Clinical trial NCT02406248
Conditions: Non ST-elevation Myocardial Infarction
Keywords: NSTEMI
Sponsor: AstraZeneca
Start date: 2015-04-23; Completion date: 2017-02-09
Enrollment: 108 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A multicenter, single arm, open label, Phase IV study to evaluate safety and to describe the cumulative incidence of major cardiovascular events of Ticagrelor in Taiwanese patients with non ST-segment (a segment in the eletrocardiogram which presents the period when ventricles are depolarized) elevation myocardial infarction

Detailed description:
This study will be conducted in approximately 8 investigational centres in Taiwan. It is expected that approximately 100 patients will be enrolled into study treatment. This study is to describe the safety and tolerability of ticagrelor, by assessment of the bleeding events and other serious adverse events (SAEs) during 1year follow up in Taiwanese non ST-elevation myocardial infarction (NSTEMI) patients.

Arms: arm 1: Ticagrelor 180mg loading dose taken orally, followed by 90mg twice daily (bd)
Interventions: intervention 1: Ticagrelor 180mg loading dose taken orally, followed by 90mg twice daily (bd)
Intervention descriptions: intervention 1: Ticagrelor 180mg loading dose taken orally, followed by 90mg twice daily (bd)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
  
Revised Clinical Study Protocol 
 
Drug Substance 
Ticagrelor 
 
Study Code 
D5130C00103 
 
Edition Number 
2.0 
 
Date 
22 Jun 2015 
 
 
 
A multicenter, single arm, open label, Phase IV study to evaluate safety and 
to describe the cumulative incidence of major cardiovascular events 
of Ticagrelor in Taiwanese patients with non ST-segment elevation 
myocardial infarction 
 
Sponsor: 
AstraZeneca Pharmaceutical Co., Ltd.,  21st Floor 207 Tun-Hwa South Road, Sec. 2, Taipei, Taiwan 
 
AstraZeneca Research and Development 
site representative 
 
Amery Chang 
Clinical Development Manager 
AstraZeneca Taiwan 
13th Fl., 207, Tun Hwa South Rd., Sec.2 
Taipei Metro Building, Taipei 10602, 
Taiwan 
T: +886 2 27302307
 Date  
 
The following Amendment(s) and Administrative Changes have been made to this protocol since the date 
of preparation: 
Amendment No. 
 Date of Amendment 
 
Local Amendment 
No: 
 
Date of Local 
Amendment 
 1 
  13th November 2014
 
  
 
  
Administrative 
Change No. 
 Date of Administrative 
Change 
 
Local Administrative 
Change No. 
 
Date of Local 
Administrative Change 
1 
 22nd June 2015 
 
  
 
  
This submission /document contains trade secrets and confidential commercial information, 
disclosure of which is prohibited without providing advance notice to AstraZeneca and 
opportunity to object. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
2(47) 
 
REVISED PROTOCOL SYNOPSIS 
A multicenter, single arm, open label, Phase IV study to evaluate safety 
and to describe the cumulative incidence of major cardiovascular events 
of Ticagrelor in Taiwanese patients with non ST-segment elevation 
myocardial infarction 
National Co-ordinating Investigator  
Dr Chun-Peng Liu, Kaohsiung Veterans General Hospital, 386 Ta-Chung 1st Rd., Kaohsiung, 
Taiwan 81362 
Study centre(s) and number of subjects planned 
This study will be conducted in approximately 15 investigational centres in Taiwan. It is 
expected that approximately 100 patients will be enrolled into study treatment. 
Study period 
 
Phase of development 
Estimated date of first subject enrolled 
Q1 2015 
Phase IV 
Estimated date of last subject completed 
Q2 2017 
Objectives 
Primary objective 
To describe the safety and tolerability of Ticagrelor, by assessment of the bleeding events and 
other serious adverse events (SAEs) during 1year follow up in Taiwanese non ST-elevation 
MI (NSTEMI) patients. 
To describe the efficacy of Ticagrelor, by cumulative incidence of major CV events 
(including CV death, MI and stroke) during 1 year follow up in Taiwanese NSTEMI patients. 
Study design 
This is a multicenter, single arm, open label, Phase IV study to evaluate safety and to describe 
the incidence of major CV events of ticagrelor in Taiwanese patients with NSTEMI.  
Target subject population 
Ticagrelor treated Taiwanese patients 20 years of age and over with non-ST elevation MI. 
Investigational product, dosage and mode of administration 
Ticagrelor 180mg loading dose taken orally, followed by 90mg bd  
Comparator, dosage and mode of administration (Not applicable) 
Duration of treatment 
12 months. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
3(47) 
 
Outcome variable(s):  
Primary variables 
 PLATO-defined fatal/life-threatening bleedings during 1year follow up in Taiwanese 
NSTEMI patients treated with ticagrelor.  
 PLATO-defined major bleedings during 1year follow up in Taiwanese NSTEMI 
patients treated with ticagrelor. 
 PLATO-defined major + minor bleedings during 1year follow up in Taiwanese 
NSTEMI patients treated with ticagrelor. 
 Serious adverse events other than bleeding during 1year follow up in Taiwanese 
NSTEMI patients treated with ticagrelor. 
 Major CV events (cardiovascular death, MI or stroke) during 1 year follow up in 
Taiwanese NSTEMI patients treated with Ticagrelor. 
Statistical methods 
The primary efficacy analysis will be based on the intent-to-treat principle using the full 
analysis set of investigator adjudicated events. The analysis set will include all patients who 
have taken at least one dose of study medication, regardless of protocol adherence or 
continued participation in the study. The cumulative incidence will be presented with K-M% 
with 95% CI. 
Statistical methods will be descriptive. For continuous data, descriptive statistics will be 
presented as number of patients (n), mean, standard deviation (SD), median, minimum and 
maximum.  For categorical data, the frequency and percentage of patients in each category 
will be presented.  Counts that are zero will be displayed as “0”.  Percentages will be based on 
non-missing data unless otherwise specified. 
 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
4(47) 
 
TABLE OF CONTENTS 
PAGE
 
TITLE PAGE ........................................................................................................... 1 
REVISED PROTOCOL SYNOPSIS ....................................................................... 2 
TABLE OF CONTENTS ......................................................................................... 4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 9 
1. 
INTRODUCTION ................................................................................................. 11 
1.1 
Background ............................................................................................................ 11 
1.2 
Research hypothesis ............................................................................................... 11 
1.3 
Rationale for conducting this study ....................................................................... 12 
1.4 
Benefit/risk and ethical assessment ........................................................................ 13 
2. 
STUDY OBJECTIVES .......................................................................................... 13 
2.1 
Primary objective ................................................................................................... 13 
2.2 
Secondary objective (Not applicable) .................................................................... 13 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 13 
3.1 
Overall study design and flow chart ...................................................................... 14 
3.1.1 
Duration of Study ................................................................................................... 17 
3.1.2 
Enrolment ............................................................................................................... 17 
3.1.3 
Protocol Visits ........................................................................................................ 17 
3.1.4 
Premature Treatment Discontinuation ................................................................... 17 
3.2 
Rationale for study design, doses and control groups ............................................ 17 
3.2.1 
Rationale for study design...................................................................................... 17 
3.2.2 
Patients and Choice of endpoints ........................................................................... 17 
3.2.3 
Dose regimens ........................................................................................................ 17 
3.2.4 
Limitations of the study ......................................................................................... 18 
4. 
SUBJECT SELECTION CRITERIA..................................................................... 18 
4.1 
Inclusion criteria .................................................................................................... 18 
4.2 
Exclusion criteria ................................................................................................... 19 
5. 
STUDY CONDUCT .............................................................................................. 21 
5.1 
Restrictions during the study.................................................................................. 21 
5.2 
Subject enrolment .................................................................................................. 21 
5.2.1 
Procedures for randomisation (Not applicable) ..................................................... 21 
5.3 
Procedures for handling subjects incorrectly enrolled ........................................... 21 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
5(47) 
 
5.4 
Blinding and procedures for unblinding the study (Not applicable) ...................... 22 
5.5 
Treatments .............................................................................................................. 22 
5.5.1 
Identity of investigational product(s) ..................................................................... 22 
5.5.2 
Doses and treatment regimens ............................................................................... 22 
5.5.3 
Additional study drug (Not applicable) ................................................................. 22 
5.5.4 
Labelling ................................................................................................................ 22 
5.5.5 
Storage ................................................................................................................... 23 
5.6 
Concomitant and post-study treatment(s) .............................................................. 23 
5.6.1 
Digoxin and other p-glycoprotein interactions ...................................................... 23 
5.6.2 
CYP450 interactions .............................................................................................. 23 
5.6.2.1 
CYP3A inhibitors ................................................................................................... 23 
5.6.2.2 
CYP3A substrates or inducers ............................................................................... 23 
5.7 
Treatment compliance ............................................................................................ 24 
5.7.1 
Accountability ........................................................................................................ 25 
5.8 
Discontinuation of investigational product ............................................................ 25 
5.8.1 
Procedures for discontinuation of a subject from investigational product............. 25 
5.8.2 
Temporary discontinuation from study medication ............................................... 25 
5.8.3 
Permanent premature discontinuation from study medication .............................. 26 
5.8.3.1 
The patient agrees to undergo the premature treatment discontinuation visit 
and then continue in-person study visits ................................................................ 27 
5.8.3.2 
The patient unwilling to continue in-person study visits but agrees to 
undergo modified follow-up .................................................................................. 27 
5.8.3.3 
The patient refuses any form of follow-up............................................................. 27 
5.9 
Withdrawal from study .......................................................................................... 27 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 27 
6.1 
Recording of data ................................................................................................... 28 
6.2 
Data collection at enrolment and follow-up ........................................................... 28 
6.2.1 
Enrolment procedures ............................................................................................ 28 
6.2.2 
Follow-up procedures ............................................................................................ 28 
6.3 
Efficacy .................................................................................................................. 28 
6.3.1 
CV death ................................................................................................................ 29 
6.3.2 
MI ........................................................................................................................... 29 
6.3.3 
Stroke ..................................................................................................................... 29 
6.4 
Safety ..................................................................................................................... 30 
6.4.1 
Definition of adverse events .................................................................................. 30 
6.4.2 
Definitions of serious adverse event ...................................................................... 30 
6.4.3 
Recording of adverse events .................................................................................. 31 
6.4.4 
Reporting of serious adverse events ....................................................................... 33 
6.4.5 
Laboratory safety assessment................................................................................. 34 
6.4.6 
Physical examination ............................................................................................. 34 
6.4.7 
ECG (Not applicable)............................................................................................. 34 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
6(47) 
 
6.4.8 
Vital signs .............................................................................................................. 34 
6.4.8.1 
Pulse and blood pressure ........................................................................................ 34 
6.4.9 
Other safety assessments ........................................................................................ 34 
6.4.9.1 
Bleeding events ...................................................................................................... 34 
6.5 
Patient reported outcomes (PRO) (Not applicable) ............................................... 36 
6.6 
Pharmacokinetics (Not applicable) ........................................................................ 36 
6.7 
Pharmacodynamics (Not applicable) ..................................................................... 36 
6.8 
Pharmacogenetics (Not applicable) ....................................................................... 36 
6.9 
Health economics (Not applicable) ........................................................................ 36 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 36 
7.1 
Volume of blood .................................................................................................... 36 
7.2 
Handling, storage and destruction of biological samples ...................................... 36 
7.3 
Labelling and shipment of biohazard samples ....................................................... 36 
7.4 
Chain of custody of biological samples ................................................................. 36 
7.5 
Withdrawal of informed consent for donated biological samples ......................... 37 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 37 
8.1 
Ethical conduct of the study ................................................................................... 37 
8.2 
Subject data protection ........................................................................................... 38 
8.3 
Ethics and regulatory review .................................................................................. 38 
8.4 
Informed consent.................................................................................................... 38 
8.5 
Changes to the protocol and informed consent form ............................................. 39 
8.6 
Audits and inspections ........................................................................................... 39 
9. 
STUDY MANAGEMENT BY ASTRAZENECA ................................................ 40 
9.1 
Pre-study activities ................................................................................................. 40 
9.2 
Training of study site personnel ............................................................................. 40 
9.3 
Monitoring of the study.......................................................................................... 40 
9.3.1 
Source data ............................................................................................................. 41 
9.4 
Study agreements ................................................................................................... 41 
9.4.1 
Archiving of study documents ............................................................................... 41 
9.5 
Study timetable and end of study ........................................................................... 41 
10. 
DATA MANAGEMENT BY ASTRAZENECA .................................................. 41 
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA ................................................................................................... 42 
11.1 
Calculation or derivation of efficacy variable(s) ................................................... 42 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
7(47) 
 
11.2 
Calculation or derivation of safety variable(s) ....................................................... 42 
11.2.1 
Other significant adverse events (OAE) ................................................................ 43 
11.3 
Calculation or derivation of patient reported outcome variables (Not 
applicable) .............................................................................................................. 43 
11.4 
Calculation or derivation of pharmacokinetic variables (Not applicable) ............. 43 
11.5 
Calculation or derivation of pharmacodynamic variable(s) (Not applicable) ........ 43 
11.6 
Calculation or derivation of pharmacogenetic variables (Not applicable) ............ 43 
11.7 
Calculation or derivation of health economic variables (Not applicable) ............. 43 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
BY ASTRAZENECA ............................................................................................ 43 
12.1 
Description of analysis sets .................................................................................... 44 
12.1.1 
Full analysis set ...................................................................................................... 44 
12.1.2 
Safety analysis set .................................................................................................. 44 
12.2 
Methods of statistical analyses ............................................................................... 44 
12.2.1 
Primary objective-primary efficacy endpoint ........................................................ 44 
12.2.2 
Primary objective-primary safety endpoint............................................................ 44 
12.3 
Determination of sample size ................................................................................. 44 
12.4 
Data monitoring committee (Not applicable) ........................................................ 44 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 45 
13.1 
Medical emergencies and AstraZeneca contacts ................................................... 45 
13.2 
Overdose ................................................................................................................ 45 
13.3 
Pregnancy ............................................................................................................... 46 
13.3.1 
Maternal exposure .................................................................................................. 46 
13.3.2 
Paternal exposure ................................................................................................... 46 
14. 
LIST OF REFERENCES ....................................................................................... 47 
 
LIST OF TABLES 
Table 1 
Efficacy and bleeding in the overall PLATO cohort, Asia and 
Taiwan ...................................................................................................... 12 
Table 2 
Study Plan ................................................................................................. 15 
Table 3 
Volume of blood to be drawn from each subject ...................................... 36 
 
 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
8(47) 
 
LIST OF FIGURES 
Figure 1 
Study flow chart........................................................................................ 15 
 
LIST OF APPENDICES 
Appendix A 
Signatures (Not Applicable) 
Appendix B 
Additional Safety Information  
Appendix C 
IATA 6.2 Guidance document 
Appendix D 
Actions required in cases of combined increase of Aminotransferase and 
Total Bilirubin – Hy’s Law 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
9(47) 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
The following abbreviations and special terms are used in this study Clinical Study Protocol 
 
Abbreviation or 
special term 
Explanation 
ACS 
Acute coronary syndrome 
AE 
Adverse event (see definition in Section 6.4.1) 
ALT 
Alanine aminotransferase 
ARR 
Absolute risk reduction 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase 
A-V 
Atrial-ventricular 
AZ 
AstraZeneca 
bd 
twice daily  
CABG 
Coronary artery bypass graft  
CI 
Confidence Interval 
CK-MB 
Creatinine kinase-MB 
eCRF 
Case Report Form (electronic) 
CSA 
Clinical Study Agreement 
CSR 
Clinical Study Report 
CV 
Cardiovascular 
CYP3A 
Cytochrome P450 3A 
DAE 
Discontinuation of Investigational Product due to Adverse Event 
ECG 
Electrocardiogram 
EC 
Ethics Committee, synonymous with Institutional Review Board (IRB) 
and Independent Ethics Committee (IEC) 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
GI 
Gastrointestinal 
Hb 
Haemoglobin  
HR 
Hazard ratio 
ICH 
International Conference on Harmonisation 
IP 
Investigational Product  


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
10(47) 
 
Abbreviation or 
special term 
Explanation 
IP 
Investigational Product  
KM 
Kaplan-Meier 
LBBB 
Left bundle branch block  
LSLV 
Last Subject Last Visit 
MedDRA 
Medical Dictionary for Regulatory Activities  
MI 
Myocardial infarction 
MRI 
Magnetic resonance imaging  
NSAIDs 
NSTEMI 
Non-steroidal anti-inflammatory drugs 
Non ST-segment elevation myocardial infarction  
OAE 
Other Significant Adverse Event (see definition in Section 11.2.1) 
PGI2 
Prostacyclins  
PCI 
Percutaneous coronary intervention  
PI 
Principal Investigator  
PLATO 
PLATelet inhibition and patient Outcomes 
PRBC 
Packed red blood cells  
PTDV 
Premature treatment discontinuation visit 
RRR 
Relative risk reduction 
SAE 
Serious adverse event (see definition in Section 6.4.2). 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TFDA 
Taiwan Food and Drug Administration 
TNT/TNI 
Troponin T or I  
ULN 
Upper limit of normal range 
WBDC 
Web Based Data  


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
11(47) 
 
1. 
INTRODUCTION 
1.1 
Background 
Ticagrelor is a direct-acting, oral, reversibly binding P2Y12 receptor antagonist approved for 
the reduction of thrombotic events in patients with acute coronary syndrome (ACS). 
The PLATO (PLATelet inhibition and patient Outcomes) study was an 18,624 patient 
randomized, double-blind, parallel group, phase III, efficacy and safety study of ticagrelor 
compared with clopidogrel for prevention of vascular events in patients with Acute Coronary 
Syndromes (Wallentin 2009). Ticagrelor was superior to clopidogrel in the prevention of 
thrombotic events (relative risk reduction (RRR) 16%, absolute risk reduction (ARR) 1.9%) 
of the composite efficacy endpoint (cardiovascular (CV) death, myocardial infarction (MI) 
and stroke) over 12 months. The difference in treatments was driven by CV death and MI 
with no difference on strokes. Ticagrelor demonstrated a statistically significant RRR of 16% 
(ARR 1.1%) for MI and a 21% RRR (ARR 1.1%) for CV death. In PLATO, time to first 
PLATO-defined Major bleeding for ticagrelor did not differ significantly from that of 
clopidogrel. There were few fatal bleeding events in the study, 20 (0.3%) for ticagrelor and 23 
(0.3%) for clopidogrel. When minor bleeding was included, combined PLATO-defined Major 
and Minor bleeding events were significantly higher on ticagrelor than on clopidogrel. 
The PLATO study included 1,056 patients with acute coronary syndrome (ACS) in Asia, as 
follows: 
Country 
Number of patients enrolled 
Taiwan 
92 
China 
416 
Hong Kong 
16 
Indonesia 
62 
Malaysia 
56 
Philippines 
78 
Singapore 
64 
South Korea 
120 
Thailand 
152 
 
Of 92 Taiwanese patients, 9 reported major bleeding events (3 patients randomised to 
ticagrelor, and 6 patients randomised to clopidogrel).  The planned study will provide further 
safety profile of ticagrelor in Taiwanese ACS patients.  
 
Further information regarding the background, pharmacological class, properties, and 
mechanism of action of ticagrelor can be found in the package insert for ticagrelor. 
1.2 
Research hypothesis 
Ticagrelor is well tolerated, and effective in Taiwanese NSTEMI patients.  


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
12(47) 
 
1.3 
Rationale for conducting this study 
Post-hoc analyses in subgroups of Asian and Taiwanese patients are shown (Table 1). 
Table 1 
Efficacy and bleeding in the overall PLATO cohort, Asia and Taiwan 
 
Ticagrelor 
Clopidogrel 
HR (95% CI) 
 
n 
N with events 
(KM%) 
n 
N with events 
(KM%) 
 
Primary efficacy endpoint (composite of CV death, MI, stroke,) 
 
  Overall  
9333 
864 (9.8) 
9291 
1014 (11.7) 
0.84 (0.77-0.92) 
  Asian  
533 
67 (13.0) 
523 
79 (16.2) 
0.82 (0.59-1.14) 
  Taiwan  
46 
7 (15.7) 
46 
5 (11.1) 
1.41 (0.45-4.46) 
Primary safety endpoint (PLATO-defined total major bleed) 
 
  Overall  
9235  
961 (11.6)  
9186  
929 (11.2)  
1.04 (0.95-1.13)  
  Asian  
526  
53 (10.9)  
515  
48 (10.8)  
1.07 (0.73-1.59)  
  Taiwan 
44  
3 (7.2)  
46  
6 (15.9)  
0.51 (0.13-2.05)  
Fatal/life-threatening bleed 
 
  Overall  
9235  
491 (5.8)  
9186  
480 (5.8)  
1.03 (0.90-1.16)  
  Asian  
526  
33 (6.8)  
515  
29 (6.1)  
1.10 (0.67-1.81)  
  Taiwan 
44  
2 (4.9)  
46  
5 (11.8)  
0.40 (0.08-2.08)  
Fatal bleed 
 
 
 
 
  Overall  
9235 
20 (0.3) 
9291 
23 (0.3) 
0.87 (0.48, 1.59) 
  Asian  
526 
2 (0.5) 
515 
2 (0.4) 
0.97 (0.14, 6.87) 
  Taiwan 
44 
0 (0) 
46 
0 (0) 
 
KM:  Kaplan-Meier, MI:  myocardial infarction, CV:  cardiovascular, HR: hazard ratio 
Efficacy analyses performed on Full analysis set, safety analyses on Safety analysis set 
 
The Taiwanese cohort had a much smaller sample size and a correspondingly wider 
confidence interval (CI) in all analyses compared with the overall study.   The hazard ration 
(HR) for the comparison of ticagrelor to clopidogrel for the primary composite endpoint of 
CV death, MI, and stroke (HR 1.41 [95% CI 0.45, 4.46]; p=0.5534) was not statistically 
significant in the Taiwan cohort alone.   
In the Taiwanese cohort, ‘Total Major’ bleeding was numerically less frequent in the 
ticagrelor patients (HR 0.51 [95% CI 0.13, 2.05]; p=0.3453).  It is concluded that this result is 
consistent with PLATO overall, and that ‘Total Major’ bleeding in the Taiwanese cohort did 
not differ between the treatment groups. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
13(47) 
 
On 11-May-2012, Ticagrelor was approved by the Taiwan Food and Drug Administration 
(TFDA); AstraZeneca (AZ) was required by TFDA on 22 July 2014 to conduct a post-
approval study to describe the efficacy and safety profile of Ticagrelor in Taiwanese NSTEMI 
patients 
1.4 
Benefit/risk and ethical assessment 
Ticagrelor is approved in more than 95 countries worldwide to prevent thrombotic events in 
patients with ACS. Current guidelines from the American Heart Association/American 
College of Cardiology, European Society of Cardiology and American College of Chest 
Physicians recommend ticagrelor and low maintenance dose acetylsalicylic acid (ASA) for 
treatment of ACS (Jneid 2012, Steg 2012, Hamm 2011, Vandvik 2012).  
More than 53000 healthy subjects or patients have been exposed to ticagrelor in the 
completed phase I, II and III studies and the overall conclusion based on these studies is that 
ticagrelor has generally been well tolerated.  In the PLATO study, ticagrelor reduced the 
primary efficacy composite endpoint of CV death/ MI/stroke by 16% (p=0.0003), MI by 16% 
(p=0.0045), CV death by 21% (p=0.0013) and all-cause mortality by 22% (nominal p value  = 
0.0003), as compared to clopidogrel. Despite greater inhibition of platelet aggregation with 
ticagrelor, the Total Major bleeding events with ticagrelor did not differ significantly from 
that of clopidogrel treatment (11.6% vs 11.2%, HR 1.04, [95% CI 0.95, 1.13]; p=0.4336).  In 
addition, ticagrelor and clopidogrel did not differ significantly in fatal bleeding, or fatal/life-
threatening bleeding.  However, more non-CABG major bleeding, including non-procedural 
bleeding, was reported with ticagrelor treatment. Thus, ticagrelor prevents more major 
adverse cardiac events after ACS, most notably reducing CV mortality, compared with 
clopidogrel, without adding clinically important safety concerns. 
2. 
STUDY OBJECTIVES 
2.1 
Primary objective 
To describe the safety and tolerability of ticagrelor, by assessment of the bleeding events and 
other serious adverse events (SAEs) during 1 year follow up in Taiwanese non ST-elevation 
MI (NSTEMI) patients. 
To describe the efficacy of Ticagrelor, by assessment of the incidence of major CV events 
(including CV death, MI and stroke) during 1 year follow up in Taiwanese NSTEMI patients 
treated with ticagrelor. 
2.2 
Secondary objective (Not applicable) 
3. 
STUDY PLAN AND PROCEDURES 
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
standard procedures. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
14(47) 
 
3.1 
Overall study design and flow chart 
This is a multicenter, single arm, open label, Phase IV study to evaluate safety and to describe 
the incidence of major CV events of ticagrelor in Taiwanese patients with NSTEMI. The 
study design and plan are summarized in Figure 1 and Table 2. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
15(47) 
 
Figure 1 
Study flow chart 
Taiwanese NSTEMI 
patients. 
≥20years male /female 
100patients will be enrolled       
Enrolment               6 weeks  
3 months  
6 months  
9 months  
12 months 
Treated with ticagrelor 180mg loading dose followed by 90mg bd plus low maintenance dose ASA(100mg/d) 
Table 2 
Study Plan  
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Premature Treatment 
Discontinuation Visit  
(PTDV) 
Visit 6   
Follow up visit 
2weeks ± 3 days 
after Visit 6  
For patients 
prematurely 
discontinuing study 
treatmentb 
 
Enrollment 
6 week 
±1 week 
3m ± 
1week 
6 m ± 
1week 
9 m ± 
1week 
Within 1week 
discontinuation of IP 
12m ± 
1week    
 
Informed consent 
X 
 
 
Inclusion/exclusion criteria 
X 
 
 
Demographics  
X 
 
 
Relevant medical/surgical 
history including type of ACS 
X 
 
 
 
 
 
 
 
Targeted physical 
examination including vital 
signs (pulse, blood pressure) 
X 
X 
 
 
 
X 
X 
 
Myocardial necrosis 
biomarkersa 
;G 
 
 
 
 
 
 
 
12-lead ECG 
;G 
 
 
 
 
 
 
 
Clinical chemistry & 
haematologyc
;G 
X 
 
 
 
X 
X 
 
Pregnancy test (urine) if 
applicable
X 
 
 
 
 
 
 
 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
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Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Premature Treatment 
Discontinuation Visit  
(PTDV) 
Visit 6   
Follow up visit 
2weeks ± 3 days 
after Visit 6  
For patients 
prematurely 
discontinuing study 
treatmentb 
Concomitant medications 
X 
X 
X 
X
X
X
X
X
Major CV events, SAEs and 
Bleeding Events 
 
X 
X 
X 
X 
X 
X 
X 
Dispense investigational 
product
X 
X 
X 
X 
X 
 
 
 
AEs 
 
X 
X 
X
X
X
X
X
Return investigational 
product
 
X 
X 
X 
X 
X 
X 
 
Compliance/drug 
accountability
 
X 
X 
X 
X 
X 
X 
 
a: Myocardial necrosis biomarkers measured for index event (local laboratory) and any subsequent suspected ACS or coronary revascularization procedure 
b: the follow up visit can be done by telephone contact. For patients who complete 12 months of study treatment, the follow up visit is to be performed 2 
weeks after visit 6. For patients discontinuing study treatment prematurely, the follow up visit procedures replace procedures for Visits 2-6  
c: the clinical chemistry and hematology test can be added according to the investigator’s discretion during each visit.  
d: Myocardial necrosis biomarkers, 12-lead ECG and clinical chemistry and haematology already collected for the index event can be used for Visit 1. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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3.1.1 
Duration of Study 
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3.1.2 
Enrolment  
Male and female patients with NSTEMI, fulfilling all of the inclusion criteria (see Section 4.1) 
and none of the exclusion criteria (see Section 4.2) can be enrolled in this study.  
 
Approximately 100 patients at approximately 8 study centres will be enrolled. 
3.1.3 
Protocol Visits 
Patients will return approximately every 3 months as outlined in Figure 1 and Table 2, for 
assessment of events related to the objectives of the study including safety and incidence of 
major CV events. The Investigator/study centre personnel will record any bleeding events and 
other adverse event (AE)/SAEs, any suspected major CV event and use of medication 
including ticagrelor. An unscheduled visit may be conducted as a result of a follow-up phone 
contact. 
3.1.4 
Premature Treatment Discontinuation 
Refer to Section 5.3. 
 
3.2 
Rationale for study design, doses and control groups 
3.2.1 
Rationale for study design 
This is a multicenter, single arm, open label, Phase IV study to evaluate safety and to describe 
the incidence of major CV events of ticagrelor in a Taiwanese NSTEMI population in order to 
provide widely applicable results. 
 
3.2.2 
Patients and Choice of endpoints 
The target population will be Taiwanese patients with NSTEMI to provide safety data in this 
patient type.  
 
Similar to the PLATO study, PLATO defined bleeding endpoints are used. To describe the 
incidence of major CV events, the composite of CV death/MI/stroke is used  in this study. 
Events will be locally adjudicated by the clinic investigator. Other non-hemorrhagic SAEs 
will also be recorded. 
 
3.2.3 
Dose regimens 
Ticagrelor dose will be consistent with prescribing information in Taiwan: 180 mg loading 
dose followed by maintenance dose of 90 mg twice daily (bd). Loading dose of ticagrelor 
should be given regardless if the patient has received previous loading dose of clopidogrel, 
and regardless if the patient had ongoing clopidogrel treatment prior to the index event. 
Patients who have received loading dose with ticagrelor or have ongoing treatment with 
maintenance dose of ticagrelor should not receive a second loading dose, unless judged 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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necessary in the opinion of the investigator. Patients currently treated with prasugrel may not 
be included in the study. Patients are expected to receive concomitant low maintenance dose 
ASA, 100 mg daily. 
 
3.2.4 
Limitations of the study 
The results of the phase IV study will be descriptive, and due to the small population of this 
study, there can be no formal statistical comparison to the data from the comparison of 
ticagrelor to clopidogrel in the PLATO study. However, the Kaplan-Meier% with 95% CI for 
the both studies will be presented.  
4. 
SUBJECT SELECTION CRITERIA 
Investigator(s) should keep a record, the subject screening log, of subjects who entered pre-
study screening. 
Each subject should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule. 
4.1 
Inclusion criteria 
For inclusion in the study, subjects should fulfil the following criteria: 
1. Provision of informed consent prior to any study specific procedures  
2. Female or male aged at least 20 years 
3. A patient who is considered as ethnic Taiwanese 
4. Index event of non-ST elevation MI. The patient should be hospitalised for chest pain 
and potential ACS and be documented by cardiac ischaemic symptomsa of ≥10 minutes 
duration at restb and: 
 Positive biomarker evidence of myocardial necrosis: Either 
 Troponin T or I (TNT/TNI) greater than the laboratory upper normal limit 
on at least one occasion in association with the index clinical event (ie, any 
elevated troponin level) 
or 
 CK-MB, preferably CK-MB mass, greater than the laboratory upper normal 
limit on at least one occasion in association with the index clinical event 
Patients should be enrolled as quickly as possible after presentation in order to maximize 
potential clinical benefits but at least within 24 hours after onset of symptoms. Patients may 
have been preloaded with clopidogrel or ticagrelor, as the dosing time of dual antiplatelet 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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treatment should follow the current requirement of critical care to ACS, that is to treat with 
dual anti-platelet agents in emergency room when indicated. 
Definition of terms 
a. Cardiac ischaemic symptoms: chest pain or discomfort or equivalent (eg, neck or jaw symptoms, 
dyspnoea believed to represent an angina pectoris equivalent) believed due to impaired coronary flow 
secondary to atherosclerotic disease. If symptoms are found not to be due to atherosclerosis related 
myocardial ischaemia before enrollment then the patient should not be enrolled (eg, pericarditis, 
myocarditis, normal coronary arteries by angiography). 
b. At rest: started spontaneously or with exercise but did not resolve with rest. 
c. Laboratory MI local decision limit: this is the value that is considered abnormal. For institutions that 
report an intermediate or indeterminate range for troponin I or T, these values are considered abnormal 
for this study 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. ST-elevation MI, defined by: 
 
Persistent ST segment elevation ≥1mm (0.1mV) in 2 or more contiguous leads 
or 
 
 New or presumed new left bundle branch block (LBBB) 
2. Ongoing treatment with prasugrel 
3. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site) 
4. Previous enrolment in the present study 
5. Participation in another clinical study with an investigational product during the last 1 
month. 
6. Contraindication or other reason that ticagrelor should not be administered (eg, 
hypersensitivity, active bleeding, moderate or severe liver disease, history of previous 
intracranial bleed, gastrointestinal (GI) bleed within past 6 months, major surgery 
within 30 days) 
7. With coagulation disorder 
8. With uric acid nephropathy 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
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9. Index event is an acute complication of PCI 
10. Patient has planned for an urgent coronary artery bypass graft (CABG) within 7 days 
from the enrolment 
11. Oral anticoagulation therapy within 30 days prior to enrolment or cannot be stopped (ie, 
patient requires chronic therapy) 
12. Fibrinolytic therapy in the 24 hours prior to enrolment, or planned fibrinolytic treatment 
following enrolment (eg, for ST elevation MI or pulmonary embolism) 
13. Nonselective non-steroidal anti-inflammatory drugs (NSAIDs) and prostacyclins 
(PGI2) therapy that cannot be stopped 
14. History of intolerance or allergy to ASA or ticagrelor 
15. Increased risk of bradycardic events (eg, no pacemaker and known sick sinus 
syndrome, second degree A-V block, third degree A-V block or previous documented 
syncope suspected to be due to bradycardia).  
16. Patient requires dialysis 
17. Platelet count less than 100Х109/L 
18. Haemoglobin (Hb) level less than 100g/L 
19. Recent (within 30 days of dosing) blood donation 
20. Women of child-bearing potential (ie, those who are not chemically or surgically 
sterilised or who are not post-menopausal) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator OR women who are pregnant OR women who are breast-feeding 
21. Concomitant oral or intravenous therapy (see examples below) with strong cytochrome 
P450 3A (CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or 
strong CYP3A inducers within 14 days of study treatment or cannot be stopped for the 
course of the study 
 Strong inhibitors: ketoconazole, itraconazole, voriconazole, telithromycin, 
clarithromycin, 
nefazadone, 
ritonavir, 
saquinavir, 
nelfinavir, 
indinavir, 
atanazavir, over 1 litre daily of grapefruit juice. 
 Substrates with narrow therapeutic index: cyclosporine, quinidine. 
 Strong inducers: rifampin/rifampicin, phenytoin, carbamazepine. 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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22. Any other condition which in the opinion of the investigator, may either put the patient 
at risk or influence the result of the study (eg, cardiogenic shock or severe 
haemodynamic instability, active cancer, risk for non-compliance, risk for being lost to 
follow up) 
Procedures for withdrawal of incorrectly enrolled subjects see Section 5.3. 
 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
There are no specific dietary or activity restrictions other than those typical for this patient 
population.  
Patients should not donate blood or bone marrow at any time during the study period. 
Restrictions regarding concomitant medications are described in Section 5.6 
5.2 
Subject enrolment  
The Investigator will: 
1. Obtain signed informed consent (ICF) from the potential subject or their guardian/legal 
representative before any study specific procedures are performed. If ICF is not signed 
by the subject himself/herself, the subject should sign the ICF after his/her capability 
recovers. 
2. Assign potential subject a unique enrolment number, beginning with ‘E#’. 
3. Determine subject eligibility. See Sections 4.1 and 4.2 
 
If a subject withdraws from participation in the study, then his/her enrolment code cannot be 
reused. 
5.2.1 
Procedures for randomisation (Not applicable) 
 
5.3 
Procedures for handling subjects incorrectly enrolled 
Subjects who fail to meet the inclusion/exclusion criteria should not, under any 
circumstances, be enrolled.  There can be no exceptions to this rule. 
If a patient does not meet the selection criteria but is enrolled in error, a discussion should 
occur between the Study Physician and the Investigator regarding whether to continue or 
discontinue the patient from study medication.  Consistent with Intent-To-Treat (ITT) 
principles, all enrolled patients should continue to be followed in the study (ie, attend protocol 
visits) and, unless treatment would be harmful, patients should continue to receive study 
medication. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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In situations where an agreement cannot be reached, the patient should have their study 
medication stopped but will continue with study assessments. The Study Physician is to 
ensure all such decisions are appropriately documented.   
 
5.4 
Blinding and procedures for unblinding the study (Not applicable) 
 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor 90 mg 
Plain, round, yellow, film-coated tablet, 90 mg 
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Ticagrelor 180mg loading dose taken orally, followed by 90mg bd 
5.5.3 
Additional study drug (Not applicable) 
5.5.4 
Labelling 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language. 
The label will include the following information: 
 Name of sponsor (AstraZeneca) 
 Study drug dosage form, route of administration, and quantity of dosage units 
 Storage conditions 
 Study code 
 Enrolment code  
 Space for Subject Number to be written 
 Directions for use 
 Space for visit number to be written 
 The name of the Investigator, where applicable (this may be pre-printed or to be added 
on the label when the investigational product / study drug is dispensed) 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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 The period of use eg, expiry date 
 Keep out of reach of children 
 For clinical trial use only 
5.5.5 
Storage 
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the pack specifies the appropriate storage. 
5.6 
Concomitant and post-study treatment(s) 
In addition to the assigned study medication, all patients will take concomitant ASA, at a 
planned dose of 100 mg once daily, from enrolment through the end of the treatment period. 
If a patient develops an indication for higher dose ASA during the treatment period (e.g. acute 
coronary syndrome or percutaneous coronary intervention), higher dosing is allowed for the 
duration of that indication, after which the dose of ASA should be reduced to 100 mg once 
daily. 
Other medication, which is considered necessary for the subject’s safety and well being, may 
be given at the discretion of the investigator and recorded in the appropriate sections of the 
electronic Case Report Form (eCRF). 
Investigators are reminded of the following potential drug-drug interactions. 
5.6.1 
Digoxin and other p-glycoprotein interactions 
Ticagrelor modestly increases digoxin levels.  Therefore digoxin levels should be monitored 
closely following initiation or discontinuation of ticagrelor.  Other p-glycoprotein substrates 
may be expected to have similar changes in pharmacokinetics. Additional details can be found 
in the package insert for ticagrelor. 
5.6.2 
CYP450 interactions 
5.6.2.1 
CYP3A inhibitors 
Strong inhibitors of CYP3A enzyme (eg, ketoconazole, itraconazole, voriconazole, 
telithromycin, clarithromycin [but not erythromycin or azithromycin], nefazadone, ritonavir, 
saquinavir, nelfinavir, indinavir, atazanavir, or over 1 litre daily of grapefruit juice) should not 
be co-administered with ticagrelor, as plasma levels of ticagrelor would be substantially 
increased.  
5.6.2.2 
CYP3A substrates or inducers 
Concomitant therapy with simvastatin or lovastatin at doses higher than 40 mg daily is not 
permitted since administration with ticagrelor will result in higher serum concentrations and 
may put patients receiving more than 40 mg per day of simvastatin or lovastatin at increased 
risk of statin-related adverse effects.  There are no restrictions to other statin therapies (ie, 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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doses of simvastatin or lovastatin ≤ 40 mg daily or any dose of any other statin is permitted).  
Investigators are advised to check lipid levels and adjust statin dosages per local practice. 
Co-administration of ticagrelor with strong inducers of CYP3A also should be avoided (eg, 
rifampin/rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital). 
5.6.3 
Oral anticoagulants 
Concomitant treatment with oral anticoagulants (ie, vitamin K antagonists, direct thrombin 
inhibitors, factor X inhibitors) is not recommended during the study. The investigator should 
carefully consider potential risks and benefits. Irrespective if study drug is stopped or not, the 
patient should remain in the study for evaluation. 
5.6.4 
Parental anticoagulants 
Short-term treatment (ie, up to 7 days) with approved parenteral anticoagulants (eg. 
unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), bivalirudin, 
fondaparinux) is allowed. However, long-term treatment with LMWH or fondaparinux in 
outpatients (at venous thrombosis treatment or atrial fibrillation doses) in combination with 
study medication is not allowed. Concomitant treatment with venous thrombosis prophylaxis 
doses is allowed. 
5.6.5 
ADP receptor antagonists 
Concomitant treatment with any other ADP receptor antagonists is not allowed in the study.  
5.6.6 
GPIIb/IIIa receptor antagonists 
Short-term treatment (ie, up to 7 days) with GPIIb/IIIa antagonists is allowed during the study. 
5.6.7 
Dipyridamole and cilostazol 
Concomitant treatment with dipyridamole or cilostazol is not permitted in the study. 
5.6.8 
Fibrinolytic treatment 
If a patient is to be treated with fibrinolytic therapy, study medication should be stopped and 
restarted no earlier than 24 hours after completion of the fibrinolytic therapy and when the risk 
of bleeding is deemed low in the judgment of the investigator. 
5.6.9 
Non-steroidal anti-inflammatory drugs (NSAIDs) 
Chronic treatment with non selective NSAID treatment or prostacyclin (PGI2) is not 
permitted. Short term treatment with NSAID or PGI2 up to 7 days is allowed. 
5.7 
Treatment compliance 
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the eCRF. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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Patients will be asked to return all unused study medications and empty packages to the clinic 
at each visit. The patient’s compliance will be assessed by the investigator and recorded in the 
eCRF. A pill count should be done at a patient level and recorded in the eCRF and a 
dispensing log by the study site personnel. 
5.7.1 
Accountability 
The study drug provided for this study will be used only as directed in the study protocol. 
The study site personnel will account for all study drugs dispensed to and returned from the 
subject. 
Study site personnel will account for all study drugs received at the site, unused study drugs 
and for appropriate destruction.  Certificates of delivery, destruction and return should be 
signed. 
5.8 
Discontinuation of investigational product 
Subjects may be discontinued from investigational product (IP) in the following situations: 
Adverse Event as judged by the investigator and/or AZ 
Severe non-compliance to study protocol as judged by the investigator and/or AZ 
Subjects should be discontinued from investigational product (IP) in the following situations: 
Subject decision.  The subject is at any time free to discontinue treatment, without prejudice 
to further treatment 
Incorrectly enrolled patient in whom the inclusion/exclusion criteria violation would put the 
patient at undue risk (see Section 5.3) 
Pregnancy 
5.8.1 
Procedures for discontinuation of a subject from investigational product  
A subject that decides to discontinue investigational product will always be asked about the 
reason(s) and the presence of any adverse events. Adverse events will be followed up (See 
Sections 6.4.3 and 6.4.4); and all study drugs should be returned by the subject.  
5.8.2 
Temporary discontinuation from study medication 
Surgery or procedures associated with major haemorrhage: It is recommended that cardiac 
surgery and major non-cardiac surgery that in the opinion of the investigator poses a risk for 
clinically major bleeding not be performed until at least 5 days after stopping study 
medication to avoid excessive bleeding. After surgery, study medications should be restarted 
when the risk of bleeding is deemed low in the judgment of the investigator.  


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Study Code D5130C00103 
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Major bleeding: Study medication must be stopped immediately in case of a bleeding deemed 
to be clinically significant in the judgment of the investigator (eg, a significant fall in 
haemoglobin, need for transfusion, haemodynamically significant, or in a critical location 
such as intracranial, intraspinal, intraocular, or pericardial), but may be reinstated when the 
risk of bleeding is deemed low in the judgment of the Investigator and if not contraindicated.  
The study medication administration need not be stopped in case of a minor bleeding.  All 
bleedings should be treated and followed up according to local clinical practice.  Major 
bleeding events should be managed according to need with general support and blood.  
Study medication should be restarted at the investigator’s discretion to minimise the risk of 
thrombotic complications 
Dyspnea: Evaluation of a patient who develops dyspnea should start with an assessment of 
timing relative to initiation of study drug, severity, and the presence of any signs or symptoms 
suggestive of cardiopulmonary disease. In patients with signs and symptoms suggestive of 
another cause of dyspnea (eg, heart failure exacerbation, chronic obstructive pulmonary 
disease flare), evaluation and treatment for those conditions should occur per local practice 
standards. Importantly, study drug should be continued in these patients without interruption.  
Also, in patients in whom the dyspnea begins soon after starting study drug and not 
associated with any signs or symptoms suggestive of significant cardiopulmonary 
disease, patients should continue study drug without interruption as the dyspnea 
typically resolves spontaneously while on treatment. The patient should be re-
evaluated after several days. It is important to note that a drug holiday and subsequent 
rechallenge often results in recurrence of dyspnea.  
In patients with dyspnea likely due to study drug that proves intolerable, 
concomitant medications should be reviewed and, when possible, moderate 
CYP3A4 inhibitors (eg, diltiazem) changed to an alternative that is not a CYP3A4 
inhibitor or discontinued. 
5.8.3 
Permanent premature discontinuation from study medication 
Patients permanently discontinuing study medication should be given conventional therapy, if 
applicable. This medication(s) will be open label and obtained locally. All patients should 
always be asked to continue the regular visits as described below.  It is essential to collect as 
much data as possible for all patients throughout the study. Complete withdrawal from 
the study (withdrawal of consent) has a direct impact on the potential validity of all 
study data and should be avoided wherever possible. 
If the patient prematurely permanently discontinues study medication, there could be several 
different options for their continuation in the study as described below. 


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Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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5.8.3.1 
The patient agrees to undergo the premature treatment discontinuation visit 
and then continue in-person study visits 
The patient agrees to undergo the Premature Treatment Discontinuation Visit (PTDV) and 
then continue in-person study visits every 3 months until 12 months after enrolment.  This is 
the preferred option and patients who discontinue study medication will always be asked if 
they agree to this approach. 
5.8.3.2 
The patient unwilling to continue in-person study visits but agrees to undergo 
modified follow-up  
If the patient agrees, the PTDV should be done.  Subsequent visits through Visit 6 will be 
done as regular telephone contacts or by other means to ascertain whether any clinical 
endpoints or AEs have occurred and to inventory concomitant medications. Such a patient has 
not withdrawn his/her consent or withdrawn from the study. 
5.8.3.3 
The patient refuses any form of follow-up 
 If the patient refuses any form of follow-up, he/she officially withdraws from the study and 
withdraws consent. This approach should be avoided if possible.  
5.9 
Withdrawal from study 
Subjects are at any time free to withdraw from study (investigational product and 
assessments), without prejudice to further treatment (withdrawal of consent).  Such subjects 
will always be asked about the reason(s).  If possible, they will be seen and assessed by an 
investigator; final visits should be 1 week after the discontinuation (See Table 2). Adverse 
events will be followed up by the investigator for as long as medically indicated, but without 
further recording in the eCRF); and all study drugs should be returned by the subject. 
The Investigator should always ask the patient to allow contact 12 months after enrolment for 
a final follow-up to ascertain AEs even if participation in other visits is not agreed. At a 
minimum, permission to ascertain vital status should be obtained if at all possible. This 
agreement should be noted and signed by both the Investigator and the patient on the 
Informed consent form, as well as entered in the medical records. The reason for 
discontinuation and the date of discontinuation from the study must be documented in the 
eCRF. 
Withdrawn subjects will not be replaced.  
6. 
COLLECTION OF STUDY VARIABLES 
The investigator will ensure that data are recorded in a timely fashion on the eCRF as 
specified in the study protocol and in accordance with the instructions provided. A copy of the 
eCRF data will be archived at the study centre. 


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Drug Substance Ticagrelor  
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6.1 
Recording of data 
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling.  The investigator will ensure that data are recorded on the eCRF as specified 
in the study protocol and in accordance with the instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed eCRF.  A copy of the completed eCRF will be 
archived at the study site. 
6.2 
Data collection at enrolment and follow-up 
6.2.1 
Enrolment procedures 
Each patient will undergo enrolment procedures at Visit 1.  The following data will be 
collected: 
x Demographics (including sex, date of birth, confirmation of Taiwanese ethnicity) 
x Relevant medical and surgical history  
x Current concomitant medications  
x Targeted physical examination including vital Signs (heart rate, blood pressure) 
x Safety laboratory blood analyses (clinical chemistry and haematology) 
x Urine pregnancy test (for females of child bearing potential) 
x 12-lead ECG 
x Myocardial necrosis biomarker  
6.2.2 
Follow-up procedures 
Patients will have routine visits as outlined in Table 2.  Any new suspected endpoint events, 
SAEs and current medications will be recorded.  In order to determine whether or not clinical 
events meet the endpoint definition, it will be the responsibility of the Investigator to obtain 
all necessary source documents, including medical records from institutions where a 
hospitalisation may have occurred. 
6.3 
Efficacy  
Suspected clinical efficacy endpoints will be collected in the eCRF.  These events will be 
identified using standard questioning of the patient at each visit, or by information that the 
investigator may receive as part of standard medical practice.  Safety endpoint events will be 
identified similarly. 


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For each suspected endpoint, the investigator will collect relevant additional source 
information where required, determine whether a safety or efficacy endpoint has occurred, and 
record their finding on the eCRF. 
6.3.1 
CV death  
All deaths reported post-enrolment will be recorded and classified by the investigator as CV 
or non-CV.  
6.3.2 
MI 
MI is diagnosed on the basis of elevation of myocardial necrosis biomarkers typical of acute 
MI with at least 1 of the following: 
1. 
Recurrent cardiac ischaemic symptoms ≥20 minutes at rest 
2. 
Development of new pathological Q waves on the ECG 
3. 
New or presumed new ECG changes indicative of ischaemia in 2 or more 
contiguous leads (ST-segment elevation, ST-segment depression or T-wave 
inversion) 
6.3.3 
Stroke 
A stroke is defined as a neurological deficit caused by an ischaemic or haemorrhagic central 
nervous system event with residual symptoms at least 24 hours after onset or leading to death. 
Stroke will be further sub-classified as:  
4. 
Ischaemic:  
Ischemic stroke is defined as an infarction of the central nervous system tissue that 
results from a thrombus or embolus impairing central nervous system perfusion (and 
not primarily due to haemorrhage) with residual signs or symptoms lasting at least 
24 hours after onset or leading to death. Haemorrhage may be a consequence of 
ischemic stroke.  In this situation, the stroke should be recorded as an ischemic 
stroke with hemorrhagic transformation rather than a hemorrhagic stroke event. 
5. 
Haemorrhagic:  
Hemorrhagic stroke is defined as an acute episode of focal or global cerebral or 
spinal dysfunction with a documented cause of intracranial haemorrhage on imaging 
(eg, computed tomography (CT) scan or magnetic resonance imaging (MRI) scan) 
either in the cerebral parenchyma, or in the subdural, epidural or subarachnoid space 
with residual signs or symptoms at least 24 hours after onset or leading to death. 
Evidence of hemorrhagic stroke obtained from lumbar puncture, neurosurgery, or 
autopsy can also confirm the diagnosis. 


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6. 
Unknown/No imaging performed: if the type of stroke could not be determined by 
imaging or other means (from lumbar puncture, neurosurgery, or autopsy) but is 
judged to fulfill the stroke definition above, the stroke will be classified as 
ischaemic for purposes of the study. 
 
6.4 
Safety 
The Principal Investigator (PI) is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.4.1 
Definition of adverse events  
An adverse event (AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. 
An undesirable medical condition can be symptoms, eg, nausea, chest pain, or 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 after the patient has signed informed consent, including run-in 
or washout periods, even if no specific treatment has been administered. 
The term AE is used to include both serious and non-serious AEs 
6.4.2 
Definitions of serious adverse event 
A serious adverse event (SAE) is an AE, occurring at 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/birth defect 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above.  
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol. 


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6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
AE/SAEs will be recorded from the time of signature of informed consent throughout the 
treatment period, including the follow-up period, to last contact. 
Follow-up of unresolved adverse events 
Any AEs that are unresolved at the subject’s last AE assessment in the study are followed up 
by the investigator for as long as medically indicated, but without further recording in the 
eCRF.  AstraZeneca retains the right to request additional information for any subject with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
Variables 
The following variables will be collect for each AE; 
z AE (verbatim) 
z The date when the AE started and stopped 
z Whether the AE is serious or not 
z Investigator causality rating against the Investigational Product (yes or no) 
z Action taken with regard to investigational product 
z Outcome. 
In addition, the following variables will be collected for SAEs: 
z Date AE met criteria for serious AE 
z Date Investigator became aware of serious AE 
z AE is serious due to 
z Date of hospitalisation 
z Date of discharge 
z Probable cause of death 
z Date of death 
z Autopsy performed 
z Causality assessment in relation to Study procedure(s) 


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z Causality assessment in relation to other medication 
Description of AE 
The following definitions for intensity rating are:  
 mild (awareness of sign or symptom, but easily tolerated) 
 moderate (discomfort sufficient to cause interference with normal activities) 
 severe (incapacitating, with inability to perform normal activities) 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would 
be a SAE. 
Causality collection 
The Investigator will assess causal relationship between Investigational Product 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’. 
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol. 
Adverse Events based on signs and symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study personnel: ‘Have you had any health problems since the previous visit/you 
were last asked?’, or revealed by observation will be collected and recorded in the eCRF. 
When collecting AEs, the recording of diagnoses is preferred (when possible) to recording a 
list of signs and symptoms.  However, if a diagnosis is known and there are other signs or 
symptoms that are not generally part of the diagnosis, the diagnosis and each sign or symptom 
will be recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
clinical study report.  Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs should therefore only be reported as AEs if they fulfil any of the SAE 
criteria or are the reason for discontinuation of treatment with the investigational product. 


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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, 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). 
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical 
examination as compared with the baseline assessment will be reported as an AE. 
NB. Cases where a subject shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN may 
need to be reported as SAEs, please refer to Appendix D ‘Actions required in cases of 
combined increase of Aminotransferase and Total Bilirubin – Hy’s Law’, for further 
instructions. 
6.4.4 
Reporting of serious adverse events 
All SAEs have to be reported, whether or not considered causally related to the 
investigational product, or to the study procedure(s). All SAEs will be recorded in the eCRF. 
If any SAE occurs in the course of the study, then investigators or other site personnel inform 
appropriate AstraZeneca representatives immediately, or no later than 24 hours of when he 
or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site on the day 
of initial receipt for fatal and life threatening events and within five calendar days of initial 
receipt for all other SAEs. 
For fatal or life-threatening 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 immediately, or 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 how to 
proceed.   


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6.4.5 
Laboratory safety assessment 
Blood samples for determination of clinical chemistry, haematology, and urinalysis will be 
taken at the times indicated in the Study Plan and Time Schedule (see Table 2). 
The following laboratory variables will be measured: 
 
S-Creatinine 
 
S-Uric acid 
 
S-Alkaline phosphatase 
 
S-Aspartate aminotransferase (AST) 
 
S-Alanine aminotransferase (ALT) 
 
S-Total Bilirubin 
(Elevated values to be fractionated) 
 
B-Haemoglobin 
 
B-Platelets 
 
NB. In case a subject shows an AST or ALT ≥3xULN and total bilirubin ≥ 2xULN please 
refer to Appendix D ‘Actions required in cases of combined increase of Aminotransferase 
and Total Bilirubin – Hy’s Law’, for further instructions. 
For blood volume see Section 7.1. 
6.4.6 
Physical examination 
A physical examination will be performed and include an assessment of the following: 
general appearance, respiratory, cardiovascular, abdomen. 
6.4.7 
ECG (Not applicable) 
6.4.8 
Vital signs 
6.4.8.1 
Pulse and blood pressure 
Supine blood pressure and pulse rate will be measured using non-invasive equipment after 10 
minutes rest on a bed.  For timings of assessments refer to the Study Plan and Time Schedule 
(see Table 2) 
6.4.9 
Other safety assessments 
6.4.9.1 
Bleeding events 
For all bleeding events, the investigator will complete information on the eCRF specific to 
that bleeding event. Additionally, bleeding events will be reported as AE and SAEs if serious 
criteria are met. Fatal/life-threatening and other major bleeding events are key components of 
primary endpoint (Wallentin 2009). 
Fatal/life-threatening bleeding events are defined by 1 or more of the following criteria: 
 
Fatal 


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 
Intracranial 
 
Intrapericardial bleed with cardiac tamponade 
 
Hypovolemic shock or severe hypotension due to bleeding and requiring pressors 
or surgery 
 
Clinically overt or apparent bleeding associated with a decrease in Hb of more 
than 50 g/L 
 
Transfusion of 4 or more units [whole blood or packed red blood cells (PRBCs)] 
for bleeding. 
 
Major other bleeding events are defined by 1 or more of the following criteria: 
 
 Significantly disabling (eg, intraocular with permanent vision loss) 
 
Clinically overt or apparent bleeding associated with a decrease in Hb of 30 g/L to 
50 g/L 
 
Transfusion of 2-3 units (whole blood or PRBCs) for bleeding. 
Minor bleed is an event requiring medical intervention to stop or treat bleeding (eg, epistaxis 
requiring visit to medical facility for packing. 
Minimal bleeds are events not requiring intervention or treatment (eg, bruising, bleeding 
gums, oozing from injection sites, etc). 
6.4.9.1.1 Bleeding associated with procedures 
Bleeding associated with procedures should be reported as an AE/SAE if exceeding normal 
bleeding for the specific procedure. 
6.4.9.1.2 Management of bleeding 
There is currently no antidote to ticagrelor and treatment of bleeding should therefore be 
symptomatic and handled according to the clinical routines at the investigational centre. 


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6.5 
Patient reported outcomes (PRO) (Not applicable) 
6.6 
Pharmacokinetics (Not applicable) 
6.7 
Pharmacodynamics (Not applicable) 
6.8 
Pharmacogenetics (Not applicable) 
6.9 
Health economics (Not applicable) 
7. 
BIOLOGICAL SAMPLING PROCEDURES  
7.1 
Volume of blood 
The total volume of blood that will be drawn from each subject in this study is as follows: 
Table 3 
Volume of blood to be drawn from each subject 
Assessment 
Sample volume 
(mL) 
No. of samples 
Total volume 
(mL) 
Safety 
Clinical chemistry 
5 
3 
15 
 
Haematology 
2 
3 
6 
Eligibility 
Myocardial 
biomarker 
5 
1 
5 
Total 
 
 
26 
7.2 
Handling, storage and destruction of biological samples 
The samples will be used up or disposed of after analyses. 
7.3 
Labelling and shipment of biohazard samples 
The Investigator ensures that samples are labelled and shipped in accordance with the 
Laboratory Manual and the Biological Substance, Category B Regulations (material 
containing or suspected contain infectious substances that do not met Catergory A criteria), 
see Appendix C ‘IATA 6.2 Guidance Document’. 
Any samples identified as Infectious Category A material are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved. 
7.4 
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle. 


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The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the subjects while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival. 
The sample receiver keeps full traceability of the samples while in storage and during use 
until used or disposed of or until further shipment and keeps documentation of receipt of 
arrival. 
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring 
of study sites and auditing of external laboratory providers. 
7.5 
Withdrawal of informed consent for donated biological samples 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, 
AstraZeneca is not obliged to destroy the results of this research. 
The Principal Investigator: 
Ensures subjects’ withdrawal of informed consent to the use of donated samples is notified 
immediately to AstraZeneca 
Ensures that biological samples from that subject, if stored at the study site, are immediately 
identified, disposed of /destroyed, and the action documented 
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn consent 
immediately and that samples are disposed/destroyed, the action documented and the signed 
document returned to the study site 
Ensures that the subject and AstraZeneca are informed about the sample disposal. 
AstraZeneca ensures the central laboratory(ies) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice (GCP), applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples. 


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8.2 
Subject data protection 
The Informed Consent Form will incorporate (or, in some cases, be accompanied by a 
separate document incorporating) wording that complies with relevant data protection and 
privacy legislation. 
8.3 
Ethics and regulatory review 
An Ethics Committee (EC) should approve the final study protocol, including the final 
version of the Informed Consent Form and any other written information and/or materials to 
be provided to the subjects.  The investigator will ensure the distribution of these documents 
to the applicable Ethics Committee, and to the study site staff. 
The opinion of the Ethics Committee should be given in writing. The investigator should 
submit the written approval to AstraZeneca before enrolment of any subject into the study.  
The Ethics Committee should approve all advertising used to recruit subjects for the study. 
AstraZeneca should approve any modifications to the Informed Consent Form that are needed 
to meet local requirements. 
If required by local regulations, the protocol should be re-approved by the Ethics Committee 
annually. 
Before enrolment of any subject into the study, the final study protocol, including the final 
version of the Informed Consent Form, is approved by the national regulatory authority or a 
notification to the national regulatory authority is done, according to local regulations. 
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities. 
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements, including Suspected 
Unexpected Serious Adverse Reactions (SUSARs), where relevant. 
8.4 
Informed consent 
The Principal Investigator(s) at each centre will: 
Ensure each subject is given full and adequate oral and written information about the nature, 
purpose, possible risk and benefit of the study 
Ensure each subject is notified that they are free to discontinue from the study at any time 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 


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Ensure each subject 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 subject 
Ensure that any incentives for subjects who participate in the study as well as any provisions 
for subjects harmed as a consequence of study participation are described in the informed 
consent form that is approved by an Ethics Committee. 
8.5 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the National Principal 
Investigator and AstraZeneca. 
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol). 
The amendment is to be approved by the relevant Ethics Committee and if applicable, also the 
national regulatory authority approval, before implementation.  Local requirements are to be 
followed for revised protocols. 
AstraZeneca will distribute any subsequent amendments and new versions of the protocol to 
each Investigator(s). For distribution to Ethics Committee see Section 8.3. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, AstraZeneca 
and the centre’s Ethics Committee are to approve the revised Informed Consent Form before 
the revised form is used.  
If local regulations require, any administrative change will be communicated to or approved 
by each Ethics Committee. 
8.6 
Audits and inspections 
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification.  The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the protocol, Good 
Clinical Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), 
and any applicable regulatory requirements.  The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the centre. 


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9. 
STUDY MANAGEMENT BY ASTRAZENECA 
9.1 
Pre-study activities 
Before the first subject is entered into the study, it is necessary for a representative of 
AstraZeneca to visit the investigational study site to: 
Determine the adequacy of the facilities 
Determine availability of appropriate subjects for the study 
Discuss with the investigator(s) (and other personnel involved with the study) their 
responsibilities with regard to protocol adherence, and the responsibilities of AstraZeneca or 
its representatives.  This will be documented in a Clinical Study Agreement between 
AstraZeneca and the investigator. 
9.2 
Training of study site personnel 
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised. 
The Principal Investigator will ensure that appropriate training relevant to the study is given 
to all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff). 
9.3 
Monitoring of the study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
Provide information and support to the investigator(s) 
Confirm that facilities remain acceptable 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are being 
performed 
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) including 
verification of informed consent of participating subjects. This will require direct access to all 
original records for each subject (eg, clinic charts) 


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Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and the 
action is documented, and reported to the subject. 
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staffs at the centre need information and advice about the study conduct. 
9.3.1 
Source data 
Location of source data can be found in the Clinical Study Agreement. 
9.4 
Study agreements 
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of subjects and in all other respects, not relating to study conduct or treatment of 
subjects, the terms of the Clinical Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or subjects are enrolled. 
9.4.1 
Archiving of study documents 
The Investigator follows the principles outlined in the Clinical Study Agreement (CSA). 
9.5 
Study timetable and end of study 
The end of the study is defined as ‘the last visit of the last subject undergoing the study’. 
The study is expected to start in Q1 2015 and to end by Q2 2017. 
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with ticagrelor. 
10. 
DATA MANAGEMENT BY ASTRAZENECA  
Data management will be performed by Cognizant, AstraZeneca Data Management Centre 
staff. 
Data will be entered in the WBDC system at the study site.  Trained personnel at study site 
will be responsible for entering data on the observations, tests and assessments specified in 
the CSP, into the WBDC system according to the eCRF instructions.  The eCRF Instruction 
will guide the study site in performing data entry.  Data entered in the WBDC system will be 


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immediately saved to a central database and changes tracked to provide an audit trail.  The 
data will then be Source Data Verified, reviewed/queried and updated as needed. 
The data collected through third party sources will be obtained and reconciled against study 
data. 
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the AstraZeneca Drug Dictionary.  The Medical Coding Team 
at the AstraZeneca Data Management Centre will perform all coding. 
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. 
When all data have been coded, validated, electronically signed and locked, clean file will be 
declared. Any treatment revealing data may thereafter be added and the final database will be 
locked. 
Data associated with biological samples will be transferred to laboratories internal or external 
to AstraZeneca. 
The Investigator ensures the accuracy, completeness and timeliness of the data recorded and 
of the provision of answers to data queries.  The Investigator will sign the completed eCRFs. 
A copy of the completed eCRFs will be archived at the study site.  
11. 
EVALUATION AND CALCULATION OF VARIABLES BY 
ASTRAZENECA  
11.1 
Calculation or derivation of efficacy variable(s) 
Efficacy assessment will describe the incidence of major CV events (composite of CV death, 
MI, stroke), analyzed according to locally adjudicated PLATO definitions. 
11.2 
Calculation or derivation of safety variable(s) 
The safety assessment will describe total major bleeding events (including the subsets of fatal 
and fatal/ life threatening events), combined major and minor bleeding events. Bleeding 
events will be analyzed according to locally adjudicated PLATO bleeding definitions. AEs 
and other SAEs other than bleeding will also be evaluated. Summaries will be presented using 
descriptive statistics.   
Primary variables 


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 
PLATO-defined fatal/life-threatening bleedings during 1year follow up in 
Taiwanese ACS patients treated with ticagrelor.  
 
PLATO-defined major bleedings during 1year follow up in Taiwanese ACS 
patients treated with ticagrelor. 
 
PLATO-defined major + minor bleedings during 1year follow up in Taiwanese 
ACS patients treated with ticagrelor. 
 
Serious adverse events other than bleeding during 1year follow up in 
Taiwanese ACS patients treated with ticagrelor. 
11.2.1 
Other significant adverse events (OAE) 
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs.  Based on the expert’s judgement, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report.  A similar review of laboratory/vital signs data will be performed for 
identification of OAEs. 
Examples of these are marked haematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 
11.3 
Calculation or derivation of patient reported outcome variables 
(Not applicable) 
11.4 
Calculation or derivation of pharmacokinetic variables (Not 
applicable) 
11.5 
Calculation or derivation of pharmacodynamic variable(s) (Not 
applicable) 
11.6 
Calculation or derivation of pharmacogenetic variables (Not 
applicable) 
11.7 
Calculation or derivation of health economic variables (Not 
applicable) 
12. 
STATISTICAL 
METHODS 
AND 
SAMPLE 
SIZE 
DETERMINATION BY ASTRAZENECA  


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12.1 
Description of analysis sets 
12.1.1 
Full analysis set 
All patients who have taken at least one dose of investigational product.  
The analyses of efficacy variables will use the full analysis set. 
12.1.2 
Safety analysis set 
All subjects who received at least one dose of investigational product, and for whom any post-
dose data are available will be included in the safety analysis set.   
The analyses of all safety variables will use the safety analysis set.   
12.2 
Methods of statistical analyses 
12.2.1 
Primary objective-primary efficacy endpoint 
The primary efficacy endpoint is the cumulative incidence of major CV events (including CV 
death, MI and stroke) during 1 year follow up in Taiwanese NSTEMI patients. The primary 
analysis will be presented with K-M% and with 95% CI. Patients who fail to record any event 
in the primary composite efficacy endpoint will be censored at the time of study closure (ie. 
date of End of Treatment Visit) or at the time of last available information, if earlier.  
No statistical comparison can be performed to the results of PLATO, due to the small 
population of this study.  
12.2.2 
Primary objective-primary safety endpoint  
Statistical methods will be descriptive. For continuous data, descriptive statistics will be 
presented as number of patients (n), mean, standard deviation (SD), median, minimum and 
maximum. For categorical data, the frequency and percentage of patients in each category 
will be presented. Counts that are zero will be displayed as “0”. Percentages will be based on 
non-missing data unless otherwise specified. 
Patients will be censored at 7 days after their last dose of ticagrelor. Patients who withdraw 
consent to participate in the study will be included up to the date of their study termination. 
12.3 
Determination of sample size 
This is a regulatory commitment study to investigate the safety profile and to describe the 
cumulative incidence of major cardiovascular events of ticagrelor including fatal/life-
threatening bleeding among Taiwanese NSTEMI patients within 1 year of follow up.  If the 
fatal/life-threatening bleeding rate is 5% then 100 patients would allow to describe the safety 
profile estimated with a precision of +/-4.3%, with a 95%CI.  
12.4 
Data monitoring committee (Not applicable) 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
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13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Medical emergencies and AstraZeneca contacts 
The Principal Investigator is responsible for ensuring that procedures and expertise are 
available to handle medical emergencies during the study. A medical emergency usually 
constitutes an SAE and is to be reported as such, see Section 6.4.4 
In the case of a medical emergency the investigator may contact the Study Delivery Team 
Leader. If the Study Delivery Team Leader is not available, contact the Study Delivery Team 
Physician at the AstraZeneca Research and Development. 
Name 
Role in the study  
Address & telephone number 
Amery 
Chang 
Clinical Development Manger 
AstraZeneca Taiwan 
13th Fl., 207, Tun Hwa South Rd., Sec.2 
Taipei Metro Building, Taipei 10602, 
Taiwan 
T: +886-2-27302307 
Wilhelm 
Ridderstråle 
Study Physician 
AstraZeneca,CVMD Global Medicines 
Development 
Pepparedsleden 1 
431 83 Mölndal 
SWEDEN Tel: +46702536121 
13.2 
Overdose  
An overdose of ticagrelor is defined as intake of 4 or more ticagrelor tablets (360 mg)/day.   
In the event of an overdose of 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 it must be decided 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 can be found in the package insert for ticagrelor. 
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the relevant 
AE modules in the eCRF and on the Overdose eCRF module. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
46(47) 
 
An overdose without associated symptoms is only reported on the Overdose eCRF module. 
If an overdose on an AstraZeneca study drug occurs in the course of the study, then 
investigators or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with SAE, standard reporting timelines apply, see Section 6.4.4.  For 
other overdoses, reporting should be done within 30 days. 
13.3 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca.  
13.3.1 
Maternal exposure 
If a subject becomes pregnant during the course of the study investigational product should be 
discontinued immediately. 
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product 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 subject was discontinued from the study. 
If any pregnancy occurs in the course of the study, then investigators or other site personnel 
inform appropriate AstraZeneca representatives immediately, or no later than 24 hours of 
when he or she becomes aware of it. 
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 days for SAEs, see Section 6.4.4 and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy. 
13.3.2 
Paternal exposure 
There are no restrictions against fathering a child when treated with ticagrelor.  If paternal 
exposure pregnancy occurs in the course of the study, then investigators or other site 
personnel should inform appropriate AstraZeneca representatives immediately or no later than 
24 hours as described in the maternal exposure Section 13.3.1. 


Revised Clinical Study Protocol 
Drug Substance Ticagrelor  
Study Code D5130C00103 
Edition Number 2.0 
Date 22 Jun 2015 
47(47) 
 
14. 
LIST OF REFERENCES 
Hamm 2011 
Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H et al. ESC Guidelines for 
the management of acute coronary syndromes in patients presenting without persistent ST-
segment elevation. Eur Heart J 2011;32:2999-3054. 
Jneid 2012 
Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr et al. 2012 
ACCF/AHA Focused Update of the Guidelines for the Management of Patients With 
Unstable Angina/Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline and 
Replacing the 2011 Focused Update). J Am Coll Cardiol 2012 1460:645-81. 
Steg 2012 
Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA et al. ESC Guidelines for 
the management of acute myocardial infarction in patients presenting with ST-segment 
elevation. Eur Heart J 2012;33:2569-619 
Vandvik 2012 
Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P et al. 
Primary and Secondary Prevention of Cardiovacular Disease: Antithrombotic Therapy and 
Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest 2012;141:e637S-e668S. 
Wallentin 2009 
Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, 
James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; 
PLATO Investigators, TICAGRELOR versus clopidogrel in patients with acute coronary 
syndromes N Engl J Med. 2009 Sep 10;361(11):1045-57