Clinical trial NCT02325466
Conditions: Peripheral Artery Disease Type 2 Diabetes
Keywords: Peripheral Artery Disease Type 2 Diabetes Blood Viscosity Ticagrelor Aspirin
Sponsor: Icahn School of Medicine at Mount Sinai
Start date: 2015-04-01; Completion date: 2018-05-04
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The hypothesis being that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period. Study participants will be randomized into 3 groups, and each group will receive each of 3 treatments in the cross-over study. At the end of each individual 4 week treatment period the investigators will determine whether there are differences in low and high shear rate dependent viscosity and investigate the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index and toe pressures. Subjects will be eligible if they have ankle-brachial index less than or equal to 0.85, or if a patient's blood vessels are calcified, patients will have toe-brachial index less than or equal to 0.6 performed using continuous-wave Doppler.

Detailed description:
Ticagrelor has been shown to significantly reduce the rate of cardiovascular disease (CVD) events and death compared with clopidogrel in patients having prior acute coronary syndrome. A number of outcome studies have demonstrated the risk of major CVD events increased with blood viscosity. Stroke patients and those with stroke risk factors were shown to have chronically elevated blood viscosity relative to healthy controls. Based on prior observations, the rationale for this study is to demonstrate that both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in the reduction of whole blood viscosity at the end of each 4 week treatment period.

The primary objectives for this study is to: (1) Compare the effect of aspirin-ticagrelor with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) shear rates at the end of each 4-week treatment period; and (2) to compare the effect of ticagrelor mono-therapy with aspirin in a double blind, randomized, cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 s-¹) and high (300 s-¹) at the end of each 4-week treatment.

The secondary objectives for this study include: (1) a determination as to whether there are differences in low and high shear rate dependent viscosity with treatment by ticagrelor alone and combination aspirin-ticagrelor. Additionally, investigated will be the effect of the treatment on peripheral arterial blood flow using pulse volume recordings, ankle brachial index, and toe pressures.

The general approach to evaluation of drug efficacy will be through blood samples collected with a standard venipuncture for viscosity testing. Blood viscosity will be measured using an automated scanning capillary tube viscometer across a physiologic range of shear rates of 1-1000 s-1 in increments of 0.1 s-1. Blood viscosity levels at 5 s-1 will be reported as low-shear viscosity, and blood viscosity measurements at 300 s-1 will be reported as high-shear viscosity. Additionally, pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal and toe bilaterally according to standard protocol, and Continuous-wave Doppler will be used to determine ankle-brachial indices or toe-brachial indices, and flow velocity profiles.

Arms: arm 1: aspirin 81 mg daily and ticagrelor placebo twice daily arm 2: aspirin 81 mg daily and ticagrelor 90 mg twice daily arm 3: aspirin placebo daily and ticagrelor 90 mg twice daily
Interventions: intervention 1: Aspirin intervention 2: Ticagrelor intervention 3: Aspirin Placebo intervention 4: Ticagrelor Placebo
Intervention descriptions: intervention 1: Aspirin 81mg intervention 2: ticagrelor 90 mg intervention 3: None intervention 4: None

Protocol documents:
Prot_SAP_000.pdf: 
Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in Peripheral 
Artery Disease Patients with Type 2 Diabetes
PI: Dr. Robert S. Rosenson
NCT02325466
Document Date: January 19, 2018


1(33)
Drug Substance 
Ticagrelor / BRILINTA / 
AZD6140 
Study Number 
ISSBRIL0174 
Version Number 
34 
Date 
2219-MayJan-20152018 
Comparative Efficacy of Ticagrelor Versus Aspirin on Blood Viscosity in 
Peripheral Artery Disease Patients with Type 2 Diabetes 
Sponsor: Robert S. Rosenson, MD 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
2(33) 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ........................................................................................................... 1 
TABLE OF CONTENTS ......................................................................................... 2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ............................ 6 
1. 
INTRODUCTION ................................................................................................... 6 
1.1 
Background .............................................................................................................. 6 
1.2 
Research hypothesis ................................................................................................. 7 
1.3 
Rationale for conducting this study ......................................................................... 7 
1.4 
Benefit/risk and ethical assessment.......................................................................... 8 
2. 
STUDY OBJECTIVES ............................................................................................ 8 
2.1 
Primary objective ..................................................................................................... 8 
2.2 
Secondary objectives ............................................................................................... 8 
2.3 
Safety objective ........................................................................................................ 9 
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 .................................................................... 11 
4.1 
Inclusion criteria .................................................................................................... 11 
4.2 
Exclusion criteria ................................................................................................... 12 
5. 
STUDY CONDUCT .............................................................................................. 15 
5.1 
Restrictions during the study ................................................................................. 15 
5.2 
Subject enrollment and randomization .................................................................. 15 
5.2.1 
Procedures for randomization ................................................................................ 15 
5.3 
Procedures for handling subjects incorrectly enrolled ........................................... 15 
5.4 
Blinding and procedures for unblinding the study ................................................. 15 
5.4.1 
Methods for ensuring blinding ............................................................................... 15 
5.4.2 
Methods for unblinding the study .......................................................................... 15 
5.5 
Treatments .............................................................................................................. 15 
5.5.1 
Identity of investigational product(s) ..................................................................... 15 
5.5.2 
Doses and treatment regimens ............................................................................... 16 
5.5.3 
Additional study drug ............................................................................................ 16 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
3(33) 
5.5.4 
Labeling ................................................................................................................. 16 
5.5.5 
Storage ................................................................................................................... 16 
5.6 
Concomitant and post-study treatment(s) .............................................................. 16 
5.7 
Treatment compliance ............................................................................................ 16 
5.7.1 
Accountability ........................................................................................................ 16 
5.8 
Discontinuation of investigational product ............................................................ 17 
5.8.1 
Procedures for discontinuation of a subject from investigational product ............ 17 
5.9 
Withdrawal from study .......................................................................................... 17 
6. 
COLLECTION OF STUDY VARIABLES ........................................................... 17 
6.1 
Recording of data ................................................................................................... 17 
6.2 
Data collection at enrollment and follow-up ......................................................... 18 
6.2.1 
Enrollment procedures ........................................................................................... 18 
6.2.2 
Follow-up procedures ............................................................................................ 18 
6.3 
Efficacy .................................................................................................................. 18 
6.3.1 
Whole Blood Viscosity .......................................................................................... 18 
6.4 
Safety ..................................................................................................................... 19 
6.4.1 
Definition of adverse events .................................................................................. 19 
6.4.2 
Definitions of serious adverse event ...................................................................... 19 
6.4.3 
Recording of adverse events .................................................................................. 20 
6.4.4 
Reporting of serious adverse events....................................................................... 22 
6.4.5 
Laboratory safety assessment ................................................................................ 23 
6.5 
Physical examination ............................................................................................. 23 
6.5.1 
ECG ........................................................................................................................ 23 
6.5.1.1 
Resting 12-lead ECG ............................................................................................. 23 
6.5.1.2 
Real time display (telemetry) ................................................................................. 24 
6.5.2 
Vital signs .............................................................................................................. 24 
6.5.2.1 
Pulse and blood pressure ........................................................................................ 24 
6.5.2.2 
Body temperature ................................................................................................... 24 
6.5.3 
Other safety assessments ........................................................................................ 24 
6.6 
Patient reported outcomes (PRO) .......................................................................... 24 
6.6.1 
PRO method or questionnaire ................................................................................ 24 
6.7 
Pharmacokinetics ................................................................................................... 24 
6.7.1 
Collection of samples ............................................................................................. 25 
6.7.2 
Determination of drug concentration ..................................................................... 25 
6.8 
Pharmacodynamics ................................................................................................ 25 
6.8.1 
Collection of pharmacodynamic markers .............................................................. 25 
6.9 
Pharmacogenetics .................................................................................................. 25 
6.9.1 
Collection of pharmacogenetic samples ................................................................ 25 
6.10 
Health economics ................................................................................................... 25 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
4(33) 
7. 
BIOLOGICAL SAMPLING PROCEDURES ....................................................... 25 
7.1 
Volume of blood .................................................................................................... 25 
7.2 
Handling, storage and destruction of biological samples ...................................... 25 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples ............................................. 25 
7.2.2 
Pharmacogenetic samples ...................................................................................... 26 
7.3 
Labeling and shipment of biohazard samples ........................................................ 26 
7.4 
Chain of custody of biological samples ................................................................. 26 
7.5 
Withdrawal of informed consent for donated biological samples ......................... 26 
8. 
ETHICAL AND REGULATORY REQUIREMENTS ......................................... 26 
8.1 
Ethical conduct of the study ................................................................................... 26 
8.2 
Ethics and regulatory review.................................................................................. 26 
8.3 
Informed consent ................................................................................................... 27 
8.4 
Changes to the protocol and informed consent form ............................................. 27 
8.5 
Audits and inspections ........................................................................................... 28 
9. 
STUDY MANAGEMENT .................................................................................... 28 
9.1 
Training of study site personnel ............................................................................. 28 
9.2 
Monitoring of the study ......................................................................................... 28 
9.2.1 
Source data ............................................................................................................. 28 
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 
11.2.1 
Other significant adverse events (OAE) ................................................................ 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 
11.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables ................................................................................... 29 
11.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables .................. 29 
11.6 
Calculation or derivation of pharmacogenetic variables........................................ 29 
11.7 
Calculation or derivation of health economic variables......................................... 30 
12. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ............ 30 
12.1 
Description of analysis sets .................................................................................... 30 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
5(33) 
12.1.1 
Efficacy analysis set ............................................................................................... 30 
12.1.2 
Safety analysis set .................................................................................................. 30 
12.2 
Methods of statistical analyses ............................................................................... 30 
12.2.1 
Interim analyses ..................................................................................................... 30 
12.3 
Determination of sample size ................................................................................. 31 
12.4 
Data monitoring committee ................................................................................... 31 
13. 
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR .................................................................................................. 31 
13.1 
Overdose ................................................................................................................ 31 
13.2 
Pregnancy ............................................................................................................... 31 
13.2.1 
Maternal exposure .................................................................................................. 31 
13.2.1.1 Paternal exposure ................................................................................................... 32 
14. 
LIST OF REFERENCES ....................................................................................... 32 
 
LIST OF TABLES 
Table 1. Study Schedule 
Table 2. Laboratory Parameters 
LIST OF FIGURES 
Figure 1. Study Flow Sheet 
LIST OF APPENDICES 
None. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
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 
ABI 
Ankle brachial index  
ASA 
Acetylsalicylic acid; Aspirin 
ANOVA 
Analysis of Variance 
BID 
Twice a day 
CVD 
Cardiovascular disease 
cP  
Centipoise  
DM 
Diabetes mellitus  
mg  
Milligrams  
MI 
Myocardial infarction 
OD 
Oral dose 
PAD 
Peripheral artery disease 
s-1 
Inverse seconds; shear rate 
WBV 
Whole blood viscosity 
 
1. 
INTRODUCTION 
1.1 
Background 
Ticagrelor is a cyclopentyltriazolopyrimidine that has been shown to reduce significantly the 
rate of cardiovascular disease (CVD) events and death compared with clopidogrel in 18,624 
patients having prior acute coronary syndrome [1].  The adenosine diphosphate receptor 
P2Y12 antagonist, clopidogrel 75 mg was more effective than aspirin 325 mg in reducing 
CVD events or death in a clinical trial of 19,185 patients with atherosclerosis, presenting with 
symptomatic peripheral artery disease (PAD), recent ischemic stroke or myocardial infarction 
(MI) [2].  In a pre-specified analysis of risk by the type of vascular events at entry, there was 
no reduction in MI, stroke or cardiovascular death rates in patients who entered the trial with 
an ischemic stroke or MI while there was a relative risk reduction of 23.8% (p=0.0028) in the 
group entering the trial with symptomatic PAD.  The disproportionate event reduction in 
patients with PAD patients suggests that mechanisms other than atherosclerosis or thrombosis 
may contribute to CVD event reduction in these patients.  Of the possible mechanisms, blood 
rheology is an important factor that influences macrovascular and microvascular flow in lower 
extremity arteries, and predicts CVD events in PAD patients.  


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
7(33) 
1.2 
Research hypothesis 
Both aspirin-ticagrelor and ticagrelor monotherapy will be superior to aspirin monotherapy in 
the reduction of whole blood viscosity at the end of each 4 week treatment period.   
1.3 
Rationale for conducting this study 
A previous study comparing 120 patients having intermittent claudication with normal age-
matched controls found blood viscosity was significantly higher among claudicants (p<0.001) 
with the greatest difference in blood viscosity observed at lowest shears [3].  At high shear 
rates, patients with blood viscosity above 4.5 cP had mean claudication distance of 126 meters 
compared to 289 meters for patients with high-shear viscosity below that threshold.  This 
report suggested the use of the term rheological claudication to describe approximately 25% 
of moderate to severe claudicants with hyperviscosity of blood having significantly worse 
prognoses.   
In a random sample of 1,581 men and women 55 to 74 years of age with symptomatic or 
asymptomatic PAD, whole blood viscosity and fibrinogen were independently associated with 
peripheral arterial narrowing [4].  Plasma viscosity was also associated with claudication. The 
risk of claudication for patients in the upper quintile of plasma viscosity was 3.4 times greater 
than the risk for those in the lowest plasma viscosity quintile.  The authors implicated blood 
rheological factors in the pathogenesis of lower limb ischemia in the general population. 
The link between blood viscosity and ischemic heart disease events or strokes was reported in 
a study of a random population of 1,592 adults followed for a mean of 5 years:  After 
adjustment for age and gender, both blood viscosity and hematocrit-corrected blood viscosity 
were higher in patients who experienced CVD events (myocardial infarction, angina pectoris, 
coronary revascularization or stroke) than in those who did not.  The difference in blood 
viscosity between the two groups of patients was significant (p=0.0003) [5].  A number of 
outcome studies have demonstrated the risk of major CVD events increased with blood 
viscosity [6,7].  Stroke patients and those with stroke risk factors were shown to have 
chronically elevated blood viscosity relative to healthy controls [8].   
A number of observational studies have reported increased blood viscosity in type 2 diabetics 
compared with nondiabetics.  In an early clinical study comparing 16 diabetics with 16 age 
and gender-matched nondiabetic control subjects, mean blood viscosity at low shear rate was 
observed to be 26% higher in diabetics (p<0.001) [9].  A study of 38 male diabetics with and 
without retinopathy compared against 38 nondiabetics, matched for age and smoking habit, 
found low-shear blood viscosity levels were on average 13% higher in diabetics without 
retinopathy and 30% higher in those with retinopathy relative to control subjects [10].  These 
differences persisted after adjusting for hematocrit.  A separate study of 64 diabetics and 61 
matched nondiabetics reported similar results: elevated mean viscosity levels in diabetics 
compared with control subjects and the highest increases in diabetics with retinopathy or 
nephropathy [11].   
 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
8(33) 
Pharmacological therapies for reducing blood viscosity have been limited to clopidogrel [12], 
aspirin-dipyridamole [13] and in some studies pentoxifylline [14,15]. A reduction in blood 
viscosity has not been observed with either cilostazol [15] or ticlopidine [16].  In a double-
blind, placebo-controlled study of 30 age and gender-matched patients with subclinical carotid 
or femoral atherosclerosis, clopidogrel was observed to reduce mean low-shear blood 
viscosity by 18% from baseline levels 3 weeks after administration (p<0.01) [12].   
1.4 
Benefit/risk and ethical assessment 
The cross-over study design exposes each randomized group to each of the three treatments, 
thus reducing treatment bias.  Aspirin monotherapy for treatment of PAD is technically an off-
label use, however, it is remains a Class I recommendation by the ACCF/AHA Task Force on 
Practice Guidelines when given in daily doses of 75 to 325 mg as a safe and effective 
antiplatelet therapy to reduce risk of CVD events in those with symptomatic lower extremity 
PAD [17].  Patients should be counseled on the importance of not taking aspirin outside of the 
study because doses greater than 100 mg/day can reduce the efficacy of ticagrelor [18].  When 
possible, if ticagrelor treatment results in bleeding, the bleeding should be managed without 
stopping therapy as increased risk of CVD events can occur.  Also, patients with history of 
hyperuricemia, gouty arthritis, hepatic impairment, and renal impairment should be monitored 
closely if taking ticagrelor. 
2. 
STUDY OBJECTIVES    
2.1 
Primary objective 
(1)  Compare the effect of aspirin-ticagrelor with aspirin in a double blind, randomized, cross-
over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both low (5 
s-¹) and high (300 s-¹) shear rates at the end of each 4-week treatment period.  
(2)  Compare the effect of ticagrelor monotherapy with aspirin in a double blind, randomized, 
cross-over study design (weeks 1-4, weeks 6-10, and weeks 12-16) on blood viscosity at both 
low (5 s-¹) and high (300 s-¹) at the end of each 4-week treatment.   
2.2 
Secondary objectives 
(1)  Determine whether there are differences in low and high shear rate dependent viscosity 
with treatment by ticagrelor alone and combination aspirin-ticagrelor.  
(2)  Investigate the effect of the treatment on peripheral arterial blood flow using pulse volume 
recordings, ankle brachial index, toe pressures and laser flow Doppler (a new emerging 
technique capable of measuring the velocity of flow and number of cells in the vessel, 
providing a normalized measure of microcirculatory flow  ( velocity of flow x number of 
cells/backscatter) 
.   


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
9(33) 
2.3 
Safety objective 
This study is not designed to compare safety between treatments. 
2.4 
Exploratory objectives 
Not applicable. 
3. 
STUDY PLAN AND PROCEDURES 
3.1 
Overall study design and flow chart 
The proposed, double-blind, placebo-controlled, cross-over design study examines and 
compares the effects of low-dose aspirin, combination aspirin-ticagrelor, and ticagrelor 
monotherapy on blood viscosity in type 2 diabetes patients with symptomatic PAD who are 18 
years of age or older. Study participants will be randomized into 3 groups, and each group will 
receive each of 3 treatments in the cross-over study.  Subjects will be eligible if they have 
ankle-brachial index less than or equal to 0.85, or if a patient’s blood vessels are calcified, 
patients will have toe-brachial index less than or equal to 0.6 performed using continuous-
wave Doppler.  Pulse volume recordings will be simultaneously obtained at the level of the 
ankle, metatarsal and toe bilaterally (Parks Flolab, Parks Medical Electronics, Aloha, OR) 
according to standard protocol as well as Laser flow Doppler (Perimed Periflux 5000, Perimed 
AB, Sweden).  Subjects will be excluded for planned revascularization or amputation, as well 
as for known hypersensitivity or allergic reactions to aspirin, bleeding disorders, history of 
intracranial hemorrhage, and those considered to be at risk of hemorrhagic events will also be 
excluded from the study. Aspirin 81 mg has been shown to have no significant effect on blood 
viscosity in healthy individuals [13], and will be used as background therapy prior to 
randomization; this treatment will serve as comparison for control.   
After 2 weeks run-in treatment with aspirin 81 mg daily, patients will be randomized to one of 
3 arms (ticagrelor placebo and aspirin 81 mg (Group A), ticagrelor and aspirin 81 mg (Group 
B), or ticagrelor monotherapy with aspirin placebo (Group C)) and treated for 4 weeks.  At 
this initial visit and every visit thereafter, laboratory assessments will be performed, including 
whole blood viscosity, complete blood count (CBC), fibrinogen, globulins, lipid profile, 
ankle/toe brachial index, and pulse volume recording (PVR).  Vital signs will also be assessed 
at each visit.  At the end of 4 weeks treatment, all 3 groups will receive aspirin 81 mg for 2 
weeks to reestablish baseline values. After the 2-week washout, the ticagrelor placebo and 
aspirin 81 mg treatment group (Group A) will be treated with aspirin 81 mg daily and 
ticagrelor; the aspirin 81 mg daily and ticagrelor treatment group (Group B) will be treated 
with ticagrelor monotherapy; and, the ticagrelor monotherapy group (Group C) will be treated 
with ticagrelor placebo and aspirin 81 mg daily for 4 weeks.  After the end of 4 weeks 
treatment, again, all 3 groups will receive aspirin 81 mg for 2 more weeks to re-establish 
baselines.  After this 2-week washout period, the third and final treatment will be for 4 weeks 
as follows:  ticagrelor monotherapy for Group A, ticagrelor placebo and aspirin 81 mg for 
Group B, and ticagrelor with aspirin 81 mg for Group C.  After randomization, the time-
window beginning with Visit 1 and for  


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Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
11(33) 
In a random sample of 1,581 men and women 55 to 74 years of age with symptomatic or 
asymptomatic PAD, whole blood viscosity and fibrinogen were independently associated with 
peripheral arterial narrowing [4].  Plasma viscosity was also associated with claudication. The 
risk of claudication for patients in the upper quintile of plasma viscosity was 3.4 times greater 
than the risk for those in the lowest plasma viscosity quintile.  The authors implicated blood 
rheological factors in the pathogenesis of lower limb ischemia in the general population. 
The link between blood viscosity and ischemic heart disease events or strokes was reported in 
a study of a random population of 1,592 adults followed for a mean of 5 years:  After 
adjustment for age and gender, both blood viscosity and hematocrit-corrected blood viscosity 
were higher in patients who experienced CVD events (myocardial infarction, angina pectoris, 
coronary revascularization or stroke) than in those who did not.  The difference in blood 
viscosity between the two groups of patients was significant (p=0.0003) [5].  A number of 
outcome studies have demonstrated the risk of major CVD events increased with blood 
viscosity [6,7].  Stroke patients and those with stroke risk factors were shown to have 
chronically elevated blood viscosity relative to healthy controls [8].   
A number of observational studies have reported increased blood viscosity in type 2 diabetics 
compared with nondiabetics.  In an early clinical study comparing 16 diabetics with 16 age 
and gender-matched nondiabetic control subjects, mean blood viscosity at low shear rate was 
observed to be 26% higher in diabetics (p<0.001) [9].  A study of 38 male diabetics with and 
without retinopathy compared against 38 nondiabetics, matched for age and smoking habit, 
found low-shear blood viscosity levels were on average 13% higher in diabetics without 
retinopathy and 30% higher in those with retinopathy relative to control subjects [10].  These 
differences persisted after adjusting for hematocrit.  A separate study of 64 diabetics and 61 
matched nondiabetics reported similar results: elevated mean viscosity levels in diabetics 
compared with control subjects and the highest increases in diabetics with retinopathy or 
nephropathy [11].   
Pharmacological therapies for reducing blood viscosity have been limited to clopidogrel [12], 
aspirin-dipyridamole [13] and in some studies pentoxifylline [14,15]. A reduction in blood 
viscosity has not been observed with either cilostazol [15] or ticlopidine [16].  In a double-
blind, placebo-controlled study of 30 age and gender-matched patients with subclinical carotid 
or femoral atherosclerosis, clopidogrel was observed to reduce mean low-shear blood 
viscosity by 18% from baseline levels 3 weeks after administration (p<0.01) [12].   
4. 
SUBJECT SELECTION CRITERIA 
4.1 
Inclusion criteria 
For inclusion in the study subjects should fulfill the following criteria: 
1. 
Provision of informed consent prior to any study specific procedures 
2. 
Subject is willing to comply with the requirements of the study protocol 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
12(33) 
3. 
Male or female ≥ 18 years of age 
4. 
Type 2 diabetes mellitus  
5. 
Symptomatic PAD 
 
6. Ankle-brachial index ≤ 0.85 or calcified blood vessels with toe-brachial index ≤ 
0.6 and/or abnormal post-exercise ankle-brachial index.7. Prior surgical or 
percutaneous intervention of the peripheral arteries ≥ -3 months with non-drug 
eluting stent placement and ≥12 months for those with drug-eluting stents 
previously with a residual stenoses of ≥ 50% in a non-dilated artery. 
8. Subject has hypersensitivity or allergic reactions to  clopidogrel 
4.2 
Exclusion criteria 
Subjects should not enter the study if any of the following exclusion criteria are fulfilled: 
1. 
Type I diabetes, poorly controlled diabetes (HbA1c ≥ 8.5 ± 09.5%), newly 
diagnosed type 2 diabetes (within 6 months of randomization), or laboratory 
evidence of diabetes during screening (fasting serum glucose ≥ 126 mg/dL [7.0 
mmol/L] or HbA1c ≥ 6.5%) without prior diagnosis of diabetes 
2. 
Uncontrolled hypertension defined as sitting systolic blood pressure (SBP) > 180 
mmHG or diastolic  BP (DBP) > 100 mmHg 
3. 
NYHA  III or IV heart failure, or last known left ventricular ejection fraction 
(LVEF) ≤ 30% 
4. 
Subject has a hypersensitivity or allergic reactions to ticagrelor 
5. 
Subject has a hypersensitivity or allergic reactions to aspirin 
6. 
Subject who has known sensitivity to any of the products or components to be 
administered during dosing or procedures 
7. 
Need for chronic oral anticoagulation therapy (e.g. cilostazole)  or chronic low-
molecular-weight heparin or long-term treatment with fondaparinux 
8. 
Planned revascularization (surgical or endovascular) in any vascular territory during 
the duration of the study 
9. 
Planned amputation due to PAD within the duration of the study or amputation due 
to PAD within the last 30 days 
10. 
Subjects who have suffered a stroke in the last 3 months 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
13(33) 
11. 
Dementia likely to jeopardize understanding of information pertinent to study 
conduct or compliance to study procedures 
12. 
Subject has a history of severe liver disease (e.g. ascites and/or clinical signs of 
coagulopathy) or obstructive liver disease [(e.g. primary biliary cirrhosis or end-
stage renal disease (eGFR ≤ 30 mL/min/m2)] 
13. 
A known bleeding diathesis, haemostatic or coagulation disorder, or systemic 
bleeding, whether  resolved or ongoing 
14. 
History of previous intracranial bleed at any time, gastrointestinal bleed within the 
past 6 months, or major surgery within the past 3 months of screening (if the 
surgical wound is judged to be associated with an increased risk of bleeding) 
15. 
Considered at risk of hemorrhagic events 
16. 
Subject who has not been on stable lipid lowering therapy in the last 3 months prior 
to LDL-C screening [e.g. red yeast rice, > 200mg/day niacin, or prescription lipid-
regulating drugs (e.g. fibrates and derivatives, statins, ezetimibe) other than bile-
acid sequestering resin, or stanols/plant stanols and stanol esters 
17. 
Treatment in the last 3 months prior to LDL-C screening with any of the following 
drugs: systemic cyclosprorine, systemic steroids (e.g. IV, intramuscular [IM], or 
PO) (Note: hormone replacement therapy is permitted), Oral vitamin A derivatives 
and retinol derivatives for the treatment of dermatologic conditions (e.g. Accutane); 
(Note: Vitamin A in a multivitamin preparation, as well as topical retinoid and 
retinol creams are permitted) 
18. 
Initiation of prescription triglyceride lowering therapy (e.g. Lovaza) which is not 
stable within 6 weeks of screening 
19. 
Subject has acute infection (e.g. bacterial, fungal) within the previous 6 weeks prior 
to screening (Note: subjects with a viral infection such as the common cold are not 
excluded) 
20. 
Subject has anemia (hemoglobin ≤ 8.5 g/dL)  that requires a potential blood 
transfusion within 6 weeks of screening 
21. 
Subject has given blood or received a blood transfusion within the previous 3 
months prior to screening  
22. 
Subject has polycythemia vera or any hyperviscosity syndrome 
23. 
Subjects with Waldenstrom’s macroglobulinemia who have an increased risk of 
hyperviscosity syndrome 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
14(33) 
24. 
Female subject who has either (1) not used at least 1 highly effective method of 
contraception for at least 1 month prior to screening or (2) is not willing to use such 
a method  during treatment and for an additional 15 weeks after the end of 
treatment, unless the subject is sterilized or postmenopausal.  Menopause is defined 
as: 12 months of spontaneous and continuous amenorrhea in a female ≥ 55 years old 
or 12 months of spontaneous and continuous amenorrhea with a follicle-stimulating 
hormone (FSH) level > 40 IU/L (or according to the definition of “postmenopausal 
range” for the laboratory involved) in a female < 55 years old unless the subject has 
undergone bilateral oophorectomy.  Highly effective methods of birth control 
include: not having intercourse or using birth control methods that work at least 
99% of the time when used correctly and include: birth control pills, shots, 
implants, or patches, intrauterine devices (IUDs), tubal ligation/occlusion, sexual 
activity with a male partner who has had a vasectomy, condom or occlusive cap 
(diaphragm or cervical/vault caps) used with spermicide 
25. 
Subject is pregnant or breast-feeding, or planning to become pregnant during 
treatment and/or within 15 weeks after the end of treatment 
26. 
Subject who is likely to not be available to complete all protocol-required study 
visits or procedures, and/or to comply with all required study procedures (e.g. blood 
collection procedures to ensure subject safety to the best of the subject and 
investigator’s knowledge 
27. 
History or evidence of any other clinically significant disorder, condition or disease 
(with the exception of those outline above) that, in the opinion of the Investigator or 
Sponsor, if consulted, would pose a risk to subject safety or interferes with the study 
evaluation, procedures or completion (e.g. active malignancy other than squamous 
cell or basal cell skin cancer, use of strong or moderate CYP2C19 inhibitors, long-
term concomitant treatment with non-steroidal anti-inflammatory  drugs [NSAIDs]) 
28. 
Unreliability as a study participant based on the Investigator’s (or designee’s) 
knowledge of the subject (e.g. alcohol or other drug abuse, inability or 
unwillingness to adhere to the protocol, or psychosis) 
29. 
Currently enrolled in another investigational device or drug study, or less than 30 
days since ending another investigational device or drug study(s), or receiving other 
investigational agent(s) 
30. 
Family members or employees of the investigator or study centers involved in the 
study 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
15(33) 
5. 
STUDY CONDUCT 
5.1 
Restrictions during the study 
• Patients must refrain from taking aspirin beyond the doses administered in the study. 
• Patients must avoid giving blood or receiving a blood transfusion during the study 
duration 
5.2 
Subject enrollment and randomization 
5.2.1 
Procedures for randomization 
Study participants will be randomized into 3 groups, and each group will receive each of 3 
treatments in the cross-over study.  Block randomization will be used to create groups which 
have equal and balanced sample sizes (i.e. for every block of 6 subjects, two will be enrolled 
to each arm of the study).   
5.3 
Procedures for handling subjects incorrectly enrolled 
Subjects who are incorrectly enrolled or randomized will no longer qualify for the study and a 
replacement subject will be enrolled, if possible. 
5.4 
Blinding and procedures for unblinding the study 
5.4.1 
Methods for ensuring blinding 
The study will be a double-blind, double-dummy (both participants and clinicians), placebo 
controlled, cross-over study.  Patient data will be coded and entered on a computer at the 
clinical site.  All data will have password protection and controlled access.  Drugs and 
placebos will also be coded to avoid bias when administering and taking the doses. 
5.4.2 
Methods for unblinding the study 
At the conclusion of the study or if a serious adverse event is experienced, data will be 
decoded to reveal patient and therapy information.   
5.5 
Treatments 
5.5.1 
Identity of investigational product(s) 
Ticagrelor   
ASA (Aspirin) 
Investigational product 
Dosage form and strength 
Manufacturer 
Ticagrelor 
90 mg Tablet 
AstraZeneca Pharmaceuticals LP 
Chewable ASA (Aspirin) 
81 mg Tablet 
Any  
 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
16(33) 
5.5.2 
Doses and treatment regimens 
The 3 treatment groups will receive: 
1. Group A: Aspirin 81 mg daily and ticagrelor placebo twice daily 
2. Group B: Aspirin 81 mg daily and ticagrelor 90 mg twice daily  
3. Group C: Aspirin placebo daily and ticagrelor 90 mg twice daily 
 
Each treatment group will receive all 3 of the above treatments in this cross-over study.  
5.5.3 
Additional study drug 
Not applicable 
5.5.4 
Labeling 
Labeling for 4 treatments (aspirin 81 mg daily, aspirin placebo daily, ticagrelor 90 mg twice 
daily, and ticagrelor placebo twice daily) will be coded.   
5.5.5 
Storage 
Ticagrelor will be stored at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 
86°F).   ASA will be stored in a cool, dry place. 
5.6 
Concomitant and post-study treatment(s) 
Not applicable. 
5.7 
Treatment compliance 
All subjects will be counseled on the importance of taking their doses as directed.  Each 
subject will be expected to document time and date of each dose in a daily dosing diary.  
Additionally, a pill count will be performed at each visit. 
5.7.1 
Accountability 
The Principal Investigator undertakes to perform the study in accordance with GCP including 
requirements stated in the Code of Federal Regulations (e.g., 21 CFR – Part 312 Subpart D 
[Responsibilities of Sponsors and Investigators]). 
The Principal Investigator is required to ensure compliance with respect to the visit schedule 
and procedures required by the protocol.  The Principal Investigator agrees to provide all 
information requested in the Case Report Form in an accurate and legible manner according to 
instructions provided. 
The Sponsor of this study has responsibilities to Health Authorities to take all reasonable steps 
to ensure the proper conduct of the study as regards ethics, protocol adherence, integrity, and 
validity of the data recorded on the Case Report Forms.  Thus, the main duty of the Medical 
Monitor and of his/her clinical research support team is to help the Investigator and the 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
17(33) 
Sponsor maintain a high level of ethical, scientific, technical, and regulatory quality in all 
aspects of the study. 
At regular intervals during the study, the center will be contacted, through site visits, letters, or 
telephone calls by a representative of the monitoring team to review study progress, Principal 
Investigator and subject adherence to protocol requirements, and any emergent problems.  
During the monitoring visits, the following points will be scrutinized with the Principal 
Investigator: subject informed consent, subject recruitment and follow-up, study device 
allocation, subject compliance to the study procedures, study device accountability, 
concomitant therapy use, AE and SAE documentation and reporting, and quality of data.  
Sections of Case Report Forms (CRFs) may be collected on a per visit basis. 
5.8 
Discontinuation of investigational product 
5.8.1 
Procedures for discontinuation of a subject from investigational product  
Subjects will be notified in person at the end of study visit, or under circumstances when this 
last visit has not been completed via telephone, or by certified mail upon determination that he 
or she will no longer receive the investigational product. 
5.9 
Withdrawal from study 
Subjects MUST be withdrawn from the study for any of the following reasons: 
• If the study appears to be medically harmful to the subject (e.g. an SAE). 
• If the subject fails to follow the directions given by the Investigator or study staff 
required to continue in the study (e.g. personal reason). 
• If it is discovered that the subject does not meet the study requirements. 
• If the study is canceled by the study sponsor. 
6. 
COLLECTION OF STUDY VARIABLES 
6.1 
Recording of data 
All CRFs should be completed in their entirety in a neat, legible manner to ensure accurate 
interpretation of data; a black ballpoint pen should be used to ensure the clarity of reproduced 
copy of all CRFs. 
Should a correction be made, the information to be modified must not be overwritten.  The 
incorrect recording will have a single neat line drawn through it.  The correct information will 
then be transcribed next to the previous value, along with the reason for the correction.  The 
authorized person making the correction will then initial and date it. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
18(33) 
6.2 
Data collection at enrollment and follow-up 
6.2.1 
Enrollment procedures 
Potential subjects will answer questions and these responses will be recorded on the CRF.  
Subjects will be asked if they are pregnant; pregnant subjects will not qualify for enrollment in 
this study.  Qualifying subjects will be requested to enroll into the study.  Subjects satisfying 
all inclusion criteria and without any reason for exclusion will be eligible for the study.  
Subjects not fulfilling the requirements are not eligible and will be replaced.  The following 
data will be recorded on the subject’s CRF:  demographics, CVD risk factors (including 
smoker/non-smoker, hypertension, diet, physical activity), clinical history, vital signs, and 
medications.  Those subjects who sign the informed consent and who pass the initial screening 
will be administered aspirin 81 mg by mouth once daily for 2 weeks.   
After 2 weeks run-in treatment with aspirin 81 mg daily, patients will be randomized to one of 
3 arms (ticagrelor placebo and aspirin 81 mg (Group A), ticagrelor and aspirin 81 mg (Group 
B), or ticagrelor monotherapy with aspirin placebo (Group C)) and treated for 4 weeks.  
Laboratory assessments will be performed, including whole blood viscosity, complete blood 
count (CBC), fibrinogen, globulins, lipid profile, ankle/toe brachial index, and pulse volume 
recording (PVR).  Some of the laboratory samples will be stored in a -70°C freezer for future 
assessments and genetic testing. Vital signs will also be assessed at each visit.  
Any adverse events (AEs) will be properly recorded on the CRF, and any Serious Adverse 
Events (SAEs) will be recorded on SAE forms (MEDWATCH 3500A Form) and the AE form 
of the CRF, and will be reported to the Sponsor.  Any AE not resolved or not resolved with 
sequelae within thirty minutes after the scheduled blood draw will be followed until such 
resolution occurs, and this resolution will be noted on the CRF.    
6.2.2 
Follow-up procedures 
The schedule for follow-up visits is described in Section 3.1. At each follow-up visit, 
laboratory assessments will be performed, including whole blood viscosity, complete blood 
count (CBC), fibrinogen, globulins, lipid profile, ankle/toe brachial index, pulse volume 
recording (PVR) and laser flow Doppler assessment.  Some of the laboratory samples will be 
stored in a -70°C freezer for future assessments and genetic testing. Vital signs, medication 
adherence, medication safety, and medication efficacy will also be assessed at each visit.  
6.3 
Efficacy 
6.3.1 
Whole Blood Viscosity 
Blood samples will be collected with a standard venipuncture.  Approximately 3 cc of blood 
will be collected into an EDTA-containing vacutainer (Becton, Dickinson and Company, 
Franklin Lakes, NJ, USA) and transported in a refrigerated shipment kit to Rheovector LLC 
(Camden, NJ) for viscosity testing.  Blood viscosity will be measured using an automated 
scanning capillary tube viscometer across a physiologic range of shear rates of 1-1000 s-1 in 
increments of 0.1 s-1.  Blood viscosity levels at 5 s-1 will be reported as low-shear viscosity, 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
19(33) 
and blood viscosity measurements at 300 s-1 will be reported as high-shear viscosity.  An 
additional 5 cc of blood will be collected for CBC testing. 
Pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal 
and toe bilaterally (Parks Flolab, Parks Medical Electronics, Aloha, OR) according to standard 
protocol 
Continuous-wave doppler will be used to determine ankle-brachial indices or toe-brachial 
indices, and flow velocity profiles. 
Perimed Inc’s laser flow doppler system will be used to determine microcirculatory flow in a 
private research subject room.  Perimed staff will train and certify study members.  Only 
trained and certified study members listed on the protocol will be permitted to perform the 
procedure on study subjects. 
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section. 
6.4 
Safety 
6.4.1 
Definition of adverse events  
An adverse event 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 (e.g., nausea, chest pain), signs (e.g., tachycardia, enlarged liver) or the 
abnormal results of an investigation (e.g., laboratory findings, electrocardiogram).  In clinical 
studies, an AE can include an undesirable medical condition occurring at any time, including 
run-in or washout periods, even if no study treatment has been administered. 
The term AE is used to include both serious and non-serious AEs. 
6.4.2 
Definitions of serious adverse event 
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
wash-out, follow-up), that fulfils one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life-threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability/incapacity or substantial disruption of 
the ability to conduct normal life functions 
• 
Is a congenital abnormality or birth defect 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
20(33) 
• 
Is an important medical event that may jeopardize the subject or may require 
medical intervention to prevent one of the outcomes listed above. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed 
by the investigator(s) and communicated to AstraZeneca. 
6.4.3 
Recording of adverse events 
Time period for collection of adverse events 
All adverse events, serious or non-serious, are to be recorded on the Adverse Event Form, 
which accompanies the CRF.  This should be done as soon as possible but no longer than 24 
hours after the event.  The Investigator should specify the date of onset, seriousness, intensity, 
action taken on the study drug/device, corrective therapies given, outcome, date of resolution 
(if any), and his/her opinion as to whether the AE can be related to therapies or procedures 
involved in the study.  The Investigator should also review with the monitor the suggested 
categories used for describing the relationship(s). 
Follow-up of unresolved adverse events 
Subjects withdrawn from the study due to any AE that is still ongoing will be followed at least 
until the outcome is determined, even if it implies that follow-up continues after the subject 
has left the study, and where appropriate until the end of the planned period of follow-up. 
In the case of an SAE that is still ongoing, the subject must be followed-up until clinical 
recovery is complete or until progression has been stabilized.  It may imply that this follow-up 
will continue after the subject has left the study. 
As obtained, additional information will be noted on follow-up “Serious Adverse Event” 
Forms.  As these are completed, the box marked “follow-up” is to be checked on these forms 
and the forms sent or faxed to the Medical Monitor. 
The Sponsor is responsible for reporting faxed SAEs within required timelines promptly to the 
Health Authorities of different countries, as appropriate, except in those countries where it is 
the Investigator’s legal responsibility. 
The following variables will be collected for each AE: 
• 
AE (verbatim) 
• 
The date and time when the AE started and stopped 
• 
Maximum intensity, intensity, or changes in intensity of AE 
• 
Select the appropriate if needed: CTCAE grade/max CTAE grade/changes in 
CTCAE grade 
• 
Whether the AE is serious or not 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
21(33) 
• 
Investigator causality rating against the Investigational Product (yes or no) 
• 
Action taken with regard to investigational product 
• 
Select the appropriate if needed: 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 
• 
Causality assessment in relation to Additional Study Drug 
• 
Description of AE. 
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Section 6.4.2.  An AE of severe 
intensity need not necessarily be considered serious.  For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE. On the other hand, a stroke 
that results in only a limited degree of disability may be considered a mild stroke but would be 
a SAE. 
Adverse Events based on signs and symptoms 
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 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
22(33) 
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 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only 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 (e.g., 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 visual loss from diabetic retinopathy, diabetic and other ischemic ulcers, 
symptomatic hyperglycemia or hypoglycemia 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 serious adverse events  
Investigators and other site personnel must inform the FDA, via a MedWatch/AdEERs form, 
of any serious or unexpected adverse events that occur in accordance with the reporting 
obligations of 21 CFR 312.32, and will concurrently forward all such reports to AZ.  A copy 
of the MedWatch/AdEERs report must be faxed to AstraZeneca at the time the event is 
reported to the FDA.  It is the responsibility of the investigator to compile all necessary 
information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to AstraZeneca at the 
same time. 
When reporting to AstraZeneca, a cover page should accompany the MedWatch/AdEERs 
form indicating the following: 
• 
Investigator Sponsored Study (ISS) 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
23(33) 
• 
The investigator IND number assigned by the FDA 
• 
The investigator’s name and address 
• 
The trial name/title and AstraZeneca ISS reference number 
Investigative site must also indicate, either in the SAE report or the cover page, the causality 
of events in relation to all study medications and if the SAE is related to disease progression, 
as determined by the principal investigator. 
Send SAE report and accompanying cover page by way of fax to AstraZeneca’s designated 
fax line: 1-866-984-7229 
Serious adverse events that do not require expedited reporting to the FDA need to be reported 
to AstraZeneca preferably using the MedDRA coding language for serious adverse events.   
In the case of blinded trials, AstraZeneca will request that the Sponsor either provide a copy of 
the randomization code/ code break information or unblind those SAEs which require 
expedited reporting. 
All SAEs have to be reported to AstraZeneca, whether or not considered causally related to 
the investigational product.  All SAEs will be documented.  The investigator is responsible for 
informing the IRB and/or the Regulatory Authority of the SAE as per local requirements. 
We will submit SAE reports to AstraZeneca using the MedDRA coding language. 
6.4.5 
  Laboratory safety assessment 
All laboratory equipment and devices will be regularly evaluated by the site and/or outside 
auditors for Good Clinical Practice and overall laboratory safety. 
For the purpose of ensuring compliance with Good Clinical Practice and regulatory agency 
guidelines, it may be necessary for the Sponsor or a regulatory agency to conduct a site audit 
or an inspection. 
For blood volume see Section 7.17.1. 
6.5 
Physical examination 
The physicians at the three sites will perform a general physical examination of all major 
organ systems. 
6.5.1 
ECG 
6.5.1.1 
Resting 12-lead ECG 
A 12-lead resting electrocardiogram will be performed at screening and end of trial. 
 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
24(33) 
6.5.1.2 
Real time display (telemetry) 
Not applicable. 
6.5.2 
Vital signs 
Vital signs will be obtained in the sitting position after five (5) minutes of rest, prior to the 
viscosity test, and recorded on the CRF.   
6.5.2.1 
Pulse and blood pressure 
Radial pulse will be measured as beats/minute. The quality of the pulse will also be noted. 
Systolic and diastolic blood pressure will be measured as mmHg. 
6.5.2.2 
Body temperature 
Body temperature will be measured as °F. 
6.5.3 
Other safety assessments 
Pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal 
and toe bilaterally (Parks Flolab, Parks Medical Electronics, Aloha, OR) according to standard 
protocol 
Continuous-wave Doppler will be used to determine ankle-brachial indices as well as toe-
brachial indices. 
Perimed, Incs laser doppler monitoring system (PeriFlux System 5000, Perimed AB, Sweden) 
will measure the total local microcirculatory blood perfusion including the perfusion in 
capillaries, arterioles, venules and shunting vessels. The technique is based on the emission of 
a beam of laser light carried by a fiber-optic probe. This probe will be connected to a 
computer system where we will be able to obtain the measurements. This assessment will take 
only 2-6 min and will not involve the use of any radiation. The measurements of the flow will 
be performed with and without Valsalva maneuvers.  
Perimed’s Periflux system has been used in other clinical trials as evidenced in published 
scientific journals.  
6.6 
Patient reported outcomes (PRO) 
Not applicable. 
6.6.1 
PRO method or questionnaire 
MedDRA. 
6.7 
Pharmacokinetics 
Not applicable. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
25(33) 
6.7.1 
Collection of samples 
Blood samples will be collected with a standard venipuncture.  Approximately 3 cc of blood 
will be collected into an EDTA containing vacutainer (Becton, Dickinson and Company, 
Franklin Lakes, NJ, USA) and utilized within the Hemathix SCV-200 automated scanning 
capillary tube viscometer.  An additional 20 cc of blood will be collected for CBC and other 
lab testing. 
6.7.2 
Determination of drug concentration 
Not applicable. 
6.8 
Pharmacodynamics 
Not applicable. 
6.8.1 
Collection of pharmacodynamic markers  
Not applicable. 
6.9 
Pharmacogenetics 
6.9.1 
Collection of pharmacogenetic samples 
6.10 
Some of the laboratory samples will be stored in a -70°C freezer for 
future assessments and genetic testing if consented by the 
subject.Health economics 
Not applicable. 
7. 
BIOLOGICAL SAMPLING PROCEDURES 
7.1 
Volume of blood 
Blood samples will be collected with a standard venipuncture.  Approximately 3 cc of blood 
will be collected into an EDTA containing vacutainer (Becton, Dickinson and Company, 
Franklin Lakes, NJ, USA) and utilized within the Hemathix SCV-200 automated scanning 
capillary tube viscometer.  An additional 20 cc of blood will be collected for CBC testing, 
fibrinogen, serum chemistry and lipid profiles.  A serum pregnancy test will be performed on 
all women who agree to participate in the trial. 
7.2 
Handling, storage and destruction of biological samples 
7.2.1 
Pharmacokinetic and/or pharmacodynamic samples 
Not applicable. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
26(33) 
7.2.2 
Pharmacogenetic samples 
Some of the laboratory samples will be stored in a -70°C freezer for future assessments and 
genetic testing if consented by the subject. For subjects that do not consent for 
pharmacogenetic, samplease would not be collected and/or will be destroyed immediately. 
7.3 
Labeling and shipment of biohazard samples 
Three preprinted labels containing the Subject ID number will be prepared for each subject.  
The labels will be affixed to the blood specimen tubes for each test as well as each subject's 
CRF.  Blood will be sent to a designated laboratory facility. 
7.4 
Chain of custody of biological samples 
The chain of custody for biological samples follows from the study coordinator and local 
principal investigator, to the central laboratory facility for blood viscosity or to the site 
medical center laboratory for all other laboratory assessments. 
7.5 
Withdrawal of informed consent for donated biological samples 
In the event that a subject withdraws his or her informed consent for donated biological 
samples, all of his or her samples will be disposed of and excluded from further study. 
8. 
ETHICAL AND REGULATORY REQUIREMENTS 
8.1 
Ethical conduct of the study 
The study will be conducted in compliance with the protocol and GCP.  In reference to other 
applicable regulatory requirements, the automated scanning capillary viscometer is an 
investigational device that requires a minimally invasive sampling procedure that presents no 
significant risk.  It does not by design or intention introduce energy into a subject, and it is not 
used as a diagnostic procedure without confirmation of the diagnosis by another medically 
established product or procedure.  In addition, the blood sample required for testing in the 
device will be collected with a standard venipuncture, which is an approved FDA procedure 
(the blood is not returned to the subject’s body).  The device is considered to be exempt from 
IDE regulation in accordance with the provisionals specified in 21 CFR 812.2 and 812.5  
8.2 
Ethics and regulatory review 
The Principal Investigator must submit this protocol to an Ethics Review Committee or a 
similar body (IRB, CCPPRB, etc.), and he/she is required to forward a copy of the written 
approval/advice signed by the Chairman to the Sponsor. 
On the approval/advice sheet, the study (title, protocol number, and version), the documents 
studied (protocol, informed consent material, advertisement, when applicable), and the date of 
the review should be clearly stated. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
27(33) 
Study device supplies will not be released, and the study will not start until a copy of this 
written approval/advice has been received by the Sponsor. 
Complementary information and/or requirements will be described in an appendix, where 
applicable. 
8.3 
Informed consent 
It is the responsibility of the Principal Investigator to obtain informed consent in compliance 
with national requirements from each subject prior to entering the study or, where relevant, 
prior to evaluating the subject’s suitability for the study. 
The informed consent document used by the Principal Investigator for obtaining subject’s 
informed consent must be reviewed and approved by the Sponsor prior to Ethics Review 
committee or similar body (IRB, CCPPRB, etc.) submission. 
Specific national requirements or specific conditions associated to the study procedures will 
be described in an appendix, where applicable. 
8.4 
Changes to the protocol and informed consent form 
It is specified that the appendices attached and referred to in the main text of this protocol 
form an integral part of the protocol. 
No change or amendment to this protocol may be made by the Principal Investigator or by the 
Sponsor after the protocol has been agreed to and signed by both parties unless such change or 
amendment has been fully discussed and agreed upon by the Principal Investigator and the 
Sponsor.  Any changes so agreed upon will be recorded in writing, and the written amendment 
will be signed by both the Principal Investigator and Sponsor.  The signed amendment will 
then be appended to this protocol. 
Approval/advice of amendments by the Ethics Review Committee or similar body (IRB, 
CCPPRB, etc.) is then required prior to their implementation, unless there are overriding 
safety reasons. 
If the change or deviation increases risk to the study population, or adversely affects the 
validity of the clinical investigation or the subject’s rights, full Ethics Review Committee 
approval/advice must be obtained prior to implementation.  For changes that do not involve 
increased risk or affect the validity of the investigation or the subject’s rights, such 
approval/advice may be obtained by expedited review, where applicable. 
In some instances, an amendment may require a change to a consent form.  The Principal 
Investigator must receive Ethics Review Committee approval/advice of the revised consent 
form prior to implementation of the change.  In addition, changes to the CRFs, if required, 
will be incorporated into the amendment. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
28(33) 
Prior to initiating the change, the protocol amendment must be submitted to the Regulatory 
Agencies, where applicable, except under emergency conditions. 
8.5 
Audits and inspections 
By signing this protocol, the Principal Investigator agrees to allow Sponsor Clinical 
Research/Quality Assurance auditors and regulatory agencies to have direct access to his/her 
study records for review.  These personnel, bound by professional secrecy, will not disclose 
any personal identity or personal medical information.   
These audits involve review of source documents supporting the adequacy and accuracy of 
data gathered in the Case Report Forms, review of documentation required to be maintained, 
and checks on drug/device accountability.  
9. 
STUDY MANAGEMENT 
9.1 
Training of study site personnel 
Training of study site personnel is the responsibility of the PI. Training of staff personnel in 
all amendments should be documented in the Regulatory Binder. 
9.2 
Monitoring of the study 
9.2.1 
Source data 
According to the guidelines on GCP, the monitor has to check the CRF entries against the 
source documents.  The consent form will include a statement by which the subjects allow the 
Sponsor’s duly authorized personnel (Study Monitoring team) to have direct access to source 
data which supports data on the CRFs (e.g. subject’s medical file, appointment books, original 
laboratory records, etc.).  These personnel, bound by professional secrecy, will not disclose 
any personal identity or personal medical information. 
9.3 
Study timetable and end of study 
See section 3.1 for complete study timetable and flow chart.  The study will conclude at week 
16 after the final collection of patient data and laboratory assessments.   
10. 
DATA MANAGEMENT 
All local legal requirements regarding the protection of personal data will be adhered to.  
Patient data will be coded with a subject ID. 
All subject data is confidential, but may be subject to review by authorized representatives of 
the sponsor, independent auditors, IRB, and/or regulatory authorities. 
All data will be secured in secure locked cabinets, and on a secure, password-protected server. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
29(33) 
11. 
EVALUATION AND CALCULATION OF VARIABLES 
11.1 
Calculation or derivation of efficacy variable(s) 
Blood samples will be collected with a standard venipuncture.  Approximately 3 cc of blood 
will be collected into an EDTA containing vacutainer (Becton, Dickinson and Company, 
Franklin Lakes, NJ, USA) and utilized within the Hemathix SCV-200 automated scanning 
capillary tube viscometer.  An additional 5 cc of blood will be collected for CBC testing. 
Pulse volume recordings will be simultaneously obtained at the level of the ankle, metatarsal 
and toe bilaterally (Parks Flolab, Parks Medical Electronics, Aloha, OR) according to standard 
protocol 
Continuous-wave Doppler will be used to determine ankle-brachial indices as well as toe-
brachial indices. 
11.2 
Calculation or derivation of safety variable(s) 
Not applicable. 
11.2.1 
Other significant adverse events (OAE) 
Not applicable. 
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. 
11.5.1 
Calculation or derivation of the relationship between pharmacokinetic and 
pharmacodynamic variables  
Not applicable. 
11.5.2 
Population analysis of pharmacokinetic/pharmacodynamic variables  
Not applicable. 
11.6 
Calculation or derivation of pharmacogenetic variables 
Not applicable. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
30(33) 
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 data will be analyzed within the crossover design framework using repeated measures 
ANOVA.  The analyses of treatment effect, period effect, and sequence effect will be 
performed at the 0.05 significance level.   
12.1.1 
Efficacy analysis set 
For the first primary aim, a pre-planned contrast statement (proc mixed) will be used to 
compare the pooled effect of aspirin-ticagrelor with aspirin.  Similarly, for the second primary 
aim, a contrast statement will be used to compare the pooled effect of ticagrelor monotherapy 
with aspirin.  A one-tailed hypothesis test will be used for each contrast, and a Bonferroni 
correction will be used to control family wise error rate; a one-tailed significance level of 
0.025 will be used for both contrasts.  The above contrasts shall act effectively as a paired t-
test on the dependent variable blood viscosity.   
For the first secondary aim, an effect size will be calculated to estimate the standardized 
difference between ticagrelor monotherapy and combination aspirin-ticagrelor.  Low-dose 
aspirin was previously reported to have no significant effect on blood viscosity.  The present 
study is powered to detect differences between ticagrelor and low-dose aspirin—not between 
ticagrelor monotherapy and combination aspirin-ticagrelor.  An effect size corresponding to a 
dependent t-test will be calculated to determine the practical magnitude of the difference in 
blood viscosity measures between the two ticagrelor arms of the study.   
12.1.2 
Safety analysis set 
Not applicable.   
12.2 
Methods of statistical analyses 
All statistical analyses will be performed using SAS (Statistical Analyses System, Cary, NC).  
Our statistical considerations assume that there is no carryover effect between treatments.  In 
order to verify this assumption, dependent t-tests will be conducted to compare day 1 and 
week 6 measures of blood viscosity, and dependent t-tests will be conducted to compare day 1 
and week 12 measures for blood viscosity. 
12.2.1 
Interim analyses 
Not applicable. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
31(33) 
12.3 
Determination of sample size 
The scanning capillary viscometer that will be used in the proposed study was employed in an 
earlier study of 47 patients with hyperhomocysteinemia in addition to stable CVD or high 
CVD risk factors based on a Framingham score of >20% [13].  In this prior CVD population, 
mean blood viscosity levels at a low shear rate of 5 s-¹ were reported to be 9.98 ± 2.42 cP in 
the control group at baseline.  A standard deviation of 2.42 cP for low-shear (5 s-¹) blood 
viscosity was used throughout our sample size calculations.  Separately, treatment by 
clopidogrel 75 mg daily for 3 weeks was reported to reduce viscosity levels by 0.6 cP and 5.0 
cP at shear rates of 94.5 s-¹ and 0.94 s-¹, respectively [12]. Using this data, blood viscosity 
reduction of 2.0 cP by clopidogrel was interpolated for a shear rate of 5 s-¹.  The present cross-
over design study is powered to detect a 2.0 cP difference in low-shear blood viscosity at a 
shear rate of 5 s-¹, relative to aspirin 81 mg, with 90% power using a type I error rate of 5%.  
Combination aspirin-ticagrelor and low-dose aspirin control will be compared, and separately, 
ticagrelor monotherapy and low-dose aspirin control will be compared.  This requires 72 
patients (24 patients in each of 3 groups).  Accounting for dropout, we will randomize 90 
patients, or 30 patients in each of 3 arms.  The effects of combination aspirin-ticagrelor and 
ticagrelor monotherapy will also be compared as a secondary aim.   
12.4 
Data monitoring committee  
Unless specifically requested by the IRBs at the clinical sites, we will not convene a DMC due 
to the short-term nature of the trial. If a formal DMC is required, the appropriate costs for the 
physician’s time will be included in a revised budget. 
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. 
13.2 
Pregnancy 
All outcomes of pregnancy should be reported to AstraZeneca. 
13.2.1 
Maternal exposure 
Not applicable. 


Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
32(33) 
13.2.1.1 Paternal exposure 
Not applicable. 
14. 
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Clinical Study Protocol 
Drug Substance Ticagrelor / BRILINTA / AZD6140 
Study Number ISSBRIL0174 
Edition: Number  2         Date 18 March 2015 
33(33) 
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