Clinical trial NCT03355742
Conditions: Bleeding Disorder Stroke, Ischemic Stroke Hemorrhagic Hematological Disease Thrombocytopenia Coagulation Disorder Anemia Renal Insufficiency Coronary Artery Disease
Keywords: XIENCE High bleeding risk (HBR) Dual antiplatelet therapy (DAPT) Coronary Artery Disease Drug eluting stent (DES)
Sponsor: Abbott Medical Devices
Start date: 2018-02-09; Completion date: 2020-04-30
Enrollment: 963 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
XIENCE 28 Global Study is a prospective, single arm, multi-center, open label, non-randomized trial to further evaluate the safety of 1-month (as short as 28 days) dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) undergoing percutaneous coronary intervention (PCI) with the approved XIENCE family (XIENCE Xpedition Everolimus Eluting Coronary Stent System \[EECSS\], XIENCE Alpine EECSS, XIENCE PROX EECSS, XIENCE ProA EECSS or XIENCE Sierra EECSS of coronary drug-eluting stents

Detailed description:
The XIENCE 28 Global Study will evaluate the safety of 1-month DAPT following XIENCE implantation in HBR patients. A minimum of 800 to a maximum of 960 subjects will be registered from approximately 50 sites globally and subject registration is capped at 120 per site. Eligibility of P2Y12 receptor inhibitor discontinuation will be assessed at 1-month follow-up. Subjects who are free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis (ARC definite/probable) within 1 month (prior to 1-month visit but at least 28 days) after stenting and have been compliant with 1-month DAPT without interruption of either aspirin and/or P2Y12 receptor inhibitor for \> 7 consecutive days are considered as "1-month clear", and will discontinue P2Y12 receptor inhibitor as early as 28 days and continue with aspirin monotherapy through 12-month follow-up.

All registered subjects will be followed at 1, 3, 6 and 12 months post index procedure. The data collected from the XIENCE 28 Global Study will be compared with the historical control of non-complex HBR subjects treated with standard DAPT up to 12 months from the XIENCE V USA Study .

Arms: arm 1: XIENCE + Short duration (1 month) of DAPT
Interventions: intervention 1: XIENCE intervention 2: DAPT
Intervention descriptions: intervention 1: Subjects who received XIENCE family stent systems will be included. intervention 2: 1-month clear subjects will receive 1 month of P2Y12 inhibitor and 12 months of aspirin after index procedure.

Protocol documents:
Prot_002.pdf: 
Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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This confidential document is the property of Abbott and shall not be reproduced, distributed, disclosed or used 
without the express written consent of Abbott. 
 
 
 
Version Number 
Version C 
Date 
November 13, 2018 
Principal Investigators 
 
Study Principal Investigator: 
Roxana Mehran, MD,  
Professor of Medicine,  
Director, Interventional Cardiovascular Research and 
Clinical Trials at the Zena and Michael A. Weiner 
Cardiovascular Institute at Mount Sinai 
School of Medicine 
New York, NY 
 
Study Co-Principal Investigator: 
Marco Valgimigli, MD, 
Associate Professor of Cardiology, 
Swiss Cardiovascular Center Bern,  
Bern University Hospital 
Bern, Switzerland 
Planned Number of Sites and 
Region(s) 
Approximately 50 sites globally 
Abbott Vascular Medical 
Expert 
Charles A. Simonton, MD  
Chief Medical Officer 
Trial Type 
Prospective, single arm, multi-center, open label trial  
Sponsor /Data Monitoring 
 
Abbott Cardiovascular Systems, Inc., 
A subsidiary of Abbott Vascular, Inc. 
3200 Lakeside Drive 
Santa Clara, CA  95054 
Trial Monitor 
Abbott Cardiovascular Systems, Inc., 
A subsidiary of Abbott Vascular, Inc. 
3200 Lakeside Drive 
Santa Clara, CA  95054 
Electronic Data Capture 
Software 
Oracle Clinical 
Clinical Events Committee 
Cardiovascular Research Foundation 
1700 Broadway, 9th Floor 
New York, NY 10019 
Data Safety Monitoring 
Board 
Axio Research 
2601 4th Avenue, Suite 200 
Seattle, WA 98121 
Protocol Author 
Vinuta Rau, PhD 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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TABLE OF CONTENTS 
Compliance Statement: .............................................................................................................. 5 
Protocol Summary: ……………………………………………………………………………6 
1.0 
INTRODUCTION .................................................................................... 14 
1.1 
Trial Design ............................................................................................................. 14 
1.2 
Trial Objective ......................................................................................................... 14 
2.0 
BACKGROUND INFORMATION ......................................................... 14 
2.1 
Background and Rationale ....................................................................................... 14 
2.2 
Device Overview ..................................................................................................... 17 
3.0 
CLINICAL TRIAL FLOW AND FOLLOW-UP SCHEDULE ............... 18 
3.1 
Number of Subjects to be Registered....................................................................... 18 
3.2 
Overall Flow of the Trial and Follow-up Schedule ................................................. 18 
3.3 
Measures Taken to Avoid and Minimize Bias ......................................................... 18 
3.4 
Early Termination of the Clinical Trial ................................................................... 18 
4.0 
ENDPOINTS ............................................................................................ 19 
4.1 
Primary Endpoint ..................................................................................................... 19 
4.2 
Secondary Endpoint(s) ............................................................................................. 19 
5.0 
SUBJECT SELECTION AND WITHDRAWAL .................................... 20 
5.1 
Subject Population ................................................................................................... 20 
5.2 
Subject Screening and Informed Consent ................................................................ 20 
5.2.1 Subject Screening................................................................................................. 20 
5.2.2 Informed Consent................................................................................................. 20 
5.3 
Eligibility Criteria .................................................................................................... 20 
5.3.1   General Eligibility Criteria ................................................................................... 20 
5.3.2 Angiographic Eligibility Criteria ......................................................................... 22 
5.4 
Subject Registration ................................................................................................. 23 
5.5 
Subject Discontinuation ........................................................................................... 23 
5.6 
Total Expected Duration of the Clinical Trial ......................................................... 24 
5.7 
Expected Duration of Each Subject’s Participation ................................................. 24 
5.8 
Number of Subjects Required to be Included in the Clinical Trial .......................... 25 
5.9 
Estimated Time Needed to Register this Number .................................................... 25 
5.10 
Trial Completion ...................................................................................................... 25 
6.0 
TREATMENT AND EVALUATION ..................................................... 25 
6.1 
Baseline and Pre-procedure ..................................................................................... 25 
6.1.1 Laboratory Assessments ...................................................................................... 25 
6.1.2 Clinical Assessments ........................................................................................... 25 
6.1.3 Pre-procedure Antiplatelet Medication ................................................................ 25 
6.2 
Index Procedure ....................................................................................................... 26 
6.3 
Post–procedure ......................................................................................................... 26 
6.3.1 Post-procedure Laboratory and Clinical Tests ..................................................... 26 
6.3.2 Antiplatelet Medications during Follow-up ......................................................... 26 
6.3.3 Other Chronic Concomitant Medications ............................................................ 27 
6.4 
Clinical Follow-up for All Subjects ......................................................................... 27 
6.5 
Additional Follow-up Visits for All Subjects .......................................................... 28 
7.0 
ADVERSE EVENTS ............................................................................... 28 
7.1 
Definition ................................................................................................................. 28 
7.1.1 Adverse Event ...................................................................................................... 28 
7.1.2 Serious Adverse Event ......................................................................................... 29 
7.1.3 Device Deficiency/Device Malfunction .............................................................. 29 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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7.2 
Device Relationship ................................................................................................. 29 
7.2.1 Unanticipated (Serious) Adverse Device Effect .................................................. 29 
7.3 
Adverse Event Reporting ......................................................................................... 30 
7.3.1 Adverse Event Reporting ..................................................................................... 30 
7.3.2 Unanticipated Serious Adverse Device Effect Reporting to Sponsor and EC..... 31 
7.3.3 Device Deficiency/Device Malfunction Reporting ............................................. 31 
7.3.4 Adverse Event Reporting to Country Regulatory Authorities by the Sponsor .... 31 
7.4 
Safety Monitoring by Data Safety Monitoring Board (DSMB) .............................. 31 
8.0 
ADJUDICATION OF EVENTS .............................................................. 32 
9.0 
STATISTICAL ANALYSES ................................................................... 32 
9.1 
Statistical Overview ................................................................................................. 32 
9.2 
Analysis Populations ................................................................................................ 32 
9.3 
Sample Size Calculations and Assumptions ............................................................ 33 
9.4 
Statistical Analyses .................................................................................................. 33 
9.4.1 Primary Endpoint Analysis .................................................................................. 33 
9.4.2 Secondary Endpoint Analyses ............................................................................. 33 
9.4.3 Subgroup Analysis ............................................................................................... 33 
9.4.4 Procedures for Accounting for Missing, Unused or Spurious Data .................... 34 
9.5  
Deviations from the Original Statistical Plan .......................................................... 34 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ...................... 34 
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE ....................... 34 
11.1 
Selection of Clinical Sites and Investigators ........................................................... 34 
11.2  Protocol Amendments .............................................................................................. 34 
11.3 
Training .................................................................................................................... 34 
11.3.1 
Site Training..................................................................................................... 34 
11.3.2 
Training of Sponsor’s Monitors ....................................................................... 35 
11.4 
Monitoring ............................................................................................................... 35 
11.5 
Deviations from the Protocol ................................................................................... 35 
11.6 
Quality Assurance Audits ........................................................................................ 36 
11.7 
Committees .............................................................................................................. 36 
11.7.1 
Steering Committee ......................................................................................... 36 
11.7.2 
Data Safety Monitoring Board (DSMB) .......................................................... 36 
11.7.3 
Clinical Events Committee (CEC) ................................................................... 37 
12.0 
DATA HANDLING AND RECORD KEEPING .................................... 37 
12.1 
Source Documentation ............................................................................................. 37 
12.2 
Electronic Case Report Form Completion ............................................................... 38 
12.3 
Record Retention ..................................................................................................... 38 
13.0 
ETHICAL CONSIDERATION ............................................................... 38 
13.1 
Medical Ethics Committee Review ......................................................................... 38 
14.0 
PUBLICATION POLICY ........................................................................ 39 
15.0 
RISK ANALYSIS .................................................................................... 39 
15.1 
Anticipated Clinical Benefits ................................................................................... 40 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects ................... 40 
15.3 
Residual Risks Associated with the Device, as Identified in the Risk Analysis 
Report ……………………………………………………………………………………..40 
15.4 
Risks Associated with Participation in Clinical Trial .............................................. 40 
15.5 
Possible Interactions with Protocol Required Concomitant Medications ................ 40 
15.6 
Steps that will be Taken to Control or Mitigate the Risks ....................................... 40 
15.7 
Risk to Benefit Rationale ......................................................................................... 41 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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APPENDIX I: 
ABBREVIATIONS AND ACRONYMS ................................................ 42 
APPENDIX II: 
DEFINITIONS ......................................................................................... 45 
APPENDIX III: 
CONTACT INFORMATION .................................................................. 54 
APPENDIX IV: 
SCHEDULE OF EVENTS ....................................................................... 55 
APPENDIX V: 
CLINICAL TRIAL FLOW ...................................................................... 56 
APPENDIX VI: 
MONITORING PLAN ............................................................................. 57 
APPENDIX VII: 
SUMMARY OF CHANGES ................................................................... 58 
 
 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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COMPLIANCE STATEMENT:  
This trial will be conducted in accordance with this Clinical Study Plan, the Declaration of 
Helsinki, ISO 14155:2011 standards and the appropriate local legislation(s). The most 
stringent requirements, guidelines or regulations must always be followed. The conduct of the 
trial will be approved by the appropriate Ethics Committee (EC) of the respective clinical site 
and as specified by local regulations. 
 
 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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PROTOCOL SUMMARY:  
Trial Name and 
Number 
XIENCE 28 Global Study: ABT-CIP-10398 
 
Title 
XIENCE 28 Global Study 
Trial Device 
The commercially approved XIENCE family of coronary drug-
eluting stents1 manufactured by Abbott Vascular, Inc, Santa Clara, 
USA, including: 
• XIENCE Xpedition (stent diameter 2.5, 2.75, 3.0, 3.25, 3.5 and 
4.0 mm, stent length 8, 12, 15, 18, 23 and 28 mm), XIENCE 
Xpedition SV (stent diameter 2.25 mm, stent length 8, 12, 15, 
18, 23, 28 mm) and XIENCE Xpedition LL Everolimus 
Eluting Coronary Stent System (stent diameter 2.5, 2.75, 3.0, 
3.25, 3.5 and 4.0 mm, stent length 33 and 38 mm). 
• XIENCE Alpine Everolimus Eluting Coronary Stent System: 
stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. Stent lengths 33 
mm and 38 mm are not available for 2.25 mm diameter stent. 
• XIENCE PROX Everolimus Eluting Coronary Stent System2: 
stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. Stent lengths 33 
mm and 38 mm are not available for 2.25 mm diameter stent. 
• XIENCE PROA Everolimus Eluting Coronary Stent System3: 
• stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. Stent lengths 33 
mm and 38 mm are not available for 2.25 mm diameter stent. 
XIENCE Sierra Everolimus Eluting Coronary Stent System: 
stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent 
length 8, 12, 15, 18, 23, 28, 33, and 38 mm. 
Only stents up to 38 mm can be used. The above listed XIENCE 
stents will hereinafter be called “XIENCE” in this trial.   
Objective 
The primary objective of this trial is to further evaluate safety of 1-
month (as short as 28 days) dual antiplatelet therapy (DAPT) in 
subjects at high risk of bleeding (HBR) undergoing percutaneous 
coronary intervention (PCI) with XIENCE. 
                                                 
1 For each geography included in the trial, only approved and commercial available XIENCE stent(s) in that 
geography will be used.  
2 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System. 
3 XIENCE PROA is a rebrand of the XIENCE Alpine Stent System. 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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Targeted Number 
of Subjects  
A minimum of 800 to a maximum of 960 subjects from 
approximately 50 sites globally. Subject registration is capped at 120 
per site.  
Clinical Trial 
Design 
A prospective, single arm, multi-center, open label, non-randomized 
trial to futher evaluate the safety of 1-month (as short as 28 days) 
DAPT in HBR subjects undergoing PCI with XIENCE. 
Primary Endpoint 
Net Adverse Clinical Endpoint (NACE, a composite rate of all-cause 
death, all myocardial infarction (modified4Academic Research 
Consortium [ARC]), stent thrombosis (ARC definite or probable), 
stroke or major bleeding (Bleeding defined by the Bleeding 
Academic Research Consortium [BARC] type 2-5) from 1 to 6 
months 
Secondary 
Endpoints 
The following endpoints will be assessed from 1 to 6 months: 
• Stent thrombosis (ARC definite/probable, ARC definite)  
• All death, cardiac death, vascular death, non-cardiovascular death 
• All myocardial infarction (MI) and MI attributed to target vessel 
(TV-MI, modified ARC) 
• Composite of cardiac death or MI (modified ARC) 
• Composite of all death or all MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI 
and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI 
and CI-TVR) 
• Bleeding defined by the Bleeding Academic Research Consortium 
(BARC) type 2-5 and type 3-5  
 
The primary endpoint of NACE and all the above secondary 
endpoints will also be assessed from 6 months to 12 months and from 
1 month to 12 months, respectively. 
                                                 
4 Patients present any of the following clinical or imaging evidence of ischemia (symptoms of ischemia;  ECG 
changes  indicative of new ischemia -  [new ST-T changes or new LBBB],  development of pathological Q 
waves;  or  imaging evidence of a new loss of  viable myocardium or a new regional wall  motion abnormality), 
AND confirmed with elevated cardiac biomarkers  per ARC criteria  (periprocedural MI: CK-MB > 3x URL or 
Troponin > 3x URL within 48 hours after PCI; CK-MB > 5x URL or Troponin > 5x URL within 72 hours after 
CABG; Assessment of CK-MB is preferred over troponin for the diagnosis of periprocedural MI, if possible. 
For spontaneous MI: CK-MB > URL or Troponin > URL) (Circulation 2007; 116: 2344-2351)  


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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Point of 
Registration  
Subject registration will occur after the index procedure but prior to 
discharge and up to 3 days post index procedure, upon confirmation 
of the following:  
• Signed informed consent has been obtained;  
• Subject has met all the inclusion and none of the exclusion 
criteria (including both general and angiographic criteria). 
Subject Follow-Up 
Subjects registered in the trial will receive the following clinical 
follow-up: 
• 1 month (28-35 days): office visit (Note: for subjects who have 
difficulty scheduling an office visit due to special circumstances, 
1-month follow-up may be performed via telephone per 
physician’s discretion) 
• 3 months (90 ± 7 days): office visit/telephone contact (office visit 
is strongly recommended whenever possible) 
• 6 months (180 ± 14 days): office visit/telephone contact (office 
visit is strongly recommended whenever possible) 
• 12 months (365 ± 28 days): office visit/telephone contact (office 
visit is strongly recommended whenever possible)  
Primary Analysis 
Sample Size 
Justification 
To further evaluate the safety of 1-month DAPT, non-inferiority (NI) 
will be tested comparing 1-month DAPT to XIENCE V USA 
historical control for the primary endpoint of NACE from 1- to 6-
month follow-up in a “1-month clear” population (defined as subjects 
who are free from myocardial infarction [modified ARC], repeat 
coronary revascularization, stroke, or stent thrombosis [ARC 
definite/probable] within 1 month (prior to 1-month visit but at least 
28 days) after stenting AND have been compliant with 1-month 
DAPT without interruption of either aspirin and/or P2Y12 receptor 
inhibitor for > 7 consecutive days).  
 
This analysis will be stratified by propensity score with the following 
assumptions: 
 
• True event rate for the primary endpoint is assumed to be 
approximately 8.1% for both arms 
• One-sided alpha = 0.05 
• Attrition rate of 10%  
• Sample size: a minimum of 800 to a maximum of 960 for the 1-
month DAPT arm and ~1,400 for the XIENCE V USA control 
arm  
• Non-inferiority margin = 4% 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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• Approximately 92% power  
Antiplatelet 
Medication  
Antiplatelet Medication Loading Dose: 
• Subjects must receive a loading dose of aspirin and/or a P2Y12 
inhibitor (Clopidogrel, Prasugrel or Ticagrelor). The dosages of 
aspirin and P2Y12 inhibitor shall be determined by physician per 
standard of care and label indication for loading dose usage. The 
choice of P2Y12 inhibitor is per site standard of care, but 
clopidogrel is strongly recommended for HBR subjects. The 
loading of P2Y12 inhibitor can be omitted only if the subject is 
on chronic usage (≥ 7 days). Subjects that are not on chronic 
usage must be loaded with P2Y12 inhibitor. It is recommended 
that the subject be loaded with aspirin, even if the subject is on 
chronic usage of aspirin (≥ 7 days). 
Antiplatelet Medication Post-Procedure Daily Dose: 
• All subjects must receive ≥75 to ≤100 mg of aspirin daily 
throughout the trial. All subjects must maintain a minimum of 75 
mg of clopidogrel daily or 5 or 10 mg of prasugrel daily (10 mg 
preferred in most subjects*) or 90 mg twice daily of ticagrelor for 
1 month (as short as 28 days) following the procedure.  
− The choice of P2Y12 inhibitor is per site standard of care, 
but clopidogrel is strongly recommended for HBR 
subjects. 
− For subjects taking chronic anticoagulants, dual therapy 
(oral anticoagulant and a P2Y12 inhibitor, clopidogrel 
preferred) may be considered within the first month per 
investigator’s discretion. 
• At 1-month follow up, subject will be assessed for their eligibility 
of P2Y12 inhibitor discontinuation. Eligible subjects will 
discontinue P2Y12 inhibitor as early as 28 days and receive ≥75 
to ≤100 mg of aspirin daily through 1-year follow-up during the 
trial if they are “1-month clear”, defined as subjects who are free 
from myocardial infarction (modified ARC), repeat coronary 
revascularization, stroke, or stent thrombosis (ARC 
definite/probable) within 1 month (prior to 1-month visit but at 
least 28 days ) after stenting AND have been compliant with 1-
month dual antiplatelet therapy (DAPT) without interruption of 
either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive 
days. Subjects who were on dual therapy during the first month 
(anticoagulant and a P2Y12 inhibitor) will discontinue the P2Y12 
inhibitor after 1 month. If they are assessed as “1-month clear”, 


Study Document No: ABT-CIP-10398 
STUDY NAME: CRD_940_XIENCE 28 Global 
PROTOCOL ABT-CIP-10398 XIENCE 28 Global Study 
 
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these subjects will start aspirin and will be on aspirin and 
anticoagulant for the remainder of the trial. 
If a subject was event-free and DAPT compliant (as defined 
above) during the first month, but does not stop P2Y12 inhibitor 
after the 1-month visit, due to physician’s or subject’s decision, 
this subject will be considered as “1-month not clear”. 
− Peri-procedural MI (occurred within 48 hours post index 
procedure) without any clinical symptoms will not be 
considered exclusionary event for the definition of “1-
month clear”.  
− Dual therapy (oral anticoagulant and a P2Y12 inhibitor, 
clopidogrel preferred) for subjects who are on chronic 
anticogulants is acceptable for the definition of “1-month 
clear”.  
• Subjects who are not “1-month clear” are NOT eligible for 
P2Y12 inhibitor discontinuation. These subjects will be treated 
per the investigator's discretion and will continue to be followed 
up through 12 months. 
*For prasugrel subjects < 60 kg in weight or ≥ 75 years of age, a 
maintenance dose of 5 mg per day is allowable.  
Cardiac 
Biomarker 
Collection 
Cardiac biomarker CK, CK-MB and/or troponin collection shall be 
done per site’s standard of care. CK and CK-MB are preferred. If CK 
and CK-MB are not available, troponin should be collected.  
Key Inclusion 
Criteria 
General Inclusion Criteria 
1. Subject is considered at high risk for bleeding (HBR), defined as 
meeting one or more of the following criteria at the time of 
registration and in the opinion of the referring physician, the risk 
of major bleeding with > 1-month DAPT outweighs the benefit: 
a) ≥ 75 years of age.  
b) Clinical indication for chronic (at least 6 months) or 
lifelong anticoagulation therapy. 
c) History of major bleeding which required medical 
attention within 12 months of the index procedure. 
d) History of stroke (ischemic or hemorrhagic).  
e) Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure 
(dialysis dependent). 
f) Systemic conditions associated with an increased bleeding 
risk (e.g. hematological disorders, including a history of or 
current thrombocytopenia defined as a platelet count 


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<100,000/mm3, or any known coagulation disorder 
associated with increased bleeding risk). 
g) Anemia with hemoglobin < 11g/dl. 
2. Subject must be at least 18 years of age.  
3. Subject must provide written informed consent as approved by the 
Ethics Committee (EC) of the respective clinical site prior to any 
trial related procedure.  
4. Subject is willing to comply with all protocol requirements, 
including agreement to stop taking P2Y12 inhibitor at 1 month, if 
eligible per protocol. 
5. Subject must agree not to participate in any other clinical trial for 
a period of one year following the index procedure. 
 
Angiographic Inclusion Criteria  
1. Up to three target lesions with a maximum of two target lesions 
per epicardial vessel. Note: 
• The definition of epicardial vessels means left anterior 
descending coronary artery (LAD), left circumflex coronary 
artery (LCX) and right coronary artery (RCA) and their 
branches. For example, the subject must not have >2 lesions 
requiring treatment within both the LAD and a diagonal 
branch in total. 
• If there are two target lesions within the same epicardial 
vessel, the two target lesions must be at least 15 mm apart per 
visual estimation; otherwise this is considered as a single 
target lesion.  
2. Target lesion must be located in a native coronary artery with 
visually estimated reference vessel diameter between 2.25 mm 
and 4.25 mm.  
3. Exclusive use of XIENCE family of stent systems during the 
index procedure. 
4. Target lesion has been treated successfully, which is defined as 
achievement of a final in-stent residual diameter stenosis of <20% 
with final TIMI-3 flow assessed by online quantitative 
angiography or visual estimation, with no residual dissection 
NHLBI grade ≥ type B, and no transient or sustained angiographic 
complications (e.g., distal embolization, side branch closure), no 
chest pain lasting > 5 minutes, and no ST segment elevation > 
0.5mm or depression lasting > 5 minutes. 
 


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Key Exclusion 
Criteria 
General Exclusion Criteria 
1. Subject with an indication for the index procedure of acute ST-
segment elevation MI (STEMI).  
2. Subject has a known hypersensitivity or contraindication to 
aspirin, heparin/bivalirudin, P2Y12 inhibitors 
(clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, 
nickel, tungsten, acrylic and fluoro polymers or contrast 
sensitivity that cannot be adequately pre-medicated. 
3. Subject with implantation of another drug-eluting stent (other 
than XIENCE) within 12 months prior to index procedure. 
4. Subject has a known left ventricular ejection fraction (LVEF) 
<30%. 
5. Subject judged by physician as inappropriate for discontinuation 
from P2Y12 inhibitor use at 1 month, due to another condition 
requiring chronic P2Y12 inhibitor use. 
6. Subject with planned surgery or procedure necessitating 
discontinuation of P2Y12 inhibitor within 1 month following 
index procedure. 
7. Subject with a current medical condition with a life expectancy 
of less than 12 months. 
8. Subject intends to participate in an investigational drug or device 
trial within 12 months following the index procedure. 
9. Pregnant or nursing subjects and those who plan pregnancy in 
the period up to 1 year 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.  
Note: Female subjects of childbearing potential should be 
instructed to use safe contraception (e.g., intrauterine devices, 
hormonal contraceptives: contraceptive pills, implants, 
transdermal patches hormonal vaginal devices, injections with 
prolonged release.) It is accepted, in certain cases, to include 
subjects having a sterilised regular partner or subjects using a 
double barrier contraceptive method. However, this should be 
explicitly justified in special circumstances arising from the trial 
design, product characteristics and/or trial population 
10. 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-


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up requirements, or impact the scientific soundness of the 
clinical investigation results. 
11. Subject is currently participating in another clinical trial that has 
not yet completed its primary endpoint. 
  
Angiographic Exclusion Criteria  
1. Target lesion is in a left main location.  
2. Target lesion is located within an arterial or saphenous vein graft. 
3. Target lesion is restenotic from a previous stent implantation. 
4. Target lesion is a chronic total occlusion (CTO, defined as lesion 
with TIMI flow 0 for at least 3 months). 
5. Target lesion is implanted with overlapping stents, whether 
planned or for bailout. 
 
Note: If there is more than one target lesion, all target lesions must 
satisfy the angiographic eligibility criteria. Non-target lesion (i.e., 
lesions that do not meet the angiographic criteria listed above) 
treatments are not allowed during the index procedure.  
Index Procedure 
• Only XIENCE stent can be used for target lesion(s). Stent 
implantation procedure should be performed according to the 
instruction for use (IFU) of the XIENCE family stent used. 
• Overlapping stents are not allowed in the trial, whether planned or 
for bailout. Subjects who received overlapping stents cannot be 
registered in this trial. 
• Bifurcation lesions are allowed in this trial. However, subjects 
who received double stenting for bifurcation lesions cannot be 
registered in this trial. 
Primary Analysis 
Population 
The primary analysis population includes “1-month clear” 
population, defined as subjects who are free from myocardial 
infarction (modified ARC), repeat coronary revascularization, stroke, 
or stent thrombosis (ARC definite/probable) within 1 month (prior to 
1-month visit but at least 28 days) after stenting AND have been 
compliant with 1-month DAPT  without interruption of either aspirin 
and/or P2Y12 receptor inhibitor for > 7 consecutive days.  
 
 


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1.0 
INTRODUCTION 
1.1 
Trial Design 
XIENCE 28 Global Study is a prospective, single arm, multi-center, open label trial to further 
evaluate the safety of 1-month (as short as 28 days) dual antiplatelet therapy (DAPT) in 
subjects at high risk of bleeding (HBR) undergoing percutaneous coronary intervention (PCI) 
with the approved XIENCE family of coronary drug-eluting stents. 
The XIENCE family stent systems include commercially approved5 XIENCE Xpedition 
Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS, XIENCE 
PROX EECSS6, XIENCE ProA EECSS7, or XIENCE Sierra EECSS which are all 
manufactured by Abbott Vascular, Inc, Santa Clara, USA.  The above listed XIENCE stents 
will hereinafter be called “XIENCE” in this trial.  
A minimum of 800 to a maximum of 960 subjects from approximately 50 sites globally will 
be registered in this trial. Subject registration is capped at 120 per site. Trial population 
consists of non-complex HBR subjects with up to three native coronary artery lesions (a 
maximum of two lesions per epicardial vessel) with reference vessel diameter between 2.25 
mm and 4.25 mm. Eligibility of P2Y12 receptor inhibitor discontinuation will be assessed at 
1-month follow-up. Subjects who are free from myocardial infarction (modified ARC), repeat 
coronary revascularization, stroke, or stent thrombosis (ARC definite/probable) within 1 
month (prior to 1-month visit but at least 28 days) after stenting AND have been compliant 
with 1-month DAPT without interruption of either aspirin and/or P2Y12 receptor inhibitor for 
> 7 consecutive days are considered as “1-month clear”, and will discontinue P2Y12 receptor 
inhibitor as early as 28 days and continued with aspirin monotherapy through 12-month 
follow-up.   
All registered subjects will be followed at 1, 3, 6 and 12 months post index procedure.  
The data collected from the XIENCE 28 Global Study will be compared with the historical 
control of non-complex HBR subjects treated with standard DAPT duration of up to 12 
months from the XIENCE V USA Study8, which is a US post-approval study to evaluate the 
safety of XIENCE V EECSS in “all-comer” population under real-world setting. 
1.2 
Trial Objective 
The primary objective of this trial is to further evaluate safety of 1-month (as short as 28 
days) dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) undergoing 
percutaneous coronary intervention (PCI) with XIENCE.  
2.0 
BACKGROUND INFORMATION 
2.1 
Background and Rationale 
Long-term dual antiplatelet therapy (DAPT) is known to increase the risk of bleeding.  
Multiple studies have demonstrated the relationship between bleeding and an increased risk 
                                                 
5 For each geography included in the trial, only approved and commercial available XIENCE stent(s) in that 
geography will be used. 
6 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System. 
7 XIENCE PROA is a rebrand of the XIENCE Alpine Stent System. 
8 Naidu et al., Contemporary incidence and predictors of stent thromobissi and other major adverse cardiac 
events in the year after XIENCE V implantation. JACC. Cardiovascular interventions. Jun 2012;5(6):626-635 


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of short- and long-term mortality9,10, with major bleeding being identified as an independent 
predictor of mortality with a weight similar to or even greater than myocardial infarction 
(MI)11.  A recent meta-analysis by Palmerini with 12 trials comprising > 34,000 patients 
randomized to different duration strategies of DAPT showed shorter DAPT was associated 
with lower rates of all-cause mortality compared with longer DAPT, which was driven by 
lower rates of bleeding-related deaths with shorter DAPT duration12.   This important finding 
underlies the most important benefit with short-term DAPT, which is especially relevant for 
patients who are at high risk of bleeding (HBR).  
HBR patients represent approximately 15% or more of the current percutaneous coronary 
intervention (PCI) population.13,14  This patient population is of a significant size but is 
usually underrepresented from traditional drug eluting stent (DES) trials.  The optimal 
duration of DAPT for HBR subjects  shall be better addressed. For some HBR patients, 
prolonging DAPT even beyond one month may be detrimental and hazardous. This is a 
challenging patient cohort requiring a trial designed to further optimize their therapy needs 
for DAPT after coronary revascularization.  Given the lack of specific data in this arena for 
DES, the current ACC/AHA guidelines recommend use of bare metal stent (BMS) with 1-
month DAPT 15. While this strategy aims to minimize the risk of bleeding in such patients, 
the use of BMS poses a higher risk of restenosis and re-intervention. Therefore, stenting with 
a DES followed by a shortened course of DAPT may represent a more favorable treatment 
option if there is no significant increase in ischemic events.  
There is limited clinical data with 1 month DAPT after DES in HBR population.  The 
LEADERS FREE study is a randomized, double-blind trial evaluating BioFreedom combined 
with 1 month of DAPT for treating HBR patients undergoing PCI as compared to BMS.16  A 
total of 2,466 HBR patients were randomized in a 1:1 ratio to BioFreedom or a similar BMS 
(Gazelle).  The primary safety endpoint, tested for both noninferiority and superiority, was a 
composite of cardiac death, MI, or stent thrombosis (definite/probable).  The primary efficacy 
endpoint was clinically driven target lesion revascularization (CD-TLR).  At 1 year, the rate 
                                                 
9 Mehran R, Pocock S, Nikolsky E, et al. Impact of bleeding on mortality after percutaneous coronary 
intervention results from a patient-level pooled analysis of the REPLACE-2 (randomized evaluation of PCI 
linking angiomax to reduced clinical events), ACUITY (acute catheterization and urgent intervention triage 
strategy), and HORIZONS-AMI (harmonizing outcomes with revascularization and stents in acute myocardial 
infarction) trials. JACC. Cardiovascular interventions. Jun 2011;4(6):654-664 
10 Pocock SJ, Mehran R, Clayton TC, et al. Prognostic modeling of individual patient risk and mortality impact 
of ischemic and hemorrhagic complications: assessment from the Acute Catheterization and Urgent Intervention 
Triage Strategy trial. Circulation. Jan 05 2010;121(1):43-51 
11 Genereux P, Giustino G, Witzenbichler B, et al. Incidence, Predictors, and Impact of Post-Discharge Bleeding 
After Percutaneous Coronary Intervention. Journal of the American College of Cardiology. Sep 01 
2015;66(9):1036-1045 
12 Palmerini T, Bacchi Reggiani L, Della Riva D, et al. Bleeding-Related Deaths in Relation to the Duration of 
Dual-Antiplatelet Therapy After Coronary Stenting. Journal of the American College of Cardiology. Apr 25 
2017;69(16):2011-2022 
13 Morice MC, et al. Why are we still using coronary bare-metal stents? Journal of the American College of 
Cardiology. Mar 12 2013;61(10):1122-1123 
14 Urban P, et al. Rationale and design of the LEADERS FREE trial: A randomized double-blind comparison of 
the BioFreedom drug-coated stent vs the Gazelle bare metal stent in patients at high bleeding risk using a short 
(1 month) course of dual antiplatelet therapy. Am Heart J. May 2013;165(5):704-709. 
15 Levine GN, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in 
Patients with Coronary Artery Disease. Circulation. 2016 134 (10): e123-55 
16 Urban P, et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med. 
Nov 19 2015;373(21):2038-2047 


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of the composite endpoint of cardiac death, MI, or stent thrombosis was significantly lower in 
the BioFreedom group than in the BMS group (9.4% (112/1221) vs. 12.9% (154/1211); p < 
0.001 for noninferiority and p=0.005 for superiority).  The 1-year rate of CD-TLR was also 
significantly lower in the BioFreedom group than in the BMS group (5.1% (59/1221) vs. 
9.8% (113/1211), p <0.001).  There was also a significant reduction in the 1-year rate of MI 
with BioFreedom compared with BMS (6.1% vs. 8.9%, p = 0.01), whereas no differences in 
the 1-year rates of stent thrombosis were observed between the two groups (2.0% vs. 2.2%, p 
= 0.75).  Consistent results were also demonstrated in a pre-specified HBR subgroup analysis 
from ZEUS trial with 1-month DAPT, which showed favorable outcomes with Endeavor 
group versus BMS group. In this HBR substudy, MACE (death, MI, or target vessel 
revascularization) occurred in 22.6% of the Endeavor group and 29% of the BMS group with 
a hazard ratio 0.75 (p=0.033) 17. The definite or probable ST was also significantly reduced in 
the Endeavor group (2.6% vs. 6.2%, p=0.016). Results from both ZEUS and LEADER FREE 
suggest that DES can be a safer choice for HBR patients than BMS with short duration of 
DAPT.  Based on these data, the most recent 2017 ESC guideline recommended 3-month 
DAPT (Class IIa) in high bleeding risk patients with stable CAD and 1-month DAPT (Class 
IIb) for those patients in whom 3-month DAPT poses safety concerns.18 
The second generation XIENCE everolimus-eluting stent (EES) has been the subject of 
extensive clinical studies. Consistently low late and very late stent thrombosis rates have been 
reported with EES from randomized controlled studies as well as real-world registry studies. 
Results from several recent large scale meta-analyses demonstrated that EES has a better 
safety profile than BMS and other DES,19,20 even in complex patient groups who are known 
at high risk of ischemic events such as diabetes and STEMI.21,22 23 The excellent safety 
profile of XIENCE is likely attributed to the unique combination of its thin struts (81 µm), 
the thromboresistant nature of the biocompatible fluoropolymer, and a low loading dose and 
release kinetics of the anti-proliferative agent, everolimus. The unique combination of the 
specific design features in XIENCE may lead to a more rapid endothelial coverage of strut 
surface and faster arterial healing compared with the other DES. Pre-clinical studies of 
endothelialization demonstrated that XIENCE V had a faster rate of strut coverage following 
                                                 
17 Ariotti S, et al. Is bare-metal stent implantation still justifiable in high bleeding risk patients undergoing 
percutaneous coronary intervention? A pre-specified analysis from the ZEUS trial. JACC Cardiovascular 
Interventions 2016; 9 (5): 426-436 
18 Valgimigli M, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease 
developed in collaboration with EACTS. European Heart Journal (2017) doi:10.1093/eurheartj/ehx419 
19 Palmerini T, et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive 
network meta-analysis. Lancet. Apr 14 2012;379(9824):1393-1402 
20 Bangalore S, et al. Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug 
eluting stents for coronary artery disease: mixed treatment comparison meta-analysis. BMJ. 2013;347:f6625 
21 Bangalore S, et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: 
mixed treatment comparison analysis of 22844 patient years of follow-up from randomized trails. BMJ 
2012;345:e5170 doi: 10.1136/bmj.e5170 (Published 10 August 2012) 
22 Bangalore S, et al. Outcomes with various drug-eluting or bare metal stents in patients with ST-segment-
elevation myocardial infarction: a mixed treatment comparison analysis of trial level data from 34 068 patient-
years of follow-up from randomized trials. Circ Cardiovasc Interv. 2013 Aug;6(4):378-90 
23 Palmerini T, et al. Clinical outcomes with drug-eluting and bare-metal stents in patients with ST-segment 
elevation myocardial infarction. Evidence from a comprehensive network meta-analysis. JACC 2013; 62 (6): 
496-504 


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stent implantation than Endeavor,24 and was equivalent to BioFreedom.25  The rapid strut 
coverage by endothelium with XIENCE V was confirmed in humans in an optical coherence 
tomography (OCT) cohort of the MECHANISM-Elective study26, which showed 93.6% strut 
coverage at 1 month and 98% strut coverage at 3 months in subjects with stable coronary 
artery disease receiving XIENCE V. Additionally, XIENCE showed a significant reduction in 
platelet adherence compared to BioFreedom stents in ex vivo studies27.  Given the large body 
of both pre-clinical and clinical evidence on the safety of the XIENCE DES platform, 
XIENCE is believed to be a safe and effective DES option for HBR population with 1-month 
DAPT.  
There is clearly an unmet medical need to be addressed for this patient population. XIENCE 
has consistently been shown to have the best safety profile among the coronary stents, even 
when compared to BMS and biodegradable polymer DES. The benefit/risk ratio of 1-month 
DAPT following XIENCE implantation in this population has not been specifically 
addressed. The XIENCE 28 Global Study will evaluate this important clinical question in a 
carefully controlled study setting. The results of the trial could potentially provide a definitive 
answer for the physicians as to the treatment of HBR patients with a safe and effective DES 
option. 
 
2.2 
Device Overview 
The following devices will be used for this clinical trial: 
 
• XIENCE Xpedition®  (stent diameter 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm, stent length 8, 
12, 15, 18, 23 and 28 mm), XIENCE Xpedition® Small Vessel (SV; stent diameter 2.25 
mm, stent length 8, 12, 15, 18, 23, 28 mm) and XIENCE Xpedition® LL (stent diameter 
2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm, stent length 8, 12, 15, 18, 23 and 28 mm) Everolimus 
Eluting Coronary Stent System (XIENCE Xpedition Stent System) 
• XIENCE Alpine® Everolimus Eluting Coronary Stent System (XIENCE Alpine Stent 
System; stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent length 8, 12, 15, 
18, 23, 28, 33, and 38 mm. Stent lengths 33 mm and 38 mm are not available for 2.25 mm 
diameter stent) 
• XIENCE PROX Everolimus Eluting Coronary Stent System (XIENCE PROX Stent 
System; stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent length 8, 12, 15, 
18, 23, 28, 33, and 38 mm. Stent lengths 33 mm and 38 mm are not available for 2.25 mm 
diameter stent)28 
• XIENCE PROA Everolimus Eluting Coronary Stent System (XIENCE PROA Stent 
System; stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent length 8, 12, 15, 
18, 23, 28, 33, and 38 mm. Stent lengths 33 mm and 38 mm are not available for 2.25 mm 
diameter stent.  
                                                 
24 Joner M, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. Journal of 
the American College of Cardiology. Jul 29 2008;52(5):333-342 
25 Yazdani S, et al. Endothelialization of polymers-free drug coated stents. EuroIntervention. 
2011;7(Supplement M) 
26 Shinke T, Itoh T, Ishida M, et al. Early vascular responses to everolimus-eluting cobalt-chromium stent for 
the treatment of stable coronary artery disease: The results of MECHANISM-Elective 1 and 3 months OCT 
follow-up cohort. ESC; 2016 
27 Data on file with Abbott Vascular 
28 XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System  


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• XIENCE Sierra Everolimus Eluting Coronary Stent System (XIENCE Sierra Stent 
System; stent diameter 2.25, 2.5, 2.75, 3.0, 3.25, 3.5 and 4.0 mm; stent length 8, 12, 15, 
18, 23, 28, 33, and 38 mm) 
Only stents up to 38 mm can be used. All the above devices (hereinafter be called as 
“XIENCE” in the trial) are manufactured by Abbott Vascular, Santa Clara, United States 
(US). All the above stent systems have received Conformité Européene (CE) mark and are 
currently in commercial use in different European countries. Please refer to the Instructions 
for Use (IFU) for details of each stent system. 
 
3.0 
CLINICAL TRIAL FLOW AND FOLLOW-UP SCHEDULE 
3.1 
Number of Subjects to be Registered 
A minimum of 800 to a maximum of 960 subjects from approximately 50 sites globally will 
be registered in this trial. Subject registration is capped at 120 per site. 
3.2 
Overall Flow of the Trial and Follow-up Schedule 
The clinical trial flow is shown in Appendix V. Subjects who satisfy eligibility criteria 
become registered in the trial. Subjects have follow-up visits at 1, 3, 6 and 12 months. 
Assessment of eligibility of DAPT discontinuation will be performed at 1-month follow-up. 
3.3 
Measures Taken to Avoid and Minimize Bias 
All the clinical endpoint events will be adjudicated by the Clinical Events Committee (CEC). 
The CEC is an independent adjudication body comprised of qualified physicians who are not 
participants in the trial. The CEC will review and adjudicate events as defined in the CEC 
charter and according to definitions provided in this protocol.  
3.4 
Early Termination of the Clinical Trial 
No formal statistical rule for early termination of the trial is defined.  
The Sponsor reserves the right to discontinue the clinical trial at any stage or reduce the 
follow up period with suitable written notice to the investigator and authorities. 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. 
• Any oversight committee (e.g., Steering/Executive Committee, Data Safety 
Monitoring Board [DSMB]) makes a recommendation to stop or terminate the trial 
(such as higher frequency of anticipated adverse device effects). 
• Further product development is cancelled. 
Should the clinical trial be discontinued by the Sponsor, subjects will be followed up as per 
routine hospital practice with device related AEs being reported to the Sponsor as per 
vigilance/commercial reporting requirements. 
Should this occur, the investigator shall return all clinical trial materials to the Sponsor, and 
provide a written statement as to why the premature termination has taken place to the EC (if 
applicable). All applicable clinical trial documents shall be subject to the same retention 
policy as detailed in Section 12 Data Handling and Record Keeping.  


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4.0 
ENDPOINTS 
4.1 
Primary Endpoint  
The primary endpoint is a composite of Net Adverse Clinical Endpoint (NACE, a composite 
rate of all-cause death, all myocardial infarction (modified 29Academic Research Consortium 
[ARC]), stent thrombosis (ARC definite or probable), stroke or major bleeding (Bleeding 
defined by the Bleeding Academic Research Consortium [BARC] type 2-5) from 1 to 6 
months. 
4.2 
Secondary Endpoint(s) 
The following endpoints will be assessed from 1 to 6 months: 
• Stent thrombosis (ARC definite/probable, ARC definite)  
• All death, cardiac death, vascular death, non-cardiovascular death 
• All myocardial infarction (MI) and MI attributed to target vessel (TV-MI, modified 
ARC) 
• Composite of cardiac death or MI (modified ARC) 
• Composite of all death or all MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI and CI-TVR) 
• Bleeding defined by the Bleeding Academic Research Consortium (BARC) type 2-5 
and type 3-5 
The primary endpoints of NACE and all the above secondary endpoints will also be assessed 
from 6 months to 12 months and from 1 month to 12 months, respectively.  
                                                 
29 Patients present any of the following clinical or imaging evidence of ischemia (symptoms of ischemia;  ECG 
changes  indicative of new ischemia -  [new ST-T changes or new LBBB],  development of pathological Q 
waves;  or  imaging evidence of a new loss of  viable myocardium or a new regional wall  motion abnormality), 
AND confirmed with elevated cardiac biomarkers  per ARC criteria  (periprocedural MI: CK-MB > 3x URL or 
Troponin > 3x URL within 48 hours after PCI; CK-MB > 5x URL or Troponin > 5x URL within 72 hours after 
CABG; Assessment of CK-MB is preferred over troponin for the diagnosis of periprocedural MI, if possible. 
For spontaneous MI: CK-MB > URL or Troponin > URL) (Circulation 2007; 116: 2344-2351)  


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5.0 
SUBJECT SELECTION AND WITHDRAWAL  
5.1 
Subject Population 
This trial will register male and female HBR subjects from the general interventional 
cardiology population who satisfy the inclusion and exclusion criteria. A minimum of 800 
subjects to a maximum of 960 will be registered. Subjects must meet all clinical and 
angiographic eligibility criteria and provide written informed consent prior to conducting any 
trial-specific procedures not considered standard of care.  
5.2 
Subject Screening and Informed Consent  
5.2.1 Subject Screening 
Subjects admitted for a percutaneous coronary artery revascularization procedure must be 
screened for clinical trial eligibility by a member of the clinical trial team (physician and/or 
research coordinator) previously trained to the clinical trial protocol and if applicable will be 
entered into a site specific screening log.  
Subjects meeting the general inclusion and exclusion criteria will be asked to sign an 
informed consent. Pre-procedure (or baseline) imaging will be used for the final assessment 
of subject eligibility (details are described in Section 5.3). Subjects who do not satisfy the 
angiographic inclusion and exclusion criteria are considered screen failures and will not be 
registered and proceed further in the trial. These subjects will be entered into the screening 
log. Also, the reason for screen failure as well as supporting data will be entered into the log. 
Subject data will be collected following registration into the trial. 
5.2.2 Informed Consent 
The Investigator or designee, who has been trained on the Protocol, will explain the nature 
and scope of the trial, potential risks and benefits of participation, and answer questions for 
the subjects. All subjects must sign and date (and time, as per applicable local standards) the 
Ethics Committee (EC) approved informed consent (ICF) prior to any clinical trial-specific 
procedures. All efforts should be made to consent a subject prior to index procedure. 
However, it is acceptable for the subject to provide consent prior to hospital discharge and up 
to 3 days after the index procedure, only if the site confirms that the protocol required DAPT 
regimen  is site’s standard of care.   
Obtaining the consent and provisioning of a copy to the subject, along with the date and time 
must be documented in the subject’s medical records. The ICF must be signed by the 
investigator or designate (if allowed per country specific regulations). In addition, the signed 
informed consent must be kept in the subject’s medical records/research chart and a copy 
must be given to the subject. 
All subjects must provide informed consent in accordance with the local EC requirements, 
using an EC-approved informed consent form. 
For Live cases at congresses the patients need to sign a specific Live Case ICF, approved by 
the EC. The investigator must notify Abbott Vascular prior to performing a Live Case.   
5.3 
Eligibility Criteria 
5.3.1   General Eligibility Criteria 
Assessment for general eligibility criteria is based on medical records of the site and 
interview with a candidate subject. If some of the clinical and laboratory tests are not 
included in site standard tests, they must be done but after written informed consent is 


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obtained. Subjects must meet ALL of the inclusion criteria to be considered for the clinical 
evaluation. If ANY of the exclusion criteria are met, the subject is excluded from the clinical 
evaluation and cannot be registered.   
5.3.1.1 
General Inclusion Criteria 
1. 
Subject is considered at high risk for bleeding (HBR), defined as meeting one or more of 
the following criteria at the time of registration and in the opinion of the referring 
physician, the risk of major bleeding with > 1-month DAPT outweighs the benefit: 
a) ≥ 75 years of age.  
b) Clinical indication for chronic (at least 6 months) or lifelong anticoagulation 
therapy. 
c) History of major bleeding which required medical attention within 12 months of 
the index procedure. 
d) History of stroke (ischemic or hemorrhagic).  
e) Renal insufficiency (creatinine ≥ 2.0 mg/dl) or failure (dialysis dependent). 
f) Systemic conditions associated with an increased bleeding risk (e.g. hematological 
disorders, including a history of or current thrombocytopenia defined as a platelet 
count <100,000/mm3, or any known coagulation disorder associated with 
increased bleeding risk). 
g) Anemia with hemoglobin < 11g/dl. 
2. Subject must be at least 18 years of age.  
3. Subject must provide written informed consent as approved by the Ethics Committee (EC) 
of the respective clinical site prior to any trial related procedure. 
4. Subject is willing to comply with all protocol requirements, including agreement to stop 
taking P2Y12 inhibitor at 1 month, if eligible per protocol. 
5. Subject must agree not to participate in any other clinical trial for a period of one year 
following the index procedure. 
5.3.1.2 
General Exclusion Criteria 
1. Subject with an indication for the index procedure of acute ST-segment elevation MI 
(STEMI).  
2. Subject has a known hypersensitivity or contraindication to aspirin, heparin/bivalirudin, 
P2Y12 inhibitors (clopidogrel/prasugrel/ticagrelor), everolimus, cobalt, chromium, 
nickel, tungsten, acrylic and fluoro polymers or contrast sensitivity that cannot be 
adequately pre-medicated. 
3. Subject with implantation of another drug-eluting stent (other than XIENCE) within 12 
months prior to index procedure. 
4. Subject has a known left ventricular ejection fraction (LVEF) <30%. 


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5. Subject judged by physician as inappropriate for discontinuation from P2Y12 inhibitor 
use at 1 month, due to another condition requiring chronic P2Y12 inhibitor use. 
6. Subject with planned surgery or procedure necessitating discontinuation of P2Y12 
inhibitor within 1 month following index procedure. 
7. Subject with a current medical condition with a life expectancy of less than 12 months 
8. Subject intends to participate in an investigational drug or device trial within 12 months 
following the index procedure. 
9. Pregnant or nursing subjects and those who plan pregnancy in the period up to 1 year 
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.  
Note: Female subjects of childbearing potential should be instructed to use safe 
contraception (e.g., intrauterine devices, hormonal contraceptives: contraceptive pills, 
implants, transdermal patches hormonal vaginal devices, injections with prolonged 
release.) It is accepted, in certain cases, to include subjects having a sterilised regular 
partner or subjects using a double barrier contraceptive method. However, this should be 
explicitly justified in special circumstances arising from the trial design, product 
characteristics and/or trial population. 
10. 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.  
11. Subject is currently participating in another clinical trial that has not yet completed its 
primary endpoint. 
5.3.2 Angiographic Eligibility Criteria 
All angiographic eligibility criteria are based on visual assessment. 
5.3.2.1 
Angiographic Inclusion Criteria 
1. Up to three target lesions with a maximum of two target lesions per epicardial vessel. 
Note: 
• The definition of epicardial vessels means left anterior descending coronary artery 
(LAD), left circumflex coronary artery (LCX) and right coronary artery (RCA) and 
their branches. For example, the subject must not have >2 lesions requiring treatment 
within both the LAD and a diagonal branch in total. 
• If there are two target lesions within the same epicardial vessel, the two target lesions 
must be at least 15 mm apart per visual estimation; otherwise this is considered as a 
single target lesion. 
2. Target lesion must be located in a native coronary artery with visually estimated reference 
vessel diameter between 2.25 mm and 4.25 mm.  
3. Exclusive use of XIENCE family of stent systems during the index procedure. 


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4. Target lesion has been treated successfully, which is defined as achievement of a final in-
stent residual diameter stenosis of <20% with final TIMI-3 flow assessed by online 
quantitative angiography or visual estimation, with no residual dissection NHLBI grade ≥ 
type B, and no transient or sustained angiographic complications (e.g., distal 
embolization, side branch closure), no chest pain lasting > 5 minutes, and no ST segment 
elevation > 0.5mm or depression lasting > 5 minutes. 
5.3.2.2 
Angiographic Exclusion Criteria  
1. Target lesion is in a left main location.  
2. Target lesion is located within an arterial or saphenous vein graft. 
3. Target lesion is restenotic from a previous stent implantation.  
4. Target lesion is a chronic total occlusion (CTO, defined as lesion with TIMI flow 0 for at 
least 3 months). 
5. Target lesion is implanted with overlapping stents, whether planned or for bailout.  
Note: If there is more than one target lesion, all target lesions must satisfy the angiographic 
eligibility criteria. Non-target lesion (i.e., lesions that do not meet the angiographic criteria 
listed above) treatments are not allowed during the index procedure. 
 
5.4 
Subject Registration  
Subject registration will occur after completion of successful index procedure (see 
“Angiographic Inclusion Criteria” above for definition of successful treatment of target 
lesion) but prior to discharge and up to 3 days post index procedure, upon confirmation of the 
following:  
• Signed informed consent has been obtained;  
• Subject has met all the inclusion and none of the exclusion criteria (including both 
general and angiographic criteria). 
5.5 
Subject Discontinuation 
All registered subjects will be considered to have completed the trial upon trial completion of 
the 12-month follow-up.  
Each registered subject shall remain in the trial until completion of the required follow-up 
period; however, a subject’s participation in any clinical trial is voluntary and the subject has 
the right to withdraw at any time without penalty or loss of benefit. Conceivable reasons for 
discontinuation may include, but not be limited to, the following: 
• Subject death 
• Subject voluntary withdrawal  
• Subject withdrawal by physician as clinically-indicated 
• Subject lost-to follow-up as described below  


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• Subject’s follow-up is terminated according to Section 3.4 Early termination of the 
Clinical Trial 
The Sponsor must be notified of the reason(s) for subject discontinuation. The site will record 
this information on the eCRF and source documents and provide this information to the 
Sponsor. Investigators must also report this to their respective EC as defined by their 
institution’s procedure(s).  
No additional follow–up will be required or data recorded from subjects once withdrawn 
from the trial, except for the status (deceased/alive). 
However, if a subject withdraws from the trial due to problems related to the device safety or 
performance, the investigator shall ask for the subject's permission to follow his/her 
status/condition outside of the clinical trial. 
Lost-to-Follow-up:   
If the subject misses two consecutive scheduled follow up time points and the attempts at 
contacting the subject detailed below are unsuccessful, then the subject is considered lost-to 
follow-up. Site personnel shall make all reasonable efforts to locate and communicate with 
the subject (and document these efforts in the source documents), including the following, at 
each contact time point: 
• A minimum of 2 telephone calls on different days over the specified follow-up windows to 
contact the subject should be recorded in the source documentation, including date, time 
and initials of site personnel trying to make contact. 
• If these attempts are unsuccessful, a letter (certified if applicable) should be sent to the 
subject. 
• If a subject misses one or more non-consecutive follow-up contact time points it will be 
considered a missed visit. The subject may then return for subsequent visits. If the subject 
misses two consecutive time points and the above-mentioned attempts at communicating 
with the subject are unsuccessful, the subject will be considered lost-to-follow-up.  
Note: Telephone contact with general practitioner, non-trial cardiologist or relative without 
presence of subject or indirect documentation obtained via discharge letters will not be 
considered as subject contact. 
Missed Visits: 
• If a subject misses one or more non-consecutive follow-up contact time points, the visit 
will be considered a missed visit and subject is not lost-to-follow-up.   
• If subject responds via written communication (including email correspondence), 
providing the protocol required data, these data will be collected in the case report form 
and the visit will not be considered a missed visit.   
5.6 
Total Expected Duration of the Clinical Trial 
The total expected duration of the clinical trial is approximately 28 months. 
5.7 
Expected Duration of Each Subject’s Participation 
The expected duration of each subject’s participation in this clinical trial is approximately 12 
months. 


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5.8 
Number of Subjects Required to be Included in the Clinical Trial  
A minimun of 800 to a maximum of 960 subjects are required to be included in the clinical 
trial. 
5.9 
Estimated Time Needed to Register this Number  
The estimated time needed to register 800-960 subjects is approximately 16 to 19 months. 
5.10 
Trial Completion 
A Trial Completion eCRF must be completed when: 
• the subject is considered lost to follow-up per the above definition or  
• the subject withdraws from the clinical trial or 
• the investigator withdraws the subject from the clinical trial or 
• the subject has died or 
• upon clinical trial completion or 
• sponsor termination of trial. 
Sponsor must be notified of the reason for subject discontinuation. The site will provide this 
information on the eCRF. Investigators must also report this to their EC as defined by their 
institution’s procedure. Subjects will not be replaced. 
6.0 
TREATMENT AND EVALUATION  
6.1 
Baseline and Pre-procedure 
6.1.1 Laboratory Assessments  
Baseline 12-lead electrocardiogram (ECG) and laboratory assessments (such as blood counts, 
chemistry panel and lipid panel, cardiac enzymes, etc) should be obtained per site’s standard 
care. Baseline laboratory results related to inclusion/exclusion criteria should be available and 
reviewed prior to the index procedure for screening. 
6.1.2 Clinical Assessments 
Subject demographics (age, gender, race), height, weight, family history of coronary artery 
disease (CAD), smoking status, cardiac history (myocardial infarction, diabetes mellitus, 
hypertension, hypercholesterolemia, and previous PCI/CABG information), subject’s current 
cardiac status (presentation of CAD and multivessel disease) and indication of high bleeding 
risk (per criteria specified in Section 5.3.1.1) will be obtained and recorded in electronic case 
report form (eCRF).   
6.1.3 Pre-procedure Antiplatelet Medication 
Subjects must receive a loading dose of aspirin and/or a P2Y12 inhibitor (Clopidogrel, 
Prasugrel or Ticagrelor). The dosages of aspirin and P2Y12 inhibitor shall be determined by 
physician per standard of care and label indication for loading dose usage. The choice of 
P2Y12 inhibitor is per site standard of care, but clopidogrel is strongly recommended for 
HBR subjects. The loading of P2Y12 inhibitor can be omitted only if the subject is on 
chronic usage (≥ 7 days). Subjects that are not on chronic usage must be loaded with P2Y12 
inhibitor. It is recommended that the subject be loaded with aspirin, even if the subject is on 
chronic usage of aspirin (≥ 7 days).  


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The details of the antiplatelet loading dose, including type of drug, dosage, date and time, 
will be recorded in eCRF. In addition, whether the subject is taking oral anticoagulants will 
also be collected. 
6.2 
Index Procedure 
Only XIENCE stent can be used for target lesion(s). Stent implantation procedure should be 
performed according to the instruction for use (IFU) of the XIENCE family stent used. If 
XIENCE stent is delivered beyond the guide catheter but not implanted, the subject cannot be 
registered in the trial. If other DES was implanted, the subject cannot be registered in the 
trial.  
In this trial, a maximum of three target lesions may be treated with a maximum of two target 
lesions per epicardial vessel. Non-target lesion (i.e., lesions that do not meet the angiographic 
eligibility criteria) treatments are not allowed during the index procedure.  
Subjects may receive appropriate anticoagulation and other therapy according to standard 
hospital practice.  
Overlapping stents are not allowed in the trial, whether planned or for bailout. Subjects who 
received overlapping stents cannot be registered in this trial.  
Bifurcation lesions are allowed in this trial. However, subjects who received double stenting 
for bifurcation lesions cannot be registered in this trial. 
Lesion characteristics (lesion location, % diameter stenosis, TIMI flow, RVD, lesion length, 
thrombus presence, bifurcation or not, lesion complexity), device (device name, size, number 
of device implanted, bailout usage, overlapping stent) and procedural information (procedure 
time, access site, procedural anticoagulant and anti-thrombotic medications, any procedure 
complications) will be collected and recorded in eCRF.  
6.3 
Post–procedure  
6.3.1 Post-procedure Laboratory and Clinical Tests 
Post-procedure ECG and cardiac enzymes are not mandatory in the trial, and shall be 
performed per site’s standard care. CK and CK-MB are preferred. If CK and CK-MB are not 
available, troponin should be collected. 
6.3.2 Antiplatelet Medications during Follow-up  
• All subjects must receive ≥75 to ≤100 mg of aspirin daily throughout the trial. All 
subjects must maintain a minimum of 75 mg of clopidogrel daily or 5 or 10 mg of 
prasugrel daily (10 mg preferred in most subjects*) or 90 mg twice daily of ticagrelor for 
1 month (as short as 28 days) following the procedure.  
− The choice of P2Y12 inhibitor is per site standard of care, but clopidogrel is strongly 
recommended for HBR subjects. 
− For subjects taking chronic anticoagulants, dual therapy (oral anticoagulant and a 
P2Y12 inhibitor, clopidogrel preferred) may be considered within the first month per 
investigator’s discretion. 
• At 1-month follow up, subject will be assessed for their eligibility of P2Y12 inhibitor 
discontinuation. Eligible subjects will discontinue P2Y12 inhibitor as early as 28 days 
and receive ≥75 to ≤100 mg of aspirin daily through 1-year follow-up during the trial if 
they are “1-month clear”, defined as subjects who are free from myocardial infarction 


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(modified ARC), repeat coronary revascularization, stroke, or stent thrombosis (ARC 
definite/probable) within 1 month (prior to 1-month visit but at least 28 days) after 
stenting AND have been compliant with 1-month dual antiplatelet therapy (DAPT) 
without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive 
days. Subjects who were on dual therapy during the first month (anticoagulant and a 
P2Y12 inhibitor) will discontinue the P2Y12 inhibitor after 1 month and if they are 
assessed as “1-month clear”. These subjects will start aspirin such that they will be on 
aspirin and anticoagulant for the remainder of the trial. 
If a subject was event-free and DAPT compliant (as defined above) during the first 
month, but does not stop P2Y12 inhibitor after the 1-month visit, due to physician’s or 
subject’s decision, this subject will be considered as “1-month not clear”. 
− Peri-procedural MI (occurred within 48 hours post index procedure) without any 
clinical symptoms will not be considered exclusionary event for the definition of “1-
month clear”. 
− Dual therapy (oral anticoagulant and a P2Y12 inhibitor, clopidogrel preferred) for 
subjects who are on chronic anticogulants is acceptable for the definition of “1-month 
clear”. 
• Subjects who are not “1-month clear” are NOT eligible for P2Y12 inhibitor 
discontinuation. These subjects will be treated per the investigator's discretion and will 
continue to be followed up through 12 months. 
*For prasugrel subjects < 60 kg in weight or ≥ 75 years of age, a maintenance dose of 5 mg 
per day is allowable.   
The use of the above antiplatelet medications, including the start and stop date, any changes, 
as well as the reason to stop, will be documented in the eCRF. 
6.3.3 Other Chronic Concomitant Medications 
Administration of concomitant medications other than any approved P2Y12 inhibitors and 
aspirin are not required in this protocol. Subjects may receive other medications as needed 
per physician’s discretion.  
6.4 
Clinical Follow-up for All Subjects 
Subjects registered in the trial will receive the following clinical follow-up: 
• 1 month (28-35 days): office visit (Note: for subjects who have difficulty scheduling 
an office visit due to special circumstances, 1-month follow-up may be performed via 
telephone per physician’s discretion.) 
• 3 months (90 ± 7 days): office visit/telephone contact (office visit is strongly 
recommended whenever possible) 
• 6 months (180 ± 14 days): office visit/telephone contact (office visit is strongly 
recommended whenever possible) 
• 12 months (365 ± 28 days): office visit/telephone contact (office visit is strongly 
recommended whenever possible) 
 


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Clinical follow-up visits should be conducted by the investigator or trial personnel who have 
been trained to the protocol. At 1-month follow-up visit, the investigator or designee will 
assess whether the subject is “1-month clear” and eligible for P2Y12 inhibitor discontinuation 
per criteria defined in Section 6.3.2.  
All registered subjects will be followed up through 12 months, regardless of eligibility to 
discontinue P2Y12 inhibitor. 
The following information will be collected at each of the time points: 
• Any adverse events  
• Use and compliance of protocol required antiplatelet medication 
• Details of any subsequent coronary interventions (e.g., repeat PCI or CABG). 
Note that information obtained through indirect contacts with a subject’s healthcare provider 
or immediate family member will NOT be considered as a trial visit. 
6.5 
Additional Follow-up Visits for All Subjects  
Additional subject visits, such as unscheduled visits, may occur as clinically warranted. The 
following information will be collected and recorded in eCRF:  
• Any adverse events  
• Use and compliance of protocol required antiplatelet medication 
• Details of any subsequent coronary interventions (e.g., repeat PCI or CABG). 
If an unscheduled visit is conducted due to a suspected ischemic cardiac event, cardiac 
enzymes and ECG may be performed per site’s standard care. CK and CK-MB are preferred. 
If CK and CK-MB are not available, troponin should be collected. 
All efforts must be made to obtain follow-up information on subjects who have undergone 
procedures or have been treated for adverse events in a non-trial-related hospital(s). 
7.0 
ADVERSE EVENTS 
To comply with worldwide standards and guidelines on clinical trial adverse event reporting, 
AV has developed uniform and worldwide applicable standard definitions and reporting 
timelines to be used and adhered to by the investigators. 
7.1 
Definition  
7.1.1 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 medicinal 
product, whether or not related to the medicinal product.  


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7.1.2 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. 
d) An important medical event that may not result in death, be life-threatening, or require 
hospitalization but may be considered serious when, based upon appropriate medical 
judgment, may jeopardize the subject and/or may require intervention to prevent one of the 
outcomes listed in this definition. 
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 
Clinical Study Plan, without a serious deterioration in health, is not considered to be a serious 
adverse event. 
7.1.3 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. 
7.2 
Device Relationship 
Determination of whether there is a reasonable possibility that a product or device caused or 
contributed to an AE is to be determined by the Investigator and recorded on the 
appropriate eCRF form. For clinical endpoint events that are sent to the CEC for adjudication, 
event relatedness to the study device will also be adjudicated by the CEC. The CEC members 
will be trained on the criteria used for determination of device relationship. Determination 
should be based on assessment of temporal relationships, evidence of alternative etiology, 
and medical/biologic plausibility. 
7.2.1 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 


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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. 
7.3 
Adverse Event Reporting 
7.3.1 Adverse Event Reporting 
For all registered subjects, AE reporting starts when the guiding catheter enters the subject’s 
vasculature. All AEs will be collected through 6-month follow-up visit.  After 6 months, only 
the following will be collected in those subjects: 
• 
All serious AEs 
• 
All cardiovascular events regardless of seriousness or device relationship  
• 
All trial device-related events and events for which the relationship to the trial device is 
unknown  
• 
All Cerebrovascular Accident (CVA) and bleeding complications 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be 
recorded on the AE eCRF page.  
Non-cardiac related abnormal laboratory values will not be considered AEs unless:  
1) the investigator determined that the value is clinically significant,  
2) the abnormal lab value required intervention, or  
3) the abnormal lab value required subject termination from the trial. 
The Investigator will monitor the occurrence of AEs for each subject during the course of the 
clinical trial and report as required by this protocol in Section 7 per AE and SAE definitions. 
AEs need to be collected as of the time point of guiding catheter enters the subject’s 
vasculature on the appropriate AE eCRF form. Additional information with regards to an 
adverse event should be updated within the appropriate case report form.  
A fax 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.  
The investigator should report all SAEs to the Sponsor as soon as possible but no later than 
outlined below.  
Trial site 
Reporting timelines 
All Trial Sites 
SAEs 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 date the site staff became aware that the event met the criteria of a serious adverse event 
must be recorded in the source document.  
Serious adverse events that occurred in the user or persons other than the trial subject should 
not be entered in the EDC system, however need to be reported via the SAE Notification 
Form.   


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The Investigator will further report the SAE to the local EC according to the institution’s EC 
reporting requirements.    
7.3.2 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.  
7.3.3 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 Trial 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.  
 
If there is a device deficiency/malfunction related to other AV products, please contact the 
Product Performance Group (PPG) by e-mail: qahotline@av.abbott.com or contact AV Sales 
person to complete a Product Experience Form (PER Form). 
7.3.4 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.  
7.4 
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. 


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8.0 
ADJUDICATION OF EVENTS 
The Clinical Events Committee (CEC) is comprised of qualified physicians who are not 
investigators in the trial. The CEC will review and adjudicate pre-specified events reported 
by trial investigators or identified by the Clinical Safety personnel/designate for the trial as 
documented in CEC Manual of Operations (MOPs).  
9.0 
STATISTICAL ANALYSES  
9.1 
Statistical Overview  
The XIENCE 28 Global Study is powered based on primary endpoint of Net Adverse Clinical 
Endpoint (NACE, a composite rate of all-cause death, all myocardial infarction (modified 
30Academic Research Consortium [ARC]), stent thrombosis (ARC definite or probable), 
stroke or major bleeding (Bleeding defined by the Bleeding Academic Research Consortium 
[BARC] type 2-5) from 1- to 6-month follow-up.  
Primary endpoint analysis for 1-month DAPT 
The primary endpoint of NACE between 1-month and 6-month follow-up will be evaluated 
based on the “1-month clear” population (as defined in section 9.2). The hypothesis test is 
designed for non-inferiority of 1-month DAPT arm compared to XIENCE V USA historical 
control for the primary endpoint with one-sided alpha of 0.05 after propensity score 
stratification. The null (H0) and alternative (HA) hypothesis are of the following form: 
                        H0: NACE1m-DAPT  -  NACEXience V USA   ≥ δ 
HA: NACE1m-DAPT  -  NACEXience V USA  < δ 
A stratified statistical method through propensity score will be performed to test non-
inferiority (NI) of 1-month DAPT to XIENCE V USA historical control. 
The trial success is defined as passing the non-inferiority test on the primary endpoint of 
NACE for the “1-month clear” population.  
9.2 
Analysis Populations  
The primary analysis population includes “1-month clear” population, defined as subjects 
who are free from myocardial infarction (modified ARC), repeat coronary revascularization, 
stroke, or stent thrombosis (ARC definite/probable) within 1 month (prior to 1-month visit 
but at least 28 days) after stenting AND have been compliant with 1-month dual antiplatelet 
therapy (DAPT) without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 
consecutive days. If a subject was event-free and DAPT compliant (as defined above) during 
the first month, but does not stop P2Y12 inhibitor after the 1-month visit, due to physician’s 
or subject’s decision, this subject will be considered as “1-month not clear” and will be 
excluded from the analysis population. 
                                                 
30 Patients present any of the following clinical or imaging evidence of ischemia (symptoms of ischemia;  ECG 
changes  indicative of new ischemia -  [new ST-T changes or new LBBB],  development of pathological Q 
waves;  or  imaging evidence of a new loss of  viable myocardium or a new regional wall  motion abnormality), 
AND confirmed with elevated cardiac biomarkers  per ARC criteria  (periprocedural MI: CK-MB > 3x URL or 
Troponin > 3x URL within 48 hours after PCI; CK-MB > 5x URL or Troponin > 5x URL within 72 hours after 
CABG; Assessment of CK-MB is preferred over troponin for the diagnosis of periprocedural MI, if possible. 
For spontaneous MI: CK-MB > URL or Troponin > URL) (Circulation 2007; 116: 2344-2351)  


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9.3 
Sample Size Calculations and Assumptions  
To evaluate the performance of the 1-month DAPT, the non-inferiority test will be performed 
on the primary endpoint of NACE between 1-month and 6-month follow-up for the 1-month 
DAPT arm against XIENCE V USA historical control after propensity score stratification 
with the following assumptions: 
• True event rate for the primary endpoint is assumed to be 8.1% for both arms    
• Non-inferiority margin: 4%  
• Attrition rate of 10%  
• One-sided alpha = 0.05 
• Sample size in the control arm: approximately 1,400 
• Approximately 92% power. 
Sample size of approximately 800 subjects in the 1-month DAPT arm will be required for 
this test.  
The sample size calculations were performed using NCSS PASS 11 (Hintze, J., 2011, NCSS, 
LLC. Kaysville, Utah). 
9.4 
Statistical Analyses  
A stratified statistical method through propensity score will be used to test non-inferiority of 
1-month DAPT to XIENCE V USA historical control at a 0.05 significant level.  
Analyses of other secondary endpoints and additional endpoints will be descriptive in nature.  
For binary variables such as TLR, TVR, counts, percentages and 95% confidence intervals 
will be calculated, and p-values may be presented for hypothesis generating purposes. 
Pearson’s Chi-squared test of Fisher’s exact test will be performed when appropriate. 
For continuous variables such as age, means, standard deviation, and 95% confidence 
intervals for the mean will be calculated and p-values may be presented for hypothesis 
generating purposes. For time-to-event variables, such as time to Death/MI, survival curves 
will be constructed using Kaplan-Meier estimates, and log rank test results will be displayed. 
Unless specified, analyses will be performed with pooled data across all trial sites. 
For further details refer to the Statistical Analysis Plan (SAP). 
9.4.1 Primary Endpoint Analysis  
A non-inferiority test will be performed on the primary endpoint of NACE between 1-month 
and 6-month follow up for the “1-month clear” population of the 1-month DAPT arm and the 
XIENCE V USA historical control stratified by propensity scores. 
Details of the analyses for the powered primary endpoint can be found in the Statistical 
Analysis Plan (SAP). 
9.4.2 Secondary Endpoint Analyses  
Other secondary and additional clinical endpoints will be descriptively analyzed.   
9.4.3 Subgroup Analysis 
Subgroup analyses will be performed for gender (male versus female), diabetes (diabetes 
versus non-diabetes), and age (age ≥ median versus < median).  


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9.4.4 Procedures for Accounting for Missing, Unused or Spurious Data 
To handle missing data, multiple imputation method will be performed to compute propensity 
scores from these datasets. For further details refer to the SAP. 
All other analyses will be based on available data with missing data excluded. Any unused or 
spurious data will be noted as appropriate in the final report.   
9.5  
Deviations from the Original Statistical Plan 
Any major changes to the statistical plan will be documented in an amendment to the 
statistical plan. Less significant changes to the planned analyses will be documented in the 
final report. 
10.0 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The investigator/institution will permit direct access to source data/documents in order for 
clinical trial-related monitoring, audits, EC review and regulatory inspections to be 
performed. 
Subjects providing informed consent are agreeing to allow Sponsor and/or its designee access 
and copying rights to pertinent information in their medical records concerning their 
participation in this clinical trial. The investigator will obtain, as part of the informed consent, 
permission for clinical trial monitors or regulatory authorities to review, in confidence, any 
records identifying the subjects in this clinical trial. This information may be shared with 
regulatory agencies; however, Sponsor undertakes not to otherwise release the subject's 
personal and private information.  
11.0 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1 
Selection of Clinical Sites and Investigators 
Sponsor will select investigators qualified by training and experience, to participate in the 
trial. Sites will be selected based upon review of a recent site assessment, if applicable, and 
the qualifications of the Principal Investigator or multidisciplinary team at the site.  
11.2  Protocol Amendments  
Approved protocol amendments will be provided to the Investigators by the Sponsor prior to 
implementing the amendment. The Principal Investigator is responsible for notifying the EC 
or equivalent committee of the protocol amendment (administrative changes) or obtaining 
EC’s approval of the protocol amendment (changes in subject care or safety), according to 
the instructions provided by the Sponsor with the protocol amendment.   
Acknowledgement/approval by the EC of the protocol amendment must be documented in 
writing prior to implementation of the protocol amendment. Copies of this documentation 
must also be provided to the Sponsor. 
11.3 
Training 
 
11.3.1 Site Training  
All Investigators/trial personnel are required to attend Sponsor training sessions, which may 
be conducted at an Investigator's meeting, a site initiation visit or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of 
Investigators/trial personnel will include, but is not limited to, the Protocol requirements, 
electronic case report form completion and trial personnel responsibilities. All 
Investigators/trial personnel that are trained must sign a training log (or an equivalent) upon 


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completion of the training. Prior to signing the training log, Investigator/trial personnel must 
not perform any trial-related activities that are not considered standard of care at the site.  
11.3.2 Training of Sponsor’s Monitors 
 
Sponsor and/or designated monitors will be trained to the Protocol and case report forms. 
Documentation of this training will be according to written procedures. 
11.4 
Monitoring 
 
Sponsor and/or designee will monitor the trial over its duration according to the pre-specified 
monitoring plan which will include the planned extent of source data verification.  
The Sponsor should be contacted for additional information on the person(s) responsible for 
monitoring activities. 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the 
following criteria are met:  
• The investigator understands and accepts the obligation to conduct the research trial 
according to the Protocol and applicable regulations, and has signed the Clinical Trial 
Agreement.  
• The Investigator and his/her staff have sufficient time and facilities to conduct the trial 
and that they have access to an adequate number of appropriate subjects to conduct the 
trial.  
• Source documentation (including original medical records) must be available to 
substantiate proper informed consent procedures, adherence to Protocol procedures, 
adequate reporting and follow-up of adverse events, accuracy of data collected on case 
report forms, and device information.  
The Investigator/site will permit access to such records. A monitoring visit sign-in log will be 
maintained at the site. The Investigator will agree to dedicate an adequate amount of time to 
the monitoring process. The Investigator and/or research coordinator will be available for 
monitoring visits. It is expected that the Investigator will provide the trial monitor with a 
suitable working environment for review of trial-related documents. 
11.5 
Deviations from the Protocol 
The Investigator will not deviate from the Protocol for any reason without prior written 
approval from Sponsor 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. All deviations must be reported to the Sponsor. In 
subject-specific deviations from the Protocol, a Protocol deviation case report form will be 
completed. The occurrence of Protocol deviations will be monitored by the Sponsor for 
evaluation of investigator compliance to the Protocol and regulatory requirements and dealt 
with according to written procedures. Investigators will inform their EC or equivalent 
committee of all Protocol deviations in accordance with their specific 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 


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• Telephoning the investigator and/or delegate 
• Corresponding with the investigator and/or delegate 
Repeated non-compliance with the signed agreement, the Protocol or any other conditions of 
the trial 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 trial.  
The following categories of protocol deviations will be considered as major: 
• Informed Consent deviation 
• Eligibility deviation 
• Serious adverse event reporting deviation 
• Treatment/procedure compliance deviation  
 
The following categories of protocol deviations will be considered as minor: 
• Data outside time window 
• Missed visit 
11.6 
Quality Assurance Audits  
A Sponsor representative or designee may request access to all clinical trial records, 
including source documentation, for inspection and duplication during a Quality Assurance 
audit. In the event that an investigator is contacted by a Regulatory Agency in relation to this 
clinical trial , 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 trial (e.g., Inspectional 
Observations, Warning Letters, Inspection Reports, etc.). Sponsor may provide any needed 
assistance in responding to regulatory audits.  
11.7 
Committees  
11.7.1 Steering Committee 
The Steering Committee is assigned by the Sponsor and comprises the Study Principal 
Investigator, the Study Co-Principal Investigators as specified on the cover page of this 
Protocol, the Trial Chairman (if applicable) and four/five dedicated members from the trial 
sites. The Sponsor will be represented by at least one person each from the Clinical Science 
and Clinical Program Management groups. The Chairman of the core laboratories and other 
sponsor’s personnel may also participate in the Committee meetings if appropriate. Meeting 
minutes from this committee will be filed with the Sponsor. 
 
The Steering Committee is responsible for overseeing the scientific and operational aspects of 
the trial. This committee will meet regularly to monitor patient registration or randomization, 
general data collection and non-compliance with the trial plan at individual centers, to review 
and act upon recommendations of the Data and Safety Monitoring Board, to review 
operational issues that may arise and warrant a Protocol amendment or other corrective action 
and to determine policy regarding any publications arising from data generated from the 
performance of the trial. 
11.7.2 Data Safety Monitoring Board (DSMB) 
 
The Data Safety Monitoring Board (DSMB) is an independent multidisciplinary group that 
that is restricted to individuals free of apparent significant conflicts of interest. The source of 


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these conflicts may be financial, scientific, or regulatory in nature. The DSMB is typically 
composed of at least two physicians with relevant interventional experience (e.g., vascular 
surgeon, interventional radiologist, interventional cardiologist) and a biostatistician and is 
responsible for making recommendations regarding endpoint analyses and any potentially 
significant patient safety-related observations. The composition of the DSMB, frequency of 
the DSMB sessions and the statistical monitoring guidelines are described in detail in the 
DSMB charter. DSMB meeting minutes and recommendations are forwarded to Abbott 
Vascular.    
In addition to an Abbott Vascular/designee safety monitor reviewing adverse events at 
regular intervals, a monthly listing of Adverse Events will be sent to the DSMB Chair or 
designee for review. If a safety signal is identified during this review then the DSMB chair 
will call for an ad hoc full DSMB meeting. 
11.7.3 Clinical Events Committee (CEC) 
 
The Clinical Events Committee (CEC) is an independent adjudication body comprised of 
qualified physicians who are not participants in the trial. The CEC will review and adjudicate 
events as defined in the CEC charter and according to definitions provided in this Protocol 
Appendix II.      
12.0 
DATA HANDLING AND RECORD KEEPING  
Data Management will include documentation of the systems and procedures used in data 
collection for the duration of the trial.  
All CRF data collection will be performed through a secure web portal and all authorized 
personnel with access to the Electronic Data Capture (EDC) system must use an electronic 
signature access method to enter, review or correct data. Passwords and electronic signatures 
will be strictly confidential.   
All CRF data will be downloaded from the EDC system and reformatted into a data structure 
acceptable to Abbott Vascular. The data will be subjected to consistency and validation 
checks within the EDC system and will be subject to supplemental validation following 
download.   
At the conclusion of the trial, completed CRF images with the date-and-time stamped 
electronic audit trail indicating the user, the data entered, and any reason for change (if 
applicable) will be archived for each trial site and a backup copy archived with Abbott 
Vascular.  
For the clinical trial duration, the Investigator will maintain complete and accurate 
documentation including, but not limited to, medical records, clinical trial progress records, 
laboratory reports, electronic case report forms, signed ICFs, device accountability records, 
correspondence with EC and clinical trial monitor/Sponsor, adverse event reports, and 
information regarding subject discontinuation or completion of the clinical trial. 
12.1 
Source Documentation 
 
Regulations and GCP require that the Investigator maintain information in the subject’s 
original medical records that corroborates data collected on the case report forms. In order to 
comply with these regulatory requirements/GCP, the following information should be 
included in the subject record at a minimum and if applicable to the trial: 
• Medical history/physical condition of the subject before involvement in the trial 
sufficient to verify protocol entry criteria 


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• Dated and signed notes on the day of entry into the trial referencing the sponsor, 
protocol number, subject ID number and a statement that informed consent was 
obtained 
• Dated and signed notes from each subject visit (for specific results of procedures and 
exams) 
• Adverse events reported and their resolution including supporting documents such as 
discharge summaries, catheterization laboratory reports, ECGs, and lab results 
including documentation of site awareness of SAEs and of investigator device 
relationship assessment of SAEs. 
• Any laboratory reports and 12-lead ECGs (if performed), reviewed and annotated for 
clinical significance of out of range results.  
• Notes regarding Protocol-required and prescription medications taken during the trial 
(including start and stop dates) 
• Subject’s condition upon completion of or withdrawal from the trial 
• 
Any other data required to substantiate data entered into the CRF 
12.2 
Electronic Case Report Form Completion  
Primary data collection based on source-documented hospital and/or clinic chart reviews will 
be performed clearly and accurately by site personnel trained on the protocol and eCRF 
completion. eCRF data will be collected for all subjects that are registered into the trial.  
12.3 
Record Retention 
 
The Sponsor will archive and retain all documents pertaining to the trial as per the applicable 
regulatory record retention requirements. The Investigator must obtain permission from 
Sponsor in writing before destroying or transferring control of any clinical trial/investigation 
records. 
13.0 
ETHICAL CONSIDERATION 
 
13.1 
Medical Ethics Committee Review  
Ethics Committee (EC) approval for the Protocol and ICF/other written information provided 
to the patient will be obtained by the Principal Investigator at each trial site prior to 
participation in this clinical trial. The approval letter must be received prior to the start of this 
clinical trial and a copy must be provided to the Sponsor. No changes will be made to the 
Protocol or ICF or other written information provided to the patient without appropriate 
approvals, including EC, the Sponsor, and/or the regulatory agencies.  
Until the clinical trial is completed, the Investigator will advise his/her EC of the progress of 
this clinical trial, per EC requirements. Further, any amendments to the Protocol as well as 
associated ICF changes will be submitted to the EC and written approval obtained prior to 
implementation, according to each institution’s EC requirements. 
No investigative procedures other than those defined in this Protocol will be undertaken on 
the registered subjects without the written agreement of the EC and the Sponsor. 


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14.0 
PUBLICATION POLICY  
The data and results from the trial 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 trial. The 
Sponsor will submit trial results for publication, regardless of trial outcome, following the 
conclusion or termination of the trial.  The Investigators will not use the Clinical trial related 
data without the written consent of the Sponsor for any other purpose than for Clinical trial 
completion or for generation of publication material, as referenced in the Clinical trial Site 
Agreement. The publication and/or presentation of results from a single clinical trial site are 
not allowed until publication and/or presentation of the multi-center results. The Sponsor 
acknowledges that the trial’s Principal Investigator intends to publish a multi-center 
publication regarding the clinical trial results. The Sponsor must receive any proposed 
publication and/or presentation materials at least 60 days prior to the proposed date of the 
presentation or the initial submission of the proposed publication in order for the materials to 
be reviewed by the Sponsor in compliance with the Sponsor’s publication policy set forth in 
the Clinical trial Site Agreement. 
The Sponsor will be responsible for determining whether to register the clinical trial on 
www.clinicaltrials.gov or any other clinical trials, in accordance with the International 
Committee of Medical Journal Editors guidelines, or any other applicable guidelines. In the 
event Sponsor determines that the Trial should be registered, Sponsor shall be responsible for 
any such registration and results posting as required by ClinicalTrials.gov. Institution and/or 
Principal Investigator(s) shall not take any action to register the Trial. 
15.0 
RISK ANALYSIS 
 
The optimal duration of DAPT remains under debate for clinicians with the current clinical 
practice, and is of particular interest to HBR patients which represent approximately 15% or 
more of patients undergoing PCI. The default management of care for HBR patients who 
undergo PCI is often stenting with BMS followed by 1 month of DAPT. The updated 2016 
ACC/AHA guideline also provided a class IIb recommendation of 3-month DAPT in SIHD 
patients with high risk of bleeding following DES implantation31. The most recent 2017 ESC 
guideline recommended 3-month DAPT (Class IIa) in high bleeding risk patients with stable 
CAD and 1-month DAPT (Class IIb) for those patients in whom 3-month DAPT poses safety 
concerns.32 
 
XIENCE has consistently been shown to have the best safety profile among the coronary 
stents, even when compared to BMS. However, the benefit/risk ratio of a shorter duration of 
DAPT following XIENCE implantation in the HBR population has not been thoroughly 
evaluated. There is clearly an unmet medical need to be addressed for the HBR patient 
population as the possible benefits of extended DAPT therapy to prevent late stent 
thrombosis and the progression of atherosclerotic disease need to be weighed against the 
increased risk of bleeding in an individual patient. Therefore, the XIENCE 28 Global Study is 
designed to prospectively evaluate the safety of XIENCE followed with 1-month (as short as 
28 days) DAPT in HBR patients. 
                                                 
31 Levine GN, et al. 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in 
Patients With Coronary Artery Disease. Circulation. 2016 134 (10): e123-55 
32 Valgimigli M, et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease 
developed in collaboration with EACTS. European Heart Journal (2017) doi:10.1093/eurheartj/ehx419 


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15.1 
Anticipated Clinical Benefits 
The excellent safety profile of XIENCE family of stents has been well demonstrated. Stent 
implantation and the following medical treatment are the same for subjects registered in this 
trial as if they are not participating in this clinical trial, except for DAPT duration. One-
month DAPT may decrease the risk of bleeding in HBR subjects. Participation of this trial 
contributes to defining the optimum duration of DAPT in HBR subjects treated with 
XIENCE. 
15.2 
Foreseeable Adverse Events and Anticipated Adverse Device Effects  
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. 
Please refer to the drug labelling (most recent versions available at www.ema.europa.eu – 
find medicine – human medicines), and published guidelines on PCI and DAPT use for 
information on bleeding and other risks associated with DAPT use. 
One-month DAPT may decrease the risk of bleeding in HBR subjects, but may increase the 
risk of late stent thrombosis and progression of atherosclerotic disease.  
15.3 
Residual Risks Associated with the Device, as Identified in the Risk Analysis 
Report 
The XIENCE Risk Assessment Report33 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. 
The benefit of treatment from the XIENCE outweighs the potential risks to the patient. 
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 the device34 . 
15.4 
Risks Associated with Participation in Clinical Trial 
All procedures required by the protocol are routine standard of care. There are no additional 
risks to the subjects, except that reduced DAPT treatment duration may increase the risk of 
stent thrombosis and ischemic events. 
15.5 
Possible Interactions with Protocol Required Concomitant Medications 
Other than DAPT, the trial protocol does not require concomitant medications. 
15.6 
Steps that will be Taken to Control or Mitigate the Risks 
In-depth recommendations, special precautions and instructions regarding patient selection, 
vessel sizing, device handling, device placement and system removal are included in the IFU. 
It is also stated in the IFU that the devices can only be used by physicians who have received 
appropriate training on how to use the device. This statement is interpreted to mean that the 
physician users are expected to be aware of the known and foreseeable safety risks associated 
                                                 
33 RAM1070000 XIENCE Xpedition/XIENCE PROx EECSS RAM; RAM 1100000 XIENCE Alpine EECSS 
RAM; RAM 1500000 XIENCE Sierra EECSS RAM 
34 RPT2098376 Rev G XIENCE EECSS Clinical Evaluation Report 


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with the use of the devices including the surgical and/or non-surgical treatment of these 
conditions. 
Risks associated with the use of the device during this clinical trial are minimized through 
device design, investigator selection and training, pre-specified patient eligibility 
requirements, trial monitoring to ensure adherence to the protocol, clinical follow-up by 
investigator or designee at pre-specified time points and the use of a DSMB.  
All adverse events and device deficiencies observed in this trial will be reported to Abbott 
Vascular, will be monitored internally for safety surveillance purposes, and will be reported 
to the regulatory authorities, as applicable. 
Abbott Vascular updates the risk assessment reports and conducts comprehensive analysis of 
product level clinical data on a regular basis. 
The XIENCE family of stents has not been tested in pregnant women. Effects on the 
developing fetus and excretion of everolimus in breast milk have not been studied. Pregnant 
or nursing subjects and those who plan pregnancy in the period up to 1 year following index 
procedure are excluded from participation in the clinical trial. Female subjects of child-
bearing potential must have a pregnancy test done within 7 days prior to the index procedure 
with negative results known to confirm eligibility prior to registration.  
15.7 
Risk to Benefit Rationale  
The XIENCE family of stent has consistently been shown to have the best safety profile 
among the coronary stents. The optimal duration of DAPT remains under debate for 
clinicians with the current clinical practice, and is of particular interest to HBR patients 
which represent approximately 15% or more of patients undergoing PCI. The XIENCE 28 
Global Study is designed to prospectively evaluate the safety of XIENCE followed with 1-
month (as short as 28 days) DAPT in HBR patients. Reduced DAPT treatment duration may 
decrease the risk of bleeding, but may increase the risk of late stent thrombosis and 
progression of atherosclerotic disease, although studies with other DES have confirmed 
safety of 1-month DAPT for HBR patients35,36. All procedures required by the protocol are 
routine standard of care, conducted according to current IFU, and participation in this trial 
carries no additional risk to the patient. 
                                                 
35 Urban P, et al. Polymer-free Drug-Coated Coronary Stents in Patients at High Bleeding Risk. N Engl J Med. 
Nov 19 2015;373(21):2038-2047 
36 Ariotti S, et al. Is bare-metal stent implantation still justifiable in high bleeding risk patients undergoing 
percutaneous coronary intervention? A pre-specified analysis from the ZEUS trial. JACC Cardiovascular 
Interventions 2016; 9 (5): 426-436 


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APPENDIX I: 
ABBREVIATIONS AND ACRONYMS 
 
Acronym or Abbreviation 
Complete Phrase or Definition 
%DS 
percent diameter stenosis 
ACS 
Acute Coronary Syndrome 
AE 
adverse event 
AMI 
acute myocardial infarction 
ARC 
Academic Research Consortium  
AV 
Abbott Vascular 
BARC 
Bleeding Academic Research Consortium 
BMS 
Bare metal stents 
CABG 
coronary artery bypass graft 
CAD 
coronary artery disease 
CASS 
Coronary Artery Surgery Study 
CCS 
Canadian Cardiovascular Society (Canada) 
CEC 
Clinical Events Committee 
CVA 
Cerebrovascular Accident 
CI 
clinically-indicated 
CI 
confidence interval 
CK 
creatine kinase 
CK-MB 
creatine kinase myocardial-band isoenzyme 
CoCr-EES 
cobalt chromium everolimus-eluting stent 
CTO 
Chronic total occlusion 
CVA 
cerebrovascular accident (or stroke) 
DAPT 
dual antiplatelet therapy 
DD 
device deficiency 
DES 
Drug-eluting stent 
DM 
device malfunction 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee (EU) 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EECS 
everolimus eluting coronary stent  
EECSS 
everolimus eluting coronary stent system   
FDA 
Food and Drug Administration 
FMEA 
Failure Modes and Effects Analysis  
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
HIPAA 
Health Insurance Portability and Accountability Act 


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Acronym or Abbreviation 
Complete Phrase or Definition 
HBR 
High bleeding risk 
ICF 
Informed Consent Form  
IDE 
Investigational Device Exemption 
IFU 
Instructions for Use 
KM 
Kaplan-Meier 
LAD 
left anterior descending coronary artery 
LCX 
left circumflex coronary artery 
LMCA 
left main coronary artery 
LVEF 
left ventricular ejection fraction 
MACCE 
major adverse cerebral and cardiovascular event 
MEC 
Medical Ethics Committee (EU) 
MOP 
Manual of Operations 
µg 
microgram 
mg 
milligram 
MI 
myocardial infarction 
mL 
milliliter 
MLD 
mean lumen diameter 
mm 
millimeter 
N 
sample size; also N 
NACE 
Net Adverse Clinical Endpoint 
NSTEMI 
non ST-segment elevation MI 
NQMI 
non-Q wave myocardial infarction 
OCT 
optical coherence tomography 
OR 
odds ratio 
OUS 
Outside of United States 
PE 
product experience 
PCI 
percutaneous coronary intervention 
PG 
performance goal 
PTCA 
percutaneous transluminal coronary angioplasty 
QCA 
quantitative coronary angiography 
RCA 
right coronary artery 
RCT 
randomized clinical trial  
RVD 
reference vessel diameter 
RX 
Rapid Exchange 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SIHD 
stable ischemic heart disease 
ST 
stent thrombosis 


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Acronym or Abbreviation 
Complete Phrase or Definition 
STEMI 
ST-segment elevation myocardial infarction 
TIA 
transient ischemic attack 
TIMI 
thrombolysis in myocardial infarction 
TLR 
target lesion revascularization 
TLF 
target lesion failure 
TVF 
target vessel failure 
TVR 
target vessel revascularization 
UADE 
unanticipated adverse device effect 
ULN 
upper limit of normal 
US 
United States 
USADE 
unanticipated serious adverse device effect 


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APPENDIX II: 
DEFINITIONS 
 
CLINICAL ENDPOINT DEFINITIONS 
 
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. 
 
MYOCARDIAL INFARCTION (MI) 
 
MI Definition (Modified ARC) 
 
Patients present any of the following clinical or imaging evidence of ischemia: 
• Clinical symptoms of ischemia;  
• ECG changes indicative of new ischemia - new ST-T changes or new left bundle branch 
block (LBBB), development of pathological Q waves*;  
• Imaging evidence of a new loss of viable myocardium or a new regional wall motion 
abnormality)  
 
AND confirmed with elevated cardiac biomarkers** per ARC criteria (Circulation 2007; 115: 
2344-2351): 
• Periprocedural MI: 
• Within 48h after PCI: CK-MB >3 x URL or Troponin > 3 x URL with baseline value 
< URL 
• Within 72h after CABG: CK-MB >5 x URL or Troponin > 5 x URL with baseline 
value < URL 
• Spontaneous MI (> 48h following PCI, > 72h following CABG): CK-MB > URL or 
Troponin > URL with baseline value < URL 
 
* Pathologic Q waves may be defined according to the Global Task Force, Minnesota code, or Novacode  
**The assessment of CK-MB is preferred over the assessment of troponin for the diagnosis of peri-procedural MI, if possible. 
Baseline biomarker value requiring before study procedure and presumes a typical rise and fall.  
 
Electrocardiographic Classification 
 
• Based on Q-Wave 


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o Q-wave MI [QMI] 
 Development of new pathological Q waves in 2 or more contiguous 
leads with or without post- procedure CK or CK-MB levels elevated 
above normal. 
 
o Non Q-wave MI [NQMI] 
 All MIs not classified as Q waves. 
 
• Relation to the Target Vessel 
All infarcts that cannot be clearly attributed to a vessel other than the target vessel 
will be considered related to the target vessel. 
 
WHO MI Definition 
 Myocardial infarctions will also be adjudicated based on the following definition:  
 Q wave MI: Development of new, pathological Q wave on the ECG  
 
 Non-Q wave MI: Elevation of CK levels to ≥ two times the upper limit of normal (ULN) 
with elevated CK-MB in the absence of new pathological Q waves 
  
 
STENT THROMBOSIS (Per ARC Circulation 2007; 115: 2344-2351) 
 
Timing:  
Acute stent thrombosis*:  
 
0 - 24 hours post stent implantation  
Subacute stent thrombosis*:   
>24 hours . 30 days post stent implantation  
Late stent thrombosis†:  
 
30 days - 1 year post stent implantation  
Very late stent thrombosis†:   
>1 year post stent implantation  
 
*  
Acute/subacute can also be replaced by early stent thrombosis. Early stent thrombosis 
(0 - 30 days) - this definition is currently used in the community.  
† 
Including “primary” as well as “secondary” late stent thrombosis; “secondary” late 
stent thrombosis is a stent thrombosis after a target segment revascularization.  
 
Categories (Definite, Probable, and Possible): 
 
Definite stent thrombosis 
Definite stent thrombosis is considered to have occurred by either angiographic or 
pathologic 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  
• New ischemic ECG changes that suggest acute ischemia  
• Typical rise and fall in cardiac biomarkers (refer to definition of spontaneous 
MI)  
• Non-occlusive  thrombosis 


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o Thrombus 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.  
• Occlusive thrombus  
o TIMI 0 or TIMI 1 intrastent or proximal to a stent up to the most 
adjacent proximal side branch or main branch (if originates from the 
side branch).  
 
Pathological confirmation of stent thrombosis  
Evidence of recent thrombus within the stent determined at autopsy or via 
examination of tissue retrieved following thrombectomy.  
 
    * 
The incidental angiographic documentation of stent occlusion in the absence 
of clinical signs or symptoms is not considered a confirmed stent thrombosis 
(silent occlusion). 
 
    † 
Intracoronary thrombus. 
 
Probable stent thrombosis 
Clinical definition of probable stent thrombosis is considered to have occurred after 
intracoronary stenting in the following cases: 
• Any unexplained death within the first 30 days‡  
• Irrespective of the time after the index procedure, any MI that is related to 
documented acute ischemia in the territory of the implanted stent without 
angiographic confirmation of stent thrombosis and in the absence of any other 
obvious cause  
 
    ‡ 
For studies with ST-elevation MI population, one may consider the exclusion 
of unexplained death within 30 days as evidence of probable stent thrombosis. 
 
Possible stent thrombosis 
Clinical definition of possible stent thrombosis is considered to have occurred with any 
unexplained death from 30 days after intracoronary stenting until end of trial follow-up. 
 
STROKE 
 
An acute symptomatic episode of neurological dysfunction attributed to a vascular cause 
lasting more than 24 hours or lasting 24 hours or less with a brain imaging study or autopsy 
showing new infarction. 
• Ischemic Stroke: An acute symptomatic episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue. 
• Hemorrhagic Stroke: An acute symptomatic episode of focal or global cerebral or 
spinal dysfunction caused by a non-traumatic intraparenchymal, intraventricular, or 
subarachnoid hemorrhage. 
• Undetermined Stroke: A stroke with insufficient information to allow categorization 
as ischemic or hemorrhagic. 
 


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Note: an event that last < 24 hours may be adjudicated as a stroke if the following treatments 
were used: 
• Pharmacologic, i.e., thrombolytic drug administration, or 
Non-pharmacologic, i.e., neurointerventional procedure (e.g., intracranial angioplasty) 
 
 
BLEEDING (Per BARC, Circulation 2011; 123: 2736-2747) 
Bleeding will also be adjudicated per Bleeding Academic Research Consortium (BARC) 
definitions: 
• Type 0: no bleeding 
• Type 1: bleeding that is not actionable and does not cause the patient to seek 
unscheduled performance of studies, hospitalization, or treatment by a healthcare 
professional; may include episodes leading to self-discontinuation of medical therapy 
by the patient without consulting a healthcare professional 
• Type 2: any overt, actionable sign of hemorrhage (eg, more bleeding than would be 
expected for a clinical circumstance, including bleeding found by imaging alone) that 
does not fit the criteria for type 3, 4, or 5 but does meet at least one of the following 
criteria: (1) requiring nonsurgical, medical intervention by a healthcare professional, 
(2) leading to hospitalization or increased level of care, or (3) prompting evaluation 
• Type 3 
o Type 3a 
 Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL* (provided 
hemoglobin drop is related to bleed) 
 Any transfusion with overt bleeding 
o Type 3b 
 Overt bleeding plus hemoglobin drop ≥ 5 g/dL*(provided hemoglobin 
drop is related to bleed) 
 Cardiac tamponade 
 Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 Bleeding requiring intravenous vasoactive agents 
o Type 3c 
 Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation, does include intraspinal) 
 Subcategories confirmed by autopsy or imaging or lumbar puncture 
 Intraocular bleed compromising vision 
• Type 4: CABG-related bleeding 
o Perioperative intracranial bleeding within 48 h 
o Reoperation after closure of sternotomy for the purpose of controlling 
bleeding 
o Transfusion of ≥ 5 U whole blood or packed red blood cells within a 48-h 
period† 
o Chest tube output ≥ 2L within a 24-h period 
• Type 5: fatal bleeding 
o Type 5a 


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 Probable fatal bleeding; no autopsy or imaging confirmation but 
clinically suspicious 
o Type 5b 
 Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 
CABG indicates coronary artery bypass graft. Platelet transfusions should be recorded 
and reported but are not included in these definitions until further information is obtained 
about the relationship to outcomes. If a CABG-related bleed is not adjudicated as at least 
a type 3 severity event, it will be classified as not a bleeding event. If a bleeding event 
occurs with a clear temporal relationship to CABG (ie, within a 48-h time frame) but does 
not meet type 4 severity criteria, it will be classified as not a bleeding event. 
* Corrected for transfusion (1 U packed red blood cells or 1 U whole blood=1 g/dL 
hemoglobin). 
† Cell saver products are not counted. 
 
 
REVASCULARIZATION (Per ARC Circulation 2007; 115: 2344-2351) 
 
Target Lesion Revascularization (TLR)  
TLR is defined as any repeat percutaneous intervention of the target lesion or bypass surgery 
of the target vessel performed for restenosis or other complication of the target lesion. All 
TLR should be classified prospectively as clinically indicated [CI] or not clinically indicated 
by the investigator prior to repeat angiography. The target lesion is defined as the treated 
segment from 5 mm proximal to the stent and to 5 mm distal to the stent. 
Target Vessel Revascularization (TVR) 
TVR is defined as any repeat percutaneous intervention or surgical bypass of any segment of 
the target vessel. The target vessel is defined as the entire major coronary vessel proximal and 
distal to the target lesion which includes upstream and downstream branches and the target 
lesion itself  
Non Target Lesion Revascularization (Non-TLR) 
Any revascularization in the target vessel for a lesion other than the target lesion is 
considered a non-TLR. 
Non Target Vessel Revascularization (Non-TVR) 
Revascularization of the vessel identified and treated as the non-target vessel at the time of 
the index procedure.  
Clinically Indicated [CI] Revascularization (TLR/TVR) 
A revascularization is considered clinically indicated if angiography at follow-up shows a 
percent diameter stenosis ≥ 50% and if one of the following occurs:  
• A positive history of recurrent angina pectoris, presumably related to the target vessel;  
• Objective signs of ischemia at rest (ECG changes) or during exercise test (or 
equivalent), presumably related to the target vessel;  
• Abnormal results of any invasive functional diagnostic test (e.g., Doppler flow 
velocity reserve, fractional flow reserve);  


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• A TLR/TVR with a diameter stenosis ≥70% in the absence of the above mentioned 
ischemic signs or symptoms. 
 
TARGET LESION FAILURE (TLF) 
TLF is defined as a composite of all cardiac death, myocardial infarction attributed to target 
vessel or clinically-indicated TLR. 
 
TARGET VESSEL FAILURE (TVF) 
TVF is defined as a composite of cardiac death, MI attributed to target vessel, clinically-
indicated TLR, or clinically-indicated TVR, non-TLR. 


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OTHER DEFINTIONS (in alphabetic order) 
 
ACC/AHA Classification Scheme of Coronary Lesions: Lesion-Specific Characteristics 
Type A Lesions (High Success, >85%; Low Risk) 
• 
Discrete (< 10 mm length) 
• 
Little or no calcification 
• 
Concentric 
• 
Less than totally occlusive 
• 
Readily accessible 
• 
Not ostial in location 
• 
Non-angulated segment, < 45° 
• 
No major branch involvement 
• 
Smooth contour 
• 
Absence of thrombus 
Type B Lesions* (Moderate Success, 60-85%; Moderate risk) 
• 
Tubular (10-20 mm length) 
• 
Moderate-to-heavy calcification 
• 
Eccentric 
• 
Total occlusions < 3 mo old 
• 
Moderate tortuosity of proximal segment 
• 
Ostial in location 
• 
Moderately angulated segment, > 45°, < 90° 
• 
Bifurcation lesions requiring double guide 
wires 
• 
Irregular contour 
• 
Some thrombus present 
* Type B1 lesions: One adverse characteristic 
* Type B2 lesions: ≥ two adverse characteristics 
Type C Lesions (Low Success, <60%; High Risk) 
• 
Diffuse (> 2 cm length) 
• 
Total occlusions > 3 mo old 
• 
Excessive tortuosity of proximal segment 
• 
Inability to protect major side branches 
• 
Extremely angulated segments > 90° 
• 
Degenerated vein grafts with friable lesions 
 
ACUTE CORONARY SYNDROME (ACS) 
ACS is defined as ischemic symptoms occurring at rest and lasting 10 minutes or more and 
occurring within 72 hours before index procedure AND either ST-segment deviation of 1 mm 
or more or elevated levels of a cardiac biomarker of necrosis (CK-MB or troponin T or I 
greater than the upper limit of normal.).  
 
DE NOVO LESION 
A native coronary artery lesion not previously treated. 
 
DISSECTION  
National Heart, Lung, and Blood Institute [NHLBI] Dissection Classification System: 
A. Minor radiolucencies within the lumen during contrast injection with no persistence 
after dye clearance. 
B. Parallel tracts or double lumen separated by a radiolucent area during contrast 
injection with no persistence after dye clearance. 
C. Extraluminal cap with persistence of contrast after dye clearance from the lumen. 
D. Spiral luminal filling defects. 
E. New persistent filling defects. 
F. Non-A-E types that lead to impaired flow or total occlusion. 
Note: Type E and F dissections may represent thrombus. 
 
MAJOR EPICARDIAL VESSELS 
• Left anterior descending artery [LAD] with septal and diagonal branches; 


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• Left circumflex artery [LCX] with obtuse marginal and/or ramus intermedius 
branches; 
• Right coronary artery [RCA] and any of its branches. 
 
MINIMUM LUMEN DIAMETER (MLD) 
The average of 2 orthogonal views (when possible) of the narrowest point within the area of 
assessment, assessed by visual estimation or online QCA by the investigator. 
 
PERCENT DIAMETER STENOSIS (% DS) 
The value calculated by the following: 
100 * (1 – minimum lumen diameter / reference vessel diameter)  
using the mean values from 2 orthogonal views (when possible) assessed by visual estimation or 
online QCA  by the investigator. 
 
STUDY PRINCIPAL INVESTIGATOR 
A physician-specialist who is responsible for the clinical investigation conduct across all 
sites, CIP compliance and relevant regulations.  
 
PRINCIPAL INVESTIGATOR 
A physician responsible for conducting the clinical investigation at each investigational site. 
 
PROCEDURE START DATE AND TIME 
Procedure start date and time is recorded as the date and time the first guiding catheter was 
inserted into the subject. 
 
PROCEDURE END DATE AND TIME 
Procedure end date and time is recorded as the time the last guiding catheter was removed 
from the subject. 
 
REFERENCE VESSEL DIAMETER (RVD) 
An approximation of the treated lesion vessel diameter. The reference vessel diameter is visually 
estimated during angiography or online QCA by the investigator. 
 
TARGET LESION  
The target lesion is defined as the lesion that has met the angiographic inclusion and 
exclusion criteria, and is implanted with XIENCE stent during the index procedure. 
 
TARGET VESSEL 
The entire epicardial vessel in which the target lesion is located, which includes upstream and 
downstream branches and the target lesion itself. 
 
 
TIMI (THROMBOSIS IN MYOCARDIAL INFARCTION) FLOW GRADES  
0. No contrast flow through the stenosis. 
 
 
1. A small amount of contrast flows through the stenosis but fails to fully opacify the 
artery beyond. 
2. Contrast material flows through the stenosis to opacify the terminal artery segment. 
However, contrast enters the terminal segment perceptibly more slowly than more 
proximal segments. Alternatively, contrast material clears from a segment distal to a 


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stenosis noticeably more slowly than from a comparable segment not preceded by a 
significant stenosis. 
3. Anterograde flow into the terminal coronary artery segment through a stenosis is as 
prompt as anterograde flow into a comparable segment proximal to the stenosis. 
Contrast material clears as rapidly from the distal segment as from an uninvolved, 
more proximal segment. 
 
 


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APPENDIX III: 
CONTACT INFORMATION 
A list of trial site coordinators can be obtained upon request from the Clinical Project 
Manager for the trial. 


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APPENDIX IV: 
SCHEDULE OF EVENTS 
 
PROCEDURE/TEST 
Baseline 
Pre-Procedure 
(within 24 hours) 
Procedure 
Post-Procedure 
1 month (28-35d) 
Office visit3 
3 month (90 ±7d) 
Office visit or 
phone contact4 
6 month (180 ± 
14d) 
Office visit or 
phone contact4 
12 month (365 ± 
28d) 
Office visit or 
phone contact4 
Unscheduled visits 
Subject Medical/Clinical History (Age, Sex, 
Risk Factors, Cardiac Status, Cardiac History) 
 
 
 
 
 
 
  
 
 
Subject Informed Consent (Must be obtained 
prior to any trial related testing or procedures)1 
 
 
 
 
 
 
 
 
 
General Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
Angiographic Inclusion/Exclusion Criteria 
 
 
 
 
 
 
 
 
 
Coronary Angiogram 
 
 
 
 
 
 
 
 
 
Stent and Procedure Information 
 
 
 
 
 
 
 
 
 
Antiplatelet Medications Loading Dose 
 
5 
5 
5 
 
 
 
 
 
P2Y12 Inhibitor Discontinuation Eligibility 
Assessment 
 
 
 
 
 
 
 
 
 
Post-procedure Antiplatelet Medications2  
 
 
 
 
 
 
 
 
 
Adverse Events  
 
 
 
 
 
 
 
 
 
1  Consenting after the index procedure but prior to hospital discharge (or up to 3 days after the index procedure) is acceptable, only if the 
site confirms that the protocol required DAPT regimen is site’s standard of care.  
2 Subject who are “1-month clear” will discontinue P2Y12 inhibitor as early as 28 days, but continue taking aspirin through 12-month 
follow-up. Subjects who are not eligible for early P2Y12 inhibitor discontinuation will be treated per site standard of care.  
3 Subjects who have difficulty scheduling an office visit due to special circumstances, 1-month follow-up may be performed via telephone 
per physician’s discretion.  
4 Office visit is strongly recommended whenever possible. 
5 It is recommended that the antiplatelet medication loading dose be given before the procedure (within 24 hours prior to procedure), at time 
of procedure, or post-procedure (recommended to be within 1 hour post-procedure). 
 
 
 


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APPENDIX V: 
CLINICAL TRIAL FLOW 
 
 
1 Consenting after the index procedure but prior to hospital discharge (or up to 3 days after the index procedure) is acceptable, only if the site 
confirms that the protocol required DAPT regimen is site’s standard of care.  
2 Subjects who have difficulty scheduling an office visit due to special circumstances, 1-month follow-up may be performed via telephone 
per physician’s discretion  
3 “1-month clear” is defined as subjects who are free from myocardial infarction (modified ARC), repeat coronary revascularization, stroke, 
or stent thrombosis (ARC definite/probable) within 1 month (prior to 1-month visit but at least 28 days ) after stenting AND have been 
compliant with 1-month dual antiplatelet therapy (DAPT) without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 
consecutive days. 
4 Office visit is strongly recommended whenever possible 
   
Yes 
1-month clear3? 
No 
Yes 
Yes 
Yes 
Informed consent signed1 
Angiographic 
inclusion/exclusion met  
1 month (28-35 days) 
Office visit2  
3-month (90±7 days) 
Office visit or telephone contact4 
6-month (180±14 days) 
Office visit or telephone contact4 
Screen failure, do 
not register 
No 
Subject registered in the trial 
No 
Discontinue 
P2Y12 inhibitor 
Continue DAPT 
per standard care 
12-month (365±28 days) 
Office visit or telephone contact
4 
Subject was screened and met general 
inclusion/exclusion criteria 


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APPENDIX VI: 
MONITORING PLAN 
A copy of the Monitoring Plan can be obtained upon request from the Clinical Project 
Manager for the trial. 


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APPENDIX VII: 
SUMMARY OF CHANGES 
 
Version # 
Date of Release 
Reason for Amendment 
1.0 
10 October 2017 
N/A, Original version 
2.0 
16 November 2017 
Add XIENCE Sierra and update on eligibility criteria 
C 
13 November 2018 
• Updated roles of Roxana Mehran, MD, and Marco Valgimigli, 
MD from Global Primary and Co-Primany to Study Principal 
and Study Co-Principal Investigators, respectively, to reflect the 
roles as in the CIP template (86357) 
• Updated Trial Monitor from Novella Clinical to Abbott to 
reflect change in responsibilities for trial monitoring 
• Updated electronic data capure software from Medidata RAVE 
to Oracle Clinical to reflect update 
• Added XIENCE PROA to the list of included study devices 
• Removed allowance for planned staged procedures to be 
consistent with the XIENCE 28 USA protocol  
• Added an upper limit to the enrollment number (from 800 to 
800-960). A total number of 1600 HBR patients will be enrolled 
between XIENCE 28 Global and XIENCE 28 USA. Per the 
FDA’s recommendation, the minimum number of subjects 
enrolled from XIENCE USA has changed from 800 to 640; 
therefore, the enrollment number has changed from 800 to 960 
patients in XIENCE 28 Global to comprise the total number of 
1600. 
• Updated the site enrollment cap from 75 to 120. 
• Updated the 1 month visit window from 28-42 to 28-35 days to 
be consistent with the XIENCE 28 USA protocol  
• Removed option for a legally authorized representative to 
provide consent on behalf of a subject to ensure that no 
vulnerable subjects are consented 
• Deleted reference to vulnerable subject population and changed 
the language to: “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” to be consistent with CIP 
template language (86357) 
• Clarification was made that the CEC will also adjudicate event 
relatedness to study device 
• Clarifications provided on antiplatelet loading and timing 
 
 

SAP_003.pdf: 
 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 1 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
 
 
 
 
 
 
 
 
 
 
PROTOCOL ABT-CIP-10235 
 
 
XIENCE 28 Global Study 
 
Statistical Analysis Plan 
 
 
Version C 
 June 19, 2020 
 
 
 
 
 
Yan Zheng 
Jin Wang 
 
 
 
 
Confidential and Proprietary 
 
Nothing herein is to be disclosed without the expressed written consent of 
Abbott Vascular 
 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 2 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
TABLE OF CONTENTS 
 
1. SYNOPSIS OF STUDY DESIGN AND PROCEDURES ............................................................... 3 
1.1 
Purpose of the Statistical Analysis Plan............................................................................. 3 
1.2 
Study Objectives ............................................................................................................ 3 
1.3 
Study Design ................................................................................................................. 3 
1.3.1 Selection of Control ....................................................................................................... 4 
1.3.2  Primary Endpoint ....................................................................................................... 5 
1.3.3  Secondary Endpoint(s) ................................................................................................ 5 
1.4 
Analysis Populations ...................................................................................................... 5 
Primary Analysis Population ................................................................................................... 5 
1.5  
Sample Size Calculations ................................................................................................ 6 
1.6 
Study Success ................................................................................................................ 7 
2. ANALYSIS CONSIDERATIONS ............................................................................................... 8 
2.1  
Statistical Methods ......................................................................................................... 8 
2.1.1 
 Descriptive Statistics for Continuous Variables ............................................................. 8 
2.1.2  Descriptive Statistics for Categorical Variables ............................................................ 10 
2.1.3 Propensity Score .......................................................................................................... 12 
2.1.3-1 Propensity Score Variable List ................................................................................13 
2.1.4  Hypothesis Testing ................................................................................................... 14 
2.1.5 
 Survival Analyses .................................................................................................... 15 
2.2  
Endpoint Analyses ....................................................................................................... 16 
2.2.1 Primary Endpoint Analysis ........................................................................................... 16 
2.2.3 Secondary Endpoint Analyses ....................................................................................... 16 
2.3  
Subgroups for Analysis ................................................................................................. 16 
2.3.1  Sex ......................................................................................................................... 17 
2.3.2 
 Diabetes ................................................................................................................. 17 
2.3.3 
Other Subgroups ...................................................................................................... 17 
2.4  
Analysis Window ......................................................................................................... 17 
2.5  
Handling of Missing Data ............................................................................................. 17 
2.6.1 Multiple Center Effect .................................................................................................. 17 
2.7  
Adjustments for Covariates ........................................................................................... 18 
2.8  
Multiplicity Issues ........................................................................................................ 18 
2.9 
Sensitivity Analysis ...................................................................................................... 18 
2.10  
Documentation and Other Considerations ....................................................................... 19 
3. ACRONYMS AND ABBREVIATIONS .................................................................................... 20 
4. REFERENCES ........................................................................................................................ 21 
5. APPENDICES ........................................................................................................................ 22 
APPENDIX A: 
Statistical Methodology for Multiple Imputation .................................................. 22 
APPENDIX B: 
SUMMARY OF CHANGES ............................................................................. 23 
 
 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 3 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
 
1. SYNOPSIS OF STUDY DESIGN AND PROCEDURES 
 
1.1 
Purpose of the Statistical Analysis Plan 
This statistical analysis plan (SAP) is intended to provide a detailed and comprehensive description 
of the planned methodology and analysis to be used for Protocol ABT-CIP-10235, the XIENCE 
28 Global clinical study. This plan is based on the Version C, November 13, 2018 study protocol.  
 
1.2 
Study Objectives 
 
The primary objective of this trial is to further evaluate safety of 1-month (as short as 28 days) 
dual antiplatelet therapy (DAPT) in subjects at high risk of bleeding (HBR) undergoing 
percutaneous coronary intervention (PCI) with XIENCE.  
 
1.3 
Study Design 
 
XIENCE 28 Global Study is a prospective, single arm, multi-center, open label trial to further 
evaluate the safety of 1-month (as short as 28 days) dual antiplatelet therapy (DAPT) in subjects 
at high risk of bleeding (HBR) undergoing percutaneous coronary intervention (PCI) with the 
approved XIENCE family of coronary drug-eluting stents. 
 
The XIENCE family stent systems include commercially approved a  XIENCE Xpedition 
Everolimus Eluting Coronary Stent System (EECSS), XIENCE Alpine EECSS, XIENCE PROX  
EECSSb, XIENCE ProA EECSSc or XIENCE Sierra EECSS which are all manufactured by Abbott 
Vascular, Inc, Santa Clara, USA.  The above listed XIENCE stents will hereinafter be called 
“XIENCE” in this trial.  
A minimum of 800 to a maximum of 960 subjects from approximately 50 sites globally will be 
registered in this trial. Subject registration is capped at 120 per site. Trial population consists of 
non-complex HBR subjects with up to three native coronary artery lesions (a maximum of two 
lesions per epicardial vessel) with reference vessel diameter between 2.25 mm and 4.25 mm. 
Eligibility of P2Y12 receptor inhibitor discontinuation will be assessed at 1-month follow-up. 
Subjects who are free from myocardial infarction (modified ARC), repeat coronary 
revascularization, stroke, or stent thrombosis (ARC definite/probable) within 1 month (prior to 1-
month visit but at least 28 days) after stenting AND have been compliant with 1-month DAPT 
                                               
 
 
a For each geography included in the trial, only approved and commercial available XIENCE stent(s) in that geography 
will be used. 
b XIENCE PROX is a rebrand of the XIENCE Xpedition Stent System. 
c XIENCE PROA is a rebrand of the XIENCE Alpine Stent System. 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 4 of 24 
 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive days are 
considered as “1-month clear”, and will discontinue P2Y12 receptor inhibitor as early as 28 days 
and continued with aspirin monotherapy through 12-month follow-up.   
All registered subjects will be followed at 1, 3, 6 and 12 months post index procedure.  
The data collected from the XIENCE 28 Global Study will be compared with the historical 
control of non-complex HBR subjects treated with standard DAPT duration of up to 12 months 
from the XIENCE V USA Study, which is a US post-approval study to evaluate the safety of 
XIENCE V EECSS in “all-comer” population under real-world setting. 
1.3.1 Selection of Control 
The XIENCE V USA historical HBR control is derived based on the following criteria: 
Definition of non-complex HBR from XIENCE V USA 
• HBR inclusion criteria (any one of the below HBR criteria):  
o Age ≥ 75 years  
o History of major bleeding  
o History of stroke 
o Receiving or scheduled to receive chronic anticoagulation therapy 
o Renal insufficiency (creatinine > 2mg/dl) 
o Anemia (Hb < 11g/dl or transfusion) 
o Thrombocytopenia (platelet count < 100.000/mm3) 
• Exclusion criteria for non-complex: 
o STEMI 
o LVEF < 30% 
o Patients with more than 3 lesions treated during index procedure 
o At least one lesion with RVD < 2.25 mm or > 4.25 mm (visual estimation) 
o At least one lesion located in left main 
o At least one lesion located in graft 
o At least one CTO lesion 
o At least one in-stent restenosis lesion 
o At least one target lesion with length > 32 mm by visual estimation. 
 
 
The above selection criteria for the XIENCE V USA historical control aligns with the key 
inclusion/exclusion criteria of the XIENCE 28 Global Study. 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 5 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
For primary analysis, the XIENCE V USA non-complex HBR control subjects must be also 1-
month clear, following the same logic as defined for the primary analysis population (refer to 
Section 1.4). 
 
1.3.2  Primary Endpoint 
The primary endpoint is a composite of Net Adverse Clinical Endpoint (NACE, a composite rate 
of all-cause death, all myocardial infarction (modified Academic Research Consortium [ARC]), 
stent thrombosis (ARC definite or probable), stroke or major bleeding (Bleeding defined by the 
Bleeding Academic Research Consortium [BARC] type 2-5) from 1 to 6 months. 
 
1.3.3  Secondary Endpoint(s) 
 
The following endpoints will be assessed from 1 to 6 months: 
• Stent thrombosis (ARC definite/probable, ARC definite)  
• All death, cardiac death, vascular death, non-cardiovascular death 
• All myocardial infarction (MI) and MI attributed to target vessel (TV-MI, modified ARC) 
• Composite of cardiac death or MI (modified ARC) 
• Composite of all death or all MI (modified ARC) 
• All stroke, ischemic stroke and hemorrhagic stroke  
• Clinically-indicated target lesion revascularization (CI-TLR)  
• Clinically-indicated target vessel revascularization (CI-TVR)  
• Target lesion failure (TLF, composite of cardiac death, TV-MI and CI-TLR)  
• Target vessel failure (TVF, composite of cardiac death, TV-MI and CI-TVR) 
• Bleeding defined by the Bleeding Academic Research Consortium (BARC) type 2-5 and 
type 3-5 
The primary endpoints of NACE and all the above secondary endpoints will also be assessed from 
6 months to 12 months and from 1 month to 12 months, respectively.  
 
1.4 
Analysis Populations 
Primary Analysis Population 
The primary analysis population includes “1-month clear” population, defined as subjects who are 
free from myocardial infarction (modified ARC), repeat coronary revascularization, stroke, or 
stent thrombosis (ARC definite/probable) within 1 month (prior to 1-month visit but at least 28 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 6 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
days) after stenting AND have been compliant with 1-month dual antiplatelet therapy (DAPT) 
without interruption of either aspirin and/or P2Y12 receptor inhibitor for > 7 consecutive days.  
If a subject was event-free and DAPT compliant (as defined above) during the first month, but 
does not stop P2Y12 inhibitor after the 1-month visit, due to physician’s or subject’s decision, this 
subject will be considered as “1-month not clear”. 
Exceptions include the following: 
• Peri-procedural MI (occurred within 48 hours post index procedure) without any clinical 
symptoms will not be considered exclusionary event for the definition of “1-month 
clear”. 
• Dual therapy (oral anticoagulant and a P2Y12 inhibitor, clopidogrel preferred) for 
subjects who are on chronic anticoagulants is acceptable for the definition of “1-month 
clear”. 
In this SAP the term ‘1-month DAPT arm’ refers to subjects who are from the XIENCE 28 Global 
Study only, unless otherwise specified. 
 
1.5  
Sample Size Calculations 
The primary endpoint of NACE from 1-month to 6-month follow-up will be evaluated based on 
the “1-month clear” population (as defined in section 1.4). The hypothesis test is designed for non-
inferiority of 1-month DAPT arm compared to standard DAPT duration from XIENCE V USA 
historical control for the primary endpoint after propensity score stratification.  
This analysis will be stratified by propensity score with the following assumptions: 
• True event rate for the primary endpoint is assumed to be 8.1% for both arms   
• Non-inferiority margin: 4%  
• Attrition rate of 10% due to “1-month clear” population and lost to follow-up for the 1-month 
DAPT arm 
• One-sided alpha = 0.05 
• Sample size in the control arm (1-month clear): ~1,400   
• Approximately 92% power. 
A sample size of approximately 800 subjects in the 1-month DAPT arm will be required for this 
test.  
The sample size calculations were performed using NCSS PASS 11 (Hintze, J., 2011, NCSS, LLC. 
Kaysville, Utah). 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 7 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
1.6 
Study Success 
The trial success is defined as passing the non-inferiority test on the primary endpoint of NACE 
for the “1-month clear” population. Detail of the test is specified in section 2.1.4. 
 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 8 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
 
2. ANALYSIS CONSIDERATIONS 
2.1  
Statistical Methods  
Baseline demographic, clinical, angiographic, procedural, and device data, and clinical results will 
be summarized using descriptive summary statistics. 
2.1.1  Descriptive Statistics for Continuous Variables 
For continuous variables (e.g., age, percent diameter stenosis and lesion length), results will be 
summarized with the numbers of observations, means, and standard deviationsand where specified 
in the table mockups, with quartiles, minimums, maximums, and two-sided 95% confidence 
intervals for the means as per the table mockups. Differences between two comparison groups of 
interest, where specified, will be summarized with the differences of the two means, and two-sided 
95% confidence intervals for the difference between the means. These calculations will be done 
under the assumption that the data for the two arms are independent and approximately normal in 
distribution. The confidence interval for the difference of two means will be calculated under the 
assumption of unequal variances. If the asymptotic assumptions fail, then nonparametric summary 
statistics (medians, 25th and 75th percentiles) may be displayed as an alternative.  
Formulas for calculation of the confidence intervals for the continuous variables are given below: 
1. 100(1- α)% Confidence Interval For A Single Mean5 
 
n
s
t
x
2


 
 
where:  
 
freedom
 
of
 
degrees
 1
for 
 
statistic
 -
 t
alpha/2
 
the
size
 
sample
deviation
 
standard
 
sample
s
mean
 
sample
2
−
=
=
=
=
n
t
n
x

 
 
2. 100(1-α)% Confidence Interval For The Difference of Two Means Under The Assumption 
Of Equal Variances Between The Two Groups5 
(
)






+

−
2
1
2
2
2
1
1
1
n
n
s
t
x
x
p

 
 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 9 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
where:  
 
freedom
 
of
 
degrees
 2
for 
 
statistic
-
 t
alpha/2
 
the
2 
group
for 
 
size
 
sample
1 
group
for 
 
size
 
sample
2 
group
for 
deviation 
 
standard
 
sample
1 
group
for 
deviation 
 
standard
 
sample
s
2
)1
(
)1
(
s
2 
group
for 
mean 
 
sample
1 
group
for 
mean 
 
sample
2
1
2
2
1
2
1
2
1
2
2
2
2
1
1
2
p
2
1
−
+
=
=
=
=
=
−
+
−
+
−
=
=
=
n
n
t
n
n
s
n
n
s
n
s
n
x
x

 
 
3. 100(1-α) % Confidence Interval for the Difference of Two Means under the Assumption of 
Unequal Variances between the Two Groups5 
 
(
)
SED
t
x
x
2
2
1


−
  
 
With the degrees of freedom for the approximate t statistic is determined by 
Satterthwaite’s formula2 as follows: 
 
(
)
1
1
2
2
2
1
2
1
2
2
1
−
+
−
+
=
n
w
n
w
w
w
df
 
 
where:  
 
2 
group
for 
mean 
 
sample
1 
group
for 
mean 
 
sample
2
1
=
=
x
x
 
2 
group
for 
deviation 
 
standard
 
sample
1 
group
for 
deviation 
 
standard
 
sample
s
2
1
=
=
s
 
2 
group
for 
 
size
 
sample
 
 
n
1 
group
for 
 
size
 
sample
 
 
n
2
1
=
=
 
 
2
2
2
1
2
1
 
 
SED
n
s
n
s
+
=
 
 
1
2
1
1
n
s
w =
  


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 10 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
2
2
2
2
n
s
w =
 
 
 
2.1.2  Descriptive Statistics for Categorical Variables 
For categorical variables such as gender, NACE and TLF, results will be summarized with subject 
counts and percentages/rates, and where specified in the table mockups, with exact two-sided 95% 
Clopper-Pearson6 confidence intervals. Differences between two comparison groups of interest, 
when specified, will be summarized with the difference in percentages and the Newcombe5 score 
two-sided 95% confidence interval for the difference of two percentages.  
For efficacy and safety endpoint(s), relative risks (i.e., the ratio of rates), confidence interval for 
the relative risks, the difference in rates and the confidence interval for difference in rates (using 
previously-described formulas), and p-values may also be presented for hypothesis generating 
purposes. The p-values will be based on either Pearson’s Chi-square test or Fisher’s exact test by 
checking the expected frequency for each cell in the 2x2 contingency table against Cochran’s rule8, 
i.e., if the expected frequencies for all cells are ≥ 5, then Pearson’s Chi-square test will be used, 
otherwise Fisher’s exact test will be used. 
For the determination of binary event rates at all time points (6 months and 12 months), the 
denominators are defined as below based on the type of events. 
• NACE event  
Subjects 
will 
be 
included 
in 
the 
analysis 
if 
they 
either 
had 
the 
Death/MI/Revascularization/Stent Thrombosis/Bleeding/Stroke (DMRSBS) event by the 
analysis time point or they did not have the DMRSBS  event but had follow-up visit through 
that time point. In other words, subjects will be included in a given analysis if it can be 
determined whether or not the subject would have had the DMRSBS event by the time 
point. 
 
• Death/MI/Revascularization (DMR) event  
Subjects will be included in the analysis if they either had the DMR event by the analysis 
time point or they did not have the DMR event but had follow-up visit through that time 
point. In other words, subjects will be included in a given analysis if it can be determined 
whether or not the subject would have had the DMR event by the time point. 
• Stent Thrombosis, Bleeding and stroke 
Subjects will be included in the analysis if they either had the specific event (for example, for 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 11 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
analysis on ST, only ST is considered) by the analysis time point or they did not have the event 
but had follow-up visit for that time point. In other words, subjects will be included in a given 
analysis if it can be determined whether or not the subject would have had the specific event by 
the time point.Formulas for calculating confidence intervals for the categorical variables are given 
below.  
1. 100(1-α) % Exact Clopper-Pearson Confidence Interval for A Single Proportion6 
)
2
),
1
(2
(
)1
(
 
Limit 
  
Confidence
Lower  
2
1
x
x
n
F
x
n
x
x
+
−
+
−
+
=
−
 
 
))
(
2
),
1
(
2
(
)1
(
))
(
2
),
1
(
2
(
)1
(
 
Limit 
 
Confidence
Upper 
2
1
2
1
x
n
x
F
x
x
n
x
n
x
F
x
−
+
+
+
−
−
+
+
=
−
−


 
where: 
 
 
2
 
and
 1
 
freedom
 
of
 
degrees
for 
 
statistic
-
F
 
alpha/2)
-
(1
 
the
)
2
,1
(
2
1
events"
" 
of
number 
size
 
sample
df
df
df
df
F
x
n
=
−
=
=

 
 
2. 100(1-α) % Newcombe Score Confidence Interval for the Difference of Two Proportions 7 
 
a. 100(1-α) % Wilson Score Confidence Interval for A Single Proportion5 
 
(
)
(
) (
)
n
n
n
p
p
Z
n
p
/
Z
1
/
/
4
/
Z
)
ˆ
1
(
ˆ
2
/
 Z
ˆ
Limit 
  
Confidence
Lower  
2
/2
2
/2
2
/
2
/2




+
+
−
−
+
=
 
 
(
)
(
) (
)
n
n
n
p
p
Z
n
p
/
Z
1
/
/
4
/
Z
)
ˆ
1
(
ˆ
2
/
 Z
ˆ
 
Limit 
 
Confidence
Upper 
2
/2
2
/2
2
/
2
/2




+
+
−
+
+
=
 
where: 
 
 
on
distributi
 
normal
 
standard
 
 the
of
 
percentile
/2)th 
-
100(1
events"
" 
of
number 
size
 
sample
/
ˆ
2
/


=
=
=
=
Z
x
n
n
x
p
 
 
b. 100(1-α) % Newcombe Score Confidence Interval for the Difference of Two 
Proportions4 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 12 of 24 
 
CONFIDENTIAL: May not be reproduced outside of Abbott Vascular without written permission from Document Control. 
XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
 
Lower Confidence Limit = (
)
2
2
2
1
1
1
2
/
2
1
/
)
1(
/
)
1(
ˆ
ˆ
n
U
U
n
L
L
Z
p
p
−
+
−
−
−

 
 
Upper Confidence Limit = (
)
2
2
2
1
1
1
2
/
2
1
/
)
1(
/
)
1(
ˆ
ˆ
n
L
L
n
U
U
Z
p
p
−
+
−
+
−

 
 
where:  
 
on
distributi
 
normal
 
standard
 
 the
of
 
percentile
/2)th 
-
100(1
for 
 
limits
 
confidence
 
Score
on 
upper Wils
 
and
lower 
 
 the
are
 
 
and
 
for 
 
limits
 
confidence
 
Score
on 
upper Wils
 
and
lower 
 
 the
are
 
 
and
 
2 
group
for 
 
proportion
 
sample
ˆ
1 
group
for 
 
proportion
 
sample
ˆ
2
/
2
2
2
1
1
1
2
1


=
=
=
Z
p
U
L
p
U
L
p
p
 
2.1.3 Propensity Score 
Given that subjects in the two comparison groups (the 1-month DAPT arm vs XIENCE V USA 
historical control) are not randomized and thus may not have balanced baseline characteristics, the 
non-inferiority and superiority tests for 1-6 month period will be carried out through stratified 
analysis in the “1-month clear” population. The stratification will be performed through propensity 
scores (PS). For each individual a propensity score (i.e., predicted probability between 0 and 1) 
for group (1-month DAPT arm) membership will be calculated using logistics regression, with 
“group” as the outcome and baseline variables including demographic, lesion characteristics, and 
risk factors as the predictors. Subjects will be categorized into 5 groups based on the calculated 
propensity scores and their quintiles. Non-inferiority and superiority will then be carried out for 
the rate of the endpoint using the method described in sections below stratified by the propensity 
quintiles.  
 
The propensity score modeling and design will be performed by an independent statistician who 
has no access to any outcome data of the XIENCE 28 Global study and the XIENCE V USA 
historical control for the integrity and interpretability of study results. The independent statistician 
will be blinded and have no access to clinical outcome and any follow-up information to avoid 
introducing bias into the analysis. The independent statistician will be requested to perform PS 
building at interims (such as enrollment of 400 subjects for the 1-month DAPT arm) and 
enrollment completion to assess the extent of PS overlapping. The independent statistician can 
inform Abbott Vascular about the distribution of patients for the two comparison groups within 
each PS quintile, while the individual PS will be blinded to Abbott Vascular.   
 
Adequacy of propensity stratification will be performed by first assessing the distribution of 
treatment groups in each quintile. If there is inadequate representation of one treatment group in 


 
Study Specific Doc No: CL1004518 Version C 
Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 13 of 24 
 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
the highest or lowest quintile (less than ten patients for a given treatment group), then quartile 
subgrouping may be attempted. If that does not succeed (still less than ten patients in a given 
quartile for at least one treatment group as in Li et al1.), an alternative approach may also be 
employed when inadequate representation is observed in each propensity score quintile. 
Specifically, control patients in the highest or lowest quintile may be excluded (depending on the 
quintile that contains mostly control patients), and the propensity score calculation will be repeated 
and the adequacy of propensity stratification will be reassessed.  No experimental patients will be 
excluded.  
 
Once the subgrouping is finalized, comparing treatments on the mean values of the baseline 
characteristics adjusting for propensity subgroup will be carried out as in D’Agostino et al2.  If the 
propensity stratification is adequate, this will result in non-significant p-values (p>0.05) for almost 
all baseline characteristics.  
 
 
2.1.3-1 Propensity Score Variable List 
Based on prior clinical experience and clinical research, below is the list of variables that are 
considered to be related to assignments modeling building: 
• Gender  
• Age  
• Creatinine 
• Chronic anticoagulant  
• History of stroke  
• History of major bleeding  
• Platelet  
• Hb 
• BMI 
• Hypertension  
• Dyslipidemia  
• Prior PCI  
• Prior CABG  
• Prior MI  
• Multivessel disease  
• Clinical presentation (ACS (NSTEMI, ACS unstable angina) vs. non-ACS) 
• Diabetes  
• ACC/AHA lesion complexity  


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
• Total lesion length per patient 
• RVD  
• Diameter stenosis%  
• Bifurcation  
• Number of lesions treated 
• Number of vessels treated 
• Number of stents per patient 
• Total stent length per patient 
• Discharge P2Y12  
• Paris bleeding score 
• PRECISE DAPT score 
The list is subject to change upon the quality of the data after the completion of the trial 
enrollment.  
2.1.4  Hypothesis Testing 
Primary endpoint analysis for 1-month DAPT 
The XIENCE 28 Global study is powered based on primary endpoint of NACE between 1-month 
and 6-month follow-up. NACE is defined as the composite rate of all-cause death, all myocardial 
infarction (modified Academic Research Consortium [ARC]), stent thrombosis (ARC definite or 
probable), stroke or major bleeding (Bleeding defined by the Bleeding Academic Research 
Consortium [BARC] type 2-5) from 1 to 6 months. This primary endpoint will be evaluated 
between 1-month DAPT arm  and XIENCE V USA historical control stratified by propensity score 
quintiles in the primary analysis population. The null (H0) and alternative (HA) hypothesis are of 
the following form: 
                        H0: NACE1m-DAPT  -  NACEXience V USA   ≥ δ 
HA: NACE1m-DAPT  -  NACEXience V USA  < δ 
Where δ is the non-inferiority margin. The test will be carried out with a one-sided significance 
level of 0.05 and a non-inferiority margin (δ) of 4.0%.  
 
The stratified Farrington-Manning method will be performed to test non-inferiority (NI) of 1-
month DAPT compared to standard DAPT duration from XIENCE V USA historical control. 
Details for stratified Farrington-Manning method   can be found below.For stratum i, let Nit and 
pit be the number of subjects and the observed proportion for the test arm, Nic and pic be the number 
of subjects and the observed proportion for active control arm, and δ be the non-inferiority margin, 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
and pimt  and  pimc be the Maximum Likelihood estimates under the null hypothesis (Farrington and 
Manning, 19903), then test statistic 
𝑍𝑤=
∑wi(𝛿𝑖̂ −𝛿)
𝑖
√∑𝑤𝑖
2𝑉(𝛿𝑖̂)
𝑖
 
follows an approximate normal distribution, where 
 
ic
imc
imc
it
imt
imt
i
i
ic
it
ic
it
i
ic
it
i
N
p
p
N
p
p
V
N
N
N
N
w
p
p
)
1(
)
1(
)
ˆ
(
)
(
)
(
ˆ
−
+
−
=
+
+
=
−
=



 
       Pimt and Pimc are calculated as follows:  
     ri = Nit/Nic 
 
  a1 =  - ( 1+ ri +pic+ ri *pit- δ *( ri +2) ) 
        a2 = δ **2 - δ *(2*pic+ ri +1) + pic + ri *pit 
 
  a3 = pic* δ *(1- δ) 
   u = a1**3/(3+3* ri)**3 - a1*a2/(6*(1+ ri)**2) + a3/(2+2* ri) 
 
  v = sign(u)*sqrt( a1**2/((3+3* ri)**2)-a2/(3+3* ri) ) 
       w = 1/3*( arcos(-1) + arcos(u/v**3) ) 
 
  pimc = 2*v*cos(w) - a1/(3+3* ri) 
        pimt = pimc + δ 
 
   
 
2.1.5  Survival Analyses 
Survival analysis may be conducted to analyze time-to-event variables. Subjects without events 
will be censored at their last known event-free time point. Survival curves will be constructed 
using Kaplan-Meier estimates.  
Summary tables for the endpoints will include failure rates (Kaplan-Meier estimates). For the 
primary analysis report, all available data will be used. 
 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
2.2  
Endpoint Analyses  
Due to the concern that inclusion of events that are related or possibly related to COVID-19 will 
falsely elevate the primary and secondary analysis as compared to the historic control, for the 
primary endpoint analysis, the secondary endpoint analysis, and other applicable endpoint analysis, 
endpoints adjudicated by CEC as COVID-19 related or possibly related will be excluded at the 
event level. 
  
2.2.1 Primary Endpoint Analysis 
Primary Analysis:  
A non-inferiority test will be performed on the primary endpoint between 1-month and 6-month 
follow up for the primary analysis population of the 1-month DAPT arm  and the XIENCE V USA 
historical control stratified by propensity score quintiles as described in section 2.1.4.  
To ensure all subjects to be included in this analysis, multiple imputations will be performed in 
calculating the propensity scores. 
 
Secondary Analysis (as a sensitivity analysis):  
In addition to the primary analysis stratified by propensity score quintile, a non-inferiority test will 
be performed on the primary endpoint stratified by propensity score quartile, with the same 
methodology as described above. 
2.2.3 Secondary Endpoint Analyses 
The secondary clinical endpoints will be descriptively analyzed for both the primary analysis 
population and all registered subjects without propensity stratification.    
 
2.3  
Subgroups for Analysis 
All of the following subgroup analyses are intended for the primary analysis population. The 
comparison between the 1-month DAPT arm  and the XIENCE V USA historical control will be 
analyzed descriptively within each quintile for the primary  in a specific subgroup. The above 
quintiles are based on the overall PS, not PS built within each subgroup, as baseline characteristics 
of subjects are likely to be comparable in each quintile of the overall PS. 
 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
2.3.1  Sex 
Sex-specific subgroup analyses will be performed on the primary analysis population for the 
primary endpoint stratified by the overall PS.  
2.3.2  Diabetes 
Diabetic subgroup analysis will be performed on the primary analysis population for the primary 
endpoint stratified by the overall PS.  Analyses will be performed within the following subgroups: 
• All diabetes mellitus, defined as any diabetics with or without medical treatment 
• Non diabetes mellitus.  
 
2.3.3 Other Subgroups 
The following subgroups analyses will be evaluated for the primary analysis population for the 
primary endpoint stratified by the overall PS. Analyses will be performed within the following 
subgroups: 
• Age (age ≥ median vs < median) 
• Clinical presentation (ACS NSTEMI, ACS unstable angina, non-ACS) 
2.4  
Analysis Window 
 
• 6 months  
• 12 months  
 
2.5  
Handling of Missing Data 
The primary analysis will be evaluated after propensity score stratification. To handle missing data 
in propensity score building, multiple imputation methods will be performed for baseline 
characteristics to compute propensity scores from these datasets.  
All other analyses will be based on available data with missing data excluded. Any unused or 
spurious data will be noted as appropriate in the final report.   
 
2.6.1 Multiple Center Effect 
Analysis will be performed by pooling data across study sites. 
The 1-month DAPT arm will have 50 sites globally.  Subject registration is capped at 120 per site. 
This cap per site will prevent the scenario where the results from a few sites dominate the overall 
study result. For the analysis of center effect, data from smaller sites may be combined for the 
analysis. Smaller sites are defined as sites with fewer than 20 subjects per site. 
The pooling of the smaller sites will be based on the following rules: 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
• Sort all smaller sites based on the number of subjects per site in an ascending order. If there 
are ties, sort further by site number. 
• Starting from the smallest site in this list, combine sites by going up the list until the 
combined group size first reaches 20 or larger. At this point, a super site is identified. 
• Repeat the above grouping process from the next smallest site above the newly formed 
super site. 
• The grouping process ends when all smaller sites have been accounted for. 
This way, the sizes of the super sites (which are a result of grouping smaller sites) will range 
between 20 and up to 38 (19+19). Abbott Vascular believes this represents a reasonable range of 
sample sizes which will provide meaningful estimates of within-sites variations and in the 
meantime will not alter between-sites variation. 
To evaluate the multiple center effect on the primary endpoint, Fisher’s exact test will be 
performed for 1-month DAPT cohort against an alpha level of 0.05. 
 
If the p-value is < 0.05, Abbott Vascular will examine subject demographics, baseline clinical, and 
angiographic characteristics for possible correlations and confounding factors.  
 
If the p-value is statistically marginal, yet the endpoint outcomes among sites are considered to 
be clinically significantly different, Abbott Vascular will examine subject demographics, 
baseline clinical, and angiographic characteristics for possible correlations and confounding 
factors.  
 
2.7  
Adjustments for Covariates 
Unless otherwise specified, no adjustments for covariates will be made for any of the variables in 
the analyses.  
 
2.8  
Multiplicity Issues 
No multiplicity adjustment is necessary because there is only one test on the primary endpoint 
 
2.9 
Sensitivity Analysis 
The primary endpoint between 1-month and 6-month follow-up will be analyzed descriptively for 
the 1-month clear population removing the patients who do not have antiplatelet medication 
compliance after 1 month.  
For the 1-month DAPT arm, antiplatelet medication non-compliance beyond 1-month follow-up 
for 1-month clear population is defined as patients who resume P2Y12 inhibitor for more than 7 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
consecutive days, and/or interrupt aspirin for more than 7 consecutive days between 1-month and 
12-month follow up. 
In order to assess the COVID-19 impact on the primary endpoint between 1-month and 6-month 
follow-up, additional sensitivity analyses will be carried out descriptively for the endpoint on the 
1-month clear population: 
• 
Without removing the concerned events that have been adjudicated by CEC to be related 
or possibly related to COVID-19 at the event level. 
• 
Removing the subjects with the concerned event that has been adjudicated by CEC to be 
related or possibly related to COVID-19 at the subject level. 
 
In order to evaluate the impact of the stratification weight on the primary endpoint analysis result, 
an additional sensitivity analysis will be performed using the statistical optimal weight [30] as below 
in stratified Farrington Manning method to replace ѡi in Section 2.1.4, and Rubin’s combination 
rule [29] for analysis consolidation: 
 

+
+
=
−
−
i
ic
it
ic
it
ic
it
ic
it
i
N
N
N
N
N
N
N
N
w
1
1
)
(
)
(
 
  
In addition, a sensitivity analysis will be performed for the primary endpoint analysis to evaluate 
the impact of the missing outcome.  The analysis will be carried out based on the primary analysis 
population, and by imputing the missing outcomes for each imputed baseline PS dataset, and 
Rubin’s combination rule [29] will be used to consolidate the final analysis for the 10 duplicates of 
the imputed dataset. 
 
 
2.10  Documentation and Other Considerations 
All analyses will be performed using SAS for Windows, version 9.1 or higher.  


 
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Page 20 of 24 
 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
3. ACRONYMS AND ABBREVIATIONS  
 
Acronym or Abbreviation 
Complete Phrase or Definition 
ACS 
Acute Coronary Syndrome 
AMI 
Acute Myocardial Infarction 
ARC 
Academic Research Consortium  
BARC 
Bleeding Academic Research Consortium 
BMI 
Body Mass Index 
CABG 
Coronary artery bypass grafting 
CTO 
Chronic Total Occlusion 
DAPT 
Dual Antiplatelet Therapy 
DMR 
Death/MI/Revascularization 
EECSS 
Everolimus Eluting Coronary Stent System 
Hb 
Hemoglobin 
HBR 
High Bleeding Risk 
LVEF 
Left Ventricular Ejection Fraction 
MI 
Myocardial Infarction 
NACE 
Net Adverse Clinical Endpoint 
NSTEMI 
non ST-segment elevation MI 
PCI 
Percutaneous Coronary Intervention 
PS 
Propensity Score 
RVD 
Reference Vessel Diameter 
SAP 
Statistical Analysis Plan 
ST 
Stent Thrombosis 
STEMI 
ST-segment elevation myocardial infarction 
TLF 
Target Lesion Failure 
TLR 
Target Lesion Revascularization 
TVR 
Target Vessel Revascularization 
US 
United States 


 
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June 19, 2020 
 
Page 21 of 24 
 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
4. REFERENCES 
 
1. Li, H., Mukhi, V., Lu, N., Xu, Y.L. and Yue, L.Q., 2016. A Note on Good Practice of 
Objective Propensity Score Design for Premarket Nonrandomized Medical Device 
Studies with an Example. Statistics in Biopharmaceutical Research, 8(3), pp.282-286. 
2. D’Agostino, R.B., 1998. Tutorial in biostatistics: propensity score methods for bias 
reduction in the comparison of a treatment to a non-randomized control group. Stat 
Med, 17(19), pp.2265-2281. 
3. Farrington, C. P., Manning, G., Test Statistics and Sample Size Formulae for Comparative 
Binomial Trials with Null Hypothesis of Non-Zero Risk Difference or Non-Unity Relative 
Risk. Statistics in Medicine, 1990, 9, 1447-1454. 
4. Hintze J. NCSS and PASS. Number Cruncher Statistical Systems. Kaysville, Utah. 2005. 
5. SAS/STAT® 9.2 User’s Guide, Second Edition, SAS Institute Inc., Cary, NC, 2009. 
6. Clopper C. J., Pearson E. S., The Use of the Confidence or Fiducial Limits Illustrated in 
the Case of the Binomial. Biometrika, 1934, 26, 404-413. 
7. Newcombe, R. G., Interval estimation for the difference between independent 
proportions: comparison of eleven methods, Statistics in Medicine, 1998, 17, 873-890. 
8. Cochran, W. G., Some Methods for Strengthening the Common χ2 Test. Biometrics, 1954, 
10, 417-451. 
9. Wilson, E. B., Probable inference, the law of succession, and statistical inference, Journal 
of the American Statistical Association, 1927, 22, 209-212. 
10. Draft Guidance for Industry and Food and Drug Administration Staff: Evaluation of Sex 
Differences in Medical Device Clinical Studies, December 19, 2011, CDRH 
11. Gail, M., Simon, R., Testing for Qualitative Interactions between Treatment Effects and 
Patient Subsets, Biometrics, 1985, 41, 361-372. 
12. Dmitrienko, A. et. al., Analysis of Clinical Trials Using SAS: A Practical Guide, SAS 
Institute, Cary, NC, 2005. 
13. Fleming TR& Harrington DP 1991. Counting Processes and Survival Analysis. New 
York: Wiley.  
14. Miller R & Halpern J 1982. Regression with censored data. Biometrika 69, 521-31. 
15. Allison PD. Survival Analysis Using the SAS system: A Practical Guide, Cary, NC: SAS 
Institute Inc., 1995.  
16. Kaplan EL, Meier P. Non-parametric estimation from incomplete observations. J Am Stat 
Assoc 1958; 53:457-481.  
17. Therneau TM, Grambsch PM. Modeling survival data: extending the Cox model. New 
York: Springer-Verlag; 2000.  
18. Allison PD. Multiple Imputation for Missing Data. Sociological Methods & Research, 
Feb 2000; Vol. 28 No. 3:301-309.  


 
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Study Name: XIENCE 28 Global  
June 19, 2020 
 
Page 22 of 24 
 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
19. Barnes SA, Lindborg SR, Seaman JW. Multiple Imputation Techniques in Small Sample 
Clinical Trials. Stat Med 2006 Jan 30; 25(2):233-45. 
20. Clopper CJ, Pearson E. The Use of the Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika 1934; 26:404-413. 
21. Lavori PW, Dawson R, Shera D. A Multiple Imputation Strategy for Clinical Trials with 
Truncation of Patient Date. Statistics in Medicine 1995; 14:1913-1925. 
22. Li X, Mehrotra DV, Barnard J. Analysis of Incomplete Longitudinal Binary Data Using 
Multiple Imputations. Stat Med. 2006 Jun 30; 25(12):2107-24. 
23. Lavori PW, Dawson R, Shera D. A multiple imputation strategy for clinical trials with 
truncation of patient data. Stat Med. 1995; 14:1913–1925.  
24. Little RJA. Rubin D B. Statistical Analysis with Missing Data. New York: John Wiley 
&Sons; 1987. 
25. Rubin DB. Inference and missing data. Biometrika. 1976; 63:581-592. 
26. Little RJA, Schenker N. Handbook of Statistical Methodology-Missing Data. New York: 
Plenum Press; 1995.  
27. D’Agostino, R. B., Jr., Rubin, D. B. (2000). Estimating and using propensity scores with 
partially missing data. Journal of the American Statistical Association 95:749–759 
28. Yue, L.Q., Lu, N. and Xu, Y., 2014. Designing premarket observational comparative 
studies using existing data as controls: challenges and opportunities. Journal of 
biopharmaceutical statistics, 24(5), pp.994-1010. 
29. Rubin DB. Multiple Imputation for Nonresponse in Surveys. Wiley: New York, 1987. 
30. Nelson Lu, Yunling Xu, and Lilly Q. Yue (2020) Some Considerations on Design and 
Analysis Plan on a Nonrandomized Comparative Study Using Propensity Score 
Methodology for Medical Device Premarket Evaluation, Statistics in Biopharmaceutical 
Research, 12:2, 155-163, DOI: 10.1080/19466315.2019.1647873 
 
5. APPENDICES 
 
APPENDIX A: 
Statistical Methodology for Multiple Imputation 
 
For a given set of baseline characteristics, it is possible that not all subjects will have value for all 
the baseline characteristics. In certain situations such as propensity score building, it is preferred 
for all subjects to have value for baseline characteristics used for PS building otherwise subjects 
with missing value in at least one baseline characteristic will have missing PS.  
 


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
In this study, multiple imputation by PROC MI[5] in SAS will be implemented with a sample seed 
= 20170204 through Markov Chain Monte Carlo (MCMC) method with 10 duplications. 
Therefore,10 sets of PS will be generated for the study through imputation. Rubin’s combination 
rule [29] will be used to consolidate the final analysis for the 10 duplicates of the imputed dataset.  
 
 
The sample SAS code is provided below: 
 
PROC 
MI 
DATA=InputData 
SIMPLE 
SEED=20170204 
NIMPUTE=10 
OUT=OutData  MINIMUM=0 
    MAXIMUM = . 1 1 1 1 1 1 . . . 1 1 
    ROUND = 0.001 1 1 1 1 1 1 . . . 1 1 
    ; 
              MCMC CHAIN=MULTIPLE DISPLAYINIT INITIAL=EM(ITPRINT); 
              VAR VarableList; 
RUN; 
 
APPENDIX B: 
SUMMARY OF CHANGES 
 
Version # 
Date of Release 
Reason for Amendment 
1.0 
10 October 2018 
N/A, Original version 
B 
December 17, 2018 
The SAP was revised mainly to align with the recent changes in 
the XIENCE 28 Global Protocol. Additional administrative or 
editorial changes were also included as appropriate. 
• Changed protocol number from 17-311 to ABT-CIP-10235 be 
to comply with protocol numbering format in new document 
control system 
• Changed version from 1.0 to B to comply with guidelines in 
new document control system 
• Changed Author/Biostatistician from Minh-thien Vu to Yan 
Zheng 
• Added XIENCE PROA EECSS to the list of included study 
devices 
• Changed upper limit to the enrollment number from 800 to 
800-960. A total number of 1600 HBR patients will be enrolled 
between XIENCE 28 Global and XIENCE 28 USA. The 
minimum number of subjects enrolled from XIENCE USA has 
changed from 800 to 640; therefore, the upper limit of 
enrollment number has changed from 800 to 960 patients in 
XIENCE 28 Global to comprise the total number of 1600 
• Updated the site enrollment cap from 75 to 120. 
• Added further clarification for 1-month clear assessment  
• Added clarification-the term of ‘1-month DAPT arm’ used in 
this SAP refers to subjects in the XIENCE 28 Global study 
only, to avoid potential confusion with the XIENCE 28 USA 
study where subjects in ‘pooled’ 1-month DAPT arm’ are 
pooled from XIENCE 28 USA and XIENCE 28 Global studies.  


 
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XIENCE 28 Global Study Statistical Analysis Plan Version C, June 19, 2020 
• Included administrative or editorial changes (e.g. added ‘for 
both arms’, ‘approximately’, etc.) in Section 1.5 Sample Size 
Calculation 
• Deleted a typo ‘pooled’ in Section 2.1.3 Propensity Score 
C 
June 19, 2020 
The SAP was revised mainly to: 
• 
Excluded ‘Restenosis vs. De Novo lesion’ (In-stent 
restenosis (ISR)) and ‘Access site’ variables from the 
Propensity Score Variable List. 
• 
Added Secondary analysis (as a sensitivity analysis) to 
perform the primary analysis stratified by propensity score 
quartile.   
• 
Indicated that the concerned events adjudicated by CEC to 
be COVID-19 related or possibly related will be excluded in 
the relevant analyses  
• 
Additional sensitivity analyses are added to evaluate the 
potential COVID-19 impact, statistical optimal weights, 
missing outcome, etc.   
• 
Updated in Appendix A for running 10 sets of MI and clarify 
using Rubin’s combination rule for the final analysis 
Additional administrative or editorial changes were also included 
as appropriate. Detail explanation for reason of changes can be 
found in a separate document (Xience 28 Global SAP B to C 
Table of Changes).