Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention
Phase: PHASE4
Conditions: Cardiovascular Disease, Interventional Cardiology
Sponsor: Icahn School of Medicine at Mount Sinai

Title: TWILIGHT Study - Ticagrelor With Aspirin or Alone in High-Risk 
Patients After Coronary Intervention  
PI Roxana Mehran 
NCT Number NCT02270242  
Date of protocol: 28-Mar-16 

Page 1 of 58 
Drug Substance 
Ticagrelor and Aspirin 
Study Number 
ISSBRIL0345 
EudraCT No. 
2014-005498-35 
ClinicalTrials.gov ID 
NCT02270242 
Version Number 
4.0 
Date 
28-Mar-2016 
TWILIGHT Study 
Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary 
Intervention  
Funding Agency: 
AstraZeneca 
Sponsor-Investigator/Academic Research Center (ARC): The Office of Interventional Cardiovascular 
Research and Clinical Trials at Icahn School of Medicine at 
Mount Sinai 
 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 2 of 58 
PROTOCOL SYNOPSIS 
 
Title of Study 
TWLIGHT Study - Ticagrelor With Aspirin or Alone in High-Risk 
Patients After Coronary Intervention 
Primary 
Investigator: 
Roxana Mehran, MD, FACC, FACP, FCCP, FESC, FAHA, FSCAI 
Professor of Medicine and Director of Interventional Cardiovascular 
Research and Clinical Trials 
Icahn School of Medicine at Mount Sinai 
Study Centers: 
Approximately 100 sites in U.S., Canada, South America, Europe, 
and China 
Study Design 
Multicenter, prospective, blinded dual-arm study 
Purposes 
Aim 1:  To determine the impact of ticagrelor alone versus ticagrelor 
plus aspirin in reducing clinically relevant bleeding among high-risk 
patients who had PCI with at least one drug-eluting stent. 
Aim 2:  To determine the impact of ticagrelor alone versus ticagrelor 
plus aspirin in reducing ischemic adverse events at one year among 
high-risk patients undergoing PCI with at least one drug-eluting stent. 
Enrollment and 
Patient Population 
Up to 9000 high-risk patients who have undergone successful PCI 
with at least one locally approved drug eluting stent discharged on 
DAPT with aspirin and ticagrelor of at least 3 months intended 
duration. 
Primary Objective 
The primary objective of this study is to determine the impact of 
antiplatelet monotherapy with ticagrelor alone versus DAPT with 
ticagrelor plus aspirin for 12 months in reducing clinically relevant 
bleeding among high-risk patients undergoing PCI who have 
completed a 3-month course of aspirin plus ticagrelor. 
Secondary 
Objectives 
The secondary objective of this study is to determine the impact of 
antiplatelet monotherapy with ticagrelor alone versus DAPT with 
ticagrelor plus aspirin for 12 months in reducing major ischemic 
adverse events among high-risk patients undergoing PCI who have 
completed a 3-month course of aspirin plus ticagrelor. 
Eligibility Criteria 
High-risk patients who have undergone successful PCI with at least 
one locally approved drug eluting stent AND discharged on DAPT 
with aspirin and ticagrelor of at least 3 months intended duration will 
be eligible for the TWILIGHT study. 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 3 of 58 
Enrollment into the study will require meeting at least one clinical 
inclusion AND at least one angiographic inclusion AND none of the 
exclusion criteria. 
Clinical Inclusion Criteria (MUST MEET AT LEAST ONE): 
 Adult patients ≥ 65 years of age 
 Female gender 
 Troponin positive acute coronary syndrome  
 Established vascular disease defined as previous MI, 
documented PAD or CAD/PAD revascularization 
 Diabetes mellitus treated with medications (oral 
hypoglycemic, subcutaneous injection of insulin) 
 Chronic kidney disease defined as an estimated glomerular 
filtration rate (eGFR) < 60 ml/min/1.73m2 or creatinine 
clearance (CrCl) < 60 ml/min 
Angiographic Inclusion Criteria (MUST MEET AT LEAST ONE): 
 Multivessel coronary artery disease 
 Target lesion requiring total stent length >30 mm 
 Thrombotic target lesion(s) 
 Bifurcation lesions with Medina X,1,1 classification requiring 
at least 2 stents 
 Left main (≥50%) or proximal LAD (≥70%) lesion 
 Calcified target lesion(s) requiring atherectomy 
Exclusion Criteria: 
 Under 18 years of age 
 Contraindication to aspirin (listed in appendix D) 
 Contraindication to ticagrelor (listed in appendix E) 
 Planned surgery within 90 days 
 Planned coronary revascularization (surgical or percutaneous) 
within 90 days 
 Need for chronic oral anticoagulation 
 Prior stroke 
 Dialysis-dependent renal failure 
 Active bleeding or extreme-risk for major bleeding (e.g. acute 
gastrointestinal ulcer or history of chronic gastrointestinal 
ulceration,  gastrointestinal pathology with a raised risk for 
bleeding, malignancies with a raised risk for bleeding) 
 Salvage PCI or STEMI presentation. 
 Liver cirrhosis 
 Life expectancy < 1  year 
 Unable or unwilling to provide informed consent 
 Women of child bearing potential (as defined in Section 4.2) 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
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 Fibrinolytic therapy within 24 hours of index PCI 
 Concomitant therapy with a strong cytochrome P-450 3A 
inhibitor or inducer  
 Platelet count < 100,000 mm3 
 Requiring ongoing treatment with aspirin ≥ 325 mg daily 
Randomization 
The eligibility for randomization for all enrolled subjects will be 
evaluated at the in-person 3-month study visit.  Subjects with any of 
the following will not be randomized: 
 Refusal of randomization by subject or treating physician  
 Withdrawal of consent 
 Lost to follow-up 
 Death 
 Major bleeding (BARC Types 3b or greater) 
 Occurrence of an ischemic event after PCI such as myocardial 
infarction, definite or probable stent thrombosis, ischemic 
stroke, coronary revascularization with drug-eluting stent 
 No longer taking DAPT with aspirin and ticagrelor 
 Non physician-guided cessation of aspirin or ticagrelor of 5 
consecutive days or greater.   
 Women of child bearing potential (as defined in Section 4.2) 
 Renal failure requiring dialysis 
 Current indication for oral anticoagulation or high dose 
aspirin 
 
Statistical Methods 
Analysis for 
Primary Bleeding 
Endpoint  
The analysis for the primary bleeding endpoint will be performed on 
the ITT population.  The primary objective is to determine if 
ticagrelor monotherapy is superior to ticagrelor plus aspirin for the 
primary bleeding endpoint (BARC Types 2, 3 or 5 bleeding).  The 
null hypothesis for this analysis is that the HR for the experimental 
group (H0) = 1.  The alternative hypothesis is that the HR for the 
experimental group (HA) ≠ 1.  A test of superiority at the two-sided 
0.05 level will be performed using a Cox proportional hazard model 
that includes treatment group as a covariate.  A point estimate and 
two-sided 95% CI for the relative risk as measured by the hazard 
ratio will be calculated based on the Cox proportional hazards model.  
Event rates will be estimated at one year and Kaplan-Meier curves 
will be plotted for the time from randomization to the first occurrence 
of confirmed BARC Type 2, 3 or 5 bleeding by treatment group.  
This analysis will be repeated in the per protocol (PP) cohort to 
support the primary results. 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 5 of 58 
Analysis for 
Primary Ischemic 
Endpoint  
The analysis for the primary ischemic endpoint will be performed on 
the PP cohort.  The primary objective is to determine if ticagrelor 
monotherapy is non-inferior to ticagrelor plus aspirin for the primary 
ischemic endpoint (all-cause death, non-fatal myocardial infarction, 
or stroke).  Event rates will be estimated at one year and Kaplan-
Meier curves will be plotted for the time from randomization to the 
first occurrence of confirmed all-cause death, non-fatal myocardial 
infarction, or stroke or by treatment group. A test of non-inferiority at 
the one-sided 0.025 level will be performed. .  . .  Assuming an event 
rate of 8.0% in the control group, a sample size of 8200 will yield 
80% power to exclude an absolute non-inferiority margin of 1.6%.  If 
the upper limit of the 95% CI for the point estimate of the absolute 
risk difference between groups is less than or equal to 1.6% then the 
criteria for non-inferiority will be met.  This non-inferiority margin 
translates to a relative risk of 20% assuming the observed event rate 
equals 8.0% in the control arm. 
Statistical Methods 
Unless otherwise stated, all hypothesis tests will be performed using 
two-sided tests at the 5% significance level.  Continuous variables 
will be summarized using descriptive statistics including means and 
standard deviations if normally distributed or median with 
interquartile ranges for skewed distributions.  Discrete variables will 
be summarized using absolute and relative frequencies. 
Sample Size 
Parameters 
A cumulative bleeding rate of 4.5% is anticipated between time of 
randomization and 1 year.  Assuming a 2% loss to follow-up and 
non-compliance / cross-over rate of 4%, the current trial will require 
8200 subjects to detect a relative reduction in bleeding of 28% with 
ticagrelor monotherapy with 80% power and a Type I error of 0.05.  
It is anticipated that approximately 8% - 10% of enrolled subjects 
will not be eligible for randomization and therefore 9000 subjects 
will be enrolled at the time of PCI. 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 6 of 58 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 7 of 58 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE .......................................................................................................................... 1 
PROTOCOL SYNOPSIS ....................................................................................................... 2 
TABLE OF CONTENTS ....................................................................................................... 7 
PROTOCOL SIGNATURE PAGE .................................................................................... 11 
LIST OF ABBREVIATIONS .............................................................................................. 12 
1. 
INTRODUCTION ....................................................................................................... 13 
1.1 
Research hypothesis ............................................................................................... 14 
1.2 
Rationale for conducting this study ....................................................................... 14 
1.3 
Benefit/risk and ethical assessment ........................................................................ 15 
2. 
STUDY OBJECTIVES ............................................................................................... 15 
2.1 
Primary objective ................................................................................................... 15 
2.2 
Secondary objective ............................................................................................... 16 
2.3 
Exploratory objectives ........................................................................................... 16 
3. 
STUDY PLAN AND PROCEDURES ....................................................................... 16 
3.1 
Overall study design and flow chart ...................................................................... 16 
3.2 
Rationale for study design, doses and control groups ............................................ 16 
4. 
SUBJECT SELECTION CRITERIA ....................................................................... 17 
4.1 
Inclusion criteria .................................................................................................... 17 
4.2 
Exclusion criteria ................................................................................................... 18 
5. 
STUDY CONDUCT .................................................................................................... 19 
5.1 
Restrictions during the study.................................................................................. 19 
5.2 
Subject randomization and initiation of investigational product ........................... 19 
5.2.1 
Procedures for randomization ........................................................................... 19 
5.3 
Procedures for handling subjects incorrectly enrolled or randomized on 
investigational product ........................................................................................... 20 
5.4 
Blinding and procedures for unblinding the study ................................................. 20 
5.4.1 
Methods for ensuring blinding ........................................................................... 20 
5.4.2 
Methods for unblinding the study ...................................................................... 21 
5.5 
Treatments .............................................................................................................. 21 
5.5.1 
Identity of investigational product ..................................................................... 21 
5.5.2 
Doses and treatment regimens ........................................................................... 21 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
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5.5.3 
Additional study drug......................................................................................... 21 
5.5.4 
Labeling ............................................................................................................. 21 
5.6 
Concomitant and post-study treatment .................................................................. 22 
5.7 
Treatment compliance ............................................................................................ 22 
5.7.1 
Accountability .................................................................................................... 22 
5.8 
Discontinuation of investigational product ............................................................ 22 
5.8.1 
Procedures for discontinuation of a subject from investigational product........ 22 
5.9 
Withdrawal from study .......................................................................................... 23 
6. 
COLLECTION OF STUDY VARIABLES .............................................................. 24 
6.1 
Recording of data ................................................................................................... 24 
6.2 
Data collection at enrollment and follow-up.......................................................... 24 
6.2.1 
Enrollment procedures ...................................................................................... 27 
6.2.2 
In-person follow-up procedure at 3 months ....................................................... 27 
6.2.3 
In-person follow-up procedure at 9 and 15 months (for randomized 
subjects) ............................................................................................................. 28 
6.2.4 
Phone-call follow-up contact at 1, 4 and 18 months post enrollment ............... 28 
6.3 
Efficacy and safety variables ................................................................................. 28 
7. 
SAFETY ....................................................................................................................... 28 
7.1 
Definition of adverse events .................................................................................. 28 
7.2 
Definitions of serious adverse event ...................................................................... 29 
7.2.1 
Definition of suspected unexpected serious adverse reactions (SUSARs) ......... 29 
7.3 
Recording of adverse events or serious adverse events ......................................... 29 
7.3.1 
Time period for collection of adverse events ..................................................... 29 
7.3.2 
Follow-up of unresolved adverse events ............................................................ 30 
7.3.3 
Information to be collected for each AE/SAE .................................................... 30 
7.3.4 
Adverse Events based on signs and symptoms ................................................... 31 
7.3.5 
Adverse Events based on examinations and tests .............................................. 31 
7.3.6 
Disease progression or pre-existing conditions ................................................ 31 
7.3.7 
Reporting of adverse events ............................................................................... 31 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ........................................... 32 
8.1 
Ethical conduct of the study ................................................................................... 32 
8.2 
Ethics and regulatory review .................................................................................. 32 
8.3 
Informed consent.................................................................................................... 32 
8.4 
Changes to the protocol and informed consent form ............................................. 33 
8.5 
Deviations from protocol ....................................................................................... 34 
8.5.1 
Compliance to protocol ..................................................................................... 34 
8.5.2 
Procedures for recording, reporting, and analyzing protocol deviations ......... 34 
8.5.3 
Corrective and preventative actions and principal investigator 
disqualification criteria ..................................................................................... 34 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 9 of 58 
8.6 
Audits and inspections ........................................................................................... 34 
9. 
STUDY MANAGEMENT .......................................................................................... 35 
9.1 
Training .................................................................................................................. 35 
9.1.1 
Training of Monitors .......................................................................................... 35 
9.1.2 
Training of study site research personnel .......................................................... 35 
9.2 
Monitoring of the study.......................................................................................... 35 
9.2.1 
Source data ........................................................................................................ 36 
9.3 
Study timetable and end of study ........................................................................... 37 
10. 
DATA MANAGEMENT ............................................................................................ 37 
11. 
EVALUATION AND CALCULATION OF VARIABLES .................................... 37 
11.1.1 
Primary Bleeding Endpoint ............................................................................... 37 
11.1.2 
Secondary Bleeding Endpoints .......................................................................... 37 
11.1.3 
Primary Ischemic Endpoint ............................................................................... 38 
11.1.4 
Secondary Ischemic Endpoints .......................................................................... 38 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............. 38 
12.1 
Description of analysis sets .................................................................................... 38 
12.1.1 
Efficacy analysis set ........................................................................................... 39 
12.1.2 
Safety analysis set .............................................................................................. 39 
12.2 
Methods of statistical analyses ............................................................................... 39 
12.3 
Determination of sample size ................................................................................. 41 
12.4 
Data and safety monitoring board .......................................................................... 42 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ........................................................................................................ 43 
13.1 
Overdose ................................................................................................................ 43 
13.2 
Pregnancy ............................................................................................................... 43 
14. 
LIST OF REFERENCES ........................................................................................... 44 
15. 
APPENDIX A – DEFINITIONS FOR STUDY ENDPOINTS ............................... 48 
15.1 
Bleeding events ...................................................................................................... 48 
15.1.1 
Bleeding Academic Research Consortium definition of bleeding ...................... 48 
15.1.2 
Thrombolysis in Myocardial Infarction definition of bleeding .......................... 49 
15.1.3 
Global Utilization of Streptokinase and TPA for Occluded Arteries 
(GUSTO) definition of bleeding ......................................................................... 51 
15.1.4 
International Society on Thrombosis and Haemostasis definition of 
bleeding .............................................................................................................. 51 
15.2 
Major Adverse Cardiovascular Events .................................................................. 52 
15.2.1 
Death .................................................................................................................. 52 
15.2.2 
Myocardial Infarction ........................................................................................ 52 
15.2.3 
Stroke ................................................................................................................. 54 
15.2.4 
Stent thrombosis ................................................................................................. 54 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 10 of 58 
15.2.5 
Clinically driven revascularization.................................................................... 55 
16. 
APPENDIX B - OTHER DEFINITIONS ................................................................. 56 
17 
APPENDIX C – Flowchart of In-Person Visits And Phone Calls…………….61 
18. 
APPENDIX D – CONTRAINDICATION TO ASPIRIN…………….………61 
19. 
APPENDIX E – CONTRAINDICAITON TO TICAGRELOR……….…….62 
 
LIST OF TABLES 
Table 1 
Identity of Investigational Product ........................................................... 21 
Table 2 
Schedule of Data Collection ..................................................................... 26 
Table 3 
Bleeding Rates/Effect Sizes for Primary Endpoint Power 
Calculations .............................................................................................. 41 
Table 4 
Power and Sample Size Scenarios for Primary Superiority 
Endpoint of BARC ≥ 2 Bleeding .............................................................. 42 
Table 5 
Sample Size/Poser Calculations for Non-inferiority MACE 
Comparison between Groups at 1 Year .................................................... 49 
Table 6 
BARC Bleeding Definition, modified from Mehran et al (22) ................ 48 
Table 7 
TIMI Bleeding Definition(23) .................................................................. 49 
Table 8 
GUSTO Bleeding Definition (24) ............................................................ 51 
Table 9 
Classification of Death(25) ....................................................................... 52 
Table 10 
Timing of Stent Thrombosis ..................................................................... 55 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
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PROTOCOL SIGNATURE PAGE 
I have read this clinical investigation plan and appendices and agree to adhere to the 
requirements. I will provide copies of this clinical investigation plan and all pertinent 
information to the trial personnel under my supervision. I will discuss this material with them 
and ensure they are fully informed regarding the study drugs and the conduct of the trial.  
I will conduct the trial in accordance with the clinical investigation plan, Good Clinical 
Practice guidelines, World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects, as well as local regulations. I also accept 
respective revisions to the clinical investigation plan approved by authorized personnel of the 
ARCC and by regulatory authorities.  
This document contains proprietary and confidential information of AstraZeneca and the 
Mount Sinai Academic Research Center. Do not copy, distribute, or share with others without 
prior written authorization from AstraZeneca and the Mount Sinai Academic Research 
Center. 
 
 
Investigator Name (print) 
 
 
 
Investigator Name (signature) 
 
 
 
Date 
 
 
 
Institution Name (print) 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 12 of 58 
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ARC 
Academic Research Center 
ASA 
Acetylsalicylic Acid (Aspirin) 
BMI 
Body Mass Index 
BMS 
Bare Metal Stent 
CAD 
Coronary Artery Disease 
CEC 
Clinical Events Committee 
CRF 
Case Report Form 
DAPT 
Dual Antiplatelet Therapy 
DES 
Drug Eluting Stent 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
FDA 
Food and Drug Administration (U.S.) 
FFR 
Fractional Flow Reserve 
ICF 
Informed Consent Form 
IND 
Investigational New Drug Application (FDA) 
IRB 
Institutional Review Board 
ISS 
Investigator Sponsored Study 
ITT 
Intention-to-Treat (analysis dataset) 
IVUS 
Intravascular Ultrasound 
IXRS 
Interactive Voice/Web Response System 
LAD 
Left Anterior Descending (Coronary Artery) 
MI 
Myocardial Infarction 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
NSTEMI 
Non ST Elevation Myocardial Infarction 
P2Y12 
The P2Y₁₂ protein is found mainly but not exclusively on the surface 
of blood platelets, and is an important regulator in blood clotting. 
PAD 
Peripheral Artery Disease 
PCI 
Percutaneous Coronary Intervention 
PP 
Per Protocol (analysis dataset) 
SAE 
Serious Adverse Event 
STEMI 
ST Elevation Myocardial Infarction 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
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The following abbreviations and special terms describe other clinical protocols or academic 
bodies. 
Abbreviation or 
special term 
Explanation 
BARC 
Bleeding Academic Research Consortium 
EXCELLENT 
Trial Name: Efficacy of Xience/Promus versus Cypher in Reducing 
Late Loss after Stenting 
GUSTO 
Trial Name: Global Utilization of Streptokinase and TPA for 
Occluded Arteries 
OPTIMIZE 
Trial Name: Optimized Duration of Clopidogrel Therapy following 
Treatment with the Endeavor Zotarolimus-Eluting Stent in the Real 
World Clinical Practice 
PLATO 
Trial Name: Platelet Inhibition and Patient Outcomes Trial 
PRODIGY 
Trial Name: Synergy between Stent and Drugs to Avoid Ischemic 
Recurrences after Percutaneous Coronary Intervention 
SYNTAX 
Trial Name: TAXUS Drug-Eluting Stent versus Coronary Artery 
Bypass Surgery for the Treatment of Narrowed Arteries 
TIMI 
Trial Name: Thrombolysis in Myocardial Infarction 
1. 
INTRODUCTION 
Pharmacologic platelet inhibition with aspirin and a P2Y12 inhibitor is a requirement in all 
patients undergoing percutaneous coronary intervention (PCI) with stenting. Such dual 
antiplatelet therapy (DAPT) is recommended by international guidelines, with duration 
varying according to clinical presentation (i.e. acute coronary syndrome) or type of stent 
implanted during PCI (bare metal vs. drug eluting)(1-3). The paradigm for DAPT is shifting to 
shorter durations, as evidenced by most recent ESC /EACTS Guidelines on myocardial 
revascularization giving a class Ib recommendation for 6 months of DAPT after DES 
(4).While clopidogrel is the most widely used P2Y12 inhibitor, its efficacy is hampered by 
substantial variability in platelet inhibition that may be attributable to clinical, genetic and 
procedural parameters (5-8). Moreover, although the novel thienopyridine prasugrel has a 
more potent and consistent effect on platelet inhibition (9, 10), bleeding risk is significantly 
higher compared to clopidogrel in acute coronary syndrome (ACS) patients following PCI 
(11). In contrast, ticagrelor, an oral, reversible, direct-acting inhibitor of the adenosine 
diphosphate P2Y12 receptor (12) has proven faster, greater and more consistent P2Y12 
inhibition than either clopidogrel or prasugrel (13-15). In the landmark Study of Platelet 
Inhibition and Patient Outcomes (PLATO) trial, ticagrelor significantly reduced death from 
vascular causes, myocardial infarction, or stroke, without significantly increasing overall 
major bleeding in patients presenting with acute coronary syndromes (16).  
Along with the advent of more potent antiplatelet pharmacotherapy, stent technology has also 
advanced in a concordant fashion with the introduction of safer and less thrombogenic 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
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Date  
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Page 14 of 58 
platforms. These devices, compared to their older-generation counterparts, yield significant 
reductions in thrombotic events that are durable over the long term (17).  As a consequence, 
classical paradigms favoring a minimum of DAPT duration of 1 year, particularly in elective 
patients, are being challenged as PCI safety continues to evolve and improve. Randomized 
comparisons of different DAPT durations such as the OPTIMIZE and the PRODIGY trials 
suggest no increased risk for thrombotic events after only 3-6 months of DAPT in PCI patients 
treated primarily with novel generation devices (18-22).   
1.1 
Research hypothesis 
The overall hypothesis of the current study is that three months post-PCI of dual antiplatelet 
therapy with aspirin and ticagrelor, continued monotherapy with ticagrelor alone versus 
ticagrelor plus aspirin for an additional year will be superior with respect to bleeding and non-
inferior with respect to ischemic events in high-risk patients undergoing elective or urgent 
PCI.  
This hypothesis will be tested in the following two specific aims: 
Aim 1:  To determine the impact of 
ticagrelor alone versus ticagrelor plus 
aspirin in reducing clinically relevant 
bleeding among high-risk patients who had 
PCI. 
Hypothesis 1: A DAPT strategy of ticagrelor + 
ASA for 3 months followed by ticagrelor alone 
for an additional 12 months will be superior to 
ticagrelor plus aspirin with respect to clinically 
relevant bleeding (BARC ≥ 2) in high-risk 
patients undergoing PCI. 
Aim 2:  To determine the impact of 
ticagrelor alone versus ticagrelor plus 
aspirin in reducing ischemic adverse events 
at one year among high-risk patients 
undergoing PCI 
Hypothesis 2: A DAPT strategy of ticagrelor + 
ASA for 3 months followed by ticagrelor alone 
for an additional 12 months will be will be non-
inferior to ticagrelor plus aspirin for with 
respect to ischemic adverse events at 1 year in 
high-risk patients undergoing PCI. 
1.2 
Rationale for conducting this study 
Despite the trend and rationale for shorter DAPT durations following PCI, certain high-risk 
patients may derive additional benefit from potent and sustained platelet inhibition extending 
beyond 3 months after PCI.  Defined by clinical and/or anatomic criteria, a short course of 
DAPT in such patients may provide sufficient protection against early stent-related thrombotic 
events while ongoing platelet inhibition may yield further reductions in systemic 
atherothrombosis.  Among diabetics undergoing PCI, for example, Brar et al. previously 
demonstrated that the benefits of DAPT compared to antiplatelet monotherapy persisted 
irrespective of BMS or DES use, suggesting a systemic rather than stent-related effect (23).  
Analogously, results from the EXCELLENT trial suggested diabetics may derive additional 
benefit from prolonged DAPT (ASA + clopidogrel) compared to ASA alone (24).  Findings 
from Dangas et al., which demonstrate a link between atherosclerosis and increased platelet 

Clinical Study Protocol TWILIGHT Study 
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Date  
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reactivity, provide a biological basis for potent platelet inhibition in high-risk patients 
characterized by diffuse vascular disease (25).  These observations are clinically relevant as 
many patients undergoing elective or urgent PCI exhibit high-risk features, such as renal 
dysfunction, diabetes, peripheral arterial disease, that are associated with systemic 
atherosclerosis.  Given the clear benefits of ticagrelor in the setting of high-risk ACS, it is 
plausible that ticagrelor alone will provide sufficient platelet inhibition to reduce thrombotic 
events compared to ticagrelor plus ASA among high-risk patients who have completed a 
requisite short course of DAPT.   
Reduction in bleeding with ticagrelor alone while preserving of the anti-ischemic benefit 
associated with DAPT use would favor such a strategy in high-risk patients undergoing 
PCI.  
Accordingly, the proposed study will examine the comparative safety and efficacy of a 
strategy of 3 month DAPT with ASA and ticagrelor followed by monotherapy using a potent 
agent (ticagrelor) compared to continued ASA and ticagrelor among high-risk patients 
undergoing PCI with DES.  Our primary hypothesis is that, among such patients, use of 
ticagrelor alone will yield a significant reduction in clinically relevant bleeding while 
preserving anti-ischemic protection compared to the combination of ticagrelor and ASA. 
1.3 
Benefit/risk and ethical assessment 
The potential benefits that subjects might realize by participating in this randomized trial is a 
reduction in clinically relevant bleeding for those who are randomly allocated to the placebo 
arm.  Other benefits applicable to all subjects include close monitoring and surveillance for 
clinical events that will be performed by study personnel during the course of the trial. 
The potential risks for subjects include an increased rate of thrombotic events for those who 
are randomized to the placebo arm and increased risk for bleeding in subjects randomized to 
the active treatment arm (low-dose ASA [81 mg – 100 mg]).   
An independent data safety monitoring board will provide external oversight to ensure safety 
of all trial participants.  In addition, subjects will be followed closely with periodic study 
contacts.  Also, clinical equipoise exists for conducting a trial with this type of randomized 
comparison.     
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
The primary objective of this study is to determine the impact of antiplatelet monotherapy 
with ticagrelor alone versus DAPT with ticagrelor plus aspirin for 12 months in reducing 
clinically relevant bleeding among high-risk patients undergoing PCI who have completed a 
3-month course of aspirin plus ticagrelor. 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
28-Mar-2016 
 
Page 16 of 58 
2.2 
Secondary objective 
The secondary objective of this study is to determine the impact of antiplatelet monotherapy 
with ticagrelor alone versus DAPT with ticagrelor plus aspirin for 12 months in reducing 
major ischemic adverse events among high-risk patients undergoing PCI who have completed 
a 3-month course of aspirin plus ticagrelor. 
2.3 
Exploratory objectives 
Exploratory objectives include assessing the comparative safety and efficacy of the different 
DAPT regimens for individual components of the primary efficacy and secondary safety 
objectives. 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
Figure 1 
TWILIGHT Trial Design 
 
 
3.2 
Rationale for study design, doses and control groups 
A randomized, double-blind study design was chosen as the most rigorous experimental 
approach to formally test the study hypotheses for the efficacy and safety of different DAPT 
regimens in high-risk patients undergoing PCI. Open label aspirin and ticagrelor per physician 
discretion will be given for the first 3 months after PCI.  After 3 months, event-free subjects 

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Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
28-Mar-2016 
 
Page 17 of 58 
will be randomized to placebo versus enteric-coated ASA for an additional 12 months. Open-
label ticagrelor at a dose of 90 mg twice daily will be continued in all randomized subjects.   
4. 
SUBJECT SELECTION CRITERIA 
4.1 
Inclusion criteria 
High-risk patients who have undergone successful PCI with at least one locally approved drug 
eluting stent (DES) discharged on DAPT with aspirin and ticagrelor of at least 3 months 
intended duration will be eligible for the TWILIGHT study.   
Enrollment into the study will require meeting at least one clinical inclusion AND at least one 
angiographic inclusion AND none of the exclusion criteria. A subject is considered enrolled if 
all these criteria are met and upon provision of informed consent. 
 
 
 
Must meet AT LEAST ONE clinical 
inclusion criterion 
Must meet AT LEAST ONE angiographic 
inclusion criterion 
Adult patients ≥ 65 years of age 
Female gender 
Troponin positive acute coronary syndrome  
Established vascular disease defined as 
previous MI, documented PAD or 
CAD/PAD revascularization 
Diabetes mellitus treated with medications 
or insulin 
Chronic kidney disease defined as an 
estimated glomerular filtration rate (eGFR) 
<60 ml/min/1.73m2 or creatinine clearance 
(CrCl) <60 ml/min 
Multivessel coronary artery disease (CAD)* 
(see Section 16) 
Target lesion requiring total stent length >30 
mm 
Thrombotic target lesion(s) 
Bifurcation lesion(s) with Medina X,1,1 
classification requiring at least 2 stents (see 
Section 16) 
Left main (≥50%) or proximal LAD (≥70%) 
lesion 
Calcified target lesion(s) requiring 
atherectomy 
*The diagnosis of multivessel CAD may be established with the angiogram performed at enrollment or an 
earlier angiogram.  A vessel previously treated with either a stent or bypass graft may also be considered 
diseased for purposes of meeting the multivessel CAD angiographic inclusion criterion. 

Clinical Study Protocol TWILIGHT Study 
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Ticagrelor & Aspirin 
Study Number 
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Edition Number  
Version 4.0 
Date  
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Page 18 of 58 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are met: 
 Under 18 years of age 
 Contraindication to aspirin, as listed in Appendix D 
 Contraindication to ticagrelor, as listed in Appendix E 
 Planned surgery within 90 days 
 Planned coronary revascularization (surgical or percutaneous) within 90 days 
 Need for chronic oral anticoagulation 
 Prior stroke 
 Dialysis-dependent renal failure 
 Active bleeding or extreme-risk for major bleeding (e.g. acute gastrointestinal ulcer or 
history of chronic gastrointestinal ulceration, gastrointestinal pathology with a raised 
risk for bleeding, malignancies with a raised risk for bleeding) 
 Salvage PCI or STEMI presentation.  
 Liver cirrhosis 
 Life expectancy < 1  year 
 Unable or unwilling to provide informed consent 
 Women of child bearing potential as defined below:  
A woman is considered of childbearing potential (WOBCP) following menarche and 
until becoming post-menopausal unless permanently sterile.  Permanent sterilization 
methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.  A 
postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
 
 Fibrinolytic therapy within 24 hours of index PCI 
 Concomitant therapy with a strong cytochrome P-450 3A inhibitor or inducer 
 Platelet count < 100,000 mm3 
 Requiring ongoing treatment with aspirin ≥325 mg daily 

Clinical Study Protocol TWILIGHT Study 
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Ticagrelor & Aspirin 
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Edition Number  
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Page 19 of 58 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
Enrolled subjects should remain on study-provided open-label ticagrelor plus open-label 
aspirin for the first three months after index PCI followed by study-provided open-label 
ticagrelor plus blinded study drug for 12 months after randomization.   
Unless clinically indicated, non-steroidal anti-inflammatory drugs (NSAIDs) and additional 
P2Y12 inhibitors (ticlopidine, prasugrel, clopidogrel) should not be taken by study participants 
during the course of the trial. In addition, ticagrelor should be administered with caution in 
patients with history of hyperuricemia or gouty arthritis.  
   
5.2 
Subject randomization and initiation of investigational product 
5.2.1 
Procedures for randomization 
The eligibility for randomization for all enrolled subjects will be evaluated at the in-person 
3-month study visit.  Subjects with any of the following will not be randomized: 
 Refusal of randomization by subject or treating physician  
 Withdrawal of consent 
 Lost to follow-up 
 Death 
 Major bleeding (BARC Types 3b or greater) 
 Occurrence of an ischemic event after PCI such as myocardial infarction, definite or 
probable stent thrombosis, ischemic stroke, coronary revascularization with drug-
eluting stent 
 No longer taking DAPT with aspirin and ticagrelor 
 Non physician-guided cessation of aspirin or ticagrelor of 5 consecutive days or 
greater.   
 Women of child bearing potential (as defined in Section 4.2) 
 
 Renal failure requiring dialysis 
 Current indication for oral anticoagulation or high dose aspirin 

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Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
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Date  
28-Mar-2016 
 
Page 20 of 58 
Randomization will be performed within the EDC system among subjects eligible for 
randomization.  The EDC will allocate the treatment group assignment for the subject and 
provide study site research personnel the appropriate bottle ID number(s).  
Upon randomization at the conclusion of the in-person 3-month visit, the study site research 
personnel will provide a 6-month supply of blinded investigational product (aspirin or 
matching placebo) and open-label ticagrelor. 
Enrolled subjects who do not meet eligibility for randomization will have completed their 
protocol required activities and therefore will not receive any further study-provided 
medications. Their treating physician will also be notified that the patient’s protocol-mandated 
study activities have concluded. Further antiplatelet therapy will be at the discretion of the 
subject’s treating physician in accordance with local standard of care. Vital status of these 
subjects will be determined at the 18-month time point.    
Enrolled subjects who do not meet eligibility for randomization prior to the in-person 3-month 
visit will not be required to complete the 3-month in-person visit.  
5.3 
Procedures for handling subjects incorrectly enrolled or 
randomized on investigational product 
Subjects who are incorrectly enrolled will be immediately withdrawn from the study. The 
subject and the treating physician will be notified. If the subject has already been randomized, 
the investigational drug (aspirin or matching placebo) will be discontinued and further 
treatment will be as per standard of care. Subjects will be advised to continue therapy with 
ticagrelor until seen by their treating physician. 
Subjects who are provided the incorrect investigational drug (study drug bottle(s) were not 
provided according to EDC randomization instructions) may be identified during monitoring 
procedure and/or drug reconciliation. In this case, the subject will be informed immediately 
and requested to return with all dispensed investigational drugs. The subject will then be 
provided with the correct investigational drug according to the randomization instructions. In 
addition, a protocol deviation form will be completed. 
5.4 
Blinding and procedures for unblinding the study 
5.4.1 
Methods for ensuring blinding 
This study has a double-blind design with aspirin and matching placebo.  The subjects, study 
site research personnel, academic research center staff, and treating physicians involved in the 
treatment and/or clinical evaluation of the subjects will not be aware of treatments received.  
There will be an independent data safety monitoring board (DSMB) to monitor the data on a 
periodic basis.  An independent statistician, not otherwise involved in the study, will prepare 
and provide the required reports to the DSMB as per the DSMB charter. 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 21 of 58 
5.4.2 
Methods for unblinding the study 
In the event of a medical emergency, in which knowledge of the investigational drug is critical 
to the subject’s medical management, the blind for that subject may be broken by the treating 
physician.  The investigator should follow the instructions provided in the EDC to obtain the 
necessary treatment information or call the 24/7 TWILIGHT Medical Monitoring Hotline at 
347-541-1376.  As the active study drug in this trial is low-dose aspirin, in most instances the 
subject may be properly managed without the need for unblinding. 
5.5 
Treatments 
5.5.1 
Identity of investigational product 
In this protocol, the investigational product is enteric coated aspirin (81 mg – 100 mg) tablets 
and matching aspirin-placebo tablets. 
Table 1           Identity of Investigational Product 
Investigational product 
Dosage form and strength 
Aspirin, EC 
81 mg – 100 mg tablet, daily 
Placebo for aspirin 
tablet daily 
 
5.5.2 
Doses and treatment regimens 
Study-provided medications including open-label ticagrelor at a dose of 90 mg twice daily 
plus open-label EC aspirin at a dose of 81mg – 100 mg daily will be dispensed to enrolled 
participants at the time of discharge and should be taken daily until the in-person 3-month 
study visit. Study-provided medications including open-label ticagrelor at a dose of 90 mg 
twice daily plus blinded study drug will be dispensed to randomized participants at the 3-
month in-person visit and should be taken daily until end of study.   
5.5.3 
Additional study drug 
Open-label ticagrelor will be administered to all subjects regardless of randomization 
assignment. 
5.5.4 
Labeling 
Each aspirin/placebo bottle will be labeled in black ink.  This label will indicate the protocol 
number, blinded batch number, container number, blinded drug name, tablet quantity, storage 
conditions, directions for use and route of administration.   
At the study site, the investigational product should be stored in a secure area according to 
local regulations.  It is the responsibility of each site investigator to ensure that the 
investigational product is only dispensed to study subjects. The investigational product must 
be dispensed only from official study sites by authorized personnel according to local 
regulations. 

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Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
28-Mar-2016 
 
Page 22 of 58 
The storage conditions for the subjects to follow will be included in the labeling on the bottles. 
5.6 
Concomitant and post-study treatment 
There are no protocol specific concomitant treatments.  
At the End of Study visit physicians caring for the patient will decide which antiplatelet 
medication the patient should receive as part of his/her ongoing clinical care. This 
medication(s) will be open label and obtained locally.  
5.7 
Treatment compliance 
Study drug compliance will be assessed using manual pill count at the 9-month and 15-month 
in-person follow-up visits.   
5.7.1 
Accountability 
Reconciliation between the quantity of shipped study drugs versus the allocation of study 
drugs via the EDC and versus distribution of study drug to subject will be monitored and 
reconciled. 
5.8 
Discontinuation of investigational product or study drug 
Study-provided medications (open-label ticagrelor or blinded study drug) may 
require temporary interruption for the following reasons: 
1. Surgery or invasive procedure:  Study-provided medications should be 
resumed after surgery once the risk of bleeding is no longer considered 
prohibitive in the judgment of the treating physician.  Minor surgeries and 
procedures, including but not limited to tooth extraction, colonoscopy and 
endoscopy, may be safely performed on low-dose aspirin and therefore do not 
require temporary interruption of blinded study drug. However, if deemed 
necessary and at the discretion of the treating physician, open-label ASA may 
be substituted for blinded study drug in the peri-operative period.  Blinded study 
drug may then be restarted at the discretion of the treating physician after 
completing the mandatory course of open-label ASA.  
2.  Balloon angioplasty or PCI with bare-metal stent:  In the event of coronary 
revascularization with balloon angioplasty alone or PCI with bare metal stent, 
blinded study drug may be temporarily interrupted for 2-4 weeks while patients 
receive open-label ASA at the discretion of the treating physician in accordance 
with local practice and standard of care.  Blinded study drug may then be 
restarted at the discretion of the treating physician after completing the 
mandatory course of open-label ASA. 
3. Clinically Significant Bleeding: Study-provided medications should be 
temporarily interrupted pending resolution of the acute bleeding episode and 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
28-Mar-2016 
 
Page 23 of 58 
may be restarted at the discretion of the treating physician if deemed clinically 
safe and in accordance with local practice and standard of care. 
   
4. Details surrounding the date, duration and reason for each episode of temporary 
interruption should be entered in the appropriate section of the EDC. 
Study-provided medications (open-label ticagrelor or blinded study drug) may 
require permanent discontinuation for the following reasons: 
1. Patient decision: The patient is at any time free to discontinue treatment, 
without prejudice to further treatment. 
2. Investigator’s decision: 
a. Incorrectly enrolled patient in whom the inclusion/exclusion criteria 
violation would put the patient at undue risk 
b. Adverse Events felt to be related to either study medication for which 
Investigator feels continued treatment would put the patient at undue 
risk, such as severe or life-threatening bleeding, myocardial infarction, 
stent thrombosis, ischemic stroke or coronary revascularization with a 
DES. 
3. Renal failure requiring dialysis 
4. Chronic oral anticoagulation 
5. Details surrounding the date, duration and reason for permanent discontinuation 
of study medication should be entered in the appropriate section of the EDC. 
6. In the event of permanent discontinuation of either study medication, further 
antiplatelet therapy is at the discretion of and is to be provided by the patient’s 
treating physician. Any remaining study-provided medication should be 
returned to the local site at the next scheduled follow-up visit.  Although these 
patients will no longer receive study-related medication, follow-up will continue 
in all randomized patients until end of study 
5.9 
Withdrawal from study 
Each enrolled 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 voluntary withdrawal  
• 
Subject withdrawal by physician as clinically indicated  
• 
Subject lost-to follow-up  

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Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
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Page 24 of 58 
The reason for subject discontinuation must be documented in the eCRF and source 
documents. The individual site Principal Investigators must also report all subject 
discontinuations to their IRB/EC as defined by their institution’s procedure. 
All data from evaluations and treatments performed prior to the withdrawal should be documented 
in the eCRFs. Source documents that pre-date the withdrawal should be submitted as required by 
the protocol. No data that post-dates the withdrawal will be collected. 
Once a subject has withdrawn from the trial, no further follow-up contact will be performed. 
However, vital status may be obtained from public records. Medical therapy after stopping the 
study will be as prescribed by the subject’s physician.   
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
The Investigator is responsible for maintaining complete and accurate documentation of the 
trial including but not limited to medical records, trial progress records, laboratory results, 
electronic case report forms, signed informed consent forms, investigational product 
accountability records, correspondence with the IRB or EC as well as trial monitors and 
sponsor, adverse event reports, and information regarding subject discontinuations.  
The Investigator is required to maintain information in the subject’s medical records which 
documents and corroborates data entered in the case report forms. As a minimum the subject 
record should contain:  
• 
Medical history/physical exam documenting that subject meets inclusion/exclusion 
criteria  
• 
Documentation of subject’s consent and subject ID number in the trial  
• 
Dated and signed notes from each subject visit  
• 
Adverse events reported and their resolution or lack thereof including supporting 
documents such as hospital records, discharge summaries, catheterization reports, 
ECGs, etc.  
• 
Record of protocol required medications during the trial  
• 
Record of the subject’s condition upon completion of or withdrawal from the trial  
6.2 
Data collection at enrollment and follow-up 
Data collection commences after the subject has provided informed consent and has been 
enrolled in the study. Data collection, including subject demographic information, laboratory 
tests, and procedural data as well as follow-up visits or telephone contacts will be conducted 

Clinical Study Protocol TWILIGHT Study 
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Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 25 of 58 
by an Investigator or site coordinator who has been trained on the protocol and electronic Case 
Report Forms (eCRFs).  
Data required for analysis will be obtained as outlined in Table 1. After discharge from the 
hospital, each enrolled subject will be followed with a phone call at 1 month post enrollment 
and an in-clinic visit at 3 months post enrollment. Enrolled subjects who do not meet 
eligibility for randomization prior to the in-person 3-month visit will not be required to 
complete the 3-month in-person visit. Subjects who are randomized at 3 months post 
enrollment will be followed with a phone call at 4 months post enrollment and will return for 
additional in-clinic visits at 9 and 15 months post enrollment. A final follow-up phone call 
will be performed at 18 months post enrollment for randomized subjects. No further follow-up 
contact will be performed for subjects who did not meet eligibility for randomization at the 3 
month visit; however, vital status may be obtained from medical or public records at 18 months 
post enrollment. A flow chart listing the planned visits and their timing can be found in 
appendix C).   
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
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Date  
28-Mar-2016 
 
Page 26 of 58 
Table 1 
Schedule of Data Collection 
Type of Data to 
be Collected 
Enrollment  
Post-
Procedure 
or 
Discharge 
1 Month 
(30d) 
(±7 days) 
Phone Call 
3 Month 
(90d) 
(±14 days) 
Office Visit 
4 Month 
(120d) 
(±7 days) 
Phone Call 
 
randomized 
9 Month 
(270d) 
(± 30 days) 
Office Visit 
 
randomized 
15 Month 
(450d) 
(± 30 days) 
Office Visit 
 
randomized 
18 Month 
(540d) 
(± 14 days) 
Phone Call 
 
randomized 
Eligibility  
Criteria 
X 
 
 
X 
 
 
 
 
Patient Informed 
Consent 
X 
 
 
 
 
 
 
 
Physical 
Assessment 
X 
 
 
 
 
 
 
 
Medical 
History/Risk 
Factors 
X 
 
 
 
 
 
 
 
Cardiac Status 
X 
 
 
 
 
 
 
 
Medications/Ant
iplatelets 
X 
 
 
 
 
 
 
 
Clinical Tests* 
Lab tests,  
ECG 
X 
 
 
X 
 
X 
X 
 
Procedure 
Information 
X 
 
 
 
 
 
 
 
DAPT 
Medication 
Status 
 
X 
X 
 
X 
 
 
X 
Angina Status 
 
 
 
X 
X 
X 
X 
X 
Randomization– 
if eligible 
 
 
 
X 
 
 
 
 
Dispense 
medication 
according to 
EDC 
 
X 
 
X 
 
X 
 
 
Randomized 
Medications – 
reconciliation of 
provided 
medication 
 
 
 
 
 
X 
X 
 
Randomized 
Medications – 
subject self-
reporting of 
compliance to 
medications 
 
 
 
X 
X 
X 
X 
X 
Adverse Events 
/ Serious 
Adverse Events 
X 
X 
X 
X 
X 
X 
X 
X 
*If performed, as per standard of care. Subject may be asked to provide an additional blood sample (10cc) for lipid profile testing if not 
already performed per standard of care. 
 
 
 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
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Edition Number  
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Date  
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Page 27 of 58 
6.2.1 
Enrollment procedures 
After successful PCI with implantation of at least one locally approved drug eluting stent and 
physician decision to treat subject with low–dose aspirin (81 mg – 100 mg) daily and 
ticagrelor 90 mg twice daily for 3 months, the investigator or designee will: 
• 
Confirm inclusion/exclusion criteria 
• 
Obtain written informed consent 
• 
Obtain a complete medical history, including lab values for hemoglobin and creatinine 
as well as an ECG, if performed per standard of care. Subject may be asked to provide 
an additional blood sample (10cc) for lipid profile testing if not already performed per 
standard of care. 
• 
Review concomitant medications taken within the last 30 days 
• 
Instruct the subject to notify the investigator of any occurrence of adverse events 
• 
Schedule next clinic visit at 3 months 
• 
Dispense 3- month supply of study medications (open-label ticagrelor and EC aspirin)  
• 
Instruct patients to return all study-provided medication at next in-person clinic visit 
6.2.2 
In-person follow-up procedure at 3 months 
• 
Assess for adverse events including MI, unstable angina, stroke, and bleeding. 
• 
Review concomitant medications with subject 
• 
Counsel subject about importance of study drug compliance 
• 
Assess for randomization eligibility , if applicable: 
o Randomize subject within EDC and obtain bottle numbers 
o Dispense study medication for next 6 months 
o Schedule next clinic visit at 9 months  
• 
Instruct the subject and/or caregiver to notify the investigator of any occurrence of 
adverse events 
• 
Instruct patients to return all study-provided medication at next in-person clinic visit 
 

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Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
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Date  
28-Mar-2016 
 
Page 28 of 58 
6.2.3 
In-person follow-up procedure at 9 and 15 months (for randomized subjects) 
• 
Assess for adverse events including MI, unstable angina, stroke, and bleeding. 
• 
Review concomitant medications with subject 
• 
Collect pill bottles, perform study medication accountability, and remind subject about 
importance of study drug compliance. 
• 
Dispense study medication for next 6 months for those patients still taking study 
provided medications at the 9-month in-person visit.  Patients who have permanently 
stopped study-provided medications prior to the 9-month in-person visit will continue 
to be followed but will not be provided additional study medication.  
• 
Instruct the subject to notify the investigator of any occurrence of any adverse events. 
• 
Schedule next clinic visit at 15 months 
• 
Instruct patients to return all study-provided medication at next in-person clinic visit 
(only pertains to 9-month in-person clinic visit) 
6.2.4 
Phone-call follow-up contact at 1, 4 and 18 months post enrollment 
• 
Assess for adverse events including MI, unstable angina, stroke, and bleeding. 
• 
Review all medications and compliance  with subject 
• 
Instruct the subject to notify the investigator of any occurrence of adverse events 
6.3 
Efficacy and safety variables 
The study site research personnel will collect data from the subjects during the follow-up 
contact for identification of the efficacy and safety variables, defined as the first occurrence of 
bleeding (efficacy variable) and all-cause death, myocardial infarction, stent thrombosis, or 
stroke (safety variables). 
7. 
SAFETY 
The Principal Investigator at each participating study site is responsible for ensuring that all 
staff involved in the study is familiar with the content of this section. 
7.1 
Definition of adverse events  
An adverse event is the development of an undesirable medical condition or the deterioration 
of a pre-existing medical condition following or during exposure to a pharmaceutical product, 
whether or not considered causally related to the product.  An undesirable medical condition 
can be symptoms (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 

Clinical Study Protocol TWILIGHT Study 
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Edition Number  
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Date  
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Page 29 of 58 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
7.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (i.e., run-in, treatment, 
wash-out, follow-up), that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 
Results in a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
The severity and causality of SAEs (their relationship to all study treatments and/or 
procedures) will be assessed by the investigator(s) and communicated to the ARC. 
7.2.1 
Definition of suspected unexpected serious adverse reactions (SUSARs) 
A SUSAR is a Suspected Unexpected Serious Adverse Reaction. To qualify as a SUSAR, the 
event must be: 
 Serious 
 Undesirable reaction to medicinal product 
 Unexpected - NOT listed as a potential risk or reaction to the product as outlined in the 
protocol, informed consent document or literature. 
7.3 
Recording of adverse events or serious adverse events 
7.3.1 
Time period for collection of adverse events 
All AEs related to bleeding and SAEs should be collected from the time the subject signs the 
informed consent through study exit. 

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Page 30 of 58 
7.3.2 
Follow-up of unresolved adverse events 
For ALL SAEs the subject’s course must be monitored until the event has subsided or, in a 
case of permanent impairment, until the event stabilizes and the overall clinical outcome has 
been ascertained.  
7.3.3 
Information to be collected for each AE/SAE 
• 
Description of AE/SAE  
• 
The dates when the AE/SAE started and stopped 
• 
Whether the AE/SAE is serious or not 
• 
Investigator causality rating against the investigational product 
• 
Action taken with regard to investigational product 
• 
Whether the AE/SAE caused subject’s withdrawal from study  
• 
Outcome 
In addition, the following variables will be collected for SAEs: 
• 
Date the study site research personnel became aware of SAE 
• 
Date when decision was made for meeting SAE criteria 
• 
Criteria met leading to classification as SAE 
• 
Date of hospitalization (if applicable) 
• 
Date of discharge (if applicable) 
• 
Date of death (if applicable) 
• 
Probable cause of death (if applicable) 
• 
Autopsy performed (if applicable) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 7.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not an SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
an SAE. 

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7.3.4 
Adverse Events based on signs and symptoms 
When collecting AEs, the recording of diagnoses (when possible) is preferred to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
7.3.5 
Adverse Events based on examinations and tests 
Deterioration as compared to baseline in laboratory values or vital signs should therefore only 
be reported as AEs if they fulfill any of the SAE criteria or are the reason for discontinuation 
of treatment with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (e.g., anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s). 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE. 
7.3.6 
Disease progression or pre-existing conditions 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied.  It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. For 
example, continued angina should be considered as disease progression and not an AE.  
Planned hospitalization for a pre-existing condition without serious deterioration in health, is not 
considered a serious adverse event. 
7.3.7 
Reporting of adverse events  
AEs must be reported to the sponsor within 7 business days of the study site research 
personnel’s knowledge of the event via the EDC.  
SAEs must be reported to the sponsor immediately, but no later than 24 hours, of the study 
site research personnel’s knowledge of the event via the EDC. 
The ARC Safety Monitor will review all submitted SAEs for qualification as a Suspected 
Unexpected Serious Adverse Reactions (SUSARs). The ARC will further report SAEs 
determined to qualify as SUSARs to the local regulatory body (IRB/EC).  
The ARC Safety Monitor will voluntarily inform the FDA, via a MedWatch/AdEERs form, 
and EudraVigilance, of any serious adverse events which qualify as SUSARs in accordance 
with reporting requirements.  

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A copy of the MedWatch/AdEERs report will be faxed or scanned and sent to the Principal 
Investigator of the applicable site for reporting according to the site’s local regulatory body’s 
reporting requirements.  
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The trial will be conducted in compliance with the protocol, Good Clinical Practice 
guidelines, and World Medical Association Declaration of Helsinki: Ethical Principles for 
Medical Research Involving Human Subjects as well as local regulations, and applicable 
regional regulatory requirements.  
The clinical investigation shall not begin until the required approvals/favorable opinions from 
the respective regulatory authority and ethics committee have been obtained. Any additional 
requirements imposed by the respective regulatory authority and/or ethics committee will also 
be followed, where specified. 
8.2 
Ethics and regulatory review 
Institutional Review Board (IRB) or Ethics Committee (EC) approval for the protocol, 
informed consent form and other trial related documents will be obtained by the Principal 
Investigator at each investigational site prior to participation in this trial. The approval letter 
must be signed by the IRB/EC chairperson or authorized representative prior to the start of 
this trial and a copy must be provided to the ARC. In addition, the Investigator or designee 
will provide the ARC with all required documentation necessary for initial and ongoing trial 
approval at their site.  
In accordance with the investigational site IRB/EC requirements, the Investigator will 
(a) advise the IRB/EC of the progress of this trial on a regular basis until trial completion; 
(b) obtain written IRB/EC approval at predetermined time points to continue the trial; and 
(c) submit any amendments to the protocol as well as associated informed consent form 
changes and obtain written IRB/EC approval obtained prior to implementation. 
8.3 
Informed consent 
All subjects must provide written informed consent in accordance with the site’s IRB/EC, 
using an IRB/EC-approved informed consent form. All subjects are to be fully informed and 
trial conduct must be in accordance to the World Medical Association Declaration of Helsinki: 
Ethical Principles for Medical Research Involving Human Subjects.  
Protocol-specific procedures or alterations of patient care must not be performed until the 
prospective subject has provided a signed informed consent. The informed consent will be in 
the prospective subject’s native language and will contain non-technical language to describe 
the investigational procedures. The informed consent form should also include a clause that 

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ensures important new information will be provided to the subject throughout the clinical 
investigation.  
After a review of the prospective subject’s medical records to determine general eligibility, 
the investigator or authorized designee who has been trained on the protocol, will approach 
the prospective subject to explain the purpose and scope of the clinical trial, prospective risks, 
and benefits of participation. The prospective subject must be given the opportunity to ask 
questions about the trial and must be given sufficient time to decide to participate in the trial 
or not. Additional information requested by the prospective subject should be provided. Any 
coercion or undue improper influence on the prospective subject is to be avoided.  
If the prospective subject agrees to participate, the informed consent form must be signed and 
personally dated by the prospective subject. The investigator or an authorized member of the 
research team who has witnessed the prospective subject’s signature must also sign and date 
the informed consent, prior to enrollment of the prospective subject. A copy of the completed 
informed consent form must be provided to the subject. Local IRB/EC regulations regarding 
obtaining informed consent must be followed. The subject’s medical record should have a 
notation regarding the signing of the informed consent.  
The subject is to be made aware that their participation in the trial is voluntary, their legal 
rights will not be waived, and that they may withdraw from the trial at any time, without 
giving specific reason for doing so. The subject must also be informed that withdrawal from 
the trial will not affect their future treatment.  
The investigator is responsible for the achievement of written consent from the prospective 
subject before they are included in the trial. All subjects must provide informed consent in 
accordance with the local IRB/EC requirements, using an IRB/EC-approved informed consent 
form. 
8.4 
Changes to the protocol and informed consent form 
If the protocol or informed consent form (ICF) needs an amendment, the ARC is required to 
submit such amendment to the Regulatory Agencies and/or other regulating body in each 
participating country for approval. Approved protocol or ICF amendments will be provided to 
the Investigators by the ARC prior to implementing the amendment.  
For administrative changes, the Principal Investigator is responsible for notifying the IRB/EC 
of the protocol or ICF amendment. For changes involving subject care or safety, the Principal 
Investigator is responsible for obtaining IRB/EC approval of the protocol or ICF amendment 
according to the instructions provided by the ARC with the protocol or ICF amendment.  
Acknowledgement/approval by the IRB/EC of the protocol or ICF amendment must be 
documented in writing prior to implementation of the protocol or ICF amendment. Copies of 
this documentation must also be provided to the ARC. 

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8.5 
Deviations from protocol 
8.5.1 
Compliance to protocol 
No investigative procedures other than those defined in this clinical investigational plan will be 
undertaken on the enrolled subjects without the written agreement of the IRB/EC and ARC.  
It is the Investigator's responsibility to ensure that there are no deviations from the clinical 
investigational plan and full compliance with all established procedures of the IRB/EC is 
maintained. The Investigator will not deviate from the clinical investigational plan for any 
reason except in cases of medical emergencies, when the deviation is necessary to protect the 
life or physical well-being of the subject. 
8.5.2 
Procedures for recording, reporting, and analyzing protocol deviations 
A deviation is an instance(s) of failure to follow, intentionally or unintentionally, the 
requirements of the protocol. All deviations must be reported to the ARC. The occurrence of 
clinical investigational plan deviations will be monitored by the ARC or designee. It is the 
Investigator's responsibility to inform their IRB/EC of clinical investigational plan deviations 
in accordance with their specific IRB/EC reporting policies and procedures.  
In the event that an investigative site does not comply with the Investigator Agreement or 
clinical investigational plan, the ARC will notify the Investigator of the site’s non-compliance. 
Continued non-compliance may result in further escalation in accordance with the ARC’s 
standard procedures. 
8.5.3 
Corrective and preventative actions and principal investigator disqualification 
criteria 
Protocol deviations and site/PI non-compliance will be closely monitored by the ARC and 
appointed study personnel. Identifying deviations and taking corrective actions at the earliest 
possible stage increases the potential for clinical trial success and reduces patient risk. The 
initiation of a corrective and preventative action (CAPA) to investigate and establish 
corrective actions may be required in some cases. The ARC reserves the right to close a 
clinical study site or replace a PI if non-compliance is observed. 
8.6 
Audits and inspections 
In the event that an Investigator is contacted by a Regulatory Agency in relation to this trial, 
the Investigator will notify the ARC immediately. The Investigator and study site research 
personnel must be available to respond to reasonable requests and inspection queries made 
during the inspection process. The Investigator must provide the ARC with copies of all 
correspondence that may affect the review of this trial. The ARC will provide any needed 
assistance in response to regulatory inspections. 

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9. 
STUDY MANAGEMENT 
9.1 
Training  
9.1.1 
Training of Monitors 
The ARC’s monitors or designee will be trained to the protocol, randomization instructions, 
electronic case report forms, and study drug usage. The ARC or designee is responsible for the 
training. Training will be conducted in accordance with the ARC’s and/or designee’s standard 
procedures. 
9.1.2 
Training of study site research personnel 
Participating investigators and study site research personnel will be trained during site 
initiation visits conducted by the Mount Sinai Clinical Coordinating Center or designee. 
All training must be documented and must include or reference the revision of materials used 
for training, who was trained, the trainer and date of training. Original training records should 
be maintained at the site in the Regulatory Binder and copies should be dispensed to Mount 
Sinai Clinical Coordinating Center. 
Site initiation/training involves a didactic session whereby the protocol, including screening 
procedures, clinical follow-up procedures, and study drug procedures are reviewed in detail 
along with investigator responsibilities. 
In addition, the Mount Sinai Clinical Coordinating Center will assure that all participating 
investigators and study personnel are trained in the following: 
 Protocol requirements, including patient screening requirements, inclusion/exclusion 
criteria, procedural requirements and subject follow-up requirements 
 Study and personnel requirements 
 Informed consent requirements 
 Adverse event reporting 
 Drug accountability procedures 
 Electronic CRF completion 
 Regulatory binder maintenance. 
9.2 
Monitoring of the study 
The ARC and/or designee will monitor the trial over its duration according to the pre-
specified monitoring plan. The trial monitor will contact each site at appropriate intervals to 
review investigational data for accuracy and completeness and ensure compliance with the 

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clinical investigation plan. The trial monitor may request all documents and required records 
that are maintained by the Investigator/Site, including medical records (office, clinic, or 
hospital) for the subjects in this trial. Source documentation 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 study 
drug information. The Investigator and/or study site research personnel will be available for 
monitoring contact. If a site visit is required, it is expected that the Investigator/Site will 
provide the trial monitor with a suitable working environment for review of study-related 
documents. 
9.2.1 
Source data 
The Investigator is responsible for maintaining complete and accurate documentation of the 
trial including but not limited to medical records, trial progress records, laboratory results, 
case report forms, signed informed consent forms, study drug accountability records, 
correspondence with the IRB/EC, the trial monitors, and the ARC, as well as adverse event 
reports and information regarding subject discontinuations.  
The Investigator is required to maintain information in the subject’s medical records which 
documents and corroborates data entered in the case report forms. As a minimum the subject 
record should contain:  
• 
Medical history/physical exam documenting that subject meets inclusion/exclusion 
criteria  
• 
Documentation of subject’s consent and subject ID number in the trial  
• 
Dated and signed notes from each subject visit  
 
Adverse events reported and their resolution or lack thereof including supporting 
documents such as hospital records, discharge summaries, catheterization reports, and 
ECGs.  
• 
Record of protocol required medications during the trial  
• 
Record of the subject’s condition upon completion of or withdrawal from the trial  
The Investigator and the associated institution will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/EC review, and regulatory 
inspections.  
Subjects providing informed consent agree to allow the ARC or designee access and copying 
rights to pertinent information in their medical records concerning their participation in this 
trial. The Investigator will obtain, as part of the informed consent, permission for trial 
monitors or regulatory authorities to review, in confidence, any records identifying the 

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subjects in this trial. This information may be shared with regulatory agencies; however, the 
ARC undertakes not to otherwise release the patient's personal and private information. 
9.3 
Study timetable and end of study 
The trial is estimated to commence February 1st, 2015. The last subject follow-up at 18 
months post-procedure is expected to occur in February 2018. The total expected duration 
of the trial is 36 months. 
10. 
DATA MANAGEMENT 
A computerized data entry and management system will be developed during the initial 
project months by an independent academic research center. A closed and password protected 
data entry system has been designed to ensure that only the responsible data entry person and 
the Data Management site supervisor can enter and/or edit data and this can be done only by 
using the programs and/or utilities available on the menu system. An audit trail will be created 
by date/time and user stamping. Range checks, review screens, and various error trapping 
routines are built into the system as quality control procedures. All possible relevant 
information on the forms is pre-coded. Specific instructions and explanation of choices will be 
provided for all data forms.  
The statistical programmer will perform additional data checks, data cleaning, and variable 
coding to create analysis datasets using SAS. The programmer will also create a reporting 
system that generates study specific tables, listings, and figures, which will be run periodically 
to monitor study and data entry. As a final check on data integrity, the Director of Clinical 
Biometrics and study biostatistician will check these outputs against the raw data in order to 
resolve any discrepancies. The Biometrics lead, statistician, and statistical programmer will be 
responsible for working with the project staff to ensure the integrity of the data entry process. 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1.1 
Primary Bleeding Endpoint  
The primary bleeding endpoint of the present study is the time to first occurrence of clinically 
relevant bleeding, defined as Bleeding Academic Research Consortium (BARC) Types 2, 3 or 
5 bleeding. 
11.1.2 
Secondary Bleeding Endpoints 
Time to first occurrence of: 
• 
Types 3 or 5 bleeding according to definitions from BARC  
• 
Minor or major bleeding according to definitions from Thrombolysis in Myocardial 
Infarction (TIMI)  

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• 
Moderate or severe or life-threatening bleeding according to definitions from GUSTO  
• 
Major bleeding according to definitions from International Society of Thrombosis or 
Hemostasis (ISTH)  
11.1.3 
Primary Ischemic Endpoint  
The primary ischemic endpoint of the present study is the time to first occurrence of 
confirmed all-cause death, non-fatal myocardial infarction, or stroke.  
11.1.4 
Secondary Ischemic Endpoints 
Time to first occurrence of: 
• 
cardiovascular death, non-fatal myocardial infarction, ischemic stroke or clinically-
driven revascularization 
• 
cardiovascular death, non-fatal myocardial infarction or ischemic stroke 
• 
definite or probable stent thrombosis 
• 
cardiovascular death 
• 
non-fatal myocardial infarction 
• 
cardiovascular death, non-fatal myocardial infarction or definite or probable stent 
thrombosis 
• 
ischemic stroke 
• 
all-cause mortality 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
The statistical analyses will be performed using SAS version 9.0 or greater and Stata versions 
12.0 or greater. 
12.1 
Description of analysis sets 
The Enrolled Population consists of all subjects who signed informed consent. 
The intention-to-treat (ITT) population will consist of all subjects who have been randomized 
(i.e. when the subject number and allocated treatment are recorded in the EDC).  Subjects will 
be analyzed in the treatment group assigned by the EDC. 

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The per-protocol population (PP) will consist of all randomized subjects without any major 
deviations from the protocol.  The following deviations will lead to exclusion from the PP 
population 
• 
Subjects not receiving the assigned treatment as allocated by the EDC or no treatment 
at all 
• 
Non-compliance to study drug (aspirin or placebo) or ticagrelor.  Non-compliance is 
defined as taking less than 80% of dispensed tablets based on manual pill bottle count 
at each study visit. 
12.1.1 
Efficacy analysis set 
All analyses for the primary bleeding endpoint will be performed on the ITT and PP 
population.  The primary analysis will be performed on the ITT population.  This analysis will 
be repeated in the PP population to support the primary results. 
The primary bleeding endpoint is the composite of BARC Types 2, 3 or 5 bleeding. 
12.1.2 
Safety analysis set 
Analyses for the primary ischemic endpoint will be performed on the PP cohort.  A secondary 
analysis for the primary ischemic endpoint will be performed in the ITT cohort. 
12.2 
Methods of statistical analyses 
Unless otherwise stated, all hypothesis tests will be performed using two-sided tests at the 5% 
significance level.  Continuous variables will be summarized using descriptive statistics 
including means and standard deviations if normally distributed or median with interquartile 
ranges for skewed distributions.  Discrete variables will be summarized using absolute and 
relative frequencies. 
Demographic and baseline characteristics will be summarized by randomized treatment group 
and for all randomized subjects combined.  Baseline characteristics that will define subgroups 
of interest for the efficacy and safety analyses are: 
• 
Age group (< 65, >= 65 years) 
• 
Race (Caucasian, non-Caucasian) 
• 
Gender (Male, Female) 
• 
Geographic Region (US, non-US) 
• 
Diabetes Mellitus (yes, no) 
• 
Chronic Kidney Disease (yes, no) 

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• 
CAD Presentation (Stable, Unstable) 
• 
PCI Status (Elective, Urgent) 
• 
Stent length implanted (< 30 mm, >=30 mm) 
• 
BMI (above median, below median) 
• 
History of Prior MI (yes, no) 
• 
Multivessel disease (yes, no) 
Censoring:  Subjects not experiencing any endpoint will be censored at time of death, last 
contact date (for subjects who withdraw consent or are lost to follow-up) or 365 days after 
randomization, whichever comes first. 
Analysis for the Primary Bleeding Endpoint:  This analysis will be performed on the ITT 
population.  The primary objective is to determine if ticagrelor monotherapy is superior to 
ticagrelor plus aspirin for the primary efficacy endpoint (BARC Types 2, 3 or 5 bleeding).  
The null hypothesis for this analysis is that the HR for the experimental group (H0) = 1.  The 
alternative hypothesis is that the HR for the experimental group (HA) ≠ 1.  A test of superiority 
at the two-sided 0.05 level will be performed using a Cox proportional hazard model that 
includes treatment group as a covariate.  A point estimate and two-sided 95% CI for the 
relative risk as measured by the hazard ratio will be calculated based on the Cox proportional 
hazards model.  Event rates will be estimated at one year and Kaplan-Meier curves will be 
plotted for the time from randomization to the first occurrence of confirmed BARC Type 2, 3 
or 5 bleeding by treatment group.  This analysis will be repeated in the PP cohort to support 
the primary results. 
Analysis for the Primary Ischemic Endpoint: The analysis for the primary ischemic endpoint 
will be performed on the PP cohort.  The primary objective is to determine if ticagrelor 
monotherapy is non-inferior to ticagrelor plus aspirin for the primary safety endpoint (all-
cause death, non-fatal myocardial infarction, or stroke).  .  A test of non-inferiority at the one-
sided 0.025 level will be performed. Event rates will be estimated at one year and Kaplan-
Meier curves will be plotted for the time from randomization to the first occurrence of 
confirmed all-cause death, non-fatal myocardial infarction, or stroke or by treatment group.  
Assuming an event rate of 8.0% in the control group, a sample size of 8200 will yield 80% to 
exclude a non-inferiority margin of 1.6%.  If the upper limit of the 95% CI for the point 
estimate of the absolute risk difference is less than or equal to 1.6% then the criteria for non-
inferiority will be met.  This non-inferiority margin translates to a relative risk of 20% 
assuming the observed event rate equals 8.0% in the control arm. 
Subgroup Analysis One year event rates for the primary efficacy and safety endpoints will be 
calculated in all subgroups described in section 12.2.  Stratum-specific HRs and 
corresponding 95% CI will be calculated for each subgroup using a Cox proportional hazards 

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model.  Formal interaction testing will be performed using the subgroup X treatment 
allocation as an additional term in the Cox model. 
12.3 
Determination of sample size 
Power calculations are based on a superiority comparison for the primary efficacy endpoint of 
clinically relevant bleeding (BARC Types 2, 3 or 5) at 1 year from randomization (15 months 
after enrollment).  Based on bleeding rates as shown in Table 3, a cumulative bleeding rate of 
4.5% is anticipated between time of randomization and 1 year. This estimate is more 
conservative than rates shown in Table 3 as subjects sustaining a major hemorrhagic event in 
the first 3 months after PCI will not be randomized.  Assuming a 2% loss to follow-up and 
non-compliance / cross-over rate of 4%, the current trial will require 8200 subjects to detect a 
relative reduction in bleeding of 28% with ticagrelor monotherapy with 80% power with a 
Type I error of 0.05.  It is anticipated that approximately 8% - 10% of enrolled subjects will 
not be eligible for randomization and therefore 9000 subjects will be enrolled.  Additional 
sample size estimates are provided in Table 4 assuming different control bleeding rates and 
risk reductions. References for the sample size estimates include Lakatos 1988, Biometrics 
volume 44 pages 229-241; and Lakatos 2002, Statistics in Medicine, Volume 21 pages 1969-
1989.   
Assuming a 1 year ischemic adverse event rate of 8% the current study will have 80% power 
to exclude a non-inferiority margin of 1.6% (upper limit of 95% CI for absolute risk 
difference).  
 
Table 2 
Bleeding Rates/Effect Sizes for Primary Endpoint Power Calculations 
Basis for Proposed Bleeding Event Rates in TWILIGHT Power Calculations 
Study 
Study Type 
Time Point 
BARC ≥ 2 Rate 
DAPT 
RCT 
18 months  
~ 4.2% 
PARIS (unpublished data) 
Registry 
 
 
  Age > 65 
Registry 
1 year 
8.6% 
  Diabetes Mellitus (on insulin) 
  Diabetes Mellitus (orals) 
Registry 
1 year 
8.3% 
6.3% 
  Renal disease 
Registry 
1 year 
13.2% 
Vranckx et al., EHJ 2013 
Post-hoc (TRACER) 
500 days 
14% 
ADAPT-DES 
 
 
 
CrCl < 60 (Baber et al, TCT 2013) 
Registry 
1 year 
10.0% 
Rao et al., JACC Int 2013 
NCDR CathPCI 
In-hospital (women) 
8.5% 
Basis for Proposed Effect Size in TWILIGHT Power Calculations 

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Study 
Study Type 
Comparators 
Relative Bleeding 
Increase 
Baigent et al., Lancet 2009 
Pooled Data from 
Randomized trials 
ASA vs. 
placebo/control 
50% (1o prevention) 
170% (2 o prevention) 
WOEST, Lancet 2013 
RCT 
ASA vs. placebo 
~ 60% 
CAPRIE, Lancet 1996 
RCT 
ASA vs. clopidogrel 
~35% (GI hemorrhage) 
Physician Health Study, NEJM 1989 
RCT 
ASA vs. Placebo 
~35% 
De Berardis et al., JAMA 2012 
Cohort study 
ASA vs. No ASA 
55% 
Seshasai et al., Archives Int Med 2012 
Meta-analysis of 9 RCTs 
ASA vs. Placebo 
~31% 
HOT Trial, Lancet 1998 
RCT 
ASA vs. Placebo 
~ 80% 
 
 
 
 
 
Table 3 
Power and Sample Size Scenarios for Primary Superiority Endpoint of 
BARC ≥ 2 Bleeding 
Control Bleeding 
Rate 
Relative Risk 
Reduction 
Total Randomized 
Sample Size 
Total Sample Size 
(Enrolled + Randomized) 
with 8% loss after 
enrollment* 
Total Sample Size 
(Enrolled + Randomized) 
with 10% loss after 
enrollment* 
5% 
30% 
6400 
7000 
7111 
5% 
28% 
7400 
8040 
8222 
5% 
26% 
8030 
9800 
10000 
4.5% 
30% 
7090 
7706 
7900 
4.5% 
28% 
8200 
8913 
9111 
4.5% 
26% 
9700 
10500 
10800 
4.0% 
30% 
8000 
8700 
8888 
4.0% 
28% 
9300 
10100 
10333 
4.0% 
26% 
10900 
11800 
12111 
We anticipate that ~10% of enrolled subjects will not be eligible or lost for randomization.  Power calculations assume 2% 
loss to follow-up and 4% cross-over/non-compliance. 
 
12.4 
Data and safety monitoring board  
The TWILIGHT study will be conducted under the auspices of an independent Data and 
Safety Monitoring Board (DSMB), whose activities will be described in a DSMB charter. 
DSMB members will not have primary affiliation with the study sponsor, the EDC supplier or 

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the principal investigator of the trial. Members of the Board will be determined prior to study 
enrollment. 
The DSMB will review data and determine reporting and stopping rules as specified in the 
DSMB charter. The DSMB members will review safety data while maintaining the scientific 
integrity of the trial. The data to be reviewed will consist of adjudicated and non-adjudicated 
MACE, Bleeding, and other Serious Adverse Events and their incidence, in order to identify 
potential safety issues. Based on the safety data, the DSMB may recommend modifications to 
the protocol, suspension or termination of the trial, and advise the Executive Committee. 
Members of the DSMB will meet or conference with steering group members before the trial 
starts to review the protocol, to determine the meeting schedule, the logistics of reporting the 
safety data and the stopping rules. Frequency of meetings can change during the study and 
will be determined by the DSMB and its charter. 
All adverse events will be reported to the DSMB and reviewed on an on-going basis 
throughout the subject enrollment and follow-up period as specified in the DSMB charter to 
ensure the safety of subjects enrolled in this trial. The DSMB may request additional 
information as needed. Based on safety data, the DSMB may recommend that the Executive 
Committee modify or discontinue the trial. All final decisions, regarding trial modifications, 
however, rest with the Executive Committee.  
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Overdose  
If an overdose on the study drug occurs in the course of the study, then investigators or other 
site personnel inform appropriate the ARC within one day, i.e., immediately but no later than 
the end of the next business day of when he or she becomes aware of it. 
The ARC will work with the investigator to ensure that all relevant information is provided to 
the ARC. 
13.2 
Pregnancy 
Due to the study enrollment criteria and proposed population, women of child bearing 
potential (as defined in Section 4.2) are excluded from participation in this study. In the 
unlikely event that pregnancy should occur during the course of the study, all outcomes of 
pregnancy should be reported to the ARC. 
 
 

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14. 
LIST OF REFERENCES 
1. 
Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Jr., et al. 
ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST-
elevation myocardial infarction: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 
Guidelines for the Management of Patients With Unstable Angina/Non ST-Elevation 
Myocardial Infarction): developed in collaboration with the American College of Emergency 
Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of 
Thoracic Surgeons: endorsed by the American Association of Cardiovascular and Pulmonary 
Rehabilitation and the Society for Academic Emergency Medicine. Circulation. 2007 Aug 
14;116(7):e148-304. PubMed PMID: 17679616. 
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Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. 
ACC/AHA guidelines for the management of patients with ST-elevation myocardial 
infarction--executive summary: a report of the American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 
Guidelines for the Management of Patients With Acute Myocardial Infarction). Circulation. 
2004 Aug 3;110(5):588-636. PubMed PMID: 15289388. 
3. 
King SB, 3rd, Smith SC, Jr., Hirshfeld JW, Jr., Jacobs AK, Morrison DA, Williams 
DO, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for 
percutaneous coronary intervention: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice guidelines. Journal of the 
American College of Cardiology. 2008 Jan 15;51(2):172-209. PubMed PMID: 18191745. 
4. 
Authors/Task Force m, Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, et al. 
2014 ESC/EACTS Guidelines on myocardial revascularization: The Task Force on 
Myocardial Revascularization of the European Society of Cardiology (ESC) and the European 
Association for Cardio-Thoracic Surgery (EACTS)Developed with the special contribution of 
the European Association of Percutaneous Cardiovascular Interventions (EAPCI). European 
heart journal. 2014 Oct 1;35(37):2541-619. PubMed PMID: 25173339. 
5. 
Dupont AG, Gabriel DA, Cohen MG. Antiplatelet therapies and the role of antiplatelet 
resistance in acute coronary syndrome. Thromb Res. 2009 May;124(1):6-13. PubMed PMID: 
19324398. Epub 2009/03/28. eng. 
6. 
Geisler T, Zurn C, Simonenko R, Rapin M, Kraibooj H, Kilias A, et al. Early but not 
late stent thrombosis is influenced by residual platelet aggregation in patients undergoing 
coronary interventions. European heart journal. 2010 Jan;31(1):59-66. PubMed PMID: 
19812059. Epub 2009/10/09. eng. 
7. 
Hochholzer W, Trenk D, Bestehorn HP, Fischer B, Valina CM, Ferenc M, et al. 
Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on 
early clinical outcome of elective coronary stent placement. Journal of the American College 
of Cardiology. 2006 Nov 7;48(9):1742-50. PubMed PMID: 17084243. Epub 2006/11/07. eng. 
8. 
Marcucci R, Gori AM, Paniccia R, Giusti B, Valente S, Giglioli C, et al. 
Cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients 
receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a 
point-of-care assay: a 12-month follow-up. Circulation. 2009 Jan 20;119(2):237-42. PubMed 
PMID: 19118249. 

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9. 
Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, et al. 
Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-
responders compared with clopidogrel in aspirin-treated patients with stable coronary artery 
disease. European heart journal. 2006 May;27(10):1166-73. PubMed PMID: 16621870. Epub 
2006/04/20. eng. 
10. 
Wallentin L, Varenhorst C, James S, Erlinge D, Braun OO, Jakubowski JA, et al. 
Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than 
clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients 
with coronary artery disease. European heart journal. 2008 Jan;29(1):21-30. PubMed PMID: 
18055486. Epub 2007/12/07. eng. 
11. 
Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, et al. 
Prasugrel versus clopidogrel in patients with acute coronary syndromes. The New England 
journal of medicine. 2007 Nov 15;357(20):2001-15. PubMed PMID: 17982182. Epub 
2007/11/06. eng. 
12. 
van Giezen JJ, Humphries RG. Preclinical and clinical studies with selective reversible 
direct P2Y12 antagonists. Semin Thromb Hemost. 2005 Apr;31(2):195-204. PubMed PMID: 
15852223. Epub 2005/04/27. eng. 
13. 
Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. 
Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist 
AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to 
clopidogrel with aspirin. European heart journal. 2006 May;27(9):1038-47. PubMed PMID: 
16476694. Epub 2006/02/16. eng. 
14. 
Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, et al. 
Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, 
compared with clopidogrel in patients with acute coronary syndromes. Journal of the 
American College of Cardiology. 2007 Nov 6;50(19):1852-6. PubMed PMID: 17980251. 
Epub 2007/11/06. eng. 
15. 
Alexopoulos D, Galati A, Xanthopoulou I, Mavronasiou E, Kassimis G, 
Theodoropoulos KC, et al. Ticagrelor versus prasugrel in acute coronary syndrome patients 
with high on-clopidogrel platelet reactivity following percutaneous coronary intervention: a 
pharmacodynamic study. Journal of the American College of Cardiology. 2012 Jul 
17;60(3):193-9. PubMed PMID: 22789884. Epub 2012/07/14. eng. 
16. 
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, et al. 
Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England 
journal of medicine. 2009 Sep 10;361(11):1045-57. PubMed PMID: 19717846. Epub 
2009/09/01. eng. 
17. 
Baber U, Mehran R, Sharma SK, Brar S, Yu J, Suh JW, et al. Impact of the 
everolimus-eluting stent on stent thrombosis: a meta-analysis of 13 randomized trials. Journal 
of the American College of Cardiology. 2011 Oct 4;58(15):1569-77. PubMed PMID: 
21924575. Epub 2011/09/20. eng. 
18. 
Valgimigli M, Campo G, Monti M, Vranckx P, Percoco G, Tumscitz C, et al. Short- 
versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized 
multicenter trial. Circulation. 2012 Apr 24;125(16):2015-26. PubMed PMID: 22438530. 
19. 
Brar SS, Kim J, Brar SK, Zadegan R, Ree M, Liu IL, et al. Long-term outcomes by 
clopidogrel duration and stent type in a diabetic population with de novo coronary artery 

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lesions. Journal of the American College of Cardiology. 2008 Jun 10;51(23):2220-7. PubMed 
PMID: 18534267. 
20. 
Schulz-Schupke S, Byrne RA, Ten Berg JM, Neumann FJ, Han Y, Adriaenssens T, et 
al. ISAR-SAFE: a randomized, double-blind, placebo-controlled trial of 6 vs. 12 months of 
clopidogrel therapy after drug-eluting stenting. European heart journal. 2015 May 
21;36(20):1252-63. PubMed PMID: 25616646. 
21. 
Gilard M, Barragan P, Noryani AA, Noor HA, Majwal T, Hovasse T, et al. 6- versus 
24-month dual antiplatelet therapy after implantation of drug-eluting stents in patients 
nonresistant to aspirin: the randomized, multicenter ITALIC trial. Journal of the American 
College of Cardiology. 2015 Mar 3;65(8):777-86. PubMed PMID: 25461690. 
22. 
Colombo A, Chieffo A, Frasheri A, Garbo R, Masotti-Centol M, Salvatella N, et al. 
Second-generation drug-eluting stent implantation followed by 6- versus 12-month dual 
antiplatelet therapy: the SECURITY randomized clinical trial. Journal of the American 
College of Cardiology. 2014 Nov 18-25;64(20):2086-97. PubMed PMID: 25236346. 
23. 
Brar SS, Kim J, Brar SK, Zadegan R, Ree M, Liu IL, et al. Long-term outcomes by 
clopidogrel duration and stent type in a diabetic population with de novo coronary artery 
lesions. Journal of the American College of Cardiology. 2008 Jun 10;51(23):2220-7. PubMed 
PMID: 18534267. Epub 2008/06/07. eng. 
24. 
Gwon HC, Hahn JY, Park KW, Song YB, Chae IH, Lim DS, et al. Six-month versus 
12-month dual antiplatelet therapy after implantation of drug-eluting stents: the Efficacy of 
Xience/Promus Versus Cypher to Reduce Late Loss After Stenting (EXCELLENT) 
randomized, multicenter study. Circulation. 2012 Jan 24;125(3):505-13. PubMed PMID: 
22179532. 
25. 
Chirumamilla AP, Maehara A, Mintz GS, Mehran R, Kanwal S, Weisz G, et al. High 
platelet reactivity on clopidogrel therapy correlates with increased coronary atherosclerosis 
and calcification: a volumetric intravascular ultrasound study. JACC Cardiovasc Imaging. 
2012 May;5(5):540-9. PubMed PMID: 22595163. Pubmed Central PMCID: 3753810. Epub 
2012/05/19. eng. 
26. 
Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, et al. 
Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from 
the Bleeding Academic Research Consortium. Circulation. 2011 Jun 14;123(23):2736-47. 
PubMed PMID: 21670242. 
27. 
Wiviott SD, Antman EM, Gibson CM, Montalescot G, Riesmeyer J, Weerakkody G, et 
al. Evaluation of prasugrel compared with clopidogrel in patients with acute coronary 
syndromes: design and rationale for the TRial to assess Improvement in Therapeutic 
Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial 
Infarction 38 (TRITON-TIMI 38). American heart journal. 2006 Oct;152(4):627-35. PubMed 
PMID: 16996826. 
28. 
An International Randomized Trial Comparing Four Thrombolytic Strategies for 
Acute Myocardial Infarction. New England Journal of Medicine. 1993;329(10):673-82. 
PubMed PMID: 8204123. 
29. 
Cutlip DE, Windecker S, Mehran R, Boam A, Cohen DJ, van Es GA, et al. Clinical 
end points in coronary stent trials: a case for standardized definitions. Circulation. 2007 May 
1;115(17):2344-51. PubMed PMID: 17470709. 

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30. 
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD, et al. Third 
universal definition of myocardial infarction. Circulation. 2012 Oct 16;126(16):2020-35. 
PubMed PMID: 22923432. 
 
 
 

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15. 
APPENDIX A – DEFINITIONS FOR STUDY ENDPOINTS 
15.1 
Bleeding events 
15.1.1 
Bleeding Academic Research Consortium definition of bleeding 
Clinically relevant bleeding is defined as any bleeding event that meets the BARC criteria types 
2, 3 or 5.  
Table 4 
BARC Bleeding Definition, modified from Mehran et al (26) 
Type Definition 
0 
No evidence of bleeding. 
1 
Bleeding that is not actionable and patient does not have unscheduled studies, 
hospitalization or treatment by a health care professional 
2 
Any clinically overt sign of hemorrhage that is actionable but does not meet criteria for 
type 3, 4 or 5 bleeding.  It must meet at least one of the following criteria: 
 requiring medical or percutaneous intervention guided by a health care 
profession, includes (but are not limited to) temporary/permanent cessation of a 
medication, coiling, compression, local injection 
 leading to hospitalization or an increased level of care 
 prompting evaluation defined as an unscheduled visit to a healthcare professional 
resulting in diagnostic testing (laboratory or imaging) 
3 
Clinical, laboratory and/or imaging evidence of bleeding with specific healthcare 
provider responses, as listed below: 
3a 
 Any transfusion with overt bleeding 
 Overt bleeding plus hemoglobin (Hb) drop ≥3 to <5g/dL* (provided Hb drop is 
related to bleeding) 
3b 
 Overt bleeding plus Hb drop ≥5g/dL* (Hb drop is related to bleed) 
 Cardiac tamponade 
 Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 Bleeding requiring intravenous vasoactive drugs 
3c 
 Intracranial hemorrhage (does not include microbleeds or hemorrhagic 
transformation; does include intraspinal). Subcategories: confirmed by autopsy, 
imaging or lumbar puncture 
                                                 
* Hemoglobin drop should be corrected for for intracurrent transfusion in which 1 unit of packed red blood cells or 
whole blood should be expected to increase hemoglobin by 1g/dL. 

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Type Definition 
 Intraocular bleed compromising vision 
4 
CABG – Related Bleeding 
 Perioperative intracranial bleeding within 48 hours 
 Reoperation following closure of sternotomy for the purpose of controlling 
bleeding 
 Transfusion of ≥5 units of whole blood or packed red blood cells within a 48 hour 
period 
 Chest tube output ≥2L within a 24 hour period 
5 
Fatal Bleeding. Bleeding directly causes death with no other explainable cause. 
Categorized further as either definite or probable. 
5a 
Probable fatal bleeding is bleeding that is clinically suspicious as the cause of death, but 
the bleeding is not directly observed and there is no autopsy or confirmatory imaging. 
5b 
Definite fatal bleeding is bleeding that is directly observed (either by clinical specimen – 
blood, emesis, stool, etc. – or by imaging) or confirmed on autopsy. 
 
15.1.2 
Thrombolysis in Myocardial Infarction definition of bleeding  
Table 5 
TIMI Bleeding Definition(27) 
Type 
Definition 
Non-CABG related bleeding 
Major 
 Any intracranial bleeding (excluding microhemorrhages <10 mm evident only 
on gradient-echo MRI) 
 Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 
g/dL or a ≥15% absolute decrease in haematocrit 
 Fatal bleeding (bleeding that directly results in death within 7 days) 
Life threatening bleeding is a TIMI major bleeding event that meets any of the 
following criteria: 
 Symptomatic intracranial hemorrhage  
 Fatal bleeding 
 Leads to hypotension requiring inotropic agents 
 Requires surgical intervention for ongoing bleeding 
 Necessitates transfusion of 4 or more units of whole blood or packed red blood 
cells over a 48-hour period 

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Type 
Definition 
Minor 
 Clinically overt (including imaging), resulting in hemoglobin drop of 3 to 
<5 g/dL or ≥10% decrease in haematocrit 
 No observed blood loss: ≥4 g/dL decrease in the haemoglobin concentration or 
≥12% decrease in haematocrit 
 Any overt sign of hemorrhage that meets one of the following criteria and does 
not meet criteria for a major bleeding event: 
o Requiring intervention (medical practitioner-guided medical or surgical 
treatment to stop or treat bleeding, including temporarily or permanently 
discontinuing or changing the dose of a medication or study drug) 
o Leading to or prolonging hospitalization 
o Prompting evaluation (leading to an unscheduled visit to a healthcare 
professional and diagnostic testing, either laboratory or imaging) 
Minimal 
 Any overt bleeding event that does not meet the criteria above 
 Any clinically overt sign of haemorrhage (including imaging) associated 
with a <3 g/dL decrease in haemoglobin concentration or <9% decrease in 
haematocrit 
Bleeding in the setting of CABG 
 
 Fatal bleeding (bleeding that directly results in death) 
 Perioperative intracranial bleeding 
 Reoperation after closure of the sternotomy incision for the purpose of 
controlling bleeding 
 Transfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver 
transfusion will not be counted in calculations of blood products. 
 Chest tube output >2 L within a 24-h period 
 
 

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15.1.3 
Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO) 
definition of bleeding 
Table 6 
GUSTO Bleeding Definition (28) 
Type 
Definition 
Severe or life-threatening 
Intracerebral bleeding or bleeding resulting in substantial 
hemodynamic compromise requiring treatment 
Moderate 
Any bleeding not meeting the requirements for severe / life-
threatening bleeding that requires transfusion 
Minor 
Other bleeding not requiring transfusion or causing 
hemodynamic compromise 
 
15.1.4 
International Society on Thrombosis and Haemostasis definition of bleeding 
The ISTH classification of major bleeding in non-surgical patients includes any one of the 
following: 
 Fatal bleeding,  
 Symptomatic bleeding in a critical area or organ such as intracranial, intraspinal, intraocular, 
retroperitoneal, intra-articular or pericardial, or intramuscular with compartment syndrome,  
 Bleeding causing a fall in haemoglobin level of 2 g/dL (1.24 mmol/L) or more, or leading to 
transfusion of two or more units of whole blood or red cells.(25) 
 
 

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15.2 
Major Adverse Cardiovascular Events  
Major adverse cardiovascular events (MACE) is the composite of cardiovascular death, non-fatal 
myocardial infarction, ischemic stroke, or clinically-driven revascularization. The definitions of 
the individual components of MACE are given below. 
15.2.1 
Death 
All-cause death comprises several subclassifications (Table 7). In general, all deaths are 
considered cardiac unless an alternate cause is unequivocally established, even among subjects 
with serious noncardiac comorbidities.  
Table 7 
Classification of Death(29) 
Cardiac death 
Any death due to proximate cardiac cause (eg, MI, low-output 
failure, fatal arrhythmia), unwitnessed death and death of 
unknown cause, all procedure-related deaths including those 
related to concomitant treatment, will be classified as cardiac 
death. 
 
Vascular death 
Death caused by noncoronary vascular causes, such as 
cerebrovascular disease, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm or other causes. 
 
Noncardiovascular death 
Any death not covered by the above definitions, such as death 
caused by infection, malignancy, sepsis, pulmonary causes, 
accident, suicide or trauma. 
 
 
15.2.2 
Myocardial Infarction 
Myocardial infarction is defined according to the third universal definition(30) and includes: 
 Type 1: spontaneous MI 
 Type 2: MI secondary to an ischemic imbalance 
 Type 3: MI resulting in death when biomarker values are unavailable 
 Type 4a. MI related to PCI 
 Type 4b: MI related to stent thrombosis 

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 Type 5: MI related to CABG 
Any one of the following criteria meets the diagnosis of MI: 
 Detection of a rise and/or fall of cardiac biomarker values (preferably cardiac troponin) 
with at least one value above the 99th percentile URL and with at least one of the 
following: 
o Symptoms of ischemia 
o (Presumed) new significant ST-T wave changes or new LBBB 
o Development of pathological Q waves  
o Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
o Identification of an intracoronary thrombus by angiography or autopsy 
 Cardiac death with symptoms suggestive of MI and presumed new ischemic ECG 
changes or new LBBB, but death occurred before cardiac biomarkers were obtained, or 
before cardiac biomarker values would be increased 
 PCI related MI is arbitrarily defined by elevation of cardiac biomarkers  
o (>5 x 99th percentile URL) in patients with normal baseline values or 
o > 20% if the baseline values are elevated and are stable or falling 
In addition, one of the following is required 
o symptoms suggestive of ischemia  
o new ischemic ECG changes  
o angiographic findings consistent with a procedural complication OR 
o imaging demonstration of new loss of viable myocardium or new regional wall 
motion abnormality  
 Stent thrombosis associated with MI when detected by coronary angiography or autopsy 
in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker 
values with at least one value above the 99th percentile URL 
 CABG related MI is arbitrarily defined by elevation of cardiac biomarkers >10 x 99th 
percentile URL in patients with normal baseline values, AND one of the following: 

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o New pathological Q waves or new LBBB 
o Angiographic documented new graft or new native coronary artery occlusion, or  
o Imaging evidence of new loss of viable myocardium or new regional wall motion 
abnormality 
15.2.3 
Stroke  
Stroke is defined as an acute symptomatic episode of neurological dysfunction, more than 24 
hours in duration in the absence of therapeutic intervention or death, due to cerebral, spinal or 
retinal tissue injury as evidenced by neuroimaging or lumbar puncture. It includes the following 
subclassifications: 
 Ischemic stroke: infarction due to prolonged ischemia. Causes include (but are not 
limited to) arterial and venous thrombosis, embolism, and systemic hypoperfusion. 
 Hemorrhagic stroke: caused by a non-traumatic intraperenchymal, intraventricular or 
subarachnoid hemorrhage 
 Undetermined: stroke with insufficient information to determine ischemic or hemorrhagic 
cause 
Transient ischemic attack (TIA) is a transient episode of neurological dysfunction (< 24 hours) 
caused by temporary cerebral, spinal or retinal ischemia with no evidence of acute infarction on 
neuroimaging. 
15.2.4 
Stent thrombosis 
Stent thrombosis is classified according to the level of certainty and timing following PCI(29) 
(Table 8). 
 Definite stent thrombosis: is highly specific and requires angiographic or pathological 
confirmation of stent thrombosis in or within 5 mm of the stent in the setting of at least 
one of the following criteria with a 48-hour time window 
o Acute ischemic symptoms at rest 
o New ischemic ECG changes 
o Typical rise and fall in cardiac biomarkers 
 Probable stent thrombosis includes 
o Any unexplained death within the first 30 days following PCI 

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o Any MI at any time following PCI that is related to documented acute ischemia in 
the territory of the implanted stent, in the absence of angiographic/pathological 
confirmation of stent thrombosis and no other obvious cause 
 Possible stent thrombosis 
o Any unexplained death after the first 30 days following PCI until the end of trial 
follow-up 
Table 8 
Timing of Stent Thrombosis 
Acute 
0-24 hours following PCI 
Subacute 
>24 hours to 30 days following PCI 
Late 
>30 days to 1 year following PCI 
Very late 
>1 year following PCI 
 
15.2.5 
Clinically driven revascularization 
Clinically driven revascularization includes repeat PCI or CABG for recurrent or persistent 
symptomatic ischemia and can be defined according to the relationship to the index PCI (target 
lesion)(29): 
 Target lesion revascularization, at the previously stented segment  
 Non-target lesion, target vessel revascularization, of the previously treated vessel or its side 
branches AND 
 Non-target vessel lesion revascularization, of a vessel other than the previously treated vessel 
 
 

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16. 
APPENDIX B - OTHER DEFINITIONS 
Coronary Artery Disease (CAD) 
Multivessel (CAD), defined as significant disease in at least 2 major epicardial vessels or 
significant left main disease plus one major epicardial vessel.  Significant coronary artery disease 
is defined as angiographic stenosis of at least 70% in a major epicardial vessel or at least 50% in 
the left main trunk.  For intermediate stenosis in major epicardial vessels (50%-70%), an 
invasive hemodynamic assessment using fractional flow reserve (FFR) with values less than or 
equal to 0.8 will be considered significant.  For intermediate left main lesions, a minimal lumen 
area by intravascular ultrasound (IVUS) less than 6.0 mm2 will be considered significant. 
Successful PCI 
PCI is considered successful for lesions treated with stent implantation if the residual diameter 
stenosis based on visual estimation is less than or equal to 10% and the final TIMI flow grade is 
3.  PCI is considered successful for lesions treated without stent implantation if the residual 
diameter stenosis based on visual estimation is less than or equal to 30% and the final TIMI flow 
grade is 3.   
Medina Classification of Bifurcations 
 
 
 
 
Indication for PCI according to National Cardiovascular Data Registry 
 
 
 
 

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17. 
APPENDIX C 
Timeline Of In-Person Visits And Phone Calls 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol TWILIGHT Study 
Drug Substance 
Ticagrelor & Aspirin 
Study Number 
ISSBRIL0345 
Edition Number  
Version 4.0 
Date  
28-Mar-2016 
 
Page 58 of 58 
18. 
APPENDIX D 
CONTRAINDICATIONS TO ASPIRIN 
Hypersensitivity to ASA, salicylates, non-steroidal anti-inflammatory drugs (NSAIDs), 
analgesics, antipyretics or other ingredients in the product, excipients or component of 
the container.  
Acute gastrointestinal ulcer, history of gastrointestinal ulcers 
Hemorrhagic diathesis and severe active bleeding 
Active or severe hepatic failure, renal failure requiring dialysis, or acute congestive heart 
failure 
Patients with a history of asthma induced by the administration of salicylates or 
substances with a similar action, notably NSAIDs 
Combination with methotrexate at doses of 15 mg/week or more 
Last trimester of pregnancy and nursing women 
Glucose-6-phosphate dehydrogenase (G6PD) deficiency 
 
19. 
APPENDIX E 
CONTRAINDICATIONS TO TICAGRELOR: 
Hypersensitivity to the active substance or to any of the excipients   
Active pathological bleeding 
History of intracranial hemorrhage 
Moderate to severe hepatic impairment 
Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g., ketoconazole, 
clarithromycin, nefazodone, ritonavir, and atazanavir) is contraindicated, as co-
administration may lead to a substantial increase in exposure to ticagrelor