Clinical trial NCT02201771
Conditions: Coronary Artery Bypass Antiplatelet Agents
Keywords: CABG Antiplatelet Ticagrelor
Sponsor: Ruijin Hospital
Start date: 2014-07-01; Completion date: 2017-01-01
Enrollment: 500 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study population will include all patients undergoing elective CABG. Consent and randomization will occur before surgery. Total 500 patients undergoing elective CABG will be randomly assigned into three groups with 1:1:1 ratio(167 patients per group) in this open-label study. All the enrolled patients will stop oral antiplatelet drugs according to local protocol before the surgery. Within the first 24 hours after surgery, study medication should be restarted and continued for 12 months. Arm A will restart oral antiplatelet drugs by giving aspirin 100mg qd, Arm B will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid plus aspirin 100mg qd and Arm C will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid. Treatment will continue for 12 months, at which time patients will undergo a multislice computed tomography angiography to assess vein graft patency.

This study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of vein graft patency.

Detailed description:
The study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of vein graft patency. The primary comparison includes two separate parts. One is to demonstrate T+A better than A and the other is T better than A.

One year rate of vein graft patency in the aspirin group is estimated as 80%. The assumed rate of ticagrelor plus aspirin is 90%. With a two-sided alpha level 0.05 and 80% power, 199 grafts to each group are required. On the other hand, if we assume the rate of ticagrelor monotherapy has the 1-year vein graft patency rate of 87%, under the same two-sided 0.05 alpha 441 grafts in each arm will offer 80% power to show the superiority of ticagrelor along for the primary efficacy end point.

Combined the above two assumptions, if the allocation rate is 1:1:1, this study needs to recruit 1,323 grafts in total (441 in each) to achieve the pre-specified power for both the two comparisons (T+A vs. A and T vs. A).

The principle investigator assumes that the average number of the vien grafts in one patient is 2.7-3.0. With this assumption, 500 patients are to be recruited, which will provide us a total of 1350 - 1500 grafts.

According to the above, this study will be a confirmatory clinical trial to the primary endpoint.

Arms: arm 1: aspirin 100mg tablet by mouth daily for 12 months arm 2: ticagrelor 90mg tablet by mouth twice daily and aspirin 100mg tablet by mouth daily for 12 months arm 3: ticagrelor 90mg tablet by mouth twice daily for 12 months
Interventions: intervention 1: Aspirin intervention 2: Ticagrelor
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
 
1(33) 
Drug Substance 
Brilinta//Ticagrelor 
Study Number 
ISSBRIL0211 
Version Number 
6.0 
Date                          
07 Mar 2017 
Compare the efficacy of different antiplatelet therapy strategy after 
Coronary Artery Bypass Graft Surgery 
Principal Investigator: Qiang Zhao, MD, PhD, Vice President of Ruijin Hospital, Professor and director, 
Department of Cardiac Surgery 
Sponsor: Ruijin Hospital, Shanghai Jiaotong University School of Medicine 
 
 
Drug Substance 
Brilinta//Ticagrelor 
 
Study Number             ISSBRIL0211 
 
Version Number 
6.0 
 
Date                            07Mar2017


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
2(33) 
TABLE OF CONTENTS 
                                          PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 6 
1. 
INTRODUCTION ................................................................................................... 7 
1.1 
Background .............................................................................................................. 7 
1.2 
Research  hypothesis ................................................................................................ 7 
1.3 
Rationale for conducting this study ......................................................................... 7 
1.4 
Benefit/risk and ethical assessment.......................................................................... 8 
2. 
STUDY OBJECTIVES ............................................................................................ 8 
2.1 
Primary objective ..................................................................................................... 8 
2.2 
Secondary objectives ............................................................................................... 8 
2.3 
Safety objective ........................................................................................................ 8 
2.4 
Exploratory objectives ............................................................................................. 9 
3. 
STUDY PLAN AND PROCEDURES .................................................................... 9 
3.1 
Overall study design and flow chart ........................................................................ 9 
3.2 
Rationale for study design, doses and control groups ............................................ 10 
4. 
SUBJECT SELECTION CRITERIA .................................................................... 10 
4.1 
Inclusion criteria .................................................................................................... 10 
4.2 
Exclusion criteria ................................................................................................... 11 
5. 
STUDY CONDUCT .............................................................................................. 12 
5.1 
Restrictions during the study ................................................................................. 12 
5.2 
Subject enrollment and randomization .................................................................. 12 
5.2.1 
Subject enrollment ................................................................................................. 12 
5.2.2 
Procedures for randomization ................................................................................ 12 
5.3 
Procedures for handling subjects incorrectly enrolled ........................................... 13 
5.4 
Blinding and procedures for unblinding the study ................................................. 13 
5.5 
Treatments .............................................................................................................. 13 
5.5.1 
Identity of investigational product(s) ..................................................................... 13 
5.5.2 
Doses and treatment regimens ............................................................................... 13 
5.5.3 
Additional study drug ............................................................................................ 13 
5.5.4 
Labeling ................................................................................................................. 13 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
3(33) 
5.5.5 
Storage ................................................................................................................... 14 
5.6 
Concomitant and post-study treatment(s) .............................................................. 14 
5.7 
Treatment compliance ............................................................................................ 14 
5.7.1 
Accountability ........................................................................................................ 14 
5.8 
Discontinuation of investigational product ............................................................ 14 
5.8.1 
Procedures for discontinuation of a subject from investigational product ............ 14 
5.9 
Withdrawal from study .......................................................................................... 15 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 15 
6.1 
Recording of data ................................................................................................... 15 
6.2 
Data collection at enrolment and follow-up ........................................................... 15 
6.2.1 
Enrollment procedures ........................................................................................... 17 
6.2.2 
Follow-up procedures ............................................................................................ 18 
6.3 
Efficacy .................................................................................................................. 18 
6.3.1 
Efficacy variable .................................................................................................... 18 
6.4 
Safety ..................................................................................................................... 19 
6.4.1 
Definition of adverse events .................................................................................. 20 
6.4.2 
Definitions of serious adverse event ...................................................................... 21 
6.4.3 
Recording of adverse events .................................................................................. 21 
6.4.4 
Reporting of serious adverse events....................................................................... 23 
6.4.5 
Laboratory safety assessment ................................................................................ 24 
6.4.6 
Physical examination ............................................................................................. 24 
6.4.7 
ECG ........................................................................................................................ 24 
6.4.7.1 
Resting 12-lead ECG ............................................................................................. 24 
6.4.7.2 
Real time display (telemetry) ................................................................................. 24 
6.4.8 
Vital signs .............................................................................................................. 24 
6.4.9 
Other safety assessments ........................................................................................ 24 
6.5 
Patient reported outcomes (PRO) .......................................................................... 24 
6.6 
Pharmacokinetics ................................................................................................... 24 
6.7 
Pharmacodynamics ................................................................................................ 25 
6.8 
Pharmacogenetics .................................................................................................. 25 
6.9 
Health economics ................................................................................................... 25 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 25 
7.1 
Volume of blood .................................................................................................... 25 
7.2 
Handling, storage and destruction of biological samples ...................................... 25 
7.3 
Labeling and shipment of biohazard samples ........................................................ 25 
7.4 
Chain of custody of biological samples ................................................................. 25 
7.5 
Withdrawal of informed consent for donated biological samples ......................... 25 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
4(33) 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 25 
8.1 
Ethical conduct of the study ................................................................................... 25 
8.2 
Ethics and regulatory review.................................................................................. 26 
8.3 
Informed consent ................................................................................................... 26 
8.4 
Changes to the protocol and informed consent form ............................................. 27 
8.5 
Audits and inspections ........................................................................................... 27 
9. 
STUDY MANAGEMENT .................................................................................... 27 
9.1 
Training of study site personnel ............................................................................. 27 
9.2 
Monitoring of the study ......................................................................................... 27 
9.2.1 
Source data ............................................................................................................. 27 
9.3 
Study timetable and end of study ........................................................................... 28 
10. 
DATA MANAGEMENT ....................................................................................... 28 
11. 
EVALUATION AND CALCULATION OF VARIABLES ................................. 29 
11.1 
Calculation or derivation of efficacy variable(s) ................................................... 29 
11.2 
Calculation or derivation of safety variable(s) ....................................................... 29 
11.3 
Calculation or derivation of patient reported outcome variables ........................... 29 
11.4 
Calculation or derivation of pharmacokinetic variables ........................................ 29 
11.5 
Calculation or derivation of pharmacodynamic variable(s) ................................... 29 
11.6 
Calculation or derivation of pharmacogenetic variables........................................ 29 
11.7 
Calculation or derivation of health economic variables......................................... 29 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 29 
12.1 
Description of analysis sets .................................................................................... 29 
12.1.1 
Efficacy analysis set ............................................................................................... 30 
12.1.2 
Safety analysis set .................................................................................................. 30 
12.2 
Methods of statistical analyses ............................................................................... 30 
12.3 
Determination of sample siz .................................................................................. 30 
12.4 
Data monitoring committee ................................................................................... 30 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 31 
13.1 
Overdose ................................................................................................................ 31 
13.2 
Pregnancy ............................................................................................................... 31 
14. 
LIST OF REFERENCES ....................................................................................... 32 
 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
5(33) 
LIST OF TABLES 
Table 1: Identity of investigational products----------------------------------------------------------13 
Table 2: Time and Events Schedule--------------------------------------------------------------------16 
Table 3: Criteria of Bleeding Events-------------------------------------------------------------------18 
Table 4: Laboratory tests--------------------------------------------------------------------------------22 
LIST OF FIGURES 
Figure 1: Schematic Overview of the Study------------------------------------------------------------9 
LIST OF APPENDICES 
None 
 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
6(33) 
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 
CABG 
ECG 
Acute Coronary Syndrome 
Coronary Artery Bypass Graft 
Electrocardiogram 
MSCTA 
OPCAB 
UCG 
CCS  
Multislice computed tomography angiography  
Off-pump Coronary Artery Bypass 
Ultrasonic Cardiogram 
Canadian Cardiovascular Society 
PLATO 
Platelet inhibition and patient Outcomes trial 
AE 
Adverse Event 
SAE 
Serious Adverse Event 
IEC 
PI 
TIMI 
Independent Ethics Committee 
Principal Investigator 
Thrombolysis in Myocardial Infarction 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
7(33) 
1. 
INTRODUCTION 
1.1 
Background 
For 30 years, antiplatelet therapy has been the gold standard for preventing saphenous vein graft 
closure after CABG.1 Aspirin is recognized as the standard of care and is generally continued 
indefinitely given its benefit in preventing subsequent clinical events.2,3 But 2010 Canadian 
guideline4 and 2012 Society of Thoracic Surgeons guideline5 recommended that in patients 
undergoing CABG after ACS, dual antiplatelet drugs should be restarted and that may have 
secondary benefit of increasing early vein graft patency. Hence, different antiplatelet therapy 
strategy after CABG is still in controversy. 
However, as many as 50% of patients do not have adequate response to aspirin on the first 
postoperative day after cardiac procedures, and this percentage increases in the first week after 
operation, especially for off-pump procedures.6-8 Interestingly, the addition of clopidogrel did 
not seem to alter this nonresponse to aspirin. The clinical consequences of this lack of response 
remain uncertain, but evidence suggests lack of response to aspirin correlates with early vein 
graft closure after CABG and with recurrent cardiac events.9,10  
In patients with high residual platelet reactivity after the usual doses of clopidogrel, the novel 
antiplatelet agents are more effective at reducing platelet reactivity compared with increasing 
dose of clopidogrel.11 In the PLATO12 trial, ticagrelor, a novel reversible inhibitor of the P2Y12 
receptor, in addition to aspirin significantly reduced cardiovascular events in patients with ACS 
as compared to aspirin plus clopidogrel. The CABG substudy of the PLATO trial13 showed 
ticagrelor compared with clopidogrel was associated with a substantial reduction in total and 
CV mortality without excess risk of CABG-related bleeding.  
1.2 
Research  hypothesis  
This study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as 
compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of 
vein graft patency. 
1.3 
Rationale for conducting this study 
For the study rationale, four recent published guidelines on CABG stated different antiplatelet 
therapy strategy for post-CABG is still in controversy. As 2010 ESC guideline on myocardial 
revascularization14 and 2011 ACCF/AHA Guideline for CABG15 recommended, aspirin 
monotherapy should be given to reduce the occurrence of vein graft closure and adverse 
cardiovascular events (Class I recommendation), but dual antiplatelet therapy is recommended 
(Class I) in 2010 Canadian guideline4 and 2012 society of thoracic surgeons guideline.5 
PLATO-CABG subgroup13 analysis showed that combination ticagrelor with aspirin is effective 
in this population, but it is still not clear which one will be more benefit for from dual antiplatelet 
or monotherapy as current controversy in patients receiving clopidogrel. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
8(33) 
A systematically review16 showed that clopidogrel treatment alone demonstrate inferior with 
combination clopidogrel with aspirin in CABG patients. 
Arterial graft patency rates are high even in the absence of antiplatelet therapy, the 
administration of antiplatelet therapy has not shown an improvement.15 In previous published 
literatures and datas in our center , compared with artery graft, vein graft patency rate is lower. 
Meanwhile, short-term(one year) stenosis or closure of vein graft is the main factor for 
thrombosis.17-18 So vein graft patency is an objective index for evaluating the effect of CABG 
postoperative. 
1.4 
Benefit/risk and ethical assessment 
The Prescription Information for ticagrelor contains the information supporting the overall 
risk/benefit assessment of the investigational agent and is available as a reference for 
investigators. It contains a summary of all the relevant pharmaceutical, nonclinical and clinical 
findings with ticagrelor.  
Patients enrolled in this study will be treated with ticagrelor. Participation will entail recording 
of medical information about the patient in a confidential manner. Patient care will not be altered 
by participation. Ticagrelor will be provided to the subjects for free. The risks to patients include 
bleeding and dyspnoea, which are believed to be adequately handled in the clinical situation. The 
study will be approved by the local research ethics committee.   
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
The primary objective of this study will be to evaluate whether, as compared with aspirin 
monotherapy, ticagrelor plus aspirin and ticagrelor monotherapy could increase saphenous vein 
graft patency at 12 months after surgery in the patients undergoing elective CABG, as assessed 
by multislice computed tomography angiography (MSCTA) or coronary angiography (CAG).  
2.2 
Secondary objectives 
1) Saphenous vein graft patency at 7th day after surgery in the patients undergoing elective 
CABG, as assessed by multislice computed tomography angiography (MSCTA) or 
coronary angiography(CAG). 
2) Time to first event of major adverse cardiovascular event (MACE), composite of CV 
death, myocardial infarction or stroke (ischaemic or unknown etiology). 
 
3）Rate of freedom from angina by questionnaire according to CCS classification at 12 months. 
4） Rate of  post-operative atrial fibrillation within 7 days post CABG. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
9(33) 
2.3 
Safety objective 
1) To compared with aspirin monotherapy, the major bleeding risk of ticagrelor plus aspirin 
and ticagrelor monotherapy according to Thrombolysis in Myocardial Infarction (TIMI) 
criteria. 
2)  Other advers events (AEs) during the study 
2.4 
Exploratory objectives 
None. 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
The study population will include all patients undergoing elective CABG. Consent and 
randomization will occur before surgery. Total 500 patients undergoing elective CABG will be 
randomly assigned into three groups with 1:1:1 ratio(167 patients per group) in this open-label 
study. All the enrolled patients will stop oral antiplatlet drugs according to local protocol before 
the surgery. Within the first 24 hours after surgery, study medication should be restarted and 
continued for 12 months. Arm A will restart oral antiplatelet drugs by giving aspirin 100mg qd, 
Arm B will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid plus aspirin 100mg 
qd and Arm C will also restart oral antiplatelet drugs by giving ticagrelor 90mg bid. Treatment 
will continue for 12 months, at which time patients will undergo a multislice computed 
tomography angiography to assess vein graft patency.  
Figure 1: Schematic Overview of the Study 
 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
10(33) 
3.2 
Rationale for study design, doses and control groups 
According to the previous CABG guideline, standard antiplatelet treatment strategy, ASA 
monotherapy should be taken lifelong after the operation. But 2012 society of thoracic surgeons 
guideline5 updated that dual antiplatelet therapy are recommended for ACS population after 
CABG (Ia). On the other hand, PLATO-CABG substudy showed compared with clopidogrel, 
ticagrelor was associated with a substantial reduction in total and CV mortality without excess 
risk of CABG-related bleeding. Meanwhile, even with routine aspirin use after CABG, 10-20% 
of vein grafts occlude within 1 year after surgery, placing these patients at high risk for future 
myocardial events. Ticagrelor has a more consistent and pronounced platelet inhibition than 
clopidogrel, and may substantially improve graft patency following CABG compared to aspirin. 
We therefore propose this pilot study to compare 1-year vein graft patency among patients 
treated after CABG with ticagrelor plus aspirin or ticagrelor monotherapy, to those treated with 
aspirin monotherapy.  
Based on the protocol and final data of PLATO study, the doses of ticagrelor and aspirin are 
recommended as below: 
Ticagrelor: 90mg twice daily for 12 months 
Aspirin: 100mg daily for 12 months 
4. 
SUBJECT SELECTION CRITERIA 
Screening for eligible subjects will be performed before CABG.  
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, 
the investigator should consult with the appropriate sponsor representative before enrolling a 
subject in the study. 
4.1 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Patients able to provide written informed consent 
2. 
Provision of informed consent prior to any study specific procedures 
3. 
Female and male patients aged 18-80 years 
4. 
 Indication for CABG surgery: 
 coronary three vessel disease, or 
 left main stenosis, or 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
11(33) 
 two vessel disease with impaired left ventricular function 
4.2 
Exclusion criteria 
Any of the following is regarded as a criterion for exclusion from the study: 
1. Cardiogenic shock, haemodynamic instablity 
2. Need for urgent revascularization within 5 days from presentation 
3. Single vessel disease 
4. Two vessel disease with normal LV function (> 50%) 
5. Need for concomitant other cardiac surgery (e.g. valve replacement) 
6. Need for dual antiplatelet treatment for the patients undergoing CABG after ACS 
7. Contraindication for aspirin and ticagrelor use(e.g. known allergy) 
8. History of bleeding diathesis within 3 months prior presentation 
9.  History of significant GI bleed within 1 year  prior presentation 
10.History of peptic ulcer without GI bleeding in past 3 years  
11. History of intracranial hemorrhage 
12. History of moderate to severe liver impairment 
13. Patient requires dialysis 
14. Patient with an increased risk of bradycardic events (as patients without a pacemaker who 
have sick sinus syndrome, 2nd or 3rd degree AV block or bradycardic-related syncope) 
15. Need VKA therapy after bypass surgery eg. persistent atrial fibrillation, mechanical valves 
16. Known, clinically important thrombocytopenia(i.e. < 100*109/L) 
17. Known, clinically important anaemia (i.e. <100g/L) 
18. Participation in another investigational drug or device study in the last 30 days 
19. Pregnancy or lactation(for premenopausal women 2 methods of reliable contraception, one 
of which must barrier method, are required) 
20. Concomitant oral or intravenous therapy with strong CYP3A4 inhibitors, CYP3A4 
substrates with narrow therapeutic indices, or strong CYP3A4 inducers which cannot be 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
12(33) 
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. Substrats with narrow therapeutic 
index: cyclosporine, quinidine. Strong inducers: rifampin, phenytoin, carbamazepine. )  
21. Any other condition such as active cancer 
22. Life expectancy less than 12 months that may result in protocol non-compliance or a risk 
for being lost to follow up 
23. Indication for major surgery(e.g. cancer treatment, carotid surgery, cerebral surgery, major 
vascular surgery) 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
There are no specific dietary or activity restrictions other than those typical for a patient with 
this disease. 
Restrictions regarding concomitant medications are described in Section 4.2 
5.2 
Subject enrollment and randomization 
5.2.1 
Subject enrollment 
Patients who are ready for CABG and ticagrelor and aspirin treatment and eligible for the study 
will be included after obtaining the informed consent form.  
5.2.2 
 Procedures for randomization 
Patient eligibility will be established before treatment randomization. Patients will be 
enrolled/randomized 
strictly 
sequentially, 
as 
patients 
become 
eligible 
for 
enrolment/randomization. If a patient discontinues from the study, the patient number will not 
be reused, and the patient will not be allowed to re-enter the study.  
After providing informed consent, patients who are consistent with the inclusion and exclusion 
criteria will be randomly assigned to one of the three treatment groups. The randomization will 
be performed by a computer equally for the three treatment regimens. Each centre will be 
provided with sealed treatment code envelopes corresponding to a list of patient randomization 
numbers. Randomization numbers will be assigned strictly sequentially as subjects become 
eligible for randomization. When a subject is allocated to a specified randomization number, 
the corresponding code envelope will be opened to identify the allocated treatment regimen. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
13(33) 
5.3 
Procedures for handling subjects incorrectly enrolled 
Every attempt will be made to detect the reason for incorrectly enrollment. Removal from the 
trial will be determined by the principal investigator (PI), and the reasons should be 
documented in the case report form (CRF). 
5.4 
Blinding and procedures for unblinding the study 
This is an open-label study, so blinding is not applicable. 
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Ticagrelor is the study drug and aspirin is the comparator. Ticagrelor will be provided by 
AstraZeneca for free to subjects. The identity of those drugs is provided in the below table. 
Table 1: Identity of investigational products 
Investigational 
product 
Physical description 
Dosage 
form 
and 
strength 
Manufacturer 
Aspirin(Bayaspirin) 
 
 
 
Ticargrelor(Brilinta) 
White, enteric-coated 
tablets 
 
 
Round, 
biconvex, 
yellow, 
film-coated 
tablets marked with 
‘90’ above ‘T’ on one 
side and plain on the 
other 
each tablet contains 
100 mg acetylsalicylic 
acid 
 
each tablet contains 
90mg ticagrelor 
Bayer 
 
 
 
AstraZeneca 
 
5.5.2 
Doses and treatment regimens 
Arm A: Aspirin 100mg qd for 12 months 
Arm B: Ticargrelor 90mg bid plus Aspirin 100mg qd for 12 months 
Arm C: Ticargrelor 90mg bid for 12 months 
5.5.3 
Additional study drug 
Not applicable. 
5.5.4 
Labeling 
The labels of study drugs will accord with applicable relevant provisions and regulations. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
14(33) 
5.5.5 
Storage 
Ticagrelor: Store at 25°C (77°F); excursions permitted to 15° -30°C (59° - 86°F).  
Aspirin: Store at 25° C (77° F); excursions permitte d to 15°–30° C (59° –86° F) . 
5.6 
Concomitant and post-study treatment(s) 
Concomitant treatment with oral anticoagulant drugs is not permitted during the study. If 
treatment with oral anticoagulant drugs is considered essential during the study, study 
medication must be discontinued but may be resumed if anticoagulant therapy can be stopped. 
In this study, the total treatment days of antiplatelet/anticoagulation therapy’s temporary 
adjustment can not exceed 60. 
 
Treatment with GPIIb/IIIa receptor antagonists is allowed pre-study.  
Patients will receive concomitant therapies in three groups as recommended by the current 
American College of Cardiology / American Heart Association guidelines.  This will include 
smoking cessation counseling and the administration of beta blockers, angiotensin converting 
enzyme inhibitors, and lipid-lowering medications as indicated. The usage of ticagrelor or 
clopidogrel after the end of the study will be determined by the doctors according to the clinical 
practice and disease conditions. 
5.7 
Treatment compliance 
Dosage and administration of medications will be verified by review of medical record. 
5.7.1 
Accountability 
Ticagrelor will be donated by AstraZeneca, while aspirin will be purchased by subjects 
themselves. The investigator is responsible for ensuring that all study drug of ticagrelor received 
at the site is inventoried and accounted for throughout the study. The dispensing of study drug 
to the subject, and the return of study drug from the subject, must be documented on the drug 
accountability form. Subjects or their legally acceptable representatives must be instructed to 
return all original containers, whether empty or containing study drug. 
5.8 
Discontinuation of investigational product 
5.8.1 
 Procedures for discontinuation of a subject from investigational product  
Patients have the right to discontinue the study drug at any time without the need to justify the 
decision. The investigator has the right to discontinue patients from the study drug for 
non-compliance, administrative or other reasons.  
Patients should discontinue the study drug prior to completion if any of the following criteria 
are observed: 
• Major protocol violation assessed by the PI (including poor compliance, inconsistency 
with the inclusion and exclusion criteria, etc.). 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
15(33) 
• In light of safety issues, it is no longer proper for the patient to participate in the trial 
because of the occurrence of AEs. 
• Withdrawal required by the patient. Patient refuses to participate or continue to 
participate in the trial. 
• Pregnancy. 
5.9 
Withdrawal from study 
It is understood that an excessive rate of withdrawals can render the study results uninterpretable; 
therefore unnecessary discontinuation of patients should be avoided. The sponsor reserves the 
right to terminate a patient from the trial for non-adherence. 
Criteria of removal of patients from the trial: 
• Discontinuation of study drug. 
• Loss to follow-up. 
• Death. 
Every attempt will be made to detect the reason for withdrawal from the trial, e.g. AEs, lack of 
efficacy, removal from the trial determined by the investigator, other reasons which should be 
documented in the CRF. AEs should be assessed, determined and followed up by the 
investigators. Study drug assigned to the withdrawn subject may not be assigned to another 
subject. Subjects who withdraw will not be replaced. If a subject discontinues treatment before 
the end of the study, end-of-treatment assessments should be obtained. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
The investigator will ensure that data are recorded on the paper Case Report Forms (CRF) as 
specified in the study protocol and in accordance with the instructions provided. We will record 
age, gender, medical history, diagnosis leading to CABG and also record key laboratory results 
including hematology, biochemistry, biomarker, coagulation, etc. 
The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The investigator will sign the completed paper CRF.  A copy of the completed 
paper CRF will be archived at the study site. 
6.2 
Data collection at enrolment and follow-up 
All data will be collected after the patients providing informed consent and before the end of 
MSCTA examination. Refer to the Time and Events Schedule below for an overview of key 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
16(33) 
procedures performed during the study, including the evaluation frequency and timing of 
efficacy, safety, and other indices. 
Table 2: Time and Events Schedule 
Phase 
Basel
ine/ 
Scree
ning4 
Treatment 
(Day 1-Day 360) 
 
 
 
 
 
 
Discha
rge2 
 
 
 
Endpo
int3 
Treatment Day1 
 
D1 
D2    
D3 
D5 +1 
D9 +2 
D30 
+7 
D90 
+7 
D180 
+14 
D360 
+14 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Informed Consent 
Form5 
Ｘ 
 
 
 
 
 
 
 
 
 
Medical History 
Ｘ 
 
 
 
 
 
 
 
 
 
Vital Signs 
Ｘ 
 
 
 
 
 
 
 
 
 
Physical Examination 
Ｘ 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
Ｘ 
 
 
 
 
 
 
 
 
 
Hematology 
Ｘ 
 
 
 
 
 
 
 
 
 
Coagulation 
Ｘ 
 
 
 
 
 
 
 
 
 
Biochemistry 
Ｘ 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
Ｘ 
 
 
 
 
 
 
 
 
Randomization 
 
Ｘ 
 
 
 
 
 
 
 
 
Ticagrelor 90mg bid 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Aspirin 100mg qd 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
ECG 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
17(33) 
UCG 
Ｘ 
 
 
 
 
 
 
Ｘ 
Ｘ 
Ｘ 
MSCTA6 
 
 
 
 
 
Ｘ 
 
 
 
Ｘ 
Pregnancy Test  
 
Ｘ 
 
 
 
 
 
 
 
 
Bleeding Events 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
AEs7 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
 
NOTE:  
1. 
CAGB procedure will be operated on Day 0 
2. 
Discharge examination on Day 9±2 may be optional according to each center’s routine care. 
3. 
Subject who prematurely terminate treatment for any reason have to complete all the tests listed in the endpoint column. Follow-up duration can 
be 12 months 
4. 
Investigators must test all the screening results before study drug administration. 
5. 
Informed consent form must be obtained before any study -related procedure.  
6. 
MSCTA: Multislice Computed Tomography Angiography 
7. 
AEs recording began from the signing of informed consent throughout the study until and including the last visit. 
6.2.1 
Enrollment procedures 
Patients undergoing CABG procedures will be pre-screened for eligibility in the study.  
Inclusion and exclusion criteria will be reviewed. Once a patient is deemed eligible for the study, 
the patient will be invited to participate. At this period, obtain the following baseline 
information: 
1. 
Medical history; 
2. 
Perform comprehensive physical examination [ hematology, biochemistry, biomarker, 
coagulation, ECG, chest radiography, color Doppler ultrasound (carotid artery /arteria cruralis 
vessel), lung function (if necessary), chest CT (if necessary), head CT (if necessary), cardiac 
MRI (if necessary) , myocardium nuclide test (if necssary) ]  EuroScore assessment according 
to the patient medical history and preoperative evaluation data]; 
3. 
Combine Syntax score with EuroScore to do the global risk classification (GRC). 
4. 
Record concomitant medications; 
5. 
Pregnancy test in women; 
6. 
Monitor adverse events. 
Eligible patients are randomly assigned to one of the following open-label treatment regimens 
at a ratio of 1:1:1. 
Subjects are randomized to one of the three treatment groups: “Aspirin” group (Arm A) or  
“Ticagrelor+Aspirin” group (Arm B)   or “Ticagrelor” group (Arm C) 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
18(33) 
6.2.2 
Follow-up procedures 
Visit 1 (the 1st day after the operation): 
Blood routine examination, myocardial injury biomarker, and ECG will be conducted. 
From visit 2 (the 2nd day after the operation) to visit 4 (the 5th±1 day after the operation):  
Blood routine examination, myocardial injury biomarker will be conducted 
24 hours ECG monitoring will be reviewed daily to exam and record the incidence of atrial 
fibrillation/supraventricular tachycardia 
Visit 5 (the 9th±2 day after operation):  
MSCTA or CAG will be conducted to assess the saphenous vein graft patency according 
to Fitzgibbon Class 
Questionnaire survey will be taken according to CCS 
Review the data of hematology and imaging exams during hospitalization 
From visit 6 (the 30th±7 day after operation):  
Questionnaire survey will be taken according to CCS 
Hamatology examination、ECG will be conducted 
From visit 7 (the 90th±7 day after operation)  to visit 8 (the 180th±14 day after operation):  
Questionnaire survey will be taken according to CCS 
Hamatology examination、ECG、UCG will be conducted 
Visit 9 (the 360th±14 day after operation):  
Questionnaire survey will be taken according to CCS 
Hamatology examination、ECG、UCG will be conducted 
MSCTA or CAG will be conducted to assess the saphenous vein graft patency according 
to Fitzgibbon Class. 
 
6.3 
Efficacy 
6.3.1 
Efficacy variable 
1.   Primary efficacy endpoint: 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
19(33) 
Angiographic vein graft patency by MSCTA or CAG at 12 months after CABG.  
The patency of grafts will be defined according to the Fitzgibbon Standards, and they will be finally 
judged by IDRC（Refer to 12.4.1） 
2.   Secondary efficacy endpoint: 
1) Angiographic vein graft patency by MSCTA or CAG at 7th day after CABG. 
The patency of grafts will be defined according to the Fitzgibbon Standards, and they will be finally 
judged by IDRC（Refer to 12.4.1） 
2) Time to first event of  MACE, composite of CV death, myocardial infarction or stroke 
(ischaemic or unknown etiology) at 12 months after CABG. 
 
The MACE will be defined according to <2014 ACC/AHA Key Data Elements and 
Definitions for Cardiovascular Endpoint Events in Clinical Trials>, and they will be finally 
judged by CEC（Refer to 12.4.2） 
 
3) Rate of freedom from angina by questionnaire according to CCS classification at 12 months 
after CABG. 
4) Rate of post-operative atrial fibrillation within 7 days after CABG. 
 
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. 
1. Bleeding events:  
Incidence of bleeding events, classified by the following TIMI criteria. 
Table 3: Criteria of Bleeding Events 
Criteria 
Bleeding Definition 
TIMI 
Non-CABG related bleeding  
Major  
o Any intracranial bleeding (excluding microhemorrhages <10 mm evident only on 
gradient-echo MRI) 
o Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL 
o Fatal bleeding (bleeding that directly results in death within 7 d) 
Minor  


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
20(33) 
o Clinically overt (including imaging), resulting in hemoglobin drop of 3 to <5 g/dL 
Requiring medical attention  
o 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  
o Requiring intervention (medical practitioner-guided medical or surgical treatment to stop 
or treat bleeding, including temporarily or permanently discontinuing or changing the dose 
of a medication or study drug)  
o Leading to or prolonging hospitalization 
o Prompting evaluation (leading to an unscheduled visit to a healthcare professional and 
diagnostic testing, either laboratory or imaging)  
Minimal  
o Any overt bleeding event that does not meet the criteria above 
Bleeding in the setting of CABG  
o Fatal bleeding (bleeding that directly results in death) 
o Perioperative intracranial bleeding 
o Reoperation after closure of the sternotomy incision for the purpose of controlling 
bleeding 
o 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.  
o Chest tube output >2 L within a 24-h period 
 
Note: TIMI: Thrombolysis in Myocardial Infarction; CABG: coronary artery bypass graft; PRBC, packed red blood 
cell; 
2. Other AEs 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.4.1 
Definition of adverse events  
An adverse event(AE) is the development of an undesirable medical condition or the 
deterioration of a pre-existing medical condition following or during exposure to a 
pharmaceutical product, whether or not considered causally related to the product. An 
undesirable medical condition can be symptoms (eg, nausea, chest pain), signs (eg, 
tachycardia, enlarged liver) or the abnormal results of an investigation (eg, laboratory 
findings, electrocardiogram). In clinical studies, an AE can include an undesirable medical 
condition occurring at any time after the patient has signed informed consent, including run-in 
or washout periods, even if no study treatment has been administered. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
21(33) 
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 dose or during any study phase (i.e., 
run-in, treatment, and washout, follow-up), that fulfills one or more of the following criteria: 
• Results in death 
• Is immediately life-threatening 
• Requires in-patient hospitalization or prolongation of existing hospitalization  
• Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions 
• 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) must be assessed 
by the investigator(s). 
6.4.3 
Recording of adverse events 
All AE/SAEs will be documented in CRF. 
• Time period for collection of adverse events 
AEs/SAEs will be collected from the signing of informed consent throughout the study until 
and including the last visit.  
 
• Follow-up of unresolved adverse events 
Any AEs that are unresolved at the last visit in the study are followed up by the Investigator 
for as long as resolved or keep stable. 
 The following variables will be collected for each AE: 
• AE (verbatim) 
• The date when the AE started and stopped 
• maximum intensity 
• Whether the AE is serious or not 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
22(33) 
• Investigator causality rating against the Investigational Product (yes or no) 
• Action taken with regard to investigational product 
• AE caused subject’s withdrawal from study (yes or no) 
• Outcome 
In addition, the following variables will be collected for SAEs: 
• Date AE met criteria for serious AE 
• Date Investigator became aware of serious AE 
• AE is serious due to 
• Date of hospitalization 
• Date of discharge 
• Probable cause of death 
• Date of death 
• Autopsy performed 
• Causality assessment in relation to Study procedure(s) 
• Causality assessment in relation to Other medication 
• Description of AE. 
The 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 
an SAE.  
Adverse Events based on signs and symptoms 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
23(33) 
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, vital signs should be reported as AEs if they 
fulfill any of the SAE criteria or are the reason for discontinuation of treatment 
with the investigational product. 
If deterioration in a laboratory value/vital sign is associated with clinical signs and 
symptoms, the sign or symptom will be reported as an AE and the associated 
laboratory result/vital sign will be considered as additional information.  
Wherever possible the reporting investigator uses the clinical, rather than the 
laboratory term (eg, anemia versus low hemoglobin value). In the absence of 
clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 
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. 
Disease progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the disease under study and/or increases in the symptoms of the disease. The 
development of existing ischemia or death from vascular cause 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. 
6.4.4 
Reporting of non-serious ADRs and serious adverse events  
Investigators are responsible for meeting all regulatory reporting requirements. The 
investigators are also responsible for reporting SAE to Ethics Committee in time per local 
requirements. 
Investigators must inform the local authority of any SAE within 24 hours in accordance with 
the local regulations and report SAE to Ethics Committee in time per local requirements.  
All non-serious ADRs related to AstraZeneca study drug has to be reported to AstraZeneca 
Patient Safety within 7 days after awareness by investigator via AZ format form. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
24(33) 
All SAEs occur on AstraZeneca study drug have to be reported to AstraZeneca Patient Safety 
within 24 hours by investigator via AZ format form, whether or not considered causally related 
to the AZ investigational product.  AZ Patient Safety contact information: Fax: +86 21 
38683551; E-mail: China.AZDrugSafety@astrazeneca.com; Tel: +86 21 52929866，+86 21 
58385073 (Emergency). 
6.4.5 
Laboratory safety assessment 
Table 4: Laboratory tests 
Category 
Test name 
Hematology   
 
Red Blood Cell Count/ Erythrocytes 
Hemoglobin (Hb) 
Platelet Count/ Thrombocytes 
Coagulation 
Partial Thromboplastin Time (APTT) 
Prothrombin time (PT) 
Biochemistry 
AST(GOT) 
ALT(GPT) 
Protein 
HbA1c 
LDL-C 
Creatinine 
Biomarker 
cTnT/cTnI 
 
For blood volume see Section 7.1. 
6.4.6 
Physical examination 
A targeted physical examination includes heart and lung. 
6.4.7 
ECG 
12-lead ECG will be performed at screening period and in hospital . 
6.4.8 
Vital signs 
An evaluation of vital signs includes respiratory rate, temperature, pulse rate, and 
systolic/diastolic blood pressure. 
6.4.9 
Other safety assessments 
Not applicable 
6.5 
Patient reported outcomes (PRO) 
Not applicable 
6.6 
Pharmacokinetics 
Not applicable  


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
25(33) 
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 
Collection of blood samples will be according to regulatory requirements. Approximately 12ml 
blood for each sample will be taken for analysis of hematology, coagulation, platelet function, 
biochemistry and biomarker at time points indicated in Table 2 (excluding optional tests).  
7.2 
Handling, storage and destruction of biological samples 
The handing, storage and destruction of biological samples will be in accordance with the 
requirements of the laboratory in each site. 
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 study will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) and Chinese GCP. Standard medical care (diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
26(33) 
8.2 
Ethics and regulatory review 
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP, Chinese GCP 
and to the regulatory and legal requirements of the participating country. Each signature must 
be personally dated by each signatory and the informed consent and any additional patient 
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative. 
The patient must be informed that his/her personal trial-related data will be used by principle 
investigator in accordance with the local data protection law. The level of disclosure must also 
be explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CRA) or Clinical Quality Assurance auditors, by appropriate IRB / IEC members, 
and by inspectors from regulatory authorities. 
8.3 
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 
• 
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. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
27(33) 
8.4 
Changes to the protocol and informed consent form 
Study procedures will not be changed without the mutual agreement of the National Co-
ordinating Investigator and Sponsor. 
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 should be approved by each Ethics Committee before implementation. Local 
requirements should be followed for revised protocols. 
Sponsor will distribute any subsequent amendments and new versions of the protocol to each 
Principal Investigator(s). For distribution to Ethics Committee see Section 8.2. 
If a protocol amendment requires a change to a centre’s Informed Consent Form, Sponsor and 
the centre’s Ethics Committee should 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. 
8.5 
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. 
9. 
STUDY MANAGEMENT 
9.1 
Training of study site personnel 
The PI should ensure adequate training and updated information or notifications have been 
delivered to study relevant personnels including physicians and nurses. 
9.2 
Monitoring of the study 
9.2.1 
Source data 
Source documents provide evidence for the existence of the patient and substantiate the integrity 
of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the CRFs that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained. The investigator may need to 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
28(33) 
request previous medical records or transfer records, depending on the trial; also current medical 
records must be available. 
For CRFs all data must be derived from source documents. 
For paper CRFs, the following data need to be derived from source documents: 
• 
Patient identification (gender, date of birth) 
• 
Patient participation in the trial (substance, trial number, patient number, date patient 
was informed) 
• 
Dates of Patient’s visits, including dispensing of trial medication 
• 
Medical history (including trial indication and concomitant diseases) 
• 
Medication history 
• 
Adverse events and outcome events (onset date (mandatory), and end date (if available)) 
• 
Serious adverse events (onset date (mandatory), and end date (if available)) 
• 
Concomitant therapy (start date, changes) 
• 
Originals or copies of laboratory results (if available) 
• 
Conclusion of Patient’s Participation in the trial 
9.3 
Study timetable and end of study 
– FSI:  06/2014 
– LSI:  06/2015 
– LSLV:  07/2016 
– Report:  10/2016 
We anticipate initiation on or before June 2014. We project accrual of 4~5 patients/week, so 
anticipate the last enrolment by June 2015 and completion of the study by July 2016. We 
anticipate that these results should be available within 3 months and that a report will be ready 
for review within 4 months after the end of enrolment.  
10. 
DATA MANAGEMENT 
A quality assurance audit/inspection of this trial may be conducted by AstraZeneca or sponsor’s 
designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
29(33) 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1 
Calculation or derivation of efficacy variable(s) 
The primary endpoint is angiographic vein graft patency by multislice computed tomography 
angiography(MSCTA) after 12 months. 
11.2 
Calculation or derivation of safety variable(s) 
The major safety variable is incidence of bleeding events. The rate ratio estimate and its 
confidence limits will be determined. 
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 
12.1 
Description of analysis sets 
The primary analysis will be done according to the ITT (intention-to-treat) principle. The 
participants who randomized and have at least one dose of investigational medication will be 
included. Only the ‘Consent Withdraw’ patients will be excluded which means the patient quit 
study just after randomization and take no medications. The analysis set according to above 
principle is defined as modified full analysis set (mFAS). 
If there are any other major protocol violations, the corresponding patients will be further 
excluded from the per-protocol analysis set (PPS) after the adjudication by principle 
investigator. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
30(33) 
12.1.1 
Efficacy analysis set 
The efficacy analysis will be conducted both on mFAS and PPS. 
12.1.2 
Safety analysis set 
The efficacy analysis will be conducted on mFAS. 
12.2 
Methods of statistical analyses 
Categorical variables will be described by counts and proportions, and continuous variables will 
be described by mean and standard deviation or median and IQR. Proportions will be compared 
by chi-square tests or fisher exact test. A Kaplan-Meier (KM) plot of the time to first MACE 
event in addition to the presentation of KM estimates at 12 months will be provided for each 
group. Cox proportional hazards model will be used to compare the time to event data between 
groups. Continuous variables will be compared through ANOVA or Mann-Whitney U tests. A 
two-sided level of significance of 0.05 is applied to general comparison.  
 
The generalized linear model will be applied to calculate the difference of vein graft patency 
rate between groups. The difference of patency and its 95% confidence interval will be 
estimated by the SAS GENMOD procedure and any potential baseline covariates will be 
adjusted through the model. To avoid the multiplicity issue induced by multiple comparisons 
among several groups in the primary endpoint, theHochberg method would be used to control 
the overall alpha level. No multiple testing adjustment will be applided to the secondary 
endpoints. All analysis will be performed using SAS 9.3 (SAS Institute Inc., Cary, NC, USA). 
12.3 
Determination of sample size 
The study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as 
compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of 
vein graft patency. The primary comparison includes two separate parts. One is to demonstrate 
T+A better than A and the other is T better than A. 
One year rate of vein graft patency in the aspirin group is estimated as 80%. The assumed rate 
of ticagrelor plus aspirin is 90%. With a two-sided alpha level 0.05 and 80% power, 199 grafts 
to each group are required. On the other hand, if we assume the rate of ticagrelor monotherapy 
has the 1-year vein graft patency rate of 87%, under the same two-sided 0.05 alpha 441 grafts 
in each arm will offer 80% power to show the superiority of ticagrelor along for the primary 
efficacy end point. 
Combined the above two assumptions, if the allocation rate is 1:1:1, this study needs to recruit 
1,323 grafts in total (441 in each) to achieve the pre-specified power for both the two 
comparisons (T+A vs. A and T vs. A).  


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
31(33) 
The principle investigator assumes that the average number of the vien grafts in one patient is 
2.7-3.0. With this assumption, 500 patients are to be recruited, which will provide us a total of 
1350 - 1500 grafts.  
 
12.4 
Data monitoring committee  
12.4.1    Image Data Review Center (IDRC) 
 
An independent IDRC will be appointed and will adjudicate all imaging results (grafts 
failure). The committee members will be blinded to the treatment group. The precise 
responsibilities and procedures applicable for the IDRC will be detailed in a separate IDRC 
charter. 
 
12.4.2 Clinical Endpoint Committee (CEC) 
 
An independent CEC will be appointed and will adjudicate all potential MACE. The 
committee members will be blinded to the treatment group. The precise responsibilities and 
procedures applicable for the CEC will be detailed in a separate CEC charter. 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR 
13.1 
Overdose  
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 within one day, ie, 
immediately but no later than the end of the next business day 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. Treatment of 
overdose should follow local standard medical practice. 
13.2 
Pregnancy 
If a subject becomes pregnant during the course of the study the 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 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
32(33) 
termination, ectopic pregnancy, normal birth or congenital abnormality) should be followed up 
and documented even if the subject was discontinued from the study. 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca. 
14. 
LIST OF REFERENCES 
1. 
Chesebro JH, Clements IP, Fuster V, et al. A platelet-inhibitor-drug trial in coronary-artery bypass 
operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft 
patency. N Engl J Med 1982;307:73-8. 
2. 
Eagle KA, Guyton RA, Davidoff R, et al. ACC/AHA 2004 guideline update for coronary artery bypass 
graft surgery: a report of the American College of Cardiology/American Heart Association Task Force 
on Practice Guidelines (Committee to Update the 1999 Guidelines for Coronary Artery Bypass Graft 
Surgery). Circulation 2004;110:e340-437. 
3. 
Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery 
disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th 
Edition). Chest 2008;133:776S-814S. 
4. 
Bell AD, Roussin A, Cartier R, et al. The use of antiplatelet therapy in the outpatient setting: Canadian 
Cardiovascular Society guidelines. Can J Cardiol. 2011 May-Jun;27 Suppl A:S1-59.  
5. 
Ferraris VA, Saha SP, Oestreich JH, et al. 2012 update to the Society of Thoracic Surgeons guideline 
on use of antiplatelet drugs in patients having cardiac and noncardiac operations. Ann Thorac Surg. 
2012 Nov;94(5):1761-81. 
6. 
Borgermann J, Kanashnik A, Sossdorf M, et al. Individual variability of response and nonresponse to 
acetyl salicylic acid after cardiac surgery. Platelets 2010;21:610 –5. 
7. 
Bednar F, Osmancik P, Hlavicka J, et al. Aspirin is insufficient in inhibition of platelet aggregation and 
thromboxane formation early after cor-onary artery bypass surgery. J Thromb Thrombol. 2009;27:394 
–9. 
8. 
Bednar F, Osmancik P, Vanek T, et al. Platelet activity and aspirin efficacy after off-pump compared 
with on-pump coronary artery bypass surgery: results from the prospective randomized trial PRAGUE 
11-Coronary Artery Bypass and Reactivity of Thrombocytes (CABARET). J Thorac Cardiovasc Surg 
2008;136:1054–60. 
9. 
Gluckman TJ, McLean RC, Schulman SP, et al. Effects of aspirin responsiveness and platelet 
reactivity on early vein graft thrombosis after coronary artery bypass graft surgery. J Am Coll Cardiol 
2011;57:1069 –77. 
10. Snoep JD, Hovens MM, Eikenboom JC, van der Bom JG, Huisman MV. Association of laboratory-
defined aspirin resistance with a higher risk of recurrent cardiovascular events: a systematic review 
and meta-analysis. Arch Intern Med 2007;167:1593–9. 


Clinical Study Protocol 
Drug Substance Brilinta//Ticagrelor 
Study Number ISSBRIL0211 
Edition Number 6.0 
Date 07 Mar 2017 
33(33) 
11. Alexopoulos D, Dimitropoulos G, Davlouros P, et al. Prasugrel overcomes high on-clopidogrel platelet 
reactivity post-stenting more effectively than high-dose (150-mg) clopidogrel: the importance of 
CYP2C19*2 genotyping. J Am Coll Cardiol Intv 2011;4:403–10. 
12. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary 
syndromes. N Engl J Med. 2009 Sep 10;361(11):1045-57. 
13. Held C, Asenblad N, Bassand JP, et al. Ticagrelor versus clopidogrel in patients with acute coronary 
syndromes undergoing coronary artery bypass surgery: results from the PLATO (Platelet Inhibition 
and Patient Outcomes) trial. J Am Coll Cardiol. 2011 Feb 8;57(6):672-84. 
14. Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the 
European Association for Cardio-Thoracic Surgery (EACTS) et al. Guidelines on myocardial 
revascularization. Eur Heart J. 2010 Oct;31(20):2501-55. 
15. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA Guideline for Coronary Artery Bypass 
Graft Surgery: executive summary: a report of the American College of Cardiology 
Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2011 Dec 
6;124(23):2610-42. 
16. Patel JH, Stoner JA, Owora A, et al. Evidence for using clopidogrel alone or in addition to aspirin in 
post coronary artery bypass surgery patients. Am J Cardiol. 2009;103(12):1687-93. 
17. FitzGibbon GM, Leach AJ, Keon WJ et al. Coronary bypass graft fate. Angiographic study of 1,179 
vein grafts early, one year, and five years after operation. J Thorac Cardiovasc Surg. 1986;91(5):773-8. 
18. Fitzgibbon GM, Kafka HP, Leach AJ, et al. Coronary bypass graft fate and patient outcome: 
angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 
years. J Am Coll Cardiol. 1996;28(3):616-26. 
19. Hicks KA, et al. 2014 ACC/AHA Key Data Elements and Definitions for Cardiovascular Endpoint 
Events in Clinical Trials. Circulation. 2015;131:000–000. 

SAP_001.pdf: 
 
Version: 4.0 28Aug2017                                         1  
 
 
 
 
 
Compare the efficacy of different antiplatelet therapy strategy 
after Coronary Artery Bypass Graft Surgery 
（Study Number ISSBRIL0211） 
 
Statistical Analysis Plan 
（Version: 4.0） 
 
 
 
 
 
 
 
 
 
 
 
 
 
Shanghai Bestudy Medical Technology Co.,Ltd 
 
28Aug2017 
 


 
Version: 4.0 28Aug2017                                         2  
 
Contents 
Contents .................................................................................................................................................. 2 
ABBREVIATIONS ................................................................................................................................. 4 
0、Introduction ....................................................................................................................................... 5 
0.1 Background ............................................................................................................................... 5 
0.2 Research Hypothesis ................................................................................................................. 5 
0.3 Rationale for Conducting this Study ......................................................................................... 5 
0.4 Benefit/risk and Ethical Assessment ......................................................................................... 5 
1、Introduction to Study ......................................................................................................................... 6 
1.1 Types of this Study .................................................................................................................... 6 
1.2 Objective ................................................................................................................................... 6 
1.3 Treatment Products in the Study ............................................................................................... 6 
1.3.1 Recommendation for the Dosage of Ticargrelor and Aspirin ......................................... 6 
1.3.2 Doses and Treatment Regimens ..................................................................................... 6 
2.  STUDY OBJECTIVES .................................................................................................................... 6 
2.1 Primary Objective ..................................................................................................................... 6 
2.2 Secondary Objectives ................................................................................................................ 7 
2.3 Safety Objective ........................................................................................................................ 7 
3. Study Design ....................................................................................................................................... 7 
3.1 
Overall Study Design and Flow Chart................................................................................ 7 
3.2 Schematic Overview of the Study ............................................................................................. 8 
3.3 Sample Size Justification .......................................................................................................... 8 
3.4 Randomization and Blinding ..................................................................................................... 8 
3.4.1 Randomization after Subjects Enrolled .......................................................................... 8 
3.4.2 Blinding .......................................................................................................................... 8 
4. Study Endpoints .................................................................................................................................. 9 
4.1 Evaluation Methods for Study Endpoints ................................................................................. 9 
4.2 Efficacy Endpoints .................................................................................................................... 9 
4.2.1 Primary Efficacy Endpoint ............................................................................................. 9 
4.2.2 Secondary Efficacy Endpoints ....................................................................................... 9 
4.3 Safety Endpoints ....................................................................................................................... 9 
4.4 Other Endpoints ........................................................................................................................ 9 
5, Data Management ............................................................................................................................. 10 
6. Analysis Specifications ..................................................................................................................... 10 
6.1 Adverse Events ........................................................................................................................ 10 
6.1.1 AE Duration ................................................................................................................. 10 
6.1.2 Imputation of Missing AE Data ................................................................................... 10 
6.2 Concomitant Medication ......................................................................................................... 10 
6.3 Age Calculation ....................................................................................................................... 10 
7. Analysis Sets ..................................................................................................................................... 10 
7.1 Intent to Treat (ITT) ................................................................................................................ 10 
7.2 Modified Full Analysis Set（mFAS）.................................................................................... 10 
7.3 Per Protocol Set（PPS） ........................................................................................................ 10 
7.4 Safety Analysis Set（SS） ..................................................................................................... 11 
8. Statistical Analysis Methods ............................................................................................................. 11 
8.1 Statistical Analysis Software ................................................................................................... 11 
8.2 General Statistical Analysis Methods Applied ........................................................................ 11 
8.2.1 Continuous Variables .................................................................................................... 11 
8.2.2 Discrete Variables ......................................................................................................... 11 
8.2.3 Ordinal Variables .......................................................................................................... 11 
8.3 Statistical Test for Primary Endpoint ...................................................................................... 11 
8.3.1 Handling in Missing Values for Primary Endpoint ...................................................... 11 


 
Version: 4.0 28Aug2017                                         3  
 
8.3.2 Statistical Test for Primary Endpoint............................................................................ 12 
8.3.3 Statistical Descriptive of Patency of Grafts.................................................................. 12 
8.4 Secondary Endpoints ............................................................................................................... 12 
8.4.1 Handling in Missing Values for Secondary Endpoint .................................................. 12 
8.4.2 Statistical Descriptive and Statistical Test for Secondary Endpoints ........................... 12 
8.5 Safety Endpoints ..................................................................................................................... 12 
8.5.1 Adverse Events ............................................................................................................. 12 
8.5.2 Smoking ....................................................................................................................... 12 
8.5.3 Bleeding Events ........................................................................................................... 12 
8.5.4 Comparison in the Chemistry and Vital Sign Endpoints among 3 Treatment Groups . 13 
8.6 Other Variables ........................................................................................................................ 13 
8.6.1 Demographic and Baseline Data .................................................................................. 13 
8.6.2 Baseline and Medical History ...................................................................................... 13 
8.6.3 Operation Information Data ......................................................................................... 13 
8.6.4 Concomitant Medication .............................................................................................. 13 
8.7 Interim Analysis ...................................................................................................................... 13 
References ............................................................................................................................................. 14 
Appendix: Time and Events Schedule .................................................................................................. 15 
 


 
Version: 4.0 28Aug2017                                         4  
 
ABBREVIATIONS 
ACS 
Acute Coronary Syndrome 
AE  
Adverse Event 
ALT  
Alanine Aminotransferase 
AST  
Aspartate Aminotransferase 
BMI  
Body Mass Index 
CABG 
Coronary Artery Bypass Grafting 
CCS 
Canadian Cardiovascular Society 
CFDA 
China Food and Drug Administration 
CMH X2 
Cochran–Mantel–Haenszel Chi-Squared Test 
CRA 
Clinical Research Associate 
CRF  
Case Report Form 
CTA 
Clinical Trial Agreement 
DM 
Data Management 
EAP 
Effective Analysis Population 
EC 
Ethics Committee 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
ICF  
Informed Consent Form 
IEC  
Independent Ethics Committee 
ITT  
Intent to Treat 
Max 
Max 
Mean 
Mean 
Median 
Median 
MedDRA 
Medical Dictionary for Regulatory Activities 
Min 
Min 
Missing 
Missing 
MSCTA 
Multi-slice Spiral Computed Tomography Angiography 
N  
Number of Subjects (Number of Analysis Records) 
OPCAB 
Off pump Coronary Artery Bypass 
PI 
Principal Investigator 
PLATO 
Platelet Inhibition and Patient Outcomes 
PP 
Per-Protocol Set 
SAE  
Serious Adverse Event 
SS  
Safety Analysis Set 
TIMI 
Thrombolysis and Thrombin Inhibition in Myocardial 
Infarction 
UCG 
Ultrasonic Cardiogram 
 
 


 
Version: 4.0 28Aug2017                                         5  
 
0、Introduction 
0.1 Background 
For 30 years, antiplatelet therapy has been the gold standard for preventing saphenous vein graft 
closure after CABG. Aspirin is recognized as the standard of care and is generally continued 
indefinitely given its benefit in preventing subsequent clinical events. But 2010 Canadian guideline4 
and 2012 Society of Thoracic Surgeons guideline5 recommended that in patients undergoing CABG 
after ACS, dual antiplatelet drugs should be restarted and that may have secondary benefit of 
increasing early vein graft patency. Hence, different antiplatelet therapy strategy after CABG is still in 
controversy. 
However, as many as 50% of patients do not have adequate response to aspirin on the first 
postoperative day after cardiac procedures, and this percentage increases in the first week after 
operation, especially for off-pump procedures. Interestingly, the addition of clopidogrel did not seem 
to alter this nonresponse to aspirin. The clinical consequences of this lack of response remain 
uncertain, but evidence suggests lack of response to aspirin correlates with early vein graft closure 
after CABG and with recurrent cardiac events.  
In patients with high residual platelet reactivity after the usual doses of clopidogrel, the novel 
antiplatelet agents are more effective at reducing platelet reactivity compared with increasing dose of 
clopidogrel. In the PLATO trial, ticagrelor, a novel reversible inhibitor of the P2Y12 receptor, in 
addition to aspirin significantly reduced cardiovascular events in patients with ACS as compared to 
aspirin plus clopidogrel. The CABG substudy of the PLATO trial showed ticagrelor compared with 
clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk 
of CABG-related bleeding.  
0.2 Research Hypothesis  
This study is designed to show the superiority of ticagrelor and ticagrelor plus aspirin as 
compared with aspirin monotherapy respectively for the 1-year primary efficacy end point of vein 
graft patency. 
0.3 Rationale for Conducting this Study 
For the study rationale, four recent published guidelines on CABG stated different antiplatelet 
therapy strategy for post-CABG is still in controversy. As 2010 ESC guideline on myocardial 
revascularization and 2011 ACCF/AHA Guideline for CABG recommended, aspirin monotherapy 
should be given to reduce the occurrence of vein graft closure and adverse cardiovascular events 
(Class I recommendation), but dual antiplatelet therapy is recommended (Class I) in 2010 Canadian 
guideline and 2012 society of thoracic surgeons guideline. 
PLATO-CABG subgroup analysis showed that combination ticagrelor with aspirin is effective in 
this population, but it is still not clear which one will be more benefit for from dual antiplatelet or 
monotherapy as current controversy in patients receiving clopidogrel. 
A systematically review showed that clopidogrel treatment alone demonstrate inferior with 
combination clopidogrel with aspirin in CABG patients. 
Arterial graft patency rates are high even in the absence of antiplatelet therapy, the administration 
of antiplatelet therapy has not shown an improvement.15 In previous published literatures and datas in 
our center , compared with artery graft, vein graft patency rate is lower. Meanwhile, short-term(one 
year) stenosis or closure of vein graft is the main factor for thrombosis. So vein graft patency is an 
objective index for evaluating the effect of CABG postoperative. 
0.4 Benefit/risk and Ethical Assessment 
The Prescription Information for ticagrelor contains the information supporting the overall 


 
Version: 4.0 28Aug2017                                         6  
 
risk/benefit assessment of the investigational agent and is available as a reference for investigators. It 
contains a summary of all the relevant pharmaceutical, nonclinical and clinical findings with 
ticagrelor.  
Patients enrolled in this study will be treated with ticagrelor. Participation will entail recording of 
medical information about the patient in a confidential manner. Patient care will not be altered by 
participation. Ticagrelor will be provided to the subjects for free. The risks to patients include bleeding 
and dyspnoea, which are believed to be adequately handled in the clinical situation. The study will be 
approved by the local research ethics committee.   
1、Introduction to Study 
1.1 Types of this Study 
This is a phase IV, multi-center, open-label, active-controlled, randomized, parallel-group study.  
1.2 Objective 
The primary objective of this study will be to evaluate whether, as compared with aspirin 
monotherapy, ticagrelor plus aspirin and ticagrelor monotherapy could increase saphenous vein graft 
patency at 12 months after surgery in the patients undergoing elective CABG, as assessed by multislice 
computed tomography angiography (MSCTA) or coronary angiography (CAG). 
Secondary objectives including： 
1) Saphenous vein graft patency at 7th day after surgery in the patients undergoing 
elective CABG, as assessed by multislice computed tomography angiography 
(MSCTA) or coronary angiography(CAG). 
2) Time to first event of major adverse cardiovascular event (MACE), composite of CV 
death, non-fatal myocardial infarction or non-fatal stroke (ischaemic or unknown 
etiology). 
 
3）Rate of freedom from angina by questionnaire according to CCS classification at 12 months. 
Rate of atrial fibrillation within 7 days post CABG. 
1.3 Treatment Products in the Study 
1.3.1 Recommendation for the Dosage of Ticargrelor and Aspirin 
Ticargrelor: 90mg bid for 12 months 
Aspirin: 100mg qd for 12 months  
1.3.2 Doses and Treatment Regimens  
Arm A: Aspirin 100mg qd for 12 months 
Arm B: Ticargrelor 90mg bid plus Aspirin 100mg qd for 12 months 
Arm C: Ticargrelor 90mg bid for 12 months 
2.  STUDY OBJECTIVES 
2.1 Primary Objective 
The primary objective of this study will be to evaluate whether, as compared with aspirin 
monotherapy, ticagrelor plus aspirin and ticagrelor monotherapy could increase saphenous vein graft 
patency at 12 months after surgery in the patients undergoing elective CABG, as assessed by multislice 
computed tomography angiography (MSCTA) or coronary angiography (CAG).  


 
Version: 4.0 28Aug2017                                         7  
 
2.2 Secondary Objectives 
1) Saphenous vein graft patency at 7th day after surgery in the patients undergoing 
elective CABG, as assessed by multislice computed tomography angiography 
(MSCTA) or coronary angiography(CAG). 
2) Time to first event of major adverse cardiovascular event (MACE), composite of CV 
death, non-fatal myocardial infarction or non-fatal stroke (ischaemic or unknown 
etiology). 
3）Rate of freedom from angina by questionnaire according to CCS classification at 12 months. 
Rate of atrial fibrillation within 7 days post CABG. 
2.3 Safety Objective 
1) To compared with aspirin monotherapy, the major bleeding risk of ticagrelor plus aspirin and 
ticagrelor monotherapy according to Thrombolysis in Myocardial Infarction (TIMI) criteria. 
2)  Other advers events (AEs) during the study 
3. Study Design 
3.1 Overall Study Design and Flow Chart 
The study population will include all patients undergoing elective CABG. Consent and 
randomization will occur before surgery. Total 500 patients undergoing elective CABG will be 
randomly assigned into three groups with 1:1:1 ratio(167 patients per group) in this open-label study. 
All the enrolled patients will stop oral antiplatlet drugs according to local protocol before the surgery. 
Within the first 24 hours after surgery, study medication should be restarted and continued for 12 
months. Arm A will restart oral antiplatelet drugs by giving aspirin 100mg qd, Arm B will also restart 
oral antiplatelet drugs by giving ticagrelor 90mg bid plus aspirin 100mg qd and Arm C will also restart 
oral antiplatelet drugs by giving ticagrelor 90mg bid. Treatment will continue for 12 months, at which 
time patients will undergo a multislice computed tomography angiography to assess vein graft 
patency.  


 
Version: 4.0 28Aug2017                                         8  
 
3.2 Schematic Overview of the Study 
 
 
3.3 Sample Size Justification 
The trial was designed to compare rates of SV graft patency 1 year post CABG in patients 
randomized to ticagrelor plus aspirin combination therapy versus aspirin monotherapy, and in patients 
randomized to ticagrelor monotherapy versus aspirin monotherapy. The 1-year vein graft patency rate 
in the aspirin monotherapy group was assumed to be 90% in the ticagrelor plus aspirin group, 87% in 
the ticagrelor group and 80% in the aspirin group. The sample size calculations were performed with a 
2-sided alpha level of 0.05 and 80% power. On the basis of these assumptions, a total of 199 SV grafts 
would be required in each group for the comparison of combination therapy versus aspirin 
monotherapy; and 441 grafts would be required in each group for the comparison of the 2 
monotherapy groups. A total of 500 patients would be required to provide a total of 1350 to 1500 SV 
grafts, assuming that each patient would receive an average of 2.7 to 3.0 SV grafts. 
3.4 Randomization and Blinding 
3.4.1 Randomization after Subjects Enrolled 
Patient eligibility will be established before treatment randomization. Patients will be 
enrolled/randomized strictly sequentially, as patients become eligible for enrolment/randomization. If 
a patient discontinues from the study, the patient number will not be reused, and the patient will not be 
allowed to re-enter the study.  
After providing informed consent, patients who are consistent with the inclusion and exclusion 
criteria will be randomly assigned to one of the three treatment groups. The randomization will be 
performed by a computer equally for the three treatment regimens. Each centre will be provided with 
sealed treatment code envelopes corresponding to a list of patient randomization numbers. 
Randomization numbers will be assigned strictly sequentially as subjects become eligible for 
randomization. When a subject is allocated to a specified randomization number, the corresponding 
code envelope will be opened to identify the allocated treatment regimen. 
3.4.2 Blinding 
This is an open-label study, so blinding is not applicable. 


 
Version: 4.0 28Aug2017                                         9  
 
4. Study Endpoints 
4.1 Evaluation Methods for Study Endpoints 
1) 
The patency of vein grafts: assessed by multi-slice computed tomography angiography 
(MSCTA) or coronary angiography（CAG） according to Fitzgibbon Class 
2) 
Recurrent angina: based on CCS Angina Class  
4.2 Efficacy Endpoints 
4.2.1 Primary Efficacy Endpoint 
Angiographic vein graft patency by MSCTA or CAG at 12 months after CABG.  
There 3 levels of patency examination in vein grafts according to the Fitzgibbon Standards, that’s 
level A, level B, and level O. The percentage of level A is the rate of vein graft patency. 
Primary endpoint will analyzed based on mFAS and PP. 
4.2.2 Secondary Efficacy Endpoints 
1) 
Angiographic vein graft patency assessed by MSCTA or CAG at 7th day post CABG. 
2) 
In this study, MACE is defined as cardiovascular death, non-fatal myocardial infarction and 
non-fatal stroke (ischemic or unexplained). The rate of MACE and time to first MACE will be 
compared among 3 treatment groups. 
3) 
Rate of recurrent angina will be compared among 3 treatment groups. 
4) 
Rate of atrial fibrillation within 7 days post CABG. This rate is the percentage of subjects who 
had at least one PAF detected on electrocardiogram within 7 days post CABG. This rate will be 
compared among 3 treatment groups.  
4.3 Safety Endpoints 
1) 
Rate of adverse events 
2) 
Rate of serious adverse events 
3) 
Rate of adverse events leading to study agent interruption or withdrawal 
4)  Bleeding events will be defined according to TIMI standards (There are 2 types of bleeding 
events, CABG related bleeding and non-CABG related bleeding). 
In this study, bleeding will also be compared among 3 treatment groups. 
4.4 Other  
1) 
Summary of the operation information, include the type of grafts, off-pump or on-pump 
CABG technique, etc.  
2) 
Interested concomitant medication used, such as beta- receptor blockers, ACEI / ARBs, 
statins, and proton pump inhibitors  
3) 
Rate of smoking at visit 9 (1 year after CABG) 
4) 
Comparison in the chemistry and vital sign endpoints among 3 treatment groups 
Rate of Glycated hemoglobin ( HbA1c)≥6.5% from visit 6 to visit 9; 
Rate of Glycated hemoglobin ( HbA1c)≥7.0% from visit 6 to visit 9; 
Rate of Low-density lipoprotein≥1.8 mmol/L from visit 6 to visit 9; 
Rate of Low-density lipoprotein≥2.6 mmol/L from visit 6 to visit 9; 
Rate of Systolic blood pressure≥140 or Diastolic blood pressure≥90mmHg from visit 6 to 
visit 9. 


 
Version: 4.0 28Aug2017                                         10  
 
5, Data Management 
A quality assurance audit/inspection of this trial may be conducted by AstraZeneca or sponsor’s 
designees or by IRBs/IECs or by regulatory authorities. The quality assurance auditor will have access 
to all medical records, the investigator’s trial-related files and correspondence, and the informed 
consent documentation of this clinical trial.  
6. Analysis Specifications 
6.1 Adverse Events 
6.1.1 AE Duration 
AE duration is in days: 
Duration = end date – start date + 1 （days） 
6.1.2 Imputation of Missing AE Data 
1．Severity 
If the severity is missing, then “severe” will be imputed.  
2．Relationship 
If the relationship is missing, then “very likely” will be imputed.  
6.2 Concomitant Medication 
Imputation won’t be applied to concomitant medication data. 
6.3 Age Calculation 
Age of subjects will be calculated based on the date of visit 1, and in years, the formula is: 
（date of visit 1 – birthday + 1）÷365.25 
7. Analysis Sets 
This study will be analyzed by the planned treatment, regardless the actual treatment this subject 
received. 
7.1 Intent to Treat (ITT) 
ITT will include all the subjects who were randomized.  
Demographic and baseline data will be analyzed on ITT.  
7.2 Modified Full Analysis Set (mFAS) 
All the subjects in ITT will be included in mFAS, except those subjects who didn’t take any study 
agent or withdraw ICF before the first dose of study agent.   
All the efficacy analysis will be based on mFAS. 
7.3 Per Protocol Set（PPS） 
The subjects in mFAS who have no drug discontinuation or drug discontinuation <=60 days, have 


 
Version: 4.0 28Aug2017                                         11  
 
no other major protocol deviation, didn’t take any forbidden concomitant medication, have the 
primary endpoints assessment at 1 year post-CABG will be included in PPS. 
PPS will only be used in primary endpoint sensitive analysis. 
7.4 Safety Analysis Set（SS） 
All the subjects who took at least one study agent will be included in safety analysis set. 
Safety endpoints, such as adverse events, bleeding events, laboratory test, vital sign, will be 
analyzed based on safety analysis set.  
8. Statistical Analysis Methods 
This part contains general and specific definitions of statistical methods for the analysis of 
collected data in this study, however, any post-hoc analyses performed that are different from this part, 
will be documented in the analyses section of the CSR. 
8.1 Statistical Analysis Software 
All the statistical analyses are done on SAS 9.3 (SAS Institute Inc.). 
8.2 General Statistical Analysis Methods Applied 
Unless otherwise stated, statistical significance level is set to 0.05 (2-sided).  
8.2.1 Continuous Variables 
Descriptive summary statistics, such as number of subjects, mean, standard deviation (SD), 
median, interquartile range (IQR), minimum, and maximum will be used for continuous variable. 
ANOVA or Kruskal-Wallis test will be applied to the statistical test in the homogeneity of 
distribution among these 3 treatment group, whether ANOVA or Kruskal-Wallis test is determined by 
the tests of normality distribution and homogeneity of variance with the alpha level 0.05 for this 
variable。 
8.2.2 Discrete Variables 
Counts and percentages will be used to summarize the discrete variables. Fisher exact test, 
Continuity Adjusted Chi-Squared test, or Pearson Chi-Squared test will be applied to test homogeneity 
of the rates among 3 treatment groups, the choice on the method will be based on the actual counts in 
the frequency cells.  
8.2.3 Ordinal Variables 
Counts and percentages will be used to summarize the ordinal variables. Kruskal-Wallis test will 
be used in the comparison of ordinal variables. 
8.3 Statistical Test for Primary Endpoint 
The primary endpoint is the patency rate of vein grafts at visit 9 (1 year after CABG). Generally, 
there will be 1 to 4 grafts be examined per a subject, this is a typical repeated measures data, since 
those grafts within a subjects are definitely correlated, the conventional statistical methods like 
Pearson Chi-Squared test isn’t appropriate to test primary endpoint in this study. GEE（Generalized 
Estimating Equation）[1] is used to test the hypothesis of this study, 95% CIs and 2-sided p values will 
be provided. 
8.3.1 Handling in Missing Values for Primary Endpoint 
If the patency examination for a graft at the visit 9 (1 year after CABG) is missing, then level O 
will be imputed, then this graft is deemed as occlusion in primary analysis. 


 
Version: 4.0 28Aug2017                                         12  
 
8.3.2 Statistical Test for Primary Endpoint 
0
:
0


A
T
P
P
H
  
0
:
1


A
T
P
P
H
 与 
0
:
0



A
A
T
P
P
H
  
0
:
1



A
A
T
P
P
H
 
A—Aspirin、T—ticagrelor、T+A—Aspirin + ticagrelor 
 
Patency results from all the 3 treatment groups will be modeled in a same Generalized Estimating 
Equation, the rate difference and its 95% CI will be derived for the comparisons of A vs A+T (or A vs 
T). If the lower of 95% CI is greater than 0, then A+T (or T) is statistical significantly higher in the 
patency rate than A, the superiority of A+T (or T) proved. 
8.3.3 Statistical Descriptive of Patency of Grafts 
There levels of patency examination in grafts according to the Fitzgibbon Standards, that’s level 
A, level B, and level O, and it’s ordinal variable. The patency of grafts at the visit 5 (7 days after 
CABG) and visit 9 (1 year after CABG) will be summarized by using the statistical method for the 
ordinal variable. 
8.4 Secondary Endpoints 
8.4.1 Handling in Missing Values for Secondary Endpoint 
For the missing values in the patency examination for any graft in any visit will be imputed by 
the worst level in Fitzgibbon Standards. 
For the other secondary endpoints, missing value won’t be imputed. 
8.4.2 Statistical Descriptive and Statistical Test for Secondary Endpoints 
GEE will be applied to the rate of patency and non-occlusion of grafts, the other secondary 
endpoints will be analyzed by using the statistical methods defined in chapter 8.2, depends on the 
property of the variables. 
For MACE, statistical methods for the discrete variables will be applied to compare the rates of 
MACE event among these 3 treatment groups, Time to MACE (measured in days) will be analyzed 
using a log-rank test. Subjects who had not experienced MACE will be right-censored. The survival 
curves will be estimated using Kaplan-Meier estimates. 
 
8.5 Safety Endpoints 
8.5.1 Adverse Events 
AEs that occurred any time over the study will be reported and coded using Medical Dictionary 
for Regulatory Activities (MedDRA). All the adverse events will be listed. AEs will be summarized by 
treatment group, system organ class and preferred term.  
The following AE summary tables will be provided for this study:  
 
Adverse event 
 
Serious adverse event (SAEs) 
 
AEs leading to study agent interruption or withdrawal 
8.5.2 Smoking 
The comparison of smoking status in these 3 treatment groups will be analyzed by using the 
statistical methods for the discrete variable  
8.5.3 Bleeding Events 
The rate of bleeding events (Major bleeding, CABG related bleeding, non CABG related 
bleeding) among these 3 treatment groups will be summarized by using the statistical method for 
discrete variable. 


 
Version: 4.0 28Aug2017                                         13  
 
8.5.4 Comparison in the Chemistry and Vital Sign Endpoints among 3 Treatment Groups 
Rate of Glycated hemoglobin ( HbA1c)≥6.5% from visit 6 to visit 9 
Rate of Glycated hemoglobin ( HbA1c)≥7.0% from visit 6 to visit 9 
Rate of Low-density lipoprotein≥1.8 mmol/L from visit 6 to visit 9 
Rate of Low-density lipoprotein≥2.6 mmol/L from visit 6 to visit 9 
Rate of Systolic blood pressure≥140 or Diastolic blood pressure≥90mmHg from visit 6 to visit 
9 
The above comparisons will be analyzed by using the statistical methods for the discrete variable. 
8.6 Other Variables 
8.6.1 Demographic and Baseline Data 
Demographic and baseline characteristic variables will be descriptively summarized in ITT, no 
formal statistical comparison is planned.  
8.6.2 Baseline and Medical History 
The collected daseline data and medical history included angina,（CCS angina grade）, history of 
myocardial infarction, New York Heart Association (NYHA) functional classification, history of 
cerebrovascular accident; history of hypertension, history of diabetes mellitus, history of 
hyperlipidemia, history of chronic obstructive pulmonary disease (COPD), history of peptic ulcer or 
digestive hemorrhage, history of chronic kidney disease (CKD) (defined as baseline creatinine > 
200umol/L), history of peripheral arterial disease (PAD) (defined as a stenosis ≥ 50% detected in 
any carotid or femoral artery by Doppler ultrasonography), history of smoking, results of ultrasonic 
cardiogram (LVED, LVEF), SYNTAX score, EuroScore, and preoperative concomitant medication 
(including aspirin, IIb/IIa antagonist, low molecular weight heparin, beta blocker, ACEI / ARB, statin 
and proton pump inhibitor). 
8.6.3 Operation Information Data 
Operation information data including type of total grafts, number of IMA grafts RA grafts and SV 
grafts; off-pump or on-pump were collected as categorical variables. 
8.6.4 Concomitant Medication 
The proportion of patients using concomitant medication was collected at each follow-up point 
and was compared among the three groups. Main concomitant medications included beta blocker, 
ACEI / ARB, statin and proton pump inhibitor, comparative statistical analysis was carried out in each 
medication. 
8.7 Interim Analysis 
No interim analysis for this study. 


 
Version: 4.0 28Aug2017                                         14  
 
References 
[1]. Liang, K. Y. and Zeger, S. L. (1986), “Longitudinal Data Analysis Using Generalized Linear 
Models,” Biometrika, 73, 13–22.  


 
Version: 4.0 28Aug2017                                         15  
 
Appendix: Time and Events Schedule 
Phase 
Base
line/ 
Scre
enin
g4 
Treatment 
(Day 1-Day 360) 
 
 
 
 
 
 
Disch
arge2 
 
 
 
Endp
oint3 
Treatment Day1 
 
D1 
D2   
D3 
D5 
+1 
D9 
+2 
D30 
+7 
D90 
+7 
D180 
+14 
D360 
+14 
Visit 
 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Informed Consent 
Form5 
Ｘ 
 
 
 
 
 
 
 
 
 
Medical History 
Ｘ 
 
 
 
 
 
 
 
 
 
Vital Signs 
Ｘ 
 
 
 
 
 
 
 
 
 
Physical 
Examination 
Ｘ 
 
 
 
 
 
 
 
 
 
Concomitant 
medications 
Ｘ 
 
 
 
 
 
 
 
 
 
Hematology 
Ｘ 
 
 
 
 
 
 
 
 
 
Coagulation 
Ｘ 
 
 
 
 
 
 
 
 
 
Biochemistry 
Ｘ 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
 
Ｘ 
 
 
 
 
 
 
 
 
Randomization 
 
Ｘ 
 
 
 
 
 
 
 
 
Ticagrelor 
90mg 
bid 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Aspirin 100mg qd 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
ECG 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
UCG 
Ｘ 
 
 
 
 
 
 
Ｘ 
Ｘ 
Ｘ 
MSCTA6 
 
 
 
 
 
Ｘ 
 
 
 
Ｘ 
Pregnancy Test  
 
Ｘ 
 
 
 
 
 
 
 
 
Bleeding Events 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
AEs7 
 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
Ｘ 
 
NOTE:  
1. 
CAGB procedure will be operated on Day 0 
2. 
Discharge examination on Day 9±2 may be optional according to each center’s routine care. 
3. 
Subject who prematurely terminate treatment for any reason have to complete all the tests listed in the endpoint 
column. Follow-up duration can be 12 months 
4. 
Investigators must test all the screening results before study drug administration. 
5. 
Informed consent form must be obtained before any study -related procedure.  
6. 
MSCTA: Multislice Computed Tomography Angiography 
7. 
AEs recording began from the signing of informed consent throughout the study until and including the last visit