be responsible for the data handling. The Sponsor and/or its affiliates will be responsible for 
compiling and submitting all required reports to governmental agencies. Data will be analyzed by the Sponsor 
and may be transferred to the Sponsor’s locations worldwide and/or any other worldwide regulatory authority 
in support of a market-approval application. 
11.1 
Protection of Personally Identifiable Information 
The Sponsor respects and protects personally identifiable information collected or maintained for this clinical 
investigation.  
 
The Sponsor implements technical and physical access controls to ensure that Personal Information is 
accessible only to and processed only on a ‘need to know’ basis, including periodic review of access rights, 
and revocation of access when an individual’s employment is terminated or the individual transitions to a role 

 
  
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that does not require access to Personal Information, and appropriate restrictions on physical access to 
premises, facilities, equipment, and records containing Personal Information. 
 
The Sponsor requires the investigational sites to transfer into Sponsor’s data management systems only 
pseudonymous Personal Information (key-coded) necessary to conduct the Clinical Investigation, such as the 
patient’s medical condition, treatment, dates of treatment, etc. The Sponsor discloses as part of the clinical 
investigation informed consent process that some Sponsor representatives still may see Personal Information 
at the participating sites for technical support of the participating physicians on the device implant or 
procedures, monitoring and quality control purposes. Confidentiality of Personal Information will be observed 
by all parties involved at all times throughout the clinical investigation. The privacy of each subject and 
confidentiality of his/her information will be preserved in reports and when publishing any data. 
 
The Sponsor data management systems and processes were designed, developed, and tested according to 
industry standards to appropriately safeguard Confidential Information (including any Personal Information) 
against unauthorized access and/or interference by third parties, intrusion, theft, destruction, loss or 
alteration. Clinical Investigation data are encrypted in transit and at rest.  
 
The Sponsor maintains a Privacy Incident procedure that complies in all respects with Applicable Law and 
industry best practices. 
11.2 
Data Management Plan 
A Data Management Plan (DMP) will describe procedures used for data review, database cleaning, and 
issuing and resolving data queries. If appropriate, the DMP may be updated throughout the clinical 
investigation duration. All revisions will be tracked and document controlled. 
 
Subject data will be captured in a validated electronic data capture (EDC) system hosted by the Sponsor. 
 
Only authorized site personnel will be permitted to enter the CRF data through the EDC system deployed by 
the Sponsor. An electronic audit trail will be used to track any subsequent changes of the entered data. 
11.3 
Document and Data Control 
11.3.1 
Traceability of Documents and Data 
The investigator will ensure accuracy, completeness legibility and timeliness of the data reported to the 
Sponsor on the CRFs and in all required reports. 
11.3.2 
Recording Data 
The CRF will be completed by the authorized site personnel. An appropriate comment will be provided to 
explain changes to data reported on the CRF. 
12 
Monitoring 
It is the responsibility of the Sponsor to ensure the clinical investigation is conducted, recorded and reported 
according to the approved CIP, subsequent amendment(s), applicable regulations and guidance documents. 
 
Monitoring will be conducted according to the Sponsor’s Clinical Monitoring work instruction.  Prior to 
beginning the clinical investigation, the Sponsor will contact the investigator or designee to discuss the 

 
  
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clinical investigation and data requirements. A designated monitor will periodically review the subject records 
and associated source documents. The investigator shall make subject and clinical investigation records 
available to the clinical monitor for monitoring. 
 
Centralized monitoring will occur through routine internal data review. This monitoring is designed to identify 
missing and inconsistent data, data outliers, and potential CIP deviations that may be indicative of site non-
compliance.  
13 
Compliance Statement 
13.1 
Statement of Compliance 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, the Declaration 
of Helsinki, applicable Good Clinical Practices and regulations (e.g., US 21 CFR Part 50, 21 CFR Part 56, 21 
CFR Part 812 and OUS ISO14155:2011) and the appropriate local legislation(s). The most stringent 
requirements, guidelines or regulations must always be followed. The conduct of the clinical investigation will 
be approved by the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) of the respective 
investigational site and by the applicable regulatory authorities (e.g., FDA, PMDA, MHRA, etc.). 
 
The investigator will sign a Clinical Trial or Investigator Agreement and agrees to be compliant with it. The 
investigator will not start enrolling subjects or requesting informed consent from any subject prior to obtaining 
IRB/EC approval and relevant Regulatory Authority approval, if applicable, and authorization from the 
Sponsor in writing for the clinical investigation. If additional requirements are imposed by the IRB/EC or 
relevant Regulatory Authority, those requirements will be followed. If any action is taken by an IRB/EC or a 
relevant Regulatory Authority with respect to the clinical investigation, that information will be forwarded to the 
Sponsor. 
 
The Sponsor has taken up general liability insurance in accordance with the requirements of the applicable 
local laws. An appropriate Sponsor’s country representative will be utilized to understand the requirements for 
the type of insurance that will be provided for subjects, and such information will be incorporated into the site 
informed consent, as applicable. If required, additional subject coverage or a clinical investigation specific 
insurance will be provided by the Sponsor. 
13.2 
Quality Assurance Audits and Regulatory Inspections 
A Sponsor representative or designee may request access to all clinical investigation records, including 
source documentation, for inspection during a Quality Assurance audit.  
 
In the event that an investigator is contacted by a Regulatory Agency in relation to this clinical investigation, 
the Investigator will notify Sponsor immediately. The Investigator and Research Coordinator must be 
available to respond to reasonable requests and audit queries made during the audit process. The 
Investigator must provide Sponsor with copies of all correspondence that may affect the review of the current 
clinical investigation (e.g., Form FDA 483, Inspectional Observations, Warning Letters, Inspection Reports, 
etc.). Sponsor may provide any needed assistance in responding to regulatory audits.  
 
The Principal Investigator or institution will provide direct access to source data during and after the clinical 
investigation for monitoring, audits, IRB/EC review and regulatory authority inspections, as required. The 
Principal Investigator or institution will obtain permission for direct access to source documents from the 
subject, hospital administration and national regulatory authorities before starting the clinical investigation. 

 
  
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Subjects providing informed consent are agreeing to allow clinical investigation monitors or regulatory 
authorities including foreign countries to review, in confidence, any records identifying the subjects in this 
clinical investigation. This information may be shared with regulatory agencies; however, Sponsor undertakes 
not to otherwise release the subject's personal and private information. 
 
13.3 
Repeated and Serious Non-Compliance 
In the event of repeated non-compliance or a one-time serious non-compliance, as determined by the 
Sponsor, a monitor or designee will attempt to secure compliance by one or more of the following actions: 
• 
Visiting the investigator, 
• 
Contacting the investigator by telephone, 
• 
Contacting the investigator in writing, 
• 
Retraining of the investigator. 
 
If an investigator is found to be repeatedly non-compliant with the signed agreement, the CIP or any other 
conditions of the clinical investigation, the Sponsor will either secure compliance or, at its sole discretion, 
terminate the investigator’s participation in the clinical investigation. In case of termination, the Sponsor will 
inform the responsible regulatory authority, as required, and ensure that the IRB/EC is notified, either by the 
Principal Investigator or by the Sponsor. 
14 
Suspension or Premature Termination of the Clinical Investigation 
The Sponsor reserves the right to terminate the clinical investigation at any stage, with appropriate written 
notice to the investigators, IRB/ECs and relevant Regulatory authorities, if required.  
 
While no formal statistical rule for early termination of the clinical investigation for insufficient effectiveness of 
the device under investigation is defined, the Sponsor reserves the right to discontinue the clinical 
investigation at any stage or reduce the follow-up period with suitable written notice to the investigator. 
Possible reason(s) may include, but are not limited to: 
• 
Unanticipated adverse device effect (e.g., UADE) occurs and it presents an unreasonable risk to the 
participating subjects 
• 
An oversight committee (e.g., Steering/Executive Committee, Data Monitoring Committee) makes a 
recommendation to stop or terminate the clinical investigation (such as higher frequency of anticipated 
adverse device effects) 
• 
Further product development is cancelled. 
 
Should the clinical investigation be discontinued by the Sponsor, subjects will be followed per routine hospital 
practice with device-related AEs reported to the Sponsor as per vigilance/commercial reporting requirements. 
The investigator shall return all clinical investigation materials (including devices) to the Sponsor, and provide 
a written statement to the IRB/EC (if applicable). All applicable clinical investigation documents shall be 
subject to the same retention policy as detailed in Section 9.4 of the CIP.  
 
A Principal Investigator, IRB/EC or regulatory authority may suspend or prematurely terminate participation in 
a clinical investigation at the investigational sites for which they are responsible. The investigators will follow 
the requirements specified in the Clinical Trial Agreement.  
 

 
  
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If the Sponsor suspends or prematurely terminates the clinical investigation at an individual investigational 
site in the interest of safety, the Sponsor will inform all other Principal Investigators. 
 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing resources to 
fulfill the obligations from the CIP and existing agreements for following up the subjects enrolled in the clinical 
investigation, and the Principal Investigator or authorized designee will promptly inform the enrolled subjects 
at his/her investigational site, if appropriate. 
 
15 
Ethical Consideration 
 
15.1 
Institutional Review Board/Medical Ethics Committee Review and Approval 
IRB)/EC approval for the CIP and ICF/other written information provided to the patient will be obtained 
by the Principal Investigator at each investigational site prior to consenting and enrolling patients in this 
clinical investigation. The approval letter must be received prior to the start of this clinical investigation 
and a copy must be provided to the Sponsor.  
 
Any amendments to the CIP as well as associated ICF changes will be submitted to the IRB/EC and 
written approval obtained prior to implementation, according to each institution’s IRB/EC requirements.  
 
No changes will be made to the CIP or ICF or other written information provided to the patient without 
appropriate approvals, including IRB/EC, the Sponsor, and the regulatory agencies (if applicable).  
 
Until the clinical investigation is completed, the Investigator will advise his/her IRB/EC of the progress of 
this clinical investigation, per IRB/EC requirements. Written approval must be obtained from the IRB/EC 
yearly to continue the clinical investigation, or according to each institution’s IRB/EC requirements.  
 
No investigative procedures other than those defined in this CIP will be undertaken on the enrolled 
subjects without the written agreement of the IRB/EC and the Sponsor. 
 
16 
Clinical Investigation Conclusion 
The clinical investigation will be concluded when: 
• 
All sites are closed AND 
• 
The final report has been provided to investigators or the Sponsor has provided formal 
documentation of clinical investigation closure. 
17 
Publication Policy 
The data and results from the clinical investigation are the sole property of the Sponsor. The Sponsor shall 
have the right to access and use all data and results generated during the clinical investigation. The 
Investigators will not use this clinical investigation-related data without the written consent of the Sponsor for 
any purpose other than for clinical investigation completion or for generation of publication materials, as 
referenced in the Clinical Trial Agreement. Single-center results are not allowed to be published or presented 
before the multi-center results. Any proposals for publications or presentations by the investigators must be 
reviewed and approved by the Sponsor in a timely manner to enable Sponsor review in compliance with the 
Sponsor’s publication policy set forth in the Clinical Trial Agreement.  
 

 
  
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18 
Reporting Results on ClinicalTrials.gov Website 
The Sponsor will register the clinical trial on www.clinicaltrials.gov, in accordance with the International 
Committee of Medical Journal Editors guidelines, or any other applicable guidelines. The Sponsor shall be 
responsible for any such registration and results posting as required by ClinicalTrials.gov. Investigational 
sites shall not take any action to register the trial. A full report of the pre-specified outcomes, including any 
negative outcomes, will be made public through the ClinicalTrials.gov website according to the requirements 
of Section 801 of the FDA Amendments Act. If this clinical investigation is terminated early, the Sponsor will 
make every effort to hasten the release of the pre-specified outcomes through ClinicalTrials.gov website. 
 
 
 

 
  
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Appendix B: Definitions 
 
Vulnerable Patient 
Vulnerable patients are defined as patients whose willingness to volunteer in a clinical investigation could be 
unduly influenced by the expectation, whether justified or not, of benefits associated with participation or of 
retaliatory response from senior members of a hierarchy in case of refusal to participate. 
 
Abrupt Closure: Intraprocedural coronary occlusion associated with clinical evidence of myocardial 
ischemia. 
 
Coronary Artery Embolism: Obstruction in the coronary artery due to an embolus such as, air, plaque, 
thrombosis or debris. 
 
Chronic Total Occlusion (CTO): Lesions with thrombolysis in myocardial infarction (TIMI) 0 flow for ≥3 
months. 
 
Crossover: Crossover from one assigned treatment to the other is strongly discouraged.  
 
De Novo Lesion: A native coronary artery lesion not previously treated. 
 
Death (Per ARC Circulation 2007; 115: 2344-2351):  All deaths are considered cardiac unless an 
unequivocal non-cardiac cause can be established. Specifically, any unexpected death even in patients with 
coexisting potentially fatal non-cardiac disease (e.g. cancer, infection) should be classified as cardiac.  
 
Cardiac death:  
Any death due to proximate cardiac cause (e.g. MI, low-output failure, fatal arrhythmia), unwitnessed 
death and death of unknown cause, all procedure related deaths including those related to 
concomitant treatment. 
 
Vascular death: 
Death due to non-coronary vascular causes such as cerebrovascular disease, pulmonary embolism, 
ruptured aortic aneurysm, dissecting aneurysm, or other vascular cause. 
   
Non-cardiovascular death: 
Any death not covered by the above definitions such as death caused by infection, malignancy, 
sepsis, pulmonary causes, accident, suicide or trauma. 
 
Dissection:  
Type 0: None 
Type A: Small radiolucent area within lumen of the vessel 
Type B: Linear, non-persisting extravasation of contrast 
Type C: Extraluminal, persisting extravasation of contrast 
Type D: Spiral shaped filling defect 
Type E: Persistent lumen defect with delayed ante/retrograde flow 
Type F: Filling defect accompanied by total arterial occlusion 
(Note: Type A and B are generally considered benign and minor dissections) 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
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Reference Vessel Diameter (RVD):   Average diameter of proximal and distal healthy segments by QCA. 
“Normal” reference segments are selected proximal and distal to the stenosis and averaged to define the 
reference vessel diameter. 
 
Minimum Lumen Diameter (MLD): The smallest measured luminal diameter in a diseased segment (as 
measured by QCA).  
 
Acute Gain: The difference between the post-PCI MLD and the pre-PCI MLD (as measured by QCA). 
 
Percent Diameter Stenosis:   The value calculated as 100 * (1 - MLD/RVD) using the mean values from two 
orthogonal views (when possible) by QCA. 
 
Ischemic Episode: An inadequate flow of blood to a part of the body resulting from low oxygen in the blood 
or tissues, generally as a result of an obstruction of the arterial blood flow. 
 
Killip Class* 
Class I: No evidence of heart failure 
Class II: Findings of mild to moderate heart failure (S3 gallop, rales < half-way up lung 
fields or elevated jugular venous pressure 
Class III: Pulmonary edema 
Class IV: Cardiogenic shock defined as systolic blood pressure < 90 and signs of 
hypoperfusion such as oliguria, cyanosis, and sweating. 
 
Major Adverse Cardiac Event (MACE): The composite of cardiac death, myocardial infarction, and 
ischemia-driven target lesion revascularization. 
 
Myocardial Infarction (Primary Protocol Definition)  
 
Periprocedural MI – Modified ARC-2 Definition20  
Periprocedural myocardial infarction occurring within 48 hours after all percutaneous coronary intervention 
(PCI) and coronary artery bypass grafting (CABG) procedures:20 
 
Absolute rise (from baseline to within 48 hours of procedure) in cardiac troponin of ≥35x the 99th percentile 
URL (or ≥35x ULN if URL is not available) or in the absence of cardiac troponin, rise in CK-MB to ≥ 5x the 
99th percentile URL (or ≥5x ULN if URL is not available). Note, cardiac troponin assessments are 
preferentially used if available; otherwise CK-MB may be used.  
 
In addition, 1 (or more) of the following measures of myocardial ischemia must be present post-procedure: 
• 
New significant Q waves (≥40 ms in duration and ≥1 mm deep in voltage in ≥2 contiguous leads) or 
equivalent 
• 
Persistent flow-limiting angiographic complications in a major epicardial vessel or branch ≥1.5 mm in 
diameter present at the end of the PCI procedure (or during angiography performed to evaluate a post-
CABG complication) as assessed at the angiographic core laboratory 
• 
New substantial loss of viable myocardium on serial imaging 
 
These assessments apply to patients: a) with baseline CK-MB or cardiac troponin levels ≤1x the 99th 
percentile URL (or ≤1x ULN if URL is not available); b) in whom the baseline biomarker is >1x the 99th 
percentile URL (or >1x ULN if URL is not available) and stable or falling; and c) with a single elevated 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 101 of 114 
 
 
baseline draw who have a chronic coronary syndrome (CCS). In the latter two groups (patients in whom the 
baseline is elevated and stable or falling and CCS patients with a single elevated baseline draw), the post-
procedural troponin (or CK-MB) must rise above the most recent baseline by an increment of the values 
above (i.e. for troponin ≥35x the 99th percentile URL (or ≥35x ULN if URL is not available) or in the absence 
of cardiac troponin, for CK-MB ≥5x the 99th percentile URL (or ≥5x ULN if URL is not available). 
 
These assessments do not apply to patients: a) in whom baseline CK-MB or troponin levels are elevated and 
rising; and b) with a single elevated baseline level who presented with a NSTEMI or STEMI in whom it is 
uncertain whether the peak has been reached. In such patients periprocedural MI will only be adjudicated if 
the troponin (or CK-MB) biomarker increases from the prior measure by the increments above, and at least 2 
of the 3 above criteria for myocardial ischemia are present. 
 
Spontaneous MI  
All MIs which are not peri-procedural are considered spontaneous MIs. Spontaneous myocardial infarctions 
are usually related to atherosclerotic plaque rupture, ulceration, fissuring, erosion, or dissection with resulting 
intraluminal thrombus in one or more of the coronary arteries leading to decreased myocardial blood flow or 
distal platelet emboli with ensuing myocyte necrosis. However, spontaneous MIs can also be due to an 
imbalance between supply and demand, or due to stent thrombosis, graft occlusion or other causes. Most 
patients with spontaneous MI have underlying severe CAD but on occasion non-obstructive or no CAD. 
Spontaneous MIs usually occur beyond 48 hours post-procedure but can occasionally occur within 48 hours 
of a revascularization procedure if the cause is clearly distinct from the index procedure (e.g. a stent 
thrombosis at 24 hours). Spontaneous MIs are defined and subclassified according to types 1, 2, 3, 4b and 
4c according to the 4th Universal Definition of MI classification21 (below).  
 
Spontaneous Myocardial Infarction: Fourth Universal Definition  
 
Type 1: MI caused by atherothrombotic coronary artery disease (CAD) and usually precipitated by 
atherosclerotic plaque disruption (rupture or erosion) is designated as a Type 1 MI.  Type 1 MI is 
characterized by detection of a rise and/or fall of cTn values with at least one value above the 99th 
percentile URL and with at least one of the following: 
• 
Symptoms of acute myocardial ischaemia; 
• 
New ischaemic ECG changes; 
• 
Development of pathological Q waves; 
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a 
pattern consistent with an ischaemic aetiology; 
• 
Identification of a coronary thrombus by angiography including intracoronary imaging or by 
autopsy13 
 
Type 2: Myocardial infarction secondary to an ischemic imbalance. 
The pathophysiological mechanism leading to ischaemic myocardial injury in the context of a 
mismatch between oxygen supply and demand has been classified as type 2 MI.  Type 2 MI is 
characterized by detection of a rise and/or fall of cTn values with at least one value above the 99th 
 
 
13 Post-mortem demonstration of an atherothrombus in the artery supplying the infarcted myocardium, or a 
macroscopically large circumscribed area of necrosis with or without intramyocardial haemorrhage, meets the 
type 1 MI criteria regardless of cTn values. 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 102 of 114 
 
 
percentile URL, and evidence of an imbalance between myocardial oxygen supply and demand 
unrelated to coronary thrombosis, requiring at least one of the following: 
• 
Symptoms of acute myocardial ischaemia; 
• 
New ischaemic ECG changes; 
• 
Development of pathological Q waves; 
• 
Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality 
in a pattern consistent with an ischaemic aetiology; 
 
Type 3: Myocardial infarction resulting in death when biomarker values are unavailable. Patients are 
designated as having Type 3 MI who suffer cardiac death, with symptoms suggestive of myocardial 
ischaemia accompanied by presumed new ischaemic ECG changes or ventricular fibrillation, but die 
before blood samples for biomarkers can be obtained, or before increases in cardiac biomarkers can 
be identified, or MI is detected by autopsy examination.  
 
Type 4b: Myocardial infarction related to stent thrombosis associated with percutaneous coronary 
intervention (PCI). 
Myocardial infarction associated with stent thrombosis is designated as Type 4b MI, detected by 
angiography or autopsy using the same criteria utilized for Type 1 MI. 
 
Type 4c: Myocardial infarction related to restenosis associated with percutaneous coronary 
intervention (PCI). 
This PCI-related MI type is designated as Type 4c MI, defined as focal or diffuse restenosis, or a 
complex lesion associated with a rise and/or fall of cTn values above the 99th percentile URL 
applying, the same criteria utilized for Type 1 MI.  
 
 
Periprocedural Myocardial Infarction (Secondary Definition)  
 
As a sensitivity analysis, periprocedural MI will also be adjudicated and reported according to the SCAI 
Definition:  
1. In patients with normal baseline CK-MB: The peak CK-MB measured within 48 hours of the procedure 
rises to ≥10x the local laboratory ULN, or to ≥5x ULN with new pathologic Q-waves in ≥2 contiguous 
leads or new persistent left bundle branch block OR in the absence of CK-MB measurements and a 
normal baseline cTn, a cTn (I or T) level measured within 48 hours of the PCI rises to ≥70x the local 
laboratory ULN, or ≥35x ULN with new pathologic Q-waves in ≥2 contiguous leads or new persistent left 
bundle branch block. 
 
2. In patients with elevated baseline CK-MB (or cTn) in whom the biomarker levels are stable or falling: The 
CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above from the most 
recent pre-procedure level. 
 
3. In patients with elevated CK-MB (or cTn) in whom the biomarker levels have not been shown to be stable 
or falling: The CK-MB (or cTn) rises by an absolute increment equal to those levels recommended above 
plus new ST-segment elevation or depression plus signs consistent with a clinically relevant MI, such as 
new onset or worsening heart failure or sustained hypotension.  
 
 
Myocardial Infarction Relation to Target Vessel: 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
 
Page 103 of 114 
 
 
Infarcts will be adjudicated according to anatomical origin based on review of coronary angiography 
performed at the time of the event.  Those that cannot be clearly attributed to a particular vessel (target or 
non-target) either because the origin of the event on the angiogram is ambiguous or the angiogram was not 
performed will be considered as indeterminate vessel MI. 
 
 
NYHA Classification: 
Class I: Subjects with cardiac disease but without resulting limitation of physical activity. Ordinary physical 
activity does not cause undue fatigue, palpitation, dyspnea, or angina pain. 
Class II: Subjects with cardiac disease resulting in slight limitation of physical activity. They are comfortable at 
rest. Ordinary physical activity results in fatigue, palpitation, dyspnea, or anginal pain. 
 
Class III: Subjects with cardiac disease resulting in marked limitation of physical activity. They are 
comfortable at rest. Less than ordinary activity causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV: Subjects with cardiac disease resulting in inability to carry on any physical activity without 
discomfort. Symptoms of heart failure or anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased. 
 
No Reflow: After treatment, the Thrombolysis In Myocardial Infarction (TIMI) score is reduced to 1 or 
0 in the absence of a severe focal mechanical obstruction (e.g., dissection). Persistent No Reflow is defined 
as a condition where the TIMI flow continues to be 1 or 0 even at the end of the procedure despite the use of 
adjunctive drugs or mechanical intervention for relief of vasospasm. 
 
Perforation Classification: 
 
Type I (Fully contained): Extraluminal crater without extravasation. 
 
Type II (Limited extravasation): Pericardial or myocardial blush without contract jet 
extravasation. 
 
Type III (Brisk extravasation): Extravasation through frank (≥1mm) perforation. 
 
Cavity spilling: Perforation into an anatomic cavity chamber, coronary sinus, etc. 
 
Procedural complications:  Defined as A) angiographic core laboratory-assessed complications listed in 
Angiographic Endpoint 11(vi) occurring anytime during the procedure; or B) site-assessed prolonged ST-
segment elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or cardioversion or 
hypotension/heart failure requiring mechanical or intravenous hemodynamic support or intubation, or 
procedural death. 
 
Procedural success:  Defined as A) angiographic core laboratory-assessed final (post-PCI) lesion 
angiographic diameter stenosis <30% and target vessel TIMI III flow without any of the angiographic 
complications listed in Angiographic Endpoint 11(vi); plus B) the absence of site-assessed prolonged ST-
segment elevation or depression (>30 minutes), cardiac arrest or need for defibrillation or cardioversion or 
hypotension/heart failure requiring mechanical or intravenous hemodynamic support or intubation, or 
procedural death. 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 104 of 114 
 
 
OCT imaging-related procedural complications:  Any procedural complications (e.g. angiographic 
dissection, perforation, thrombus, acute closure, etc.) requiring any active intervention (e.g. prolonged balloon 
inflations, additional stent implantation, pericardiocentesis, intubation, hemodynamic support or pressors, 
defibrillation or cardioversion) or death adjudicated by the CEC as definitely or likely attributable to the 
physical performance of OCT-imaging (e.g. passing the catheter through the vasculature or stent, or injecting 
contrast to clear the blood for imaging). For this definition, adverse events that arise due to changes in PCI 
strategy as the result of OCT findings are NOT considered OCT imaging-related procedural complications. 
 
Principal Investigator:  An individual who actually oversees and conducts a clinical investigation. In the 
event of an investigation being conducted by a team of individuals, “PI” refers to the responsible leader of the 
team. 
 
Slow Flow: After treatment, the TIMI score is reduced to 2 or less in the absence of a severe focal 
mechanical obstruction (e.g., dissection). Persistent Slow Flow is defined as a slow flow condition present at 
the procedure end that is not resolved by adjunctive drugs or mechanical intervention for relief of vasospasm. 
 
Severe Calcification:  
By angiography: presence of radiopacities noted without cardiac motion prior to contrast injection usually 
involving both sides of the arterial wall in at least one (1) location, with total length of calcium (including 
segmented) ≥15 mm and extending partially into the target lesion. 
 
By OCT: presence of ≥180° of calcium in at least one (1) cross section with minimal thickness >0.5mm. 
 
Intraprocedural stent thrombosis: new or increasing thrombus developing within or adjacent to the stent 
during the index PCI procedure 
 
Stent Thrombosis (definite or probable; modified ARC definitions):  
 
Acute stent thrombosis (*): from completion of PCI procedure to 24 hours after stent implantation 
 
Subacute stent thrombosis (*): >24 hours – 30 days after stent implantation 
 
Late stent thrombosis (**): >30 days – 1 year after stent implantation 
 
Very late stent thrombosis (**): >1 year after stent implantation 
 
(*) acute or subacute can also be replaced by the term early stent thrombosis. 
(**) including ‘primary’ as well as ‘secondary’ late stent thrombosis; ‘secondary’ late stent thrombosis is a 
stent thrombosis after a target lesion revascularization. 
 
Stent Thrombosis, Definite*: 
Definite stent thrombosis is considered to have occurred by either angiographic or pathological confirmation. 
 
Angiographic confirmation of stent thrombosis 
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 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 105 of 114 
 
 
• 
New ischemic ECG changes that suggest acute ischemia 
• 
Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous MI) 
*The incidental angiographic documentation of stent occlusion in the absence of clinical signs or symptoms is 
not considered a confirmed stent thrombosis (silent occlusion). 
 
Stent Thrombosis, Probable: 
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. 
 
Successful and Uncomplicated: 
For non-target lesion treatment during the index procedure, defined as angiographic diameter stenosis <10% 
for all treated non-target lesions, with TIMI III flow in this vessel, without final dissection ≥ NHLBI type B, 
perforation anytime during the procedure, prolonged chest pain (>5 minutes) or prolonged ST-segment 
elevation or depression (>5 minutes), or cardiac arrest or need for defibrillation or cardioversion or 
hypotension/heart failure requiring mechanical or intravenous hemodynamic support or intubation). 
 
Target Lesion: The target lesion is the treated lesion starting 5mm proximal to the stented lesion and ending 
5mm distal to the stented lesion. 
 
Target Lesion Failure (TLF): The composite of cardiac death, target vessel related myocardial infarction, or 
ischemia-driven target lesion revascularization. 
 
Target Lesion Revascularization (TLR): Repeat revascularization of the target lesion. 
 
Target Vessel Failure (TVF): The composite of cardiac death, target vessel related myocardial infarction, or 
ischemia driven target vessel revascularization. 
 
Target Vessel Revascularization (TVR): Repeat revascularization of the target vessel (inclusive of the 
target lesion). 
 
Ischemia-Driven [ID] Revascularization (TLR/TVR): A revascularization is considered ischemia driven if 
associated with any of the following: 
• 
Positive functional ischemia study including positive FFR, iFR, etc. 
• 
Ischemic symptoms and angiographic diameter stenosis ≥50% by core laboratory QCA 
• 
Angiographic diameter stenosis ≥ 70% by core laboratory QCA without angina or positive functional 
study 
 
COVID-19 Relatedness Definitions  
The COVID-19 relatedness to an adverse event, is adjudicated by the CEC committee into 3 categories: 
likely related, possibly related, or not likely related, based on the COVID-19 relatedness definitions that are 
described on the CEC charter. Please refer to the CEC charter for the COVID-19 relatedness definitions.  
 
Thrombolysis In Myocardial Infarction (TIMI) Flow Grading System: 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 106 of 114 
 
 
Grade 0 (no perfusion): There is no antegrade flow beyond the point of occlusion. 
 
Grade 1 (penetration without perfusion): The contrast material passes beyond the area of obstruction but 
“hangs up” and fails to opacify the entire coronary bed distal to the obstruction for the duration of the 
cineangiographic filming sequence. 
 
Grade 2 (partial perfusion): The contrast material passes across the obstruction and opacifies the coronary 
bed distal to the obstruction. However, the rate of entry of contrast material into the vessel distal to the 
obstruction or its rate of clearance from the distal bed (or both) is perceptibly slower than its entry into or 
clearance from comparable areas not perfused by the previously occluded vessel (e.g., the opposite coronary 
artery or the coronary bed proximal to the obstruction). 
 
Grade 3 (complete perfusion): Antegrade flow into the bed distal to the obstruction occurs as promptly as 
antegrade flow into the bed from the involved bed and is as rapid as clearance from an uninvolved bed in the 
same vessel or the opposite artery. 
 
Thrombus, Nonocclusive: Intracoronary thrombus is defined as a (spheric, ovoid or irregular) non-calcified 
filling defect or lucency surrounded by contrast material (on 3 sides or within a coronary stenosis) seen in 
multiple projections, or persistence of contrast material within the lumen, or a visible embolization of 
intraluminal material downstream. 
 
Thrombus, Occlusive: TIMI 0 or TIMI 1 intra-stent or proximal to a stent up to the most adjacent proximal 
side branch or main branch (if originates from the side branch). 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
86357_CIP Template_Rev_D 
Page 107 of 114 
 
 
Appendix C: Labels 
 
  
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 110 of 114 
 
 
Appendix F: Pre-specified Powered Analysis of XIENCE in the In-Stent Restenosis 
(ISR) Population 
 
Introduction 
Abbott is evaluating the safety and effectiveness of treating in-stent restenosis (ISR) lesions with the XIENCE 
family of stents within the ILUMIEN IV trial.  The trial enrolls patients undergoing planned XIENCE stent 
implantation during a clinically indicated PCI procedure who satisfy the eligibility criteria described in Section 
5.4 of this CIP.  A pre-specified powered analysis of XIENCE is being conducted in randomized ILUMIEN IV 
subjects with ISR and is described below.  The XIENCE ISR analysis is intended to support an indication 
expansion for treatment of ISR lesions with the XIENCE family of stents in the USA. 
  
The XIENCE ISR analysis is independent of the main ILUMIEN IV study objective outlined in Section 1.1 of 
the CIP, which is to demonstrate the superiority of an OCT-guided stent implantation strategy as compared to 
an angiography-guided stent implantation strategy.   
  
Objective 
The objective of the XIENCE ISR analysis is to demonstrate the safety and effectiveness of XIENCE in the 
treatment of ISR lesions.  
  
Analysis Population 
The XIENCE ISR analysis population is comprised of randomized subjects pooled from both study arms and 
enrolled under the ILUMIEN IV regulated protocol 
or the post-market protocol 
, who have had at least one XIENCE stent implanted in an ISR target lesion.    
  
Endpoints 
The primary endpoint for the XIENCE ISR analysis is target lesion failure (TLFISR).  TLFISR is the event rate of 
the composite outcome of cardiac death, target vessel myocardial infarction (TV-MI) (per primary protocol 
definition [see Appendix B]), or ischemia-driven target lesion revascularization (ID-TLR), assessed at 1 year.  
 
Non-powered secondary endpoints for the XIENCE ISR analysis to be assessed at 1 year are as follows: 
1. Cardiac death ISR 
2. TV-MIISR 
3. ID-TLRISR 
4. Stent thrombosis ISR 
5. All-cause mortality ISR 
 
In addition, the following outcomes will be reported as sensitivity analyses at 1 year: 
6. TV-MIISR,SCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol 
definition) 
7. Periprocedural MIISR,SCAI (by SCAI definition) 
8. All MIISR,SCAI (periprocedural MI by SCAI definition and spontaneous MI by protocol definition) 
9. TLFISR,SCAI; the composite of cardiac death, TV-MIISR,SCAI or ID-TLR 
 
Note:   In the XIENCE ISR analysis population, TV-MIISR and TV-MIISR,SCAI include MI events with confirmed 
target vessel involvement and indeterminate vessel MI events.  
 
Procedures 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 111 of 114 
 
 
The procedures for the ISR analysis population are the same as for the full ILUMIEN IV population.  
  
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 112 of 114 
 
 
Statistical Considerations 
The hypothesis for the XIENCE ISR analysis is as follows: 
H0: TLFISR ≥ PG  
Ha: TLFISR < PG,  
  
 The null hypothesis will be tested using a one-sided alpha of 2.5%. 
  
 
 
  
 
 
  
  
For subjects with multiple target vessels, TLFISR in any vessel with at least one XIENCE stent implanted on 
an ISR target lesion constitutes an endpoint event. 
  
The primary endpoint TLFISR is assessed to evaluate the safety and effectiveness of XIENCE in ISR lesions. 
This endpoint must be met to demonstrate success for XIENCE in ISR lesions.   
  
 
   
 
Details on subgroup analyses of the XIENCE ISR primary endpoint TLFISR can be found in the separate 
Statistical Analysis Plan (SAP).  
  
Other Study Considerations 
Unless otherwise noted in this appendix, study conduct for the ISR analysis population is the same as for the 
full ILUMIEN IV population. This consideration applies to risks and benefits, investigator records and 
reporting, adverse events, clinical data handling, monitoring, compliance, suspension or premature 
termination of the clinical investigation, ethical considerations, clinical investigation conclusion, publication 
policy and results reporting on clinicaltrials.gov website.  
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
Page 113 of 114 
 
 
Appendix G: References 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
  
Study Name: ILUMIEN IV 
 
Clinical Investigation Plan 
 
 
 
 
 
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