Clinical trial NCT03354429
Conditions: Acute Ischaemic Stroke Transient Ischaemic Attack
Keywords: Acute ischaemic stroke; Transient Ischaemic Attack (TIA); Stroke
Sponsor: AstraZeneca
Start date: 2018-01-22; Completion date: 2019-12-13
Enrollment: 11016 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Study to investigate if the study drug ticagrelor and ASA is more effective than Placebo (inactive tablet) and ASA in preventing new stroke events

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: Ticagrelor intervention 2: Placebo
Intervention descriptions: intervention 1: Ticagrelor arm: Day 1, loading dose of ticagrelor followed by daily maintenance dose until Day 30. intervention 2: Placebo arm: Day 1, loading dose of placebo followed by placebo daily maintenance dose until Day 30.

Protocol documents:
Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
This submission document contains confidential commercial information, disclosure of which 
is prohibited without providing advance notice to AstraZeneca and opportunity to object.
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures.  The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Clinical Study Protocol 
Drug Substance
Ticagrelor
Study Code
D5134C00003
Version
3.0
Date
08 May 2019
A Randomised, Double-Blind, Placebo-Controlled, International, 
Multicentre, Phase III Study to Investigate the Efficacy and Safety of 
Ticagrelor and ASA Compared with ASA in the Prevention of Stroke and 
Death in Patients with Acute Ischaemic Stroke or Transient Ischaemic 
Attack
[THALES - Acute STroke or Transient IscHaemic Attack Treated with 
TicAgreLor and ASA for PrEvention of Stroke and Death]
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden


Clinical Study Protocol
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
2 (73)
VERSION HISTORY
Version 3.0, 08 May 2019
Changes to the protocol are summarised below.
Section Protocol Synopsis (International co-ordinating Investigator(s)): Contact details for 
Pierre Amarenco, MD were updated.
Section Protocol Synopsis (International co-ordinating Investigator(s)): Contact details for S. 
Claiborne Johnston, MD, PhD were updated.
Section Protocol Synopsis (Study site(s) and number of patients planned): Adjusted the 
total number of randomised patients to approximately 11000. Adjusted the required number of 
primary events to 647.
Section Protocol Synopsis (Statistical methods): Adjusted interim analysis to be conducted 
after approximately 70% of primary events have been collected. Adjusted significance level of 
the final analysis to 4.996%. Adjusted the primary endpoint hazard ratio (HR) at which the 
study may be stopped for futility to >0.933. 
Section 1.1 (Background and rationale for conducting this study): Added description and 
reference to a relevant clinical study completed during the course of this study (Johnston et al 
2018).
Section 1.4 (Study design): Adjusted interim analysis to be conducted after approximately 
70% of primary events have been collected. Adjusted sample size to approximately 11 000.
Section 9.2 (Sample size estimate): Adjusted the assumed primary endpoint HR to 0.775. 
Adjusted the power to show an effect on the primary endpoint to 90%. Adjusted the required 
number of primary endpoint events to 647. Adjusted significance level of the final analysis to 
4.996%. Adjusted critical value for the final analysis to 0.857. Adjusted the total number of 
randomised patients to approximately 11000. Adjusted interim analysis to be conducted after 
approximately 70% of primary events have been collected.
Section 9.5.1 (Analysis of the primary variable): Adjusted significance level of the primary 
endpoint analysis to 4.996%.


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Study Code D5134C00003
Version 3.0
Date 08 May 2019
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Section 9.5.2 (Analysis of the secondary variables): Adjusted significance level of the 
primary and secondary endpoint analyses to 4.996%.
Section 9.5.6 (Interim analysis): Adjusted interim analysis to be conducted after 
approximately 70% of primary events (453 events) have been collected. Adjusted critical 
value for interim analysis to 0.734. Adjusted significance level of the final analysis to 4.996%. 
Adjusted the primary endpoint HR at which the study may be stopped for futility to >0.933.
Section 12 (List of references): Added reference to Johnston et al 2018.
Version 2.1, 05 February 2019
Changes to the protocol are summarised below.
Section Version History. Date of Version 1 was updated on page 3 from 15 October 2018 
to 08 February 2017.
Version 2, 15 October 2018
Changes to the protocol are summarised below,
Section Protocol Synopsis (International co-ordinating Investigator(s)): Postal address of the 
international co-ordinating investigator S. Claiborne Johnston was updated.
Section Protocol Synopsis (Study site(s) and number of patients planned): Adjusted total 
number of the required primary events to 764.
Section Protocol Synopsis (Study period): Amended study period to the first patient in Q1 
2018 and to the last patient in Q4 2019, to align with the most current study plan.  
Section Protocol Synopsis (Statistical methods): An update to the stopping boundary at the 
interim, which is a 2-sided p-value of <0.001. Increase in value of significance level to 
4.988%. Futility analysis has been added.
Section 1.2 (Rationale for study design, doses, and control groups): Added annotation of the 
terms “stroke” and “death”. 
Section 1.4 (Study design): The Visit’s 4 name adjusted to ‘end of follow-up period’, to 
standardise with the collective understanding of study timelines vs follow up period. 
Clarification on the IP availability at the time of randomisation.
Section 3 (Patient selection, enrolment, randomisation, restrictions, discontinuation, and 
withdrawal): Added annotation of the ABCD2 score.


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Date 08 May 2019
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Section 3.4 (Procedures for handling incorrectly enrolled or randomised patients): Additional 
information about collecting a patient vital status at the end of study follow up (V4) consistent 
with the intention-to-treat principle.
Section 4.1 (Visit 1, enrolment/randomisation (Day 1)): Administrative update about 
availability of IP at the time of randomisation.
Section 4.4 (Visit 4 end of study (Day 60 +4 days)): Changes stated in above Section 1.4
Section 5.3.4 (Cerebrovascular atherosclerosis phenotyping): The Figure 2 Cerebrovascular 
atherosclerosis phenotyping was updated to align stenosis percentage values of the artery with 
CRF guidance.
Section 5.3.5 (mRS score): The Figure 3: Simplified modified Rankin Scale questionnaire 
was added.
Section 6.4.1 (Reporting of SAEs that are also endpoints in the study): Clarification on SAE 
reporting process for events that are also endpoints.
Section 8.5 (Compliance): Clarification on responsibilities of AZ representative regarding 
verification of the amount of returned IP for each patient.
Section 8.7 (Concomitant medications and other treatments): Added information on recording 
of concomitant medications including all changes within 30 days prior to randomization.
Section 9 (Statistical analyses by AstraZeneca) Sub-Sections (9.2), (9.5.1), (9.5.2), (9.5.6): 
Changes already stated above in Section Protocol Synopsis.
Section 10.3 (Study timetable and end of study): Amended study period to the first patient in 
Q1 2018 and to the last patient in Q4 2019, to align with the most current study plan.
Section 12 (List of references): Updated Amarenco et al 2017, Bruno et al 2011 was added.
Version 1, 08 February 2017 
Initial creation.




Clinical Study Protocol Synopsis
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
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Secondary objectives
Variables
To demonstrate superior efficacy of ticagrelor and ASA 
compared with placebo and ASA in AIS/TIA patients in 
the prevention of ischaemic stroke at 30 days
Time from randomisation to first 
subsequent ischaemic stroke
To demonstrate superior efficacy of ticagrelor and ASA 
compared with placebo and ASA in AIS/TIA patients in 
reducing overall disability at 30 days
mRS score >1 at Visit 3
Safety objective
Variables
To assess the safety of ticagrelor and ASA compared 
with that of placebo and ASA in AIS/TIA patients, in 
particular with respect to major bleeding events
Time from randomisation to first bleeding 
event that fulfils SAE criteria and is 
categorised as GUSTO Severe
Time from randomisation to first ICH or 
fatal bleeding event
Time from randomisation to first bleeding 
event that fulfils SAE criteria and is 
categorised as GUSTO Moderate/Severe
Time from randomisation to premature 
permanent discontinuation of IP due to 
bleeding
Occurrence of SAE
Occurrence of DAE
AIS acute ischaemic stroke; ASA acetylsalicylic acid; DAE premature permanent discontinuation of 
investigational product due to adverse event; ICH intracranial haemorrhage; TIA transient ischaemic attack; 
SAE serious adverse event
Target patient population
Patients ≥40 years of age with non-cardioembolic AIS with NIHSS score ≤5 OR TIA with 
ABCD2 score ≥6 or with large-vessel disease (ie, ipsilateral ≥50% stenosis of extra- or 
intracranial artery) will be randomised within 24 hours of symptom onset.
Duration of treatment and follow-up
Patients will be treated for 30 days, and thereafter followed for an additional 30 days during 
which they will receive standard-of-care treatment.


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Study Code D5134C00003
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Investigational product, dosage, and mode of administration
At randomisation (Visit 1/Day 1), eligible patients will be randomly assigned to 1 of 2 
treatments: ticagrelor or placebo.  Treatments will be given orally with loading doses on 
Day 1 followed by maintenance treatment until Visit 3/Day 30.  Patients will be treated with:
!
A loading dose of ticagrelor (2 tablets ticagrelor 90 mg) on Day 1, followed by 
ticagrelor 90 mg twice daily, OR
!
A loading dose of placebo (2 tablets matching ticagrelor 90 mg) on Day 1, followed 
by placebo (matching ticagrelor 90 mg) twice daily.
Concomitant ASA treatment
In addition to the IP, all patients should be treated with ASA.  Patients should receive an ASA 
loading dose on Day 1.  The recommended loading dose is 300 to 325 mg ASA.  Any dose of 
ASA given after symptom onset but before randomisation should be taken into account (for 
instance, if a patient has received 300 mg ASA just prior to randomisation, the patient does 
not need to receive a second loading dose after randomisation).  Thereafter, patients should be 
treated with ASA 75 to 100 mg once daily.
Statistical methods
All analyses will be based on the intention-to-treat principle using the full analysis set 
including all randomised patients.  The primary and secondary variables are included in the 
confirmatory analyses and will be tested in sequential order; the secondary variables will only 
be tested in a confirmatory sense if the primary comparison is significant.  The time-to-event 
variables will be analysed using the Cox proportional hazards model with a factor for 
treatment group.  The hazard ratio, 95% confidence interval, and p-value will be reported. 
One interim analysis will be conducted after approximately 70% of the primary events have 
been collected.  The stopping boundary at the interim is a 2-sided p-value of <0.001.  The 
final analysis will be conducted at a significance level of 4.996% with the family-wise error 
rate controlled at 5.00%.The study may be stopped for futility if the observed HR for the 
primary endpoint is >0.933, corresponding to a predictive power of 5%.


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Study Code D5134C00003
Version 3.0
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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
PROTOCOL SYNOPSIS.....................................................................................................5
TABLE OF CONTENTS.....................................................................................................8
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS.........................................13
1.
INTRODUCTION .............................................................................................14
1.1
Background and rationale for conducting this study ...........................................14
1.2
Rationale for study design, doses, and control groups.........................................15
1.3
Benefit/risk and ethical assessment ....................................................................17
1.4
Study design ...................................................................................................... 18
2.
STUDY OBJECTIVES......................................................................................19
2.1
Primary objective...............................................................................................19
2.2
Secondary objectives..........................................................................................19
2.3
Safety objective..................................................................................................19
2.4
Exploratory objectives ....................................................................................... 20
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL.................... 20
3.1
Inclusion criteria ................................................................................................20
3.2
Exclusion criteria ............................................................................................... 21
3.3
Patient enrolment and randomisation..................................................................23
3.4
Procedures for handling incorrectly enrolled or randomised patients ..................23
3.5
Methods for assigning treatment groups.............................................................24
3.6
Methods for ensuring blinding ...........................................................................24
3.7
Methods for unblinding......................................................................................24
3.8
Restrictions........................................................................................................25
3.9
Discontinuation of investigational product .........................................................25
3.9.1
Management of IP in case of dyspnoea or bleeding ............................................25
3.9.2
Procedures for discontinuation of IP...................................................................25
3.9.3
Criteria for temporary discontinuation of IP .......................................................26
3.9.4
Criteria for permanent discontinuation of IP.......................................................26


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3.10
Withdrawal of consent .......................................................................................27
3.11
Termination of the study ....................................................................................27
4.
STUDY PLAN AND TIMING OF PROCEDURES...........................................27
4.1
Visit 1, enrolment/randomisation (Day 1)........................................................... 28
4.2
Visit 2 (Day 7 ±2 days) ...................................................................................... 29
4.3
Visit 3, end of treatment period (Day 30 +4 days) ..............................................29
4.4
Visit 4, end of follow-up period (Day 60 +4 days)..............................................30
4.5
Unscheduled visits ............................................................................................. 30
5.
STUDY ASSESSMENTS..................................................................................30
5.1
Efficacy assessments.......................................................................................... 30
5.1.1
Stroke ................................................................................................................30
5.1.1.1
Ischaemic stroke ................................................................................................31
5.1.1.2
Haemorrhagic stroke..........................................................................................31
5.1.1.3
Undetermined category of stroke........................................................................ 32
5.1.2
Death .................................................................................................................32
5.2
Safety assessments............................................................................................. 32
5.3
Other assessments.............................................................................................. 32
5.3.1
ABCD2 score .....................................................................................................32
5.3.2
NIHSS score ......................................................................................................33
5.3.3
Vessel imaging for assessment of symptomatic ipsilateral stenosis.....................33
5.3.4
Cerebrovascular atherosclerosis phenotyping .....................................................33
5.3.5
mRS score..........................................................................................................34
5.3.6
EQ-5D-5L..........................................................................................................35
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 36
6.1
Definition of AE ................................................................................................36
6.2
Definition of SAE .............................................................................................. 36
6.3
Recording of AEs............................................................................................... 37
6.3.1
Time period for collection of AEs ......................................................................37
6.3.2
Follow-up of unresolved AEs.............................................................................37
6.3.3
Variables............................................................................................................37
6.3.4
Causality collection............................................................................................38
6.3.5
AEs based on signs and symptoms.....................................................................38
6.3.6
AEs based on examinations and tests .................................................................38
6.3.7
Bleedings........................................................................................................... 38
6.3.8
Myocardial infarctions .......................................................................................39
6.4
Reporting of SAEs ............................................................................................. 39
6.4.1
Reporting of SAEs that are also endpoints in the study.......................................39
6.5
Recording of cerebrovascular interventions........................................................40


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6.6
Overdose............................................................................................................40
6.7
Pregnancy .......................................................................................................... 40
6.8
Medication error ................................................................................................41
7.
STUDY GOVERNANCE AND OVERSIGHT ..................................................42
7.1.1
Executive Committee.........................................................................................42
7.1.2
Steering Committee............................................................................................42
7.1.3
Data Monitoring Committee...............................................................................42
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ...................43
8.1
Identity of investigational product......................................................................43
8.2
Dose and treatment regimens .............................................................................43
8.2.1
Investigational product.......................................................................................43
8.2.2
Concomitant ASA treatment ..............................................................................43
8.2.3
Timing of loading doses and first maintenance doses .........................................43
8.3
Labelling............................................................................................................44
8.4
Storage............................................................................................................... 44
8.5
Compliance........................................................................................................ 44
8.6
Accountability....................................................................................................44
8.7
Concomitant medications and other treatments...................................................45
8.7.1
Concomitant medications...................................................................................45
8.7.2
Surgery and other invasive procedures ...............................................................46
9.
STATISTICAL ANALYSES BY ASTRAZENECA..........................................47
9.1
Statistical considerations....................................................................................47
9.2
Sample size estimate ..........................................................................................47
9.3
Definitions of analysis sets................................................................................. 47
9.4
Variables for analyses ........................................................................................48
9.4.1
Primary variable.................................................................................................48
9.4.2
Secondary variables ........................................................................................... 48
9.4.3
Safety variables..................................................................................................48
9.4.4
Exploratory variables .........................................................................................48
9.5
Methods for statistical analyses..........................................................................49
9.5.1
Analysis of the primary variable.........................................................................49
9.5.2
Analysis of the secondary variables....................................................................49
9.5.3
Analysis of the safety variables ..........................................................................50
9.5.4
Analysis of the exploratory variables..................................................................50
9.5.5
Subgroup analysis..............................................................................................50
9.5.6
Interim analysis..................................................................................................50
10.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA.........................51


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10.1
Training of study site personnel .........................................................................51
10.2
Monitoring of the study......................................................................................51
10.2.1
Risk-based quality management .........................................................................52
10.2.2
Source data ........................................................................................................ 52
10.2.3
Study agreements............................................................................................... 52
10.2.4
Archiving of study documents............................................................................ 52
10.3
Study timetable and end of study........................................................................52
10.4
Data management by AstraZeneca .....................................................................53
11.
ETHICAL AND REGULATORY REQUIREMENTS.......................................53
11.1
Ethical conduct of the study ...............................................................................53
11.2
Patient data protection........................................................................................53
11.3
Ethics and regulatory review ..............................................................................53
11.4
Informed consent ...............................................................................................54
11.5
Changes to the protocol and Informed Consent Form.........................................54
11.6
Audits and inspections .......................................................................................55
12.
LIST OF REFERENCES ...................................................................................55
LIST OF TABLES
Table 1
Study plan.............................................................................................27
Table 2
GUSTO definitions ...............................................................................32
Table 3
ABCD2 score ........................................................................................33
Table 4
mRS scores ...........................................................................................34
LIST OF FIGURES
Figure 1
Study design .........................................................................................18
Figure 2
Cerebrovascular atherosclerosis phenotyping ........................................34
Figure 3
Simplified modified rankin scale questionnaire .....................................35
LIST OF APPENDICES
Appendix A
NIHSS questionnaire.............................................................................59
Appendix B
EQ-5D-5L (English version for the United Kingdom) ...........................67


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Appendix C
Additional safety information................................................................72


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation or special 
term
Explanation
AE
Adverse event
ABCD2
A 7-point risk assessment tool designed to improve the prediction of stroke risk 
after a TIA (composite of age, blood pressure, clinical features, duration of 
symptoms, diabetes history)
AIS
Acute ischaemic stroke
ASA
Acetylsalicylic acid
(e)CRF
(electronic) Case Report Form
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CT
Computed tomography
DAE
Premature permanent discontinuation of IP due to adverse event
DMC
Data monitoring committee
EC
Executive committee
EQ-5D-5L
A questionnaire used to measure health outcomes
FAS
Full analysis set
GCP
Good Clinical Practice
GUSTO
Bleeding scale: Global Utilization of Streptokinase and Tissue plasminogen 
activator for Occluded coronary arteries
HR
Hazard ratio
ICH
Intracranial haemorrhage
IRB/IEC
Institutional review board/independent ethics committee
International co-ordinating 
Investigator
The Investigator who co-ordinates Investigators and/or activities internationally. 
IP
Investigational product
IxRS
Interactive Voice/Web Response System
MI
Myocardial infarction
MRI
Magnetic resonance imaging
mRS
Modified Rankin scale
NIHSS 
National Institute of Health Stroke Scale
Principal Investigator
The Investigator at a site who is overall accountable for study procedures at the 
site.  ‘Investigator’ refers to both Principal Investigators and co-Investigators. 
SAE
Serious adverse event 
TIA
Transient ischaemic attack
WBDC
Web Based Data Capture


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Cerebrovascular disease is a leading cause of death and serious long-term disability 
worldwide.  In 2013, there were an estimated 6.5 million stroke-related deaths, and 113 
million disability-adjusted life-years (DALYs) were lost globally due to stroke. Of 10.3 
million strokes, 6.9 million were ischaemic, with 3.3 million deaths and 47.4 million DALYs 
lost due to ischaemic stroke (Feigin et al 2015). The prevalence/incidence of transient 
ischaemic attack (TIA) is difficult to determine due to diagnostic challenges and 
underreporting, but estimates of the incidence rate of TIA range from 0.37 to 1.1 per 1000 
person-years (AHA/ASA 2009).
Antiplatelet drugs are central to the management of ischaemic stroke and TIA.  In the acute 
setting of non-cardioembolic cerebral ischaemic events, the cyclo-oxygenase inhibitor 
acetylsalicylic acid (ASA) is the antiplatelet therapy that has been most extensively studied.  
Current treatment guidelines recommend ASA to reduce the risk of death or subsequent stroke 
after acute ischaemic stroke (AIS)/TIA (Class I, Level of Evidence A) (AHA/ASA 2013, 
AHA/ASA 2014, ESO 2008). 
The results of 3 studies, (1 in Canada and 1 in China and 1 primarily in the US), on the 
antiplatelet agent clopidogrel in combination with ASA suggest that dual antiplatelet therapy 
may improve outcomes in stroke/TIA patients when initiated in the acute setting (Kennedy et 
al 2007, Wang et al 2013, Johnston et al 2018). The latter was completed while this trial was 
ongoing. The combination of clopidogrel and ASA for treatment within 24 hours of a minor 
ischaemic stroke/TIA is also included in US treatment guidelines (Class IIb, Level of 
Evidence B) (AHA/ASA 2014), although there is no approved indication for clopidogrel in 
patients with AIS/TIA in the acute setting.
The efficacy and safety of ticagrelor monotherapy compared with ASA in preventing major 
vascular events in patients with AIS or TIA were evaluated in the AstraZeneca-sponsored 
SOCRATES study (Johnston et al 2016).  Treatment was initiated within 24 hours of 
symptom onset and was continued for 90 days.  There were numerically fewer primary 
endpoint events (stroke, myocardial infarction [MI], and death) in the ticagrelor group 
compared with the ASA group.  However, the difference was not statistically significant.  The 
majority of the primary endpoint events were strokes, and there were fewer strokes overall and 
ischaemic strokes in the ticagrelor group compared with the ASA group.  A subgroup analysis 
indicated that the benefit of ticagrelor was greater in patients who received ASA within 7 days 
of randomisation, including those who received a single dose on Day 1.  These patients would 
effectively have received dual antiplatelet therapy during the first days of the study.
Thus, while the SOCRATES study did not show ticagrelor monotherapy to be superior to 
ASA, these data suggest that dual antiplatelet therapy with ticagrelor and ASA could be a 


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promising treatment to prevent subsequent stroke events in patients with acute cerebral 
ischaemia.
Further information regarding the pharmacological class, mechanism of action, and clinical 
development programme of ticagrelor can be found in the Investigator’s Brochure.
1.2
Rationale for study design, doses, and control groups
The study will be randomised, double-blind, placebo-controlled, and have a parallel-group 
design.  Randomisation and double blinding will minimise potential bias.  The study will be 
multicentre and conducted in numerous geographic regions, ensuring that a variety of 
nationalities, ethnicities, and races are represented and that the results of the study are widely 
applicable.  Advice from the US Food and Drug Administration, European Medicines Agency, 
and China Food and Drug Administration was sought and taken into consideration during the 
design of the study. 
Rationale for choice of study population
The target population will include patients ≥40 years of age with non-cardioembolic AIS or 
high-risk TIA randomised within 24 hours of symptom onset.  The ≥40-year age cut-off was 
selected to minimise the number of patients with events stemming from rare causes (eg, 
dissection, coagulation disorders, and other inherited disorders), who are less likely to benefit 
from antiplatelet therapy.
To be eligible, patients with AIS must have a neurological deficit of acute onset indicative of 
focal ischaemia and a National Institute of Health Stroke Scale (NIHSS) score ≤5.  The 
NIHSS is widely accepted, used both in clinical studies and in clinical practice, and a reliable 
and non-invasive way to measure stroke-related neurological deficits quantitatively, evaluate 
acuity of stroke patients, determine appropriate treatment, and predict functional outcome.  
The ≤5 NIHSS score cut-off was chosen as these patients have a substantial short-term risk of 
new ischaemic events and limited risk of intracranial haemorrhage (ICH).
To be eligible, patients with TIA must have a neurological deficit of acute onset attributed to 
focal ischaemia of the brain by history or examination with complete resolution of the deficit, 
and either an ABCD2 score ≥6 or large-vessel occlusive arterial disease, ie, ipsilateral stenosis 
≥50% of an extra- or intracranial artery.  
The ABCD2 score predicts the early risk of stroke after TIA, and is recommended by the 
American Stroke Association (AHA/ASA 2009).  The score is reliable in predicting the risk of 
subsequent stroke within 2, 30, and 90 days after a TIA.  The ABCD2 score cut-off of ≥6 is 
different from that used in the SOCRATES study (ABCD2 score ≥4).  The cut-off of ≥6 was 
chosen to risk-enrich the TIA population further, as TIA patients with ABCD2 scores ≥6 may 
be at particularly high risk for subsequent stroke events (Amarenco et al 2016).  The higher 
cut-off may also reduce the risk of including TIA mimics, ie, patients later determined not to 
have had a true TIA (Josephson et al 2008).  


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Patients with ipsilateral stenosis (ie, extracranial or intracranial stenosis of a vessel supplying 
the ischaemic field) are at high risk of stroke (Amarenco et al 2016).  Subgroup analyses of 
such patients in the SOCRATES study showed high stroke rates and suggested that these 
patients would benefit from ticagrelor treatment (Amarenco et al 2017). 
The use of the NIHSS score ≤5 criterion for stroke patients and the ABCD2 score ≥6 and 
ipsilateral stenosis criteria for TIA patients allows inclusion of a clinically well-defined study 
population of patients with similar and well-characterised risk levels.
Rationale for choice of dosing and control treatment
The investigational products (IP) are ticagrelor and placebo.  Additionally, both treatment 
groups will be taking open-label ASA as a concomitant medication during the treatment 
period.  Placebo with concomitant ASA treatment was chosen as the control treatment because 
ASA is the only antiplatelet therapy approved and recommended for use in patients for the 
acute management of ischaemic stroke, and is the standard-of-care treatment.
The 180 mg ticagrelor loading dose results in a rapid, high degree of inhibition of platelet 
activation (IPA) and the 90 mg twice daily maintenance dose showed high and consistent 
levels of IPA (Gurbel et al 2009).  The ticagrelor dose is the same as that used in the target 
population of patients with ischaemic stroke or TIA in the SOCRATES study, in which it was 
well-tolerated and had a similar safety profile as ASA with respect to major bleedings.  The 
same ticagrelor dose was effective and had an acceptable safety profile when administered 
concomitantly with ASA in the acute setting in patients with acute coronary syndrome in the 
PLATO study (Wallentin et al 2009).
Both treatment groups should be treated with ASA, with a 300 to 325 mg ASA loading dose 
followed by a 75 to 100 mg once daily maintenance dose recommended.  Treatment 
guidelines recommend an ASA maintenance dose of 50 to 325 mg/day after a TIA or 
ischaemic stroke to prevent future strokes (AHA/ASA 2013, AHA/ASA 2014).  Current US 
and EU prescribing information for the approved indications for ticagrelor recommend an 
ASA dose no higher than 100 mg (US) or 150 mg (EU) when treating with both ticagrelor and 
ASA.  The ASA maintenance doses in this study align with the treatment guidelines and was 
considered optimal to maximise efficacy while minimising the risk for gastrointestinal toxicity 
and bleeding events.
Rationale for choice of treatment duration
Individuals who survive an ischaemic stroke or experience a TIA are at high risk for a 
subsequent ischaemic event in the early period after the initial event (Coull et al 2004, 
AHA/ASA 2009).  In the SOCRATES study, most of the primary endpoint events (stroke, MI, 
and death) occurred during the first 30 days of the study (728 of 939 events).  The 30-day 
treatment duration in this study therefore corresponds to the period during which the largest 
number of vascular events (eg, strokes) occur in this population.  The early randomisation 
(within 24 hours of index event) will enable an assessment of treatment effect immediately 
after the initial event, when patients are the most vulnerable to subsequent events and may 


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benefit the most from dual antiplatelet therapy.  Few other therapies are approved or have 
been investigated in large outcome trials during this early period.
Rationale for choice of endpoints
The primary endpoint (the composite of stroke and death1) was chosen as stroke is the most 
relevant outcome in this patient population, and as death is a competing risk to stroke.  
Patients with acute cerebral ischaemic events have a higher risk of stroke than of any other 
vascular outcome during the initial months after the event (Albers 2000, Petty et al 1998, 
AHA/ASA 2009).  This was also true in the SOCRATES study, where 836 of 939 primary 
endpoint events (stroke, MI, and death) occurring during the 90-day treatment period were 
strokes (Johnston et al 2016).  Stroke can be objectively and consistently assessed and 
represents a clinically meaningful event causing irreversible loss of organ function with 
important medical consequences. 
Antiplatelet therapy may reduce subsequent ischaemic strokes in patients with AIS or TIA.  
However, because antiplatelet drugs increase the risk of bleeding, they could potentially 
increase the rate of haemorrhagic events.  Inclusion of all strokes, including haemorrhagic 
strokes, in the primary endpoint therefore ensures that the net benefit of treatment with 
ticagrelor in preventing strokes is adequately captured.  Additionally, bleedings classified as 
GUSTO Severe are included as a key safety endpoint.  The GUSTO bleeding scale was 
chosen because it captures clinically relevant events, is widely used, and is easily applied.
The first secondary endpoint (ischaemic stroke) was chosen because prevention of ischaemic 
stroke is expected to be the main benefit of ticagrelor treatment.  The second secondary 
endpoint (modified Rankin Scale [mRS] score >1) was chosen to assess potential differences 
in disability as a result of study treatment.
1.3
Benefit/risk and ethical assessment
Patients who experience ischaemic stroke or TIA are at high risk for subsequent stroke events 
even when treated with ASA, the current standard of care.  Because the risk for a new stroke 
is highest soon after the initial event, urgent initiation of treatment is warranted.  However, 
treatment options are limited, particularly in the acute time-frame after the initial event. 
Major bleeding is the most important risk for all antiplatelet agents, and the risk for 
intracerebral bleeding is particularly important to consider in patients with AIS.  The risk for 
intracerebral bleeding is mitigated in this study by including patients with non-severe AIS 
(NIHSS ≤5) and excluding patients with acute or previous intracerebral haemorrhage.
In the recent SOCRATES study, ticagrelor and ASA monotherapy were compared in a similar 
population to that of the current study.  Although the primary endpoint of the SOCRATES 
study was not statistically significant, the results indicated a positive benefit-risk profile when 
                                               
1 The term “stroke” in this document refers to all-cause stroke (ischaemic and haemorrhagic), and the term 
“death” refers to all-cause death.


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analysing the number of subsequent strokes prevented in relation to the occurrence of ICH and 
fatal bleeding events.
The available data suggest a positive benefit-risk profile for dual antiplatelet treatment with 
ticagrelor and ASA in patients with AIS or high-risk TIA, and the efficacy of the treatment in 
preventing stroke events is expected to be greater compared with that of ASA, the current 
standard of care.  However, this treatment could only be made available to patients if proven 
to be statistically significantly superior to ASA in a randomised controlled trial.  AstraZeneca 
therefore considers the proposed study justified from an ethical standpoint.
1.4
Study design 
This is a randomised, placebo-controlled, double-blind, parallel-group, international, 
multicentre Phase III study to test the hypothesis that ticagrelor and ASA is superior to ASA 
in preventing stroke and death in patients with acute cerebral ischaemia.  Patients with AIS or 
TIA before randomisation who fulfil all of the inclusion criteria (see Section 3.1) and none of 
the exclusion criteria (see Section 3.2) will be randomised within 24 hours of symptom onset 
in a 1:1 ratio to ticagrelor or placebo, with all patients receiving ASA.  The study includes 4 
visits: on Day 1 (enrolment/randomisation; Visit 1), on Day 5 to 9 (Visit 2), on Day 30 to 34 
(end of treatment period; Visit 3), and on Day 60 to 64 (end of follow-up period; Visit 4) 
(Figure 1).
A loading dose of 180 mg ticagrelor or placebo will be given on Day 1 as soon as possible 
after randomisation. Therefore, IP should be available for dispensation at the time of 
randomisation. Thereafter, patients will receive either ticagrelor 90 mg twice daily or placebo 
twice daily. All patients should be treated with open-label ASA. Patients should receive an 
ASA loading dose on Day 1. The recommended loading dose is 300 to 325 mg ASA. 
Thereafter, patients should be treated with ASA 75 to 100 mg once daily. Additionally, 
patients should receive medical treatment and be counselled on lifestyle modifications for 
cerebrovascular risk factors according to local and global guidelines. 
Figure 1
Study design
ASA (concomitant medication) = open-label.  Loading dose at the Investigator’s discretion (300 to 325 mg 
recommended) followed by 75 to 100 mg once daily. 
Ticagrelor (investigational product) = 180 mg loading dose followed by 90 mg twice daily
ASA acetylsalicylic acid; R randomisation; TC telephone contact


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Approximately 11 000 patients will be randomised at approximately 450 study sites.  The 
study is event-driven and the final number of randomised patients will be determined based on 
blind data review.  
A data monitoring committee (DMC) (see Section 7.1.3) will conduct an interim analysis for 
efficacy after approximately 70% of the primary events have been collected. 
2.
STUDY OBJECTIVES
2.1
Primary objective
Primary objective
Variables
To demonstrate superior efficacy of ticagrelor and ASA 
compared with placebo and ASA in AIS/TIA patients in 
the prevention of the composite of stroke and death at 30 
days
Time from randomisation to first 
subsequent stroke or death
2.2
Secondary objectives
Secondary objective
Variables
To demonstrate superior efficacy of ticagrelor and ASA 
compared with placebo and ASA in AIS/TIA patients in 
the prevention of ischaemic stroke at 30 days
Time from randomisation to first 
subsequent ischaemic stroke
To demonstrate superior efficacy of ticagrelor and ASA 
compared with placebo and ASA in AIS/TIA patients in 
reducing overall disability at 30 days
mRS score >1 at Visit 3
2.3
Safety objective
Safety objective
Variables
To assess the safety of ticagrelor and ASA compared 
with that of placebo and ASA in AIS/TIA patients, in 
particular with respect to major bleeding events
Time from randomisation to first bleeding 
event that fulfils SAE criteria and is 
categorised as GUSTO Severe
Time from randomisation to first ICH or 
fatal bleeding event
Time from randomisation to first bleeding 
event that fulfils SAE criteria and is 
categorised as GUSTO Moderate/Severe
Time from randomisation to premature 
permanent discontinuation of IP due to 
bleeding


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Occurrence of SAE
Occurrence of DAE
2.4
Exploratory objectives
Exploratory objectives
Variables
To assess the efficacy of ticagrelor and ASA compared 
with placebo and ASA in AIS/TIA patients with 
ipsilateral atherosclerotic stenosis in the prevention of 
stroke or death at 30 days
Time from randomisation to first 
subsequent stroke or death in patients with 
ipsilateral atherosclerotic stenosis 
To assess the efficacy of ticagrelor and ASA compared 
with placebo and ASA in AIS/TIA patients in reducing 
disabling stroke at 30 days
mRS score >2 at Visit 3 in patients with 
subsequent stroke
To describe health-related quality of life in AIS/TIA 
patients after treating with ticagrelor and ASA or 
placebo and ASA for 30 days
EQ-5D-5L profile
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION, AND WITHDRAWAL 
The study population is defined as patients ≥40 years of age who have experienced a non-
cardioembolic AIS (NIHSS score ≤5) OR high-risk TIA (defined as ABCD2 score2 ≥6 or 
ipsilateral atherosclerotic stenosis ≥50% in an extra/intracranial artery) who could be 
randomised within 24 hours of symptom onset. 
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.
3.1
Inclusion criteria
For inclusion in the study, patients should fulfil the following criteria:
1.
Provision of signed informed consent prior to any study-specific procedure 
2.
≥40 years of age 
3.
Acute onset of cerebral ischaemia due to
(a)
AIS with NIHSS ≤5.  AIS is defined as acute onset of neurological deficit 
attributed to focal brain ischaemia, and either of the following:
                                               
2 ABCD2 score is a clinical score based on: age, blood pressure, clinical features, duration of TIA and diabetes.


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∀
Persistent signs or symptoms of the ischaemic event at the time of 
randomisation, OR
∀
Acute ischaemic brain lesion documented before randomisation by 
computed tomography (CT) scan or magnetic resonance imaging (MRI) 
(diffusion-weighted imaging) and that could account for the clinical 
presentation
(b)
High-risk TIA, defined as neurological deficit of acute onset attributed to 
focal ischaemia of the brain by history or examination with complete 
resolution of the deficit, and at least one of the following:
∀
ABCD2 score ≥6 and TIA symptoms not limited to isolated numbness, 
isolated visual changes, or isolated dizziness/vertigo
∀
Symptomatic intracranial arterial occlusive disease that could account 
for the clinical presentation, documented by transcranial Doppler or 
vascular imaging and defined as at least 50% narrowing in the diameter 
of the vessel lumen
∀
Internal carotid arterial occlusive disease that could account for the 
clinical presentation, documented by Doppler, ultrasound, or vascular 
imaging and defined as at least 50% narrowing in diameter of the vessel 
lumen
4.
Randomisation occurring within 24 hours after onset of symptoms; for wake-up 
strokes (when the time of symptom onset is not known), within 24 hours from the 
time point at which the patient was reported to be in their normal condition
5.
CT or MRI performed after symptom onset ruling out intracranial haemorrhage or 
other pathology, such as vascular malformation, tumour, or abscess that according 
to the Investigator could explain symptoms or contraindicate study treatment
3.2
Exclusion criteria
Patients fulfilling any of the exclusion criteria must not be randomised.
1.
Need for or an anticipated need for any of the following:
(a)
Dual antiplatelet therapy with ASA and P2Y12 inhibitors (including patients 
with carotid artery stenting and percutaneous coronary intervention)
(b)
Antiplatelets other than ASA (eg, GPIIb/IIIa inhibitors, clopidogrel, 
ticlopidine, prasugrel, dipyridamole, ozagrel, cilostazol, ticagrelor) and other 
antithrombotic agents with antiplatelet effects, including traditional/herbal 
medicine agents


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(c)
Anticoagulants (eg, warfarin, oral thrombin and factor Xa inhibitors, 
bivalirudin, hirudin, argatroban, fondaparinux, or unfractionated heparin and 
long-term treatment with low-molecular weight heparins).  Short-term 
treatment (≤7 days) with low-dose low-molecular weight heparin may be 
used in immobilised patients at the discretion of the Investigator
2.
Any history of atrial fibrillation/flutter, ventricular aneurysm, or suspicion of other 
cardioembolic pathology for TIA or stroke
3.
Patients who should receive or have received any intravenous or intra-arterial 
thrombolysis or mechanical thrombectomy within 24 hours prior to randomisation
4.
Planned carotid endarterectomy that requires halting investigational product within
3 days of randomisation or is expected to require unblinding of investigational 
product (planned carotid endarterectomy is in itself not an exclusion criterion)
5.
History of previous intracranial haemorrhage at any time (asymptomatic 
microbleeds do not qualify), gastrointestinal haemorrhage within the past 6 months, 
or major surgery within 30 days
6.
Patients considered to be at risk of bradycardic events (eg, known sick sinus 
syndrome or second- or third-degree atrioventricular block) unless already treated 
with a permanent pacemaker
7.
Inability of the patient to understand and/or comply with study procedures and/or 
follow-up, in the opinion of the Investigator
8.
Known hypersensitivity to ticagrelor or ASA
9.
Need for or an anticipated need for oral or intravenous therapy with any of the 
following:
(a)
Strong cytochrome P450 3A (CYP3A4) inhibitors (eg,  ketoconazole, 
clarithromycin [but not erythromycin or azithromycin], nefazadone, 
ritonavir, atazanavir) that cannot be stopped for the course of the study
(b)
Long-term (>7 days) non-steroidal anti-inflammatory drugs
10.
Known bleeding diathesis or coagulation disorder (eg, thrombotic 
thrombocytopenic purpura)
11.
Known severe liver disease (eg, ascites or signs of coagulopathy)
12.
Renal failure requiring dialysis


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13.
Pregnancy or breastfeeding.  Women of child-bearing potential who are not willing 
to use a medically accepted method of contraception that is considered reliable in 
the judgment of the Investigator
14.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
15.
Previous enrolment or randomisation in the present study
16.
Participation in another clinical study with an investigational product at any time 
during the 30 days prior to randomisation (regardless of when treatment with the 
investigational product was discontinued)
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.  The Investigator(s) will:
1.
Obtain signed informed consent from the patient and/or legal representative before 
any study specific procedures are performed
2.
Assign (using the Interactive Voice/Web Response System [IxRS], see Section 3.5) 
each patient a unique enrolment number, beginning with ‘E#’
3.
Determine patient eligibility (see Section 3.1 and 3.2)
4.
Obtain unique randomisation code (patient number) for each eligible patient from 
IxRS (see Section 3.5)
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused.  Only the enrolment number will be used for patient identification in 
the eCRF.
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who are enrolled but subsequently found not to be eligible (eg, not meeting all of the 
inclusion criteria or fulfilling any of the exclusion criteria) must not be randomised or initiated 
on treatment.
If a patient is not eligible but is randomised in error, or incorrectly started on treatment, the 
Investigator should inform the AstraZeneca representative immediately, and a discussion 
should occur between the Investigator and the AstraZeneca study physician (usually via the 
AstraZeneca representative) regarding whether to continue or discontinue the patient from 
treatment. Treatment must be discontinued in all cases where continued treatment is deemed 
to pose a safety risk to the patient.  The AstraZeneca study physician must ensure that all 


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decisions, including the rationale for continuing or discontinuing treatment, are appropriately 
documented.
Regardless of whether study treatment is discontinued, the patient should still remain in the 
study for follow-up in accordance with defined study procedures including follow-up of 
endpoints. The majority of patients will have their vital status collected at V4. For unforeseen 
potentially lost to follow-up patients, efforts will be made to collect the vital status until data 
base lock, which is consistent with the intention-to-treat principle.
3.5
Methods for assigning treatment groups
Randomisation codes will be assigned strictly sequentially within each centre as patients 
become eligible for randomisation.  The randomisation codes will be computer-generated by 
AstraZeneca R&D using the AstraZeneca Global Randomisation system AZRand and loaded 
into the IxRS database.  The randomisation codes will be generated in blocks to ensure 
approximate balance (1:1) between the 2 treatment groups.  Once a block is exhausted, the 
next available block will be allocated by IxRS system to a centre upon their next 
randomisation. 
3.6
Methods for ensuring blinding
The blinding is ensured by using double-blind technique.  The ticagrelor tablets and the 
placebo tablets for ticagrelor will be identical in size, colour, smell, and taste.  Each bottle will 
be labelled with a unique kit ID number that will be used to assign the treatment to the patient 
but will not indicate treatment allocation to the Investigator or patient.
No member of the extended study delivery team at AstraZeneca, personnel at investigational 
centres, or any contract research organisation handling study data will have access to the 
randomisation scheme during the study.  The AstraZeneca personnel or delegate generating 
the randomisation scheme and the Supply Chain Study Management department may be able 
to access the randomisation scheme.
3.7
Methods for unblinding 
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment allocation.  Individual 
treatment codes, indicating the treatment allocation for each randomised patient, will be 
available to the Investigator(s) or pharmacists from the IxRS.  Routines for unblinding will be 
described in the IxRS user manual that will be provided to each centre.  The Investigator 
documents and reports the action and its rationale 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 IP should be continued, or re-initiated if interrupted, if considered appropriate.


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AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an investigational product (IP) and that potentially require 
expedited reporting to regulatory authorities.  Treatment codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.
Unblinding for data monitoring committee (DMC)
An independent DMC will review accumulating study data by treatment group in order to 
monitor patient safety and efficacy, ensure the validity and integrity of the study, and make a 
benefit/risk assessment.  The DMC will have access to unblinded data.  The personnel 
involved in the clinical study at AstraZeneca will have no knowledge of unblinded results 
presented to the DMC.  For details, see the DMC Charter.
3.8
Restrictions
Patients should not donate blood or bone marrow at any time during the study period.
Restrictions regarding concomitant medications are described in Section 8.7.
3.9
Discontinuation of investigational product
At any time, patients are free to discontinue IP without prejudice to further treatment.  IP 
refers to ticagrelor or placebo.
3.9.1
Management of IP in case of dyspnoea or bleeding
Dyspnoea, usually mild to moderate intensity, is an identified adverse drug reaction to 
ticagrelor and a common reason for discontinuing IP.  However, if the dyspnoea is tolerable to 
the patient, IP can be continued without interruption.  For further details, see the Investigator’s 
Brochure.
IP does not need to be discontinued in case of minimal or minor bleeding.  IP must be stopped 
immediately in case of a bleed judged by the Investigator to be clinically significant (eg, a 
significant fall in haemoglobin, need for transfusion, haemodynamically significant, or in a 
critical location such as intracranial, intraspinal, intraocular, or pericardial bleeds), but may be 
reinstated when the risk of bleeding is judged by the Investigator to be low.  All bleedings 
should be treated and followed up according to standard clinical practice and treatment 
guidelines.
Platelet transfusion did not reverse the antiplatelet effect of ticagrelor in healthy volunteers.  
There is currently no available antidote to reverse the effects of ticagrelor, and ticagrelor is not 
expected to be dialyzable.  For further details, see the Investigator’s Brochure.
3.9.2
Procedures for discontinuation of IP
The patient should contact the site before or at the time IP is stopped.  A patient who decides 
to discontinue IP will always be asked about the reason(s) and the presence of any adverse 
events (AEs).  The date of last intake of IP should be documented in the eCRF.  All IP should 


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be returned by the patient at their next on-site study visit or unscheduled visit.  Patients 
permanently discontinuing IP should be given standard-of-care therapy, at the discretion of the 
Investigator.
Premature discontinuation of IP, for any reason, does not impact on the patient’s participation 
in the study.  The patient should continue attending subsequent study visits and data collection 
should continue according to the Clinical Study Protocol (CSP).  If the patient does not agree 
to continue in-person study visits, a modified follow-up must be arranged and documented in 
medical records to ensure the collection of endpoints and safety information.  This could be a 
telephone contact with the patient at Visit 3 and 4, a contact with a relative or treating 
physician, or information from medical records.  A patient that agrees to modified follow-up 
is not considered to have withdrawn consent or to have withdrawn from the study.
3.9.3
Criteria for temporary discontinuation of IP
If IP must be temporarily discontinued, it should be restarted as soon as possible.  Reasons for 
temporary discontinuation of IP include:
!
Severe thrombocytopenia (platelet count <50,000/uL).  Patients may restart IP once 
the severe thrombocytopenia resolves
!
Major bleeding, see Section 3.9.1
!
Surgery or procedures associated with major haemorrhage, see Section 8.7.2
!
Need for treatment with prohibited concomitant medications, see Section 8.7.1
IP may be continued or interrupted temporarily for other surgery or invasive procedures at the 
discretion of the Investigator (see Section 8.7.2).
3.9.4
Criteria for permanent discontinuation of IP
!
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, regardless of whether the AE is thought to be related to IP
∀
Severe non-compliance to protocol
∀
Pregnancy
∀
Atrial fibrillation for which the patient receives anticoagulation therapy


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3.10
Withdrawal of consent
Patients who are enrolled but not randomised (eg, because they do not fulfil the eligibility 
criteria) are not considered to have withdrawn from the study.  Patients who are enrolled but 
not randomised will be recorded as “screening failures” in the eCRF.
Patients are free to withdraw from the study at any time, without prejudice to further 
treatment.  Discontinuation of IP is not a reason to withdraw from the study.  A patient who 
considers withdrawing from the study must be informed by the Investigator about modified 
follow-up options (eg, telephone contact at Visit 3 and 4, a contact with a relative or treating 
physician, or information from medical records).  Withdrawal of consent must be ascertained 
(ie, patient must have been informed of the option of modified follow-up and subsequently 
refused any type of follow-up) and documented by the Investigator in the medical records and 
recorded in the eCRF.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The contact must be recorded in the eCRF as a scheduled/unscheduled visit.  The 
Investigator will follow up serious AEs (SAEs)/premature permanent discontinuations of IP 
due to AEs (DAEs) outside of the clinical study.  AstraZeneca or its delegate will request 
Investigators to collect information on patients’ Day 60 vital status (dead or alive; date of 
death when applicable) from publicly available sources, in accordance with local regulations.  
Knowledge of the Day 60 vital status in all patients is crucial for the integrity of the study.
3.11
Termination of the study
The study may be terminated if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk.  The judgment may be based on recommendations from the DMC (see the DMC 
Charter for details).  In terminating the study, AstraZeneca will ensure that adequate 
consideration is given to the protection of the patients’ interests.
4.
STUDY PLAN AND TIMING OF PROCEDURES 
Table 1
Study plan
Visit
1 
2 
3 
4 
For details 
see section:
Day
1
7 (±2 days)
30 (+4 days)
60 (+4 days)
Signed informed consent
√
Eligibility criteria
√
3.1, 3.2
Specific medical and 
surgical history
√
Smoking status
√
Demographics
√


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Visit
1 
2 
3 
4 
For details 
see section:
Day
1
7 (±2 days)
30 (+4 days)
60 (+4 days)
Weight and height
√
BP and heart rate
√
√
NIHSS score
√
Appendix A
ABCD2 score for TIA 
patients
√
5.3.1
Cerebrovascular  
atherosclerosis 
phenotyping
√
5.3.4
EQ-5D-5L
√
√
Appendix B
Dispense IP
√
Compliance reminder
√
8.5
mRS score
√
5.3.5
Return IP
√
Compliance/drug 
accountability
√
8.5, 8.6
Concomitant medications
√
√
√
√
8.7
SAEs, DAEs, and 
endpointsa
√
√
√
√
5.1, 6
a 
Endpoints (death, stroke), bleedings fulfilling SAE/DAE criteria and classified according to the GUSTO
bleeding scale.  SAEs will be recorded from the time of informed consent.  Endpoints will be collected from 
the time of randomisation.  DAEs will be collected from the first intake of investigational product until the 
end of study treatment.
BP blood pressure; DAE premature permanent discontinuation of IP due to adverse event; IP investigational 
product; mRS modifed Rankin scale; NIHSS National Institute of Health Stroke Scale; rand randomisation, 
SAE serious adverse event, TIA transient ischaemic attack
4.1
Visit 1, enrolment/randomisation (Day 1)
Consenting patients are assessed to ensure they are eligible for the study (meet all inclusion 
criteria and none of the exclusion criteria), including by evaluation of ECG and CT/MRI or 
vessel imaging performed as standard of care.  Patients who are not eligible must not be 
randomised in the study.
Patients should be enrolled/randomised as soon as possible and within 24 hours after onset of 
symptoms.  For wake-up strokes (when the time of symptom onset is not known), patients 
should be randomised within 24 hours from the time point at which the patient was reported to 
be in their normal condition.  


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The following will occur during Visit 1, which is an on-site visit:
!
Obtaining of signed informed consent before any study-related procedures
!
Assignment of an E-code in IxRS to the patient
!
Confirmation of patient eligibility
!
For patients not eligible for randomisation:
∀
Collection of data in CRF (visit date; date of informed consent; eligibility 
criteria; reason for non-randomisation; SAEs; demography). If the patient has 
an SAE, data on specific medical and surgical history and concomitant 
medications will also be collected.
!
For patients eligible for randomisation:
∀
Randomisation using IxRS
∀
Dispense IP, and ensure the loading dose is available at the time of 
randomisation
∀
Ensure patient has received loading dose of ASA and has been prescribed ASA 
∀
Collection of data in CRF (visit date; date of informed consent; eligibility 
criteria [including NIHSS score, ABCD2 score for TIA patients, and the 
presence of ipsilateral stenosis at randomisation]; specific medical and surgical 
history; concomitant medications; endpoints, SAEs, and DAEs; demography; 
smoking status; weight and height; blood pressure and heart rate; 
cerebrovascular atherosclerosis phenotyping of index event; EQ-5D-5L)
4.2
Visit 2 (Day 7 ±2 days)
The following will occur during Visit 2, which can be a telephone contact or on-site visit:
!
Collection of data in CRF (visit date; type of visit; endpoints, SAEs, and DAEs; 
concomitant medications)
!
Remind the patient of the importance of compliance with IP and other medications, 
either by TC or during hospitalisation
If an SAE/DAE or endpoint is reported by telephone, an unscheduled visit to evaluate the 
patient may be needed (at the Investigator’s discretion).
4.3
Visit 3, end of treatment period (Day 30 +4 days)
The following will occur during Visit 3, which is an on-site visit:


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!
Collection of data in CRF (visit date; type of visit; endpoints, SAEs, and DAEs; 
blood pressure and heart rate; mRS; return of IP; drug accountability; concomitant 
medications; EQ-5D-5L)
!
Return of IP
!
Initiation of standard-of-care therapy (treatment[s] at the Investigator’s discretion)
4.4
Visit 4, end of follow-up period (Day 60 +4 days)
The following will occur during Visit 4, which is a telephone contact:
!
Collection of data in CRF (visit date; type of visit; endpoints and SAEs; 
concomitant medications)
4.5
Unscheduled visits
An unscheduled visit may occur in-between scheduled visits, eg, to follow up on potential 
endpoint events, to initiate standard-of-care therapy after IP discontinuation, or to evaluate 
SAEs/DAEs. 
5.
STUDY ASSESSMENTS
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 on the eCRF as specified 
in the CSP 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).  
The Investigator will sign the completed eCRFs.  A copy of the completed eCRFs will be 
archived at the study site.
Endpoints 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.  It is 
essential that Investigators collect all relevant and required endpoint data as soon as possible.  
For each suspected endpoint, the Investigator will record information specific to that type of 
endpoint on the eCRF.
5.1
Efficacy assessments
5.1.1
Stroke
The definition for stroke is based on the standardised definitions for endpoints (Hicks et al 
2015).  All strokes occurring post-enrolment will be recorded as SAEs.  All strokes occurring 
post-randomisation will be considered endpoints.  Stroke is defined as an acute episode of 
focal or global neurological dysfunction caused by cerebral vascular injury as a result of 
infarction or haemorrhage not caused by trauma.  Investigators will classify strokes into 1 of 3 


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mutually exclusive categories: ischaemic, haemorrhagic, or undetermined.  Whenever 
possible, stroke diagnoses should be confirmed using neuroimaging (CT or MRI) to minimise 
the number of strokes classified as “undetermined”.
5.1.1.1
Ischaemic stroke
An acute episode of focal cerebral dysfunction caused by cerebral infarction.  Either of the 
following is considered to be an ischaemic stroke:
1.
Rapid onset (or existence on awakening) of a new focal neurological deficit with 
clinical or imaging evidence of infarction and not attributable to a non-ischaemic 
aetiology (not associated with brain infection, trauma, tumour, seizure, severe 
metabolic disease, or degenerative neurological disease)
2.
Rapid worsening of an existing focal neurological deficit (eg, the index stroke 
event) that is judged by the Investigator to be attributable to a new infarction or 
extension of a previous infarction in the same vascular bed, based on persisting 
symptoms or imaging evidence of infarction and no evidence of a non-ischaemic 
aetiology.  In case imaging is inconclusive, persistent symptoms is defined as 
duration of ≥24 hours or until death
Haemorrhagic transformation of an ischaemic stroke (not an efficacy endpoint)
Haemorrhage may be a consequence of an ischaemic stroke (the index event or a subsequent 
stroke), ie, a haemorrhagic transformation.  Haemorrhagic transformations are not considered 
to be haemorrhagic strokes nor to be stroke endpoints. 
Haemorrhagic transformations may be either symptomatic or asymptomatic.  Symptomatic 
haemorrhagic transformation of an ischaemic stroke must have imaging evidence of 
extravascular blood within an area of known acute/subacute infarction that is judged to be 
nontraumatic and at least partially responsible for the patient’s clinical neurological 
deterioration with neurological symptoms out of proportion to what would be expected for the 
size and location of the infarction.  These should be reported as SAEs and be GUSTO-
classified as an ICH.
Asymptomatic haemorrhagic transformation of an ischaemic stroke must have imaging 
evidence of any extravascular blood within an area of known acute/subacute infarct, judged to 
be nontraumatic, with no detected worsening of neurological symptoms related to the 
haemorrhage.  These should not be recorded as SAEs.  However, if the Investigator chooses to 
discontinue IP permanently and prematurely due to an asymptomatic haemorrhagic 
transformation, the event should be recorded as DAE and be GUSTO-classified as “No
GUSTO Bleeding Event.”
5.1.1.2
Haemorrhagic stroke
An acute episode of focal or global cerebral dysfunction caused by intraparenchymal, 
intraventricular, or subarachnoid haemorrhage not caused by trauma.  Subdural haematomas 
are ICH events but not strokes.


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5.1.1.3
Undetermined category of stroke 
An acute episode of focal or global neurological dysfunction caused by presumed brain 
vascular injury as a result of haemorrhage or infarction but with insufficient information to 
allow categorisation as either ischaemic or haemorrhagic.  Strokes of undetermined category 
will be analysed as ischaemic strokes.
5.1.2
Death
All deaths occurring post-enrolment will be recorded as SAEs with fatal outcome.  All deaths 
occurring post-randomisation will be considered endpoints.
5.2
Safety assessments
The safety objective of the study is to assess safety particularly with respect to major bleeding 
events.  Bleeding events that fulfil SAE or DAE criteria will be classified by the Investigator 
according to GUSTO bleeding definitions and by provocation (Table 2).
Table 2
GUSTO definitions
Classification
Definition
GUSTO Severe Bleeding
Any one of the following:
-
Fatal
-
Intracraniala
-
Bleeding that caused haemodynamic compromise requiring 
intervention (eg, systolic blood pressure <90 mm Hg that 
required blood or fluid replacement, or vasopressor/inotropic 
support, or surgical intervention).
GUSTO Moderate Bleeding
Bleeding requiring transfusion of whole blood or packed red blood 
cells without haemodynamic compromise (as defined above)
GUSTO Mild Bleeding
Bleeding without blood transfusion or haemodynamic compromise
No GUSTO Bleeding Event
Asymptomatic haemorrhagic transformations and microhaemorrhages
a
Excluding asymptomatic haemorrhagic transformations of ischaemic brain infarctions and excluding 
microhaemorrhages <10 mm evident only on gradient-echo MRI.  This is an adaptation of the standard 
GUSTO definition to better distinguish clinically relevant events in the acute stroke population.
5.3
Other assessments
5.3.1
ABCD2 score
The ABCD2 score is a risk assessment tool designed to improve the prediction of short-term 
stroke risk after a TIA.  The score is optimised to predict the risk of stroke within 2 days after 
a TIA, but also predicts stroke risk within 30 and 90 days.  The ABCD2 score is calculated by 
summing points for 5 independent factors (Table 3).


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Table 3
ABCD2 score
Risk Factor
Points
Age ≥60 yrs 
1
BP ≥140/90 mmHga
1
Clinical features
speech disturbance without weakness
unilateral weakness
1
2
Duration of TIA
10–59 minutes
≥60 minutes
1
2
Diabetes
1
a
Systolic BP ≥140 mmHg or diastolic BP ≥90 mmHg (first assessment after TIA)  
BP blood pressure; TIA transient ischaemic attack
5.3.2
NIHSS score 
NIHSS scores at the time of randomisation will be collected for all patients to verify patient 
eligibility.  The scores will also be used in the analysis of the disability endpoint to adjust for 
baseline stroke severity.  A patient with an index event of TIA may have a NIHSS score above 
0 if the patient has remaining neurological deficit from a previous cerebrovascular event.  See 
Appendix A for the NIHSS questionnaire.
5.3.3
Vessel imaging for assessment of symptomatic ipsilateral stenosis
For TIA patients, the presence of symptomatic ipsilateral stenosis is a potential eligibility 
criterion.  Presence of known symptomatic ipsilateral stenosis should be recorded for all 
patients at randomisation.
5.3.4
Cerebrovascular atherosclerosis phenotyping
For all patients, the Investigator should record in the eCRF whether or not imaging (as part of 
clinical practice) of intra- or extracranial arteries following the index event was performed.  If 
performed, data should be collected for extra- and intracranial arteries supplying the ischaemic 
field (ipsilateral) as well as for other arteries, and the results of the examination should be 
documented in the eCRF.  The documentation of the cerebrovascular atherosclerosis 
phenotyping should comprise data supporting a diagnosis of atherosclerosis as well as 
negative findings (Figure 2).
In addition, the presence or absence of aortic atheroma and any history of coronary artery 
bypass grafting, MI, percutaneous coronary intervention, and peripheral artery disease should 
be recorded.  Thereby, the cerebrovascular as well as the generalised atherosclerosis 
phenotypes can be described for all patients.


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Figure 2
Cerebrovascular atherosclerosis phenotyping 
CABG coronary artery bypass grafting; CTA computed tomography angiography; MRA magnetic resonance 
angiography; PAD peripheral artery disease; PCI percutaneous coronary intervention
5.3.5
mRS score
mRS scores will be collected for all patients at Visit 3. No mRS scores will be collected on 
Visit 1; NIHSS scores at Visit 1 will be used to adjust for baseline stroke severity.  The 
following questionnaire will be used to determine the mRS score:
Table 4
mRS scores
Score
Description
0
No symptoms at all
1
No significant disability despite symptoms; able to carry out all usual duties and 
activities
2
Slight disability; unable to carry out all previous activities, but able to look after own 
affairs without assistance
3
Moderate disability; requiring some help, but able to walk without assistance
4
Moderately severe disability; unable to walk without assistance and unable to attend 
to own bodily needs without assistance
5
Severe disability; bedridden, incontinent and requiring constant nursing care and 
attention
6
Dead
Derived from: the Internet Stroke Center at www.strokecenter.org


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Figure 3
Simplified modified Rankin Scale questionnaire
Derived from Bruno et al 2011
5.3.6
EQ-5D-5L
The EQ-5D-5L questionnaire, developed by the EuroQol Group, will be used to explore the 
impact of treatment and disease state (eg, the occurrence of stroke) on health state utility 
values.  The EQ-5D-5L questionnaire will be filled in by the patients or, if needed, by a proxy 
(site personnel or family member).  Study staff will transfer the responses into the eCRF.  All 
patients will be asked to complete EQ-5D-5L questionnaire at Visit 1 and Visit 3.  The 
questionnaire will only be administered in countries where an official language version is 
available.  See Appendix B for an English version of the questionnaire.
The EQ-5D-5L profile will be converted into a weighted health state utility value, termed the 
EQ-5D-5L index, by applying a country-specific equation to the EQ-5D-5L profile that 
represents the comparative value of health states.  This equation is based on national valuation 
sets elicited from the general population and the base case will be the UK perspective.  The 
EQ-Visual Analogue Scale component of the questionnaire is reported separately.  The EQ-
5D-5L data will be combined with economic data and life expectancy data collected 
independently of the study for health economic analyses.


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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
6.1
Definition of AE
An 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.
In this study, serious AEs (SAEs) and premature permanent discontinuations of IP due to AEs 
(DAEs) will be collected.
6.2
Definition of SAE
An 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 details, see Appendix C.
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria above.  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 unless it meets the criteria above.  Conversely, it 
is possible for an event to be mild in intensity but still be considered an SAE if it fulfils the 
criteria above.


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6.3
Recording of AEs
6.3.1
Time period for collection of AEs
SAEs will be recorded from the time of informed consent.  DAEs will be recorded from the 
first intake of IP until Visit 3 (ie, the end of the treatment period).
6.3.2
Follow-up of unresolved AEs
Any AEs 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 CRF.  
AstraZeneca retains the right to request additional information for any patient with ongoing 
AE(s)/SAE(s) at the end of the study, if judged necessary.
6.3.3
Variables 
The following variables will be collected for each AE fulfilling SAE or DAE critera:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity 
!
Whether the AE is serious or not
!
Investigator causality rating against the IP (yes or no)
!
Action taken with regard to IP
!
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


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!
Causality assessment in relation to study procedure(s)
!
Causality assessment in relation to other medication
!
Description of AE 
In addition, the following variables will be collected for all bleedings fulfilling SAE/DAE 
criteria:
!
GUSTO classification
!
Provocation
6.3.4
Causality collection
The Investigator will assess causal relationship between IP (ticagrelor/placebo) 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 investigational product?’
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’.  See Appendix C for a guide to the interpretation of the causality question.
6.3.5
AEs based on signs and symptoms
All SAEs and DAEs 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?’, or revealed by observation will be recorded in the CRF.  
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.
6.3.6
AEs based on examinations and tests 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom should be reported as an AE, if fulfilling SAE or DAE criteria, and the 
associated laboratory result/vital sign will be considered as additional information.  Whenever 
possible, the reporting Investigator uses the clinical rather than the laboratory term (eg, 
anaemia versus low haemoglobin value).  In the absence of clinical signs or symptoms, 
clinically relevant deteriorations in non-mandated parameters should be reported as AE(s), if 
fulfilling SAE or DAE criteria.
6.3.7
Bleedings
Bleedings should be recorded as SAEs/DAEs when appropriate.  The Investigator should also 
classify the severity of the bleeding according to GUSTO bleeding definitions (see Section 
5.2) and by provocation.  Bleeding associated with procedures should only be reported as an 


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SAE/DAE if it exceeds what can be expected for the procedure.  See Section 3.9.3 for 
management of IP in case of bleeding.
6.3.8
Myocardial infarctions 
MIs are not endpoints in this study but should be recorded as SAEs (and DAEs when 
appropriate).  The diagnosis of an MI should be made according to standard clinical practice 
but is expected to align with the criteria from Third Universal Definition of MI, ie, detection 
of a rise and/or fall of cardiac biomarkers such as troponin and at least one of the following: 
typical clinical symptoms, ischaemic ECG findings, imaging evidence of myocardial injury, 
or detection of an intracoronary thrombus by angiography or autopsy (Thygesen et al 2012).  
The diagnosis should be made by, or in consultation with, a cardiologist.  The findings 
supporting the diagnosis should be documented in the description of the SAE in the eCRF.
6.4
Reporting of SAEs
All SAEs have to be reported to the appropriate AstraZeneca representative, whether or not 
considered causally related to the IP, or to the study procedure(s).  All SAEs will be recorded 
in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within 1 day, ie, immediately but 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 1 calendar day of initial receipt for fatal 
and life threatening events and within 5 calendar days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events 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 
within 1 calendar day, ie, immediately but no later than 24 hours of when he or she becomes 
aware of it.
Once the Investigators 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 reports a SAE to the 
appropriate AstraZeneca representative by telephone.  The AstraZeneca representative will 
advise the Investigator/study site personnel on how to proceed.
6.4.1
Reporting of SAEs that are also endpoints in the study
Efficacy endpoints should be reported by Investigator and AZ representatives according to 
same timelines as for all SAEs. Efficacy endpoints in the study (stroke, death) will not be 
reported to health authorities as SAEs by the Sponsor to avoid unnecessary unblinding of 
efficacy endpoints that are also SAEs. 


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6.5
Recording of cerebrovascular interventions
Invasive cerebrovascular procedures or surgery following the index event (ie, carotid 
endarterectomy) or a subsequent stroke event (ie, carotid endarterectomy, carotid 
angioplasty/stenting, thrombectomy, or thrombolysis) should be recorded in the eCRF.
6.6
Overdose
An overdose is defined as an intake of greater than 4 tablets of IP (ticagrelor or placebo) per 
day.  In the event of an overdose with ticagrelor, the Investigator must ascertain the time and 
extent of the overdose regardless of severity.  The Investigator should determine the causative 
circumstance and whether haemorrhagic or toxic complications have occurred or are likely to 
do so.  Depending on these facts, the Investigator must decide whether 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, and decompression or drainage may be required 
depending on the 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.  For other symptoms that 
can be expected after an overdose of ticagrelor and additional information, see the 
Investigator’s Brochure.
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the CRF, if SAE/DAE criteria are fulfilled, and on the Overdose CRF module.  
An overdose without associated symptoms is only reported on the Overdose CRF module.
If an overdose on an AstraZeneca IP occurs in the course of the study, then the Investigator 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 a SAE, the 
standard reporting timelines apply (see Section 6.4).  For other overdoses, reporting must 
occur within 30 days.
6.7
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca.  If a patient 
becomes pregnant during the course of the study, IP should be discontinued immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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.


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If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1 day, ie, immediately but 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 calendar days for SAEs (see 
Section 6.4) and within 30 days for all other pregnancies.  The same timelines apply when 
outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used 
to report the outcome of the pregnancy.
6.8
Medication error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an AstraZeneca study drug that either causes harm to the patient 
or has the potential to cause harm to the patient. 
A medication error is not lack of efficacy of the drug, but rather a human or process-related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error:
!
occurred
!
was identified and intercepted before the subject received the drug
!
did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:
!
Drug name confusion
!
Dispensing error, eg, medication prepared incorrectly, even if it was not actually 
given to the subject
!
Drug not administered as indicated, eg, wrong route or wrong site of administration
!
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as
a solid tablet 
!
Drug not stored as instructed, eg, kept in the fridge when it should be at room 
temperature 
!
Wrong patient received the medication (excluding IxRS errors)
!
Wrong drug administered to patient (excluding IxRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:


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!
Errors related to or resulting from IxRS, including those which lead to one of the 
above listed events that would otherwise have been a medication error 
!
Subject accidentally missed drug dose(s), eg, forgot to take medication
!
Accidental overdose (will be captured as an overdose)
!
Patient failed to return unused medication or empty packaging
!
Errors related to background and rescue medication, or standard-of-care medication 
in open-label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
If a medication error occurs during the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but 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 completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.
7.
STUDY GOVERNANCE AND OVERSIGHT
7.1.1
Executive Committee
The Executive Committee (EC) will be responsible for the overall design, interpretation, 
supervision, and reporting (presenting at international congresses and publishing in peer-
reviewed journals) of the study, including the development of the CSP and any CSP
amendments.  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 
AstraZeneca representatives, and will operate under a separate charter.
7.1.2
Steering Committee
The International Steering Committee is comprised of national lead investigators from each 
country where the study is conducted 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 countries.
7.1.3
Data Monitoring Committee
An independent DMC will be appointed and will report to the EC.  The DMC will be 
responsible for safeguarding the interests of the patients by assessing the benefit/risk profile of 
the intervention during the study, and for reviewing the overall conduct of the study.  The 


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DMC will review all safety and efficacy data (endpoint data, SAEs, DAEs), overall and by 
region, on an ongoing basis.  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.  If the 
DMC expresses safety concerns that suggest study conduct should be amended, information 
will be sent to the EC and regulatory authorities.   The DMC will also conduct an interim 
analysis for efficacy (see Section 9.5.6).   The DMC Charter details roles, responsibilities, and 
procedures to ensure maintenance of the blinding and integrity of the study.
8.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
At randomisation (Visit 1/Day 1), eligible patients will be randomly assigned to 1 of 2 
treatments: ticagrelor or placebo (IP).  In addition, all patients should be treated with open-
label ASA, which will not be supplied by AstraZeneca.  Treatments will be given orally with 
loading doses on Day 1 followed by maintenance treatment until Visit 3/Day 30.  
8.1
Identity of investigational product
Investigational product
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, 
placebo to match 90 mg
AstraZeneca
8.2
Dose and treatment regimens
8.2.1
Investigational product
Patients will be treated with:
!
A loading dose of ticagrelor (2 tablets ticagrelor 90 mg) on Day 1, followed by 
ticagrelor 90 mg twice daily, OR
!
A loading dose of placebo (2 tablets matching ticagrelor 90 mg) on Day 1, followed 
by placebo (matching ticagrelor 90 mg) twice daily.
8.2.2
Concomitant ASA treatment
All patients should be treated with ASA.  Patients should receive an ASA loading dose on Day 
1.  The recommended loading dose is 300 to 325 mg ASA.  Any dose of ASA given after 
symptom onset but before randomisation should be taken into account (for instance, if a 
patient has received 300 mg ASA just prior to randomisation, the patient does not need to 
receive a second loading dose after randomisation).  Thereafter, patients should be treated 
with ASA 75 to 100 mg once daily.
8.2.3
Timing of loading doses and first maintenance doses 
Randomisation and treatment pack assignment will be managed via the IxRS, and the first 
doses of IP and ASA (loading doses) should be taken on Day 1. 


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Ticagrelor/placebo
Patients should be randomised as soon as possible after symptom onset, and the loading dose 
of ticagrelor/placebo should be given immediately after randomisation. 
The first maintenance dose should be given >6 to ≤12 hours after the loading dose.  The 
second maintenance dose should be given >6 to ≤12 hours after the first maintenance dose, 
adjusting the timing such that subsequent doses can be taken in the morning and evening.  
Thereafter, ticagrelor/placebo should be taken morning and evening at approximately 12-hour 
intervals for the remainder of the treatment period.
ASA
The ASA loading dose should be given on Day 1 (as directed in Section 8.2.2) and the first 
maintenance dose of ASA should be taken in the morning of Day 2.
8.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice and local regulatory 
guidelines.  The labels will fulfil Good Manufacturing Practice Annex 13 requirements for 
labelling.  Label text will be translated into local language.
8.4
Storage
All IPs should be kept in a secure place under appropriate storage conditions.  The IP label 
specifies the appropriate storage.
8.5
Compliance
At Visit 1, patients will receive enough IP to last until Visit 3.  The administration of all IPs 
should be recorded in the appropriate sections of the eCRF.  At Visit 2, any patient found to 
be non-compliant will be counselled on the importance of taking their IP as prescribed.  
Patients will be asked to return all unused IP and empty packages to the clinic at Visit 3.  The 
amount of returned tablets for each patient should be verified by an AstraZeneca 
representative.
8.6
Accountability
The IP provided for this study will be used only as directed in the CSP.  The study personnel 
will account for all IP dispensed to and returned from the patient.
The eCRF includes information regarding identification of the person to whom the drug is 
dispensed, the quantity dispensed, the date of dispensing, the quantity returned, and the date 
returned.  Any IP deliberately or accidentally destroyed must be recorded.  Any discrepancy 
between dispensed and returned IP should be explained.
Patients will be asked to return all unused IPs and empty packages to the clinic at Visit 3.  The 
Investigator will retain the returned medication, along with any medication not dispensed, 
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confirming that the quantities of returned and unused tablets for each patient has been 
recorded before the medication is destroyed.  Unused IP (including empty bottles) will be 
destroyed according to local procedure at an authorised site.  Certificates of delivery, return, 
and destruction must be signed by an AstraZeneca representative.
8.7
Concomitant medications and other treatments 
Recording of concomitant medications will be made at all visits, including all changes within 
30 days prior to randomization and during study treatment and follow-up period. Particular 
attention should be given to antithrombotic medications, antihypertensives, lipid-lowering 
drugs including statins, insulin, and oral glucose-lowering drugs.
Prohibited medications are medications that cannot be given concomitantly with IP; however, 
they may be given during the study after temporary or permanent discontinuation of IP 
without constituting a protocol deviation.
8.7.1
Concomitant medications
Medications considered necessary for the patient’s health, other than those described below, 
may be given at the discretion of the Investigator. 
All patients are to receive ASA concomitantly with the IP (see Section 8.2.2).  Additionally, 
patients should receive medical treatment and be counseled on lifestyle modifications for 
cerebrovascular risk factors (eg, diabetes, hypertension, dyslipidaemia, atherosclerosis, and 
smoking) according to local and global guidelines (eg, AHA/ASA 2014). 
Restricted medication/class of drug
Usage
Low-molecular weight heparins
Short-term treatment (≤7 days) with low-dose low-
molecular weight heparin may be used in 
immobilised patients if required and at the 
Investigator’s discretion
Non-steroidal anti-inflammatory drugs 
(NSAIDs)
Short-term treatment (≤7 days) is allowed at the 
Investigator’s discretion
Treatment with selective cycloxygenase-2 inhibitors 
is permitted, although use is cautioned
Digoxin
Ticagrelor modestly increases digoxin levels, which 
should therefore be monitored closely following 
initiation of IP
Strong CYP3A4 inducers (eg, rifampicin, 
phenytoin, carbamazepine, phenobarbital)
Co-administration with ticagrelor could decrease 
plasma levels of ticagrelor
If required, treatment can be given at the 
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CYP3A substrates with narrow therapeutic 
index (eg, quinidine, simvastatin at doses >40 
mg daily or lovastatin at doses >40 mg daily)
Co-administration with ticagrelor could increase 
plasma levels of simvastatin or lovastatin, which may 
put the patient at increased risk of statin-related 
adverse effects
Treatment with lower doses or with other statins is 
not prohibited
P-glycoprotein/CYP3A inhibitors (eg, 
cyclosporine)
Co-administration with ticagrelor could increase 
plasma levels of ticagrelor
If required, treatment can be given at the 
Investigator’s discretion
Prohibited medication/class of drug
Usage
Antiplatelet agents other than ASA (eg, 
GPIIb/IIIa inhibitors, clopidogrel, ticlopidine, 
prasugrel, dipyridamole, ozagrel, and 
cilostazol; ticagrelor other than as IP)
Patients who develop an indication (acute coronary 
syndrome or percutaneous coronary intervention) for 
dual antiplatelet therapy must discontinue IP and be 
treated with standard of care
Anticoagulants (eg, warfarin, oral thrombin 
and factor Xa inhibitors, bivalirudin, hirudin, 
argatroban, fondaparinux, long-term or high-
dose use of low-molecular weight heparin) 
Anticoagulants in combination with antiplatelet 
therapy increase the risk for bleedings
Strong CYP3A inhibitors (eg, ketoconazole, 
clarithromycin, nefazadone, ritonavir, 
atazanavir)
Co-administration with ticagrelor could increase 
plasma levels of ticagrelor
Traditional/herbal medicines known to have 
antiplatelet or anticoagulant properties (eg, 
Salvia miltiorrhiza, breviscapine)
These agents in combination with antiplatelet therapy 
may increase the risk of bleeding
Rescue/supportive medication/class of drug
Usage
Thrombolytic therapy (eg, alteplase)
If intravenous or intraarterial thrombolytic therapy is 
required, IP must be discontinued for at least 24 hours 
after thrombolytic therapy
8.7.2
Surgery and other invasive procedures
IP (ticagrelor/placebo) should be discontinued at least 5 days prior to any elective/subacute 
major surgery.  This is particularly important for surgery with potential for major bleeding.  
To minimise the risk of thrombotic complications while off IP, it is also recommended that IP 
not be discontinued for significantly longer than 5 days prior to surgery.  For reference, ESC 
guidelines recommend discontinuation of ticagrelor 3 to 5 days prior to coronary artery bypass 
grafting (ESC 2014).  Potential discontinuation of ASA prior to major surgery should occur 
according to local practice. After surgery, IP and ASA should be restarted at the 
Investigator’s discretion, taking the risk of bleeding versus the risk of new thrombotic events 
into consideration.


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For carotid endarterectomy and other invasive procedures such as coronary angiography, IP 
and/or ASA may be continued or interrupted temporarily at the discretion of the Investigator, 
based on the risk of bleeding versus the risk of new thrombotic events.  The Society for 
Vascular Surgery guidelines recommend that perioperative antithrombotic therapy for carotid 
endarterectomy should include ASA (Grade 1, Level of Evidence A; Ricotta et al 2011).  
After the surgical or interventional procedure, IP and/or ASA should be restarted (if 
interrupted) as soon as possible.
If a patient suffers an acute stroke during the study with a potential indication for 
thrombectomy and/or thrombolysis, the treating physician should determine the appropriate 
treatment, taking into consideration the potential benefit of aggressive treatment and the 
increased risk of bleeding during simultaneous treatment with several antithrombotic agents.  
If thrombolysis is administered, IP should be discontinued for at least 24 h afterwards.
9.
STATISTICAL ANALYSES BY ASTRAZENECA
9.1
Statistical considerations
A comprehensive Statistical Analysis Plan will be prepared prior to first patient  randomised 
and any subsequent amendments will be documented, with final amendments completed prior 
to unblinding of the data.  Analyses will be performed by AstraZeneca.  
9.2
Sample size estimate
At least 647 primary endpoint events are needed to provide 90% power assuming a hazard 
ratio (HR) of 0.775 in favour of ticagrelor at the significance level of 4.996%, adjusted for the 
planned efficacy interim analysis (647 events corresponding to a critical value of 0.857).  
Based on data from the SOCRATES study, a primary endpoint rate of 6.7% in the placebo 
group is assumed at 30 days following randomisation.  Hence, randomising approximately 11 
000 patients to ticagrelor or placebo in a 1:1 ratio is expected to yield the 647 events needed.  
The study is event-driven and the final number of randomised patients will be determined 
based on blind data review.
9.3
Definitions of analysis sets
All variables, including safety variables, will be analysed using the full analysis set (FAS).  
All patients who have been randomised to IP will be included in the FAS irrespective of their 
protocol adherence and continued participation in the study.  Patients will be analysed 
according to their randomised IP irrespective of whether the event occurred before or 
following discontinuation of IP.


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9.4
Variables for analyses
9.4.1
Primary variable
The primary variable is the time from randomisation to first subsequent stroke or death.  
Patients who have not experienced either of these events will be censored at Visit 3, Day 34, 
or the date of the last event assessment, whichever occurs earlier. 
9.4.2
Secondary variables
The secondary variables, presented in the hierarchical order in which they will be tested, are:
1.
Time from randomisation to first subsequent ischaemic stroke
2.
mRS score >1 at Visit 3
For the time-to-event variable, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of the last event assessment, whichever occurs earlier.  The 
mRS score for patients who have died prior to Visit 3 will by definition be 6.  No other 
imputation for missing data will be made.
9.4.3
Safety variables
The safety variables are:
!
Time from randomisation to first bleeding event that fulfils SAE criteria and is 
categorised as GUSTO Severe
!
Time from randomisation to first ICH or fatal bleeding event
!
Time from randomisation to first bleeding event that fulfils SAE criteria and is 
categorised as GUSTO Moderate/Severe
!
Time from randomisation to premature permanent discontinuation of IP due to 
bleeding 
!
Occurrence of SAE
!
Occurrence of DAE
For the time-to-event variables, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of last event assessment, whichever occurs earlier; or, for the 
time from randomisation to discontinuation due to bleeding variable only, the day of the last 
dose of IP, if earlier. 
9.4.4
Exploratory variables
The exploratory variables are:


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Time from randomisation to first subsequent stroke or death in patients with 
ipsilateral atherosclerotic stenosis
!
mRS score >2 at Visit 3 in patients with subsequent stroke
!
EQ-5D-5L profile
For the time-to-event variable, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of last event assessment, whichever occurs earlier.  The mRS 
score for patients who have died prior to Visit 3 will by definition be 6.
9.5
Methods for statistical analyses
All analyses will be based on the intent-to-treat principle, using the FAS.  In time-to-event 
analyses, the treatment groups will be compared using a Cox proportional hazards model with 
a factor for treatment group, using the Efron method for ties.  P-values and 95% confidence 
intervals for the HR will be based on the Wald statistic.  In summary tables of these analyses, 
in addition to HR with confidence intervals and p-values, presentations will include the 
number and percentage of patients with events and Kaplan-Meier estimates of the event rate 
per treatment group.  Kaplan-Meier estimates of the cumulative proportion of patients with 
events will be calculated and plotted, with the number of patients at risk indicated below the 
plot at specific time points.  If the total number of events is less than 15, only the number and 
percentage of patients with events will be presented, but no Kaplan-Meier estimates, HRs, 
confidence intervals, or p-values.
No multiplicity adjustment will be made to confidence intervals as they will be interpreted 
descriptively and used as a measure of precision.  The primary variable and the secondary 
variables will be included in a confirmatory testing procedure.
Continuous variables will be summarised by treatment group 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. 
9.5.1
Analysis of the primary variable 
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 the 4.996% 2-sided significance level.
As an explorative analysis, primary events up to the end of the follow-up period will be 
analysed by repeating the primary analysis with event-free patients censored at Visit 4 (or Day 
64) instead of Visit 3 (or Day 34).
9.5.2
Analysis of the secondary variables
The secondary variables will be included in the confirmatory testing procedure.  Only if the 
treatment effect on the primary variable is significant at the 4.996% level will the secondary 
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The hypothesis testing will continue at the 4.996% significance level until the first statistically 
non-significant treatment difference (p ≥0.04996) is observed.
The time from randomisation to first subsequent ischaemic stroke will be analysed in the same 
manner as the primary variable.  The proportion of patients with mRS score >1 at Visit 3 will
be analysed using a logistic regression model with treatment group, history of stroke, and 
baseline NIHSS score as explanatory variables.
9.5.3
Analysis of the safety variables
The time-to-event safety variables will be analysed in the same manner as the primary 
variable, but will not be included in the confirmatory testing procedure.  SAEs and DAEs, 
summarised by system organ class and preferred term using the Medical Dictionary for 
Regulatory Activities, will be presented by treatment group using descriptive statistics.
9.5.4
Analysis of the exploratory variables
The time from randomisation to first subsequent stroke or death in patients with ipsilateral 
atherosclerotic stenosis will be analysed in the same manner as the primary variable.  The 
proportion of patients with subsequent stroke and mRS score >2 at Visit 3 will be analysed 
using a logistic regression model with treatment group, history of stroke, and baseline NIHSS 
score as the explanatory variables.  EQ-5D-5L data will be presented by treatment group using 
descriptive statistics.
9.5.5
Subgroup analysis
Subgroup analyses will be performed to evaluate variation of treatment effect on the primary 
variable and on GUSTO Severe bleeding events.  The subgroup variables (eg, “age”) and their 
categories (eg, “<65 years”) will be defined in the Statistical Analysis Plan.  Tests for 
interaction between treatment and each subgroup variable will be performed in Cox 
proportional hazards models with factors for treatment, subgroup variable, and the interaction 
between treatment and subgroup variable if at least 15 events have occurred in each subgroup 
category.  The subgroup categories will be examined in Cox proportional hazards models with 
a factor for treatment group.  Kaplan-Meier estimates, HRs, and 95% confidence intervals will 
be reported if at least 15 events have occurred within the subgroup category.  
9.5.6
Interim analysis
One interim analysis will be performed by the DMC following the accrual of 70% of the 
planned primary events (453).  The efficacy stopping boundary at the interim is a 2-sided p-
value <0.001 for the primary endpoint (corresponding to a critical value of 0.734).  The 
interim p-value is small enough for the final analysis, based on the accrual of all events, to be 
conducted at a significance level of 4.996%, with the family-wise error rate controlled at 
5.00%.  This boundary was estimated in East V6.4 (copyright 1994-2016, Cytel Inc) using the 
Haybittle-Peto procedure.
If a recommendation to stop the study for efficacy is made at the interim, all subsequent 
testing of secondary variables will be done at a significance level of 0.1%.


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The study may be stopped for futility if the observed HR for the primary endpoint is >0.933 
(taking all available study information into account), corresponding to a predictive power of 
5%.
10.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
10.1
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 CSP and related documents with the investigational staff and 
also train them in any study-specific procedures and WBDC system utilised.
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).
10.2
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 CRFs, and that study drug accountability 
checks are being performed
!
Perform source data verification (a comparison of the data in the CRFs 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)
!
Perform source data review, ie, review source documents for important areas where 
there is no associated eCRF data field, and monitoring of the research centre’s 
critical processes
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.


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10.2.1
Risk-based quality management
Quality by design will be implemented, including a focus on identifying key risks to patient 
safety, data quality, and good clinical practice (GCP)/regulatory compliance.  A risk-based 
approach to monitoring will be applied.  A mix of monitoring strategies will be implemented: 
on-site monitoring, remote monitoring (site-level monitoring activities performed at a location 
other than the research centre), and centralised monitoring systems.  Monitoring strategies will 
be tailored to risks, permit timely oversight (through central/remote monitoring and use of 
technology), and will be focused on Critical Processes and Critical Data.  Central monitoring 
will be used to check that data is consistent and complete, identify unusual distribution of 
data, identify higher risk sites to target additional monitoring, and to ensure routine review of 
data is completed in real time.
10.2.2
Source data
The location of source data is defined in the CSA.  The Principal Investigator must provide 
direct access to source data/documents for trial-related monitoring, audits, institutional review 
board/independent ethics committee (IRB/IEC) review, and regulatory inspection.
10.2.3
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 CSP and the CSA, the terms of CSP 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.
10.2.4
Archiving of study documents
The Investigator follows the principles outlined in the CSA for archiving study documents.
10.3
Study timetable and end of study
The study is event-driven and expected to start in Q1 2018 and to end by Q4 2019.  The end of 
the study is defined as ‘the last visit of the last patient undergoing the study’.  The expected 
recruitment period is 21 months.  AstraZeneca will notify Investigators when recruitment is 
complete.
Individual sites can be closed if the study procedures are not being performed according to 
GCP (including late data entry), or if recruitment is slow.  All eCRFs should be completed and 
cleaned and all patients should be followed up for endpoints and vital status before a site is 
closed.  AstraZeneca may also terminate the entire study prematurely if concerns for safety 
arise within this study or in any other study with ticagrelor.


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10.4
Data management by AstraZeneca 
Data management will be performed by AstraZeneca Data Management Centre staff at 
Cognizant according to the Data Management Plan.  AEs and medical/surgical history will be 
classified according to the terminology of the latest version of the Medical Dictionary for 
Regulatory Activities.  Medications will be classified according to the World Health 
Organisation Drug Dictionary.  Classification coding will be performed by the Medical 
Coding Team at the AstraZeneca Data Management Centre.
The data collected through third party sources will be obtained and reconciled against study 
data.  Data queries will be raised for inconsistent, impossible or missing data.  All entries to 
the study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  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 Management Plan will also clarify the roles and 
responsibilities of the various functions and personnel involved in the data management 
process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.
SAE reconciliation
SAE reports are reconciled between the eCRF and the Patient Safety database.
11.
ETHICAL AND REGULATORY REQUIREMENTS
11.1
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 International Conference on 
Harmonisation/GCP, applicable regulatory requirements and the AstraZeneca policy on 
Bioethics and Human Biological Samples.
11.2
Patient 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.
11.3
Ethics and regulatory review
An IRB/IEC should approve the final CSP, including the final version of the Informed 
Consent Form and any other written information and/or materials to be provided to the 
patients.  The Principal Investigator will ensure the distribution of these documents to the 
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in writing.  The Principal Investigator should submit the written approval to AstraZeneca 
before enrolment of any patient into the study.  The IRB/IEC 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 CSP should be re-approved 
by the IRB/IEC annually.
Before enrolment of any patient into the study, the final CSP, 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.  
AstraZeneca will provide Regulatory Authorities, IRB/IECs, and Principal Investigators with 
safety updates/reports according to local requirements.
11.4
Informed consent
The Principal Investigator(s) 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 procedure specifically for the study
!
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 IRB/IEC
11.5
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 CSP, then these changes will be documented in a 
CSP amendment and where required in a new version of the CSP (Revised CSP).  The 


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amendment is to be approved by the relevant IRB/IEC and if applicable, also the national 
regulatory authority approval, before implementation.  Local requirements are to be followed 
for revised CSPs.  AstraZeneca will distribute any subsequent amendments and new versions 
of the CSP to each Principal Investigator(s).  For distribution to IRB/IEC, see Section 11.3.
If a CSP amendment requires a change to a centre’s Informed Consent Form, AstraZeneca and 
the centre’s IRB/IEC 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 IRB/IEC.
11.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an IRB/IEC 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 CSP, GCP, guidelines of the 
International Conference on Harmonisation, and any applicable regulatory requirements.  The 
Investigator will contact AstraZeneca immediately if contacted by a regulatory agency about 
an inspection at the centre.
12.
LIST OF REFERENCES
AHA/ASA 2009
Easton JD, Saver JL, Albers GW, Alberts MJ, Chaturvedi S, Feldmann E, et al.  Definition 
and evaluation of transient ischemic attack.  A scientific statement for health care 
professionals from the American Heart Association/American Stroke Association.  Stroke 
2009;40:2276-93.
AHA/ASA 2013 
Jauch EC, Saver JL, Adams HP, Bruno A, Connors JJ, Demaerschalk BM et al.  Guidelines 
for the early management of patients with acute ischemic stroke: a guideline for healthcare 
professional from the American Heart Association/American Stroke Association.  Stroke 
2013; 44:870–947.
AHA/ASA 2014 
Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekowitz MD, et al.  
Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: A 
guideline for healthcare professionals from the American Heart Association/American Stroke 
Association.  Stroke 2014;45:2160-236.


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Study Code D5134C00003
Version 3.0
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Albers 2000
Albers GW.  Choice of endpoints in antiplatelet trials: which outcomes are most relevant to 
stroke patients?  Neurology. 2000 Mar 14;54(5):1022-8.
Amarenco et al 2016
Amarenco P, Lavallée PC, Labreuche J, Albers GW, Bornstein NM, Canhão P, et al.  One-
Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke.  N Engl J Med. 2016 
Apr 21;374(16):1533-42.
Amarenco et al 2017
Amarenco P, Albers G, Denison H, Easton D, Evans S, Held P, et al. Efficacy and safety of 
ticagrelor versus aspirin in acute stroke or transient ischaemic attack of atherosclerotic origin: 
a subgroup analysis of SOCRATES, a randomised, double-blind, controlled trial. Lancet 
Neurology. 2017 February 23; 16: 301-10.
Bruno et al 2011
Bruno A, Akinwuntan AE, Lin C, Close B, Davis K, Baute V, et al. Simplified modified 
rankin scale questionnaire: reproducibility over the telephone and validation with quality of 
life. Stroke. 2011;42:2276-2279.
Coull et al 2004
Coull AJ, Lovett JK, Rothwell PM.  Population based study of early risk of stroke after 
transient ischemic attack or minor stroke: implications for public education and organisation 
of services.  BMJ 2004;328(7435):326-8.
ESC 2014
Windecker S, Kolh P, Alfonso F, Collet JP, Cremer J, Falk V, et al.  2014 ESC/EACTS 
Guidelines on myocardial revascularization.  Eur Heart J. 2014 Oct 1;35(37):2541-619.  
ESO 2008
European Stroke Organisation (ESO) Executive Committee, ESO Writing Committee.  
Guidelines for management of ischaemic stroke and transient ischaemic attack 2008.  
Cerebrovasc Dis. 2008;25(5):457-507.
Feigin et al 2015
Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA et al.  Update 
on the global burden of ischemic and hemorrhagic stroke in 1990-2013: The GBD 2013 Study 
Neuroepidemiology 2015;45:161-76.
Gurbel et al 2009
Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, et al.  Randomized double-
blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus 
clopidogrel in patients with stable coronary artery disease: the ONSET/OFFSET study.  
Circulation 2009;120(25):2577-85.


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Version 3.0
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Hicks et al 2015
Hicks KA, Tcheng JE, Bozkurt B, Chaitman BR, Cutlip DE, Farb A, et al.  2014 ACC/AHA 
key data elements and definitions for cardiovascular endpoint events in clinical trials 
[published erratum appears in J Am Coll Cardiol. 2015 Aug 25;66(8):982].  J Am Coll 
Cardiol. 2015 Jul 28;66(4):403-69.
Johnston et al 2016
Johnston SC, Amarenco P, Albers GW, Denison H, Easton JD, Evans SR, et al.  Ticagrelor 
versus aspirin in acute stroke or transient ischemic attack.  N Engl J Med. 2016 Jul 
7;375(1):35-43.
Johnston et al 2018
Johnston SC, Easton JD, Farrant M, Barsan W, Conwit RA, Elm JJ, et al.  Clopidogrel and 
aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018;379(3):215-25.
Josephson et al 2008
Josephson SA, Sidney S, Pham TN, Bernstein AL, Johnston SC.  Higher ABCD2 score 
predicts patients most likely to have true transient ischemic attack.  Stroke 2008;39(11):3096-
8.
Kennedy et al 2007 
Kennedy J, Hill MD, Ryckborst KJ, Eliasziw M, Demchuk AM, Buchan AM for the FASTER 
Investigators.  Fast assessment of stroke and transient ischemic attack to prevent early 
recurrence (FASTER): a randomised controlled pilot trial.  Lancet Neurol 2007;6:961-9.
Petty et al 1998
Petty GW, Brown RD Jr, Whisnant JP, Sicks JD, O'Fallon WM, Wiebers DO.  Survival and 
recurrence after first cerebral infarction: a population-based study in Rochester, Minnesota, 
1975 through 1989.  Neurology. 1998 Jan;50(1):208-16.
Ricotta et al 2011
Ricotta JJ, Aburahma A, Ascher E, Eskandari M, Faries P, Lal BK; et al.  Updated Society for 
Vascular Surgery guidelines for management of extracranial carotid disease.  J Vasc Surg. 
2011 Sep;54(3):e1-31. 
Thygesen et al 2012
Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD et al.  Third 
universal definition of myocardial infarction.  Eur Heart J. 2012 Oct;33(20):2551-67
Wallentin et al 2009
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, for the PLATO 
Investigators.  Ticagrelor versus clopidogrel in patients with acute coronary syndromes.  N 
Engl J Med 2009;361:1045-57.


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Wang et al 2013
Wang Y, Wang Y, Zhao X, Liu L, Wang D, Wang C, Johnston C, et al. for the CHANCE 
investigators.  Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N 
Engl J Med 2013;369:11-19.


Clinical Study Protocol Appendix A
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Study Code D5134C00003
Version 3.0
Date 08 May 2019
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Appendix A
NIHSS questionnaire
Interval: [ ] Baseline  [ ] 2 hours post treatment  [ ] 24 hours post onset of symptoms ±20 minutes 
[ ] 7-10 days   [ ] 3 months   [ ] Other ________________________________(___ ___) 
Time: ___ ___:___ ___ [ ]am [ ]pm
Person Administering Scale _____________________________________ 
Administer stroke scale items in the order listed. Record performance in each category after each 
subscale exam. Do not go back and change scores. Follow directions provided for each exam 
technique. Scores should reflect what the patient does, not what the clinician thinks the patient can do. 
The clinician should record answers while administering the exam and work quickly. Except where 
indicated, the patient should not be coached (i.e., repeated requests to patient to make a special 
effort).
Instructions
               Scale Definition
      Score
1a. Level of Consciousness: The investigator must 
choose a response if a full evaluation is prevented by 
such obstacles as an endotracheal tube, language 
barrier, orotracheal trauma/bandages. A 3 is scored 
only if the patient makes no movement (other than 
reflexive posturing) in response to noxious 
stimulation. 
0= Alert: keenly responsive
1= Not alert: but arousable by minor stimulation 
to obey, answer, or respond
2= Not alert: requires repeated stimulation to 
attend, or is obtunded and requires strong or 
painful stimulation to make movements
3=  Responds only with reflex motor or 
autonomic effects or totally unresponsive, 
flaccid and areflexic
____
1b. LOC Questions: The patient is asked the month 
and his/her age. The answer must be correct - there 
is no partial credit for being close. Aphasic and 
stuporous patients who do not comprehend the 
questions will score 2. Patients unable to speak 
because of endotracheal intubation, orotracheal 
trauma, severe dysarthria from any cause, language 
barrier, or any other problem not secondary to 
aphasia are given a 1. It is important that only the 
initial answer be graded and that the examiner not 
"help" the patient with verbal or non-verbal cues. 
0= Answers both questions correctly
1= Answers one question correctly
2= Answers neither question correctly
____
1c. LOC Commands: The patient is asked to open 
and close the eyes and then to grip and release the 
non-paretic hand. Substitute another one step 
command if the hands cannot be used. Credit is 
given if an unequivocal attempt is made but not 
completed due to weakness. If the patient does not 
respond to command, the task should be 
demonstrated to him or her (pantomime), and the 
result scored (i.e., follows none, one or two 
commands). Patients with trauma, amputation, or 
other physical impediments should be given suitable 
one-step commands. Only the first attempt is scored. 
0= Performs both tasks correctly
1=  Performs one task correctly
2= Performs neither task correctly
____
2. Best Gaze: Only horizontal eye movements will 
be tested. Voluntary or reflexive (oculocephalic) eye 
0=   Normal


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Version 3.0
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movements will be scored, but caloric testing is not 
done. If the patient has a conjugate deviation of the 
eyes that can be overcome by voluntary or reflexive 
activity, the score will be 1. If a patient has an 
isolated peripheral nerve paresis (CN III, IV or VI), 
score a 1. Gaze is testable in all aphasic patients. 
Patients with ocular trauma, bandages, pre-existing 
blindness, or other disorder of visual acuity or fields 
should be tested with reflexive movements, and a 
choice made by the investigator. Establishing eye 
contact and then moving about the patient from side 
to side will occasionally clarify the presence of a 
partial gaze palsy. 
1= Partial gaze palsy: gaze is abnormal in one 
or both eyes, but forced deviation for total 
gaze paresis is not present
2= Forced deviation: or total gaze paresis not
overcome by the oculocephalic maneuver
____
3. Visual: Visual fields (upper and lower quadrants) 
are tested by confrontation, using finger counting or 
visual threat, as appropriate. Patients may be 
encouraged, but if they look at the side of the moving 
fingers appropriately, this can be scored as normal. If 
there is unilateral blindness or enucleation, visual 
fields in the remaining eye are scored. Score 1 only if 
a clear-cut asymmetry, including quadrantanopia, is 
found. If patient is blind from any cause, score 3. 
Double simultaneous stimulation is performed at this 
point. If there is extinction, patient receives a 1, and 
the results are used to respond to item 11. 
0= No visual loss
1= Partial hemianopia
2= Complete hemianopia
3= Bilateral hemianopia (blind including 
cortical blindness)
____
4. Facial Palsy: Ask – or use pantomime to 
encourage – the patient to show teeth or raise 
eyebrows and close eyes. Score symmetry of 
grimace in response to noxious stimuli in the poorly 
responsive or non-comprehending patient. If facial 
trauma/bandages, orotracheal tube, tape or other 
physical barriers obscure the face, these should be 
removed to the extent possible. 
0=   Normal: symmetrical movements
1=   Minor paralysis: flattened nasolabial fold, 
asymmetry on smiling
2=   Partial paralysis: total or near total 
paralysis of lower face
3=   Complete paralysis: one or both sides
____
5. Motor Arm: The limb is placed in the appropriate 
position: extend the arms (palms down) 90 degrees
(if sitting) or 45 degrees (if supine). Drift is scored if 
the arm falls before 10 seconds. The aphasic patient 
is encouraged using urgency in the voice and 
pantomime, but not noxious stimulation. Each limb is 
tested in turn, beginning with the non-paretic arm. 
Only in the case of amputation or joint fusion at the 
shoulder, the examiner should record the score as 
untestable (UN), and clearly write the explanation for 
this choice. 
0= No drift: limb holds 90 (or 45) degrees for a 
full 10 seconds
1= Drift: limb holds 90 (or 45) degrees, but 
drifts down before full 10 seconds, does not 
hit bed or other support
2= Some effort against gravity: limb cannot 
get to or maintain 90 (or 45) degrees, drifts 
down to bed, but has some effort against 
gravity
3= No effort against gravity: limb falls
4= No movement
5a. Left Arm
5b. Right Arm
____
6. Motor Leg: The limb is placed in the appropriate 
position: hold the leg at 30 degrees (always tested 
supine). Drift is scored if the leg falls before 5 
0= No drift: leg holds 30-degree position for full 
5 seconds


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Study Code D5134C00003
Version 3.0
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seconds. The aphasic patient is encouraged using 
urgency in the voice and pantomime, but not noxious 
stimulation. Each limb is tested in turn, beginning with 
the non-paretic leg. Only in the case of amputation or 
joint fusion at the hip, the examiner should record the 
score as untestable (UN), and clearly write the 
explanation for this choice. 
1= Drift: leg falls by the end of the 5- second 
period but does not hit bed
2= Some effort against gravity: leg falls to bed 
by 5 seconds, but has some effort against 
gravity
3= No effort against gravity: leg falls to bed 
immediately
4=  No movement
6a. Left Leg
6b. Right Leg
____
7. Limb Ataxia: This item is aimed at finding 
evidence of a unilateral cerebellar lesion. Test with 
eyes open. In case of visual defect, ensure testing is 
done in intact visual field. The finger-nose-finger and 
heel-shin tests are performed on both sides, and 
ataxia is scored only if present out of proportion to 
weakness. Ataxia is absent in the patient who cannot 
understand or is paralyzed. Only in the case of 
amputation or joint fusion, the examiner should 
record the score as untestable (UN), and clearly write 
the explanation for this choice. In case of blindness, 
test by having the patient touch nose from extended 
arm position.
0= Absent
1= Present in one limb
2= Present in two limbs
UN= Amputation or joint fusion
     Explain: ___________
____
8. Sensory: Sensation or grimace to pinprick when 
tested, or withdrawal from noxious stimulus in the 
obtunded or aphasic patient. Only sensory loss 
attributed to stroke is scored as abnormal and the 
examiner should test as many body areas (arms [not 
hands], legs, trunk, face) as needed to accurately 
check for hemisensory loss. A score of 2, “severe or 
total sensory loss,” should only be given when a 
severe or total loss of sensation can be clearly 
demonstrated. Stuporous and aphasic patients will, 
therefore, probably score 1 or 0. The patient with 
brainstem stroke who has bilateral loss of sensation 
is scored 2. If the patient does not respond and is 
quadriplegic, score 2. Patients in a coma (item 1a=3) 
are automatically given a 2 on this item. 
0= Normal: no sensory loss
1= Mild to moderate sensory loss: patient 
feels pinprick is less sharp or is dull on the 
affected side, or there is a loss of superficial 
pain with pinprick, but patient is aware of 
being touched
2= Severe to total sensory loss: patient is not 
aware of being touched in the face, arm and 
leg
____
9. Best Language: A great deal of information about 
comprehension will be obtained during the preceding 
sections of the examination. For this scale item, the 
patient is asked to describe what is happening in the 
attached picture, to name the items on the attached 
naming sheet and to read from the attached list of 
sentences. Comprehension is judged from responses 
here, as well as to all of the commands in the 
preceding general neurological exam. If visual loss 
interferes with the tests, ask the patient to identify 
objects placed in the hand, repeat, and produce 
speech. The intubated patient should be asked to 
write. The patient in a coma (item 1a=3) will 
automatically score 3 on this item. The examiner 
0= No aphasia: normal
1= Mild to moderate aphasia: some obvious     
loss of fluency or facility of 
comprehension,without significant limitation 
on ideas expressed or form of expression. 
Reduction of speech and/or comprehension 
however makes conversation about provided 
material difficult or impossible. For example, 
in conversation about provided materials, 
examiner can identify picture or naming card 
content from patient’s response
____


Clinical Study Protocol Appendix A
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Study Code D5134C00003
Version 3.0
Date 08 May 2019
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must choose a score for the patient with stupor or 
limited cooperation, but a score of 3 should be used 
only if the patient is mute and follows no one-step 
commands. 
2= Severe aphasia: all communications is 
through fragmentary expression, great need 
for inference, questioning, and guessing by 
the listener. Range of information that can 
be exchanged is limited, listener carries 
burden of communication. Examiner cannot 
identify materials provided from patient 
response
3=   Mute, global aphasia: no usable speech or 
auditory comprehension 
10. Dysarthria: If patient is thought to be normal, an 
adequate sample of speech must be obtained by 
asking patient to read or repeat words from the 
attached list. If the patient has severe aphasia, the 
clarity of articulation of spontaneous speech can be 
rated. Only if the patient is intubated or has other 
physical barriers to producing speech, the examiner 
should record the score as untestable (UN), and 
clearly write an explanation for this choice. Do not tell 
the patient why he or she is being tested. 
0= Normal
1= Mild to moderate dysarthria: patient slurs 
at least some words and, at worst, can be 
understood with some difficulty
2= Severe dysarthria: patient speech is so 
slurred as to be unintelligible in the absence  
of or out of proportion to any dysphasia, or is 
mute/anarthric
UN=   Intubated: or other physician barrier
____
11. Extinction and Inattention (formerly Neglect): 
Sufficient information to identify neglect may be 
obtained during the prior testing. If the patient has a 
severe visual loss preventing visual double 
simultaneous stimulation, and the cutaneous stimuli 
are normal, the score is normal. If the patient has 
aphasia but does appear to attend to both sides, the 
score is normal. The presence of visual spatial 
neglect or anosagnosia may also be taken as 
evidence of abnormality. Since the abnormality is 
scored only if present, the item is never untestable. 
0= No abnormality
1= Visual, tactile, auditory, spatial, or 
personal inattention: extinction to bilateral
simultaneous stimulation in one of the 
sensory modalities
2= Profound hemi-inattention or extinction 
to more than one modality: does not 
recognize own hand or orients to only one 
side of space
____
                        _____________


Clinical Study Protocol Appendix A
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Study Code D5134C00003
Version 3.0
Date 08 May 2019
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Clinical Study Protocol Appendix A
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Study Code D5134C00003
Version 3.0
Date 08 May 2019
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You know how.
Down to earth.
I got home from work.
Near the table in the dining
    room.
They heard him speak on the
    radio last night.


Clinical Study Protocol Appendix A
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
65 (73)


Clinical Study Protocol Appendix A
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
66 (73)
MAMA
TIP – TOP
FIFTY – FIFTY
THANKS
HUCKLEBERRY
BASEBALL PLAYER


Clinical Study Protocol Appendix B
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
67 (73)
Appendix B
EQ-5D-5L (English version for the United Kingdom)
A copy of the English version of the EQ-5D-5L questionnaire for the United Kingdom follows 
on the next 3 pages.


UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
Health Questionnaire
English version for the UK


UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group
Under each heading, please tick the ONE box that best describes your health TODAY 
MOBILITY
I have no problems in walking about 

I have slight problems in walking about 

I have moderate problems in walking about 

I have severe problems in walking about 

I am unable to walk about 

SELF-CARE
I have no problems washing or dressing myself 

I have slight problems washing or dressing myself 

I have moderate problems washing or dressing myself 

I have severe problems washing or dressing myself 

I am unable to wash or dress myself 

USUAL ACTIVITIES (e.g. work, study, housework, 
family or leisure activities)
I have no problems doing my usual activities 

I have slight problems doing my usual activities 

I have moderate problems doing my usual activities 

I have severe problems doing my usual activities 

I am unable to do my usual activities 

PAIN / DISCOMFORT
I have no pain or discomfort 

I have slight pain or discomfort 

I have moderate pain or discomfort 

I have severe pain or discomfort 

I have extreme pain or discomfort 

ANXIETY / DEPRESSION
I am not anxious or depressed 

I am slightly anxious or depressed 

I am moderately anxious or depressed 

I am severely anxious or depressed 

I am extremely anxious or depressed 





UK (English) v.2 © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group


Clinical Study Protocol Appendix C
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
72 (73)
Appendix C
Additional safety information
Further guidance on the definition of a serious adverse event (SAE)
Life threatening
‘Life-threatening’ means that the patient 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 patient’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 patient 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 patient 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.  The following are examples of events that are medically important:
!
Angioedema not severe enough to require intubation but requiring IV 
hydrocortisone treatment
!
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
A guide to interpreting the causality question
When making an assessment of causality consider the following factors 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 patient  actually received the 
suspect drug?  Did the AE occur in a reasonable temporal relationship to the 
administration of the suspect drug?


Clinical Study Protocol Appendix C
Drug Substance Ticagrelor
Study Code D5134C00003
Version 3.0
Date 08 May 2019
73 (73)
!
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?
!
De-challenge 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.
!
Re-challenge experience.  Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.
!
Laboratory tests.  A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognized feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.






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Document Name: d5134c00003-csp-v3
Document Title:
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Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
Statistical Analysis Plan
Study Code
D5134C00003
Edition Number
5
Date
09 December 2019
A Randomised, Double-Blind, Placebo-Controlled, International, 
Multicentre, Phase III Study to Investigate the Efficacy and Safety of 
Ticagrelor and ASA Compared with ASA in the Prevention of Stroke and 
Death in Patients with Acute Ischaemic Stroke or Transient Ischaemic 
Attack
[THALES – Acute Stroke or Transient IscHaemic Attack Treated with 
TicAgreLor and ASA for PrEvention of Stroke and Death]


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
2
A Randomised, Double-Blind, Placebo-Controlled, International, 
Multicentre, Phase III Study to Investigate the Efficacy and Safety of 
Ticagrelor and ASA Compared with ASA in the Prevention of Stroke and 
Death in Patients with Acute Ischaemic Stroke or Transient Ischaemic 
Attack
[THALES – Acute Stroke or Transient IscHaemic Attack Treated with 
TicAgreLor and ASA for PrEvention of Stroke and Death]
Study Statistician
Date


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
3
A Randomised, Double-Blind, Placebo-Controlled, International, 
Multicentre, Phase III Study to Investigate the Efficacy and Safety of 
Ticagrelor and ASA Compared with ASA in the Prevention of Stroke and 
Death in Patients with Acute Ischaemic Stroke or Transient Ischaemic 
Attack
[THALES – Acute Stroke or Transient IscHaemic Attack Treated with 
TicAgreLor and ASA for PrEvention of Stroke and Death]
Global Product Statistician
Date


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
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..................................................................................7
1
STUDY DETAILS...............................................................................................9
1.1
Study objectives...................................................................................................9
1.1.1
Primary objective.................................................................................................9
1.1.2
Secondary objectives............................................................................................9
1.1.3
Safety objective....................................................................................................9
1.1.4
Exploratory objectives .........................................................................................9
1.2
Study design ........................................................................................................9
1.3
Number of subjects ............................................................................................10
2
ANALYSIS SETS .............................................................................................10
2.1
Definition of analysis sets .................................................................................. 10
2.2
Violations and deviations ................................................................................... 10
3
PRIMARY AND SECONDARY VARIABLES.................................................11
3.1
Primary variable.................................................................................................11
3.2
Secondary variables ........................................................................................... 11
3.3
Safety variables..................................................................................................11
3.4
Exploratory variables ......................................................................................... 12
4
ANALYSIS METHODS....................................................................................12
4.1
General principles.............................................................................................. 12
4.2
Analysis methods...............................................................................................13
4.2.1
Analysis of the primary variable......................................................................... 13
4.2.1.1
Subgroup analyses of the primary variable .........................................................14
4.2.2
Analysis of the secondary variables....................................................................15
4.2.3
Analysis of the safety variables ..........................................................................15
4.2.4
Analysis of the exploratory variables..................................................................15
5
INTERIM ANALYSES .....................................................................................16


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
5
6
CHANGES OF ANALYSIS FROM PROTOCOL (NOT APPLICABLE)..........17
7
REFERENCES (NOT APPLICABLE)...............................................................17
8
APPENDIX (NOT APPLICABLE).................................................................... 17


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
6
LIST OF ABBREVIATIONS
Abbreviation or 
special term
Explanation
AE
Adverse event
AIS
Acute ischaemic stroke
ASA
Acetylsalicylic acid
BMI
Body mass index
DAE
Premature permanent discontinuation of IP due to adverse event
DMC
Data monitoring committee
FAS
Full analysis set
GUSTO
Bleeding scale: Global Utilization of Streptokinase and Tissue plasminogen 
activator for Occluded coronary arteries
HR
Hazard ratio
IP
Investigational product
mRS
Modified Rankin scale
NIHSS
National Institute of Health Stroke Scale
SAE
Serious adverse event
TIA
Transient ischaemic attack


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
7
AMENDMENT HISTORY
Date
Brief description of change
09 February 2017
First version published
14 December 2017
1.3 Decimal places added to the significance level
3.2 Clarification that ischaemic strokes will include strokes classified as 
“Undetermined” added
4.1 Reference to the Integrated Quality and Risk Management Plan added
4.2.1 Decimal places added to the significance level
4.2.1 Sensitivity analysis updated
4.2.3 AEs with outcome death added to the safety variables that will be 
summarised
5 Decimal places added to significance levels
5 Critical value added
11 June 2018
1.3 Number of events decreased from 770 to 764, significance level increased 
from 4.760% to 4.988%, and critical value increased from 0.867 to 0.868, based 
on updates to the Interim Analysis section
4.2.1 Significance level updated to 4.988%
4.2.2 Significance level updated to 4.988%
4.2.4 Clarifications added regarding the analysis of patients with ipsilateral 
atherosclerotic stenosis
5 The p-value at the interim decreased from 0.00762 to 0.001 and Lan-DeMets 
changed to the Haybittle-Peto procedure. Based on this update, the number of 
events at the interim have decreased from 462 to 458, the critical value at the 
interim has decreased from 0.780 to 0.735, and the significance level at the final 
analysis has increased from 4.760% to 4.988%
5 A futility analysis has been added
27 May 2019
Signature pages. New study statistician (
) and global product 
statistician (
)
1.2 Number of patients decreased from 13000 to 11000 based on updated study 
assumptions. Timing of interim analysis changed from 60% to 70% of the 
primary events
1.3 Assumed hazard ratio decreased from 0.805 to 0.775 and power increased 
from 85% to 90%. Based on these changes, the number of events has decreased 
from 764 to 647, the number of patients has decreased from 13000 to 11000, the 
significance level has increased from 4.988% to 4.996%, and the critical value 
has decreased from 0.868 to 0.857


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
8
Date
Brief description of change
3 Rules for handling of data when Visit 3 has occurred outside of the visit 
window added
3.3 Clarification regarding patients who never received any dose of IP added
4.2.1 Significance level updated to 4.996%
4.2.1 Sensitivity analysis ‘on treatment’ added
4.2.1 Rule for handling of data when Visit 4 has been performed outside of the 
visit window added
4.2.1.1 Time from index event to loading dose added to subgroup variables
4.2.2 Significance level updated to 4.996%
4.2.3 Analyses ‘on treatment’ added
4.2.4 Clarification that strokes need to occur prior to or at the date of mRS 
measurement to be classified as non-disabling/disabling added
5 Timing of interim analysis changed from 60% to 70% of the primary events. 
The number of events at the interim has decreased from 458 to 453, the critical 
value at the interim has decreased from 0.735 to 0.734, and the significance 
level at the final analysis has increased from 4.988% to 4.996%.  The futility 
limit has decreased from 0.956 to 0.933
09 December 2019
2.1 Definition of safety analysis set and actual treatment added
3.2 Clarification added to censoring rules in the event of last clinical event
assessment occurring later than the date of death
4.2.4 Added statement that ipsilateral atherosclerotic stenosis ≥30% is the main
category
4.2.4 Added peripheral arterial occlusive disease to definition of atherosclerosis
in any vascular bed


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
9
1
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objective
!
To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA 
in AIS/TIA patients in the prevention of the composite of stroke and death at 30 days
1.1.2
Secondary objectives
!
To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA 
in AIS/TIA patients in the prevention of ischaemic stroke at 30 days
!
To demonstrate superior efficacy of ticagrelor and ASA compared with placebo and ASA 
in AIS/TIA patients in reducing overall disability at 30 days
1.1.3
Safety objective
!
To assess the safety of ticagrelor and ASA compared with that of placebo and ASA in 
AIS/TIA patients, in particular with respect to major bleeding events
1.1.4
Exploratory objectives
!
To assess the efficacy of ticagrelor and ASA compared with placebo and ASA in 
AIS/TIA patients with ipsilateral atherosclerotic stenosis in the prevention of stroke and 
death at 30 days
!
To assess the efficacy of ticagrelor and ASA compared with placebo and ASA in 
AIS/TIA patients in reducing disabling strokes at 30 days
!
To describe health-related quality of life in AIS/TIA patients after treating with ticagrelor 
and ASA or placebo and ASA for 30 days
1.2
Study design
This is a randomised, placebo-controlled, double-blind, parallel-group, international, 
multicentre Phase III study to test the hypothesis that ticagrelor and acetylsalicylic acid (ASA)
is superior to ASA in preventing stroke and death in patients with acute cerebral ischaemia.  
Patients with acute ischaemic stroke (AIS) or transient ischaemic attack (TIA) before 
randomisation and who fulfil all of the eligibility criteria will be randomised within 24 hours 
of symptom onset in a 1:1 ratio to ticagrelor or placebo, with all patients receiving ASA.  The 
study includes 4 visits: on Day 1 (enrolment/randomisation; Visit 1), on Day 5 to 9 (Visit 2),
on Day 30 to 34 (end of treatment period; Visit 3), and on Day 60 to 64 (end of study; Visit 4).


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
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A loading dose of 180 mg ticagrelor or placebo will be given on Day 1 as soon as possible 
after randomisation.  Thereafter, patients will receive either ticagrelor 90 mg twice daily or 
placebo twice daily. All patients should be treated with open-label ASA.
Approximately 11000 patients will be randomised at approximately 450 study sites.  The 
study is event-driven and the final number of randomised patients will be determined based on 
blind data review.  A data monitoring committee (DMC) will conduct an interim analysis for 
efficacy after approximately 70% of the primary events have been collected.
1.3
Number of subjects
At least 647 primary endpoint events are needed to provide 90% power assuming a hazard 
ratio (HR) of 0.775 in favour of ticagrelor at the significance level of 4.996%, adjusted for the 
planned efficacy interim analysis (647 events corresponding to a critical value of 0.857). 
Based on data from the SOCRATES study, a primary endpoint rate of 6.7% in the placebo 
group is assumed at 30 days following randomisation.  Hence, randomising approximately 
11000 patients to ticagrelor or placebo in a 1:1 ratio is expected to yield the 647 events 
needed.  The study is event-driven and the final number of randomised patients will be 
determined based on blind data review.
2
ANALYSIS SETS
2.1
Definition of analysis sets
All variables, including safety variables, will be analysed using the full analysis set (FAS).  
All patients who have been randomised to investigational product (IP) will be included in the 
FAS irrespective of their protocol adherence and continued participation in the study.  Patients 
will be analysed according to their randomised IP irrespective of whether the event occurred 
before or following discontinuation of IP.
Although the study objectives will be analysed based on the FAS and randomised treatment, a
safety analysis set and actual treatment group will be included in the Analysis Data Model
datasets. The safety analysis set will include all patients who have received at least 1 dose of
randomised IP. Actual treatment will be the treatment actually given irrespective of
randomisation. If a patient has received both ticagrelor and placebo, actual treatment group
will be the treatment group the patient was randomised to.
2.2
Violations and deviations
Important protocol deviations will be identified prior to database lock, and will include, but 
not be limited to:
!
Patients who were randomised but did not meet eligibility criteria


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
11
!
Patients who received prohibited concomitant medication
!
Patients who received the wrong IP at any time during the study
!
Patients who were randomised but took no IP
Protocol deviations will not imply exclusion from any analyses.
3
PRIMARY AND SECONDARY VARIABLES
3.1
Primary variable
The primary variable is the time from randomisation to first subsequent stroke or death.  
Patients who have not experienced either of these events will be censored at Visit 3, Day 34, 
or the date of last event assessment, whichever occurs earlier.  If Visit 3 has occurred within 
the visit window, Day 30 to 34, events will be included up to the date of Visit 3 (inclusive).  If 
Visit 3 has occurred outside of the visit window (or is missing), it will be replaced by Day 34 
for event inclusion and censoring.
Time will be calculated as the number of days plus one between the date of randomisation and 
the date of the first occurrence of the event, or, if no event has occurred, the date of censoring.
3.2
Secondary variables
The secondary variables, presented in the hierarchical order in which they will be tested, are:
1
Time from randomisation to first subsequent ischaemic stroke (including strokes 
classified as “Undetermined”)
2
mRS score >1 at Visit 3
For the time-to-event variable, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of last event assessment, whichever occurs earlier.  If Visit 3 has 
occurred outside of the visit window (or is missing), see Section 3.1. Furthermore, if the last
clinical event assessment has occurred later than the date of death, the date of death will be
used as the date of last clinical event assessment (applicable for all time-to-event variables not
including death).
The mRS score for patients who have died prior to Visit 3 will by definition be 6.  No other 
imputation for missing data will be made.  However, if Visit 3 has occurred prior to Day 30 
and the patient has died prior to or at Day 34, the mRS score will be 6.
3.3
Safety variables
The safety variables are:


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
12
!
Time from randomisation to first bleeding event that fulfils SAE criteria and is
categorised as GUSTO Severe
!
Time from randomisation to first intracranial haemorrhage or fatal bleeding event
!
Time from randomisation to first bleeding event that fulfils SAE criteria and is
categorised as GUSTO Moderate/Severe
!
Time from randomisation to premature permanent discontinuation of IP due to bleeding
!
Occurrence of SAE
!
Occurrence of DAE
For the time-to-event variables, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of last event assessment, whichever occurs earlier; or, for the 
time from randomisation to discontinuation due to bleeding variable only, the day of the last 
dose of IP, if earlier.  Patients who never received any dose of IP will be censored at Day 1 for
the discontinuation due to bleeding variable.  If Visit 3 has occurred outside the visit window
(or is missing), see Section 3.1.
3.4
Exploratory variables
The exploratory variables are:
!
Time from randomisation to first subsequent stroke or death in patients with ipsilateral 
atherosclerotic stenosis
!
mRS score >2 at Visit 3 in patients with subsequent stroke
!
EQ-5D-5L profile
For the time-to-event variable, patients who have not experienced the event will be censored 
at Visit 3, Day 34, or the date of last event assessment, whichever occurs earlier.  If Visit 3 has 
occurred outside the visit window (or is missing), see Section 3.1.
The mRS score for patients who have died prior to Visit 3 will by definition be 6.  If Visit 3
has occurred prior to Day 30 and the patient has died prior to or at Day 34, the mRS score will 
be 6.  Furthermore, for the disabling stroke variable (mRS score >2 at Visit 3 in patients with 
subsequent stroke), the stroke must have occurred prior to or at the date of the mRS 
measurement.
4
ANALYSIS METHODS
4.1
General principles
All analyses will be based on the intent-to-treat principle, using the FAS.  In time-to-event 
analyses, the treatment groups will be compared using a Cox proportional hazards model with
a factor for treatment group, using the Efron method for ties.  P-values and 95% confidence 


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
13
intervals for the HR will be based on the Wald statistic.  In summary tables of these analyses, 
in addition to HR with confidence intervals and p-values, presentations will include the 
number and percentage of patients with events and Kaplan-Meier estimates of the event rate 
per treatment group.  Kaplan-Meier estimates of the cumulative proportion of patients with 
events will be calculated and plotted, with the number of patients at risk indicated below the 
plot at specific time points.  If the total number of events is less than 15, only the number and 
percentage of patients with events will be presented, but no Kaplan-Meier estimates, HRs, 
confidence intervals, or p-values.
No multiplicity adjustment will be made to confidence intervals as they will be interpreted 
descriptively and used as a measure of precision.  The primary variable and the secondary 
variables will be included in a confirmatory testing procedure.
Continuous variables will be summarised by treatment group 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.
For a description of the critical to quality factors, and processes to ensure the quality of study 
conduct and the validity of study results, see the Integrated Quality and Risk Management 
Plan.
4.2
Analysis methods
4.2.1
Analysis of the primary variable
For the primary variable, time from randomisation to first subsequent stroke or death, 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 the 4.996% 2-sided significance level.
In the summary table of the primary analysis, separate analyses of each of the components 
(stroke, death) will also be presented.
If there are patients lost to follow-up in the ticagrelor group, a sensitivity (“tipping point”)
analysis may be performed by adding events to the ticagrelor group (at the time of censoring) 
until a non-significant result is obtained.
A sensitivity analysis ‘on treatment’ will be performed, including events from the date of the 
first dose of IP up to the date of the last dose of IP + 7 days (inclusive).  Event-free patients 
will be censored at the date of the last dose of IP + 7 days or the date of last event assessment, 
whichever occurs earlier.  Patients who never received any dose of IP will be censored at 
Day 1.


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
14
As an explorative analysis, primary events up to the end of the follow-up period will be 
analysed by repeating the primary analysis with event-free patients censored at Visit 4 (or 
Day 64) instead of Visit 3 (or Day 34).  If Visit 4 has occurred within the visit window, Day 
60 to 64, events will be included up to the date of Visit 4 (inclusive).  If Visit 4 has occurred
outside of the visit window (or is missing), it will be replaced by Day 64 for event inclusion 
and censoring.
4.2.1.1
Subgroup analyses of the primary variable
Subgroup analyses of the primary variable will be performed to evaluate variation of treatment 
effect.  Tests for interaction between treatment and each subgroup variable will be performed 
in Cox proportional hazards models with factors for treatment, subgroup variable, and the 
interaction between treatment and subgroup variable if at least 15 events have occurred in 
each subgroup category.  
The subgroup categories will be examined in Cox proportional hazards models with a factor 
for treatment group.  Kaplan-Meier estimates, HRs, and 95% confidence intervals will be 
reported if at least 15 events have occurred within the subgroup category.  The following 
subgroup variables and categories will be assessed:
!
Age (<65, 65-75, >75 years)
!
Sex (Male, Female)
!
Race (White, Black, Asian, Other)
!
Weight (<70, ≥70 kg)
!
BMI (<30, ≥30 kg/m2)
!
Geographic region (Asia and Australia, Europe, North America, Central and South 
America)
!
Diagnosis of index event (Stroke NIHSS score ≤3, Stroke NIHSS score >3, TIA)
!
Time from index event to randomisation (<12, ≥12 hours)
!
Time from index event to loading dose (<12, ≥12 hours)
!
Diabetes mellitus (Yes, No)
!
Hypertension (Yes, No)
!
Prior ischaemic stroke or TIA (Yes, No)
!
Prior ischaemic heart disease [defined as any of coronary artery bypass grafting, 
myocardial infarction, percutaneous coronary intervention, or coronary artery disease]
(Yes, No)
!
Prior ASA (Yes, No)
!
Prior statin treatment (Yes, No)
!
Smoking status (Current, Former, Never)


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
15
The effect of age, weight, BMI, time from index event to randomisation, and time from index 
event to loading dose may also be further analysed using continuous measurements.
4.2.2
Analysis of the secondary variables
The secondary variables will be included in the confirmatory testing procedure.  Only if the 
treatment effect on the primary variable is significant at the 4.996% level will the secondary 
variables be tested in a confirmatory sense in the hierarchical order specified in Section 3.2.  
The hypothesis testing will continue at the 4.996% significance level until the first statistically 
non-significant treatment difference (p ≥0.04996) is observed.
The time from randomisation to first subsequent ischaemic stroke will be analysed in the same
manner as the primary variable.  The proportion of patients with mRS score >1 at Visit 3 will 
be analysed using a logistic regression model with treatment group, history of stroke, and
baseline NIHSS score as explanatory variables.  A sensitivity analysis will be performed 
where missing mRS scores will be imputed as >1. 
4.2.3
Analysis of the safety variables
The time-to-event safety variables will be analysed in the same manner as the primary 
variable, but will not be included in the confirmatory testing procedure.  Sensitivity analyses 
‘on treatment’ will be performed (see Section 4.2.1).  Subgroup analyses, as specified in 
Section 4.2.1.1, will be performed for GUSTO Severe bleeding events.  Furthermore, the 
analysis of GUSTO Severe bleeding events will be repeated with event-free patients censored 
at Visit 4 (or Day 64) instead of Visit 3 (or Day 34).
SAEs, DAEs, and AEs with outcome death summarised by system organ class and preferred 
term using the Medical Dictionary for Regulatory Activities, will be presented by treatment 
group using descriptive statistics.
4.2.4
Analysis of the exploratory variables
The time from randomisation to first subsequent stroke or death in patients with ipsilateral 
atherosclerotic stenosis will be analysed in the same manner as the primary variable.  
Analyses in four categories will be performed:
!
Patients with ipsilateral atherosclerotic stenosis ≥50% (extracranial and intracranial 
combined and separately)
!
Patients with ipsilateral atherosclerotic stenosis ≥30% (extracranial and intracranial 
combined and separately) [main category for reporting]
!
Patients with atherosclerosis in any vascular bed (including cerebrovascular 
atherosclerosis or medical history of coronary artery bypass grafting, myocardial 
infarction, percutaneous coronary intervention, coronary artery disease, or peripheral
arterial occlusive disease)


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
16
!
Patients with ipsilateral stenosis who undergo carotid endarterectomy/intervention
The proportion of patients with subsequent stroke and mRS score >2 at Visit 3 will be 
analysed using a logistic regression model with treatment group, history of stroke, and 
baseline NIHSS score as explanatory variables.  Additional analyses of disabling stroke will 
be performed by varying the threshold for the mRS score (>1 and >3), and by utilising the 3
categories no stroke, non-disabling stroke (mRS score ≤2), disabling stroke (mRS score >2).  
Strokes need to occur prior to or at the date of the mRS measurement to be classified as non-
disabling/disabling.
EQ-5D-5L data will be presented by treatment group using descriptive statistics.
5
INTERIM ANALYSES
One interim analysis will be performed by the DMC following the accrual of 70% of the 
planned primary events (453).  The efficacy stopping boundary at the interim is a 2-sided p-
value <0.001 for the primary endpoint (corresponding to a critical value of 0.734). The 
interim p-value is small enough for the final analysis, based on the accrual of all events, to be 
conducted at a significance level of 4.996%, with the family-wise error rate controlled at 
5.00%.  This boundary was estimated in East V6.4 (copyright 1994-2016, Cytel Inc) using the 
Haybittle-Peto procedure.
If a recommendation to stop the study for efficacy is made at the interim, all subsequent 
testing of secondary efficacy variables will be done at a significance level of 0.1%.
The study may be stopped for futility if the observed HR for the primary endpoint is >0.933
(taking all available study information into account), corresponding to a predictive power of 
5%.
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.  AstraZeneca will not be made aware 
of the treatment codes, and will have no knowledge of unblinded results, until after clean file
and database lock have been declared.  The DMC charter details roles, responsibilities, and 
procedures to ensure maintenance of the blinding and integrity of the study.


Statistical Analysis Plan 
Study Code D5134C00003
Edition Number 5
Date 09 December 2019
17
6
CHANGES OF ANALYSIS FROM PROTOCOL (NOT 
APPLICABLE)
7
REFERENCES (NOT APPLICABLE)
8
APPENDIX (NOT APPLICABLE)


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d5134c00003-sap-ed-4
Document Title:
Statistical Analysis Plan Edition 4
Document ID:
Doc ID-003386933
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
17-Dec-2019 07:56 UTC
Content Approval
12-Dec-2019 21:06 UTC
Content Approval
16-Dec-2019 21:54 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.