Clinical trial NCT01991795
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Coronary artery disease Outcome Prevention Antiplatelet
Sponsor: AstraZeneca
Start date: 2014-02-10; Completion date: 2019-01-25
Enrollment: 19271 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the effect of ticagrelor versus placebo in patients with Type 2 Diabetes Mellitus.

Detailed description:
A multinational, randomised, double-blind, placebo-controlled phase IIIb trial to evaluate the effect of ticagrelor twice daily on the incidence of cardiovascular death, myocardial infarction or stroke in patients with type 2 diabetes mellitus

Arms: arm 1: Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1. arm 2: Initially ticagrelor 90 mg or corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or corresponding placebo in Clinical Study Protocol Amendment No 1.
Interventions: intervention 1: Ticagrelor 60 mg intervention 2: Ticagrelor placebo
Intervention descriptions: intervention 1: Ticagrelor 60 mg bd taken orally as tablets intervention 2: Ticagrelor placebo bd taken orally as tablets

Protocol documents:
Prot_000.pdf: 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
2
PROTOCOL SYNOPSIS
A Multinational, Randomised, Double-Blind, Placebo-Controlled Trial to 
Evaluate the Effect of Ticagrelor twice daily on the Incidence of 
Cardiovascular Death, Myocardial Infarction or Stroke in Patients with 
Type 2 Diabetes Mellitus
[THEMIS - Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus 
patients Intervention Study]
International Co-ordinating Investigators 
Study centres and number of patients planned
This study will be conducted at approximately 1200 study centres in about 40 countries 
worldwide. It is expected that approximately 19000 patients will be randomised to study 
treatment.
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2014
Phase IIIb
Estimated date of last patient completed
Q4 2018
Objectives
Primary objective
The primary objective of the study is to compare the effect of long-term treatment with 
ticagrelor twice daily (bd) vs. placebo for the prevention of major cardiovascular (CV) events 
(composite of CV death, myocardial infarction [MI] or stroke) in patients with T2DM at high 
risk of CV events, but without a medical history of previous MI or stroke.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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The primary efficacy variable is time from randomisation to first occurrence of any event 
from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown 
etiology). 
Secondary objectives
The secondary objectives of the study (presented in hierarchical order) are to compare the 
effect of long-term treatment with ticagrelor vs. placebo for:
1.
Prevention of CV death. The efficacy variable is time from randomisation to death of 
CV cause
2.
Prevention of MI. The efficacy variable is time from randomisation to first 
occurrence of MI
3.
Prevention of ischaemic stroke. The efficacy variable is time from randomisation to 
first occurrence of ischaemic stroke
4.
Prevention of all-cause death. The efficacy variable is time from randomisation to 
death of any cause.
Exploratory objectives
Other objectives are to explore other long-term treatment effects of ticagrelor vs. placebo on:
•
Prevention of the composite of all-cause death, MI or stroke. The efficacy variable is 
time from randomisation to first occurrence of any event from the composite of all-
cause death, MI or stroke
•
Prevention of stroke. The efficacy variable is time from randomisation to first 
occurrence of stroke
•
Effect on irreversible harm events, the composite of all-cause mortality, MI, stroke, 
intracranial haemorrhage and fatal bleeding. The efficacy variable is time from 
randomisation to first occurrence of any event from the composite of all-cause 
mortality, MI, stroke, intracranial haemorrhage and fatal bleeding
•
Health care resource utilisation and utilities assessed by Euro Quality of Life-5 
Dimensions (EQ-5D) questionnaire to support health technology assessment and 
health economic modelling.
Safety objectives
The overall safety objective of this study is to assess the safety and tolerability of long-term 
therapy with ticagrelor compared to placebo in patients with T2DM at high risk of CV events, 
with or without background low-dose ASA therapy. Bleeding events will be analyzed using 
the Thrombolysis in Myocardial Infarction Study Group (TIMI) definitions, those used in the 
PLATO (PLATelet inhibition and patient Outcomes) study, and the Bleeding Academic 
Research Consortium (BARC) definitions. Specific focus will be on:


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
4

Time to first TIMI Major bleeding event (primary safety objective)

Time to first TIMI Major or Minor bleeding event

Time to first PLATO Major bleeding event

Time to permanent discontinuation of study medication due to any bleeding 
event.
Non-serious AEs of interest (ie, dyspnoea, renal impairment, bradyarrhythmia, gout, and 
pneumonia), adverse events that leads to permanent discontinuation of study medication 
(DAEs) and all serious adverse events (SAEs) will be reviewed within the context of the 
earlier safety experience with the drug.
Study design
This is an event-driven, randomised, double blind, placebo controlled, parallel group, 
international multi-centre study to evaluate the effect of ticagrelor bd vs. placebo for 
prevention of major CV events in patients with T2DM at high risk of CV events, but without a 
medical history of previous MI or stroke. Patients will be managed consistent with local 
standard of care including provision of dietary and lifestyle advice according to local diabetes 
treatment guidelines. Patients should be treated with low-dose acetylsalicylic acid 
(ASA)/AspirinTM 75 150 mg once daily (od), unless contraindicated or not tolerated, in 
accordance with national and international clinical practice guidelines.
Target patient population
Men and women ≥50 years of age with T2DM at high risk of CV events, but without a 
medical history of previous MI or stroke. 
Study medication, dosage and mode of administration
Ticagrelor bd given orally or corresponding placebo. Initially ticagrelor 90 mg or 
corresponding placebo was the selected dose, but reduced to ticagrelor 60 mg or 
corresponding placebo in Clinical Study Protocol Amendment No 1.
Duration of treatment
The study is event-driven and 19000 randomised patients are estimated to be required in order 
to collect 1385 adjudicated primary endpoint events. The anticipated maximal duration of 
treatment with study medication for an individual patient is 58 months. However, the actual 
duration of the study will be based on accrual of the pre-determined number of adjudicated 
primary endpoint events, and therefore the final treatment time may be shorter or longer than 
58 months. The expected minimum follow-up period is 29 months and the expected average 
follow-up period is 40 months, based on an enrolment period of 28 months.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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Statistical methods
All efficacy analyses will be based on the intention to treat (ITT) principle using the full 
analysis set (FAS) including only adjudicated endpoint events. For time to event variables, 
treatments will be compared using a Cox proportional hazards model with a factor for 
treatment group. The p-value, hazard ratio (HR) and 95% confidence interval will be reported. 
Kaplan-Meier estimates of the cumulative risk will also be presented. The family wise error 
rate will be controlled for the primary and secondary efficacy analyses by applying a 
hierarchical test sequence. 
The final primary treatment comparison will be made at a significance level of 4.96%, 
adjusted for the planned efficacy interim analysis. Assuming a true hazard ratio of 0.84 
between ticagrelor and placebo, 1385 primary endpoint events will provide a power of 90%. 
With an annual event rate of 2.5% in the placebo treatment group, 19000 patients, randomised 
in a 1:1 ratio, are estimated to provide the required number of primary events after receiving 
study medication for an anticipated average of 40 months.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
6
TABLE OF CONTENTS
PAGE
TITLE PAGE...........................................................................................................1
PROTOCOL SYNOPSIS.........................................................................................2
TABLE OF CONTENTS.........................................................................................6
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS..........................11
1.
INTRODUCTION .................................................................................................15
1.1
Background............................................................................................................15
1.1.1
Medical need..........................................................................................................15
1.1.2
Role of antiplatelet therapy in patients with DM...................................................15
1.1.3
Product background ...............................................................................................16
1.1.4
Ticagrelor in patients with DM..............................................................................17
1.2
Research hypothesis...............................................................................................17
1.3
Rationale for conducting this study .......................................................................17
1.4
Benefit/risk and ethical assessment........................................................................18
2.
STUDY OBJECTIVES..........................................................................................19
2.1
Primary objective...................................................................................................19
2.2
Secondary objectives .............................................................................................20
2.3
Exploratory objectives ...........................................................................................20
2.4
Safety objective......................................................................................................20
3.
STUDY PLAN AND PROCEDURES ..................................................................21
3.1
Overall study design and flow chart ......................................................................21
3.2
Rationale for study design, doses and control groups............................................28
4.
PATIENT SELECTION CRITERIA.....................................................................29
4.1
Inclusion criteria ....................................................................................................29
4.2
Exclusion criteria ...................................................................................................30
5.
STUDY CONDUCT..............................................................................................31
5.1
Restrictions during the study .................................................................................31
5.2
Patient enrolment and randomisation.....................................................................31
5.2.1
Procedures for randomisation ................................................................................32
5.3
Procedures for handling patients incorrectly enrolled or randomised ...................32
5.4
Blinding and procedures for unblinding the study.................................................33


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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5.4.1
Methods for ensuring blinding...............................................................................33
5.4.2
Methods for unblinding the study..........................................................................33
5.5
Treatments..............................................................................................................34
5.5.1
Identity of study medication(s) ..............................................................................34
5.5.2
Doses and treatment regimens ...............................................................................34
5.5.3
Development of indication for ADP receptor antagonist during study .................35
5.5.4
Duration of treatment.............................................................................................35
5.5.5
Labelling ................................................................................................................35
5.5.6
Storage ...................................................................................................................36
5.6
Concomitant and post-study treatments.................................................................36
5.6.1
Recording of concomitant medication...................................................................36
5.6.2
Anti-diabetic treatment and risk factor management.............................................36
5.6.3
Oral antiplatelet therapies ......................................................................................36
5.6.3.1
Low Dose ASA (defined as 75 to 150 mg od).......................................................36
5.6.3.2
High Dose ASA (>150 mg od) ..............................................................................36
5.6.3.3
ADP receptor antagonists ......................................................................................36
5.6.3.4
Dipyridamole .........................................................................................................37
5.6.3.5
Approved PDE3 inhibitors for claudication (eg, cilostazol)..................................37
5.6.4
Parenteral antiplatelet therapies .............................................................................37
5.6.4.1
GPIIb/IIIa receptor antagonists..............................................................................37
5.6.5
Oral anticoagulants ................................................................................................37
5.6.6
Parenteral anticoagulants .......................................................................................37
5.6.7
Fibrinolytics ...........................................................................................................37
5.6.8
Non-steroidal anti-inflammatory drugs (NSAIDs) ................................................38
5.6.9
Digoxin and other p-glycoprotein interactions ......................................................38
5.6.10
CYP450 interactions ..............................................................................................38
5.6.10.1
CYP3A4 inhibitors.................................................................................................38
5.6.10.2
CYP3A4 substrates or inducers .............................................................................38
5.6.11
Surgery...................................................................................................................39
5.6.12
Other surgery and invasive non-cardiovascular procedures ..................................39
5.7
Treatment compliance............................................................................................39
5.7.1
Accountability........................................................................................................39
5.8
Discontinuation of study medication .....................................................................40
5.8.1
Temporary discontinuation from study medication...............................................40
5.8.2
Permanent discontinuation from study medication................................................40
5.8.3
Procedures for permanent discontinuation of a patient from study 
medication..............................................................................................................41
5.8.3.1
Patient agrees to undergo the Premature Treatment Discontinuation Visit 
and then continue in-person study visits................................................................41
5.8.3.2
Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up ................................................................................................41
5.8.3.3
Patient refuses any form of follow-up ...................................................................41
5.8.3.4
Restart of study medication ...................................................................................42
5.8.4
Study Closure Visit................................................................................................42


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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5.9
Withdrawal from study (study medication and assessments)................................42
5.10
Study committees...................................................................................................43
5.10.1
Executive Committee (EC)....................................................................................43
5.10.2
International Steering Committee..........................................................................43
5.10.3
Clinical Endpoint Committee (CEC).....................................................................43
5.10.4
Data Monitoring Committee (DMC) .....................................................................43
6.
COLLECTION OF STUDY VARIABLES...........................................................44
6.1
Recording of data...................................................................................................44
6.2
Data collection at enrolment and follow-up...........................................................44
6.2.1
Enrolment and randomisation procedures .............................................................44
6.2.2
Follow-up procedures ............................................................................................45
6.3
Efficacy..................................................................................................................47
6.3.1
Classification of Death...........................................................................................47
6.3.2
Universal classification of Myocardial Infarction (MI).........................................47
6.3.3
Definition of Stroke ...............................................................................................47
6.4
Safety .....................................................................................................................48
6.4.1
Definition of adverse events ..................................................................................48
6.4.1.1
Adverse Events of interest .....................................................................................48
6.4.2
Definitions of serious adverse event......................................................................49
6.4.3
Recording of adverse events ..................................................................................49
6.4.4
Reporting of serious adverse events.......................................................................52
6.4.4.1
Reporting of serious adverse events considered to be potential endpoint 
events .....................................................................................................................52
6.4.5
Bleeding assessments.............................................................................................53
6.4.5.1
Bleeding associated with procedures.....................................................................53
6.4.5.2
Procedures for Study Medication in case of bleeding ...........................................53
6.4.6
Laboratory safety assessment ................................................................................54
6.4.6.1
Collection of specific information for liver related SAEs or DAEs ......................54
6.4.7
Electrocardiogram (ECG) ......................................................................................54
6.4.8
Vital signs ..............................................................................................................55
6.5
Patient reported outcomes (PRO) ..........................................................................55
6.6
Pharmacokinetics (Not Applicable).......................................................................55
6.7
Pharmacodynamics (Not Applicable)....................................................................55
6.8
Pharmacogenetics (Not Applicable) ......................................................................55
6.9
Health economics...................................................................................................55
6.9.1
Health economic assessment (EQ-5D) ..................................................................55
6.9.2
Health care resource utilisation..............................................................................55
7.
BIOLOGICAL SAMPLING PROCEDURES.......................................................56
7.1
Volume of blood ....................................................................................................56


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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7.2
Handling, storage and destruction of biological samples ......................................57
8.
ETHICAL AND REGULATORY REQUIREMENTS.........................................57
8.1
Ethical conduct of the study...................................................................................57
8.2
Subject data protection...........................................................................................57
8.3
Ethics and regulatory review..................................................................................57
8.4
Informed consent ...................................................................................................58
8.5
Changes to the protocol and informed consent form.............................................58
8.6
Audits and inspections ...........................................................................................59
9.
STUDY MANAGEMENT BY ASTRAZENECA................................................59
9.1
Pre-study activities.................................................................................................59
9.2
Training of study site personnel.............................................................................59
9.3
Monitoring of the study .........................................................................................60
9.3.1
Source data.............................................................................................................60
9.4
Study agreements...................................................................................................60
9.4.1
Archiving of study documents...............................................................................61
9.5
Study timetable and end of study...........................................................................61
10.
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE......................61
11.
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE ......................................................................62
11.1
Calculation or derivation of efficacy variables (Not Applicable)..........................62
11.2
Calculation or derivation of safety variable(s) (Not Applicable) ..........................62
11.3
Calculation or derivation of patient reported outcome variables...........................62
11.4
Calculation or derivation of pharmacokinetic variables (Not Applicable)............62
11.5
Calculation or derivation of pharmacodynamic variables (Not Applicable).........62
11.6
Calculation or derivation of pharmacogenetic variables (Not Applicable) ...........62
11.7
Calculation or derivation of health economic variables.........................................62
12.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA ............................................................................................63
12.1
Description of analysis sets....................................................................................63
12.1.1
Full analysis set......................................................................................................63
12.1.2
Safety analysis set..................................................................................................63
12.2
Methods of statistical analyses...............................................................................63
12.2.1
Efficacy analysis ....................................................................................................63
12.2.1.1
Primary efficacy variable.......................................................................................64
12.2.1.2
Secondary efficacy variables .................................................................................64


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Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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12.2.1.3
Exploratory variables.............................................................................................64
12.2.2
Safety variables......................................................................................................65
12.2.2.1
Bleeding events......................................................................................................65
12.2.2.2
SAEs and AE of interest ........................................................................................66
12.2.3
Interim analysis for efficacy ..................................................................................66
12.2.4
Censoring ...............................................................................................................66
12.3
Determination of sample size.................................................................................67
12.4
Independent Data monitoring committees.............................................................67
12.4.1
Clinical Endpoint Committee (CEC).....................................................................67
12.4.2
Data Monitoring Committee (DMC) .....................................................................67
13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR ..................................................................................................68
13.1
Medical emergencies and AstraZeneca contacts ...................................................68
13.2
Overdose ................................................................................................................68
13.3
Pregnancy...............................................................................................................69
13.3.1
Maternal exposure..................................................................................................69
13.3.2
Paternal exposure...................................................................................................70
14.
LIST OF REFERENCES.......................................................................................71
LIST OF TABLES
Table 1 
Assessment Schedule................................................................................26
Table 2 
Identity of study medication.....................................................................34
Table 3
Volume of blood to be drawn from each patient......................................56
LIST OF FIGURES
Figure 1
Study flow chart .......................................................................................25
LIST OF APPENDICES
Appendix A
Signatures (Not Applicable)
Appendix B
Additional Safety Information 
Appendix C
ADA/EASD Treatment Algorithm for Antihyperglycemic Therapy in T2DM


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol.
Abbreviation or 
special term
Explanation
ACS
Acute Coronary Syndrome
ACCEPT-D
Study acronym - Aspirin and Simvastatin Combination for Cardiovascular 
Events Prevention Trial in Diabetes
ACCF
American College of Cardiology Foundation
Adjudicated endpoint 
event
An event that fulfils study specific endpoint criteria as confirmed during 
adjudication by the independent CEC
ADA
American Diabetes Association
ADP
Adenosine diphosphate
AE
Adverse event (see definition in Section 6.4.1)
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
ARR
Absolute Risk Reduction
ASA
Acetylsalicylic acid/AspirinTM
ASCEND
Study acronym - A Study of Cardiovascular Events iN Diabetes
AST
Aspartate aminotransferase
AUC
Area under the curve
BARC
Bleeding Academic Research Consortium
bd
Twice daily dosing
BP
Blood Pressure
CABG
Coronary Artery Bypass Grafting 
CAD
Coronary Artery Disease
CAPRIE
Study acronym – Clopidogrel vs. Aspirin in Patients at Risk of Ischemic 
Events
CCU
Coronary Care Unit
CHD
Coronary Heart Disease
CHARISMA
Study acronym – Clopidogrel for High Atherothrombotic Risk and 
Ischaemic Stabilisation, Management and Avoidance
CEC
Clinical Endpoint Committee
CI
Confidence Interval


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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Abbreviation or 
special term
Explanation
CRF
Case Report Form (electronic/paper)
Cmax
Maximum free plasma concentration
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CV
Cardiovascular
CVD
Cardiovascular Disease
CYP450
Cytochrome P450
DAE
Discontinuation of Study medication due to Adverse Event
DCCT
Diabetes Control and Complication Trials
DM
Diabetes Mellitus
DMC
Data Monitoring Committee
EASD
European Association for the study of Diabetes
EC
Executive Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EQ-5D
Euro Quality of Life – 5 dimensions
EUCLID
Study Acronym -Examining Use of tiCagreLor In paD
FAS
Full Analysis Set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GI
Gastrointestinal
GMP
Good Manufacturing Practice
GPIIb/IIIa
Glycoprotein IIb/IIIa
GRand
AstraZeneca Global Randomisation system
HbA1c
Haemoglobin A1c
HECON
Health Economics
HR
Hazard Ratio
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IFCC
International Federation of Clinical Chemistry
ICU
Intensive Care Unit


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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Abbreviation or 
special term
Explanation
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IPA
Inhibition of platelet aggregation
IRB
Institutional Review Board
ITT
Intention-to-treat
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LBBB
Left bundle branch block
LDL-C
Low-density lipoprotein cholesterol
LMWH
Low-molecular-weight heparin
LTFU
Lost To Follow-Up
LVH
Left Ventricular Hypertrophy
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial Infarction
MRI
Magnetic Resonance Imaging
NSAID
Non Steroidal Anti-Inflammatory Drug
od
Once daily
PACD
Primary Analysis Censoring Date 
PAD
Peripheral Artery Disease
PCI
Percutaneous Coronary Intervention
PD
Pharmacodynamics
PEGASUS
Study Acronym – PrEvention with ticaGrelor of secondAry thrombotic 
events in high riSk patients with prior acUte coronary Syndrome 
PI
Principal Investigator 
PLATO
Study Acronym – a study of PLATelet inhibition and patient Outcomes
Potential endpoint event
An event submitted to the independent CEC for adjudication in relation to 
study specific endpoint criteria
PPI
Proton Pump Inhibitor
PRO
Patient Reported Outcomes
PTDV
Premature Treatment Discontinuation Visit
RRR
Relative Risk Reduction


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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Abbreviation or 
special term
Explanation
SAE
Serious adverse event (see definition in Section 6.4.2)
SCV
Study Closure Visit
SDV
Source Data Verification
SUSAR
Suspected Unexpected Serious Adverse Reactions
TBL
Total Bilirubin
TIA
Transient Ischaemic Attack
TIMI
Thrombolysis In Myocardial Infarction
T2DM
Type 2 Diabetes Mellitus
UFH
Unfractionated heparin
ULN
Upper Limit of Normal
URL
Upper Reference Limit
WBDC
Web Based Data Capture


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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1.
INTRODUCTION
1.1
Background
Cardiovascular disease (CVD), which includes coronary heart disease (CHD), cerebrovascular 
disease, and peripheral artery disease (PAD), is the leading cause of death in most developed 
countries. In the United States, CVD accounted for approximately 1 of every 3 deaths in 2009 
(Go et al 2013). The totality of evidence from basic research, clinical investigations, 
observational epidemiologic studies, and randomised clinical trials has provided strong 
support for the net benefits of acetylsalicylic acid (ASA)/AspirinTM in decreasing the risk of 
CVD events in a wide range of patients with established CHD (Antithrombotic Trialists’ 
Collaboration 2002). Diabetes substantially increases the risk of major cardiovascular (CV) 
complications in patients with and without established CVD (Preis et al 2009, Bhatt et al 
2010) such that most patients with diabetes die of CV diseases (Roger et al 2011).
1.1.1
Medical need
Diabetes mellitus (DM) is commonly associated with macrovascular complications, clinically 
resulting in premature CHD and increased risk of cerebrovascular disease (Vazzana et al 
2012). Patients with Type 2 DM (T2DM) have an increase in the risk of CHD (Schramm et al 
2008, Krempf et al 2010), and patients with DM but without previous myocardial infarction 
(MI) carry the same level of risk for subsequent acute coronary events as patients without DM 
but with previous MI (Haffner et al 1998). Several mechanisms contribute to this increased 
risk. There are common coexisting CV risk factors in patients with DM, eg, hypertension, 
dyslipidaemia, obesity and renal dysfunction, as well as a diabetic prothrombotic state, 
including endothelial dysfunction, impaired fibrinolysis, increased levels of coagulation 
factors and platelet hyperreactivity (Angiolillo and Suryadevara 2009).
1.1.2
Role of antiplatelet therapy in patients with DM
Based on meta-analyses, antiplatelet agents are recommended for patients with established 
CHD with or without DM (Antithrombotic Trialists’ Collaboration 2002, Antithrombotic 
Trialists' Collaboration 2009), while the benefits and risks of ASA for primary prevention of 
atherotrombotic events in patients with DM remains a matter of debate (Mehran et al 2011). In 
a recent meta-analysis (De Berardis et al 2009), patients with DM derived less benefit from 
ASA than expected. ASA compared to placebo did not achieve a statistically significant 
reduction in the risk of major CV events; in subgroup analysis ASA significantly reduced the 
risk of MI in men but not in women. The uncertainty on benefit risk relation using ASA in this 
patient population is also illustrated by inconsistent international guidelines and updates
without any major new data available (Buse et al 2007, Rydén et al 2007, Pignone et al 2010, 
Rydén et al 2013). Due to the remaining uncertainty regarding the benefit of ASA for primary 
prevention of CV events in patients with DM, two randomised controlled trials are currently 
evaluating ASA in patients with T2DM. The ongoing ACCEPT-D trial evaluates the safety 
and efficacy of ASA at the dose of 100 mg vs. no ASA in 5170 patients with DM (De 
Berardis et al 2007). The ASCEND trial evaluates the effect of ASA vs. placebo in more than 
15000 patients with DM and is expected to report in 2017.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
16
One of the hypotheses for the poor efficacy of ASA in patients with DM is that they have a 
rapid platelet turnover, and that administration of ASA once a day may not be sufficient to 
effectively inhibit thromboxane generation. This is supported by several small 
pharmacodynamic and pharmacokinetic studies (DiChiara et al 2007, Addad et al 2010, 
Capodanno et al 2011, Smith et al 2011, Spectre et al 2011, Henry et al 2011).
1.1.3
Product background
Ticagrelor is an orally active, reversibly binding, selective P2Y12 adenosine diphosphate 
(ADP) receptor antagonist that prevents ADP mediated platelet activation and aggregation. 
Ticagrelor 90 mg twice daily (bd) dosing has greater platelet inhibition than clopidogrel 
75 mg once daily (od). Unlike clopidogrel, ticagrelor does not require metabolic activation. As 
a result, ticagrelor provides greater and more consistent interpatient antiplatelet effect (Htun 
and Steinhubl 2013).
No dosing adjustment is needed in patients with renal impairment. No dose adjustment is 
needed for patients with mild hepatic impairment. Cmax and AUC for ticagrelor were 12% 
and 23% higher in patients with mild hepatic impairment compared to matched healthy 
subjects, respectively, however the Inhibition of Platelet Activation (IPA) effect of ticagrelor 
was similar between the two groups. Caution is advised in patients with moderate hepatic 
impairment because ticagrelor has not been studied in these patients. Use of ticagrelor is 
contraindicated in patients with severe hepatic impairment.
In the pivotal PLATO study of 18624 acute coronary syndrome (ACS) patients, ticagrelor was 
superior to clopidogrel in reducing the rate of the composite efficacy endpoint of CV death, 
MI, and stroke (RRR 16%, ARR 1.9%; HR 0.84 [95% CI 0.77, 0.92]; p=0.0003) for up to 
12 months of treatment. Ticagrelor reduced CV death (HR 0.79, 95% CI 0.69, 0.91; 
p= 0.0013) and all-cause mortality (HR 0.78, 95% CI .69, 0.89; nominal p =0.0003) compared 
with clopidogrel (Wallentin et al 2009). There was no difference as to PLATO defined major 
bleeding, but compared to clopidogrel, patients treated with ticagrelor experienced an increase 
in combined major and minor bleeding, and more major bleeding unrelated to procedures. 
Dyspnoea occurred more commonly with ticagrelor compared to clopidogrel. In a subgroup 
analysed with Holter monitoring, there was a higher incidence of ventricular pauses observed 
during the first week. Pauses were rarely associated with symptoms; the two treatment groups 
did not differ significantly with respect to the incidence of syncope or pacemaker 
implantation. The levels of creatinine and uric acid increased slightly more during the 
treatment period with ticagrelor than with clopidogrel (Wallentin et al 2009). In addition, 
pulmonary AEs like pneumonia less often resulted in death in the ticagrelor group (Storey et 
al 2013).
Further information regarding the background, pharmacological class, properties, and 
mechanism of action of ticagrelor can be found in the current Investigator’s Brochure (IB).


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
17
1.1.4
Ticagrelor in patients with DM
Ticagrelor effectively inhibits platelet function in patients with T2DM. In patients with T2DM 
with ongoing ACS, ticagrelor achieves a high platelet inhibition, and effectively treats high 
platelet reactivity (Alexopoulos et al 2013).
In the PLATO subgroup of patients with DM (4662 patients including 1036 patients on 
insulin), the benefits and risks of ticagrelor were consistent with the overall study results;
ticagrelor reduced the primary composite endpoint of CV death, MI or stroke
(HR 0.88, 95% C 0.76, 1.03) and all-cause mortality (HR 0.82, 95% CI 0.66–1.01) with no 
increase in total major bleeding. There was no heterogeneity between patients with or without 
ongoing insulin treatment (James et al 2010).
1.2
Research hypothesis
This study is designed to test the hypothesis that ticagrelor is superior to placebo, in 
prevention of major CV events, as measured by time to first event of the composite of CV 
death, MI, or stroke in patients with T2DM at high risk of CV events.
1.3
Rationale for conducting this study
Presently neither ASA, nor any ADP receptor antagonist, are indicated specifically for 
prevention of CV events in patients with DM without previous MI or stroke. However, 
diabetic patients with documented coronary artery stenosis are generally considered to be at 
high CV risk and antiplatelets should be used unless contraindicated or not tolerated (Rydén et 
al 2013, Smith et al 2011).
In the CAPRIE trial, patients with DM and previous MI, stroke or PAD were found to derive 
more benefit from clopidogrel than from ASA (CAPRIE Steering Committee 1996, Bhatt et al 
2002), indicating that potent antiplatelet therapy is useful among patients with DM. 
Although the CHARISMA trial failed to meet its primary study endpoint, patients with T2DM 
and previous MI/established CHD, stroke or PAD also suggested a reduction in CV events 
when antiplatelet therapy was intensified from ASA alone to ASA and clopidogrel (Bhatt et al 
2002, Bhatt et al 2006).
Ticagrelor has several potential advantages as an oral antiplatelet agent for prevention of CV 
events in patients with T2DM but without a medical history of previous MI or stroke. 
Ticagrelor requires no metabolic activation, providing a rapid onset and a consistent 
interpatient antiplatelet effect. It is a more powerful antiplatelet agent than both ASA and 
clopidogrel, and it inhibits erythrocyte adenosine uptake hypothesized to promote 
preconditioning, decrease infarct size and possibly prevent sudden cardiac death (Htun and 
Steinhubl 2013). The reversible binding of ticagrelor on the P2Y12 ADP receptor and the bd 
dosing would address concerns with ASA or thienopyridines of insufficient platelet inhibition 
related to rapid platelet turnover (Henry et al 2011). 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
18
Patients with T2DM and documented coronary artery atherosclerosis have a particularly high 
risk of major CV events and could potentially benefit from ticagrelor. 
The current study is designed to evaluate the effects of ticagrelor on MI, stroke, CV death and 
bleeding events in the long-term management of patients with T2DM at high risk of CV 
events.
1.4
Benefit/risk and ethical assessment
Currently, the benefit of ASA is well documented for secondary prevention following a CV 
event irrespective of diabetes status. However, evidence for use of ASA in prevention of CV 
events in patients with T2DM without prior MI is unclear as reflected by differences in 
recommendations given by treatment guidelines and current position papers (Buse et al 2007, 
Rydén et al 2007, Pignone et al 2010, Rydén et al 2013).
T2DM is associated with multiple factors promoting macrovascular and microvascular disease 
including increased atherothrombotic CHD risk, demonstrating an unmet need for well-
tolerated and effective antithrombotic treatment in patients with T2DM and at high risk of CV 
events, including those without prior MI or stroke. Among patients receiving local standard of 
care including lifestyle counselling and risk factor management, a placebo controlled study 
allowing individualized concomitant low dose ASA is warranted and justified.
More than 25,000 healthy subjects or patients have been exposed to ticagrelor in the 
completed phase I, II, III and IV studies and the overall conclusion based on these studies is 
that Ticagrelor reduces the risk of recurrent thrombotic events and is generally well tolerated. 
The key large, international Phase III studies were PLATO (D5130C05262) and PEGASUS 
(D5132C00001).
In PLATO, ticagrelor demonstrated superiority to clopidogrel in the prevention of thrombotic 
events (relative risk reduction [RRR] 16%, absolute risk reduction [ARR] 1.9%, number 
needed to treat [NNT] = 54) of the composite efficacy endpoint (CV death, MI, and stroke) 
over 12 months.  The difference in treatments was driven by CV death and MI with no 
difference on strokes.  Ticagrelor demonstrated a statistically significant RRR of 16% (ARR 
1.1%) for MI and a 21% RRR (ARR 1.1%) for CV death.  The treatment effect of ticagrelor 
over clopidogrel appeared consistent across multiple patient subgroups by demographic 
characteristics including weight, gender, medical history, concomitant therapy, and by final 
index event diagnosis (STEMI, NSTEMI, and UA).  The treatment effect was evident early 
(ARR 0.6% and RRR of 12% at 30 days), with a constant treatment effect over the entire 12 
month period, suggesting it is appropriate to treat for at least 12 months.
In PEGASUS, Both the 90 mg and 60 mg regimens of ticagrelor were superior to placebo, 
both in combination with ASA, in the prevention of thrombotic events (composite efficacy 
endpoint: CV death, MI and stroke), with a consistent treatment effect over the entire study 
period, yielding a 15% RRR and 1.2% ARR at 36 months for ticagrelor 90 mg and a 16% 
RRR and 1.3% ARR at 36 months for ticagrelor 60 mg.  Each of the components of the 
composite endpoint contributed to the treatment effect (CV death 13% and 17% RRR; MI 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
19
19% and 16% RRR; stroke 18% and 25% RRR; for ticagrelor 90 mg and 60 mg, respectively).  
This effect was consistent throughout the study, with duration of treatment up to 48 months 
(median 33 months).  The treatment effect was consistent across most pre-defined patient 
subgroups, including patients with diabetes mellitus; the differences observed in hazard ratio 
point estimates across subgroups were as expected given the large number of patient 
characteristics analysed.
The most commonly reported adverse events in ticagrelor-treated patients in both PLATO and 
PEGASUS were bleeding and dyspnoea.  Despite greater inhibition of platelet aggregation 
(IPA) with ticagrelor, results from the PLATO study showed that PLATO Major bleeding 
with ticagrelor did not differ from that with clopidogrel.  There were few fatal bleeding events 
in the study, 20 (0.2%) for ticagrelor and 23 (0.3%) for clopidogrel.  When minor bleeding 
was included, combined PLATO-defined Major and Minor bleeding events were significantly 
higher on ticagrelor than on clopidogrel.  Overall rates of TIMI-defined bleeding events did 
not differ significantly between ticagrelor and clopidogrel. Bleeding occurred with similar 
frequency in the ticagrelor and clopidogrel groups independent of DM status (James et al 
2010).
In PEGASUS, TIMI Major bleeding for ticagrelor was higher than for placebo, both on a 
background of ASA consistent in patients with or without diabetes.  No increased bleeding 
risk was seen for fatal bleeding and only a minor increase was observed for intracranial 
haemorrhage (ICH), as compared to placebo.  There were few fatal bleeding events in the 
study, 6 (0.1%) for ticagrelor 90 mg, 11 (0.3%) for ticagrelor 60 mg and 12 (0.3%) for 
placebo.  Therefore, the observed increased risk of TIMI Major bleeding with ticagrelor was 
primarily due to a higher frequency of Other TIMI Major bleeding (ie, excluding ICH and 
fatal bleeding) driven by events in the gastrointestinal System Organ Class.
Adverse events other than bleeding and dyspnoea observed across these 2 studies in adult 
patients given ticagrelor include small increases in serum creatinine, increased serum uric acid 
concentrations, gout, and higher event rates for terms related to dizziness, hypotension, and 
syncope on ticagrelor compared with placebo; however, these latter events were not associated 
with an increase in events of bradyarrhythmia.
Efficacy and safety will be monitored by an independent Data Monitoring Committee (DMC).
2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective of the study is to compare the effect of long-term treatment with 
ticagrelor bd vs. placebo for the prevention of major CV events (composite of CV death, MI 
or stroke) in patients with T2DM at high risk of CV events, but without a medical history of 
previous MI or stroke.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
20
The primary efficacy variable is time from randomisation to first occurrence of any event 
from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown
etiology).  
2.2
Secondary objectives
The secondary objectives of the study (presented in hierarchical order) are to compare the 
effect of long-term treatment with ticagrelor vs. placebo for:
1.
Prevention of CV death. The efficacy variable is time from randomisation to death of 
CV cause
2.
Prevention of MI. The efficacy variable is time from randomisation to first 
occurrence of MI
3.
Prevention of ischaemic stroke. The efficacy variable is time from randomisation to 
first occurrence of ischaemic stroke
4.
Prevention of all-cause death. The efficacy variable is time from randomisation to 
death of any cause.
2.3
Exploratory objectives
Other objectives are to explore other long-term treatment effects of ticagrelor vs. placebo on:

Prevention of the composite of all-cause death, MI or stroke. The efficacy variable 
is time from randomisation to first occurrence of any event from the composite of 
all- cause death, MI or stroke

Prevention of stroke. The efficacy variable is time from randomisation to first 
occurrence of stroke

Effect on irreversible harm events, the composite of all-cause mortality, MI, stroke, 
intracranial haemorrhage and fatal bleeding. The efficacy variable is time from 
randomisation to first occurrence of any event from the composite of all-cause 
mortality, MI, stroke, intracranial haemorrhage and fatal bleeding

Health care resource utilisation and utilities assessed by Euro Quality of Life-5 
Dimensions (EQ-5D) questionnaire to support health technology assessment and 
health economic modelling.
2.4
Safety objective
The overall safety objective of this study is to assess the safety and tolerability of long-term 
therapy with ticagrelor compared to placebo in patients with T2DM at high risk of CV events, 
with or without background low-dose ASA therapy. Bleeding events will be analyzed using 
the Thrombolysis in Myocardial Infarction Study Group (TIMI), PLATO (PLATelet 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
21
inhibition and patient Outcomes), and the Bleeding Academic Research Consortium (BARC) 
definitions. Specific focus will be on:

Time to first TIMI Major bleeding event (primary safety objective)

Time to first TIMI Major or Minor bleeding event

Time to first PLATO Major bleeding event

Time to permanent discontinuation of study medication due to any bleeding 
event.
Non-serious AEs of interest (ie, dyspnoea, renal impairment, bradyarrhythmia, gout, and 
pneumonia), adverse events that leads to permanent discontinuation of study medication 
(DAEs) and all serious adverse events (SAEs) will be reviewed within the context of the 
earlier safety experience with the drug.
3.
STUDY PLAN AND PROCEDURES
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures.
3.1
Overall study design and flow chart
This is an event-driven, randomised, double blind, placebo controlled, parallel group,
international multi-centre study to evaluate the effect of ticagrelor bd vs. placebo for 
prevention of major CV events in patients with T2DM at high risk of CV events, but without a
medical history of previous MI or stroke. Approximately 19000 patients at approximately
1200 study centres in about 40 countries will be randomised (1:1) to receive either ticagrelor 
bd or placebo bd. Patients will be managed consistent with local standard of care including
dietary and lifestyle advice (see Appendix C). Patients should be treated with low-dose ASA
75-150 mg od, unless contraindicated or not tolerated, in accordance with national and 
international clinical practice guidelines. The study design is shown in Figure 1. 
The study is designed and will be directed and published by an Executive Committee (EC [see 
Section 5.10.1]). The following additional committees will be selected: an independent Data 
Monitoring Committee (DMC) (see Section 5.10.4) an International Steering Committee (see 
Section 5.10.2) and a Clinical Endpoint Committee (CEC) (see Section 5.10.3).
Duration of treatment
The study is event-driven and 19000 randomised patients are estimated to be required in order 
to collect 1385 adjudicated primary endpoint events. The anticipated maximal duration of 
treatment with study medication for an individual patient is 58 months. However, the actual 
duration of the study will be based on accrual of the pre-determined number of adjudicated 
primary endpoint events, and therefore the final treatment time may be shorter or longer than 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
22
58 months. The expected minimum follow-up period is 29 months and the expected average 
follow-up period is 40 months, based on an enrolment period of 28 months. A study closure 
plan will be developed that accounts for the patient recruitment pattern and the event rate to 
reach the predetermined number of adjudicated primary endpoint events (1385).
As an interim analysis for efficacy is planned and safety is continuously monitored, the study 
may be terminated early if either a clear beneficial or harmful effect of the study treatment is 
detected during the DMC review. 
Visit 1 - Enrolment (7 ± 7 days prior to randomisation)
All potentially eligible patients will undergo an enrolment visit after the informed consent 
form has been signed. Eligibility criteria including relevant medical and surgical history will 
be reviewed. Demography, vital signs (pulse and BP), and weight and height will be assessed. 
Dietary and life-style advice will be given according to local diabetes treatment guidelines. 
Women of childbearing potential will be tested for pregnancy.  
Visit 2 - Randomisation (Day 0)
The enrolment visit (Visit 1) and randomisation visit (Visit 2) should preferably be separated 
by at least 7 days (mandatory for women of childbearing potential) and up to a maximum of 
14 days but can be combined into one single visit given that the patient has had sufficient time 
to consider study information, and that all information necessary to assess eligibility is 
available. 
Men and women ≥50 years of age with T2DM at high risk of CV events, but without a 
medical history of previous MI or stroke, fulfilling all of the inclusion criteria (see Section 
4.1) and none of the exclusion criteria (see Section 4.2) can be randomised into the study 
(there can be no exceptions to this rule). 
For patients randomised into the study, vital signs (pulse and BP) and an electrocardiogram 
(ECG) including assessment of heart rate will be obtained. Blood samples for local laboratory 
analysis (baseline) will be taken preferably after 6 hours fasting, if not already collected 
within previous 30 days (See Section 6.4.6). Detailed recording of all concomitant 
medications (baseline recording) will be made. (NB. Post randomisation (except for the study 
closure visit), detailed recording of concomitant medication only includes ASA and ADP 
receptor antagonist use and any medication given in association with SAEs and potential 
endpoint events, from one month prior to start date of the event until one month post start date 
of the event). Patients will complete the EQ-5D form. The urine pregnancy test will be 
repeated for women of childbearing potential. Dietary and lifestyle advice will be provided to 
the patients according to local diabetes treatment guidelines. Study medication will be 
dispensed. SAEs will be recorded.
Visit 3 and 4 - scheduled telephone contacts 7 and 30 days after randomisation
At visit 3 and 4 (telephone contacts) AEs of interest, SAEs, potential endpoint events 
including bleeding events (unexpected or of unanticipated quantity) and DAEs will be 
recorded. A compliance reminder regarding study medication will be given.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
23
Visit 5 - On-site visit 3 months after randomisation
At visit 5 (on-site visit), AEs of interest, SAEs, potential endpoint events including bleeding 
events (unexpected or of unanticipated quantity) and DAEs will be recorded. The patient will 
return study medication dispensed at the previous on-site visit (visit 2). New study medication 
will be dispensed and drug accountability of the returned medication will be checked. A 
compliance reminder regarding study medication will be given and dietary and lifestyle advice 
will be provided according to local diabetes treatment guidelines. 
Visit 6, 8, 10, 12, 14 etc. - On-site visits 6, 12, 18, 24, 30 months etc. after randomisation
During the scheduled on-site visits every 6 months after randomisation, AEs of interest, SAEs, 
potential endpoint events including bleeding events (unexpected or of unanticipated quantity) 
and DAEs will be recorded.  The patient will complete the EQ-5D form and return study 
medication dispensed at the previous on-site visit. New study medication will be dispensed 
and drug accountability of the returned medication will be checked. A compliance reminder 
regarding study medication will be given and dietary and lifestyle advice will be provided 
according to local diabetes treatment guidelines.
Visit 7, 9, 11, 13 etc. - Scheduled telephone contacts at 9, 15, 21, 27 months etc. after 
randomisation
During the scheduled phone contacts AEs of interest, SAEs, potential endpoint events 
including bleeding events (unexpected or of unanticipated quantity) and DAEs will be 
recorded. A compliance reminder regarding study medication will be given.
Unscheduled visits
An unscheduled visit may occur in-between scheduled visit eg, to follow-up on potential 
endpoint events. 
Study Closure Visit (SCV) 
When the predetermined number of adjudicated primary endpoint events is anticipated, the 
Primary Analysis Censoring Date (PACD) will be declared by the EC (see Section 12.2.4). All 
randomised patients (including any patients who have discontinued treatment with study 
medication and thus attended a Premature Treatment Discontinuation Visit [PTDV]) should 
return for their SCV as soon as possible but no later than 2 months (60 days) after the PACD. 
The actual time-window agreed for individual sites will depend on eg, the number of patients 
per site. 
AEs of interest, SAEs, potential endpoint events including bleeding events (unexpected or of 
unanticipated quantity) and DAEs will be recorded. The patient will complete the EQ-5D 
form and return study medication (if not returned at a PTDV). Vital signs (pulse and BP) will 
be assessed and detailed recording of all concomitant medication will be made. Drug 
accountability of the returned medication will be checked.
Study patients will be instructed to discontinue study medication but to continue low-dose 
ASA if clinically indicated and as judged by the investigator according to individual risk 


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
24
evaluation and local standard of care. Patients currently on open-label treatment with an ADP 
receptor antagonist (see Section 5.6.3.3), should continue on this treatment for as long as 
medically indicated and in accordance with local medical guidelines and standard of care.
All randomised patients, whether taking study medication or not, should be followed up at the 
end of the study at a minimum for CV events and survival. In cases where patients have 
withdrawn consent, survival based on publicly available sources will be investigated at the 
study end, in accordance with local regulations.
The study flow chart is shown in Figure 1 and the assessment schedule in Table 1.
Premature Treatment Discontinuation Visit (PTDV)
Patients who prematurely and permanently discontinue treatment with study medication 
should return for a PTDV, which will be done as soon as possible but no later than 15 days 
after prematurely discontinuing treatment with study medication. AEs of interest, SAEs, 
potential endpoint events including bleeding events (unexpected or of unanticipated quantity) 
and DAEs will be recorded. The patient will complete the EQ-5D form and return study 
medication dispensed at the previous on-site visit. Drug accountability of the returned 
medication will be checked and vital signs (pulse and BP) will be assessed. Dietary and 
lifestyle advice will be provided according to local diabetes treatment guidelines.
Patients who discontinue treatment prematurely still need to attend the Study Closure Visit 
(SCV).
For further details on procedures for discontinuing patients from study medication, refer to 
Section 5.8 and for the rare patient who must withdraw from study (study medication and visit 
assessments) refer to Section 5.9.


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
25
Figure 1
Study flow chart


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
26
Table 1
Assessment Schedule
Visit 
1
Enrol-
menta
Visit 
2
Rando-
misationa
Visit 
3
TCb
Visit 
4
TC
Visit 
5
Visit 
6
Visit 
7
TC
Visit 
8
Visit 
9, 11, 13 
etc.
TC
Visit 
10, 12, 14 
etc.
PTDVc
Study 
Closure 
Visit 
(SCV)d
Assessment
Day
– 7 
± 7 d
Day 
0
Day 7
± 3 d
Day 30
± 7 d
Day 90
± 7 d
Day 180
± 7 d
Day 270
± 14 d
Day 360
± 14 d
~15, 21, 
27 etc. 
monthse
± 14 d
~18, 24, 
30 etc. 
monthse
± 14 d
≤15 d 
after 
last 
dose
≤60 days 
after 
PACDf
Signed Informed Consent
√
Eligibility criteria
√
√
Medical and surgical history
√
Demographics
√
Vital signs (pulse, BP)
√
√
√
√
Weight and height
√
Urine Pregnancy testg
√
√
Local laboratory analysesh
√
Electrocardiogram (ECG) 
√
Health Economic Assessmenti
√
√
√
√
√
√
Dispense Study Medication
√
√
√
√
√
Return Study Medication
√
√
√
√
√
√
Drug accountability
√
√
√
√
√
√
Compliance reminder
√
√
√
√
√
√
√
√
Dietary and lifestyle advicej
√
√
√
√
√
√
√
Concomitant medicationsk
√
√
√
√
√
√
√
√
√
√
√
AEs of interest and DAEsl
√
√
√
√
√
√
√
√
√
√
Potential endpoint events 
including bleeding eventsl
√
√
√
√
√
√
√
√
√
√
Serious Adverse Eventsm 
√
√
√
√
√
√
√
√
√
√
√


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
27
a
The enrolment and randomisation visits should preferably be separated by at least 7 days (mandatory for women of childbearing potential) but can be 
combined into one single visit given that the patient has had sufficient time to consider study information, and that all information necessary to assess 
eligibility is available 
b
TC = Telephone Contact
c
The PTDV (Premature Treatment Discontinuation Visit) is conducted only for patients who prematurely and permanently stop study medication. PTDV 
patients should also perform SCV at the end of the study
d
The SCV may be a telephone contact in exceptional cases
e
1 month = 30 calendar days
f 
PACD = Primary Analysis Censoring Date (see Section 12.2.4)
g
Only applicable for women of childbearing potential (ie, those who are not chemically or surgically sterilised or post-menopause) 
h
For laboratory assessment details, see Section 6.4.6
i
To collect health care utilisation associated with hospitalisations and utilities assessed by Euro Quality of Life-5 dimensions (EQ-5D) to support health 
technology assessment and health economic modelling 
j
According to local treatment guidelines
k
Detailed recording of all concomitant medication at randomisation (baseline) and at the study closure visit. In between, detailed recording of 
concomitant medication only includes of ASA and ADP receptor antagonist use and any medication given in association with SAEs and potential 
endpoint events, from one month prior to start date of the event until one month post start date of the event.
l
AEs of interest, endpoint events and DAEs will be collected from randomisation throughout the study until and including the SCV
m
SAEs will be collected from the time of informed consent throughout the study until and including the SCV


Revised Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
28
3.2
Rationale for study design, doses and control groups
This is a randomised, double blind, placebo controlled parallel group event-driven study. The 
primary objective of the study is to compare the effect of long-term treatment with ticagrelor 
bd vs. placebo for the prevention of major CV events (composite of CV death, MI or stroke) 
in patients with T2DM at high risk of CV events, but without a medical history of previous MI 
or stroke. The selection of CV death and all-cause mortality as secondary endpoints in this 
study allows further exploration of the effects of ticagrelor on mortality in patients with 
T2DM at high CV risk.
The ticagrelor dose (90 mg bd) is the dose that was evaluated in PLATO, the pivotal phase III 
efficacy and safety study in patients with ACS. The dose in PLATO was based on pharmaco-
dynamics (PD), efficacy, and safety information gained from phase II studies, which 
demonstrated that the 90 mg dose was well tolerated and showed high and consistent levels of 
inhibition of platelet aggregation (IPA) with an acceptable safety profile.
The efficacy and safety of the 90 mg bd dose was established in PLATO, in which ticagrelor 
showed superiority to clopidogrel 75 mg od in reducing the rate of the composite efficacy 
endpoint of CV death, MI, or stroke after ACS events, with a RRR of 16%, without an 
increase in major bleeding, although non-CABG major bleeding did show greater rates with 
ticagrelor compared to clopidogrel. Ticagrelor at 90 mg bd was associated with a positive 
benefit: risk profile in patients with ACS. The benefit: risk profile in a subgroup of patients 
with DM was consistent with the overall results of PLATO.
Available data do not support a higher ticagrelor dose, as the proposed 90 mg bd dose is 
expected to generate near maximal inhibition of platelet aggregation. Neither do available data 
support a lower dose, since a lower ticagrelor dose would result in a 2-3 times increase in 
variability in IPA and substantially lower mean trough IPA, similar to that achieved with 
clopidogrel.
A placebo controlled study on a background of low-dose ASA, unless contraindicated or not 
tolerated, has been chosen since low-dose ASA is standard therapy for prevention of 
atherothrombotic events in diabetic patients with coronary artery disease (Rydén et al 2013, 
Smith et al 2011).
To explore effects on quality of life, EQ-5D will be used. It has been extensively used within 
CV research to assess patient health related quality of life in trials of new treatments, and has 
showed both high validity and reliability (Brooks 1996).
In PEGASUS, both the 90 mg and 60 mg regimens of ticagrelor were superior to placebo in 
the prevention of thrombotic CV events (composite endpoint: CV death, MI and stroke) with a 
consistent treatment effect over the entire study period, yielding a 15% RRR for 90 mg and
16% RRR for 60 mg. Although the efficacy profiles of ticagrelor 90 mg and 60 mg were 
similar to each other, there is evidence that the lower dose has a better tolerability and safety 
profile in relation to dyspnoea and risk of bleeding, and leads to fewer discontinuations from 


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study drug. No patient subgroups were identified as having a different efficacy and safety 
profile to that of the overall study population.
The critical endpoints selected for the benefit-risk assessment were all-cause mortality, MI,
and stroke, which are considered against the risks of fatal bleeding and intracranial 
haemorrhage, all describing irreversible harm events. For the composite endpoints 
representing death or irreversible harm, both ticagrelor doses clearly showed a positive 
benefit-risk balance, with more events of death or irreversible harm prevented than caused. 
For the ticagrelor 60 mg group, all-cause mortality, CV death, MI and stroke all contributed to 
the benefit. For the ticagrelor 90 mg group, CV death, MI and stroke all contributed to the 
benefit, while all-cause mortality was neutral.
In PEGASUS, the efficacy profiles of ticagrelor 90 mg and 60 mg administered with low-dose 
ASA, were similar to each other.  The lower dose had a better tolerability profile with regard 
to dyspnoea, less risk of bleeding, and lead to fewer discontinuations from study drug. Patients 
with diabetes did not have a different efficacy and safety profile to that of the overall study 
population. Hence, in order to use the lowest effective dose and taking the overall benefit-risk 
into consideration the dose in THEMIS will be ticagrelor 60 mg bd.
4.
PATIENT SELECTION CRITERIA
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
4.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of informed consent prior to any study specific procedures 
2.
Men or women ≥50 years of age
3.
Diagnosed with T2DM defined by ongoing glucose lowering drug treatment 
prescribed by a physician for treatment of T2DM since at least 6 months prior to 
Visit 1
4.
At high risk of CV events, defined as history of percutaneous coronary intervention 
or coronary artery bypass graft or angiographic evidence of ≥ 50% lumen stenosis 
of at least 1 coronary artery.


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4.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Previous MI** (with the exception of definite secondary MI [eg, due to coronary 
revascularization procedure, profound hypotension, hypertensive emergency, 
tachycardia, or profound anaemia])
2.
Previous stroke (transient ischaemic attack [TIA] is not included in the stroke 
definition) 
3.
Planned use of ADP receptor antagonists (eg, clopidogrel, ticlopidine, prasugrel), 
dipyridamole, or cilostazol. Planned use of ASA treatment at doses >150 mg od
4.
Planned coronary, cerebrovascular, or peripheral arterial revascularization
5.
Anticipated concomitant oral or intravenous therapy with strong cytochrome P450 
3A4 (CYP3A4) inhibitors or CYP3A4 substrates with narrow therapeutic indices 
that cannot be stopped for the course of the study:

Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, 
clarithromycin (but not erythromycin or azithromycin), nefazadone, ritonavir, 
saquinavir, nelfinavir, indinavir, atanazavir

CYP3A4 substrates with narrow therapeutic index: quinidine, simvastatin at doses >40 
mg daily or lovastatin at doses >40 mg daily
6.
Need for chronic oral anticoagulant therapy or chronic low-molecular-weight 
heparin (at venous thrombosis treatment not prophylaxis doses)
7.
Patients with known bleeding diathesis or coagulation disorder, or with 
uncontrolled hypertension (defined as a systolic BP ≥180 mmHg and/or diastolic 
BP ≥100 mmHg) 
8.
History of previous intracerebral bleed at any time, gastrointestinal (GI) bleed 
within the past 6 months prior to randomisation, or major surgery within 30 days 
prior to randomisation
9.
Increased risk of bradycardic events (eg, known sick sinus syndrome, second or 
third degree AV block or previous documented syncope suspected to be due to 
bradycardia) unless treated with a pacemaker 
10.
Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy)
11.
Renal failure requiring dialysis
                                                
* Previous MI herein refers to a documented hospitalisation with a final diagnosis of spontaneous MI


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12.
Women of child-bearing potential (ie, those who are not chemically or surgically 
sterilised or who are not post-menopause) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator OR women who have a positive pregnancy test at enrolment or 
randomisation OR women who are breast-feeding
13.
Inability of the patient to understand and/or comply with study procedures and/or 
follow up, in the opinion of the investigator, OR any conditions that, in the opinion 
of the investigator, may render the patient unable to complete the study 
14.
Any condition which in the opinion of the investigator would make it unsafe or 
unsuitable for the patient to participate in this study (eg, long-term concomitant 
treatment with non-steroidal anti-inflammatory drugs [NSAIDs]), or any condition 
outside the atherothrombotic study area with a life expectancy of less than 2 years 
based on investigator’s judgement
15.
Participation in another clinical study with an investigational product within 
28 days prior to enrolment or previous randomisation to an investigational product 
in another ongoing clinical study. Participation in any previous study with 
ticagrelor. Previous randomisation in the present study
16.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study centre).
Procedures for withdrawal of incorrectly enrolled patients see Section 5.3.
5.
STUDY CONDUCT
5.1
Restrictions during the study
Patients should be fasting (at least 6 hours) before blood sampling for baseline laboratory 
analysis.
Patients should not donate blood or bone marrow at any time during the study.
Restrictions regarding concomitant medications are described in Section 5.6.
5.2
Patient enrolment and randomisation
The Principal Investigator or delegate will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed
2.
Determine patient eligibility (see Sections 4.1 and 4.2)


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3.
Assign (using the Interactive Voice Response System/Interactive Web Response 
System [IVRS/IWRS], see Section 5.2.1) potential patients a unique enrolment 
number, beginning with ‘E#’
4.
Assign enrolled patient a unique randomisation code (patient number) in 
IVRS/IWRS.
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Patients can only be randomised into the study once.
5.2.1
Procedures for randomisation
The randomisation codes will be computer generated by AstraZeneca R&D using the AZ 
Global Randomisation system (GRand) and loaded into the IVRS/IWRS database. 
Randomisation codes will be generated in blocks to ensure approximate balance (1:1) between 
the two treatment arms. Randomisation will be done via IVRS/IWRS at Visit 2. The 
IVRS/IWRS will allocate randomisation codes sequentially within each centre as patients 
become eligible for randomisation. Once a block of randomisation codes is exhausted, the 
next available block will be allocated by the IVRS/IWRS to the centre. For each patient 
randomised the IVRS/IWRS will provide the investigator with a unique Kit ID number 
matching the treatment arm assigned to the patient. Following randomisation, the first dose of 
study medication will be administered to the patient as soon as possible.
At randomisation and every subsequent dispensing visit the patient should always be provided 
medication with the Kit ID(s) allocated by the IVRS/IWRS. If a patient receives the incorrect 
randomised treatment at any time during the study, this must be corrected as soon as 
discovered.
5.3
Procedures for handling patients incorrectly enrolled or
randomised
Patients who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled or randomised. There can be no exceptions to this rule.
The following steps should be taken in the event that a patient, who does not meet 
inclusion/exclusion criteria, is found to have been inadvertently randomised in an AstraZeneca 
study:
(a)
The investigator or monitor should inform the AstraZeneca study team physician 
immediately. Ensuring patient safety must always be the number one priority
(b)
Study treatment must be discontinued in all cases where continued treatment is 
deemed to pose a safety risk to the patient. After a discussion between the study 
team physician and investigator, a decision may be reached that the patient should 
discontinue study medication. The rationale for discontinuing study medication 
must be clearly documented. The patient should remain in the study for follow up in 
accordance with defined study procedures including follow-up on endpoints 
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Study Code D513BC00001
Edition Number 5
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(c)
In those cases where continuation of study therapy is judged not to present a 
concern related to safety and disease management, the rationale for continuing 
study therapy must be clearly documented. The patient should continue follow up in 
accordance with defined study procedures.
5.4
Blinding and procedures for unblinding the study 
5.4.1
Methods for ensuring blinding
The treatment allocation in this study will be double blind. Ticagrelor tablets and matching 
ticagrelor placebo tablets will be provided (see Section 5.5.1), identical in appearance and 
with the same number, size, and packaging of tablets. Each pack will be labelled with a unique 
pack ID number that will be used to assign the treatment to the patient but will not indicate 
treatment allocation to the investigator.
No member of the extended study team at AstraZeneca, the EC, International Steering 
Committee, or the CEC, personnel at investigational centres or any CRO handling data will 
have access to the randomisation scheme during the conduct of the study, with the exception 
of the Supply Chain Study Management department, and the Patient Safety department at 
AstraZeneca.
A DMC will have access to the individual treatment codes and will be able to merge these 
with the collected study data while the study is ongoing (see Section 12.4.2). The DMC will 
review safety data on a periodic basis, including the incidence of AEs, and conduct safety 
assessments to ensure the ongoing safety of study patients. The DMC responsibilities, 
authorities, and procedures will be documented in a DMC charter. The personnel involved in 
the clinical study at AstraZeneca will remain blinded to these analyses and will have no 
knowledge of the results presented to the DMC.
5.4.2
Methods for unblinding the study
Individual treatment codes, indicating the treatment allocation for each randomised patient, 
will be available to the investigator(s) or pharmacists from the IVRS/IWRS. Routines for this 
will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment. The AstraZeneca physician or 
delegate should be consulted whenever possible prior to the investigator breaking the blind. 
The investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to the patient to the AstraZeneca staff. The number of individuals at the study 
site who become aware of the treatment status should be kept to an absolute minimum 
including keeping the patient blinded if possible. Treatment with study medication should be 
continued if considered appropriate. 
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to a study drug and that potentially require expedited 
reporting to regulatory authorities. Treatment codes will not be broken for the planned 


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analyses of data until all decisions on the evaluability of the data from each individual patient 
have been made and documented.
5.5
Treatments
5.5.1
Identity of study medication(s)
Table 2
Identity of study medication
Study Medication
Dosage form and strength
Manufacturer
Ticagrelor 90 mg
Plain, round, yellow, film-
coated tablet, 90 mg
AstraZeneca
Ticagrelor 90 mg placebo
Plain, round, yellow, film-
coated tablet, containing zero 
active therapy (identical in 
appearance to active)
AstraZeneca
Ticagrelor 60 mg
Plain, round, white, film-coated 
tablet, 60 mg
AstraZeneca
Ticagrelor 60 mg placebo
Plain, round, white, film-coated
tablet, containing zero active 
therapy (identical in appearance 
to active)
AstraZeneca
5.5.2
Doses and treatment regimens
At the randomisation visit eligible patients will be randomly assigned to 1 of 2 treatments (see 
Table 2):

•
Ticagrelor 60 mg, one tablet bd given orally

•
Ticagrelor 60 mg placebo, one tablet bd given orally
Until the new ticagrelor 60 mg bd study medication with matching placebo is available at the 
individual study site, ticagrelor 90 mg, one tablet bd given orally, or corresponding placebo, 
will be used.
Randomisation and treatment pack assignment will be managed via the IVRS/IWRS and the 
first dose of study medication should be taken as soon as possible after randomisation. 
Subsequent maintenance doses should be taken morning and evening, at approximately 
12-hour intervals, during the treatment period. 
Study medication should be swallowed whole with water. Study medication can be taken with 
or without food. Study medication should not be altered (eg, crushed, put in another vehicle) 
and should not be given by nasogastric tube or other routes.


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5.5.2.1
Dose Switch strategy
When the new study medication comprising of ticagrelor 60 mg or corresponding placebo is 
locally available at study site, patients already randomized to ticagrelor 90 mg or 
corresponding placebo will be switched to the new study medication at the next planned visit.
The dose switch must occur on an on-site visit. If the next planned visit is a scheduled 
telephone contact (e.g. Visit 3, 4, 7, 9, 11, 13 etc.), the patient must be re-scheduled to come in 
for an on-site visit. By following this strategy all patients at a study site that currently are 
treated with ticagrelor 90 mg or corresponding placebo, will be switched to the new 
medication (ticagrelor 60 mg or corresponding placebo) within a 3 months period counted 
from when the new study medication is available at site.
At the discretion of the PI, an additional visit can be scheduled to allow for a dose switch 
ahead of next planned visit.
5.5.3
Development of indication for ADP receptor antagonist during study
If a patient randomised to study medication develops an indication for use of an ADP receptor 
antagonist according to medical guidelines (eg, an ACS or PCI), selection of the appropriate 
agent for individual patients is at the discretion of the investigator or treating physician and 
should be made in accordance with local medical guidelines and standard of care.
The patient must temporarily stop study medication during the open-label therapy with the 
ADP receptor antagonist. Patients should return to randomised treatment (ticagrelor or 
placebo) when there is no longer an indication for ADP receptor antagonist therapy according 
to medical guidelines.
5.5.4
Duration of treatment
The study is event-driven and 19000 randomised patients are estimated to be required in order 
to collect 1385 adjudicated primary endpoint events. The anticipated maximal duration of 
treatment with study medication for an individual patient is 58 months. However, the actual 
duration of the study will be based on accrual of the pre-determined number of adjudicated 
primary endpoint events, and therefore the final treatment time may be shorter or longer than 
58 months. The expected minimum follow-up period is 29 months and the expected average 
follow-up period is 40 months, based on an enrolment period of 28 months. A study closure 
plan will be developed that accounts for the patient recruitment pattern and the event rate to 
reach the predetermined number of adjudicated primary endpoint events (1385).
As safety is continuously monitored, the study may be terminated early if either a clear 
beneficial or harmful effect of the study treatment is detected during the DMC review.
5.5.5
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.


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5.5.6
Storage
All study drugs should be kept in a secure place under appropriate storage conditions and in 
the original container. The study medication label and the IB specify appropriate storage.
5.6
Concomitant and post-study treatments
5.6.1
Recording of concomitant medication
Detailed recording of all concomitant medications (baseline recording) will be made only at 
the randomisation visit (visit 2) and at the study closure visit. Detailed recording of ASA and 
ADP receptor antagonist use will continue from randomisation throughout the study. In 
addition, concomitant medication will be recorded in association with SAEs and potential 
endpoint events from one month prior to start date of the event until one month post start date 
of the event. 
5.6.2
Anti-diabetic treatment and risk factor management
All patients will receive dietary and life-style advice during the study (including 
recommendation on smoking cessation when applicable), in accordance with local diabetes 
treatment guidelines. Anti-diabetic medication and medications to treat concomitant risk 
factors (eg, dyslipidemia and hypertension) should be prescribed, aiming at target levels for
glycemic control and risk factor management, according to guidelines.
5.6.3
Oral antiplatelet therapies
Patients requiring antiplatelet therapy other than low-dose ASA will be excluded at study 
entry.
5.6.3.1
Low Dose ASA (defined as 75 to 150 mg od)
In accordance with national and international clinical practice guidelines, all patients should 
take open label ASA at a dose of 75 – 150 mg once daily throughout the study, unless 
contraindicated or not tolerated. The patient will be responsible for the ASA supply 
throughout the study. 
5.6.3.2
High Dose ASA (>150 mg od)
The concomitant use of ASA in any dose >150 mg od during the study is permitted only as a 
single loading dose, regardless of circumstances (ie, prior MI, ACS, stroke, stent placement of 
any kind, etc). Long-term maintenance dose of ASA >150 mg od is not permitted in 
combination with study medication. 
5.6.3.3
ADP receptor antagonists 
Planned concomitant treatment with any of other ADP receptor antagonists is not allowed in 
the study.  Patients who develop an indication for treatment with an ADP-receptor antagonist 
during the study may be treated open-label at the discretion of the investigator, as described in 
Section 5.5.3. Blinded study medication must then be discontinued but should be resumed 
when open-label treatment with the ADP receptor antagonist is stopped. 


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5.6.3.4
Dipyridamole
Planned concomitant chronic treatment with dipyridamole is not allowed in the study.  If open 
label treatment with dipyridamole, whether or not in combination with ASA, is considered 
essential during the study, blinded study medication must be discontinued but should be 
resumed when open-label treatment with dipyridamole is stopped. 
5.6.3.5
Approved PDE3 inhibitors for claudication (eg, cilostazol)
Planned concomitant treatment with any approved PDE3 inhibitor (ie, cilostazol) is not 
allowed during the study.  If open label treatment with a PDE3 inhibitor, whether or not in 
combination with ASA, is considered essential during the study, blinded study medication 
must be discontinued but should be resumed when open-label treatment with the PDE3 
inhibitor is stopped.
5.6.4
Parenteral antiplatelet therapies
5.6.4.1
GPIIb/IIIa receptor antagonists
Short-term treatment (ie, up to 7 days) with GPIIb/IIIa receptor antagonists is allowed during 
the study. 
5.6.5
Oral anticoagulants 
Concomitant treatment with oral anticoagulant drugs (ie, vitamin K antagonists, direct 
thrombin inhibitors, factor X inhibitors) is not permitted during the study.  If treatment with 
oral anticoagulant drugs is considered essential during the study, study medication must be 
discontinued, but should be resumed if oral anticoagulant therapy is stopped.  Patients should 
continue to be followed as defined in Section 5.8.1.
5.6.6
Parenteral anticoagulants
Short-term treatment (ie, up to 7 days) with approved parenteral anticoagulants (eg. 
unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), bivalirudin, 
fondaparinux) is allowed.  However, long-term treatment with LMWH or fondaparinux in 
outpatients (at venous thrombosis treatment or atrial fibrillation doses) in combination with 
study medication is not allowed.  Concomitant treatment with venous thrombosis prophylaxis 
doses is allowed.  If long-term treatment with parenteral anticoagulant drugs at therapeutic 
doses is considered essential during the study, study medication must be discontinued, but 
should be resumed if parenteral anticoagulant therapy is stopped.
5.6.7
Fibrinolytics
Clinical experience with fibrinolytics in combination with ticagrelor is limited at this time and 
caution should be used.  If a patient is to be treated with fibrinolytic therapy, study medication 
should be stopped and restarted no earlier than 24 hours after completion of fibrinolytic 
therapy and when the risk of bleeding is deemed low in the judgment of the investigator.


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5.6.8
Non-steroidal anti-inflammatory drugs (NSAIDs)
Clinical experience with NSAIDs in combination with ticagrelor is limited at this time.  
Treatment with NSAIDs is allowed during the study at the investigator’s discretion.  However, 
chronic daily dosing with non-selective NSAIDs (eg, patients with rheumatoid arthritis) may 
increase the potential for gastrointestinal bleeding, so either alternative therapy or concomitant 
acid suppression therapy is recommended.  Treatment with selective cycloxygenase-2 
inhibitors is permitted, although use is cautioned. When pain management is needed, 
acetaminophen/paracetamol is preferred.
5.6.9
Digoxin and other p-glycoprotein interactions
Ticagrelor modestly increases digoxin levels.  Therefore digoxin levels should be monitored 
closely following initiation of study medication and with any change in study medication.  
Other p-glycoprotein substrates may be expected to have similar changes in pharmacokinetics. 
Additional details can be found in the IB.
5.6.10
CYP450 interactions
5.6.10.1
CYP3A4 inhibitors
Strong inhibitors of CYP3A4 enzyme (eg, ketoconazole, itraconazole, voriconazole, 
telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, 
saquinavir, nelfinavir, indinavir, atazanavir, or over 1 litre daily of grapefruit juice) should not 
be co-administered with ticagrelor, as plasma levels of ticagrelor would be substantially 
increased. 
5.6.10.2
CYP3A4 substrates or inducers
Concomitant therapy with simvastatin or lovastatin at doses higher than 40 mg daily is not 
permitted since administration with ticagrelor will result in higher serum concentrations and 
may put patients receiving more than 40 mg per day of simvastatin or lovastatin at increased 
risk of statin-related adverse effects.  There are no restrictions to other statin therapies (ie, 
doses of simvastatin or lovastatin ≤ 40 mg daily or any approved dose of any other statin is 
permitted).  Investigators are advised to check lipid levels and adjust statin dosages per local 
practice and appropriate guidelines. Standard monitoring of patients for possible statin-
associated myopathy should be conducted.
Co-administration of ticagrelor with strong inducers of CYP3A4 also should be avoided (eg, 
rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, dexamethsaone) as 
plasma levels of ticagrelor could be reduced.
Discontinuation of study medication is up to the judgment of the investigator.  If continued 
antiplatelet medication is judged necessary, there may be a need for extra caution regarding 
bleeding tendency. 


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5.6.11
Surgery
It is recommended that cardiac surgery and major non-cardiac surgery that in the opinion of 
the investigator or treating physician poses a risk for clinically major bleeding should not be 
performed until at least 5 days after stopping study medication to avoid excessive bleeding.  
However, local treatment guidelines should be followed.  There is a trade-off between 
stopping study medication too early and risking thrombotic events vs. continuing treatment 
too close to surgery and risking haemorrhage. Thus it is also recommended that study 
medication should not be discontinued for significantly longer than 5 days aiming to minimise 
the risk of thrombotic complications while off study medication.
After surgery, study medications should be restarted when the risk of bleeding is deemed low 
in the judgment of the investigator or treating physician.
5.6.12
Other surgery and invasive non-cardiovascular procedures
For other surgery or other invasive procedures, study medication may be continued or 
interrupted temporarily at the discretion of the investigator or treating physician. As with all 
other surgeries, investigators should collect and record all bleeding events occurring during 
the surgery or invasive procedurals. After the surgery or procedure, study medications should 
be restarted (if interrupted) as soon as possible. 
Other medication, which is considered necessary for the patient’s safety and wellbeing, may 
be given at the discretion of the investigator or treating physician.
5.7
Treatment compliance
The administration of study medication should be recorded in the eCRF. All stops of study 
medication prescribed by the investigator or treating physician should be recorded. In 
addition, any non-prescribed temporary stops (>1 week) of study medication should be 
recorded.
Missed doses of ticagrelor or placebo blinded study medication should not be compensated for 
(ie, if a dose is missed the next regularly scheduled dose should be taken and should not be 
doubled). 
5.7.1
Accountability
The study medication provided for this study will be used only as directed in the study 
protocol.
The study personnel will account for all study medication dispensed to and returned from the 
patient.
Patients will be asked to bring all unused study medication and empty packages to the 
investigational centre at each on-site visit. The investigator or delegate will enter the amount 
of returned tablets in the eCRF and make an assessment regarding patient treatment 


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compliance. Any patient found to be noncompliant would be counselled on the importance of 
taking their study medication as prescribed.
Any study medication deliberately or accidentally destroyed must be recorded. Any 
discrepancy between dispensed and returned study medication should be explained.
The investigator will retain the returned medication until the study monitor or delegate 
collects it, along with any medication not dispensed. The monitor is responsible for 
confirming the investigator or delegate has recorded the quantities of returned and unused 
tablets at a patient level before medication is returned to the sponsor and/or destroyed. The 
study monitor or delegate will advise on the appropriate method for destruction of unused 
study medication. Destruction of study medication must only be conducted by an authorised 
centre.
5.8
Discontinuation of study medication
Patients should be discontinued from study medication in the following situations:
5.8.1
Temporary discontinuation from study medication

Severe thrombocytopenia (platelet count < 50,000/uL). Patients may restart study 
medication once the severe thrombocytopenia resolves and if considered 
appropriate by the investigator

Surgery or procedures associated with major bleeding, see Section 5.6.11

Major bleeding, see Section 6.4.5.2

Need of treatment with prohibited concomitant medications, see Section 5.6.
For other surgery or other invasive procedures, study medication may be continued or 
interrupted temporarily at the discretion of the investigator, see Section 5.6.12.
5.8.2
Permanent discontinuation from study medication

Patient decision: The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Investigator’s decision, including but not limited to these examples:

Incorrectly randomised patient in whom the inclusion/exclusion criteria 
violation would put the patient at undue risk

AE for which the investigator thinks continued treatment may put the patient at 
undue risk

Severe non-compliance to study protocol 

Pregnancy.


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Each permanent discontinuation from study medication should be communicated to the study 
team. For decisions around permanent discontinuation the Study Physician can be consulted as 
appropriate. NB. Discontinuation of study medication does not mean discontinuation of 
follow-up or termination of study participation. Study assessments or telephone follow-up 
should be continued in all cases if possible, see Sections 5.8.3 and Section 5.9.
5.8.3
Procedures for permanent discontinuation of a patient from study medication 
Patients permanently discontinuing study medication should be given conventional therapy, if 
applicable, and should continue the regular visits (see Section 5.8.3.1). 
A patient that decides to discontinue study medication will always be asked about the 
reason(s) for their desire to discontinue study medication and the presence of AEs (if any). 
These data will be ascertained and documented by the investigator and recorded in the eCRF 
as appropriate. AEs will be followed up (see Sections 6.4.3 and 6.4.4); and the patient should 
return all study medications.
It is essential to collect as much data as possible for all patients throughout the study and 
especially all potential endpoint events. Discontinuation from study medication is not the 
same as complete withdrawal from the study (withdrawal of consent), which has a direct 
impact on the potential validity of all study data, and should be avoided wherever 
possible.
5.8.3.1
Patient agrees to undergo the Premature Treatment Discontinuation Visit and 
then continue in-person study visits
The patient agrees to undergo the Premature Treatment Discontinuation Visit (PTDV) and 
then continue in-person study visits according to plan. This is the preferred option and patients 
who discontinue study medication will always be asked if they agree to this approach. If 
agreed, as above, the patient will undergo their PTDV within 15 days after the study 
medication is stopped. The patient will continue attending subsequent study visits according to 
schedule (Table 1) until PACD is declared by the EC. The patient will then return for their 
SCV as soon as feasible but no later than 60 days after the PACD has been declared. It is 
essential that the patients attend the SCV in person whenever possible.  
5.8.3.2
Patient refuses to continue in-person study visits but agrees to undergo 
modified follow-up 
If the patient refuses to continue in-person study visits, but agrees to undergo modified follow 
up, the in-person PTDV visit should be done within 15 days after the study medication is 
stopped. The subsequent visits until the end of study date will be done as modified follow-ups 
(eg, regular telephone contacts, a contact at study closure, or other means) in order to ascertain 
whether any endpoints or safety events had occurred. Such a patient has not withdrawn his/her 
consent or withdrawn from the study.
5.8.3.3
Patient refuses any form of follow-up
If the patient refuses any form of follow-up, he/she officially withdraws from the study and 
withdraws consent. This decision must be documented (see Section 5.9). At the end of the 


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study, vital status on all such patients will be collected from publicly available sources, in 
accordance with local regulations. 
5.8.3.4
Restart of study medication
Whenever possible, restart of randomised study medication should be encouraged, even if a 
PTDV was previously completed. 
5.8.4
Study Closure Visit
All randomised patients should return for their SCV as soon as possible, but no later than 2 
months (60 days), after the PACD is declared by the EC (see Section 12.2.4). The actual time-
window will depend on eg the number of patients per site. 
If a patient is unable to attend the SCV in person, telephone contact should be made to 
ascertain endpoint and AE information. At the SCV physicians caring for the patient will 
decide which medication the patient should receive as part of his/her ongoing clinical care.
5.9
Withdrawal from study (study medication and assessments)
Patients are at any time free to withdraw from the study (ie, discontinue study medication 
permanently and withdraw from visit assessments), without prejudice to further treatment 
(withdrawal of consent). Withdrawal of consent from the study must be ascertained and 
documented by the investigator and recorded in the eCRF as well as in the Informed Consent 
Form (ICF) addendum – Withdrawal of consent. The ICF addendum should be signed and 
dated by both the patient and the investigator, if possible. Such patients will always be asked 
about the reason(s) and the presence of any AEs. The reason for permanent discontinuation of 
treatment with the study medication and the date of the last intake of the study medication 
must be documented in the eCRF. 
N.B. Patients permanently discontinuing from study medication should be given 
conventional therapy, if applicable, and should always be asked to continue to attend 
protocol visits as described in Section 5.8.3. 
If the patient denies any additional protocol follow-up and officially withdraws consent from 
the study one of the alternatives a) to c) should be followed:
(a)
At the time of discontinuation of treatment and withdrawal of consent from 
continued assessment the patient should, if possible, undergo the PTDV. The patient 
should return all study medication 
(b)
If the patient does not agree to this option (which must be documented), a modified 
PTDV (eg, a telephone contact) should be arranged. The approach taken should be 
documented. The patient should return all study medication 
(c)
If the patient does not agree to a) or b) this must be documented in the patient’s 
medical record. The patient should return all study medication. 


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To ensure validity of study data, it is very important to collect as much data as possible 
throughout the study and especially vital status (dead or alive) at the SCV. The investigator or 
delegate will therefore attempt to collect information on all patients’ vital status from publicly 
available sources at the SCV, in accordance with local regulations, even if informed consent 
has been withdrawn completely.
5.10
Study committees
5.10.1
Executive Committee (EC)
The EC will be responsible for the overall design, including the development of the protocol 
and any protocol amendments, supervision, interpretation and reporting (presentations at 
international congresses and publications in peer reviewed journals) of the study. The EC will 
make recommendations to AstraZeneca with regard to early stopping or modifications of the 
study based on the information received from the DMC. The EC will be comprised of 
designated international academic leaders and non-voting members of the Sponsor, and will 
operate under a separate charter.
To achieve an appropriate subgroup final distribution ratio, the Executive Committee will 
monitor particular subgroups and primary event rates and may cap enrolment to a particular 
subgroup based on the overall distribution and event rates. In particular, the enrolment of 
patients without ASA background treatment will be capped if it is considered inappropriately 
high or more than 5%.
5.10.2
International Steering Committee
The International Steering Committee is comprised of national lead investigators from each 
country where the study is conducted, and of relevant experts, and will be supervised by the 
EC. Members of the committee will be responsible for providing clinical guidance on study 
implementation and conduct in their respective country. 
5.10.3
Clinical Endpoint Committee (CEC)
An independent CEC will be appointed and will adjudicate all potential endpoint events. The 
committee members will not have access to individual treatment codes for any patient or 
clinical efficacy and safety event. The precise responsibilities and procedures applicable for 
the CEC will be detailed in a separate CEC charter.
5.10.4
Data Monitoring Committee (DMC)
An independent DMC will be appointed and will report to the EC. 
The DMC will be responsible for safeguarding the interests of the patients in the outcome 
study by assessing the safety of the intervention during the study, and for reviewing the 
overall conduct of the clinical study. The DMC will have access to the individual treatment 
codes and will be able to merge these with the collected study data while the study is ongoing. 
The EC and AstraZeneca will not be made aware of the treatment codes until after clean file 
and database lock are declared. Similarly, all summary output reviewed at each DMC meeting 


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will be held in confidence by the DMC members until the end of the study when clean file and 
database lock are declared.
The DMC charter will be prepared to detail precise roles and responsibilities and procedures 
to ensure maintenance of the blinding and integrity of the study in the review of accumulating 
data and interactions with the EC.
An interim analysis for efficacy will be performed by the DMC (see Section 12.2.3).
6.
COLLECTION OF STUDY VARIABLES
6.1
Recording of data
The Rave® Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded in the electronic Case 
Report Forms (eCRF) as specified in the study protocol and in accordance with the 
instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
Data will be entered in the eCRF using the Rave® Web Based Data Capture (WBDC) system 
at the study site. Study personnel will be trained and responsible for entering data specified in 
the protocol into the WBDC system and according to the eCRF Instructions. When data have 
been entered, reviewed, edited, and Source Data Verification (SDV) performed as appropriate 
by an AstraZeneca representative, the data will be frozen to prevent further editing. The 
Principal Investigator or a trained sub-investigator will be notified to sign the eCRF 
electronically as per the eCRF instructions. A copy of the eCRF data will be archived at the 
study site.
6.2
Data collection at enrolment and follow-up
6.2.1
Enrolment and randomisation procedures
Enrolment visit (Visit 1)
The following data will be collected in the eCRF at enrolment: 

Date of signed informed consent

Eligibility criteria

Demographics (including sex, date of birth, race, ethnic group)

Relevant medical and surgical history

Vital Signs (pulse and BP). 


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
Weight and height 

Urine pregnancy test (only applicable for women of childbearing potential).
Randomisation visit (Visit 2)
Patients that fulfil the eligibility criteria will undergo randomisation procedures. The 
following data will be collected in the eCRF: 

Eligibility criteria

Vital Signs (pulse and BP)

ECG (including recording of Heart Rate)

Blood sampling for laboratory assessments (see Section 6.4.6)

Urine pregnancy test (only applicable for women of childbearing potential)

Dispensed study medication

Concomitant medications (baseline recording, see Section 5.6.1)

SAEs 

EQ-5D questionnaire (baseline for patients’ health related quality of life, will be 
collected at clinic visits every 6th month in countries where an official language 
version is available).
6.2.2
Follow-up procedures
Dietary and lifestyle advice will be provided at each visit according to local diabetes treatment 
guidelines. The following assessments will be done at the follow-up visits:
Visit 3, 4, 7, 9, 11, 13 etc. (scheduled telephone contacts)

AEs of interest, SAEs, potential endpoint events including bleeding events 
(unexpected or of unanticipated quantity) and DAEs

Concomitant medications (only ASA and ADP receptor antagonist use and 
concomitant medication in association with SAEs and potential endpoint events, see 
Section 5.6.1).
Visit 5 (on-site visit)

Dispensed and returned study medication

AEs of interest, SAEs, potential endpoint events including bleeding events 
(unexpected or of unanticipated quantity) and DAEs


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
Concomitant medications (only ASA and ADP receptor antagonist use and 
concomitant medication in association with SAEs and potential endpoint events, see 
Section 5.6.1).
Visit 6, 8, 10, 12, 14 etc. (on-site visits)

EQ-5D questionnaire 

Dispensed and returned study medication

AEs of interest, SAEs, potential endpoint events including bleeding events 
(unexpected or of unanticipated quantity) and DAEs

Concomitant medications (only ASA and ADP receptor antagonist use and 
concomitant medication in association with SAEs and potential endpoint events, see 
Section 5.6.1).
Dose Switch

For procedures describing the dose switch please refer to section 5.5.2
Premature Treatment Discontinuation Visit (PTDV)

Vital signs (pulse and BP)

EQ-5D questionnaire 

Return of study medication

AEs of interest, SAEs, potential endpoint events including bleeding events 
(unexpected or of unanticipated quantity) and DAEs

Concomitant medications (only ASA and ADP receptor antagonist use and 
concomitant medication in association with SAEs and potential endpoint events, see 
Section 5.6.1).
Study Closure Visit

Vital signs (pulse and BP)

EQ-5D questionnaire 

Return of study medication (not applicable for patients who have previously 
attended a PTDV)

AEs of interest, SAEs, potential endpoint events including bleeding events 
(unexpected or of unanticipated quantity) and DAEs


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
Detailed recording of all concomitant medications and concomitant medication in 
association with SAEs and potential endpoint events, see Section 5.6.1.
6.3
Efficacy 
Clinical efficacy endpoints will be collected in the eCRF. These events will be identified using 
standard questioning of the patient at each visit, or by information that the investigator may 
receive as part of standard medical practice. Safety endpoint events will be identified 
similarly.
For each potential endpoint event, the investigator will complete information specific to that 
type of endpoint in the eCRF and compile relevant additional source information into an 
‘Endpoint Package’, as described in the Event Reporting Manual for Investigators. The 
Endpoint Package will be sent to the CEC for central adjudication. The investigator should use 
the following definitions in assessing potential endpoint events. Additional details about the 
evaluations of potential endpoint events will be contained in the CEC charter.
6.3.1
Classification of Death
For the purpose of the efficacy analysis, deaths will be sub-classified by CV and non-CV 
primary cause. CV death includes sudden cardiac death, death due to acute MI, death due to 
heart failure, death due to a cerebrovascular event, death due to other CV causes (eg, 
pulmonary embolism, aortic disease, CV intervention), and deaths for which there was no 
clearly documented non-CV cause (presumed CV death). 
Additionally, deaths will be sub-classified by coronary heart diseases death (CHD death) and 
non-CHD death. CHD death includes Sudden Cardiac Death, Death due to Acute MI, and the 
subset of Death due to other CV Causes that are secondary to a coronary revascularization 
procedure.
6.3.2
Universal classification of Myocardial Infarction (MI)
The independent CEC will use the Third Universal MI definition (Thygesen et al 2012) as 
study specific MI criteria during adjudication. Additional details about the evaluations of 
potential MI events will be contained in the CEC charter.
6.3.3
Definition of Stroke
Stroke is defined as an acute episode of neurologic dysfunction attributed to a central nervous 
system vascular cause. Stroke should be documented by imaging (eg, CT scan or magnetic 
resonance imaging [MRI] scan). Evidence obtained from autopsy can also confirm the 
diagnosis. Stroke will be sub classified, when possible, as either: 
Primary ischaemic stroke
Primary ischaemic stroke is defined as an acute episode of focal brain, spinal, or retinal 
dysfunction caused by an infarction of central nervous system tissue and documented by 
imaging. A primary ischemic stroke may also undergo hemorrhagic transformation (ie, no 
evidence of haemorrhage on an initial imaging study, but appearance on a subsequent scan).


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Primary haemorrhagic stroke
Primary haemorrhagic stroke is defined as an acute episode of focal or global brain, spinal, or 
retinal dysfunction caused by non-traumatic intraparenchymal, intraventricular, or 
subarachnoid haemorrhage as documented by neuroimaging or autopsy. Microhaemorrhages 
(<10 mm) evident only on MRI are not considered to be a hemorrhagic stroke. Subdural and 
epidural bleeding will be considered intracranial haemorrhage, but not strokes.
Unclassified stroke
Stroke with unknown aetiology will be classified as unclassified stroke if the type of stroke 
could not be determined by imaging or other means.
Additional details about the evaluations of potential stroke events will be contained in the 
CEC charter.
6.4
Safety
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.
6.4.1
Definition of adverse events
An adverse event (AE) 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 (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, 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.
6.4.1.1
Adverse Events of interest 
Secondary objectives will include an assessment of the long-term effects of ticagrelor on the 
following AEs of interest: 

Dyspnoea

Renal impairment

Bradyarrhythmia

Gout

Pneumonia.
Any other non-serious AE unless discontinuation of study medication due to AE (DAE) will 
not be collected in the study.


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6.4.2
Definitions of serious adverse event
A serious adverse event (SAE) is an AE occurring during any study phase (ie, run-in, 
treatment, washout, follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient or may require
medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.4.3
Recording of adverse events
Time period for collection of adverse events
AEs of interest (see Section 6.4.1.1) and DAEs will be collected from randomisation 
throughout the study until and including the SCV.
SAEs will be recorded from the time of informed consent throughout the study until and 
including the SCV.
Follow-up of unresolved adverse events
Any AEs of interest, DAEs and SAEs that are unresolved at the patient’s last visit in the study 
are followed up by the investigator for as long as medically indicated, but without further 
recording in the electronic case report form (eCRF). AstraZeneca retains the right to request 
additional information for any patient with ongoing AE(s) of interest /SAE(s) at the end of the 
study, if judged necessary.
Variables
The following variables will be collect for each non-serious AE of interest and DAEs:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity


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
Whether the AE is serious or not

Investigator causality rating against the study medication (yes or no)

Action taken with regard to study medication

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date Investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed (if performed)

Autopsy results

Causality assessment in relation to Study procedure(s)

Causality assessment in relation to Other medication

Description of AE.
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 6.4.2. 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 a 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 
a SAE.
The following definitions for intensity rating are:
1.
Mild (awareness of sign or symptom, but easily tolerated)
2.
Moderate (discomfort sufficient to cause interference with normal activities)


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3.
Severe (incapacitating, with inability to perform normal activities).
Causality collection
The investigator will assess causal relationship between study medication and each AE, and 
answer “yes” or “no” to the question “Do you consider that there is a reasonable possibility 
that the event may have been caused by the study medication?”.
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as “yes.”
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
Adverse Events based on signs and symptoms
All AEs of interest (see Section 6.4.1.1) spontaneously reported by the patient or reported in 
response to the open question from the study personnel: ‘Have you had any health problems 
since the previous visit/you were last asked?’ or revealed by observation will be collected and 
recorded in the eCRF. When collecting AEs, the recording of diagnoses is preferred (when 
possible) 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.
Adverse Events based on examinations and tests
Laboratory safety assessments will not be routinely done (except at baseline), but may be 
performed during the study at the investigators discretion. In association with an AE of 
interest, DAEs, SAE or potential endpoint event, different assessments may have to be 
undertaken, which could include local laboratory assessments, and which will be collected in 
the eCRF as appropriate.
The results from protocol-mandated vital signs are to be summarised in the clinical study 
report (CSR). Deterioration as compared to baseline in investigator-initiated assessment of 
laboratory values and protocol-mandated vital signs should therefore only be reported as AEs 
if they fulfil any of the SAE criteria or are the reason for discontinuation of treatment with the 
study medication.
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 (eg, renal failure vs. increasing creatinine). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AEs and SAEs.


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6.4.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the study 
medication, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within one
calendar day of initial receipt for fatal and life threatening events and within five calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE immediately, or 
no later than 24 hours of when he or she becomes aware of it.
Once the investigator(s) or other site personnel indicate an AE is serious in the WBDC 
system, an automated email alert is sent to the designated AstraZeneca representative. 
If the WBDC system is not available, then the investigator or other study site personnel should 
report the SAE to the appropriate AstraZeneca representative by telephone, recognizing that 
the same reporting timeframe (24 hours) still apply. The AstraZeneca representative will 
advice the investigators how to proceed.
If the initial or subsequent reports are made by means other than WBDC, necessary 
information on any SAEs should finally be entered into eCRF via WBDC system by the 
investigator as soon as the system becomes available again.
6.4.4.1
Reporting of serious adverse events considered to be potential endpoint events
If a potential endpoint event meets the SAE criteria it must be reported in the eCRF by the 
investigator within the regular SAE reporting timelines (see Section 6.4.4). 
All events involving non-fatal MI, non-fatal stroke, all-cause death or bleeding events will be 
defined as ‘potential endpoint events’. Once one of these potential endpoint event has been 
identified, the investigator will record this in the respective appropriate modules of the eCRF 
and report it to the CEC for central adjudication (see Section 12.4.1). Events of unstable 
angina pectoris and TIA that are judged by investigators to fulfil SAE criteria will be sent for 
adjudication to ensure that they are not MI or stroke.
The following events adjudicated to endpoints in the study, although qualifying as SAEs, will 
only be reported as primary endpoint events in the Clinical Study Report (CSR): 

Non-fatal MI


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
Primary Ischaemic Stroke

CV Death.
These adjudicated endpoint events will not be reported to health authorities as SAEs as they 
are considered part of the natural history of the condition under investigation and will be 
monitored by the independent DMC throughout the study. This approach aims to avoid 
unnecessary unblinding of treatment in patients with endpoint events that are also SAEs.
If it is determined by the CEC that a potential endpoint event does not meet the endpoint 
criteria, but is judged by investigators to fulfil SAE criteria, the event will be captured as an 
SAE and reported to the health authorities. 
6.4.5
Bleeding assessments
Bleeding events that are self-limited, and do not prompt medical evaluation or intervention, 
need not to be reported. For all bleeding events that are unexpected or of unanticipated 
quantity, the investigator will complete information in the eCRF specific to that bleeding 
event. In addition, for all reported bleeding events relevant information will be compiled and 
sent to the CEC for central adjudication according to the following bleeding definitions: TIMI, 
PLATO (Wallentin et al 2009) and BARC (Mehran et al 2011). Additional details can be 
found in the CEC Charter.
Additionally, all bleeding events (including haemorrhagic stroke) fulfilling the SAE criteria 
will be reported as SAEs by the sponsor to the authorities. If the adjudication of a potential 
endpoint event unveils a bleeding event, eg, haemorrhagic stroke, not yet reported as SAE, it 
will be reported by AZ as SAE to the authorities. 
6.4.5.1
Bleeding associated with procedures
Bleeding associated with procedures should only be reported as a bleeding event and AE/SAE 
if the bleeding exceeds what can be expected for the procedure.
6.4.5.2
Procedures for Study Medication in case of bleeding
Study medication must be stopped immediately in case of a bleed deemed to be clinically 
significant in the judgment of the investigator (eg, a significant fall in haemoglobin, need for 
transfusion, haemodynamically significant, or in a critical location such as intracranial, 
intraspinal, intraocular, or pericardial). Study medication may be resumed when the risk of 
bleeding is deemed low in the judgment of the investigator. The study medication 
administration need not be stopped in case of a minor bleeding. All bleedings should be 
treated and followed up according to local clinical practice. Major bleeding events should be 
managed according to need with general support and transfusions. It should be noted that 
platelet transfusion is unlikely to reverse bleeding in a patient receiving ticagrelor, as the new 
platelets are likely to be inhibited by ticagrelor as long as it is circulating in the blood.
There is no antidote to ticagrelor and treatment of bleedings should therefore be symptomatic 
and handled according to the clinical routines at the investigational site.


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6.4.6
Laboratory safety assessment
A urine pregnancy test (U-HCG) will be taken at visit 1 and repeated at visit 2 in women of 
childbearing potential.
The following baseline laboratory variables will be analyzed at local laboratories for all 
patients, preferably after 6 hours of fasting, and must have been collected between 30 days 
prior of randomization and at the latest on the day of the randomization, before first intake of 
study medication:
Clinical Chemistry (Serum or Plasma)
Haematology (Whole blood)
S/P-Creatinine
B-Haemoglobin 
S/P-LDL-C
B-Platelet count
S/P-Triglycerides
B-Haemoglobin A1c
Urinanalysis
U-HCG (pregnancy test, only applicable for 
women of childbearing potential)
At the follow-up visits, laboratory safety assessments will not be routinely done, but may be 
performed locally at the investigators discretion. In association with SAEs or potential 
endpoint events, different assessments may have to be undertaken which could include local 
laboratory assessments.  Follow-up testing for abnormal laboratory results should be 
performed according to local practice.
See Section 6.4.3 for AEs based on examinations and tests.
For blood volume see Section 7.1.
6.4.6.1
Collection of specific information for liver related SAEs or DAEs
In patients with liver related SAEs or DAEs as judged by the investigator, in addition to the 
completion of the appropriate SAE/DAE eCRF, specific information should also be reported 
using the eCRF liver modules unless drug induced liver injury reasonably excluded (eg 
gallstone disease, liver tumours).
6.4.7
Electrocardiogram (ECG)
A 12-lead ECG (standard ECG with a paper speed of 25-50 mm/second covering at least 6 
sequential beats) will be recorded at baseline (visit 2) after the patient has been lying down to 
rest for at least 5 minutes. Heart rate will be reported in the eCRF. The baseline ECG should 
be made available to the CEC upon request, to facilitate adjudication of potential cardiac 
ischaemic events.


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6.4.8
Vital signs
Pulse and systolic and diastolic BP will be assessed using non-invasive equipment after the 
patient has been at rest for 5 minutes. Results will be recorded in the eCRF.
6.5
Patient reported outcomes (PRO)
Patients’ health related quality of life will be measured using the EQ-5D quality of life 
questionnaire, see Section 6.9.1.
6.6
Pharmacokinetics (Not Applicable)
6.7
Pharmacodynamics (Not Applicable)
6.8
Pharmacogenetics (Not Applicable)
6.9
Health economics
Patients’ health related quality of life will be measured using EQ-5D quality of life 
questionnaire (see Section 6.9.1). The EQ-5D-5L version of the questionnaire will be used.
6.9.1
Health economic assessment (EQ-5D)
The EQ-5D consists of two parts: the EQ-5D descriptive system and the EQ-Visual Analogue 
Scale (EQ-VAS). The EQ-5D descriptive system is a self-administered instrument consisting 
of five questions, each representing one dimension (Brooks 1996). The 5 dimensions are 
mobility, self-care, usual activities, pain and discomfort, and anxiety and depression. 
For each dimension of the EQ-5D-5L questionnaire responders are asked to state their status 
on a five level (5L=5 levels) ordinal scale; whether they experience no problems (level 1), 
slight problems (level 2), moderate problems (level 3), severe problems (level 4), or extreme 
problems (level 5).
Health states defined by the 5 dimensions can be converted into a weighted health state index 
(health state utility) by applying scores from the EQ-5D value sets elicited from general
population samples (Dolan 1997, Dyer et al 2010) The EQ-VAS records the respondent’s self-
rated health on a vertical, visual analogue scale where the endpoints are labelled ‘Best 
imaginable health state’ and ‘Worst imaginable health state’.
The EQ-5D paper form will be filled in by the patients under the supervision of the site staff. 
The site staff will transfer the responses into the eCRF. All patients will be asked to complete 
the EQ-5D questionnaire every 6 months at on-site visits from Visits 2 throughout the study 
until SCV. The EQ-5D will only be administered in countries where an official language 
version is available.
6.9.2
Health care resource utilisation
Information on health care resource utilisation associated with hospitalisation admissions and 
health related quality of life is to be collected until SCV to enable health technology 
assessment, health economic analysis and health economic modelling. Resource utilisation


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and health related quality of life are to be recorded in the eCRF beginning at randomisation. 
The following types of resources will be recorded for all hospitalisations:

Admission date

Discharge date 

Discharge destination

Ward type information including duration of stay, for example:

General

CCU (Coronary Care unit)

ICU (Intensive Care Unit)

Final discharge diagnosis

Major secondary discharge diagnosis (if present)

Main procedures.
The variables collected to support health economic evaluation are the EQ-5D questionnaire at 
randomisation and every 6 months thereafter at on-site visits, and information on all 
hospitalizations during the course of the study.
7.
BIOLOGICAL SAMPLING PROCEDURES 
7.1
Volume of blood
The total volume of blood that will be drawn from each patient for this study is listed in Table 
3 below.  The collection of additional samples is performed locally at the discretion of the 
investigator and recorded in the eCRF as appropriate, thus requiring additional sample 
volumes. 
Table 3
Volume of blood to be drawn from each patient
Assessment
Sample volume 
(mL)
No. of samples
Total volume 
(mL)
Clinical chemistry
5
1
5
Haematology
3
1
3
Total
8 mL


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7.2
Handling, storage and destruction of biological samples
The baseline laboratory samples (see Section 6.4.6) and any additional laboratory safety 
samples taken at the investigators discretion or connected to an endpoint event will be 
analysed locally. The safety samples will be disposed after analyses.  
8.
ETHICAL AND REGULATORY REQUIREMENTS
8.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (GCP), applicable 
regulatory requirements and the AstraZeneca policy on Bioethics.
8.2
Subject data protection
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation.
8.3
Ethics and regulatory review
An Ethics Committee/Institutional Review Board (IRB) should approve the final study 
protocol, including the final version of the Informed Consent Form and any other written 
information and/or materials to be provided to the patient. The investigator/Head of the study 
site will ensure the distribution of these documents to the applicable Ethics Committee/IRB, 
and to the study site staff.
The opinion of the Ethics Committee should be received in writing. The investigator should 
submit a notification of direction/determination as well as a copy of the IRB written approval 
to AstraZeneca before enrolment of any patient into the study.
The Ethics Committee/IRB should approve all advertising used to recruit patients for the 
study.
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements.
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.


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AstraZeneca will provide Regulatory Authorities, Ethics Committees/IRB and Principal 
Investigators with safety updates/reports according to local requirements, including SUSARs 
(Suspected Unexpected Serious Adverse Reactions), where relevant.
Each Principal Investigator is responsible for providing the Ethics Committees/IRB with 
reports of any serious and unexpected adverse drug reactions from any other study conducted 
with the study medication. AstraZeneca will provide this information to the Principal 
Investigator so that he/she can meet these reporting requirements.
8.4
Informed consent
The Principal Investigator(s) or delegate at each centre will:

Ensure each patient is given full and adequate oral and written information about 
the nature, purpose, possible risk and benefit of the study

Ensure each patient is notified that they are free to discontinue from the study at any 
time

Ensure that each patient is given the opportunity to ask questions and allowed time 
to consider the information provided

Ensure each patient provides signed and dated informed consent before conducting 
any study specific procedure

Ensure the original, signed Informed Consent Form(s) is/are stored in the 
Investigator’s Study File

Ensure a copy of the signed Informed Consent Form is given to the patient

Ensure that any incentives for patients who participate in the study as well as any 
provisions for patients harmed as a consequence of study participation are described 
in the informed consent form that is approved by an Ethics Committee.
8.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the EC and 
AstraZeneca.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.


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AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Principal Investigator(s). For distribution to Ethics Committee see Section 8.3.
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee.
8.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, GCP, 
guidelines of the International Conference on Harmonisation (ICH), and any applicable 
regulatory requirements. The investigator will contact AstraZeneca immediately if contacted 
by a regulatory agency about an inspection at the centre.
9.
STUDY MANAGEMENT BY ASTRAZENECA
9.1
Pre-study activities
Before the first patient is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to:

Determine the adequacy of the facilities

Determine availability of appropriate patients for the study

Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of 
AstraZeneca or its representatives. This will be documented in a Clinical Study 
Agreement between AstraZeneca and the investigator.
9.2
Training of study site personnel
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised.


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The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.3
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs and that study drug accountability 
checks are being performed

Perform source data verification (a comparison of the data in the eCRFs with the 
patient’s medical records at the hospital or practice, and other records relevant to 
the study) including verification of informed consent of participating patients. This 
will require direct access to all original records for each patient (eg, clinic charts)
The AstraZeneca representative will be available between visits if the investigator(s) or other 
study site personnel need information and advice about the study conduct.
9.3.1
Source data
The Clinical Study Agreement (CSA) will specify the location of source data.
Access to source documents and source data is essential to inspection and review of clinical 
studies by the Food and Drug Administration (FDA).
9.4
Study agreements
The Principal Investigator at each centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study. In the event of any inconsistency 
between this Clinical Study Protocol and the CSA, the terms of Clinical Study Protocol shall 
prevail with respect to the conduct of the study and the treatment of patients and in all other 
respects, not relating to study conduct or treatment of patients, the terms of the CSA shall 
prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.


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9.4.1
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.5
Study timetable and end of study
The study is expected to start in Q1 2014 and to end by Q4 2018.
Planned average treatment duration in the study: 40 months.
AstraZeneca will notify investigators when recruitment is complete.
The end of the entire study is defined as ‘the last visit of the last patient undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. The EC may terminate enrolment in a 
country in order to ensure a reasonable international distribution of patients. AstraZeneca may 
also terminate the entire study prematurely if concerns for safety arise within this study or in 
any other study with ticagrelor.
10.
DATA MANAGEMENT BY ASTRAZENECA OR DELEGATE
Data management will be performed by AstraZeneca Data Management Centre staff. 
Data will be entered in the WBDC system at the study site. Trained site staff will be 
responsible for entering data on the observations, tests and assessments specified in the 
protocol into the WBDC system and according to the eCRF instructions. The eCRF 
instructions will also guide the study site in performing data entry. Data entered in the WBDC 
system will be immediately saved to a central database and changes tracked to provide an 
audit trail. The data will then be Source Data Verified, reviewed/queried and updated as 
needed. The Principal Investigator is responsible for signing the eCRF and this can be 
delegated to a trained sub-investigator. The eCRF is signed electronically as per the eCRF 
instructions. The data will be validated as defined in the Data Management Plan. Data queries 
will be raised for inconsistent, impossible or missing data. All entries to the study database 
will be available in an audit trail. Quality control procedures will be applied to each stage of 
data handling to ensure that all data are reliable and have been processed correctly.
The data will be frozen and then locked to prevent further editing. When all data have been 
coded, validated, signed, and locked, a clean file will be declared. Any treatment revealing 
data may thereafter be added and the final database will be locked. A copy of the eCRF will 
be archived at the study site when the study has been locked.
The patients will fill in PRO (EQ-5D) paper form under the supervision of the site staff. The 
site staff will transfer the responses into the eCRF.


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Dictionary coding
Medical coding is done using the most current version of MedDRA (Medical Dictionary for 
Regulatory Activities) and AstraZeneca Drug Dictionary. 
Management of external data
The data collected through third party sources will be obtained and reconciled against study 
data. The Data Management Centre determines the format of the data to be received from 
external vendors and coordinates the flow of data to an external environment or clinical 
database (if applicable). Data Management will ensure that the data collection tool 
(IVRS/IWRS, etc) will be tested/validated as needed. External data reconciliation will be done 
with the clinical database as applicable.
Serious Adverse Event (SAE) Reconciliation
SAE Reconciliation Reports are produced and reconciled with Patient Safety database.
11.
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA OR DELEGATE
11.1
Calculation or derivation of efficacy variables (Not Applicable)
11.2
Calculation or derivation of safety variable(s) (Not Applicable)
11.3
Calculation or derivation of patient reported outcome variables
See Section 12.2.1.3.
11.4
Calculation or derivation of pharmacokinetic variables (Not 
Applicable)
11.5
Calculation or derivation of pharmacodynamic variables (Not 
Applicable)
11.6
Calculation or derivation of pharmacogenetic variables (Not 
Applicable)
11.7
Calculation or derivation of health economic variables
See Section 12.2.1.3.


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12.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION BY ASTRAZENECA
12.1
Description of analysis sets
12.1.1
Full analysis set
All patients who have been randomised to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study. 
Patients will be analysed according to their randomised study medication irrespective of 
whether the event occurred before or following discontinuation of study medication. Patients 
who withdraw consent to participate in the study will be included up to the date of their study 
termination except for vital status known through public records (for use in the analysis of all 
cause death). All efficacy variables will be analysed using the FAS.
12.1.2
Safety analysis set
All patients who received at least 1 dose of randomised ticagrelor or placebo, will be included 
in the safety analysis set. Throughout the safety results sections, erroneously treated patients 
(e.g., those randomised to ticagrelor but actually given placebo) will be accounted for in the 
actual treatment group. A patient who in error has received both ticagrelor and placebo will be 
accounted for in the randomised treatment group. 
12.2
Methods of statistical analyses
This section provides a summary of the planned statistical analyses. Further details will be 
provided in a Statistical Analysis Plan.
12.2.1
Efficacy analysis
All efficacy analyses will be based on the ITT principle using the FAS, including only 
adjudicated endpoint events. Investigators are instructed to report all potential endpoint events 
in the eCRF, even those that may not meet strict endpoint definitions, to ensure all potential 
events are reviewed and adjudicated by the CEC. 
For time to event variables, treatments will be compared using a Cox proportional hazards 
model with a factor for treatment group, using the Efron method for ties. Censoring principles 
are described in Section 12.2.4. The p-value (calculated using the Wald test), hazard ratio
(HR) and 95% confidence interval will be reported. Kaplan-Meier estimates of the cumulative
risk will also be presented.
The family wise error rate will be controlled for the primary and secondary efficacy analyses 
by applying a hierarchical test sequence as described in Section 12.2.1.2. No other 
adjustments for multiple comparisons will be made. 
As supportive analyses, data from patients with diabetes in PEGASUS (patients with MI 
within 1-3 years) and EUCLID (PAD patients) will be pooled and analyzed with and without 


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data from this study. These analyses will be described in a separate SAP and reported 
separately.
12.2.1.1
Primary efficacy variable
The primary efficacy variable, time from randomisation to the first occurrence of any event 
from the composite of CV death, MI or stroke, will be analysed using the methodology 
described in Section 12.2.1. The null hypothesis of no treatment effect, 
H0: HR (ticagrelor divided by placebo) = 1, 
vs. the alternative hypothesis, 
H1: HR ≠ 1, 
will be tested at 4.96% two-sided significance level.
The assumption of proportional hazards will be assessed visually using log-cumulative hazard 
plots. The effect of any departures from proportional hazards will be discussed as part of the 
presentation of results.
To assess possible effects of missing data, sensitivity analyses will be done as follows. The 
event rate in the placebo arm will be used to estimate the intensity of a Poisson process. Based 
on the missing follow-up time, i.e. the time from censoring to PACD, the expected number of 
events in the ticagrelor group that could have been observed if the patients had completed the 
study will be estimated from the Poisson process. The comparison of ticagrelor and placebo 
will be recalculated with these additional events. If the result is still significant with these 
additional events, the intensity of the Poisson process will be increased and events will be 
added to the ticagrelor group until the primary analysis is non-significant.
Subgroup analyses on the primary efficacy variable will be performed to evaluate variation of 
treatment effect. Relevant subgroups, eg age, sex, race, ASA use and medical history, will be 
examined. Hazard ratios and 95% confidence intervals will be reported for each subgroup as 
well as p-values for the tests of interaction between treatment and each subgroup.
12.2.1.2
Secondary efficacy variables 
The secondary efficacy variables will be analysed using the methodology described in Section
12.2.1.

1.
Time from randomisation to death of CV cause

2.
Time from randomisation to first occurrence of MI

3.
Time from randomisation to first occurrence of ischaemic stroke

4.
Time from randomisation to death of any cause.


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Endpoints 1-4 will be included in the confirmatory testing procedure. Only if the treatment 
effect on the primary efficacy variable is significant at the 4.98% level, will the secondary 
efficacy variables be tested in a confirmatory sense in the order given above. The hypothesis 
testing will continue at the 4.98% significance level until the first statistically non-significant 
treatment difference (p≥0.0498) is observed.
12.2.1.3
Exploratory variables
Other objectives are exploratory, with the purpose of comparing other long-term treatment 
effects of ticagrelor vs. placebo.
Time to event variables will be analysed using the methodology described in Section 12.2.1:

Time from randomisation to first occurrence of any event from the composite of
all- cause death, MI or stroke

Time from randomisation to first occurrence of stroke

Time from randomisation to first occurrence of any event from the composite
of all- cause mortality, MI, stroke, intracranial haemorrhage and fatal bleeding 
(irreversible harm events).
Descriptive reporting of the resource utilisation data and health related quality of life
data based on the EQ-5D are to be documented in the CSR. The data will be combined
with economic data and life expectancydata collected independentlyof the study to 
construct comparative health economic analyses between treatment groups. The
economic analysis and cost-effectiveness analyses that include data external to the study
will not be included in the CSR.
12.2.2
Safety variables
All analyses of safety variables will be based on the safety analysis set as described in Section 
12.1.2. 
12.2.2.1
Bleeding events
Analysis of time from randomisation to each of the following endpoints will be performed 
using the methodology described in Section 12.2.1:

Time to first TIMI Major bleeding event

Time to first TIMI Major or minor bleeding event 

Time to first PLATO major bleeding event 

Time to permanent discontinuation of study medication due to any bleeding event.
The assessment of time to bleeding events will focus on the items above but will also include 
analysis of time to first adjudicated event for additional categories of bleeding according to 


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the TIMI, PLATO and BARC definitions. Exploration of potential risk factors for bleeding 
events will be performed. All AEs relating to bleeding will be summarised separately and the 
total number of bleeding events will be assessed. Exploration of potential risk factors for AEs 
that are increased with ticagrelor dosing may be done.
12.2.2.2
SAEs and AE of interest
AEs of interest, DAEs as well as SAEs will be evaluated. Summaries, by system organ class 
and preferred term using MedDRA, will be presented by treatment group using descriptive 
statistics. 
12.2.3
Interim analysis for efficacy
An interim analysis will be performed by the DMC. The interim analysis will be performed 
following the accrual and confirmation by adjudication of 517 primary events . The stopping 
boundary at the interim analysis is a 2-sided p-value <0.001 for both the primary endpoint 
(CV death, MI, or stroke) and for the CV death endpoint (the 1st secondary
efficacy endpoint). The interim p-value is small enough for the final analysis to be conducted 
at a significance level of 4.96%, with the family wise error rate controlled at 5.00%. These 
boundaries were determined using a Haybittle-Peto procedure (Haybittle 1971, Peto et al 
1976). 
If a recommendation to stop the study is made at the interim, all subsequent testing will be 
done at the same significance level as for the interim.
12.2.4
Censoring
The EC will monitor the accrual of the number of primary events and when appropriate 
predict and define a PACD at which time the pre-defined target number of events for the 
primary composite endpoint are expected to have occurred.
The PACD will be the common date at which all patients who are event free for the given 
endpoint and have not withdrawn consent for participating in the study will be censored in 
efficacy time-to-event analyses. Events that occur after the PACD but before the SCV will 
also be collected and adjudicated. These events will be included in sensitivity analyses but not 
in the primary analysis. 
Patients who have not had the event(s) in question will be censored at the earlier of (1) the 
PACD and (2) the last study contact when all components of the endpoint in question were
assessed. In the analysis of CV death and composites including CV death censoring will occur 
at the earliest of (1), (2) and (3) the date of death from non-cardiovascular causes. For 
endpoints not including death, all deaths are censoring events. In safety time-to-event analysis 
of bleeding, patients not having suffered any bleeding event in the given category will be 
censored at the earlier of SCV, 7 days after last dose of study drug, death, last contact or 
withdrawal of consent.
Complete endpoint information will be pursued with every effort for all patients regardless of 
their study medication status, unless they exercise their right to withdraw consent. Patients 


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who have a non-fatal event will continue study follow-up. For patients who withdraw consent
and for whom only vital status (known to be alive at study closure, or date of death) may be 
obtained from public records, the occurrence of all components of the primary endpoint 
cannot be assessed. Thus, in the main analyses patients will be censored at the time of consent 
withdrawal. However, the determination of all-cause death will utilise all publicly known 
mortality data, even that extending beyond date of consent withdrawal. The vital status 
information will be included in the analysis of all cause death as a single endpoint, in 
sensitivity analysis and tabulations.
Similarly, complete information on the primary endpoint may not be obtained for patients who 
are lost to follow-up (LTFU). Any such patient will be censored in the analysis of the primary 
composite endpoint at the last contact where all elements of the endpoint were assessed. A 
patient will not be recorded as LTFU until the end of the study, after every allowable effort to 
get in contact has been made. Hence, it is anticipated that the number of patients LTFU will be 
limited.
12.3
Determination of sample size
Based on clinical studies and epidemiological information, the event rate for the composite of 
CV death, MI or stroke has been estimated to be 2.5% annually in a population consisting of 
patients with T2DM at high risk of CV events without medical history of previous MI or 
stroke.
The final primary treatment comparison will be made at a significance level of 4.96% adjusted 
for the planned efficacy interim analysis. Assuming a true hazard ratio of 0.84 between 
ticagrelor and placebo, 1385 primary endpoint events will provide a power of 90%.
With an annual event rate of 2.5% in the placebo treatment group, 19000 patients, randomised 
in a 1:1 ratio, with an average follow-up period of 40 months, are estimated to provide the 
required number of primary events. The expected minimum follow-up period is 29 months, 
based on an enrolment period of 28 months.
The expected number of patients who will be lost-to-follow-up is negligible and hence not 
considered in the determination of samples size. 
12.4
Independent Data monitoring committees 
12.4.1
Clinical Endpoint Committee (CEC)
See Section 5.10.3.
12.4.2
Data Monitoring Committee (DMC)
See Section 5.10.4.


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13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR
13.1
Medical emergencies and AstraZeneca contacts
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.4.4
In the case of a medical emergency the investigator may contact the Study Team Physician at 
AstraZeneca R&D Mölndal.
Name 
Role in the study 
Address & telephone number
Lead Study Team Physician 
responsible for the protocol 
at AstraZeneca R&D 
Mölndal
 
 
 
Global Clinical Lead 
responsible for the protocol 
at AstraZeneca R&D 
Mölndal
 
Study Team Leader
13.2
Overdose 
An overdose of study medication is defined as intake of more than 360 mg 
ticagrelor/ticagrelor placebo per day. In the event of an overdose of study medication ascertain 
the time and extent of the overdose regardless of severity. Determine the causative 
circumstance and whether haemorrhagic or toxic complications have occurred or are likely to 
do so. Depending on these facts it has to be decided if the patient should be hospitalised for 
observation or not. Bleeding is one of the most likely pharmacological effects of excessive 
ticagrelor dosing, and appropriate supportive measures such as volume replacement, local 
haemostatic measures (eg, compression), and decompression or drainage may be required 
depending on the localisation, extent of bleeding or volume of blood lost. Patients with 
overdose-related bleeding should be cautioned to avoid unnecessary activity, mechanical 
tissue stress, and minor trauma for at least 24 hours after the bleeding has stopped. The IB 
documents other symptoms that can be expected after an overdose of ticagrelor..


Revised Clinical Study Protocol
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Study Code D513BC00001
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
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.

An overdose without associated symptoms is only reported on the Overdose eCRF 
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.4.4. For 
other overdoses, reporting should be done within 30 days.
13.3
Pregnancy
All outcomes of pregnancy should be reported to AstraZeneca.
13.3.1
Maternal exposure
Pregnant women have not been included in any studies with ticagrelor.
If a patient becomes pregnant during the course of the study, the study medication should be 
discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study medication 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 days for SAEs, see Section 6.4.4 and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.


Revised Clinical Study Protocol
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Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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13.3.2
Paternal exposure
There are no restrictions against fathering a child when treated with ticagrelor. If paternal 
exposure pregnancy occurs in the course of the study, then investigators or other study site 
personnel should inform appropriate AstraZeneca representatives within 1 day as described in 
the maternal exposure Section 13.3.1.
The Informed Consent Form for Pregnant Partners should be completed in order to collect 
additional information regarding outcome of pregnancy.


Revised Clinical Study Protocol
Drug Substance Ticagrelor  
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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14.
LIST OF REFERENCES
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Int J Hematol 2010;92:296–301.
Alexopoulos et al 2013
Alexopoulos D, Xanthopoulou I, Mavronasiou E, Stavrou K, Siapika A, Tsoni E et al. 
Randomized assessment of ticagrelor versus prasugrel antiplatelet effects in patients with 
diabetes. Diabetes Care 2013;36:2211-6
Angiolillo and Suryadevara 2009
Angiolillo DJ, Suryadevara S. Aspirin and clopidogrel: efficacy and resistance in diabetes 
mellitus. Best Pract Res Clin Endocrinol Metab 2009;23:375-88.
Antithrombotic Trialists’ Collaboration 2002
Antithrombotic Trialists’ (ATT) Collaboration. Collaborative meta-analysis of randomised 
trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high 
risk patients. BMJ 2002;324:71–86.
Antithrombotic Trialists' Collaboration 2009
Antithrombotic Trialists' (ATT) Collaboration. Aspirin in the primary and secondary 
prevention of vascular disease: collaborative meta-analysis of individual participant data from 
randomised trials. Lancet 2009;373:1849-60.
Becker et al 2011
Becker RC, Bassand JP, Budaj A, Wojdyla DM, James SK, Cornel JH et al. Bleeding 
complications with the P2Y12 receptor antagonists clopidogrel and ticagrelor in the PLATelet 
inhibition and patient Outcomes (PLATO) trial. Eur Heart J. 2011;32:2933-44.
Bhatt et al 2002
Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Amplified benefit of 
clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90:625-8.
Bhatt et al 2006
Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE et al. Clopidogrel and aspirin 
versus aspirin alone for the prevention of atherothrombotic events. 
N Engl J Med 2006;354:1706-17.
Bhatt et al 2010
Bhatt DL, Eagle KA, Ohman EM, Hirch AT, Goto S, Mahoney EM et al. Comparative 
determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with 
atherothrombosis. JAMA 2010;304:1350-7.


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Drug Substance Ticagrelor  
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
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Brooks 1996
Brooks R. EuroQol: the current state of play. Health Policy 1996;37:53-72.
Buse et al 2007
Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R et al. American Heart 
Association, American Diabetes Association. Primary prevention of cardiovascular diseases in 
people with diabetes mellitus: a scientific statement from the American Heart Association and 
the American Diabetes Association. Diabetes Care 2007;30:162–72.
Capodanno et al 2011
Capodanno D, Patel A, Dharmashankar K, Ferreiro JL, Ueno M, Kodali M et al. 
Pharmacodynamic effects of different aspirin dosing regimens in type 2 diabetes mellitus 
patients with coronary artery disease. Circ Cardiovasc Interv 2011;4:180–7.
CAPRIE Steering Committee 1996
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in 
patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.
De Berardis et al 2007
De Berardis G, Sacco M, Evangelista V, Filippi A, Giorda CB, Tognoni G et al. Aspirin and 
Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-
D): design of a randomised study of the efficacy of low-dose aspirin in the prevention of 
cardiovascular events in subjects with diabetes mellitus treated with statins. Trials 2007;8:21
De Berardis et al 2009
De Berardis G, Sacco M, Strippoli GF, Pellegrini F, Graziano G, Tognoni G et al. Aspirin for 
primary prevention of cardiovascular events in people with diabetes: meta-analysis of 
randomised controlled trials. BMJ 2009;339:b4531.
DiChiara et al 2007
DiChiara J, Bliden KP, Tantry US, Hamed MS, Antonino MJ, Suarez TA et al. The effect of 
aspirin dosing on platelet function in diabetic and nondiabetic patients. An analysis from the 
aspirin-induced platelet effect (ASPECT) study. Diabetes 2007;56:3014–9.
Dolan 1997
Dolan P. Modeling valuations for EuroQol health states. Med Care 1997;35:1095-108.
Dyer et al 2010
Dyer MTD, Goldsmith KA, Sharples LS, Buxton MJ. A review of health utilities using the 
EQ-5D in studies of cardiovascular disease. Health Qual Life Outcomes 2010;8:13.
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Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB et al. Heart disease 
and stroke statistics--2013 update: a report from the American Heart Association. Circulation 
2013;127:e6-e245.


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Drug Substance Ticagrelor  
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
73(75)
Haffner et al 1998
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart 
disease in subjects with type-2 diabetes and in nondiabetic subjects with and without 
priormyocardial infarction. N Engl J Med 1998;339:229–34.
Haybittle 1971
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Brit J 
Radiology 1971;44:793-7.
Henry et al 2011
Henry P, Vermillet A, Boval B, Guyetand C, Petroni T, Dillinger JG et al. 24-hour time-
dependent aspirin efficacy in patients with stable coronary artery disease. Thromb Haemost 
2011;105:336-44.
Htun and Steinhubl 2013
Htun WW, Steinhubl SR. Ticagrelor: the first novel reversible P2Y(12) inhibitor. Expert Opin 
Pharmacother 2013;14:237-45.
James et al 2010
James S, Angiolillo DJ, Cornel JH, Erlinge D, Husted S, Kontny F et al. Ticagrelor vs. 
clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the 
PLATelet inhibition and patient Outcomes (PLATO) trial. Eur Heart J 2010;31:3006-16.
Krempf et al 2010
Krempf M, Parhofer KG, Steg PG, Bhatt DL, Ohman EM, Röther J et al. Cardiovascular event 
rates in diabetic and nondiabetic individuals with and without established atherothrombosis 
(from the REduction of Atherothrombosis for Continued Health [REACH] Registry). Am J 
Cardiol 2010;105:667-71.
Mehran et al 2011
Mehran R, Rao S, Bhatt D, Gibson M, Caixeta A, Eikelboom J et al. Standardized Bleeding 
Definitions for Cardiovascular Clinical Trials: A Consensus Report From the Bleeding 
Academic Research Consortium. Circulation 2011;123:2736-47
Peto et al 1976
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV et al. Design and analysis of 
randomized clinical trials requiring prolonged observation of each patient: I. Introduction and 
design. Brit J Cancer 1976;34:585-612.
Pignone et al 2010
Pignone M, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D et al. Aspirin for 
primary prevention of cardiovascular events in people with diabetes: a position statement of 
the American Diabetes Association, a scientific statement of the American Heart Association, 
and an expert consensus document of the American College of Cardiology Foundation. 
Circulation 2010;121:2694-701.


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Drug Substance Ticagrelor  
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
74(75)
Preis et al 2009
Preis SR, Hwang SJ, Coady S, Pencina MJ, D’Agostino RB, Savage PJ et al. Trends in all-
cause and cardiovascular disease mortality among women and men with and without diabetes 
mellitus in the Framingham Heart Study, 1950 to 2005. 
Circulation 2009;119:1728-35.
Roger et al 2011
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM et al. Heart Disease 
and Stroke Statistics -- 2011 update: a report from the American Heart Association. 
Circulation 2011;123:e18-e209
Rydén et al 2007
Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de Boer MJ et al. Task Force 
on Diabetes, Cardiovascular Diseases of the European Society of Cardiology (ESC); European 
Association for the Study of Diabetes (EASD). Guidelines on diabetes, prediabetes, and 
cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular 
Diseases of the European Society of Cardiology (ESC) and of the European Association for 
the Study of Diabetes (EASD). Eur Heart J 2007;28:88–136.
Rydén et al 2013
Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N et al. ESC Guidelines on 
diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: 
The Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society 
of Cardiology (ESC) and developed in collaboration with the European Association for the 
Study of Diabetes (EASD). Eur Heart J 2013;34:3035–87.
Schramm et al 2008
Schramm TK, Gislason GH, Køber L, Rasmussen S, Rasmussen JN, Abildstrøm SZ et al. 
Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial 
infarction carry the same cardiovascular risk: a population study of 3.3 million people. 
Circulation 2008;117:1945–54.
Smith et al 2011
Smith SC, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA et al. AHA/ACCF 
Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other 
Atherosclerotic Vascular Disease: 2011 Update: A Guideline From the American Heart 
Association and American College of Cardiology Foundation. Circulation. 2011;124:2458-73
Spectre et al 2011
Spectre G, Arnetz L, Ostenson CG, Brismar K, Li N, Hjemdahl P. Twice daily dosing of 
aspirin improves platelet inhibition in whole blood in patients with type 2 diabetes mellitus 
and micro- or macrovascular complications. Thromb Haemost 2011;106:491–9.


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Drug Substance Ticagrelor  
Study Code D513BC00001
Edition Number 5
Date 7 February 2017
75(75)
Storey et al 2013
Storey R, James S, Siegbahn A, Varenhorst C, Held C, Ycas J et al. Lower mortality 
following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the 
PLATO study. Platelets 2013 [in press]
Thygesen et al 2012
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD et al. Third 
Universal MI definition. J Am Coll Cardiol 2012;60:1581-98.
Vazzana et al 2012
Vazzana N, Ranalli P, Cuccurullo C, Davì G. Diabetes mellitus and thrombosis. Thromb Res 
2012;129:371-7.
Wallentin et al 2009
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C et al; PLATO 
investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl 
J Med 2009;361:1045-57


 
 
Clinical Study Protocol Appendix B 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D513BC00001 
 
Edition Number 
1 
 
Date 
25 October 2013 
 
 
 
 
 
 
 
 
 
 
Appendix B 
Additional Safety Information 
 


Clinical Study Protocol Appendix B 
Drug Substance Ticagrelor 
Study Code D513BC00001 
Edition Number 1 
Date 25 October 2013 
2(3) 
FURTHER GUIDANCE ON THE DEFINITION OF A SERIOUS 
ADVERSE EVENT (SAE) 
Life threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalisation 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important medical event or medical intervention 
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious.  
These should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used. 
Examples of such events are: 
• 
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment 
• 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine 
• 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
• 
Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation 
• 
Development of drug dependency or drug abuse. 


Clinical Study Protocol Appendix B 
Drug Substance Ticagrelor 
Study Code D513BC00001 
Edition Number 1 
Date 25 October 2013 
3(3) 
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION 
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug. 
• 
Time Course.  Exposure to suspect drug.  Has the subject actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug? 
• 
Consistency with known drug profile.  Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? OR could the AE be anticipated from its pharmacological 
properties? 
• 
Dechallenge experience.  Did the AE resolve or improve on stopping or reducing 
the dose of the suspect drug? 
• 
No alternative cause.  The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors. 
• 
Rechallenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge. 
• 
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed 
the relationship? 
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist. 
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE. 
In difficult cases, other factors could be considered such as: 
• 
Is this a recognised feature of overdose of the drug? 
• 
Is there a known mechanism? 
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility. 


 
 
Clinical Study Protocol Appendix C 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D513BC00001 
 
Edition Number 
2 
 
Date 
19 June 2014 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C 
ADA/EASD Treatment Algorithm for Antihyperglycemic Therapy in 
Type 2 Diabetes Mellitus 
 


Clinical Study Protocol Appendix C 
Drug Substance Ticagrelor 
Study Code D513BC00001  
Edition Number 2 
Date 19 June 2014 
2(5) 
1. 
ADA/EASD TREATMENT ALGORITHM FOR 
ANTIHYPERGLYCEMIC THERAPY IN TYPE 2 DIABETES 
MELLITUS 
This appendix contains an excerpt from Inzucchi et al 2012, “Management of Hyperglycemia 
in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of the American 
Diabetes Association (ADA) and the European Association for the Study of Diabetes 
(EASD)” 
Full text available at doi: 10.2337/dc12-0413. Diabetes Care June 2012 vol. 35 no. 6 1364-79. 
Figure 1 Depiction of the elements of decision making used to determine appropriate 
efforts to achieve glycemic targets 
Inzucchi S E et al. Dia Care 2012;35:1364-1379
 
Depiction of the elements of decision-making used to determine appropriate efforts to achieve 
glycemic targets. Greater concerns about a particular domain are represented by increasing 
height of the ramp. Thus, characteristics/predicaments toward the left justify more stringent 
efforts to lower HbA1c, whereas those toward the right are compatible with less stringent 
efforts. Where possible, such decisions should be made in conjunction with the patient, 
reflecting his or her preferences, needs, and values. This “scale” is not designed to be applied 


Clinical Study Protocol Appendix C 
Drug Substance Ticagrelor 
Study Code D513BC00001  
Edition Number 2 
Date 19 June 2014 
3(5) 
rigidly but to be used as a broad construct to help guide clinical decisions. Adapted with 
permission from Ismail-Beigi et al. (20). 
Figure 2 Antihyperglycemic therapy in type 2 diabetes: general recommendations 
Inzucchi S E et al. Dia Care 2012;35:1364-1379
Copyright © 2011 American Diabetes Association, Inc.
 
Moving from the top to the bottom of Figure 2, general recommendations of potential 
sequences of antihyperglycemic therapy is given. In most patients, begin with lifestyle 
changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit 
contraindications). If the HbA1c target is not achieved after ~3 months, consider one of the 
five treatment options combined with metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-
1 receptor agonist, or basal insulin (the order in the chart is determined by historical 
introduction and route of administration and is not meant to denote any specific preference). 
Choice is based on patient and drug characteristics, with the over-riding goal of improving 
glycemic control while minimizing side effects. Shared decision making with the patient may 
help in the selection of therapeutic options. The figure displays drugs commonly used both in 
the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may be used in place of 
sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine 
agonists, pramlintide) may be used where available in selected patients but have modest 
efficacy and/or limiting side effects. In patients intolerant of, or with contraindications for, 
metformin, select initial drug from other classes depicted and proceed accordingly. In this 


Clinical Study Protocol Appendix C 
Drug Substance Ticagrelor 
Study Code D513BC00001  
Edition Number 2 
Date 19 June 2014 
4(5) 
circumstance, while published trials are generally lacking, it is reasonable to consider three-
drug combinations other than metformin. Insulin is likely to be more effective than most other 
agents as a third-line therapy, especially when HbA1c is very high (e.g., ≥9.0%). The 
therapeutic regimen should include some basal insulin before moving to more complex insulin 
strategies (Figure 3). Dashed arrow line on the left-hand side of the figure denotes the option 
of a more rapid progression from a two-drug combination directly to multiple daily insulin 
doses, in those patients with severe hyperglycemia (e.g., HbA1c ≥10.0–12.0%). DPP-4-i, 
DPP-4 inhibitor; Fx's, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor 
agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at this stage in patients with 
very high HbA1c (e.g., ≥9%). bConsider rapid-acting, nonsulfonylurea secretagogues 
(meglitinides) in patients with irregular meal schedules or who develop late postprandial 
hypoglycemia on sulfonylureas. cSee Table 11 for additional potential adverse effects and 
risks, under “Disadvantages”. dUsually a basal insulin (NPH, glargine, detemir) in 
combination with noninsulin agents. eCertain noninsulin agents may be continued with insulin 
(see text). Refer to Figure 3 for details on regimens. Consider beginning at this stage if patient 
presents with severe hyperglycemia (≥16.7–19.4 mmol/L [≥300–350 mg/dL]; HbA1c ≥10.0–
12.0%) with or without catabolic features (weight loss, ketosis, etc.). 
Figure 3 Sequential insulin strategies in type 2 diabetes  
Inzucchi S E et al. Dia Care 2012;35:1364-1379
Copyright © 2011 American Diabetes Association, Inc.
 
                                                 
1 Table 1 available in full text at doi: 10.2337/dc12-0413. Diabetes Care June 2012 vol. 35 no. 6 1364-79. 


Clinical Study Protocol Appendix C 
Drug Substance Ticagrelor 
Study Code D513BC00001  
Edition Number 2 
Date 19 June 2014 
5(5) 
Basal insulin alone is usually the optimal initial regimen, beginning at 0.1–0.2 units/kg body 
weight, depending on the degree of hyperglycemia. It is usually prescribed in conjunction with 
one to two noninsulin agents. In patients willing to take more than one injection and who have 
higher HbA1c levels (≥9.0%), twice daily (bd) premixed insulin or a more advanced basal 
plus mealtime insulin regimen could also be considered (curved dashed arrow lines). When 
basal insulin has been titrated to an acceptable fasting glucose but HbA1c remains above 
target, consider proceeding to basal plus mealtime insulin, consisting of one to three injections 
of rapid-acting analogs (see text for details). A less studied alternative—progression from 
basal insulin to twice-daily premixed insulin—could be also considered (straight dashed arrow 
line). If this is unsuccessful, move to basal and in addition mealtime insulin. Figure 3 
describes the number of injections required at each stage, together with the relative 
complexity and flexibility. Once a strategy is initiated, titration of the insulin dose is 
important, with dose adjustments made based on the prevailing glucose levels as reported by 
the patient. Noninsulin agents may be continued; although insulin secretagogues 
(sulfonylureas, meglitinides) are typically stopped once more complex regimens beyond basal 
insulin are utilized. Comprehensive education regarding self-monitoring of blood glucose, 
diet, exercise, and the avoidance of, and response to, hypoglycemia are critical in any patient 
on insulin therapy.  
2. 
LIST OF REFERENCES 
Inzucchi et al 2012 
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M et al. Management 
of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Position Statement of 
the American Diabetes Association (ADA) and the European Association for the Study of 
Diabetes (EASD). Diabetes Care 2012;35:6:1364-79 
 
 

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D513BC00001
Edition Number
3
Date
17 September 2018
A Multinational, Randomised, Double-Blind, Placebo-Controlled Trial to 
Evaluate the Effect of Ticagrelor twice daily on the Incidence of 
Cardiovascular Death, Myocardial Infarction or Stroke in Patients with 
Type 2 Diabetes Mellitus
[THEMIS - effect of Ticagrelor on Health outcomes in diabEtes Mellitus 
patients Intervention Study]






Statistical Analysis Plan 
Study Code D513BC00001
Edition Number 3
Date 17 September 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................................3
TABLE OF CONTENTS.....................................................................................................4
LIST OF ABBREVIATIONS ..............................................................................................6
AMENDMENT HISTORY..................................................................................................8
1.
STUDY DETAILS............................................................................................. 12
1.1
Study objectives................................................................................................. 12
1.1.1
Primary objective............................................................................................... 12
1.1.2
Secondary objectives.......................................................................................... 12
1.1.3
Exploratory objectives ....................................................................................... 12
1.1.4
Safety objectives................................................................................................ 14
1.2
Study design ...................................................................................................... 14
1.3
Number of subjects ............................................................................................ 15
2.
ANALYSIS SETS ............................................................................................. 15
2.1
Definition of analysis sets .................................................................................. 15
2.1.1
Full analysis set (FAS)....................................................................................... 15
2.1.2
Safety analysis set.............................................................................................. 15
2.1.3
Analysis set for U.S. Food and Drug Administration regulatory purposes........... 15
2.2
Violations and deviations ................................................................................... 16
3.
PRIMARY AND SECONDARY VARIABLES................................................. 16
3.1
Adjudication of clinical endpoint events............................................................. 16
3.2
Efficacy variables............................................................................................... 16
3.2.1
Primary efficacy variable ................................................................................... 17
3.2.2
Secondary efficacy variables.............................................................................. 17
3.2.3
Exploratory efficacy variables............................................................................ 17
3.3
Safety variables.................................................................................................. 18
3.3.1
Adverse events................................................................................................... 18
3.3.2
Bleeding events.................................................................................................. 18
3.4
Treatment compliance........................................................................................ 19
4.
ANALYSIS METHODS.................................................................................... 19
4.1
General principles.............................................................................................. 19


Statistical Analysis Plan 
Study Code D513BC00001
Edition Number 3
Date 17 September 2018
5
4.1.1
Censoring........................................................................................................... 20
4.1.2
Premature permanent discontinuation of study medication ................................. 21
4.1.3
Investigation of informative censoring ............................................................... 21
4.2
Analysis methods............................................................................................... 21
4.2.1
Primary efficacy variable ................................................................................... 21
4.2.1.1
Model checking and sensitivity analyses ............................................................ 22
4.2.1.2
Exploratory analyses and subgroup analyses of the primary efficacy 
variable.............................................................................................................. 23
4.2.2
Secondary efficacy variables.............................................................................. 25
4.2.3
Confirmatory analysis ........................................................................................ 25
4.2.4
Exploratory efficacy variables............................................................................ 25
4.2.5
Health Economics .............................................................................................. 25
4.2.6
Analysis of safety data ....................................................................................... 26
4.2.6.1
Bleeding events.................................................................................................. 26
4.2.6.2
Time to event analysis of bleedings.................................................................... 26
4.2.6.3
SAE and non-serious AE of interest ................................................................... 27
5.
INTERIM ANALYSES ..................................................................................... 27
6.
CHANGES OF ANALYSIS FROM PROTOCOL ............................................. 28
7.
REFERENCES .................................................................................................. 28
LIST OF TABLES
Table 1
Characteristics and categories for subgroup analysis of the primary 
composite endpoint ...............................................................................24


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LIST OF ABBREVIATIONS
Abbreviation 
or special term
Explanation
Adjudicated 
endpoint event
An event that fulfils study specific endpoint criteria as confirmed during 
adjudication by the independent CEC
AE
Adverse Event 
ALI
Acute Limb Ischaemia
ASA
Acetylsalicylic acid
BARC
Bleeding Academic Research Consortium
bd
Twice daily dosing
CEC
Clinical Endpoint Committee
CSP
Clinical Study Protocol
CV
Cardiovascular
DAE
Discontinuation of study medication due to an Adverse Event.  
DMC
Data Monitoring Committee
DVT
Deep Vein Thrombosis
eCRF 
Electronic Case Report Form
EQ-5D
Euro Quality of Life – 5 dimensions 
FAS
Full Analysis Set
HR
Hazard Ratio
ITT
Intention-to-treat
LTFU
Lost To Follow-Up
MedDRA
Medical dictionary for regulatory activities
MI
Myocardial infarction
PACD
Primary analysis censoring date
PEGASUS
Study acronym - PrEvention with TicaGrelor of SecondAry Thrombotic 
Events in High-RiSk Patients with Prior AcUte Coronary Syndrome
PLATO
A study of PLATelet inhibition and patient Outcomes
SAE
Serious Adverse Event 
SCV
Study Closure Visit
T2DM
Type 2 Diabetes Mellitus


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Abbreviation 
or special term
Explanation
TIMI
Thrombolysis In Myocardial Infarction


Statistical Analysis Plan 
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Edition Number 3
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AMENDMENT HISTORY
Date
Brief description of change
31 January 2014
First version published
27 March 2017
Title changed to reflect the reduced dose in clinical study protocol amendment, by 
replacing “Ticagrelor 90 mg twice daily” with “Ticagrelor twice daily”.
1.1.1 Changed “Ticagrelor 90 mg twice daily” to “Ticagrelor twice daily”.
1.1.2 Changed secondary objectives to reflect clinical study protocol amendment, 
from prevention of the composite of all-cause death/MI/stroke, CV death, all-
cause death (presented in hierarchical order) to prevention of CV death, MI, 
ischaemic stroke, all-cause death (presented in hierarchical order).
1.1.3 Changed exploratory objectives to reflect clinical study protocol 
amendment: Composite of all-cause death/MI/stroke and composite of irreversible 
harm added, while MI and ischaemic stroke are moved to secondary objectives. 
The analysis of the composite CV death, non-fatal MI, non-fatal stroke and major 
bleeding (TIMI major) removed. 
1.1.3 The composite of arterial and venous thrombotic events fulfilling serious 
adverse event criteria added as an exploratory analysis. The analysis of prevention 
of coronary arterial revascularisation added.
First paragraph in 1.2 changed to reflect clinical study protocol amendment,
increasing from expected 17000 to 19000 to be randomised, 750 to 1385 primary 
endpoint events, 35 to 58 months maximal study duration of treatment, 15 to 29
months minimum follow-up, 24 to 40 months average follow-up and enrolment 
period increased from18 to 28 months. 
1.3 Second paragraph changed to reflect clinical study protocol amendment, 
assumed HR changed from 0.80 to 0.84, from expected 750 to 1385 collected 
adjudicated events and changed power from 86 % to 90 %. 
1.3 Third paragraph: changed timelines and number of patients due to clinical 
study protocol amendment.
2.1.2 Changed definition of safety analysis set according to clinical study protocol 
Amendment 3.
2.1.3 Changed from “at the time of enrolment” to “at time of randomisation visit”
to reflect the time of collecting the information.
2.2 Changed section name from “Deviations” to “Violations and deviations” 
according to standards.
2.2 Study drug non compliance was eliminated from the protocol deviations.
2.2 Inserted information of how the analysis will be made when a patient is 
randomised more than once and for patients randomised on site 5730.


Statistical Analysis Plan 
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Date
Brief description of change
3.2 Clarification added: for the analysis of all-cause death, the analysis will 
include collected vital status information known through public records and not be 
limited to adjudicated death events.
3.2.2 Changed secondary efficacy variables, corresponding to changes made in 
section 1.1.2
3.2.3 Changed exploratory efficacy variables, corresponding to changes made in 
section 1.1.3
3.4 Changes made to reflect CSP amendment, to include ticagrelor 60 mg and 
ticagrelor 60 mg placebo as alternative doses.
3.4 Definition of compliant removed (in earlier versions defined as 80% of 
planned study medication) and the sentence about that interruptions >1 week are 
reported (captured in the clinical study protocol). 
First paragraph of 4.1: eliminated sentence “If collected, these events will be 
included in listings and tables”.
4.1 The score statistic replaced by the Wald statistic for the calculation of p-values 
and confidence intervals for HR using the Cox proportional hazards model.
4.1 Included minimum number of events requirement.
4.1.1 A clarification made in the 4th paragraph: from “Thus, in the main analyses 
patients will be censored at the time of consent withdrawal” to “Thus, in the main 
analyses patients will be censored at the time when all elements of the endpoint 
were assessed for those patients who withdraw consent and for whom only vital 
status is known from public records”.
4.1.1 Changed censoring rule for analysis of discontinuation due to bleeding 
event, the same censoring rule as for time-to-event analysis of bleeding will be 
applied.
4.1.3 Removed sentences “To examine this assumption, variables that may be 
related to censoring, e.g. the occurrence of SAEs, bleeding or certain AEs, will be 
explored. Frequencies will be calculated per treatment group and compared 
between patients censored prior to PACD, and those with complete follow-up. As 
discussed above patients censored prior to PACD are expected to almost 
exclusively be patients who have withdrawn consent. Note that any subjects 
withdrawing consent after a primary event will be included in the analysis of the 
primary endpoint.”
4.2.1.1 The sensitivity analysis of missing data has been modified to reflect 
amendment 3 of the clinical study protocol.
4.2.1.1 Sensitivity analysis of the primary variable: on treatment, with investigator 
reported events, with REACH risk score, blood pressure, heart rate and pulse 
pressure has been added.
4.2.1.1 A recurrent event analysis with the Wei-Lin-Weissfeld model and with the 
Lin-Wei-Yang-Ying model has been added.


Statistical Analysis Plan 
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Date
Brief description of change
4.2.1.1 Sensitivity analyses to examine the dose-switch have been added, since the 
dose was reduced in the first amendment of the clinical study protocol.
4.2.1.1 Changed definition of complete follow-up, that a patient have died of non-
CV death will not imply that the patient have complete follow-up.
4.2.1.2 Changed model for estimating the hazard ratio: from model with treatment, 
subgroup and interaction between treatment and subgroup as factors to only 
treatment as factor. Included minimum number of events requirement.
4.2.1.2 The last paragraph about compliance analyses has been removed.
4.2.1.2 The subgroups ASA use at any time during the study and lipid lowering 
drug use have been removed. History of PCI, stent implantation and type of stent 
have been combined, the categories for ASA dose have been changed from 
previous cut at 75 mg to 81 mg while the categories for HbA1c have been changed 
from a cut at 6.5 % to 7%. The ‘≥’ symbol has been replaced by ‘>’, and ‘<’ has 
been replaced by ‘≤’ for the categories of the subgroups BMI and creatinine 
clearance. The subgroups History of coronary arterial revascularisation, Duration 
of diabetes and History of any diabetes complications have been added.
All subgroups that are based on medication or lab values are changed to “at 
baseline”, except ASA that is changed to “at randomisation”.
Time since most recent PCI, time since most recent CABG history of poly-
vascular disease and number of prior vascular beds added to the list of subgroups.
First sentence in 4.2.3 changed number of secondary efficacy variables due to 
CSP amendment. 
4.2.6 Concomitant medications and protocol deviations removed from what will 
be presented for the safety analysis set since it will be presented for the full 
analysis set.
Second paragraph in 4.2.6: ‘results from physical examination’ removed from 
since such results are not collected in the study.
4.2.6.2 Exploration of concomitant antithrombotic therapy as potential risk factor 
eliminated. Analysis of the subgroup with a history of prior spontaneous bleeding 
removed (not collected).
4.2.6.2 Sensitivity analyses of TIMI Major bleeding have been added.
4.2.6.3 Changed definition of treatment period in order to conform with time to 
safety endpoint analyses.
4.2.6.3 Added sensitivity analysis of reported AEs, SAEs and DAEs for patients 
randomised to ticagrelor 60 mg or ticagrelor 60 mg placebo.
Second paragraph in 5: changes made to reflect CSP amendment, from 375 to 517 
planned primary events, and changed from second to first order secondary 
efficacy variable for CV death.
Section 6 Changes of analysis from protocol has been added.
Three references added: Wei 1989, Lin 2000 and Wilson 2012, respectively.


Statistical Analysis Plan 
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Date
Brief description of change
17 September
2018
Signature page: new Global product statistician Mikael Knutsson
Amendment history: Clarifying changes made in March 2017 in Section 1.1.3 
Exploratory endpoints added to Section 1.1.3 and Section 3.2.3
Section 2.2 sensitivity analysis that included patients randomised at a specific site 
has been removed.
Section 3.2.2: added clarification that strokes classified as “Unknown type of 
stroke/No imaging performed” will be included in the analysis of ischaemic 
stroke.
4.2.1.2 Subgroup analyses for each component of the primary efficacy variable 
added. Also, sentence added that analyses in a specific country subgroup may be 
done and reported separately. 
4.2.1.2, Table 1: “History of PCI, Yes/No” inserted as a new subgroup 
characteristic in table and the “No” category therefore removed from the subgroup 
of stent types and the title of that subgroup characteristic clarified to “Type of 
stent”. The category “No history of CABG” removed from subgroup “Time since 
most recent CABG”, since already covered in subgroup “History of CABG 
Yes/No”. The “No” category has also been removed from “ASA dose at baseline” 
and “Time since PCI”, covered in “ASA use at randomisation” and “History of 
PCI”, respectively. Creatinine clearance replaced by eGFR, name of subgroup 
characteristic corrected to better reflect the variable defining the subgroup.
4.2.2 Added sentence of repeating the subgroup analyses for the secondary 
efficacy variables.
Section 6, changed from two to eight exploratory objectives.


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1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
The primary objective of the study is to compare the effect of long-term treatment with 
ticagrelor twice daily (bd) vs. placebo for the prevention of major cardiovascular (CV) events 
(composite of CV death, myocardial infarction [MI] or stroke) in patients with Type 2 
Diabetes Mellitus (T2DM) at high risk for CV events, but without a medical history of 
previous MI or stroke.
The primary efficacy variable is time from randomisation to first occurrence of any event 
from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown 
aetiology).  
1.1.2
Secondary objectives
The secondary objectives of the study (presented in hierarchical order) are to compare the 
effect of long-term treatment with ticagrelor vs. placebo for:
1.
Prevention of CV death. The efficacy variable is time from randomisation to death of 
CV cause
2.
Prevention of MI. The efficacy variable is time from randomisation to first 
occurrence of MI
3.
Prevention of ischaemic stroke. The efficacy variable is time from randomisation to 
first occurrence of ischaemic stroke
4.
Prevention of all-cause death. The efficacy variable is time from randomisation to 
death of any cause.
1.1.3
Exploratory objectives
Other objectives are to explore other long-term treatment effects of ticagrelor vs. placebo on:

Prevention of the composite of all-cause death, MI or stroke. The efficacy variable 
is time from randomisation to first occurrence of any event from the composite of 
all-cause death, MI or stroke

Prevention of stroke. The efficacy variable is time from randomisation to first 
occurrence of stroke

Effect on irreversible harm events, the composite of all-cause mortality, MI, stroke, 
intracranial haemorrhage and fatal bleeding. The efficacy variable is time from 


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randomisation to first occurrence of any event from the composite of all-cause 
mortality, MI, stroke, intracranial haemorrhage and fatal bleeding

Prevention of the composite of arterial and venous thrombotic events that fulfills 
any SAE criteria. The efficacy variable is time from randomisation to the first 
occurrence of any event from the composite of arterial and venous thrombotic
events that fulfills any SAE criteria (not included in CSP, see section 6)

Prevention of coronary arterial revascularisations. The efficacy variable is time 
from randomization to the first occurrence of any coronary arterial revascularisation 
(not included in CSP, see section 6)

Prevention of the composite of acute limb ischaemia (ALI) and major amputation of 
vascular aetiology. The efficacy variable is time from randomisation to first 
occurrence of any event from the composite of ALI and major amputation of 
vascular aetiology (not included in CSP, see section 6)

Prevention of the composite of urgent peripheral arterial revascularisation, venous 
thrombotic event (defined as deep vein thrombosis [DVT] or pulmonary embolism), 
ALI and major amputation of vascular aetiology. The efficacy variable is time from 
randomisation to first occurrence of any event from the composite of urgent 
peripheral arterial revascularisation, venous thrombotic event, ALI and major 
amputation of vascular aetiology (not included in CSP, see section 6)

Prevention of the composite of all-cause mortality, MI, stroke, ALI and major 
amputation of vascular aetiology. The efficacy variable is time from randomisation 
to first occurrence of any event from the composite of all-cause mortality, MI, 
stroke, ALI and major amputation of vascular aetiology (not included in CSP, see 
section 6)

Prevention of the composite of CV death, MI, stroke, ALI, major amputation of 
vascular aetiology and venous thrombotic event. The efficacy variable is time from 
randomisation to first occurrence of any event from the composite of CV death, MI, 
stroke, ALI, major amputation of vascular aetiology and venous thrombotic event 
(not included in CSP, see section 6)

Prevention of the composite of CV death, MI, stroke, ALI, major amputation of 
vascular aetiology and urgent peripheral arterial revascularisation. The efficacy 
variable is time from randomisation to first occurrence of any event from the 
composite of CV death, MI, stroke, ALI, major amputation of vascular aetiology 
and urgent peripheral arterial revascularisation (not included in CSP, see section 6)

Prevention of the composite of all-cause mortality, MI, stroke, ALI, major
amputation of vascular aetiology, venous thrombotic event, urgent peripheral 
arterial revascularisation and coronary revascularisation. The efficacy variable is 
time from randomisation to first occurrence of any event from the composite of all-


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cause mortality, MI, stroke, ALI, major amputation of vascular aetiology, venous 
thrombotic event, urgent peripheral arterial revascularisation and coronary 
revascularisation (not included in CSP, see section 6)

Health care resource utilisation and utilities assessed by Euro Quality of Life-5 
Dimensions (EQ-5D) questionnaire to support health technology assessment and 
health economic modelling.
1.1.4
Safety objectives
The overall safety objective of this study is to assess the safety and tolerability of long-term 
therapy with ticagrelor compared to placebo in patients with T2DM at high risk of CV events, 
with or without background low-dose aspirin therapy. Bleeding events will be analysed using 
the Thrombolysis in Myocardial Infarction Study Group (TIMI), PLATO (PLATelet 
inhibitation and patient Outcomes) and the Bleeding Academic Research Consortium (BARC) 
definitions. Specific focus will be on:

Time to first TIMI Major bleeding event (primary safety objective)

Time to first TIMI Major or Minor bleeding event

Time to first PLATO Major bleeding event

Time to permanent discontinuation of study medication due to any bleeding event.
Non-serious AEs of interest (i.e. dyspnoea, renal impairment, bradyarrhythmia, gout, and 
pneumonia), adverse events that leads to permanent discontinuation of study medication 
(DAEs) and all serious adverse events (SAEs) will be reviewed within the context of the 
earlier safety experience with the drug.
1.2
Study design
The study is event-driven and 19000 randomised patients are estimated to be required in order 
to collect 1385 adjudicated primary endpoint events. The anticipated maximal duration of 
treatment with study medication for an individual patient is 58 months. However, the actual 
duration of the study will be based on accrual of the pre-determined number of adjudicated 
primary endpoint events, and therefore the study may be shorter or longer than 58 months. 
The expected minimum follow-up period is 29 months and the expected average follow-up 
period is 40 months, based on an enrolment period of 28 months. A study closure plan will be 
developed that accounts for the patient recruitment pattern and the event rate to reach the 
predetermined number of adjudicated primary endpoint events (1385).
As safety is continuously monitored, the study may be terminated early if either a clear 
beneficial or harmful effect of the study treatment is detected during the Data Monitoring 
Committee (DMC) review.


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1.3
Number of subjects
Based on clinical studies and epidemiological information, the event rate for the composite of 
CV death, MI or stroke has been estimated to be 2.5% annually in a population consisting of 
patients with T2DM at high risk for CV events without previous medical history of MI or 
stroke.
The final primary treatment comparison will be made at a significance level of 4.96% adjusted 
for the planned efficacy interim analysis. Assuming a true hazard ratio (HR) of 0.84 between 
ticagrelor and placebo, 1385 primary endpoint events will provide a power of 90%. 
With an annual event rate of 2.5% in the placebo treatment group, 19000 patients, randomised 
in a 1:1 ratio, with an average follow-up period of 40 months, are estimated to provide the 
required number of primary events. The expected minimum follow-up period is 29 months, 
based on an enrolment period of 28 months.
The expected number of patients who will be lost-to-follow-up is negligible and hence not 
considered in the determination of samples size.
2.
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Full analysis set (FAS)
All patients who have been randomised to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study. 
Patients will be analysed according to their randomised study medication irrespective of 
whether the event occurred before or following discontinuation of study medication. Patients 
who withdraw consent to participate in the study will be included up to the date of their study 
termination except for vital status known through public records (for use in the analysis of all-
cause death). All efficacy variables will be analysed using the FAS.
2.1.2
Safety analysis set
All patients who received at least 1 dose of randomised ticagrelor or placebo, will be included 
in the safety analysis set. Throughout the safety results sections, erroneously treated patients 
(e.g., those randomised to ticagrelor but actually given placebo) will be accounted for in the 
actual treatment group. A patient who in error has received both ticagrelor and placebo will be 
accounted for in the randomised treatment group.
2.1.3
Analysis set for U.S. Food and Drug Administration regulatory purposes
The primary analysis will be on the FAS in a subset of patients on acetylsalicylic acid (ASA) 
therapy at the day of randomisation visit. 


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2.2
Violations and deviations
Important protocol deviations will be summarised by treatment group and will include but not 
be limited to:

Patients who were randomised but did not meet inclusion and exclusion criteria

Patients who received prohibited concomitant medication

Patients who received the wrong study medication at any time during the study

Patients who were randomised but took no study medication.
Protocol deviations will be identified by programmed checks prior to database lock. However, 
as full analysis set (FAS) is the primary analysis set, protocol deviations will not imply 
exclusion from the analysis.
If one patient has been randomised more than once in the study, the patient will be analysed 
according to the first randomisation and all collected data will be reconciled at the discretion 
of the investigator.
Patients that were randomised at site 5730 will not be included in any analysis sets. 
AstraZeneca has reported the investigator to authorities for potential scientific misconduct and 
made the decision to exclude the patients from the analyses.
3.
PRIMARY AND SECONDARY VARIABLES
3.1
Adjudication of clinical endpoint events
Clinical efficacy endpoint events and bleeding events will be evaluated by a Clinical Endpoint 
Committee (CEC) that is independent of the sponsor and investigators. Events will be 
identified using standard questioning of the patient at each visit, or by information the 
investigator may receive as part of standard medical practice. Safety endpoint events will be 
identified similarly. The investigator will complete endpoint event specific forms on the 
electronic case report form (eCRF) and compile additional source information into an 
‘Endpoint Package’ which will be sent to the CEC for central adjudication.
3.2
Efficacy variables
The efficacy objectives will be evaluated using analysis of time from randomisation to first 
event, using only events positively adjudicated by the CEC (except for the analysis of all-
cause death where also vital status known from public records will be used). Time will be 
calculated as the number of days plus one between the date of randomisation and date of the 
first occurrence of the event, or, if no event has occurred, the date of censoring (see Section 
4.1.1).


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When the first event is a MI or stroke, the time to the primary event will be the time to the MI 
or stroke, irrespective of whether or not the patient dies as a sequel of the event. 
Deaths where cause of death is unknown will be accounted for as CV deaths in the efficacy 
analyses. 
3.2.1
Primary efficacy variable
The primary efficacy variable is time from randomisation to first occurrence of any event 
from the composite of CV death, MI or stroke (ischaemic, haemorrhagic or unknown 
aetiology).  
3.2.2
Secondary efficacy variables
Secondary efficacy variables are:
1.
Time from randomisation to death of CV cause
2.
Time from randomisation to first occurrence of MI
3.
Time from randomisation to first occurrence of ischaemic stroke (including strokes 
classified as “Unknown type of stroke/No imaging performed”)
4.
Time from randomisation to death of any cause.
3.2.3
Exploratory efficacy variables
Other efficacy variables are:

Time from randomisation to first occurrence of any event from the composite of all-
cause death, MI or stroke

Time from randomisation to first occurrence of stroke

Time from randomisation to first occurrence of any event from the composite of all-
cause mortality, MI, stroke, intracranial haemorrhage and fatal bleeding 
(irreversible harm events)

Time from randomisation to the first occurrence of any event from the composite of 
arterial and venous thrombotic events that fulfils any SAE criteria 

Time from randomisation to first occurrence of coronary arterial revascularisation 

Time from randomisation to first occurrence of any event from the composite of 
ALI and major amputation of vascular aetiology 

Time from randomisation to first occurrence of any event from the composite of 
urgent peripheral arterial revascularisation, venous thrombotic event, ALI and 
major amputation of vascular aetiology 


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
Time from randomisation to first occurrence of any event from the composite of all-
cause mortality, MI, stroke, ALI and major amputation of vascular aetiology

Time from randomisation to first occurrence of any event from the composite of CV 
death, MI, stroke, ALI, major amputation of vascular aetiology and venous 
thrombotic event 

Time from randomisation to first occurrence of any event from the composite of CV 
death, MI, stroke, ALI, major amputation of vascular aetiology and urgent 
peripheral arterial revascularisation

Time from randomisation to first occurrence of any event from the composite of all-
cause mortality, MI, stroke, ALI, major amputation of vascular aetiology, venous 
thrombotic event, urgent peripheral arterial revascularisation and coronary 
revascularisation

Health care resource utilisation and utilities assessed by EQ-5D questionnaire to 
support health technology assessment and health economic modelling.
3.3
Safety variables
3.3.1
Adverse events
AEs of interest (i.e., dyspnoea, renal impairment, bradyarrhythmia, gout, and pneumonia) and 
DAEs (Discontinuations of Study Medication due to Adverse Event) will be collected from 
randomisation throughout the study until and including the Study Closure Visit (SCV).
All SAEs will be recorded from the time of informed consent throughout the study until and 
including the SCV. Events adjudicated to the endpoint events non-fatal MI, primary ischaemic 
stroke or CV death, although qualifying as SAEs, will only be reported as primary endpoint 
events in the Clinical Study Report.
Section 6.4 in the Clinical Study Protocol (CSP) gives more detailed information on adverse 
event data collection.
3.3.2
Bleeding events
Bleeding events that are self-limited, and do not prompt medical evaluation or intervention, 
need not to be reported. For all bleeding events that are unexpected or of unanticipated 
quantity, the investigator will complete information on the eCRF specific to that bleeding 
event. In addition, for all reported bleeding events relevant information will be compiled and 
sent to the CEC for central adjudication according to the following bleeding definitions: TIMI, 
PLATO and BARC. Additional details can be found in the CEC Charter.
Additionally, all bleeding events (including haemorrhagic stroke) fulfilling the SAE criteria 
will be reported as SAEs by the sponsor to the health authorities. If the adjudication of a 
stroke event unveils a haemorrhagic stroke not yet reported as SAE, it will be reported as SAE 
to the health authorities. Further details can be found in Section 6.4.5 in the CSP. 


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Specific focus will be on the following bleeding variables, from time of randomisation:

Time to first TIMI Major bleeding event (primary safety objective)

Time to first TIMI Major or Minor bleeding event

Time to first PLATO Major bleeding event

Time to permanent discontinuation of study medication due to any bleeding event.
3.4
Treatment compliance
Patients will be asked to return all unused study medication and empty packages to the clinic 
at each visit.  The number of dispensed and returned pills (determined by pill count) will be 
recorded in the eCRF. Based on the pill counts, the percentage treatment compliance will be 
calculated as the number of pills taken (dispensed minus returned) relative to the expected 
number of taken pills. The expected number of pills taken will be calculated as:
(number of pills to be taken daily)×(number of days between visits – number of days 
of planned interruption)
The number of pills to be taken daily is 2, initially either 2 ticagrelor 90 mg or 2 ticagrelor 90 
mg placebo, while after Clinical Study Protocol Amendment No 1, either 2 ticagrelor 60 mg 
or 2 ticagrelor 60 mg placebo.
4.
ANALYSIS METHODS
4.1
General principles
Clinical events reported after database lock will not be included in the primary efficacy and 
safety analysis. 
For time to event variables, treatments will be compared using a Cox proportional hazards 
model with a factor for treatment group, using the Efron method for ties. Censoring principles 
are described in Section 4.1.1.  The p-values (calculated using the Wald test), HR and 95% 
confidence intervals for the HR will be reported. Summary tables of these analyses will also 
include the number of patients with an event and Kaplan-Meier estimates of the event rates 
per treatment group estimated at a time point determined on the basis of the available follow-
up. Kaplan-Meier estimates of the cumulative proportion of patients with events will be 
estimated and plotted, with the number of patients at risk indicated below the plot at specific 
time points. If the total number of events in an endpoint or subgroup category is <15, only 
percentage of patients with events will be presented, but no Kaplan-Meier estimates, HRs,
confidence intervals or p-values.
The primary and secondary efficacy variables will be included in a confirmatory testing 
procedure described in Section 4.2.3. No further multiplicity adjustment will be made to 


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confidence intervals or p-values. Analyses of efficacy or safety variables that are not part of 
the confirmatory analyses are considered exploratory and any p-value and confidence interval 
will be used as a measure of precision only. 
In addition to specific analyses and presentations that are detailed in the following sections, 
results will be summarised using descriptive statistics, including the number of patients, mean, 
standard deviation, median and range as appropriate. For categorical variables counts and 
percentage per treatment group will be presented. Summaries of continuous variables will be 
based on non-missing observations. Percentage for categorical variables will be calculated 
based the total number of patients in the treatment group, i.e. the denominator includes the 
number of patients with missing values for the variable.
Demographic characteristics, qualifying risk factors and other specific medical and surgical 
history will be summarised for the FAS using descriptive statistics.
4.1.1
Censoring
The executive committee will monitor the accrual of the number of primary events and when 
appropriate predict and define a primary analysis censoring date (PACD) at which time the 
pre-defined target number of events for the primary composite endpoint are expected to have 
occurred. 
The PACD will be the common date at which all patients who are event free for the given 
endpoint and have not withdrawn consent for participating in the study will be censored in 
efficacy time-to-event analyses. Events that occur after the PACD but before the SCV will 
also be collected and adjudicated. These events will be included in sensitivity analyses but not 
in the primary analysis. Events that occur after SCV will be described in text or tabulated 
descriptively. 
Patients who have not had the event(s) in question will be censored at the earlier of (1) the 
PACD and (2) the last study contact when all components of the endpoint in question were 
assessed. In the analysis of CV death and composites including CV death censoring will occur 
at the earlier of (1), (2) and (3) the date of death from non-cardiovascular causes. For 
endpoints not including death, all deaths are censoring events.
Complete endpoint information will be pursued with every effort for all patients regardless of 
their study medication status, unless they exercise their right to withdraw consent. Patients 
who have a non-fatal event will continue study follow-up. For patients who withdraw consent 
and for whom only vital status (known to be alive at study closure, or date of death) may be 
obtained from public records, the occurrence of all components of the primary endpoint 
cannot be assessed. Thus, in the main analyses patients will be censored at the time when all 
elements of the endpoint were assessed for those patients who withdraw consent and for 
whom only vital status is known from public records. However, the determination of all-cause 
death will utilise all publicly known mortality data, even that extending beyond date of 
consent withdrawal. The vital status information will be included in the analysis of all-cause 
death as a single endpoint, and in sensitivity analysis and tabulations.


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Similarly, complete information on the primary endpoint may not be obtained for patients who 
are lost to follow-up (LTFU). Any such patient will be censored in the analysis of the primary 
composite endpoint at the last contact where all elements of the endpoint were assessed. A 
patient will not be recorded as LTFU until the end of the study, after every allowable effort to 
get in contact has been made. Hence, it is anticipated that the number of patients LTFU will be 
limited.
In safety time-to-event analysis of bleeding and discontinuation of study drug due to bleeding, 
patients not having suffered any bleeding event in the given category will be censored at the 
earlier of  SCV, 7 days after last dose of study drug, death, last contact or withdrawal of 
consent. 
4.1.2
Premature permanent discontinuation of study medication
Discontinuation from study medication is not the same as withdrawal from the study. As 
described in Section 5.8.3 in the CSP there are several options for continuation in the study. 
It is expected that complete information on the primary composite endpoint event (and as 
much as possible of the eCRF data for patients contacted by telephone) will be obtained for all 
patients who prematurely discontinue study medication, unless they refuse any form of 
follow-up and withdraw consent or are LTFU. Thus, event free patients who prematurely 
permanently discontinue study medication will in general not be censored before PACD in the 
primary ITT analysis.
4.1.3
Investigation of informative censoring
The time-to-event analysis (Cox regression) relies on the assumption of non-informative 
censoring. 
Sensitivity analyses to assess possible effects of informative censoring on the primary 
endpoint event are described in Section 4.1.1 and Section 4.2.1.1.
4.2
Analysis methods
4.2.1
Primary efficacy variable
The primary efficacy variable, time from randomisation to the first occurrence of any event 
from the composite of CV death, MI and stroke, will be analysed using the methodology 
described in Section 4.1. The null hypothesis of no treatment effect, 
H0: HR(ticagrelor divided by placebo) = 1, 
versus the alternative hypothesis, 
H1: HR ≠ 1, 
will be tested at 4.96% two-sided significance level to account for the planned interim 
analyses with the overall type I error preserved at 5% (see Section 5). 


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4.2.1.1
Model checking and sensitivity analyses
The assumption of proportional hazards for the factor for treatment group will be assessed 
visually using log-cumulative hazard plots. The effect of any departures from proportional 
hazards will be discussed as part of the presentation of results of the analyses.
To assess possible effects of missing data, sensitivity analyses will be done as follows. The 
event rate in the placebo arm will be used to estimate the intensity of a Poisson process. Based 
on the missing follow-up time, i.e. the time from censoring to PACD, the expected number of 
events in the ticagrelor group that could have been observed if the patients had completed the 
study will be estimated from the Poisson process. The comparison of ticagrelor and placebo 
will be recalculated with these additional events. If the result is still significant with these 
additional events, the minimum intensity of the Poisson process that on average gives non-
significant results when adding events to the ticagrelor group will be estimated using 
simulations. 
Sensitivity analysis of the primary composite endpoint event will also include analysis 

Including vital status information from patients who have withdrawn consent, 
where deaths are assumed to be CV deaths

Including events that occur after PACD but before SCV (i.e. patients who have not 
had the events will be censored at the earlier of the SCV date, last study contact 
when all components were assessed or date of death from non-CV causes)

With a Wei-Lin-Weissfeld model for recurrent event analysis of the events in the 
primary composite endpoint (Wei 1989), where 3 are the maximum number of 
events  

With a Lin-Wei-Yang-Ying model for recurrent event analysis of the events in the 
primary composite endpoint (Lin 2000)

On treatment, where patients who have not had a primary event will be censored 3, 
7 and 30 days after last dose of study drug, respectively 

With events as reported by the investigator

With treatment and Reduction of Atherothrombosis for Continued Health (REACH) 
risk score for secondary CV events as covariates in a Cox proportional hazards 
model (Wilson 2012)

With treatment and a risk factor as explanatory variables in a Cox proportional 
hazards model, for the risk factors systolic blood pressure, diastolic blood pressure, 
pulse pressure and heart rate at baseline, respectively

With treatment and duration of diabetes (continuous) as explanatory variables in a 
Cox proportional hazards model.


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The proportion of patients with complete follow-up will be presented per treatment group. 
Patients for whom all components of the primary endpoint event have been ascertained on or 
after PACD are considered to have complete follow-up.
To explore the consistency between the treatment effect of ticagrelor 60 mg and the overall 
treatment effect of ticagrelor, a sensitivity analysis of the primary efficacy variable with a Cox 
proportional hazards model with time dependent covariates will be performed. In this model a 
factor for treatment group and a time dependent indicator of the dose of study drug for 
patients treated with ticagrelor are included as covariates. The model can be written:
h(t, x1, x2(t))=h0(t)exp{β1∙x1+β2∙x2(t)}
where h0(t) is the baseline hazard, β1 is the coefficient for treatment group, x1 is defined as 0 
for placebo and 1 for ticagrelor, β2 is the coefficient for the time dependent study drug dose 
variable for ticagrelor and x2(t) is equal to 1 if the patient is treated with ticagrelor 60 mg at 
time t and otherwise equal to 0. Thus, the hazard ratio of ticagrelor 60 mg versus placebo is 
exp{β1+β2}. 
Further sensitivity analysis of the consistency of treatment effect for the 60 mg dose compared 
to the overall treatment effect will be performed by assessing the effect in patients randomised 
to ticagrelor 60 mg compared to those randomised to ticagrelor 60 mg placebo.
Sensitivity analysis of the primary composite endpoint event will also include analysis on-
treatment in patients randomised ticagrelor 60 mg or ticagrelor 60 mg placebo and in patients 
randomised to ticagrelor 90 mg or ticagrelor 90 mg placebo, respectively. The treatment effect 
of the randomised dose of ticagrelor versus the randomised dose of ticagrelor placebo will be 
estimated with a Cox proportional hazards model with treatment as the only explanatory 
variable. Events that occur up to and including 7 days after last randomised dose of study drug 
will be included in the analysis, and event free patients will be censored at the earlier of 7 days 
after last randomised dose of study drug, last contact, non-CV death, SCV or withdrawal of 
consent.
A landmark analysis of the primary composite endpoint to explore the consistency of 
treatment effect over treatment dose will be performed. In the analysis, the incidence of 
primary composite events when the patients are treated with ticagrelor 90 mg or ticagrelor 90 
mg placebo, and when patients are treated with ticagrelor 60 mg or ticagrelor 60 mg placebo 
for patients who were event free up to the day of the first 60 mg dose are examined. 
4.2.1.2
Exploratory analyses and subgroup analyses of the primary efficacy variable
Subgroup analyses on the primary efficacy variable, and its components, will be performed to 
evaluate variation of treatment effect. The subgroups in Table 1 will be examined in Cox 
regression models with a factor for treatment. Kaplan-Meier estimates, hazard ratios and 95% 
confidence intervals will be reported for each subgroup category if at least 15 events have 
occurred within the subgroup category. A test of interaction between treatment and each 
subgroup will be performed in a Cox proportional hazards model with factors for treatment, 


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subgroup and the interaction between treatment and subgroup for each subgroup where at least 
15 events have occurred in each category.
Table 1
Characteristics and categories for subgroup analysis of the primary 
composite endpoint
Characteristic
Categories
Age (years) 
< 65,  65-75,  >75
Sex
Male, Female
Race 
White, Black or African American, Asian, Other
BMI (kg/m2)
≤ 30, >30
Geographic region
Asia and Australia, Europe and South Africa, 
North America, Central and South America
ASA use at randomisation
Yes, No
ASA dose at baseline (mg)
≤81, >81
HbA1c at baseline (%)
≤ 7 , > 7
eGFR (MDRD) at baseline (mL/min/1.73 m2)
≤ 60, > 60 
Insulin use at baseline
Yes, No
History of Angina
Yes, No
Multivessel Coronary Artery Disease (>1 vessel)
Yes, No
History of PCI
Yes, No
Type of stent
PCI and any DES (including patients with both 
DES and BMS), PCI and BMS, PCI without stent 
implantation
History of CABG
Yes, No
History of Coronary Arterial Revascularisation
Yes, No
Statin use at baseline
Yes, No
PPI use at baseline
Yes, No
Current smoker 
Yes, No
Duration of diabetes (years)
≤10, >10
History of any diabetes complications at baseline
Yes, No
Number of prior diabetes complications
0, 1, 2, 3-4
History of Peripheral Arterial Occlusive disease
Yes, No
History of Poly-vascular disease
Yes, No
Number of prior vascular beds
1, 2, 3
Time since most recent PCI (years)
<1, 1-3, >3


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Characteristic
Categories
Time since most recent CABG (years)
≤5, >5
BMI = Body Mass Index, BMS = Bare metal stent, CABG = Coronary Artery Bypass, DES = Drug eluting 
stent, eGFR = estimated Glomerular Filtration Rate, HbA1c = Haemoglobin A1c, MDRD = Modification 
of Diet in Renal Disease, PCI = Percutaneous Coronary Intervention, PPI = Proton Pump Inhibitor.
Baseline is defined as before or at the day of randomisation visit. Poly-vascular disease is defined as 
history of more than one vascular bed (out of the three possible vascular beds: coronary arterial disease, 
peripheral arterial occlusive disease, and carotid artery stenosis or cerebral revascularisation. 
In addition to subgroup characteristics listed in Table 1, analyses in a specific country 
subgroup may be done and reported separately to meet requirements for regulatory 
submissions to local authorities.
4.2.2
Secondary efficacy variables
The secondary efficacy variables will be analysed using the methodology described in Section 
4.1. The analyses in section 4.2.1.2 will be repeated for the secondary efficacy variables.
4.2.3
Confirmatory analysis
The analysis of the primary variable described in Section 4.2.1 and the four secondary 
efficacy variables listed in Section 3.2.2 will comprise the confirmatory analysis. In order to 
address the issue of multiple testing a hierarchical test sequence will be used. The sequence 
will start with the primary variable and then follow in the order specified in Section 3.2.2. 
The testing at the interim analysis will be at the two-sided 0.1% significance level, while a 
two-sided 4.96% significance level will be used at the final analysis. In what follows the 
testing at the final analysis is described, while further detail about the testing at the interim 
analysis is provided in Section 5.
Only if the treatment effect on the primary efficacy variable is significant at the two-sided 
4.96% significance level, will the secondary efficacy variables be tested in a confirmatory 
sense in the order given in Section 3.2.2. The hypothesis testing will continue at the two-sided 
4.96% significance level until the first statistically non-significant treatment difference (p ≥ 
0.0496) is observed. Secondary efficacy variable will be tested in an exploratory manner if 
there has been at least one non-significant test earlier in the sequence.  
4.2.4
Exploratory efficacy variables
Time to event variables will be analysed using the methodology described in Section 4.1.
4.2.5
Health Economics
The variables collected to support health economic evaluation are the EQ-5D questionnaire, 
administered every 6 months at on-site visits from Visits 2 throughout the study until SCV, 
and health care resource utilisation data for hospitalisations will be presented descriptively for 
the FAS per treatment. Further details and other health economic analyses will be specified in 


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a separate health economic analysis plan and presented in a separate report and are therefore 
not addressed in this SAP.
4.2.6
Analysis of safety data
All safety analyses will be based on the safety analysis set defined in Section 2.1.2.
Exposure to study drug, reasons and time to discontinuation of study drug, local laboratory 
data at baseline and vital signs will be summarised per treatment group using descriptive 
statistics.
4.2.6.1
Bleeding events
Bleeding events will be categorised on the basis of

Category according to TIMI and PLATO definitions (as defined in the CEC 
charter), BARC bleeding profiles

Provocation (ie, spontaneous, procedural and traumatic).
Bleeding events will be summarised by treatment group. The number of transfused blood units 
will be summarised per treatment group.
The total number of bleeding events, counting multiple events per patient, will be presented.
4.2.6.2
Time to event analysis of bleedings
Time to bleeding event variables will be analysed using the same methodology as for the 
efficacy variables as described in Section 4.1.
Explorative analysis of time to bleeding for selected subgroups will be performed for the main 
bleeding categorisations (TIMI major, TIMI major or minor, and PLATO major). Subgroups 
will be the groups defined for the efficacy analysis in Section 4.2.1.2.
Sensitivity analysis of TIMI major bleeding to address the consistency of the overall effect of 
ticagrelor on bleeding compared to the 60 mg dose will be performed with a Cox proportional 
hazards model with time dependent covariates, as described in Section 4.2.1.1 for the primary 
variable.
Furthermore, a sensitivity analysis of TIMI major bleeding on-treatment in patients 
randomised to ticagrelor 60 mg or ticagrelor 60 mg placebo and in patients randomised to 
ticagrelor 90 mg or ticagrelor 90 mg placebo will be performed. These analyses include events 
that occur up to and including 7 days after last randomised dose of study drug, and event free 
patients will be censored at the earlier of 7 days after last randomised dose of study drug, last 
contact, death, SCV or withdrawal of consent.
A landmark analysis of TIMI major bleeding to explore the consistency of treatment effect
over treatment dose will be performed. In the analysis, the incidence of TIMI major bleedings 


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when the patients are treated with ticagrelor 90 mg or ticagrelor 90 mg placebo, and when 
patients are treated with ticagrelor 60 mg or ticagrelor 60 mg placebo for patients who were 
event free up to the day of the first 60 mg dose are examined. 
4.2.6.3
SAE and non-serious AE of interest
Each AE will be assigned to on/off treatment period as

Baseline period: The time before randomisation

On treatment: The time from randomisation until 7 days after last dose study drug

Off treatment: More than 7 days after last dose of study drug.
AEs will be assigned to the period where they start.
AEs of interest, DAEs as well as SAEs will be evaluated. Summaries, by system organ class 
and preferred term using MedDRA, will be presented by treatment group using descriptive 
statistics. All AEs relating to bleeding will be summarised separately. A subset of these 
summaries will be repeated for patients randomised to ticagrelor 60 mg or ticagrelor 60 mg 
placebo as a sensitivity analysis.
5.
INTERIM ANALYSES
One efficacy interim analysis will be performed by the DMC. The DMC charter contains more 
information about the DMC procedures. A copy of the treatment codes will be made available 
to the statistician on the DMC. The Executive Committee and AstraZeneca will not be made 
aware of the treatment codes until after clean file and database lock are declared. Similarly, all 
summary output reviewed at each DMC meeting will be held in confidence by the DMC 
members until the end of the study when clean file and database lock are declared. 
The interim analysis will be performed following the accrual and confirmation by adjudication 
of 517 primary events. The stopping boundary at the interim analysis is a two-sided p-value 
<0.001 for both primary endpoint event (CV death, MI, and stroke) and for CV death (the 1st
secondary efficacy variable). The interim p-value is small enough for the final analysis to be 
conducted at a significance level of 4.96%, with the family wise error rate controlled at 
5.00%. These boundaries were estimated using a Haybittle-Peto procedure (Haybittle 1971, 
Peto 1976).
If a recommendation to stop the study is made at the interim, all subsequent testing will be 
done at the same significance level as for the interim.


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6.
CHANGES OF ANALYSIS FROM PROTOCOL
Eight exploratory objectives have been added since these were considered to be of interest for 
scientific exchange.
7.
REFERENCES
Wei 1989
Wei LJ, Lin DY and Weissfeld L. Regression Analysis of Multivariate Incomplete Failure 
Time Data by Modeling Marginal Distributions. Journal of the American Statistical 
Association 1989;84:1065-1073. 
Lin 2000
Lin DY, Wei LJ, Yang I and Ying Z. Semiparametric regression for the mean and rate 
functions of recurrent events. J. R. Stat. Soc. B 2000:62:711-730.
Wilson 2012
Wilson PWF, D’Agostino Sr R, Bhatt DL, Eagle K, Pencina MJ, Smith SC, et al. An 
international Model to Predict Recurrent Cardiovascular Disease. The American Journal of 
Medicine 2012;125:695-703.
Haybittle 1971
Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Brit J 
Radiology 1971;44:793-7.
Peto 1976
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. Design and analysis 
of randomized clinical trials requiring prolonged observation of each patient: I. Introduction 
and design. Brit J Cancer 1976;34:585-612.