Ticagrelor in Remote Ischemic Preconditioning Study
Phase: PHASE4
Conditions: Periprocedural Myocardial Infarction
Sponsor: Hellenic Society of Interventional Cardiology

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
1 
 
Drug Substance 
<<Ticagrelor>> 
Study Number 
<<ESR-14-10310>> 
Version Number 
<<2>> 
Date 
<<11 01 2017>> 
D-Code 
D5130L00138. 
Ticagrelor in Remote Ischemic Preconditioning (TRIP) Study 
EudraCT number: 2016-002288-32 
Sponsor:  Hellenic Society of Interventional Cardiology 
 
CONFIDENTIAL 
 
 
 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
2 
 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................................. 5 
1. 
INTRODUCTION ................................................................................................... 6 
1.1 
Background .............................................................................................................. 6 
1.2 
Research hypothesis ................................................................................................. 7 
1.3 
Rationale for conducting this study ......................................................................... 7 
1.4 
Benefit/risk and ethical assessment.......................................................................... 8 
2. 
STUDY OBJECTIVES ............................................................................................ 9 
2.1 
Primary objective ..................................................................................................... 9 
2.2 
Secondary objectives ............................................................................................... 9 
2.3 
Safety objective ........................................................................................................ 9 
3. 
STUDY PLAN AND PROCEDURES .................................................................. 10 
3.1 
Overall study design and flow chart ...................................................................... 10 
3.2 
Rationale for study design, doses and control groups ............................................ 13 
4. 
SUBJECT SELECTION CRITERIA .................................................................... 13 
4.1 
Inclusion criteria .................................................................................................... 13 
4.2 
Exclusion criteria ................................................................................................... 13 
5. 
STUDY CONDUCT .............................................................................................. 14 
5.1 
Subject enrollment, randomization, and initiation of investigational 
product ................................................................................................................... 14 
5.1.1 
Procedures for randomization ................................................................................ 14 
5.2 
Procedures for handling subjects incorrectly enrolled or randomized or 
initiated on investigational product ........................................................................ 15 
5.3 
Blinding and procedures for unblinding the study ................................................. 15 
5.4 
Treatments .............................................................................................................. 15 
5.4.1 
Identity of investigational product(s) ..................................................................... 15 
5.4.2 
Doses and treatment regimens ............................................................................... 17 
5.4.3 
Additional study drug ............................................................................................ 17 
5.4.4 
Labeling ................................................................................................................. 17 
5.4.5 
Storage ................................................................................................................... 17 
5.5 
Concomitant and post-study treatment(s) .............................................................. 17 
5.6 
Treatment compliance ............................................................................................ 17 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
3 
 
5.6.1 
Accountability ........................................................................................................ 17 
5.7 
Discontinuation of investigational product ............................................................ 18 
5.7.1 
Procedures for discontinuation of a subject from investigational product ............ 18 
5.8 
Withdrawal from study .......................................................................................... 19 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 19 
6.1 
Recording of data ................................................................................................... 19 
6.2 
Data collection at enrolment and follow-up ........................................................... 19 
6.3 
Efficacy .................................................................................................................. 21 
6.3.1 
Efficacy variables ................................................................................................... 21 
6.4 
Safety ..................................................................................................................... 22 
6.4.1 
Definition of adverse events .................................................................................. 22 
6.4.2 
Definitions of serious adverse event ...................................................................... 22 
6.4.3 
Recording of adverse events .................................................................................. 22 
Reporting of serious adverse events ....................................................................................... 25 
6.4.4 
Laboratory safety assessment ................................................................................ 27 
6.4.5 
Physical examination ............................................................................................. 27 
6.4.6 
ECG ........................................................................................................................ 27 
6.4.6.1 
Resting 12-lead ECG ............................................................................................. 27 
6.4.6.2 
Real time monitoring ............................................................................................. 27 
6.4.7 
Vital signs .............................................................................................................. 27 
6.4.8 
Other safety assessments ........................................................................................ 27 
6.5 
Patient reported outcomes (PRO) .......................................................................... 27 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 27 
7.1 
Volume of blood .................................................................................................... 28 
7.2 
Handling, storage and destruction of biological samples ...................................... 28 
7.3 
Labeling and shipment of biohazard samples ........................................................ 28 
7.4 
Chain of custody of biological samples ................................................................. 28 
7.5 
Withdrawal of informed consent for donated biological samples ......................... 28 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 28 
8.1 
Ethical conduct of the study ................................................................................... 28 
8.2 
Ethics and regulatory review.................................................................................. 28 
8.3 
Informed consent ................................................................................................... 29 
8.4 
Changes to the protocol and informed consent form ............................................. 29 
8.5 
Audits and inspections ........................................................................................... 29 
9. 
STUDY MANAGEMENT .................................................................................... 29 
9.1 
Training of study site personnel ............................................................................. 29 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
4 
 
9.2 
Monitoring of the study ......................................................................................... 29 
9.2.1 
Source data ............................................................................................................. 29 
9.3 
Study timetable and end of study ........................................................................... 30 
10. 
DATA MANAGEMENT ....................................................................................... 30 
11. 
EVALUATION AND CALCULATION OF VARIABLES ................................. 31 
11.1 
Calculation or derivation of efficacy variable(s) ................................................... 31 
11.2 
Calculation or derivation of safety variable(s) ....................................................... 31 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 32 
12.1 
Description of analysis sets .................................................................................... 32 
12.1.1 
Efficacy analysis set ............................................................................................... 32 
12.1.2 
Safety analysis set .................................................................................................. 32 
12.2 
Methods of statistical analyses ............................................................................... 32 
12.2.1 
Interim analyses ..................................................................................................... 33 
12.3 
Determination of sample size ................................................................................. 33 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 33 
13.1 
Overdose ................................................................................................................ 33 
13.2 
Pregnancy ............................................................................................................... 34 
14. 
LIST OF REFERENCES ....................................................................................... 34 
 
LIST OF TABLES 
Table 1 
 
page 15 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
5 
 
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 
CAD 
Coronary Artery Disease 
CNT2/3 
Concentrative Nucleoside Transporters 
CRUSADE 
Can Rapid risk stratiﬁcation of Unstable angina patients Suppress 
ADverse outcomes with Early implementation of the ACC/AHA 
guidelines 
EMA 
European Medicines Agency 
ENT 1/2 
Equilibrative Nucleoside Transporters  
ESC 
European Society of Cardiology 
GCP 
Good Clinical Practice 
IPC 
Ischemic Preconditioning 
I/R 
Ischemia/ Reperfusion  
MI 
Myocardial Infarction 
NSTE-ACS 
non ST-segment elevation Acute Coronary Syndrome 
 PCI 
Percutaneous Coronary Intervention 
PMI 
Periprocedural Myocardial Injury  
RIPC 
Remote Ischemic Preconditioning  
STEMI 
ST-segment elevation MI  
 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
6 
 
1. 
INTRODUCTION 
1.1 
Background 
Remote Ischemic Preconditioning in PCI 
Even though technical advances in percutaneous coronary intervention (PCI), over the past 
two decades, have resulted in a safe procedure with minimal complications, in several patients 
the procedure is complicated by peri-procedural injury, detected by elevated values of 
biomarkers of myocardial necrosis. According to the biomarker used, the incidence of peri-
procedural myocardial injury in elective procedures ranges between 20% and 45%, with 
widespread adoption of troponin tests allowing detection of smaller amounts of necrosis.1, 2 
Peri-procedural cardiac troponin elevation has been associated with new irreversible 
myocardial injury, detected by delayed-enhancement magnetic resonance imaging,3 and even 
though the prognostic significance of peri-procedural CK-MB and cardiac troponin elevation 
has been highly debated, several studies have reported that peri-procedural injury is associated 
with worst prognosis.4, 5  
Peri-procedural myocardial injury may be categorized according to its pathogenesis into two 
types.2 Type 1 or proximal type of peri-procedural myocardial injury is mainly attributed to 
side branch occlusion during balloon inflation or stent deployment. Side branch occlusion, 
occurring in 12.5-19% of cases, is mainly caused by plaque shift, thrombus formation, or 
dissection at the takeoff of the side branch. Type 2 or distal type of peri-procedural 
myocardial injury, which accounts for 50-75% of all cases, results from distal embolism of 
atheromatous material, platelet activation and thrombosis precipitating microvascular 
plugging, neurohormonal activation and modulation of vascular and myocardial functions, and 
oxidative stress with inflammation. 
If peri-procedural injury incidence could be attenuated, then clinical outcomes of stable CAD 
following PCI may be expected to improve. One approach to reducing myocardial injury is 
through cardioprotective intervention.2 Conditioning the myocardium to protect against 
procedural ischemia/ reperfusion (I/R) injury is such an intervention used in both the 
experimental and clinical setting.6 Conditioning refers to an intrinsic myocardial mechanism 
of cardioprotection triggered by inducing brief, sub-lethal episodes of ischemia and 
reperfusion.6 Conditioning can be defined according to the temporal relationship between the 
conditioning intervention and onset of the ischemic insult - conditioning before the sustained 
insult is preconditioning, conditioning during the sustained insult is perconditioning, whilst 
conditioning after the sustained insult is postconditioning.7 Furthermore, preconditioning of 
the myocardium can be achieved from a remote organ, via a non-invasive approach.7 Here, 
focus is on remote ischemic preconditioning (RIPC) and its potential effect to reduce 
myocardial I/R injury induced during PCI, thus improving clinical outcomes of elective PCI. 
Mechanism of preconditioning and the role of adenosine 
The mechanism behind the protective effects of RIPC in the setting of PCI has been recently 
reviewed by our group.8  Mechanistically, preconditioning is best considered in terms of 
triggers, mediators, and effectors.6, 9 The activators of the preconditioning cascade are termed 
“triggers” and are broadly extracellular receptor/ligand interactions with autocoid, endocrine 
or paracrine signaling molecules. The ischemic conditioning signal is a summation of signals 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
7 
 
derived from multiple disparate receptor/ligand interactions, which reaches a threshold once 
sufficient combined signals are generated.6, 9 
Among the most well-established preconditioning triggers, are adenosine, bradykinin and 
opioids. Adenosine is thought to be crucial in initiating the preconditioning cascade.10 
Activation of the G-coupled adenosine A1 receptor triggers IPC protection, whereas 
adenosine receptor antagonists can block IPC protection.11 In a similar manner, bradykinin 
infusion induces cardioprotection which can be abolished by bradykinin receptor blockers.12 
Adenosine is a purine nucleoside produced primarily through the metabolism of ADP, and  its 
plasma levels increase after cellular stresses such as injury, ischemia/reperfusion, or 
inflammation.13 Adenosine is rapidly taken up by cells through sodium-independent 
equilibrative nucleoside transporters (ENT 1/2) and sodium-dependent concentrative 
nucleoside transporters (CNT 2/3).14  
Intracellular adenosine is metabolized to inosine by adenosine deaminase or transformed into 
adenine nucleotides by adenosine kinase.15 Because of its rapid cellular uptake and 
metabolism, extracellular adenosine has a half-life of a few seconds, which can be prolonged 
by inhibition of its transport into cells.16 
Several studies provide evidence that ticagrelor inhibits cellular uptake of adenosine.14, 17, 18 
Ticagrelor inhibited adenosine uptake by washed human erythrocytes and by human, dog, and 
rat cell lines. Considering that the experiments were performed under sodium-free conditions 
and with cell lines that express ENT1 but not ENT2, it was assumed that ticagrelor inhibits 
sodium-independent ENT1.17 The identity of the target transporter was recently confirmed 
with cells transfected with human transporters (ENT1, ENT2,CNT2, and CNT3). In these 
experiments, ticagrelor significantly inhibited adenosine uptake only in cells that expressed 
ENT1 .14 
 
1.2 
Research hypothesis 
We will study the effect of ticagrelor on the reduction of PMI and the incidence of post-PCI 
MI with the use of RIPC. Our primary research hypothesis is that treatment with ticagrelor 
will potentiate the effects of RIPC and, therefore, reduce PMI, as assessed by post-procedural 
troponin release. 
 
1.3 
Rationale for conducting this study 
Our research group has significant experience in utilizing RIPC for the prevention of 
periprocedural myocardial injury (PMI) in the setting of PCI.8 We have recently demonstrated 
in a randomized clinical trial that RIPC can effectively reduce PMI and post-PCI myocardial 
infarction in the setting of ad hoc PCI for stable coronary artery disease.19 Furthermore, we 
have recently published a meta-analysis, providing compelling evidence for the beneficial 
effects of RIPC in the setting of elective PCI.20. 
In this setting we have designed a randomized clinical trial to assess the effect of ticagrelor on 
the reduction of PMI and the incidence of post-PCI MI with the use of RIPC. 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
8 
 
 
1.4 
Benefit/risk and ethical assessment 
Peri-procedural cardiac troponin elevation has been associated with new irreversible 
myocardial injury and several studies have reported that peri-procedural injury is associated 
with worst prognosis. According to the available evidence, the prognostic significance of PMI 
is more pronounced when pre-procedural troponin is increased, i.e. in the setting of acute 
coronary syndromes. Data from the Cardiac Remote Ischemic Preconditioning in Coronary 
Stenting (CRISP Stent) study support that implementation of a RIPC protocol during PCI may 
reduce major adverse cardiovascular events during long-term follow-up and that post-
procedural troponin I concentration associated with the development of major adverse 
cardiovascular events.21 If this protective effect is potentiated with treatment with ticagrelor, 
patients are expected to further benefit. 
Ticagrelor has been shown to reduce significantly the rate of death from vascular causes, 
myocardial infarction, or stroke in patients with an acute coronary syndrome (ACS) with or 
without ST-segment elevation, compared to clopidogrel. These benefits were obtained without 
an increase in the rate of overall major bleeding but with an increase in the rate of non-
procedure-related bleeding.22 Accordingly, treatment with ticagrelor in patients undergoing 
PCI for non ST-segment elevation ACS (NSTE-ACS) or ST-segment elevation MI (STEMI) 
has been approved by the European Medicines Agency (EMA) and carries a Class I level of 
evidence B recommendation from the European Society of Cardiology (ESC)23 
Even though ticagrelor has not received approval in patients with stable CAD, several clinical 
trials have assessed its pharmacodynamic and pharmacokinetic effects in comparison with 
clopidogrel in this patient population, proving superior efficacy in platelet inhibition with a 
safety profile consistent with previous studies.24,25,26,27     
In treating patients with stable CAD with a more potent antiplatelet drug, lies a risk of 
increased bleeding, even though according to previous studies this is expected to be minor and 
non-life threatening (PLATO).22 To minimize patient risk, patients with a CRUSADE [Can 
Rapid risk stratiﬁcation of Unstable angina patients Suppress ADverse outcomes with Early 
implementation of the ACC/AHA guidelines] bleeding risk score >50 will be excluded from 
the study. Furthermore, duration of ticagrelor treatment will be kept minimal (1 month). 
Furthermore, since use of ticagrelor is not recommended as part of initial triple 
anticoagulation therapy, patients with an indication for oral anticoagulation will also be 
excluded. 
Finally, even though all efficacy endpoints of the present study are to be evaluated at 24 hours 
following PCI, it is considered in the subjects’ interest to continue study treatment for a period 
of a month, during which period all enrolled subjects will be monitored for the safety end-
point and other adverse events. This is a result of a lack of available evidence to support 
switching from a more potent to a less potent antiplatelet drug within 24 hours of PCI, and a 
paucity of studies regarding the optimal clopidogrel loading dose when switching from 
ticagrelor to clopidogrel.27 Furthermore, receiving a loading dose of ticagrelor and within 24 
hours a loading dose of clopidogrel combined with peri-procedural anticoagulation, may 
significantly increase bleeding risk.  

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
9 
 
 
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
The primary objective of this study is to demonstrate superior efficacy of a combination of 
ticagrelor and RIPC in the reduction of PMI compared to a clopidogrel-RIPC combination or 
ticagrelor alone, by evaluating post-procedural cardiac Troponin I (cTnI) levels, defined as 
cTnI at 24 hours post-PCI. 
 
2.2 
Secondary objectives 
Evaluation of chest pain during coronary balloon occlusion. Chest pain severity assessed with 
a numerical 10 point scale (0: no pain, 10: most severe discomfort ever experienced) 
Evaluation of ECG evidence of ischemia during coronary balloon occlusion.  ST-segment 
deviation as monitored during coronary balloon occlusion. 
 
2.3 
Safety objective 
Safety monitoring will be performed daily during the index hospitalization. The presence of 
adverse events will be assessed by history, detailed physical examination and appropriate 
laboratory tests that will be described in the protocol accordingly. 
In addition patients will be instructed to contact the study personnel in case of any emergency 
situation whereas an adverse event reporting system will be available throughout the study. 
In detail, bleeding according to the Thrombolysis in Myocardial Infarction (TIMI) bleeding 
criteria will be recorded and assessed throughout study duration. According to these criteria 
bleeding is defined as follows: 
Non-CABG Related Bleeding: 
1. Major 
• 
Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on 
gradient-echo MRI) 
• 
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL 
or a ≥15% absolute decrease in haematocrit 
• 
Fatal bleeding (bleeding that directly results in death within 7 d) 
2. Minor 
• 
Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL or 
≥10% decrease in haematocrit 
• 
No observed blood loss: ≥4 g/dL decrease in the haemoglobin concentration or ≥12% 
decrease in haematocrit 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
10 
 
• 
Any overt sign of hemorrhage that meets one of the following criteria and does not 
meet criteria for a major or minor bleeding event, as defined above 
• 
Requiring intervention (medical practitioner-guided medical or surgical treatment to 
stop or treat bleeding, including temporarily or permanently discontinuing or changing 
the dose of a medication or study drug) 
• 
Leading to or prolonging hospitalization 
• 
Prompting evaluation (leading to an unscheduled visit to a healthcare professional and 
diagnostic testing, either laboratory or imaging) 
3. Minimal 
• 
Any overt bleeding event that does not meet the criteria above 
• 
Any clinically overt sign of haemorrhage (including imaging) associated with a <3 
g/dL decrease in haemoglobin concentration or <9% decrease in haematocrit 
Bleeding in the Setting of CABG: 
• 
Fatal bleeding (bleeding that directly results in death) 
• 
Perioperative intracranial bleeding 
• 
Reoperation after closure of the sternotomy incision for the purpose of controlling 
bleeding 
• 
Transfusion of ≥5 U PRBCs or whole blood within a 48-h period; cell saver 
transfusion will not be counted in calculations of blood products. 
• 
Chest tube output >2 L within a 24-h period 
 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
The TRIP study will be a randomized, assessor-blind, active comparator-controlled, clinical 
trial using a 2×2 factorial design, with 1:1 patient allocation to ticagrelor or clopidogrel and 
within each treatment a 1:1 allocation to RIPC or control. 
According to the study plan, patients who are referred for coronary angiography or NSTE-
ACS may be screened for randomization. 
 
Day 1/ 
Screening 
Day 2 
Day 3 
Day 30 (±5days) 
Informed 
consent form 
x 
 
 
 
Inclusion criteria 
x 
 
 
 
Exclusion 
criteria 
x 
x 
x 
 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
11 
 
Medical history 
x 
 
 
x 
Concomitant 
disease 
x 
 
 
x 
Concomitant 
medication 
x 
x 
x 
x 
Physical 
examination 
(vital signs) 
x 
x 
x 
x 
ECG 
x 
x 
 
 
Local laboratory 
values 
x 
x 
x 
 
Randomization 
x 
x 
 
 
Treatment 
initiation 
x 
 
 
 
RIPC 
 
x 
 
 
Coronary 
angiography 
assessment 
 
x 
 
 
PCI 
 
x 
 
 
 
Day 1 of the study is defined as the day of randomization to ticagrelor versus clopidogrel. This 
should be chosen by the investigator to be the day before the scheduled PCI procedure. 
Day 2 of the study is defined as the day of randomization to RIPC or control and subsequent 
(within 1 hour) coronary angiography and PCI. 
In patients already treated with clopidogrel for 3 to 7 days, actions performed on Day 1 and 
Day 2 may be combined into a single day provided that; 
a. Twenty four hours have elapsed between the last dose of clopidogrel and the 
randomization to the ticagrelor or clopidogrel group, and 
b. There is sufficient time (2-4 hours) between the randomization and subsequent 
intake of clopidogrel or ticagrelor and the 2nd randomization to the RIPC or 
control group. 
If for unforeseen reasons, PCI is not conducted within the prespecified timeframe the patient 
should be withdrawn from the study. 
 
 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
12 
 
Patient with stable or NSTE-ACS and a decision for coronary angiography 
Evaluation for eligibility in the study (inclusion/exclusion criteria) 
Randomization procedure [1:1 allocation to ticagrelor or clopidogrel] 
Ticagrelor Group 
Initiation of ticagrelor (180 mg loading dose) 1 
day before the procedure. (2nd dose preferably 2-3 
hours before procedure) * 
Clopidogrel Group 
Initiation of clopidogrel (300 mg loading dose) 1 
day before the procedure. (2nd dose 75 mg at the 
procedure). ** 
Ticagrelor Group 
(Within 1 hour before the procedure) 
Baseline cTnI sampling. 
Randomization procedure [1:1 allocation to RIPC 
or control] 
Ticagrelor + 
Control 
 
BP cuff uninflated 
around the non-
dominant arm 
(sham) 
 
(24 hours after the 
procedure) 
Post-procedural 
cTnI determination 
Clopidogrel + RIPC 
3 cycles of 5min 
ischemia/ 5min 
reperfusion using a 
BP cuff at 200mmHg 
around the non-
dominant arm 
 
 
 
(24 hours after the 
procedure) 
Post-procedural cTnI 
determination 
Clopidogrel Group 
(Within 1 hour before the procedure) 
Baseline cTnI sampling. 
Randomization procedure [1:1 allocation to RIPC 
or control] 
Ticagrelor + RIPC 
3 cycles of 5min 
ischemia/ 5min 
reperfusion using a 
BP cuff at 
200mmHg around 
the non-dominant 
arm 
 
 
(24 hours after the 
procedure) 
Post-procedural 
cTnI determination 
Clopidogrel + 
Control 
 
BP cuff uninflated 
around the non-
dominant arm (sham) 
 
 
 
(24 hours after the 
procedure) 
Post-procedural cTnI 
determination 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
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* In case of a patient already on clopidogrel for 3-7 days, ticagrelor loading dose is 
administered on the day of the procedure (24 hours after the last clopidogrel dose), and no 2nd 
ticagrelor dose is administered. ** In case of a patient already on clopidogrel for 3-7 days, no 
loading dose of clopidogrel is administered, but the patient ideally receives 75mg clopidogrel 
2-3 hours before the procedure. 
3.2 
Rationale for study design, doses and control groups 
Patients allocated to RIPC will undergo a RIPC protocol within 60 minutes prior to PCI, 
according to previously established preconditioning protocols (CRISP stent study).21 
Antiplatelet doses in the ticagrelor and the control group are according to established practice 
guidelines ( ESC Guidelines for Revascularization 2014).23 
 
4. 
SUBJECT SELECTION CRITERIA 
A total number of 152 patients (38 patients of each group) will be recruited from patients with 
stable CAD or NSTE-ACS undergoing coronary angiography, eligible for PCI 
 
4.1 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Patients (Female and male)  ≥ 18 of age  
3. 
Patients with NSTE-ACS undergoing coronary angiography, eligible for PCI 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. Women of childbearing potential  
2. Severe comorbidity (estimated life expectancy <6 months) 
3. Baseline cTnI before PCI that is not stable or falling or is > 5 ×99th percentile URL. 
4. End-stage renal disease(eGFR<15 ml/min/1.73 m2) 
5. CRUSADE Bleeding Score >50 
6. Patients with an indication for oral anticoagulation 
7. On maintenance therapy with ticagrelor or those that have received clopidogrel for less 
than 3 days 
8. Use of nicorandil or glibenclamide 
9. Concomitant theophylline/aminophylline use 
I. 
Known contraindications to the use of ticagrelor Hypersensitivity to the active 
substance or to any of the excipients 
II. 
Active pathological bleeding 
III. 
History of intracranial haemorrhage 
IV. 
Moderate to severe hepatic impairment 
V. 
Co-administration of ticagrelor with strong CYP3A4 inhibitors (e.g., 
ketoconazole, clarithromycin, nefazodone, ritonavir, and atazanavir). 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
14 
 
5. 
STUDY CONDUCT 
5.1 
Subject enrollment, randomization, and initiation of investigational 
product 
According to the study protocol, patients who are referred for coronary angiography or NSTE-
ACS may be screened for randomization. Subjects meeting the inclusion and none of the 
exclusion criteria will be evaluated and their demographic, medical history and current clinical 
characteristics will be recorded.  
During the screening period the eligibility check and physical examination will be performed 
with assessment of vital signs (heart rate and blood pressure measurement). During the 
screening period obtained local laboratory results should be examined for exclusion criteria 
(eGFR, HAS-BLED score, cardiac troponin). The subject will then be informed about the 
study and will sign the Informed Consent Form. 
Day 1 of the study is defined as the day of randomization to ticagrelor versus clopidogrel. This 
should be chosen by the investigator to be the day before the scheduled PCI procedure.  
Day 2 of the study is defined as the day of randomization to RIPC or control and subsequent 
(within 1 hour) coronary angiography and PCI. 
In patients already treated with clopidogrel for 3 to 7 days, actions performed on Day 1 and 
Day 2 may be combined into a single day provided that; 
a. Twenty-four hours have elapsed between the last dose of clopidogrel and the 
randomization to the ticagrelor or clopidogrel group, and 
b. There is sufficient time (2-4 hours) between the randomization and subsequent 
intake of clopidogrel or ticagrelor and the 2nd randomization to the RIPC or 
control group. 
In these case patients are 1:1 randomized to ticagrelor or clopidogrel, and undergo the 
second randomization within 2-4 hours 
If for unforeseen reasons, PCI is not conducted within the prespecified timeframe the patient 
should be withdrawn from the study. 
5.1.1 
Procedures for randomization 
The TRIP study will be a randomized, assessor-blind, active comparator-controlled, clinical 
trial using a 2×2 factorial design, with 1:1 patient allocation to ticagrelor or clopidogrel and 
within each treatment a 1:1 allocation to RIPC or control. Patient randomization in the 
ticagrelor and the clopidogrel group will take place using sealed, opaque envelopes containing 
a computer-generated randomization scheme. Using a similar procedure, patients will be 
randomly assigned to RIPC or no RIPC within 1 hour before the procedure. 
 

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Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
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5.2 
Procedures for handling subjects incorrectly enrolled or 
randomized or initiated on investigational product 
Subjects who fail to meet the inclusion and exclusion criteria are defined as screening failures. 
The investigator will maintain a Screening Log which includes screen failures.  The log will 
document the subject number, subject initials, demographics and the reason(s) for excluding 
the patient from the study.  This log will be kept in the Investigator's Study File.  It will be 
used to determine systematic bias in selection of patients for entry into the study. 
Subjects who withdraw or are withdrawn from the study following randomization, before 
investigational product initiation should: 
• Have the reason(s) for their withdrawal recorded 
Subjects who withdraw or are withdrawn from the study following randomization and 
investigational product initiation should:  
• Have the reason(s) for their withdrawal recorded  
• Be asked about the presence of any AEs and if so should be followed up by regular 
scheduled visits, telephone contact, correspondence or home visits until satisfactory 
clinical resolution of AEs is achieved.  
• Be seen by an investigator and all final assessments will be performed and recorded in 
the termination page of CRF.  
• Have at least one follow-up contact for safety evaluation during the 30 days following 
the last dose of study treatment.  
• In the event of pregnancy, the subject should be monitored until conclusion of the 
pregnancy and the outcome of pregnancy reported. 
• Have study treatment returned (according to accountability practices) 
5.3 
Blinding and procedures for unblinding the study 
The TRIP study will be an open label study with a blinded assessor. Accordingly, two 
investigators unaware of the patients’ allocation will assess outcomes. In detail, each study 
patient will have a post-procedural cTnI measurement and a pain measurement not amenable 
to assessment; however the ST-segment deviation will be decided by two blinded expert 
investigators. In the event of discrepant assessments, final outcome will be defined by 
consensus between the two assessors. 
5.4 
Treatments 
5.4.1 
Identity of investigational product(s) 
 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor 
90 mg film coated tablet – BID 
AstraZeneca 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
16 
 
Clopidogrel 
75 mg film coated tablet – QD 
To be defined (PIs decide which 
clopidogrel will be used) 
 
300 mg film coated tablet – QD 
 
 
Ticagrelor 
Chemical name (IUPAC): (1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-
(3,4Difluorophenyl)cyclopropyl]amino}-5-(propylthio)3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-
yl]-5-(2hydroxyethoxy)cyclopentane-1,2-diol Laboratory code: AZD6140 (previously AR-
C126532XX)  
 Chemical structure  
Ticagrelor has 6 asymmetric carbon atoms, all of which are prepared by synthesis.  All 
stereocentres are introduced by stereo-selective chemistry early in the synthetic pathway 
where correct configuration is established.  
Molecular formula:    C23H28F2N6O4S 
Relative molecular mass:  522.57 
Partition coefficient, log P (octanol/water):  >4.0  
General properties  
Ticagrelor is a crystalline powder with an aqueous solubility of approximately 10 μg/mL at 
room temperature.  During routine manufacture solid ticagrelor is only isolated as a single 
polymorph, which has been used in all toxicological and clinical studies to date. 
 Drug product 
Presentation 
 Ticagrelor will be provided as Brilique tablets. The drug product is a conventional immediate 
release (IR) tablet for oral use.  One tablet strength will be available:90 mg tablets - presented 
as round, biconvex, yellow, film coated tablets 
Composition 
The composition of the ticagrelor tablet core is ticagrelor, mannitol, dibasic calcium 
phosphate, sodium starch glycolate, hydroxypropyl cellulose, and magnesium stearate. The 
composition of the tablet coating is: hydroxypropyl methylcellulose, titanium dioxide, talc, 
polyethylene glycol 400, and iron oxide yellow (45 mg and 90 mg tablet strengths); and 
hydroxypropyl methylcellulose, titanium dioxide, talc and polyethylene glycol 400 (60 mg 
tablet strength). 
Clopidogrel 
Clopidogrel is a thienopyridine class inhibitor of P2Y₁₂ ADP platelet receptors. Chemically it 
is methyl (+)-(S)--(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H) acetate sulfate 
(1:1). The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and its 
molecular weight is 419.9. 

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Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
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Clopidogrel will be provided as Plavix 75mg tablets or equivalent according to local 
availability.  
 
5.4.2 
Doses and treatment regimens 
For the ticagrelor group: loading dose 180 mg ticagrelor (2×90mg tablets). Thereafter, 90mg 
(1 tablet) b.i.d. At the end of the study period, treatment should be continued according to the 
prescription of the investigator and the attending physician. 
For the clopidogrel group: Patients not on clopidogrel - loading dose 300 mg clopidogrel 
(4×75mg tablets). At the time of PCI an additional 75 mg dose. Thereafter, 75mg o.d. Patients 
already on clopidogrel – continuation of maintenance dose. At the end of the study period, 
treatment should be continued according to the prescription of the investigator and the 
attending physician. 
5.4.3 
Additional study drug 
Ticagrelor or clopidogrel will be given as part of dual antiplatelet treatment in combination 
with aspirin at an initial loading dose of 150-300mg (according to primary investigator 
preference) and 100mg maintenance dose thereafter. 
5.4.4 
Labeling 
Packaging and labelling procedures for the study medication will be followed according to the 
local regulatory requirements and regulations for interventional studies. 
5.4.5 
Storage 
The product should be stored in the pack provided and used according to the instructions on 
the label. 
5.5 
Concomitant and post-study treatment(s) 
All medications taken by the patient during the treatment period in addition to the study 
medication, are termed concomitant medication. All concomitant medication taken during the 
treatment period of the study will be documented on the case report form (trade name, start 
and stop date and daily dose). Concomitant medication must also be recorded in the patient’s 
records. All prior medications administered within 1 week of enrolment into the study must be 
documented on the case report form. 
5.6 
Treatment compliance 
Inpatient administration will be documented (date, time, dose, and signature of dispensing 
person). A patient diary will be used to document outpatient administration. Drug 
accountability of the unused study medication will be performed. The treatment compliance 
should be between 80% and 120%. 
5.6.1 
Accountability 
Each patient will be dispensed sufficient medication for one month of therapy. Upon 
dispensation, the investigator must write the following in the Investigational Product 
Dispensing Log: subject ID and initials and date dispensed, the total dose given 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
18 
 
weekly/monthly and frequency of dosage, total bottles dispensed, batch number and expiry 
date of product. 
The investigator or designee must maintain current and accurate record of the receipt, 
inventory and dispensing, including shipping invoices, of all study supplies. The 
Investigational Product Accountability Log must include:  
• Date received  
• Delivery order (D.O.#) reference number and amount received and placed in storage 
• Name of study medication and dosage 
• Amount currently in storage area 
• Label ID number or batch number/Lot number 
• Name and initial of person responsible for each investigational product inventory 
entry/movement 
• Amount dispensed to and returned by each subject, including unique subject identifiers 
• Amount transferred to another area for dispensing or storage 
• Non-study disposition (eg. Lost, wasted, broken) 
• Amount returned to sponsor 
• Amount destroyed at study site ID number or batch number/Lot number 
 
5.7 
Discontinuation of investigational product 
Patients who require discontinuation of ticagrelor are at increased risk for cardiac events.  
Premature discontinuation of treatment should be avoided.  If ticagrelor must be temporarily 
stopped due to an adverse event(s), it should be re-initiated as soon as possible when the 
benefits outweigh the risks of the adverse event or when the adverse event has come to 
resolution. 
5.7.1 
Procedures for discontinuation of a subject from investigational product  
Patients who require discontinuation of ticagrelor should receive dual antiplatelet treatment 
for a period, which is defined by disease presentation (stable CAD or NSTE-ACS) and type of 
stent (or stents) used during PCI. The investigator and the subjects’ physicians should base the 
decision for ticagrelor discontinuation, switch to clopidogrel, and required loading doses on 
relevant clinical practice guidelines and established local clinical practice.23 
Subjects who discontinue the investigational product should:  
• Have the reason(s) for discontinuation recorded  
• Be asked about the presence of any AEs and if so should be followed up by regular 
scheduled visits, telephone contact, correspondence or home visits until satisfactory 
clinical resolution of AEs is achieved.  

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
19 
 
• Be seen by an investigator and all final assessments will be performed and recorded in 
the termination page of CRF.  
• Have at least one follow-up contact for safety evaluation during the 30 days following 
the last dose of study treatment.  
• In the event of pregnancy, the subject should be monitored until conclusion of the 
pregnancy and the outcome of pregnancy reported. 
• Have study treatment returned (following previously described accountability 
practices) 
5.8 
Withdrawal from study 
 Subjects have the right to withdraw from the study at any time for any reason, including 
personal reasons.  The Investigator also has the right to withdraw subjects from the study in 
the event of:  
• An adverse event which is considered intolerable by the subject or the Investigator and 
to interfere with the continuation of the survey or the subject evaluation. 
• An abnormal laboratory test result which is considered clinically significant by the 
Investigator and possibly interfering with the continuation of the survey or the subject 
evaluation.  
• The development of an exclusion criterion.   
It is understood by all concerned Investigators that an excessive rate of withdrawals can 
render the study uninterpretable; therefore, unnecessary withdrawals of subjects should be 
avoided.  
However, should a subject definitely decide to withdraw, all efforts will be made by the 
Investigator to complete and report the final observations as thoroughly as possible. A 
complete final evaluation at the time of the withdrawal will be performed with an explanation 
of the exact reason why the subject is withdrawing from the study in the “Study Completion 
Summary” of the CRF.  
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
Data collection and recording will be performed through paper case report forms (pCRFs) that 
will be provided by the Sponsor to the participating site for each subject separately. The use of 
a waterproof ballpoint black pen is recommended for the record of data on the pCRF. The 
investigator should record all relevant data in the appropriate CRF and should ensure the 
accuracy, completeness, legibility and timeliness of the data reported to the sponsor in the 
CRFs and in all required reports. Accurate and reliable data collection will be assured by 
verification and cross-check of 100% of the CRFs against the investigator's records (source 
document verification). 
6.2 
Data collection at enrolment and follow-up 
Screening (in most cases expected to be the same day with first randomization-Day1) 

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Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
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During this period the investigator will evaluate and record 
• Indication for coronary angiography or PCI (stable CAD, NSTE-ACS) 
• Demographics (age, gender, height, weight, body mass index) 
• History of risk factors for cardiovascular disease (Diabetes mellitus, dyslipidemia, 
hypertension, smoking) 
• Medical history including history of previous MI, previous PCI, previous CABG, New 
York Heart Association Class, Canadian Cardiology Society Angina Class 
• Prior and concomitant medication 
• Physical examination with vital signs (heart rate, blood pressure) 
• Electrocardiogram 
• Local laboratory values (hemoglobin, complete blood count including platelet count, 
serum creatinine, AST, ALT, INR, cardiac Troponin I) 
Day 2 - Pre-procedural assessment 
• Physical examination with vital signs (heart rate, blood pressure). At this time signs 
and symptoms of bleeding should be specifically examined. 
•  Local laboratory values (hemoglobin, complete blood count including platelet count, 
serum creatinine, AST, ALT, INR, cardiac Troponin I) 
In the case of patients already on clopidogrel there will be one combined assessment for 
screening and pre-procedurally. 
Day 2 - Preconditioning 
• The timing of the last cycle of RIPC in relation to subsequent PCI should be 
specifically recorded 
Day 2 - Peri-procedural 
• Angiographic parameters (number of diseased vessels, target vessel, jeopardy score, 
rentrop score, American heart association lesion type, stenosis severity, acute gain, 
timi flow score) 
• Procedural parameters (access site, stent length, type of stent used, screen time, 
radiation dose, contrast dose, number of predilations, predilation time, number of 
postdilations, postdilation time) 
• Complications (jailed side branch, dissection) 
• ST-segment deviation during balloon occlusion will be monitored as a secondary 
efficacy variable. It will be defined as the absolute value of ST-segment deviation at 
60-80ms after the J-point in mm at the beginning of coronary angiography minus ST-
segment deviation at 60-80ms after the J-point in mm during balloon occlusion. 
Day 2 - Post-procedural 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
21 
 
• Physical examination with vital signs (heart rate, blood pressure). At this time signs 
and symptoms of access site bleeding should be specifically examined. 
• Electrocardiogram 
• Chest pain during PCI will be assessed during the post-PCI clinical examination of the 
subject by the investigator or by an appropriately qualified person to whom the 
investigator has delegated this duty. A numerical 10 point scale will be used (0: no 
pain, 10: most severe discomfort ever experienced) 
Day 3  
• Physical examination with vital signs (heart rate, blood pressure). At this time signs 
and symptoms of access site bleeding should be specifically examined. 
• Local laboratory values, i.e. hemoglobin, complete blood count including platelet 
count, serum creatinine, AST, ALT, INR, and Cardiac troponin I at 24 hours post-PCI 
Day 4-day 29 (Follow-up) 
• Physical examination with vital signs (heart rate, blood pressure), while admitted in 
the hospital. After discharge the patiens will be instructed to inform the investigator 
for potential adverse events. 
Day 30 Follow-up visit 
• Physical examination with vital signs (heart rate, blood pressure). Signs and symptoms 
of bleeding should be specifically examined. 
6.3 
Efficacy 
6.3.1 
Efficacy variables 
The primary efficacy variable, cardiac troponin I at 24 hours post-PCI will be determined 
according to local standard clinical practice. In detail, cTnI will be analyzed with an 
automated immunoassay (Bayer ADVIA IMS Troponin-I Ultra method, Bayer, Berlin, 
Germany). The 99th percentile of the cTnI level in a reference population (upper reference, 
limit, URL) of healthy volunteers was below the lower limit of detection of 0.04 ng/mL. The 
coefficient of variation (CV) of the assay was <10%, complying with the recommendations of 
the European Society of Cardiology (ESC)/ American College of Cardiology (ACC)/ 
American Heart Association (AHA) for optimal precision. The analytical range was 0.01 to 
50ng/mL, with an assay sensitivity of 0.006 ng/mL. 
Chest pain during PCI is a secondary efficacy variable. It will be assessed during the post-PCI 
clinical examination of the subject by the investigator or by an appropriately qualified person 
to whom the investigator has delegated this duty. An analog 10 point scale will be used (0: no 
pain, 10: most severe discomfort ever experienced). 
ST-segment deviation during balloon occlusion will be monitored as a secondary efficacy 
variable. It will be defined as the absolute value of ST-segment deviation at 60-80ms after the 
J-point in mm at the beginning of coronary angiography minus ST-segment deviation at 60-
80ms after the J-point in mm during balloon occlusion.  

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
22 
 
 
6.4 
Safety 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.4.1 
Definition of adverse events  
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, tachycardia, enlarged liver, or an abnormal laboratory finding), symptom (eg, nausea, 
chest pain), or disease temporally associated with the use of a study drug, whether or not 
considered related to the study drug. In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including run-in or washout periods, even if no study 
treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.4.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect 
• 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
Adverse Events will be collected from the time of signature of informed consent throughout 
the study treatment period (including the 30-day follow-up period post-PCI), up to 30 days 
after randomization. 
SAEs will be recorded from the time of informed consent and up to 30 days after 
randomization. 
Follow-up of unresolved adverse events 

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Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
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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 
CRF. Sponsor or its designee 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; 
1. AE (verbatim) 
2. The date and time when the AE started and stopped 
3. Severity  
Note: the following severity rating scale will be used: 
- mild (awareness of sign or symptom, but easily tolerated for outpatients, and 
awareness of sign or symptom, but easily tolerated for in-patients) 
- moderate (discomfort sufficient to cause interference with normal activities for 
outpatients, and disturbing but still tolerable for in-patients) 
- severe (incapacitating, with inability to perform normal activities for outpatients, and 
intolerable for outpatients) 
4. Whether the AE is serious or not 
5. Investigator causality rating against the Investigational Product (not related, possible,  or 
probable) 
6. Action taken with regard to investigational product(s) 
7. AE caused subject’s withdrawal from study (yes or no) 
8. Outcome. 
In addition, the following variables will be collected for SAEs: 
1. Date AE met criteria for serious AE 
2. Date Investigator became aware of serious AE 
3. AE is serious due to 
4. Date of hospitalisation 
5. Date of discharge 
6. Probable cause of death 
7. Date of death 
8. Autopsy performed 
9. Causality assessment in relation to Study procedure(s) 
10.Causality assessment in relation to Other medication 
11.Description of AE. 

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Edition Number <<2>> 
Date <<11 01 2017>> 
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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
The Sponsor or its designee will classify events using Medical Dictionary for Regulatory 
Activities (MedDRA). 
Causality collection 
The Investigator will assess causal relationship between Investigational Product and each 
Adverse Event, 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’. 
 
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 you were last 
asked?>> or revealed by observation will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms.  However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
Adverse Events based on examinations and tests 
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values and 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. 
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. 

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Edition Number <<2>> 
Date <<11 01 2017>> 
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Disease progression or worsening of pre-existing conditions 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease (i.e., STEMI) for which the investigational product is being studied.   
It may be an increase in the severity of the disease under study and/or increases in the 
symptoms of the disease.  The development of ischaemia and symptoms of coronary artery 
disease, artery disorders, cardiac failure, pericardium disorders, arrhythmias and other MI-
related cardiac symptoms/disorders should be considered as disease progression and not an 
AE.  
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 
Worsening of the disease under study will be recorded as an AE only if one of the following 
criteria is met: 
− 
Worsening of disease meets the criteria for an SAE. 
− 
Action is taken with investigational drug, i.e. dose is reduced or treatment 
discontinued or increased. 
− 
Concomitant medication is added or changed. 
− 
The investigator believes a subject has shown a clear, unexpected deterioration from 
baseline symptoms. 
The same criteria as above apply for the recording of AEs that result from worsening of other 
pre-existing diseases/conditions.  In particular, the following will not qualify for recording as 
an AE: 
− 
Pre-existing conditions present at baseline, which remain unchanged during the study. 
− 
Expected fluctuations or expected deterioration of a pre-existing disease/condition. 
 
Reporting of serious adverse events  
The Sponsor and Principal Investigator are responsible for meeting all local regulatory 
requirements and obligations. 
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 on the SAE page as well as 
on the relevant AE module of the pCRF. 
If any SAE occurs in the course of the study, then Investigator or other site personnel should 
inform the Sponsor or its designee immediately, or no later than 24 hours from awareness of 
the event. 
The Sponsor or its designee will work with the Investigator to ensure that all the necessary 
information is provided to the Safety database, as appropriate. 
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigator or other site personnel should inform 

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Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
26 
 
the Sponsor or its designee of any follow-up information on a previously reported SAE 
immediately, or no later than 24 hours from awareness of the event. 
Investigator or other site personnel send relevant SAE form by fax or e-mail (scanned copies) 
to the Sponsor or its designee. 
The reference documents for definition of expectedness of an AE is the investigational 
products’ latest approved prescribing information (SmPCs).  
The Sponsor or its designee is responsible for reporting to the National Ethics Committee and 
the European Medicines Agency (EMA),  of the Serious Unexpected Suspected Adverse Drug 
Reactions (SUSARs) occurring in the study, including SUSARs associated with active 
comparator(s).  
SUSARs are forwarded electronically by the Sponsor or its designee to Receiver ID 
"EVCTMPROD" in the production environment of Eudravigilance.  
The reporting timelines are the following: 
• 
Fatal or life-threatening SUSARs: within 7 days of Sponsor's (or its designee) date of 
awareness   
• 
All other SUSARs within 15 days of Sponsor's (or its designee) date of awareness. 
 
Sponsor’s or its designee contact details are the following:  
Name of Responsible Person: Theodoros Zografos 
Address: Artemidos 8,Vari, Athens, Greece 
Tel.: +302108976005 
Mob.: +306956161001 
Fax: +302108976005 
E-mail: theodoroszografos@gmail.com 
The Sponsor or its designee or the Principal Investigator is required, to notify AstraZeneca of 
all SUSARs, as soon as possible and at least at the same time that the reports are sent to the 
Eudravigilance. Reports should be sent to AstraZeneca on a CIOMS form to the following e-
mail address: <AEMailboxClinicalTrialTCS@astrazeneca.com .     
In addition, the Principal Investigator must provide AstraZeneca with the same report of all 
other SAEs that did not qualify for expedited reporting at the same e-mail address and on an 
expedited basis. These reports must be submitted to AstraZeneca quarterly.  
The Sponsor or its designee when providing local periodic study reports to the local 
Regulatory Authority and any IRB/IEC updates shall at the same time forward a copy of such 
documentation to AstraZeneca. 
The Principal Investigator is responsible for reconciling the clinical data of the ISS on an 
ongoing basis to ensure that all new and updated information regarding SAEs has been sent to 
AstraZeneca either as individual expedited SUSARs or as part of a line listing.  

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Edition Number <<2>> 
Date <<11 01 2017>> 
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The Sponsor shall ensure that safety information provided by AstraZeneca is promptly 
distributed to local Regulatory Authority, National Ethics Committee and to any other 
Investigators participating in the ISS, in accordance with Applicable Laws and Regulations. 
6.4.4 
Laboratory safety assessment 
Daily tests for hemoglobin, complete blood count including platelet count, serum creatinine, 
AST, ALT, INR, cardiac Troponin I on Day 1, Day 2, and Day 3. 
For blood volume see Section 7.1. 
 
6.4.5 
Physical examination 
Daily physical examination will be performed on Day 1, Day2, Day 3 and until discharge. 
Final examination on day 30 (follow-up visit) 
6.4.6 
ECG 
6.4.6.1 
Resting 12-lead ECG 
On Day 1 and Day 2. Furthermore, whenever it is considered appropriate according to 
symptoms and physical findings. Particular inspection for bradycardia, conduction 
disturbances, ventricular pauses. 
6.4.6.2 
Real time monitoring 
Will be only applied during the coronary angiography and the PCI procedure, unless patient 
status dictates further monitoring or CCU admission, depending on the investicator’s 
judgement. 
6.4.7 
Vital signs 
Daily physical examination with vital signs (heart rate, blood pressure) will be performed on 
Day 1, Day2, Day 3 and until discharge. Final examination with vital signs (heart rate, blood 
pressure) on day 30 (follow-up visit) 
6.4.8 
Other safety assessments 
During physical examination after antiplatelet initiation and after PCI, physical examination 
will be specifically guided to include assessment of symptoms and signs indicative of general 
or access site bleeding 
6.5 
Patient reported outcomes (PRO) 
Chest pain severity during balloon occlusion at the time of PCI will be reported by the patients 
during the post-PCI assessment according a numerical 10 point scale (0: no pain, 10: most 
severe discomfort ever experienced) 
 
7. 
BIOLOGICAL SAMPLING PROCEDURES 
All laboratory parameters will be determined in a local laboratory according to standard 
clinical practice. No additional tests will be performed on the patients enrolled in the study, 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
28 
 
apart from the ones performed as standard clinical practice on patients with stable CAD or 
NSTE-ACS undergoing coronary angiography and PCI 
7.1 
Volume of blood 
According to local clinical practice, approximately 8 ml of blood will be drawn each time for 
laboratory testing  
7.2 
Handling, storage and destruction of biological samples 
All biological samples will be handled according to local standard clinical practice. No 
storage of biological samples will be performed. 
7.3 
Labeling and shipment of biohazard samples 
Not applicable. 
7.4 
Chain of custody of biological samples 
Not applicable. 
7.5 
Withdrawal of informed consent for donated biological samples 
Not applicable 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and 
documentation of this study, are designed to ensure that the Sponsor and investigator abide by 
Good Clinical Practice Guidelines and under the guiding principles detailed in the declaration 
of Helsinki. The study will also be carried out in keeping with applicable local laws and 
regulations. This may include an inspection by the Sponsor representatives and/or Regulatory 
Authority representatives at any time. The investigator must agree to the inspection of study-
related records by the Regulatory Authority/Sponsor representatives, and must allow direct 
access to source documents to the Regulatory Authority/ Sponsor representatives. 
Modifications to the study protocol will not be implemented by either the Sponsor or the 
investigator without agreement by both parties. However, the investigator may implement a 
deviation form, or a change of, the protocol to eliminate an immediate hazard to the trial 
subjects without prior EC/IRB/Sponsor approval/favorable opinion. As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the EC/IRB/Sponsor. Any deviations from the protocol 
must be fully explained and documented by the investigator. 
8.2 
Ethics and regulatory review 
Documented approval from appropriate EC(s)/IRBs will be obtained for all participating 
centers prior to study start, according to GCP, local laws, regulations, and organizations. 
When necessary, an extension, amendment, or renewal of the Ethics Committee approval must 
be obtained and also forwarded to the Sponsor. The Ethics Committees must supply to the 
Sponsor, upon request, a list of the Ethics Committee members involved in the vote and a 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
29 
 
statement to confirm that the Ethics Committee is organized and operates according to GCP 
and applicable laws and regulations. 
Regulatory Authority approvals/ authorizations/ notifications, where required, must be in 
place and fully documented prior to study start 
8.3 
Informed consent 
A core information and Informed Consent Form will be provided. Prior to the beginning of the 
study, the investigator must have the ECs/IRB written approval/ favorable opinion of the 
written Informed Consent Form (ICF) and any other written information to be provided to 
subjects. The written approval of the EC/ IRB together with the approved subject information/ 
ICFs together with the approved subject information/ICFs must be filed in the study files. 
Written informed consent must be obtained before any study specific procedure taked place. 
Participation in the study and date of informed consent given by the subject should be 
documented appropriately in the subject’s files. 
8.4 
Changes to the protocol and informed consent form 
No protocol, informed consent process, or informed consent document may be modified 
without prior approval from the IRB unless it is necessary to eliminate an apparent and 
immediate hazard to one or more of the participants.  Such modifications consist of revisions 
of or amendments to existing study documents. Any planned modification must be submitted 
to the IRB for review and approval before being implemented or used with participants 
8.5 
Audits and inspections 
Monitoring and auditing procedures defined/ agreed by the Sponsor will be followed, in order 
to comply with Good Clinical Practice (GCP) guidelines. The center will be visited at regular 
intervals by a monitor to ensure compliance with the study protocol, GCP and legal aspects. 
This will include on-site checking of the case report forms (CRF) for completeness and 
clarity, cross-checking with source documents, and clarification of administrative matters. 
9. 
STUDY MANAGEMENT 
9.1 
Training of study site personnel 
Investigators involved in this study must not enroll any patient prior to completion of a formal 
meeting conducted by the Clinical Research Associate designated by the Sponsor. This 
meeting will include an inventory of study supplies, a detailed review of the protocol and 
CRF, training on study procedures and other procedures required of GCP.  Investigators who 
are not GCP certified will undergo GCP training during the study. 
9.2 
Monitoring of the study 
9.2.1 
Source data 
The investigator must maintain adequate and accurate records to document the conduct of the 
study and substantiate the study data. These documents comprise Essential Documents Source 
Documents. Source documents are original hospital records, clinical charts, subject screening 
checklist, original laboratory reports, pharmacy dispensing records, recorded data from 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
30 
 
automated instruments, transcriptions certified after verification as being accurate, electronic 
media, subjects' files, and records kept at the pharmacy, at the laboratories and at medicolegal 
departments involved in the study.  
The investigator must maintain source documents for each patient in the study. All 
information on CRFs must be traceable to these source documents.  
9.3 
Study timetable and end of study 
Contract execution to IRB/EC Approval 
6 months 
IRB/EC approval to first subject In 
1 month 
First subject in to 50% enrollment  
6 months 
50% enrollment to last subject in  
6 months 
Last subject in to last subject last visit 
1 month 
Last subject last visit to completion of final 
study report 
3 months 
Last subject last visit to abstract submission 
4 months 
Last subject last visit to manuscript 
submission 
6 months 
 
10. 
DATA MANAGEMENT 
Data collection and recording will be performed through paper case report forms (pCRFs) that 
will be provided by the Sponsor to the participating site for each subject separately. The use of 
a waterproof ballpoint black pen is recommended for the record of data on the pCRF.  
The Principal Investigator must review the CRFs for completeness and accuracy and must 
sign and date the appropriate CRF page. All CRFs must be filled out legibly.  
Corrections to the data on the CRFs must only be made by drawing a straight line through the 
incorrect data and by writing the correct value/data next to the information that has been 
crossed out. Corrections must only be performed by the Principal Investigator or his qualified 
designees. Each correction must be initialed and dated by the Principal Investigator or his/her 
authorized staff.  
Erasures of incorrect data with the use of correction fluid or tape are not allowed. 
The monitor of the study will review and check all CRFs, for accuracy (including source data 
verification) and completeness and subsequently the Investigator shall correct all forms with  
missing information and/or incorrect entries. Every documentation inserted on the CRF, 
corrections and other changes shall be performed exclusively by the responsible Investigator 
or the authorized by the Investigator person.  
With the exception of the evident errors, all corrections must be accompanied with 
explanatory comments.  

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
31 
 
 
Clinical data will be managed by appropriate Data-management staff, who will be responsible 
for constructing a database containing all previously described data for the purpose of data 
analysis. The data-management staff will perform checks of data consistency and 
completeness. The data review will permit the generation of queries for the clarification of 
unclear/ missing/ inconsistent data. The errors found will be assessed by the Data Manager of 
the study and investigators will be involved in resolving them. All changes to the database 
will be recorded in an audit trail file. If a change is necessary once the investigator has no 
further access to the database, a query will be sent to the investigator for confirmation of the 
change. The investigator’s signature is requested to demonstrate approval of the change that 
was made. 
The investigator will be responsible for retaining all records pertaining to the study as 
specified in the appropriate contract. 
At the end of the study, a copy of all data-sets will be provided to the Sponsor on electronic 
support. A study report will be written at the end of the study. Information on the study results 
will be given to the Regulatory Authorities, within required times, as indicated by local 
regulations. 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1 
Calculation or derivation of efficacy variable(s) 
The primary efficacy variable, cardiac troponin I at 24 hours post-PCI will be determined 
according to local standard clinical practice. In detail, cTnI will be analyzed with an 
automated immunoassay (Bayer ADVIA IMS Troponin-I Ultra method, Bayer, Berlin, 
Germany). The 99th percentile of the cTnI level in a reference population (upper reference, 
limit, URL) of healthy volunteers was below the lower limit of detection of 0.04 ng/mL. The 
coefficient of variation (CV) of the assay was <10%, complying with the recommendations of 
the European Society of Cardiology (ESC)/ American College of Cardiology (ACC)/ 
American Heart Association (AHA) for optimal precision. The analytical range was 0.01 to 
50ng/mL, with an assay sensitivity of 0.006 ng/mL. 
Chest pain during PCI is a secondary efficacy variable. It will be assessed during the post-PCI 
clinical examination of the subject by the investigator or by an appropriately qualified person 
to whom the investigator has delegated this duty. A numerical 10 point scale will be used (0: 
no pain, 10: most severe discomfort ever experienced). 
ST-segment deviation during balloon occlusion will be monitored as a secondary efficacy 
variable. It will be defined as the absolute value of ST-segment deviation at 60-80ms after the 
J-point in mm at the beginning of coronary angiography minus ST-segment deviation at 60-
80ms after the J-point in mm during balloon occlusion.   
11.2 
Calculation or derivation of safety variable(s) 
The frequency of bleeding according the TIMI criteria will be recorded. 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
32 
 
12. 
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1 
Description of analysis sets 
All variables will be analyzed descriptively with appropriate statistical methods: categorical 
variables by frequency tables and continuous variables by sample statistics (i.e. mean, 
standard deviation, minimum, median, quartiles, and maximum).  
Demographic variables and baseline characteristics will be summarized by treatment group for 
2 analysis populations (i.e. valid for safety analysis and valid for per protocol analysis of 
primary efficacy endpoint). Medical history findings and adverse events will be coded by 
Medical Dictionary for Regulatory Activities (MedDRA) codes and medications by Anatomic 
Therapeutic Chemical Classification System (ATC) codes (World Health Organization-Drug 
Dictionary [WHO-DD]). 
12.1.1 
Efficacy analysis set 
A randomized subject will be considered valid for per protocol efficacy analysis if the subject: 
• has received study medication according to the study protocol 
• has been subjected to a RIPC or a sham procedure according to the study protocol 
• has undergone PCI within one hour after RIPC or sham procedure 
• has provided a valid blood sample for cTnI determination at 24 hours post-pCI 
12.1.2 
Safety analysis set 
A randomized subject will be considered valid for safety analysis if at least 1 dose of study 
medication has been administered. 
12.2 
Methods of statistical analyses 
The efficacy analysis will be performed in the population of subjects valid for safety analysis. 
The statistical assessment of the primary outcome measure (post-procedural cTnI) will be 
performed using ANCOVA (analysis of covariance), with post-procedural cTnI as a 
dependent variable, -ticagrelor/clopidogrel treatment and –RIPC/no RIPC as fixed factors and 
pre-procedural cTnI as a covariate. If not mentioned otherwise, all statistical tests will be 
performed tow-sided with a type I error rate of 5% and 95% confidence intervals (two-sided) 
will be given. 
The statistical assessment of the secondary outcome measures (pain score, and ST-segment 
deviation) will be performed using ANOVA (analysis of variance). The ANOVA tests the null 
hypothesis that samples in two or more groups are drawn from populations with the same 
mean values. If the ANOVA test is statistically significant, pairwise comparison of subgroups 
will be performed with the Tukey-Kramer test. If not mentioned otherwise, all statistical tests 
will be performed tow-sided with a type I error rate of 5% and 95% confidence intervals (two-
sided) will be given. 
The safety analysis will be performed in the population of subjects valid for safety analysis. 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
33 
 
The incidence of the composite of major and non-major bleeding according to the TIMI 
criteria and the incidence of major bleeding will be tabulated and further analyzed using 
Fisher’s exact test. Fisher's exact test is a significance test for a 2x2 table. This test evaluates 
all distribution probabilities for a 2 x 2 table and produces an exact probability for a given set 
of observed frequencies. The null hypothesis is that the row and column variables are 
unrelated, or that there is no difference in the respective proportions. If not mentioned 
otherwise, all statistical tests will be performed two-sided with a type I error rate of 5% and 
95% confidence intervals (two-sided) will be given. 
 
12.2.1 
Interim analyses 
No interim analysis will be scheduled 
12.3 
Determination of sample size 
According to our previous research19 and other available studies on the subject20 we have 
assumed post-procedural cTnI to be approximately 0.10ng/mL in the RIPC group (0.08ng/mL 
for the ticagrelor group and 0.12 for the clopidogrel group) and approximately 0.19ng/mL for 
the control group (0.14ng/mL for the ticagrelor group and 0.24 for the clopidogrel group), 
with a standard deviation of 0.20 for both groups. According to our previous experience the 
correlation coefficient between preprocedural and postprocedural cTnI is approximately 0.7. 
Based on previously published methods,28,29 we have estimated a sample size of 152 patients 
(38 patients for each group) to achieve a statistical power of 80% with a=0.05, incorporating a 
dropout rate of 15% (pci failure, revoked consent, etc.) 
Statistical analyses have been performed using IBM SPSS Statistics v21, (IBM Corporation), 
and Power Analysis v1.4 (A&X Analytics). 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Overdose 
There is currently no known antidote to reverse the effects of ticagrelor, and ticagrelor is not 
expected to be dialyzable. Treatment of overdose should follow local standard medical 
practice. 
The expected effect of excessive ticagrelor dosing is prolonged duration of bleeding risk 
associated with platelet inhibition. If bleeding occurs, appropriate supportive measures should 
be taken. 
Ticagrelor is well tolerated in single doses up to 900 mg. Gastrointestinal toxicity was 
dose-limiting in a single ascending dose study. Other clinically meaningful adverse effects 
which may occur with overdose include dyspnoea and ventricular pauses. 
In the event of overdose, observe for these potential adverse effects and consider 
electrocardiogram monitoring. 

Clinical Study Protocol 
Drug Substance <<Ticagrelor>> 
Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
34 
 
13.2 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. The Investigator should 
substitute ticagrelor with an acceptable alternative, according to local practice, if dual 
antiplatelet treatment is considered appropriate. 
 
14. 
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Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
35 
 
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Study Number <<ESR-14-10310>> 
Edition Number <<2>> 
Date <<11 01 2017>> 
36 
 
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