Clinical trial NCT03317002
Conditions: Coronary Artery Disease
Sponsor: AstraZeneca
Start date: 2017-10-30; Completion date: 2020-04-08
Enrollment: 129 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, single-blind, placebo-controlled, parallel-group, multicentre study in patients with CAD. The study will be conducted at approximately 10 centres in 3 countries. Approximately 138 CAD patients will be randomized to AZD5718 or placebo (treatment duration 12 weeks).

Detailed description:
This is a randomized, single-blind, placebo-controlled, parallel-group, multicentre study in patients with CAD. The study will be conducted at approximately 10 centres in 3 countries (Denmark, Finland and Sweden).

Patients suitable for the study will be identified and screened for eligibility after being hospitalized for Acute Coronary Syndrome (ACS) (Visit 1) comprising ST Elevation Myocardial Infarction (STEMI) or Non-ST Elevation Myocardial Infarction (non-STEMI). At Visit 1, after signing informed consent, study measurements will take place at days 1, 2, 3 and 5 post ACS, where feasible. It is planned that approximately 138 CAD patients will be randomized to ensure at least 66 evaluable patients receiving AZD5718 Dose B or placebo are included with 12 weeks treatment. For supporting dose selection in future studies, a treatment arm with 28 randomized patients receiving AZD5718 Dose A is included in the study. The study was originally designed to be a 4-week study and was amended to be a 12-week study. Therefore, the total number of patients is greater than required for a 12 weeks study (about 100), since some patients will only have 4 weeks of treatment.

An evaluable patient is defined as a patient with a valid Coronary Flow Velocity Reserve (CFVR) measurement at Visit 2 and one post baseline visit as judged by the CFVR Core lab.

On Day 1 (Visit 2), 7 to 28 days after the ACS event, patients willing to participate in the study will complete the screening procedure and, if eligible, be randomized. Treatment duration will be 12 weeks. During the treatment phase, patients will come in to the clinic for study measurements at 2 weeks (visit 3), 4 weeks (visit 4), 8 weeks (visit 4b) and 12 weeks (visit 4c).

A follow-up visit (Visit 5) will be performed at 4 weeks (±4 days) after last dose in order to ensure safety and well-being of the patients

Arms: arm 1: AZD5718 Dose A once daily arm 2: AZD5718 Dose B once daily arm 3: Matching placebo once daily
Interventions: intervention 1: AZD5718 intervention 2: AZD5718 intervention 3: Placebo
Intervention descriptions: intervention 1: Oral dose of AZD5718 (tablet) intervention 2: Oral dose of AZD5718 (tablet) intervention 3: Matching placebo (tablet)

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD5718
Study Code
D7550C00003
Version
Version 5.0
Date
11 February 2019
A 12-week, randomized, single-blind, placebo-controlled, multi-centre, 
parallel group, phase IIa study to evaluate efficacy, safety and tolerability of 
oral AZD5718 after 4- and 12-weeks of treatment in patients with coronary 
artery disease (CAD)
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden






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placebo arm (exact number will be known at the unblinding at the end of the trail). This is 
due to the fact that patients that are already randomized to the study (approximately 38) will 
have a treatment period of 4 weeks while future randomized patients (approximately 100) 
will have a treatment period of 12 weeks. 
Section 1.4 (Study Design) has been updated to reflect this change, however, the updated 
numbers are reflected in all relevant sections of the CSP.
Interim analysis
The interim analysis is updated as follows: The text is revised to alter the futility interim 
analysis to two administrative interim analyses for internal decision making. The futility 
analysis has been removed to be able to evaluate the sustained effect on u-LTE4 at 12 
weeks. The focus of the study extended to 12 weeks aiming on evaluation 5-LO pathway 
inhibition, ie not only at the end of 4 weeks but at the end of 12 weeks to ensure the use of 
the drug in a chronic setting. The futility analysis has therefore been changed into two 
administrative interim analyses for internal decision making. In the event of positive 
outcome at any of the administrative interim analyses an evaluation of exposure-response 
relationship may be performed. This is reflected in the Study Synopsis (Statistical methods) 
and Section 8.5.6 (Interim analysis).
Biomarker sampling
An additional biomarker sample will be collected at day 2 after the ACS. 
The rationale for adding a day 2 sample is to be able to model the kinetics of inflammatory 
biomarkers post ACS. A minimum of three samples from each patient (ideally before and 
after the peak expression) is required for mathematical modelling. Individual differences 
between the patients are expected. Therefore, several samples from the same patient are 
required. Since, the peak expression is expected to take place at around day 1-3 post ACS, 
namely this timeframe is the most crucial for the biomarker kinetics and therefore a day 2 
sample has been added.
The following sections have been updated to reflect this change: Section 1.4 (Study Design) 
and Section 4.1(Study Procedures Visit 1 as well as Table 1).
Safety sampling
TSH, free T3, free T4 and total T4 has been added to the safety laboratory assessments at 
Visit 2 (Baseline at Randomization), Visit 4 (4 weeks), Visit 4c (12 weeks) and Visit 5 
(Follow-up). This decision is based on a recently completed 3 months toxicity study in rats. 
In rats, though not in dogs, treatment with AZD5718 in doses of QD 1000 mg/kg/day (> 
200 folds higher than clinical exposure) caused minimal follicular cell hypertrophy in the 
thyroid gland which is considered as adaptive rather than adverse and based upon 
experience, most likely reversible. This risk is not anticipated in humans, however repeated 
safety assessment of thyroid functions will be performed in study subjects.
This is reflected in the List of abbreviations and definition of terms, Section 1.3








Clinical Study Protocol Synopsis
Drug Substance AZD5718
Study Code D7550C00003
Version Version 5.0
Date 11 February 2019
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Objectives
Primary Objective:
Outcome Measure:
To assess the pharmacodynamic (PD) effect of 
AZD5718 by assessment of urine-leukotriene 
E4 (u-LTE4) at 4 weeks in CAD patients. 
Percentage change from baseline in levels of u-LTE4 
(see Section 8.4.1)
Secondary Objectives:
Outcome Measures:

To assess the pharmacodynamics (PD) 
effect of AZD5718 by assessment of urine-
leukotriene E4 (u-LTE4) at 12 weeks in 
CAD patients.
Percentage change from baseline in levels of u-LTE4 
(see Section 8.4.1)

To assess the effect of AZD5718 on 
change from baseline in Coronary Flow 
Velocity Reserve (CFVR) at 12 weeks in 
CAD patients.
Change from baseline in Coronary Flow Velocity 
Reserve (CFVR) in the mid-distal segment of the left 
anterior descending (LAD) coronary artery under 
adenosine infusion measured by Transthoracic 
Doppler Echocardiography (TDE)

To assess the effect of AZD5718 on 
change from baseline in Coronary Flow 
Velocity Reserve (CFVR) at 4 weeks in 
CAD patients.
Change from baseline in Coronary Flow Velocity 
Reserve (CFVR) in the mid-distal segment of the left 
anterior descending (LAD) coronary artery under 
adenosine infusion measured by Transthoracic 
Doppler Echocardiography (TDE)

To assess the pharmacokinetics (PK) of 
AZD5718 after repeated oral dosing at 4 
and 12 weeks in CAD patients
Standard model population pharmacokinetic (PK) 
parameters to be reported in a separate report.

To assess the effect of AZD5718 on 
coronary flow parameters at 4 weeks in 
CAD patients
Change from baseline in:
- LAD resting mean diastolic flow velocity
- LAD hyperaemic flow velocity

To assess the effect of AZD5718 on 
change in echocardiographic parameters at 
4 weeks in CAD patients. 
Change from baseline in:
- Left Ventricular (LV) Ejection Fraction (LVEF)
- LV global longitudinal strain (GLS)
- LV global circumferential strain (GCS)
- LV longitudinal early diastolic strain rate




Clinical Study Protocol Synopsis
Drug Substance AZD5718
Study Code D7550C00003
Version Version 5.0
Date 11 February 2019
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Investigational product
Dosage form and strength
Dose
Manufacturer
Placebo to match (PTM) 
AZD5718 
PTM AZD5718 
 tablet 
AstraZeneca
Placebo to match (PTM) 
AZD5718 
PTM AZD5718
 
tablet
AstraZeneca
Statistical methods 
The primary efficacy and the first secondary variable will each test the null hypothesis that 
patients given AZD5718 
 have less than 80% inhibition of u-LTE4 compared to 
placebo, versus the alternative hypothesis that patients given AZD5718 
 have equal or 
more than 80% inhibition of u-LTE4 compared to placebo (one-sided 95% confidence 
interval). 
The second and third secondary efficacy variable measuring change from baseline in CFVR 
will test the null hypothesis of no increase in CFVR in patients given AZD5718 
 
compared to placebo, versus the alternative hypothesis of an increase in CFVR in patients 
given AZD5718 
 compared to placebo (one-sided 95% confidence interval).
The primary efficacy variable and the three first secondary efficacy variables measuring will 
be analysed using a repeated measurement model with treatment, type of Myocardial 
Infarction (MI) (STEMI vs NSTEMI) as factors and baseline value as covariate, with spatial 
power covariance structures (generalisation of an auto regressive covariance structure 
allowing for none-equidistant time points).
Efficacy variables will be analysed using the intention to treat (ITT) population. The 
randomization will be stratified with type of MI as a factor ST-elevation MI vs non-ST-
elevation MI (STEMI vs NSTEMI).
Given anticipated effect size, 40 randomized patients on AZD5718 
 and 40 randomized 
patients on placebo is needed accounting for non-evaluable patients to achieve an overall 
power of approximately 80% for the primary endpoint and secondary endpoints analysing 
change in CFVR. For dose selection in future studies, a treatment arm with patients receiving 
AZD5718 
 is included in the study. 
Two administrative interim analyses will be conducted. The first one is planned after at least 
45 patients have performed their CFVR measurement at Visit 4 and the second after at least 
100 patients have performed their CFVR measurement at Visit 4. 


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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
VERSION HISTORY..........................................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................................7
TABLE OF CONTENTS................................................................................................... 11
1.
INTRODUCTION ............................................................................................. 20
1.1
Background and rationale for conducting this study ........................................... 20
1.2
Rationale for study design, doses and control groups.......................................... 21
1.2.1
Dosing rationale................................................................................................. 23
1.3
Benefit/risk and ethical assessment .................................................................... 23
1.4
Study Design...................................................................................................... 24
2.
STUDY OBJECTIVES...................................................................................... 27
2.1
Primary objective............................................................................................... 27
2.2
Secondary objectives.......................................................................................... 27
2.3
Safety objectives................................................................................................ 28
2.4
Exploratory objectives ....................................................................................... 28
3.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 29
3.1
Inclusion criteria ................................................................................................ 29
3.2
Exclusion criteria ............................................................................................... 29
3.3
Patient enrolment and randomization ................................................................. 31
3.4
Procedures for handling incorrectly enrolled or randomized patients.................. 31
3.5
Methods for assigning treatment groups............................................................. 32
3.6
Methods for ensuring blinding ........................................................................... 32
3.7
Methods for unblinding...................................................................................... 32
3.8
Restrictions........................................................................................................ 33
3.8.1
Medication restrictions....................................................................................... 33
3.8.2
Dietary restrictions............................................................................................. 33
3.8.3
Alcohol, Drugs of abuse, Tobacco and Caffeine Restrictions.............................. 33
3.8.4
Restrictions for male study subjects ................................................................... 33
3.8.5
Other Restrictions .............................................................................................. 34


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3.9
Discontinuation of investigational product ......................................................... 34
3.9.1
Procedures for discontinuation of a subject from IP............................................ 34
3.10
Criteria for withdrawal....................................................................................... 35
3.10.1
Screen failures ................................................................................................... 35
3.10.2
Withdrawal of the informed consent................................................................... 35
3.11
Discontinuation of the study............................................................................... 35
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 36
4.1
Study Procedures ............................................................................................... 36
4.2
Screening/Enrolment period............................................................................... 45
4.3
Treatment period................................................................................................ 45
4.4
Follow-up period................................................................................................ 45
5.
STUDY ASSESSMENTS.................................................................................. 45
5.1
Efficacy assessments.......................................................................................... 45
5.1.1
Urine-leukotriene E4 (u-LTE4)........................................................................... 45
5.1.2
Echocardiography .............................................................................................. 45
5.1.3
Transthoracic Doppler echocardiography (TDE) with coronary flow 
velocity reserve (CFVR) measurement............................................................... 46
5.1.4
Carotid-femoral Pulse Wave Velocity (cfPWV) and brachial Pulse Wave 
Analysis (bPWA)............................................................................................... 46
5.2
Safety assessments............................................................................................. 46
5.2.1
Laboratory safety assessments............................................................................ 46
5.2.2
Physical examination ......................................................................................... 48
5.2.3
Body weight....................................................................................................... 48
5.2.4
ECG................................................................................................................... 48
5.2.4.1
Resting 12-lead ECG ......................................................................................... 49
5.2.5
Vital signs.......................................................................................................... 49
5.2.5.1
Pulse and blood pressure.................................................................................... 49
5.3
Other assessments.............................................................................................. 49
5.3.1
Other research biomarker assessments................................................................ 49
5.3.2
Clinical Outcome Assessments........................................................................... 50
5.4
Pharmacokinetics ............................................................................................... 51
5.4.1
Collection of samples......................................................................................... 51
5.4.2
Determination of drug concentration.................................................................. 51
5.4.3
Storage and destruction of pharmacokinetic samples.......................................... 52
5.5
Pharmacodynamics ............................................................................................ 52
5.5.1
Collection of samples......................................................................................... 52
5.5.2
Storage, re-use and destruction of pharmacodynamics samples .......................... 52
5.6
Genetics (optional)............................................................................................. 52
5.7
Biomarkers ........................................................................................................ 52


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5.7.1
Storage, re-use and destruction of biological samples......................................... 53
5.7.2
Labelling and shipment of biological samples .................................................... 53
5.7.3
Chain of custody of biological samples .............................................................. 53
5.7.4
Withdrawal of Informed Consent for donated biological samples....................... 54
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 54
6.1
Definition of adverse events............................................................................... 54
6.2
Definitions of serious adverse event ................................................................... 55
6.3
Recording of adverse events............................................................................... 55
6.3.1
Time period for collection of adverse events ...................................................... 55
6.3.2
Follow-up of unresolved adverse events............................................................. 55
6.3.3
Variables............................................................................................................ 55
6.3.4
Causality collection............................................................................................ 56
6.3.5
Adverse events based on signs and symptoms.................................................... 57
6.3.6
Adverse events based on examinations and tests ................................................ 57
6.3.7
Hy’s Law ........................................................................................................... 57
6.4
Reporting of serious adverse events ................................................................... 57
6.5
Overdose............................................................................................................ 58
6.6
Pregnancy .......................................................................................................... 59
6.6.1
Maternal exposure.............................................................................................. 59
6.6.2
Paternal exposure............................................................................................... 59
6.7
Medication Error................................................................................................ 59
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 61
7.1
Identity of investigational product(s).................................................................. 61
7.2
Dose and treatment regimens ............................................................................. 61
7.3
Labelling............................................................................................................ 61
7.4
Storage............................................................................................................... 62
7.5
Compliance........................................................................................................ 62
7.6
Accountability.................................................................................................... 62
7.7
Concomitant and other treatments ...................................................................... 62
7.7.1
Other concomitant treatment .............................................................................. 62
8.
STATISTICAL ANALYSES............................................................................. 63
8.1
Statistical considerations .................................................................................... 63
8.2
Sample size estimate .......................................................................................... 63
8.3
Definitions of analysis sets................................................................................. 64
8.3.1
Efficacy analysis set........................................................................................... 64
8.3.2
Safety analysis set.............................................................................................. 64
8.3.3
PK analysis set................................................................................................... 64


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8.4
Outcome measures for analyses.......................................................................... 64
8.4.1
Efficacy variables............................................................................................... 64
8.4.2
Safety variables.................................................................................................. 65
8.4.3
Exploratory variables ......................................................................................... 65
8.4.4
Exploratory biomarkers...................................................................................... 66
8.5
Methods for statistical analyses.......................................................................... 66
8.5.1
Analysis of the primary variable(s)..................................................................... 67
8.5.2
Analysis of the secondary variables.................................................................... 67
8.5.3
Analysis of safety variables................................................................................ 68
8.5.4
Subgroup analysis.............................................................................................. 68
8.5.5
Exploratory analysis........................................................................................... 68
8.5.6
Interim analysis.................................................................................................. 69
9.
STUDY AND DATA MANAGEMENT............................................................ 70
9.1
Training of study site staff.................................................................................. 70
9.2
Monitoring of the study...................................................................................... 70
9.2.1
Source data ........................................................................................................ 70
9.2.2
Study agreements............................................................................................... 71
9.2.3
Archiving of study documents............................................................................ 71
9.3
Study timetable and end of study........................................................................ 71
9.4
Data management............................................................................................... 71
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 72
10.1
Ethical conduct of the study ............................................................................... 72
10.2
Patient data protection........................................................................................ 72
10.3
Ethics and regulatory review .............................................................................. 72
10.4
Informed consent ............................................................................................... 73
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 74
10.6
Audits and inspections ....................................................................................... 74
11.
LIST OF REFERENCES ................................................................................... 74
LIST OF TABLES
Table 1
Study assessment schedule....................................................................39
Table 2
Standard Clinical Laboratory Evaluation Panels....................................46
Table 3
Other Clinical Safety Panels..................................................................48
Table 4
Research biomarkers .............................................................................49
Table 5
Investigational products – dosage form and strength..............................61


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LIST OF FIGURES
Figure 1
Study flow chart....................................................................................26
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................78
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................80
Appendix C
Genetic Research ..................................................................................81
Appendix D
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ........................................................................84


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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
AE
Adverse Event
ACS
Acute Coronary Syndrome
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ApoB
Apolipoprotein B
ApoA1
Apolipoprotein A1
APTT
Activated partial thromboplastin time
AST
Aspartate aminotransferase
AV-block
Atrioventricular block
bPWA
Brachial Pulse Wave Analysis
CABG
Coronary artery bypass grafting
CAD
Coronary Artery Disease
CBFV
Coronary blood flow velocity
CCS
Canadian Cardiovascular Society grading of angina pectoris
cfPWV
Carotid-femoral Pulse Wave Velocity
CFVR
Coronary Flow Velocity Reserve
CKD
Chronic Kidney Disease
COPD
Chronic obstructive pulmonary disease
CRF
Case Report Form (electronic/paper)
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
CV
Cardiovascular
DAE
Discontinuation of Investigational Product due to Adverse Event
DCCT
Diabetes Control and Complications Trial
DMP
Data Management Plan
DNA
Deoxyribonucleic acid 
EF
Ejection Fraction


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Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
5-LO
5-lipoxygenase
FLAP
5-lipoxygenase activating protein
Free T3
Free Triiodothyronine
Free T4
Free Thyroxine
FSH
Follicle-Stimulating Hormone
GCP
Good Clinical Practice
GDF15
Growth/differentiation factor 15
GLS
Global Circumferential Strain
GRACE
Global Registry of Acute Coronary Events
HbA1c
Haemoglobin A1c (glycated haemoglobin)
HBsAg
Hepatitis B surface antigen
HCT
Haematocrit
HDL
High Density Lipoprotein
HIV
Human immunodeficiency virus
HR
Heart Rate
hsCRP 
High-sensitivity C-Reactive Protein
hsTnI 
High-sensitive Troponin I
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IFCC
International Federation of Clinical Chemistry
IL-1B
Interleukin 1 beta
IL-6
Interleukin 6
International 
Co-ordinating 
investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
INR
International normalized ratio
IP
Investigational Product 
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System


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Abbreviation or 
special term
Explanation
LAD
Left Anterior Descending artery
LDL
Low Density Lipoprotein
LH
Luteinizing Hormone
Lp(a)
Lipoprotein a
LV
Left Ventricle
LVEF
Left Ventricular Ejection Fraction
LVESV
Left Ventricular End Systolic Volume
LSLV
Last Subject Last Visit
LIMS
Laboratory Information Management System
LTB4
Leukotriene B4
LTE4
Leukotriene E4
MCH
Mean corpuscular haemoglobin
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities 
MoP
Manual of Procedures
MPO
Myeloperoxidase
MPO mass
Myeloperoxidase protein level measurement
NSTEMI
Non-ST Elevation Myocardial Infarction
NT-proBNP 
N-Terminal Prohormone of Brain Natriuretic Peptide
OAE
Other Significant Adverse Event
PCI
Percutaneous coronary intervention
PD
Pharmacodynamics
PI
Principal Investigator 
PK
Pharmacokinetics
PRO
Patient Reported Outcomes
PT
Preferred Term
PTM
Placebo to Match
RBC
Red Blood Cell
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SMAD
Single and Multiple Ascending Dose


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Abbreviation or 
special term
Explanation
SRC
Safety Review Committee
STEMI
ST Elevation Myocardial Infarction
TIMI
Thrombolysis In Myocardial Infarction
TDE
Transthoracic Doppler Echocardiography
Total T4
Total Thyroxine
TSH
Thyroid Stimulating Hormone
u-
Urine
ULN
Upper Limit of Normal
WBC
White blood cell
WBDC
Web Based Data Capture


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Cardiovascular diseases are leading causes of death globally, accounting for 17 million deaths, 
and for 39% of deaths in individuals under 70 years of age (WHO 2011). In United States 
alone 1.350.000 individuals suffer an acute coronary syndrome (ACS) annually (Lloyd-Jones 
D et al 2010). Atherothrombosis, i.e. the sudden rupture of an atherosclerotic plaque, is the 
principal cause of cardiovascular morbidity and mortality. Erosion and rupture of an 
atherosclerotic plaque leads to activation and aggregation of circulating platelets, resulting in 
the formation of a thrombi, which partially or totally occludes the coronary artery. However, 
while the clinical manifestations of plaque ruptures are the most prominent clinical signs of 
the disease, the whole atherosclerotic process in the arterial wall is characterized by lipid 
accumulation in the vessel wall thus forming the atherosclerotic plaques (Libby P 2013). 
Nevertheless another component of atherosclerosis and its subsequent clinical manifestations 
like ACS, is inflammation. Inflammation, in fact, is considered playing a critical role in 
plaque ruptures where it weakens the plaque’s fibrous cap making it more prone for rupture. 
Secondly inflammation is a key component in event occurring after ACS. Besides the effect 
on plaque itself, post ACS myocardial damage and remodelling is essentially modulated by 
inflammation (Frangogiannis NG 2012).
Traditional cardiovascular pharmaceutical therapies, such as aspirin and statins, improve 
outcomes in patients with atherosclerotic cardiovascular disease. Patients with established 
coronary artery disease (CAD), especially with recent ACS however, still have residual 
cardiovascular risk even with these therapies. In the process of atherosclerosis, subsequent 
plaque rupture and eventual infarction area remodelling inflammation possesses a key role 
(Frangogiannis NG 2012). This is considered to be a consequence of various biochemical 
processes, including especially leukotrienes and its enzymatic regulator 5-Lipoxygenase 
(5-LO) (Spanbroek R et al 2003, Dwyer JH et al 2004, Bäck M 2008). During the reperfusion 
in ACS, leukocytes are activated and release a variety of oxidative stress response molecules 
and pro inflammatory lipid and peptide mediators (Funk CD 2005). Expression and activity of 
the 5-LO pathway has been linked to atherosclerotic plaque inflammation and progression 
(Qiu H et al 2006, Cipollone F at al 2005, van den Borne P et al 2014, Allen S at al 1998). In 
more detail, expression and activity of 5-LO pathway is elevated in unstable plaques (Qiu H et 
al 2006, Cipollone F at al 2005, van den Borne P et al 2014) and this has also been associated 
with vasoconstriction in atherosclerotic coronary arteries (Allen S at al 1998). 
CAD can be divided to macrovascular and microvascular disease, both as different 
manifestations of atherosclerosis. Macrovascular CAD, i.e. obstructive CAD of epicardial 
coronary arteries has traditionally been the focus of CAD treatment (Montalescot G et al 
2013). Microvascular circulation, on the other hand, consists of arterioles (diameter <100 μm) 
within myocardium and abnormalities in this arterial bed may also impair myocardial 
perfusion and result in ischaemia (Camici PG et al 2007). An indication of microvascular 
disease can be achieved with coronary flow velocity reserve (CFVR) which is an integrated 
measure of flow through both large epicardial arteries and coronary microcirculation (Camici 
PG et al 2015). Thus, an adequate assessment of microcirculation can be obtained when the 


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epicardial coronary arteries are free from significant stenosis (>50%). CFVR measurement is 
the ratio of resting coronary artery mean diastolic flow velocity in comparison to hyperaemic 
coronary artery mean diastolic flow velocity, where hyperaemia is often induced with 
pharmacologic agent such as adenosine infusion. CFVR of the left anterior descending (LAD) 
coronary artery during pharmacologic stress echocardiography has been found to provide 
effective prognostic information in patients with known or suspected CAD (Rigo F et al 
2008). This seems evident across patient populations, such as those with diabetes or chronic 
kidney disease (Murthy VL et al 2012), or older age (Uren NG et al 1995). Particularly, a 
CFVR <2.0 has been associated with markedly increased cardiovascular (CV) risk in an 
unselected patient population (Rigo F et al 2008). However, cardiac microvascular function 
seems dynamic in nature as marked improvements in CFVR with pharmacotherapy have been 
induced within 8 weeks treatment (Tagliamonte E et al 2015). CFVR also reflects well both 
systolic and diastolic cardiac function consequently emphasizing the essential role of 
myocardial microvascular function in cardiac physiology (Blomster J et al 2016).
Several publications support the biological rationale and target validation for 5-LO-activating 
protein (FLAP) inhibitor in cardiovascular disease. Tardif et al. has shown that 5-LO Inhibitor 
VIA 2291 reduced ex vivo stimulated leukotriene B4 (LTB4) production, non-calcified plaque 
volume and appearance of new coronary lesions in ACS patients. Moreover, VIA 2291 
reduced plaque progression with treatment initiation 3 weeks after ACS (Tardif JC et al 2010). 
Additionally, human genetic associations that link FLAP and the 5-LO pathway to 
atherosclerotic cardiovascular disease (increased risk of myocardial infarction) have been 
made in Icelandic population (Helgadottir A et al 2004). Neutrophil adhesion in 
microvasculature can reduce coronary perfusion via FLAP-dependent mechanism whilst 
inhibition of FLAP pathway seems to improve microvascular function (Sala A et al 1993, Sala 
A et al 1996). Given the previous evidence from inhibition of this pathway it seems apparent 
that mechanism is involved in the processes of both macrovascular and microvascular CAD. 
AZD5718, is a selective, reversible 5-lipoxygenase activating protein (FLAP) inhibitor which 
will attenuate production of pro-inflammatory and vasoactive leukotrienes by leukocytes e.g. 
neutrophils in the circulation encompassing both downstream cysteinyl leukotrienes measured 
as urine-leukotriene E4 (u-LTE4) and leukotrienes measured as plasma LTB4.
This Phase IIa Proof-of-Principle study will investigate if AZD5718, a FLAP inhibitor, can 
decrease u-LTE4 levels and secondly if AZD5718 can improve CFVR as a measure of 
myocardial microvascular function. The study will also address safety and tolerability of 
AZD5718 on top of standard of care in CAD patients e.g. a post-ACS population. The result 
of the study will form the basis for the future clinical development programme for AZD5718 
with the overall aim to investigate if AZD5718 can improve cardiovascular mortality and 
morbidity on top of standard of care in CAD patients.
1.2
Rationale for study design, doses and control groups
A randomized, blinded, parallel-group, multi-centre, placebo-controlled study design is 
standard in Proof-of-Principle studies and is considered the best design to achieve the 
objectives of the study, from both safety and efficacy perspectives. Overall, the study is 


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single-blinded regarding treatment strengths, but double-blinded in terms of active or placebo. 
This is due to the 
 and 
 tablets being of different size and number of 
tablets to digest differs between the treatment arms. To avoid a large pill burden, the 
participants are receiving matching placebo film-coated tablets for each corresponding tablet 
strength. Hence, the patients, the investigators and study personnel are double blinded in terms 
of who receives active or placebo, but given the different film-coated tablet sizes and number 
of tablets to digest, one can discern if either 
/placebo or 
/placebo is given and, 
thus, the study is labelled as single-blind. The study is designed to demonstrate efficacy versus 
placebo; a placebo control arm in the trial will enable placebo-corrected analysis of safety and 
efficacy. 
Treatment period is extended up to 12 weeks to assess the sustained effects of AZD5718 on 
the prolonged inhibition of 5-LO pathway mediated inflammation, following the impact of 
initial 4-week treatment duration.
Based on information available, 4 weeks treatment duration is capable to decrease the level of 
leukotriene-mediated inflammation, though, prolonged treatment (up to 12 weeks) with 5-LO 
inhibitor showed significant reduction in blood (LTB4) and urine (LTE4) leukotriene levels 
and suggested potential influence on atherosclerosis (Tardif JC et al 2010).
In the current study, with CAD population of post-ACS patients, with the LAD stenosis less 
than 50% and TIMI flow ≥ 2, macrovascular component of coronary function and echo 
parameters probably will demonstrate rapid improvement on top of standard care initiated 
during the ACS. However, cardiac microvascular function seems to be dynamic in nature and 
noticeable improvements in CFVR with pharmacotherapy have been induced within 8 weeks 
treatment (Tagliamonte E et al 2015).
Consequently, treatment prolonged up to 12 weeks will allow to achieve and to assess 
sustained inhibition of leukotriene-mediated inflammation (urine-LTE4 and blood-LTB4) 
following the initial decrease after 4 weeks treatment. In addition, treatment with AZD5718 
prolonged up to 12 weeks will allow to assess sustained dynamics, gradual and steady 
improvement of myocardial microvascular function (coronary flow reserve and 
echocardiography parameters) in post-ACS patients on top of long-term Standard of Care.
Extended up to 12 weeks treatment period will provide with more complete AZD5718 safety 
and tolerability profile with longer treatment exposure, on top of long-term Standard of Care 
in post ACS patients with CAD and support further clinical development.
The result of the study with prolonged treatment will facilitate the scientific and clinical basis 
for further investigation of AZD5718 in improving cardiovascular mortality and morbidity in 
CAD population.
CAD patients within four weeks after an ACS, either ST-segment Elevation Myocardial 
Infarction (STEMI) or non-ST-Segment Elevation Myocardial Infarction (NSTEMI), are 
chosen in order to have a population similar to the future target population. The patients will 
be recruited immediately after an ACS and treatment will commence earliest on day 7 after an 




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improve left ventricle ejection fraction. Based on prior SMAD study, the effect of AZD5718 
can be detected in decreased u-LTE4 concentrations under the designed 4weeks of study 
treatment period, though potentially reaching even more stable and sustainable effect with the 
treatment prolongation up to 12 weeks.
The extended treatment period up to 12 weeks, will also provide with more complete safety 
profile data in CAD patients (post-ACS population) with longer treatment exposure.
The essential imaging modality in the trial is cardiac ultrasound. The Transthoracic colour 
Doppler Echocardiography (TDE) with CFVR measurement has the advantage of being non-
radioactive, non-invasive and utilizing equipment readily available in the departments of 
cardiology. The cardiac ultrasound examination itself does not involve any discomfort. To 
measure the ability to increase blood flow, intravenous adenosine will be used in connection 
to the ultrasound examination. Adenosine is approved as tool for cardiovascular examinations. 
It can provide a fast and transient (one minute) heat sensation and a slight chest discomfort. 
The most common adverse reactions are warmth, shortness of breath, flushing and headache. 
In rare cases, heart palpitations, nausea, anxiety or blurred vision may occur. Under the 
medical attention provided in this trial, ultrasound CFVR measurement with adenosine 
infusion is not considered to pose a risk for the patients.
1.4
Study Design
This is a randomized, single-blind, placebo-controlled, parallel-group, multicentre study in 
subjects with CAD. 
NB. The study was originally designed to be a 4-week study and was amended to be a 12-week 
study. As a consequence, some patients will have a treatment period of 4 weeks only while 
others will have a treatment period of 12 weeks. Visits 4b and 4c only apply to patients 
included under the amended CSP.
The study will be conducted at approximately 10 centres in 3 countries (Denmark, Finland and 
Sweden). 
Patients suitable for the study will be identified and screened for eligibility after being 
hospitalized for ACS (Visit 1) comprising STEMI or NSTEMI. At Visit 1, after signing 
informed consent, biomarker sampling will take place at days 1, 2, 3 and 5 post ACS, where 
feasible. It is planned that approximately 138 CAD patients will be randomized to ensure at 
least 66 evaluable patients receiving AZD5718 
 or placebo are included with 12 weeks 
treatment. An evaluable patient is defined as a patient with a valid CFVR measurement at 
Visit 2 (baseline) and one postbaseline visit as judged by the CFVR Core lab. For supporting 
dose selection in future studies, a treatment arm with 20% of randomized patients receiving 
AZD5718 
 is included in the study.


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On Day 1 (Visit 2), 7-28 days after the ACS event, patients willing to participate in the study 
will complete the screening procedure and, if eligible, be randomized in a ratio 2:1:2 to 
receive either AZD5718 (
), AZD5718 
) or Placebo. Treatment duration will be 
12 weeks, once daily administration in the morning. Dose on Visit 2 (Day 1), Visit 3 (2 
weeks), Visit 4 (4 weeks), and Visit 4c (12 weeks) will be given by study personnel at the 
study site. 
During the treatment phase, patients will come in to the clinic for study measurements at 2 
weeks (Visit 3), 4 weeks (Visit 4), 8 weeks (Visit 4b) and 12 weeks (Visit 4c). 
A follow-up visit (Visit 5) will be performed at 4 weeks (±4 days) after last dose in order to 
ensure safety and well-being of the patients. 
Study overview is presented in Figure 1 below. For details and timings of the study 
assessments refer to Table 1 Section 4.
Based on emerging data from the study AstraZeneca may decide to use the plasma/serum 
and/or urine samples collected in the study to address other study objectives than the pre-
specified for a specific sample.




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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure: 
To assess the pharmacodynamics (PD) 
effect of AZD5718 by assessment of urine-
leukotriene E4 (u-LTE4) at 4 weeks in 
CAD patients. 
Percentage change from baseline in levels of 
u-LTE4 (see Section 8.4.1)
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To assess the pharmacodynamics (PD) 
effect of AZD5718 by assessment of 
urine-leukotriene E4 (u-LTE4) at 12 
weeks in CAD patients.
Percentage change from baseline in levels of 
u-LTE4 (see Section 8.4.1)
To assess the effect of AZD5718 on 
change from baseline in Coronary Flow 
Velocity Reserve (CFVR) at 12 weeks 
in CAD patients.
Change from baseline in Coronary Flow Velocity 
Reserve (CFVR) in the mid-distal segment of the 
left anterior descending (LAD) coronary artery 
under adenosine infusion measured by 
Transthoracic Doppler Echocardiography (TDE)
To assess the effect of AZD5718 on 
change from baseline in Coronary Flow 
Velocity Reserve (CFVR) at 4 weeks in 
CAD patients.
Change from baseline in Coronary Flow Velocity 
Reserve (CFVR) in the mid-distal segment of the 
left anterior descending (LAD) coronary artery 
under adenosine infusion measured by 
Transthoracic Doppler Echocardiography (TDE)
To assess the pharmacokinetics (PK) of 
AZD5718 after repeated oral dosing at 
4 and 12 weeks in CAD patients
Standard model population pharmacokinetic 
(PK) parameters to be reported in a separate 
report
To assess the effect of AZD5718 on 
coronary flow parameters at 4 weeks in 
CAD patients
Change from baseline in:
- LAD resting mean diastolic flow velocity
- LAD hyperaemic flow velocity
To assess the effect of AZD5718 on 
change in echocardiographic 
parameters at 4 weeks in CAD patients. 
Change from baseline in:
- Left Ventricular (LV) Ejection Fraction 
(LVEF)
- LV global longitudinal strain (GLS)
- LV global circumferential strain (GCS)
- LV longitudinal early diastolic strain rate


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2.3
Safety objectives
Safety Objective:
Outcome Measure:
To assess the safety and tolerability of 
AZD5718 in CAD patients
-
Adverse Events/Serious Adverse Events 
(AEs/SAEs)
-
Vital signs 
-
Clinical chemistry/haematology parameters 
-
Electrocardiogram (ECG) assessments 
2.4
Exploratory objectives 

To assess the effect of AZD5718 on coronary flow parameters at 12 
weeks in CAD patients

To assess the effect of AZD5718 on change in echocardiographic 
parameters at 12 weeks in CAD patients.

To assess the effect of AZD5718 on change in arterial stiffness, by 
assessment of carotid-femoral pulse wave velocity (cfPWV) and brachial 
pulse wave (bPWA) analysis at 4 and 12 weeks in CAD patients 

To evaluate the effect of AZD5718 on cardiovascular biomarkers 

To explore if any baseline variables are predictive of changes in any PD, 
efficacy, safety and tolerability variable related to AZD5718 treatment 

To explore the effect of AZD5718 on changes in patient reported 
outcomes (PRO) questionnaires at 4 and 12 weeks

To evaluate GRACE 2.0 score in CAD patients

To explore the relationship between AZD5718 exposure and the efficacy 
and exploratory endpoints (echocardiographic, coronary flow, PD, pulse 
wave analysis, cardiovascular biomarkers) at 4 and 12 weeks

To explore the effect of AZD5718 on change in additional 
echocardiographic parameters in CAD patients at 4 and 12 weeks

To collect and store samples for potential current and future exploratory 
research aimed at exploring biomarkers involved in PK, PD, efficacy, 
safety and tolerability related to AZD5718 treatment

Optional: To collect and store samples for potential current and future 
exploratory genetic research aimed at identifying/exploring genetic 


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variations that may affect PK, PD, efficacy, safety and tolerability related 
to AZD5718 treatment
Note: For details regarding exploratory variables, measurements and analyses refer to 
Sections 8.4.3, 8.5.5 and 5.3.1 (Table 4).
3.
PATIENT SELECTION, ENROLMENT, RANDOMIZATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study. Under no circumstances can there be exceptions to this rule.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Males and females: 
a.
Males must be surgically sterile or using an acceptable method of contraception (see 
Section 3.8.4)
b.
Females must be of non-childbearing potential confirmed at screening by fulfilling one 
of the following criteria 
a) postmenopausal defined as amenorrhoea for at least 12 months or more following 
cessation of all exogenous hormonal treatments and follicle-stimulating hormone 
(FSH) levels in the postmenopausal range,  
b) documentation of irreversible surgical sterilisation by hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy but not tubal ligation
2.
Age  ≥18 to ≤75
3.
BMI ≥18 to ≤35 kg/m2
4.
CAD patients, here defined as: 
a.
ACS 7-28 days prior to study randomization (ACS defined as STEMI, non-STEMI 
event documented by ECG, cardiac enzymes [troponin] and angiogram) 
b.
Possible post procedure LAD stenosis is <50% and TIMI flow is ≥ 2
5.
Provision of signed and dated, written informed consent prior to any study specific 
procedures
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:


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1
Alanine aminotransferase (ALT) >2 x ULN (i.e., above the normal range) at visit 2, cirrhosis, 
recent hepatitis, or positive screening test for hepatitis B (hepatitis B surface antigen) or 
hepatitis C
2
Uncontrolled Type 1 or Type 2 diabetes defined as haemoglobin A1c (HbA1c) Diabetes 
Control and Complications Trial (DCCT)> 9% or International Federation of Clinical 
Chemistry (IFCC) >74.9 mmol/mol
3
Patients with atrial fibrillation (chronic or current) or history of ventricular tachycardia 
requiring therapy for termination, or symptomatic sustained ventricular tachycardia or sick 
sinus syndrome or AV blockage degree 2-3
4
Patients with pacemaker
5
Prior coronary artery by-pass graft (CABG) to LAD
6
Left ventricle ejection fraction < 30% 
7
Unacceptable level of angina despite maximal medical therapy or unstable angina at entry 
Canadian Cardiovascular Society (CCS) ≥ 3 (Visit 1 or Visit 2)
8
Stroke within the previous 6 months from ACS or ongoing treatment with Persantin or 
Asasantin
9
Planned treatment with zileuton, leukotriene receptor antagonists (e.g. montelukast), coumadin 
or steroids during trial
10
Planned statin therapy dose regimen changes during trial
11
Chronic use of anticoagulants on therapeutic dose (not including thrombosis prophylaxis) 
during the study
12
Planned additional cardiac intervention (e.g., PCI, CABG) within next 6 months
13
NYHA class III-IV heart failure or decompensated heart failure at discharge or hospitalization 
for exacerbation of chronic heart failure within the previous 3 months from ACS 
14
Previously known severe renal disease (CKD stage 4 or 5) or previously known creatinine 
clearance calculated by Cockcroft Gault equation <30 ml/min*m2
15
Aortic or mitral valvular disease or valvular disease classified as severe
16
Known allergy to adenosine and mannitol, or experience of previous adverse effects of 
adenosine stress testing
17
Known elevated intracranial pressure
18
Heart rate < 40 bpm
19
Systolic blood pressure < 90 mmHg
20
Asthma or COPD with strong reactive component in judgment of investigator
21
Treatment with dipyridamole, theophyllamine, fluvoxamine, rifampicin, fenytoin or 
carbamazepine
22
Inability to comply with the study protocol 
23
History of severe allergy/hypersensitivity or ongoing clinically important 
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24
Patients unable to give their consent or communicate reliably with the investigator or 
vulnerable patients e.g., kept in detention, protected adults under guardianship, trusteeship, or
committed to an institution by governmental or juridical order
25
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff 
and/or staff at the study site)
26
Participation in another interventional clinical study with an investigational pharmaceutical 
product during the last 3 months also including drug eluting stents 
27
Previous randomization in the present study
28
Known history or current abuse of drugs or alcohol 
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomization
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.
The Investigator(s) will:
1.
Obtain signed ICF from the potential study patient before any study specific 
procedures are performed
2.
Assign (using the Interactive Voice Response System/ Interactive Web Response 
System (IVRS/IWRS)) potential study patient a unique enrolment number, 
beginning with ‘E#
3.
Determine patient eligibility. See Section 3.1 and 3.2
4.
Assign enrolled patient a unique randomization code (patient number) in 
IVRS/IWRS at Visit 2. See Section 3.5
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused.
3.4
Procedures for handling incorrectly enrolled or randomized 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive study medication. There can be no exceptions to this rule. Patients who are 
enrolled, but subsequently found not to meet all the eligibility criteria must not be 
randomized or initiated on treatment, and must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca study 
physician immediately, and the patient must discontinue the treatment and be 


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withdrawn from the study. The AstraZeneca study physician must ensure all decisions are 
appropriately documented.
3.5
Methods for assigning treatment groups
At randomization the IVRS/IWRS will assign eligible patients a unique randomization code 
and blinded investigational product (IP) kit number(s) to the patient. Specific information 
concerning the use of the IVRS/IWRS will be provided in the separate user manual.
Block randomization using IVRS/IWRS will be used to randomize patients in a 6:3:4:2 ratio 
to receive a fixed dose of AZD5718 
, AZD5718 
, placebo 
 or placebo 
. Upon completion of the randomization request form, the randomization will be 
produced by PAREXEL Informatics using the AstraZeneca randomization solution (AZRand).
The randomization will be stratified with type of MI as a factor (STEMI vs NSTEMI).
3.6
Methods for ensuring blinding
The study will have a single blind design. Placebo film-coated tablets will match appearance 
of each AZD5718 film-coated tablet strength. Identical package configuration will be used for 
each placebo tablets and AZD5718 tablet strength.
No member of the study team at AstraZeneca, or representative, personnel at study centres, or 
any clinical research organization (CRO) handling data will have access to the randomization 
scheme during the conduct of the study, with the exception of the PAREXEL Informatics 
personnel generating the randomization scheme as well as AstraZeneca Supply Chain, and the 
CRO companies conducting PK sample analyses, providing the IVRS/IWRS and carrying out 
the packaging and labelling of the study medication. This documentation will be kept in a 
secure location until the end of the study. 
3.7
Methods for unblinding 
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or pharmacists from the IVRS/IWRS. Routines 
for this will be described in the IVRS/IWRS user manual that will be provided to each centre.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomization. The 
Investigator documents and reports the action to AstraZeneca, without revealing the treatment
given to patient to the AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to an IP and that potentially require expedited reporting to 
regulatory authorities. Treatment codes will not be broken for the planned analyses of data 
until all decisions on the evaluability of the data from each individual patient have been made 
and documented.


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For the interim analysis, independent personnel with no other involvement in the study will be 
unblinded to certain data. A detailed description of the interim analysis including the 
unblinding process will be included in the interim analysis plan. 
3.8
Restrictions
Restrictions for the study are listed in sections below.
AstraZeneca should be contacted if the investigator is informed of any restriction violations. 
AstraZeneca will decide whether a subject with restriction violation will be allowed to 
continue study participation
3.8.1
Medication restrictions
Abstain from taking any medications contraindicated in the study protocol. For the list of 
medications prohibited during the study refer to Section 7.7.
3.8.2
Dietary restrictions

Patient should arrive at the clinic after fasting overnight (no food or liquid 
[except for water] intake permitted from 10 p.m. the evening before) for Visits 
2, 3, 4, 4c and 5 for sampling for PK/PD and safety assessments. CFVR 
measurement at Visits 2, 4 and 4c requires fasting for at least 4 hours 

Abstain from use of grapefruit juice and St John’s Wort during the study
3.8.3
Alcohol, Drugs of abuse, Tobacco and Caffeine Restrictions

Prior to Visits 2, 4 and 4c, avoid intake of coffee or other caffeine containing 
beverages 12 hours before and until after completion of the study specific clinical 
assessments (CFVR, Echo)

Abstain from tobacco/nicotine for at least 120 minutes prior to CFVR 
measurements, or whenever study procedures demand it. Nicotine substitutes 
will be offered at the discretion of the Investigator

Abstain from alcohol for 48 hours preceding the clinical visits

Abstain from drugs of abuse during the entire study
3.8.4
Restrictions for male study subjects
Male subjects must be surgically sterile or using an acceptable method of contraception 
(defined as barrier methods [condom or occlusive cap] in conjunction with spermicides) for 
the duration of the study (from the time they sign ICF) and for 3 months after the last dose of 
IP (AZD5718/matching placebo) to prevent pregnancy in partners.
Sperm Donation:
Male subjects should not donate sperm for the duration of the study and for at least 3 months 
after the last day of IP administration.


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3.8.5
Other Restrictions
Subjects who are blood donors should not donate blood during the study and for 3 months 
following their last dose of AZD5718.
3.9
Discontinuation of investigational product
Patients may be discontinued from IP in the following situations:

Patient decision. The patient is at any time free to discontinue treatment, 
without prejudice to further treatment

An adverse event that, in the opinion of the Investigator or AstraZeneca, 
warrants discontinuation from further dosing

Patient noncompliance that, in the opinion of the Investigator or sponsor, 
warrants withdrawal (e.g. refusal to adhere to scheduled visits)

Patient is determined to have met one or more of the exclusion criteria or failed 
to meet all of the inclusion criteria for study participation at study entry and 
continuing IP, in the decision of the Investigator, might constitute a safety risk
If the patient is discontinued from IP, the scheduled study visits, data collection and 
procedures should continue according to the Clinical Study Protocol (CSP) until study closure. 
Alternatively, if the subject does not agree to this option, a modified follow up through e.g., 
regular telephone contacts or a contact at study closure should be arranged, if agreed to by the 
subject and in compliance with local data privacy laws/practices. The approach taken should
be registered in the CRF.
If patient is required to or chooses to discontinue the IP, every reasonable effort should be 
made for the patient to remain in the study for follow-up and to complete all other study 
procedures until the scheduled end of the study.
3.9.1
Procedures for discontinuation of a subject from IP 
At any time, patients are free to discontinue IP or withdraw from the study (i.e., 
investigational product and assessments – see Section 3.10), without prejudice to further 
treatment. A patient who decides to discontinue IP will always be asked about the reason(s) 
and the presence of any adverse events. If possible, they will be seen and assessed by an 
Investigator(s). Adverse events will be followed up (See Section 6); diary cards, and all study 
drugs should be returned by the patient.
If a patient is withdrawn from study, see Section 3.10.


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3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomized. These patients should have the reason for study withdrawal 
recorded as ‘Screen failure’(the potential patient who does not meet one or more criteria 
required for participation in a trial, this reason for study withdrawal is only valid for not 
randomized patients). ‘Failure to meet randomization criteria’ should be selected for an 
indication that the patient has been unable to fulfil/satisfy the criteria required for assignment 
into a randomized group (it is only applicable for randomized studies and should be used for 
patient withdrawal post-screening).
3.10.2
Withdrawal of the informed consent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any adverse events (AE). The Investigator will follow up AEs outside of the clinical study. 
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused. Withdrawn patients will not be replaced. 
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AstraZeneca, trial patients are placed at 
undue risk because of clinically significant findings that:

meet individual stopping criteria or are otherwise considered significant 

are assessed as causally related to IP, 

are not considered to be consistent with continuation of the study
Regardless of the reason for termination, all data available for the patient at the time of 
discontinuation of follow-up must be recorded in the CRF. All reasons for discontinuation of 
treatment must be documented.
In terminating the study, AstraZeneca will ensure that adequate consideration is given to the 
protection of the patients’ interests.


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4.
STUDY PLAN AND TIMING OF PROCEDURES 
4.1
Study Procedures 
General information
For Visits 2, 3, 4, 4c and 5, patients will come to the clinic in the morning after fasting 
overnight (see 3.8.2). 
Patients will record drug intake in diary cards for out-patient administration of IP. Diary cards 
will be handed-out to the patients after randomization at Visit 2 and reviewed during 
subsequent visits and at the end of treatment (Visits 3, 4, 4b and 4c).
For the full list of assessments and sampling/measurement time points, see assessment 
schedule (Table 1).
Visit 1 (Screening)
Visit 1 will take place at the clinic during the in-house hospital stay post ACS-event. It should 
be noted that Visit 1 can last over several days. Biomarker sampling, where feasible, will take 
place at 1, 2, 3 and 5 days post ACS. If the patient is discharged from hospital early, he/she 
may be asked to come back for biomarker sampling. 

Screening of patients will be done by review of hospital medical records 
and by evaluation of inclusion and exclusion criteria. If a patient is found 
potentially suitable, he/she will be asked about participation in this study. 
Before any study related procedures are conducted, the patient will 
receive information about the study and will be asked to sign Informed 
Consent Form (ICF). Medical and Surgical History will be collected.

ACS-related in-hospital invasive coronary angiogram is required to 
assess Thrombolysis-In-Myocardial-Infarction (TIMI) flow score from 
the three epicardial coronary arteries.

Patients will be assessed for GRACE Score (Global Registry of Acute 
Coronary Events GRACE) - a ACS Risk Calculator that provides the 
percentage probability of death or death/MI at time-points up to 3 years 
following admission with ACS.  

Measurements and sampling for PD (u-LTE4), safety and exploratory 
variables will be performed. 
Visit 2 (Randomization)

Patients will arrive at the clinic after fasting overnight and baseline 
sampling (PD [u-LTE4], exploratory biomarkers and safety lab [incl. liver 
panels]), clinical assessments (physical examination, vital signs, and 
ECG) and AE-review will be conducted.

Screening will be completed by evaluation of inclusion and exclusion 
criteria 


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
Patients will undergo baseline measurements for secondary and 
exploratory endpoints (cfPWV/bPWA, CFVR and echocardiography).

Randomization and dosing will take place after baseline assessments in 
the morning.

After randomization the following assessments will be conducted: PRO 
assessments and sampling for PK

In case of sustained discomfort after CFVR measurement, the patient 
should stay at the clinic until 2 hours after status stabilization.

IP for the first 4 weeks will be dispensed
Visit 3 (2 weeks, During Treatment)

Visit including AE-review, clinical safety assessments, collection of 
samples and IP intake at the clinic
Visit 4 (4 weeks, During Treatment)

The following assessments will be conducted during the visit: urine 
collection for assessment of LTE4, sampling for PK, safety and 
exploratory biomarkers as well as measurement of clinical safety, 
efficacy and exploratory endpoints such as BP, ECG, CFVR, 
cfPWV/bPWA, echocardiography and PRO questionnaires 

The dose will be taken at the clinic and the patients will return the 
remaining IP and receive a new bottle of IP for weeks 5-8

The patients will leave the clinic after completed measurements, but in 
case of sustained discomfort after CFVR measurement, the patient should 
stay until 2 hours after status stabilization.
Visit 4b (8 weeks, During Treatment)

Visit including AE-review, concomitant medication review

The patient will return the remaining IP and receive a new bottle of IP for 
weeks 9-12
Visit 4c (12 weeks, End of Treatment)

The following assessments will be conducted during the visit: urine 
collection for assessment of LTE4, sampling for PK, safety and 
exploratory biomarkers as well as measurement of clinical safety, 
efficacy and exploratory endpoints such as BP, ECG, CFVR, 
cfPWV/bPWA, echocardiography and PRO questionnaires 

The last dose will be taken at the clinic and the patient will return the 
remaining IP


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
The patient will leave the clinic after completed measurements, but in 
case of sustained discomfort after CFVR measurement, the patient should 
stay until 2 hours after status stabilization.
Visit 5 (Follow-up)

In the morning, urine collection for assessment of LTE4, clinical 
assessments and sampling for PK, safety and exploratory biomarkers as 
well as measurement of clinical safety, efficacy and exploratory 
endpoints such as BP, ECG, cfPWV/bPWA and echocardiography.


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Table 1
Study assessment schedule
ACS 
event
Visit 1
Screening
Visit 2
Randomization
Visit 3 
(2 weeks)
During 
Treatment
Visit 4 
(4 weeks)
During 
Treatment
Visit 4b
(8 weeks)
During 
Treatment
Visit 4c
(12 weeks)
End of 
Treatment
Visit 5
Follow-up
Comments
Study Day
-7 days
xa
day 1
day 14
day 28 
28 days after 
Visit 4
28 days after 
Visit 4b
28 days after 
last dose
Time Window
1-5 days post 
ACS event
7-28days post 
ACS event
±2
±3
±2
±3
±4 days
Informed consent 
(ICF)
x
Inclusion/exclusion 
criteria
x
x
Demographic data
x
Smoking history 
and alcohol 
consumption to 
be included
Height
x
Body weight b
x
x
x
x
x
x
Collect date for 
ACS event
x
TIMI flow score
x
Medical and 
surgical history
x
Concomitant 
medication
x
x
x
x
x
x
x


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Table 1
Study assessment schedule
ACS 
event
Visit 1
Screening
Visit 2
Randomization
Visit 3 
(2 weeks)
During 
Treatment
Visit 4 
(4 weeks)
During 
Treatment
Visit 4b
(8 weeks)
During 
Treatment
Visit 4c
(12 weeks)
End of 
Treatment
Visit 5
Follow-up
Comments
Study Day
-7 days
xa
day 1
day 14
day 28 
28 days after 
Visit 4
28 days after 
Visit 4b
28 days after 
last dose
Time Window
1-5 days post 
ACS event
7-28days post 
ACS event
±2
±3
±2
±3
±4 days
Serology (see Table 
3)
x
FSH and luteinizing 
hormone (LH) 
sampling (females 
only)  
x
Randomization
x
Diary card hand-out
x
Diary card review
x
x
x
x
Diary card hand-in
x
IP dispensed
x
x
x
IP returned
x
x
x
IP intake at the 
clinic
x
x
x
x
Safety and 
tolerability:
Adverse event (AE) 
review 
x (SAE only)
x
x
x
xm
x
x


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Table 1
Study assessment schedule
ACS 
event
Visit 1
Screening
Visit 2
Randomization
Visit 3 
(2 weeks)
During 
Treatment
Visit 4 
(4 weeks)
During 
Treatment
Visit 4b
(8 weeks)
During 
Treatment
Visit 4c
(12 weeks)
End of 
Treatment
Visit 5
Follow-up
Comments
Study Day
-7 days
xa
day 1
day 14
day 28 
28 days after 
Visit 4
28 days after 
Visit 4b
28 days after 
last dose
Time Window
1-5 days post 
ACS event
7-28days post 
ACS event
±2
±3
±2
±3
±4 days
Blood pressure and 
pulse rate (supine)
x
x
x
x
x
x
12-lead pECG with 
electronic source 
file 
x
x
x
x
x
x
Physical 
examination c
x
x
x
x
x
x
Blood and urine 
samples for safety 
laboratory 
evaluations 
(including fasting 
glucose) d
xe,n
xf
xn
x
x
x
Efficacy 
Assessments:
Spot urine for 
analysis of LTE4
levels and urinary 
creatinine
xl
xg
x (pre-dose)
x (pre-dose)
x(pre-dose)
x
Screening 
sample will not 
be used for 
assessment of 
primary 
endpoint


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Table 1
Study assessment schedule
ACS 
event
Visit 1
Screening
Visit 2
Randomization
Visit 3 
(2 weeks)
During 
Treatment
Visit 4 
(4 weeks)
During 
Treatment
Visit 4b
(8 weeks)
During 
Treatment
Visit 4c
(12 weeks)
End of 
Treatment
Visit 5
Follow-up
Comments
Study Day
-7 days
xa
day 1
day 14
day 28 
28 days after 
Visit 4
28 days after 
Visit 4b
28 days after 
last dose
Time Window
1-5 days post 
ACS event
7-28days post 
ACS event
±2
±3
±2
±3
±4 days
CFVR 
measurement
x
x
x
Echocardiography
x
x
x
x
cfPWV/bPWA
x
x
x
x
Pharmacokinetics:
Plasma for 
AZD5718
xh
xi
xj
xi
xk
Exploratory 
Clinical Variables:
-PRO 
questionnaires
x (post-dose)
x (post-dose)
x (post-dose)
-GRACE 2.0 Score
x
Exploratory 
Biomarkers:
-Plasma for analysis 
of LTB4 levels
xl
x (pre-dose)
x (pre-dose)
x (pre-dose)
x (pre-dose)
x


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Table 1
Study assessment schedule
ACS 
event
Visit 1
Screening
Visit 2
Randomization
Visit 3 
(2 weeks)
During 
Treatment
Visit 4 
(4 weeks)
During 
Treatment
Visit 4b
(8 weeks)
During 
Treatment
Visit 4c
(12 weeks)
End of 
Treatment
Visit 5
Follow-up
Comments
Study Day
-7 days
xa
day 1
day 14
day 28 
28 days after 
Visit 4
28 days after 
Visit 4b
28 days after 
last dose
Time Window
1-5 days post 
ACS event
7-28days post 
ACS event
±2
±3
±2
±3
±4 days
-Blood samples for 
cardiovascular 
biomarkers 
xl
x (pre-dose)
x (pre-dose)
x (pre-dose)
x (pre-dose)
x
-Plasma samples to 
be stored in 
biobank for 
exploratory 
analyses
xl
x (pre-dose)
x (pre-dose)
x (pre-dose)
x (pre-dose)
x
-Optional Genetic 
sampling
xo
a
Screening during in-house stay after ACS event. Assessments can take place over several days. If the patient is discharged from hospital early, he/she 
may be asked to come back for blood sampling.
b
Body weight assessments to be conducted in the mornings after an overnight fast, except for non-fasting at screening (Visit 1)
c
Full physical examination at Screening (Visit 1) and at Follow-up (Visit 5), and brief physical examination on the other occasions (Visits 2, 3, 4 and 4c).
d
Fasting plasma samples for glucose measurements to be obtained after an overnight fast (from 10 p m. the evening before) at the same time point at 
Visits 2, 3, 4, 4c and 5 to the extent possible.
e
Will exclude fasting glucose measurement.
f
Liver panel analyses results will be used for assessment of exclusion criteria. Samples need to be analysed as acute samples.
g
Spot urine sample to be collected in the morning prior to screening and baseline assessments.
h
Baseline sample to be obtained in the morning before screening assessments. The other sample to be taken between 1-8 h post-dose. 
i
CTrough sample to be collected before dose administration at 20-28 hours after previous dose (dose on day 13 (day before Visit 3) and on day before Visit 
4c).
j
Sampling times: pre-dose and then 0-2 h, 2-4 h, 4-8 h post dose. Sampling will be separated with at least 1 hour.
k
One PK-sample to be collected as suitable in relation to the other follow-up measurements. Exact sampling time to be entered in the CRF.


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l
Sampling, where feasible, at 1, 2, 3 and 5 days post ACS. Exact sampling time to be entered in the CRF.
m
Unscheduled safety assessments (blood and urine samples for safety lab and ECG) may be performed as judged by the investigator
n
Will exclude TSH, Free T3, Free T4 and Total T4
o
The genetic sample may be collected at any time after randomization, however, ideally samples should be collected at Visit 2
Order of assessments:
1.
Spot urine sample for LTE4 (u-LTE4)
2.
Safety labs, ECG, AE-review, physical examination and vital signs
3.
Echocardiography, cfPWV/bPWA, (Vis 2, 4, 4c and 5) CFVR (Vis 2, 4 and 4c)
4.
Sampling for Exploratory biomarkers and PK
5.
Intake of IP
6.
Meal
7.
Post-dose PK sample no. 1 (Vis 2 and 4)
8.
PRO (Vis 2, 4 and 4c)
9.
Post-dose PK sample no. 2 (Vis 4)
10.
Post-dose PK sample no. 3 (Vis 4)


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4.2
Screening/Enrolment period
Procedures will be performed according to the Study Plan in Table 1. 
At screening, consenting patients are assessed to ensure that they meet eligibility criteria. 
Patients who do not meet these criteria must not be enrolled in the study.
4.3
Treatment period
Descriptions of the procedures for this period are included in Section 4.1 and in the Study 
assessment schedule (Table 1). 
4.4
Follow-up period
Descriptions of the procedures for this period are included in Section 4.1 and in the Study 
assessment schedule (Table 1). 
5.
STUDY ASSESSMENTS
The Rave Web Based Data Capture (WBDC) system will be used for data collection and 
query handling. The investigator will ensure that data are recorded on the electronic Case 
Report Forms (eCRFs) as specified in the CSP and in accordance with the instructions 
provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement (CSA). 
The investigator will sign the completed eCRFs. A copy of the completed eCRFs will be 
archived at the study site.
5.1
Efficacy assessments
5.1.1
Urine-leukotriene E4 (u-LTE4) 
Efficacy will be evaluated by assessment of change from baseline of creatinine-normalised 
urine-leukotriene E4 (u-LTE4) measured in spot urine. 
For timings of the assessments refer to Section 4 and Table 1. 
Details of the sampling and analyses will be given in the Laboratory Manual.
5.1.2
Echocardiography
Comprehensive echocardiographic examination will be performed with patients in the left
recumbent position at rest. Standard clinical cardiac transducers will be used for B-mode, 
colour Doppler, and tissue Doppler imaging. CINE-loops1 of the parasternal long- and short-
                                               
1 A CINE-loop is a period of images, stored digitally as a sequence of individual frames. CINE-loops recorded at 
high frame rates may contain more frames than were displayed during the examination


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axis views, apical 4-, 2-, and 3-chamber views, and subcostal views will be obtained and 
stored for off-line analysis of cardiac structure and function, as detailed in Manual of 
Procedures (MoP) for Echocardiography (detailed echocardiography protocol) that will be 
supplied to all study sites. Doppler and tissue Doppler echocardiography will be performed to 
obtain indices necessary for comprehensive assessment of left ventricular (LV) diastolic 
function and non-invasive hemodynamic measurements, as detailed in MoP.
5.1.3
Transthoracic Doppler echocardiography (TDE) with coronary flow velocity 
reserve (CFVR) measurement 
Coronary flow velocity reserve is measured in the LAD coronary artery before, and during 
constant adenosine infusion at a rate of 140 µg/kg/min for 1-5 minutes using conventional 
colour Doppler ultrasound equipped with coronary imaging protocol. For details see MoP. 
5.1.4
Carotid-femoral Pulse Wave Velocity (cfPWV) and brachial Pulse Wave 
Analysis (bPWA)
Carotid-femoral pulse wave velocity (cfPWV) is measured in a single step with a 
simultaneous measurement by femoral cuff and carotid placed tonometer. Brachial pulse wave 
analysis is conducted with a brachial cuff recording. For details see MoP.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
serology and urinalysis will be taken at the times indicated in the Study Plan (see Section 4, 
Table 1).
The clinical chemistry, haematology, serology and urinalysis will be performed at a local 
laboratory at or near to the Investigator site. Sample tubes and sample sizes may vary 
depending on laboratory method used and routine practice at the site. AstraZeneca will 
provide the same type of urine dipstick test kit to all sites.
The following laboratory variables will be measured:
Table 2
Standard Clinical Laboratory Evaluation Panels
Haematology/Haemostasis (whole blood)
Clinical Chemistry* (serum or plasma)
White blood cell (WBC) count
Sodium
Red blood cell (RBC) count
Potassium
Haemoglobin (Hb)
Urea
Haematocrit (HCT)
Creatinine
Mean corpuscular volume (MCV)
Albumin


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Haematology/Haemostasis (whole blood)
Clinical Chemistry* (serum or plasma)
Mean corpuscular haemoglobin (MCH)
Calcium
Mean corpuscular haemoglobin 
concentration (MCHC)
Phosphate
Neutrophils absolute count 
Glucose (fasting) (Not at Visit 1 - Screening)
Lymphocytes absolute count 
Alkaline phosphatase (ALP) “LIVER PANEL”
Monocytes absolute count 
Alanine aminotransferase (ALT) “LIVER PANEL”
Eosinophils absolute count 
Aspartate aminotransferase (AST) “LIVER PANEL”
Basophils absolute count 
Total bilirubin “LIVER PANEL”
Platelets
FSH (Screening only)
Reticulocytes absolute count 
LH (Screening only)
Coagulation 
TSH, Free T3, Free T4, Total T4
International normalized ratio (INR)
Activated partial thromboplastin time 
(APTT)
Fibrinogen
Urinalysis
Glucose (dipstick)
Albumin (quantification/semi-quantification)
Protein (dipstick)
Blood (dipstick) 
WBC (Leukocytes) (dipstick)
Creatinine (quantification)
* In case that ALT, AST>2ULN, ALP increase by 100%, bilirubin (total)>1.5ULN, intensified and extensive 
liver panel will be conducted.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
The Investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
centre as source data for laboratory variables. For information on how AEs based on 
laboratory tests should be recorded and reported, see Section 6.3.


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NB. In case a subject shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer 
to Appendix D ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
Table 3
Other Clinical Safety Panels
Panel Name
Markers
Serology (Screening only)
Human immunodeficiency virus (HIV) I and II 
Hepatitis B surface Antigen (HBsAg)
Hepatitis C virus antibody
5.2.2
Physical examination
A complete physical examination will be performed at Screening (Visit 1) and at Follow-up 
(Visit 5) and will include an assessment of the following: general appearance, respiratory, 
cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and throat), lymph 
nodes, thyroid, abdomen, musculoskeletal (including spine and extremities) and neurological 
systems. On the other occasions (Visit 2, 3, 4 and 4c) a brief physical examination (general 
appearance, skin, abdomen and musculoskeletal, cardiovascular and respiratory systems) will 
be conducted. 
For handling of AEs based on examinations and tests see Section 6.3.6.
5.2.3
Body weight
Body weight assessments will be conducted in the mornings after an overnight fast (except for 
non-fasting at screening) with the patients in underwear/light clothes and after a lavatory visit. 
Assessments are to be done on the same calibrated scale at all occasions.
5.2.4
ECG
12-lead ECG recordings will be collected according to the assessments schedule presented in 
Section 4, Table 1. The investigator will make an overall evaluation of the ECG as normal or 
abnormal. If abnormal, it will be decided whether or not the abnormality is clinically 
significant or not clinically significant and the reason for the abnormality will be recorded on 
the eCRF. 
Abnormal values shall not be recorded as AEs unless deemed clinically significant. The 
printout of the ECG is to be signed, dated and filed in the ISF along with a signed and dated 
copy (if the printouts are not on archive-quality paper).
To ensure robust data to evaluate and confirm potential outliers in the coming increased 
cardiovascular risk population, the requirement is to use digitally stored 12-lead safety ECGs 
where the digital source file is later available to adjudicate in case of events.


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Digital ECGs refers to the storage of digital safety ECG source files that are retrievable for 
adjudication if required. The study will be performed in an unstable ischemic cardiac 
population with increased cardiovascular risk and primarily the ECGs will be assessed in real 
time for safety signals by experienced ECG readers as part of the standard clinical safety 
evaluation on site.
Based on data from the phase I studies, no trends or findings of safety concerns on any ECG 
parameter have been identified.
5.2.4.1
Resting 12-lead ECG
The following parameters or time intervals will be recorded for each ECG: RR, PR, QRS, QT, 
QTcF and heart rate (HR).
5.2.5
Vital signs
Vital signs will include pulse, and systolic and diastolic blood pressure. Vital signs will be 
obtained at time points indicated in Section 4, Table 1(and ad-hoc as medically indicated).
5.2.5.1
Pulse and blood pressure
Pulse (beats/minute, radial artery, during 30 seconds) and pulse oximetry will be measured 
before blood pressure and in a lying position after 10 minutes of rest. Thereafter, systolic and 
diastolic blood pressure (mmHg, the cuff method on the arm opposite to the one used for 
blood sampling) will be measured using the same cuff, appropriate for arm circumference, and 
in the same position, throughout the study. Patients should be in the same position for the vital 
signs measurements throughout the study.
5.3
Other assessments
5.3.1
Other research biomarker assessments
Samples for additional research biomarker assessments will be collected at time points listed 
in the schedule of assessments in Section 4. Table 1. The research biomarkers are listed in 
Table 4.
Table 4
Research biomarkers
Panel Name
Biomarkers
FLAP Biomarkers
Plasma LTB4 
Cardiovascular Biomarkers
Proseek Multiplex CVD II 96×96 panel
Proseek Multiplex CVD III 96×96 panel
Lipid profile (total cholesterol, low density lipoprotein cholesterol 
(LDL-C), high density lipoprotein cholesterol (HDL-C), 
triglycerides)*
hsTnI (high sensitive Troponin I)


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Panel Name
Biomarkers
hsCRP (High-sensitivity C-Reactive Protein)
NT-proBNP (N-Terminal Prohormone of Brain Natriuretic Peptide)
Lp(a)* (Lipoprotein a)
GDF 15 (Growth/differentiation factor 15)
MPO mass (Myeloperoxidase protein level measurement)
IL-6 (Interleukin 6)
IL-1B (Interleukin 1 beta)
ApoA1* (Apolipoprotein A)
ApoB*
*Analysis will be performed at a local laboratory at or near to the Investigator site. Sample tubes and sample 
sizes may vary depending on laboratory method used and routine practice at the site.
5.3.2
Clinical Outcome Assessments
PRO questionnaires will be used to address exploratory objectives.
Two general health-related quality of life instruments will be applied: SF-36 and EQ-5D. 
Both dyspnoea and fatigue symptoms are of particular relevance in patients with CAD and 
ACS. For assessment of dyspnoea Rose Dyspnoea Score will be administered and FACIT 
fatigue scale will be used to assess fatigue. 
The PRO questionnaires used in this study will all be collected by paper, subject-self 
completed and do not require training. Site personnel should enter the responses in the 
appropriate sections of the Case Report Form. The total time estimated to complete the 
questionnaires at the clinic visit is 15 min. The questionnaires to be used are listed below:

SF-36 V2 (The Short Form (36) Health Survey - a 36-item, patient-
reported survey of patient health. SF-36 is a general well-validated 
questionnaire which encompasses eight health concepts: physical 
functioning, bodily pain, role limitations due to physical health problems, 
role limitations due to personal or emotional problems, emotional well-
being, social functioning, energy/fatigue, and general health perceptions. 
It also includes a single item that provides an indication of perceived 
change in health.)

EQ-5D-5Lfrom EuroQol Group (a 5-dimensional, standardised 
instrument for use as a measure of health outcome applicable to a wide 
range of health conditions and treatments.)


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
Rose Dyspnoea score (a standardized 4-item survey to measure patient 
related outcomes entailing symptoms of dyspnoea for patients with 
coronary artery disease.)

FACIT-Fatigue scale (part of the FACIT Measurement System. 
Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue 
Scale - a short, 13-item, easy to administer tool that measures an 
individual’s level of fatigue during their usual daily activities.) 
The time points for the above listed PRO assessments are given in the schedule of assessments 
in Section 4, Table 1.
PRO questionnaires should be completed by the subject in private. Appointed site staff should 
remind subjects that there are no right or wrong answers and avoid clarifying items in order to 
avoid bias. 
Subject must not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. If a subject uses visual aids (e.g., spectacles or contact lenses) for reading and 
does not have them when he attends the clinic, the subject will be exempted from completing 
the PROs. 
The subject should be given sufficient time to complete the PRO questionnaires at his/her own 
speed. Appointed site staff must monitor compliance to ensure all data is captured.
5.4
Pharmacokinetics
5.4.1
Collection of samples
Venous blood samples for the determination of plasma concentrations of AZD5718 will be 
collected at the time points presented in the study assessments schedule, Section 4, Table 1.
Placebo samples will only be analysed on Day 14, unless specified.
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual. 
Standard model population PK parameters will be reported in a separate report. 
5.4.2
Determination of drug concentration
Samples for determination of drug concentration in plasma will be analysed using an 
appropriate bioanalytical method. Full details of the analytical method used will be described 
in a separate bioanalytical report. Additional analyses may be conducted on the biological 
samples to further investigate the presence and/or identity of drug metabolites. 


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5.4.3
Storage and destruction of pharmacokinetic samples
PK samples will be disposed of after the Bioanalytical Report finalization or six months after 
issuance of the draft Bioanalytical Report (whichever is earlier), unless requested for future 
analyses. 
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the Clinical Study Report (CSR).
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report.
5.5
Pharmacodynamics
5.5.1
Collection of samples
Samples for determination of LTE4 and creatinine in spot urine will be taken at the times 
presented in the study assessments schedule, Section 4, Table 1.
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.
5.5.2
Storage, re-use and destruction of pharmacodynamics samples
Samples will be stored for a maximum of 15 years from the date of the Last Patient’s Last 
Visit, after which they will be destroyed. The results of any investigation will be reported 
either in the CSR itself or as an addendum, or separately in a scientific report or publication.
For storage and handling details of PD-samples refer to the Laboratory Manual.
5.6
Genetics (optional)
An optional genetic blood sample will be obtained from the study patients who have signed 
the genetic ICF. The genetic sample may be collected at any time after randomization, 
however, ideally samples should be collected at Visit 2 i.e. early in the study (see Table 1) to 
avoid bias in the sample collection (i.e. failure to collect samples from subjects who have 
suffered an AE etc.). Information regarding genetic research is detailed in Appendix C.
For details of sampling, handling, storage and transportation of the samples refer to the 
Laboratory Manual.
5.7
Biomarkers
The patient’s consent to the use of donated exploratory research biomarker samples is 
mandatory. 


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Biological samples (e.g. blood samples) will be collected and may be analysed for exploratory 
biomarkers to assess correlations with disease activity, effects of AZD5718, clinical outcomes 
and toxicity.
Samples for determination of research biomarkers (see Section 5.3.1, Table 4) will be taken at 
the times presented in the study assessments schedule, Section 4, Table 1.
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.
5.7.1
Storage, re-use and destruction of biological samples
Exploratory biomarker research samples will be stored for a maximum of 15 years from the 
date of the Last Patient’s Last Visit, after which they will be destroyed. The results of this 
biomarker research will be reported either in the CSR itself or as an addendum, or separately 
in a scientific report or publication. The results of this biomarker research may be pooled with 
biomarker data from other studies with AZD5718 to generate hypotheses to be tested in future 
research.
5.7.2
Labelling and shipment of biological samples
The Principal Investigator ensures that samples are labelled and shipped in accordance with 
the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria 
(see Study Protocol Appendix B - IATA 6.2 Guidance Document).
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labelling, shipment and containment provisions are approved.
5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each centre keeps full traceability of collected biological samples 
from the patients while in storage at the centre until shipment or disposal (where appropriate) 
and keeps documentation of receipt of arrival.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.
AstraZeneca keeps oversight of the entire life cycle through internal procedures, monitoring of 
study sites and auditing of external laboratory providers.
Samples retained for further use are registered in the AstraZeneca Gothenburg Biobank during 
the entire life cycle.


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5.7.4
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological samples is an integral part of the study, then the patient is 
withdrawn from further study participation.
The Principal Investigator:

Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified immediately to AstraZeneca

Ensures that biological samples from that patient, if stored at the study 
site, are immediately identified, disposed of /destroyed, and the action 
documented

Ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site

Ensures that the patient and AstraZeneca are informed about the sample 
disposal.
AstraZeneca ensures the organizations holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of/destroyed and the action 
documented and returned to the study site.
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The safety of all AstraZeneca clinical studies is closely monitored on the on-going basis by 
AstraZeneca representatives in consultation with Patient Safety. Issues identified will be 
addressed: for example this could involve amendments to the CSP and letters to Investigators. 
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a subject or 
clinical study subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (e.g. an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 


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The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.
6.2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (i.e. run-in, treatment, 
washout and follow-up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-subject hospitalization or prolongation of existing 
hospitalization 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the subject or may 
require medical intervention to prevent one of the outcomes listed above.
For further guidance on the definition of a SAE, see Appendix A to the CSP.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from time of the first dose throughout the treatment period 
and including the follow-up period.
SAEs will be recorded from the time of signing ICF.
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last AE assessment in the study are 
followed up by the Investigator for as long as medically indicated, but without 
further recording in the CRF. AstraZeneca retains the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if 
judged necessary.
6.3.3
Variables 
The following variables will be collect for each AE;

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity

Whether the AE is serious or not


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
Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

AE caused patient’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 to other medication

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 6.2. 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 unless it meets the criteria 
shown in Section 6.2. 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 when it satisfies the criteria 
shown in Section 6.2.
6.3.4
Causality collection
The Investigator will assess causal relationship between IP and each Adverse Event, and
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix A to the CSP.


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6.3.5
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the CRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
6.3.6
Adverse events based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
CSR. Deterioration as compared to baseline in protocol-mandated laboratory values, vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the IP.
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., anaemia versus low haemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
If clinically non-significant ECG findings are reported they are not required to be recorded as 
AEs, unless there are clinical symptoms and actions taken that merit for AE/SAE reporting on 
their own.
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. 
6.3.7
Hy’s Law
Cases where a patient shows elevations in liver biochemistry may require further evaluation 
and occurrences of AST or ALT ≥ 3xULN together with total bilirubin ≥ 2xULN may need to 
be reported as SAEs. Please refer to Appendix D for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
6.4
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s). All SAEs will be recorded in the CRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AstraZeneca representatives within one day i.e., immediately but no later 
than 24 hours of when he or she becomes aware of it.


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The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by fax (+46 31 776 37 34) or E-mail 
(AEMailboxWBDCTCS@astrazeneca.com).
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug 
6.5
Overdose
An overdose is defined as a patient receiving a dose of AZD5718 in excess of that specified in 
this protocol. No specific treatment is recommended for an overdose. The Investigator will use 
clinical judgement to treat any overdose.

An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the CRF and on the 
Overdose CRF module.

An overdose without associated symptoms is only reported on the 
Overdose CRF module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 6.4. 
For other overdoses, reporting must occur within 30 days.


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6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except if the 
pregnancy is discovered before the study subject has received any study drug.
6.6.1
Maternal exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the IP should be discontinued immediately and the pregnancy reported 
to AstraZeneca.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the IP 
under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
patient was discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 6.4) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
In case of pregnancy, the pregnancy data and the outcome of the pregnancy will be collected.
6.6.2
Paternal exposure 
As a precaution, all male patients should avoid fathering a child by either true abstinence or 
the use of two effective means of contraception with their partner from the time of IP 
administration until 3 months after the last dose of IP.
Sperm donation
Male subjects should not donate sperm for the duration of the study and for at least 3 months 
after the last day of IP administration.
6.7
Medication Error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an AstraZeneca study drug that either causes harm to the patient or 
has the potential to cause harm to the patient. 


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A medication error is not lack of efficacy of the drug, but rather a human or process related 
failure while the drug is in control of the study site staff or patient.
Medication error includes situations where an error: 

occurred

was identified and intercepted before the patient received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually given 
to the patient

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 

Wrong patient received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to patient (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error 

Patient accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Patient failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day i.e., immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is completed within 1 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 6.4) and within 30 days for all other medication errors.


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7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS
7.1
Identity of investigational product(s)
Table 5
Investigational products – dosage form and strength
Investigational product
Dosage form and strength
Dose
Manufacturer
AZD5718
 of AZD5718 
 
 tablet
AstraZeneca 
AZD5718
 of AZD5718 
 
-
 tablet 
AstraZeneca 
Placebo to match (PTM) 
AZD5718 
PTM AZD5718 
 
tablet
AstraZeneca
Placebo to match (PTM) 
AZD5718 
PTM AZD5718
 
tablet
AstraZeneca
AstraZeneca R&D Supply Chain (or contract research organisation) will pack, label, and
supply AZD5718 and matching placebo for this study.
AZD5718 and Placebo will be packed into white high-density polythene bottles with child
resistant, tamper evident closures. Study drug must be kept out of the reach of children.
7.2
Dose and treatment regimens 
On Day 1 (Visit 2), 7-28 days after the ACS event, patients willing to participate in the study 
will complete the screening procedure and if eligible be randomized to a once daily 
administration, to be taken with approximately 200 ml water in the morning with no 
restrictions on food intake. Randomized patients will be dispensed with one bottle of IP at 
each dispensing visit. Dispensation will take place at the following study visits: Visit 2 
(Randomization), Visit 4 (4 weeks), Visit 4b (8 weeks), see Table 1. Dose at Visit 2 (day 1), 
Visit 3 (day 14), Visit 4 (4 weeks) and Visit 4c (week 12) will be given by study personnel at 
the study site following an overnight fast. The exact dose intake time before Visit 3, Visit 4 
and Visit 4c will be recorded on a Diary Card. The Diary Cards will be given to the patients at 
the randomization visit and the patients will be asked to fill in the dose intake information 
(date and time) at home.
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labelling. Label 
text will be translated into local language.


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7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions. The IP 
label on the bottle specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including IPs) should be recorded in the appropriate 
sections of the Case Report Form.
7.6
Accountability
The IP provided for this study will be used only as directed in the CSP.
The study site staff will account for all IPs dispensed to and returned from the patient.
IP kits will be uniquely coded and assigned through the randomization and subsequent visits 
via the IVRS/IWRS. On receipt of IP supplies the Investigator/designee will check the 
supplies against the shipment manifest and will confirm receipt of IP shipments via the 
IVRS/IWRS. The system will then issue an acknowledgement receipt. Sites are required to 
place all shipment manifests and acknowledgement receipts in the site regulatory binder.
The study site staff is also responsible for maintaining accurate records accounting for the 
receipt, dispensing and final disposition of all IPs using the appropriate IP logs provided by 
AstraZeneca. 
7.7
Concomitant and other treatments 
The concomitant medications not allowed at entry and/or during the study are listed below:
Prohibited Medication/Class of drug:
Usage:
Zileuton, leukotriene receptor antagonists (e.g. 
Montelukast), Coumadin or steroids during study
Rifampicin, Fenytoin, Carbamazepine
Planned or ongoing treatment during the study
Persantin or Asasantin.
Dipyridamole, Theophyllamine or Fluvoxamine
Ongoing treatment at entry and during the study
Anticoagulants on therapeutic dose (not including 
thrombosis prophylaxis) 
Chronic use, during the study
7.7.1
Other concomitant treatment
Other medication than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the Case Report Form.


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8.
STATISTICAL ANALYSES
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and identification of protocol violations. Analyses will be performed by AstraZeneca or its 
representatives.
A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to the interim 
analysis. Any subsequent amendments to the SAP will be documented, with final amendments 
completed prior to unblinding of the data for the analysis. Details of all analyses will be fully 
documented in the SAP.
8.2
Sample size estimate 
The study has been powered to show a statistically significant result for the primary endpoint, 
first, second and third secondary endpoints. To preserve the overall type1-error at 5% when 
testing these four endpoints a Hierarchical Procedures will be used (Dmitrienko A. et al 2006). 
This procedure implies that one will test the four endpoints in a predefined sequence: test of 
main objective, test of first secondary objective, test of second secondary objective, test of 
third secondary objective. The test procedure will stop as soon as the first none-significant 
test, one-sided test at a 5% level, occur and all following test will be declared as none-
significant.
The Hierarchical testing sequence for the four endpoints are:
1. u-LTE4 at 4 weeks
2. u-LTE4 at 12 weeks
3. CFVR at 12 weeks
4. CFVR at 4 weeks
Data from MAD study shows inhibition of u-LTE4 by AZD5718 
 can be assumed to be 
log-normally distributed, with an expected inhibition of u-LTE4 of approximately 96% and a 
standard deviation of <4%. Patients given placebo are expected to have no inhibition of 
u-LTE4 with the same standard deviation (on the logarithmic scale) as patients given 
AZD5718 
. Given this, 33 evaluable patients in the AZD5718 
 group and 33 
evaluable patients given placebo will be sufficient to achieve > 99% power to show a 
statistically significant inhibition of u-LTE4 of at least 80%, using a one-sided confidence 
interval of 95% at week 12.
Assuming a log-normal distribution of the CFVR and an expected 20% increase in CFVR in 
the AZD5718 
 group compared to placebo with a coefficient of variation (CV) of 30%, 
33 evaluable patients per arm is required to achieve 80% power with a one-sided confidence 
interval of 95%. 


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About 40 randomized patients per arm (AZD5718 
 or placebo) treated for 12 weeks is 
needed to account for non-evaluable patients (approximate 18% dropout). 
For supporting dose selection in future studies, a treatment arm with about 20 randomized 
patients receiving AZD5718 
 for 12 weeks is included in the study, in order to get 17 
evaluable patients. This number of subjects, 17, patients has been deemed to provide sufficient 
exposure-response information.
8.3
Definitions of analysis sets
8.3.1
Efficacy analysis set
The efficacy analysis set for efficacy will be analysed using the intention to treat (ITT) 
population. This is in accordance to the ICH E9 guideline suggesting that the analysis of the 
primary endpoint should be analysed according to the treatment to which patients were 
actually randomized. The ITT population will include all patients who were randomised, 
received at least one dose of study medication and have at least one baseline or postbaseline 
measurement.
8.3.2
Safety analysis set
The safety analysis set will include all patients who were randomized and received at least one 
dose of study medication. Patients will be analysed according to the treatment which they 
actually received. If a patient received IP from the wrong kit for only a part of the treatment 
duration and then switched to another, the associated treatment group for that patient will be 
the treatment group that patient was randomized to. Any important protocol deviations from 
randomized treatment will be listed and considered when interpreting the safety data. 
Important protocol deviations will be defined in the SAP.
8.3.3
PK analysis set
The PK analysis set will consist of all patients in the efficacy analysis set who has received at 
least one dose of AZD5718, and who has at least one PK sample post dose.
8.4
Outcome measures for analyses
8.4.1
Efficacy variables
The primary efficacy variable is percentage change at Visit 4 from baseline (Visit 2) in 
creatinine-normalised u-LTE4. Summary statistics per time point the variables are measured 
will also be presented.
The following secondary efficacy variables are all measured as change from baseline (Visit 2):

u-LTE4 at week 12

CFVR at week 4 and 12


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
LAD resting mean diastolic flow velocity

LAD hyperaemic flow velocity 

Measurements of left ventricular (LV) systolic and diastolic function, more specifically
-
LV ejection fraction (LVEF) at rest
-
LV Global Longitudinal Strain (GLS) at rest and at hyperaemia
-
LV Global Circumferential Strain (GCS) at rest
-
LV longitudinal early diastolic strain rate 
Summary statistics per time point the variables are measured will also be presented.
8.4.2
Safety variables
Adverse Events, vital signs (blood pressure and pulse rate), physical examination, clinical 
laboratory safety evaluations (haematology, serum biochemistry and urinalysis [see Table 2
and Table 3]) and 12-lead ECG.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
8.4.3
Exploratory variables

Carotid-femoral pulse wave velocity and brachial pulse wave analysis (cfPWV/bPWA) 
parameters. The output variables – measured as change from baseline - will be:

Augmentation index,

Carotid-femoral pulse wave velocity

Pulse pressure amplification (derived variable)

Central pulse pressure

Central blood pressure systolic/diastolic

Brachial blood pressure systolic/diastolic
Summary statistics per time point the variables are measured will also be presented.

Quality of life questionnaires – measured as change from baseline: 

SF-36 – overall score and per each dimension

EQ-5D – overall score

Rose Dyspnoea score – overall score

FACIT-Fatigue – overall score


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Summary statistics per time point the variables are measured will also be presented.

GRACE 2.0 Score at baseline
Exploration of changes in additional echocardiographic variables parameters that will be 
captured are to be referred in an exploratory SAP and results will be described in a separate 
report.
Variables handling exploration of the relationship between AZD5718 exposure and the 
exploratory objectives, as well as exploration of changes in efficacy and safety endpoints 
based on baseline assessments are also to be referred in an exploratory SAP and results will be 
described in a separate report.
8.4.4
Exploratory biomarkers
The exploratory research biomarkers are listed below and in Table 4.

Cardiovascular biomarkers – measured as change from baseline:
-
hsTnI
-
hsCRP
-
NT-proBNP
-
total cholesterol
-
LDL-cholesterol
-
HDL-Cholesterol
-
Triglycerides
-
ApoA1
-
ApoB
-
Lp(a)
Summary statistics per time point the variables are measured will also be presented.
Proseek Multiplex CVD II and CVD III panels, MPO mass, plasma LTB4, GDF15, IL-1B, IL-
6 and responder analysis of PD biomarkers, as well as genetic variations that may affect PK, 
PD, efficacy, safety and tolerability related to AZD5718 treatment are to be referred in an 
exploratory SAP and results will be described in a separate report.
8.5
Methods for statistical analyses
All efficacy and safety variables will be summarised by treatment groups using descriptive 
statistics (n, mean, geometric mean, standard deviation [SD], coefficient of variation [CV], 
median, minimum, and maximum for continuous data and absolute and relative frequencies 
for categorical data). Data will be summarised for baseline, endpoint and by visit (if 
applicable). P-values will be unadjusted and tests will be two-sided except for the primary 
efficacy variable, first secondary, second secondary and third secondary efficacy variable, 
which will have one-sided tests. All tests will be performed between the AZD5718 
 
group versus placebo, or the AZD5718 
 group versus placebo.


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Descriptive statistics will be presented to assess the distribution of the baseline variables 
across treatment groups.
The analysis and presentation of efficacy variables, exploratory variables and exploratory 
biomarkers will be based on patients in the efficacy analysis set. All efficacy variables will be 
summarised descriptively displaying parameter values at visits where they were measured. 
The analysis and presentation of safety variables will be based on patients in the safety 
analysis set.
To preserve the overall type1-error at 5% when testing the primary endpoint, first secondary, 
second secondary and third secondary endpoint a Hierarchical test procedure will be used as 
described in the section 8.2 Sample size estimate. 
The statistical methods will be further detailed in the SAP.
8.5.1
Analysis of the primary variable(s)
The primary efficacy variable will test the null hypothesis that patients given AZD5718 
 have less than 80% inhibition of u-LTE4 compared to placebo, versus the alternative 
hypothesis that patients given AZD5718 have equal or more than 80% inhibition of u-LTE4
compared to placebo (one-sided confidence interval) at week 4. 
The primary efficacy variable will be analysed as change from baseline using a repeated 
measures model with type of MI (STEMI vs NSTEMI), time from randomization (days), 
treatment and time treatment interaction as fixed effects with baseline value as covariate. The 
covariance structure will be spatial power law covariance structures (generalisation of an auto 
regressive covariance structure allowing for none equidistant time points). All available data 
from each patient will be used for the analysis. The analysis will be done on loge scale. 
However, the result will be back transformed to original scale. 
8.5.2
Analysis of the secondary variables
The first secondary, second secondary and third secondary efficacy variable will be analysed 
in the same type of model as for the primary endpoint, that is, a repeated measurement model 
with the same structure as described for the primary variable. All three endpoints will be 
measured as change from baseline and the analyses will be done on logarithmic transformed 
data. However, the result will be back transformed to original scale.
The models for analysis of all other secondary variables will be defined in the SAP. In 
general, an analysis of covariance or as a repeated measurement model will be used. The SAP 
will also describe which variable that will be analysed on original scale or on log scale. All 
results from transformed variables will be back transformed to the original scale.
If data permits a population PK model will be developed, possibly with the support of PK data 
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analysis in NONMEM. Furthermore, if data allows, the population PK model may be coupled 
with separate PD models for u-LTE4 and for CFVR.
All PK/PD modelling will be described in a separate data analysis plan. Moreover, the results 
of any such modelling will be provided in a separate population PK/PD report (as an appendix 
to the CSR or as a stand-alone report).
8.5.3
Analysis of safety variables
AEs will be summarised by treatment group by means of counts summaries by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term 
(PT). All AEs will be listed and assigned to on/off treatment period as:

Baseline period: The time before first administration of IP.

On treatment: The time from first administration of IP until 7 days after 
last dose of IP.

Off treatment: More than 7 days after last dose of IP. 
AEs will be assigned to the period where they start. 
Laboratory data for haematology and clinical chemistry will be summarized by treatment 
group. The frequency of changes with respect to normal ranges between baseline and end of 
treatment will be tabulated. Shifts from normal to abnormal between baseline and end of 
treatment time point will be evaluated for urinalysis. Descriptive statistics might need to be 
applied to evaluate some of the reported urine laboratory values changes. The incidence of 
markedly abnormal values and changes from baseline in the ECG parameters will be 
summarised by treatment group. Categorical outliers may be presented by numbers but need 
to be considered in context of inclusion/exclusion criteria. Physical examination and vital 
signs variables will be summarised by treatment group.
Other safety variables will be summarised as appropriate. Further details will be provided in 
the SAP.
8.5.4
Subgroup analysis
Type of MI (STEMI or NSTEMI) is used as a stratification factor in the randomization. For 
variables measuring change from baseline that uses type of MI as covariate in the model, 
estimates of change from baseline will be presented for each type of MI.
8.5.5
Exploratory analysis
All exploratory variables and biomarkers will be analysed in a similar way as the secondary 
variables.  The models for analysis will be defined in the SAP. In general, an analysis of 
covariance or as a repeated measurement model will be used. The SAP will also describe 


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which variable that will be analysed on original scale or on log scale. All results from 
transformed variables will be back transformed to the original scale.
As described in section 8.4, there are exploratory variables and exploratory biomarkers where 
the analysis will be described in an exploratory SAP and results will be described in a separate 
report.
8.5.6
Interim analysis 
Two administrative interim analyses will be conducted. The first one is planned after at least 
45 patients have performed their CFVR measurement at Visit 4 and the second after at least 
100 patients have performed their CFVR measurement at Visit 4. The variables for the 
analyses will be CFVR and LV Global Longitudinal Strain (GLS). These analyses will not 
have any impact on the overall type-1 error because no changes will be made to the trial based 
on the outcome of the analyses. The purpose with the interim analyses is to trigger external 
activities not connected to the trial. Both interim analyses will be performed by study 
independent personnel. 
The models for the interim analysis will be analysed using Analysis of Covariance with 
treatment, type of MI (STEMI vs NSTEMI) and baseline value as covariates, with compound 
symmetry as covariance structure. Change from baseline will be used as endpoint and the 
analysis will be done on loge scale. The result will be back transformed to original scale. 
For the second interim analysis, all data available will be used to measure change from 
baseline in a repeated measures model with treatment, type of MI, time (from randomization) 
and treatment*time interaction as fixed effects, baseline value will be used as covariate. The 
exact model will be prespecified in the interim analysis plan. Change from baseline will be 
used as endpoint and the analysis will be done on loge scale. The result will be back 
transformed to original scale
In the event of positive outcome at any of the administrative interim analyses an evaluation of 
exposure-response relationship may be performed. This analysis has the intention to guide the 
dose setting for the next study. This will be performed by non-study personnel with no other 
involvement in the study. Data for this analysis will be based on PK, u-LTE4 and CFVR.
In connection to the first administrative interim analysis, a safety review committee (SRC) 
will be unblinded to safety data including AEs, SAEs and safety labs to ensure no safety 
concerns are associated with AZD5718 treatment. 
An interim analysis plan will be prepared and finalized prior to the first administrative interim 
analysis. A separate analysis plan will also be prepared for the evaluation of exposure-
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9.
STUDY AND DATA MANAGEMENT
9.1
Training of study site staff
Before the first subject is entered into the study, an AstraZeneca representative or delegate 
will review and discuss the requirements of the CSP and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC 
system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
Monitoring of the study
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to:

Provide information and support to the Investigator(s)

Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the CSP, that data are 
being accurately and timely recorded in the CRFs, that biological samples 
are handled in accordance with the Laboratory Manual and that study 
drug accountability checks are being performed

Perform source data verification (a comparison of the data in the CRFs 
with the subject’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent 
of participating patients. This will require direct access to all original 
records for each patient (e.g., clinic charts)

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AstraZeneca representative will be available between visits if the Investigator(s) or other 
staff at the centre needs information and advice about the study conduct.
9.2.1
Source data
Refer to the CSA for location of source data.


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9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the CSA, or equivalent, for this study. In the event of any inconsistency 
between this CSP and the CSA, the terms of CSP shall prevail with respect to the conduct of 
the study and the treatment of patients and in all other respects, not relating to study conduct 
or treatment of patients, the terms of the CSA shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.
The study may be terminated at individual centres if the study procedures are not being 
performed according to GCP, or if recruitment is slow. AstraZeneca may also terminate the 
entire study prematurely if concerns for safety arise within this study or in any other study 
with AZD5718. 
9.4
Data management 
Data Management will be performed by AstraZeneca/Chiltern according to the Data 
Management Plan (DMP). 
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgical history will be classified according to the terminology of 
the latest version of MedDRA. Medications will be classified according to the WHO Drug 
Dictionary. All coding will be performed by the Medical Coding Team at Chiltern.
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the DMP. Quality control procedures will be applied 
to each stage of data handling to ensure that all data are reliable and have been processed 
correctly. The DMP will also clarify the roles and responsibilities of the various functions and 
personnel involved in the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared. Any 
treatment revealing data may thereafter be added and the final database will be locked.


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Serious Adverse Event (SAE) Reconciliation
Where necessary SAE reconciliation reports are produced and reconciled with the Patient 
Safety database and/or the investigational site. 
Data Management of genotype data
Any genotype data generated in this study will be stored in the AstraZeneca genotyping LIMS 
database, or other appropriate secure system within AstraZeneca and/or any other organization 
contracted to work with AstraZeneca to analyse samples. The results from this genetic 
research may be reported in the CSR for the main study, or in a separate report as appropriate.
Data associated with human biological samples
Data associated with biological samples will be transferred from laboratory (ies) internal or 
external to AstraZeneca.
Management of external data
The data management vendor will receive and manage all external data according to the DMP.
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with ICH/Good Clinical Practice, applicable 
regulatory requirements and the AstraZeneca policy on Bioethics and Human Biological 
Samples.
10.2
Patient data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.
10.3
Ethics and regulatory review
An Ethics Committee should approve the final CSP, including the final version of the ICF and 
any other written information and/or materials to be provided to the patients. The Investigator 
will ensure the distribution of these documents to the applicable Ethics Committee, and to the 
study site staff.
The opinion of the Ethics Committee should be given in writing. The Investigator should 
submit the written approval to AstraZeneca before enrolment of any patient into the study. 
The Ethics Committee should approve all advertising used to recruit patients for the study.


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AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the CSP should be re-approved by the Ethics Committee 
annually.
Before enrolment of any patient into the study, the final CSP, including the final version of the 
ICF, where relevant, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.
AstraZeneca will handle the distribution of any of these documents to the national regulatory 
authorities.
AstraZeneca will provide Regulatory Authorities, Ethics Committees and Principal 
Investigators with safety updates/reports according to local requirements.
10.4
Informed consent
The patients potentially eligible for this study, as assessed by the review of Inclusion and 
Exclusion criteria, will be given written and oral information about the study and will be 
asked to sign the ICF for inclusion in the study. The main ICF will include consent for 
biological sampling and for storage of biological samples for future research. There will also 
be an optional Genetic consent to be signed if the patient agrees to donate a genetic sample. 
The Principal Investigator(s) at each centre will:

Ensure each patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of the 
study

Ensure each patient is notified that they are free to discontinue from the 
study at any time

Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided

Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study

Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study 
File

Ensure a copy of the signed ICF is given to the patient

Ensure that any incentives for patients who participate in the study as 
well as any provisions for patients harmed as a consequence of study 
participation are described in the ICF that is approved by an Ethics 
Committee.


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10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the International co-
ordinating Investigator, the Principal Investigators and AstraZeneca.
If there are any substantial changes to the CSP, then these changes will be documented in a 
new version of the study protocol.
The new version of the CSP is to be approved by the relevant Ethics Committee and if 
applicable, also the national regulatory authority approval, before implementation. Local 
requirements are to be followed for new versions of Clinical Study Protocols.
AstraZeneca will distribute any new versions of the CSP to each Principal Investigator. For 
distribution to Ethics Committee see Section 10.3.
If a change to a CSP requires a change to a centre’s ICF, AstraZeneca and the centre’s Ethics 
Committee are to approve the revised ICF before the revised form is used. 
10.6
Audits and inspections
Authorised representatives of AstraZeneca, a regulatory authority, or an Ethics Committee 
may perform audits or inspections at the centre, including source data verification. The 
purpose of an audit or inspection is to systematically and independently examine all study-
related activities and documents, to determine whether these activities were conducted, and 
data were recorded, analysed, and accurately reported according to the CSP, Good Clinical 
Practice (GCP), guidelines of the International Conference on Harmonisation (ICH), and any 
applicable regulatory requirements. The Investigator will contact AstraZeneca immediately if 
contacted by a regulatory agency about an inspection at the centre.
11.
LIST OF REFERENCES
WHO 2011
World Health Organization. Global status report on noncommunicable diseases 2010. April 
2011.
Lloyd-Jones D et al 2010
Lloyd-Jones D, Adams RJ, Brown TM et al. Heart disease and stroke statistics — 2010 
update: a report from the American Heart Association. Circulation 2010;121(7):e46-e215 
Libby P 2013
Libby P. Mechanisms of acute coronary syndromes and their implications for therapy. N Engl 
J Med 2013;368:2004-13


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Frangogiannis NG 2012
Frangogiannis NG. Regulation of the inflammatory response in cardiac repair. Circ Res 
2012;110:159-73
Spanbroek R et al 2003
Spanbroek R, Grabner R, Lotzer K, Hildner M, Urbach A, Ruhling K et al. Expanding 
expression of the 5-lipoxygenase pathway within the arterial wall during human 
atherogenesis. Proc Natl Acad Sci USA 2003;100(3):1238-43
Dwyer JH et al 2004
Dwyer JH, Allayee H, Dwyer KM, Fan J, Wu H, Mar R et al. Arachidonate 5-lipoxygenase 
promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 
2004;350(1):29–37  
Bäck M 2008 
Bäck M. Inflammatory signaling through leukotriene receptors in atherosclerosis. Curr 
Atheroscler Rep 2008;10:244–51
Funk CD 2005
Funk, Colin D. Leukotriene Modifiers as potential therapeutics for cardiovascular disease.
Nature Reviews Drug Discovery 2005;4:664-72
Qiu H et al 2006
Qiu H, Gabrielsen A, Agardh HE, Wan M, Wetterholm A, Wong C H et al. Expression of 
5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with 
symptoms of plaque instability. Proc Natl Acad Sci USA 2006;103(21):8161-6
Cipollone F at al 2005
Cipollone F, Mezzetti A, Fazia ML, Cuccurullo C, Iezzi A, Ucchino S et al. Association 
Between 5 Lipoxygenase Expression and Plaque Instability in Humans. Arterioscler Thromb 
Vasc Biol 2005;25(8):1665-70
van den Borne P et al 2014
van den Borne P, van der Laan SW, Bovens SM, Koole D, Kowala MC, et al. Leukotriene B4 
Levels in Human Atherosclerotic Plaques and Abdominal Aortic Aneurysms. PLoS One 
2014;9(1):e86522
Allen S at al 1998
Allen S, Dashwood M, Morrison K, Yacoub M. Differential Leukotriene Constrictor 
Responses in Human Atherosclerotic Coronary Arteries. Circulation. 1998;97:2406-2413
Tardif JC et al 2010
Tardif JC, L'allier PL, Ibrahim R, Grégoire JC, Nozza A et al. Treatment With 
5-Lipoxygenase Inhibitor VIA 2291 (Atreleuton) in Patients With Recent Acute Coronary 
Syndrome. Circ Cardiovasc Imaging. 2010;3:298-307


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Helgadottir A et al 2004
Helgadottir A, Manolescu A, Thorleifsson G, Gretarsdottir S et al. The gene encoding 
5-lipoxygenase activating protein confers risk of myocardial infarction and stroke. 
Nat Genet 2004;36(3):233–39
Sala A et al 1993
Sala A, Rossoni G, Buccellati C, Berti F, Folco G and Maclouf J. Formation of 
sulphidopeptide-leukotrienes by cell-cell interaction causes coronary vasoconstriction in 
isolated, cell-perfused heart of rabbit. Br J Pharmacol 1993;110:1206-12
Sala A et al 1996
Sala A, Aliev GM, Rossoni G, Berti F, Buccellati C, Burnstock G, Folco G and Maclouf J. 
Morphological and functional changes of coronary vasculature caused by transcellular 
biosynthesis of sulfidopeptide leukotrienes in isolated heart of rabbit. 
Blood 1996;87(5):1824-32
Montalescot G et al 2013
Montalescot G, Sechtem U, Achenbach S et al. 2013 ESC guidelines on the management of 
stable coronary artery disease: the Task Force on the management of stable coronary artery 
disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003
Camici PG et al 2007
Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med 2007;356:830-40
Camici PG et al 2015
Camici PG, d'Amati G, Rimoldi O et al. Coronary microvascular dysfunction: mechanisms 
and functional assessment. Nat Rev Cardiol 2015;12:48–62
Rigo F et al 2008
F. Rigo, R. Sicari, S. Gherardi, et al., The additive prognostic value of wall motion 
abnormalities and coronary flow reserve during dipyridamole stress echo, Eur. Heart J. 
2008;29:79–88.
Tagliamonte E et al 2015
Tagliamonte E, Rigo F, Cirillo T, Astarita C, Quaranta G, Marinelli U, Caruso A, Romano C, 
Capuano N. Effects of ranolazine on noninvasive coronary flow reserve in patients with 
myocardial ischemia but without obstructive coronary artery disease. Echocardiography. 
2015;32:516-21
Uren NG et al 1995
N.G. Uren, P.G. Camici, J.A. Melin, et al., Effect of aging on myocardial perfusion reserve, J. 
Nucl. Med. 1995;36:2032-36 
Murthy VL et al 2012
V.L. Murthy, M. Naya, C.R. Foster, et al., Coronary vascular dysfunction and prognosis in 
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Blomster J et al 2016
J. Blomster, S. Svedlund, H. U Westergren, L-M Gan. Coronary flow reserve as a link 
between exercise capacity, cardiac systolic and diastolic function. Int J Cardiol 
2016;217:161-6
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Alex Dmitrienko, Ajit C. Tamhane, Xin Wang, and Xun Chen. Stepwise Gatekeeping 
Procedures in Clinical Trial Applications. Biometrical Journal 48 (2006) 6, 984–991 


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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the subject was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (e.g., hepatitis that resolved without hepatic failure).
Hospitalization
Out-subject treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study.
Important medical event or medical intervention
Medical and scientific judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment 
with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization
Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.


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
Time Course. Exposure to suspect drug. Has the subject actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of 
the suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the 
dose of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology 
such as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support a 
re-challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 
information to make an informed judgment. With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.


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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories. For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition 
(2005). Infectious substances are now classified either as Category A, Category B or Exempt. 
There is no direct relationship between Risk Groups and categories A and B.
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. Category A pathogens are e.g., Ebola, Lassa fever 
virus:

are to be packed and shipped in accordance with IATA Instruction 602.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2. They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA regulations

Clinical trial samples will routinely be packed and transported at ambient temperature 
in IATA 650 compliant packaging 

Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content

IATA compliant courier and packaging materials should be used for packing and 
transportation and packing should be done by an IATA certified person, as applicable

Samples routinely transported by road or rail are subject to local regulations which 
require that they are also packed and transported in a safe and appropriate way to 
contain any risk of infection or contamination by using approved couriers and 
packaging / containment materials at all times. The IATA 650 biological sample 
containment standards are encouraged wherever possible when road or rail transport is 
used.


Clinical Study Protocol Appendix C
Drug Substance AZD5718
Study Code D7550C00003
Version Version 5.0
Date 11 February 2019
81 (87)
Appendix C
Genetic Research
Rationale and Objectives
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic Research Plan and Procedures
Selection of genetic research population
Study selection record
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study.
Inclusion criteria
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the CSP and:

Provide informed consent for the genetic sampling and analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Discontinuation of subjects from this genetic research
Specific reasons for discontinuing a subject from this genetic research are:
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Sections 3.9 to 3.11 of the main CSP.


Clinical Study Protocol Appendix C
Drug Substance AZD5718
Study Code D7550C00003
Version Version 5.0
Date 11 February 2019
82 (87)
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2. Although 
DNA is stable, early sample collection is preferred to avoid introducing bias through 
excluding subjects who may withdraw due to an adverse event (AE), such subjects would be 
important to include in any genetic analysis. If for any reason the sample is not drawn at 
Visit 2 it may be taken at any visit until the last study visit. Only one sample should be 
collected per subject for genetics during the study. Samples will be collected, labelled, stored 
and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples will be stored for a maximum of 
15 years or as per local regulations from the date of the Last Patient’s Last Visit, after which 
they will be destroyed. DNA is a finite resource that may be used up during analyses. Samples 
will be stored and used until no further analyses are possible or the maximum storage time has 
been reached.
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA).
The link between the subject enrolment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent.
Ethical and Regulatory Requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 10 of the main CSP.
Informed consent
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study centre. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
subject understands that they may freely discontinue from the genetic aspect of the study at 
any time.


Clinical Study Protocol Appendix C
Drug Substance AZD5718
Study Code D7550C00003
Version Version 5.0
Date 11 February 2019
83 (87)
Subject data protection
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organization or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical Methods and Determination of Sample Size
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan will be prepared where appropriate.


84 (87)
Appendix D
Actions Required in Cases of Increases in Liver 
Biochemistry and Evaluation of Hy’s Law
1. Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP). 
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAE) and Adverse Events (AE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
2. Definitions
Potential Hy’s Law (PHL)
Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥ 3x Upper Limit of 
Normal (ULN) together with Total Bilirubin (TBL) ≥ 2xULN at any point during the study 
following the start of study medication irrespective of an increase in Alkaline Phosphatase 
(ALP). 
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2xULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, e.g., elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 


85 (87)
For PHL and HL the elevation in transaminases must precede or be coincident with (i.e. on the 
same day) the elevation in TBL, but there is no specified timeframe within which the 
elevations in transaminases and TBL must occur.
3. Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3xULN

AST ≥ 3xULN

TBL ≥ 2xULN
The Investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the AstraZeneca representative

Determine whether the subject meets PHL criteria (see Section 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits

Promptly enter the laboratory data into the laboratory CRF
4. Follow-up
4.1 Potential Hy’s Law Criteria not met
If the subject does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the subject has not met PHL criteria.

Perform follow-up on subsequent laboratory results according to the guidance 
provided in the Clinical Study Protocol.
4.2 Potential Hy’s Law Criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE 
of Potential Hy’s Law; serious criteria ‘Important medical event’ and causality 
assessment ‘yes/related’ according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required 
to submit a PHL SAE unless there is a significant change# in the subject’s condition.


86 (87)

The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study subjects’ follow-up (including any further laboratory testing) 
and the continuous review of data. 
Subsequent to this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate 
clinical symptoms and signs return to normal or baseline levels, or as long 
as medically indicated. Complete follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations 
as discussed with the Study Physician.

Complete the three Liver CRF Modules as information becomes available.
5. Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days 
from date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and 
Global Safety Physician will also be involved in this review together with other subject matter 
experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
Whether there is an agreed alternative explanation for the ALT or AST and TBL
elevations, a determination of whether the alternative explanation is an AE will be made and 
subsequently whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 


87 (87)

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE 
reporting.
Continue follow-up and review according to agreed plan. Once the necessary supplementary 
information is obtained, repeat the review and assessment to determine whether HL criteria 
are still met. Update the previously submitted PHL SAE report following CSP process for 
SAE reporting, according to the outcome of the review and amending the reported term if an 
alternative explanation for the liver biochemistry elevations is determined.
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7550c00003-csp-v5
Document Title:
D7550C00003 Clinical Study Protocol version 5
Document ID:
Doc ID-003493628
Version Label:
7.0 CURRENT LATEST APPROVED
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13-Feb-2019 07:44 UTC
Qualified Person Approval
12-Feb-2019 07:02 UTC
Content Approval
11-Feb-2019 16:09 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: 
































































































































































SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7550c00003-sap-ed-7
Document Title:
Statistical Analysis Plan Edition 7
Document ID:
Doc ID-003886729
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19-May-2020 09:29 UTC
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20-May-2020 16:27 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.