Clinical trial NCT03370887
Conditions: Heart Failure
Sponsor: AstraZeneca
Start date: 2018-02-05; Completion date: 2021-06-30
Enrollment: 11 participants; Allocation: RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is a randomized, double-blind, placebo-controlled, sequential design, multicentre study in patients with moderately impaired systolic function undergoing CABG surgery. Twenty four (24) patients scheduled for elective bypass surgery will be randomized (up to approximately 33 patients if replacements are needed). The objective is to investigate safety and tolerability of AZD8601 following epicardial injection in patients undergoing Coronary Artery Bypass Grafting (CABG) surgery with moderately impaired systolic function. At Visit 3 patients will receive either AZD8601 or placebo as epicardial injections and will then be followed up at 14 days (telephone visit) and 1, 3 and 6 months (on-site) post-surgery.

Detailed description:

Arms: arm 1: 8 patients will be randomised to receive 3 mg AZD8601 arm 2: 8 patients will be randomised to receive 30 mg AZD8601 arm 3: 8 patients will be randomised to receive placebo injections
Interventions: intervention 1: AZD8601 intervention 2: Placebo
Intervention descriptions: intervention 1: AZD8601 solution for injection, 0,5 mg/mL and 5 mg/mL will be given as 30 injections of 0.1 mg (3 mg per patient), or 1 mg (30 mg per patient) respectively on a single occasion intervention 2: Placebo for AZ8601 injection for solution will be given as 30 injections per patient on a single occasion

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Drug Substance
AZD8601
Study Code
D9150C00003
Version
5.0
Date
27 Feb 2020
A randomized, double-blind, placebo-controlled, multi-centre, sequential 
design, phase IIa study to evaluate safety and tolerability of epicardial 
injections of AZD8601 during coronary artery bypass grafting surgery
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden












Clinical Study Protocol
Drug Substance AZD8601
Study Code D9150C00003
Version 5.0
Date 27 Feb 2020
7 (100)
updated, so that the unblinded Safety Review Committee included external experts and had 
decision right about the progress of the study. The process has been adjusted to meet this 
request.
It was also required to add Study specific stopping criteria.
In addition, an unblinded Data Monitoring Group (DMG) has been added to enable internal 
clinical project and business decision separate from the study.
Sections 1.3, 1.4, 3.6 and 3.11 have been adjusted accordingly.
To increase operational feasibility for patient and site staff, it has been added that if a 
patient is referred to another hospital for the 15O PET assessment, CT can also be 
performed there.
Sections 4.1.3, 4.3.2, 4.3.3 and 5.3.1 have been adjusted accordingly.
A cross was missing in Table 1 to indicate that Medical history is to be checked on Visit 3, 
day -1. 
This has been adjusted accordingly in Section 4 .
An erroneous sentence has been deleted in Section 7.1. Text previously indicated that each 
syringe would be labelled with a patient-specific dosing label in local language. Each 
syringe is not labelled by pharmacy personnel due to a combination of sterility requirement 
and that syringes are too small to accommodate the labels. 


Clinical Study Protocol
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Study Code D9150C00003
Version 5.0
Date 27 Feb 2020
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This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations. 






Clinical Study Protocol
Drug Substance AZD8601
Study Code D9150C00003
Version 5.0
Date 27 Feb 2020
11 (100)
If not otherwise specified, baseline refers to the last measurement prior to administration of 
investigational product.
Analysis of the primary variable(s)
The analysis and presentation of safety variables will be based on patients in the safety 
analysis set. 
All safety variables will be summarised by treatment groups and visit using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum for continuous 
data and absolute and relative frequencies for categorical data).
AEs will be summarised by treatment group, treatment related and severity by means of 
counts summaries by Medical Dictionary for Regulatory Activities (MedDRA) System 
Organ Class and Preferred Term (PT). 
Laboratory data for haematology and clinical chemistry will be summarized by treatment 
group and visit. The number and percentages of patients with haematology and clinical 
chemistry treatment emergent laboratory changes with respect to normal ranges between 
baseline and post treatment will be tabulated. 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.
Unless otherwise stated, the following rules will apply to any repeated safety assessments:

If the repeated measurement of a specific parameter occurs prior to IP administration 
(Day 1), the last obtained value prior to dosing will be used in the descriptive statistics 
and in the calculation of changes from baseline.
Exploratory analysis 
The analysis and presentation of exploratory variables will be based on patients in the 
exploratory analysis set. 
All exploratory variables will be summarised by treatment group and visit using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum and geometric 
mean and geometric SD if applicable for continuous data and absolute and relative frequencies 
for categorical data). P-values will be unadjusted and tests will be two-sided.
Mean values per treatment will be plotted against visit.
Geometric mean per treatment and individual plasma levels of VEGF-A will be plotted 
against time after dosing. Calculation of VEGF AUC - Area under the concentration-time 
curve (μmol*h/L) will be done by linear up/ log down trapezoidal summation. 


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Study Code D9150C00003
Version 5.0
Date 27 Feb 2020
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Change from baseline will be analysed for all exploratory variables with baseline and post-
dose measurements. Change from baseline for some exploratory variables will be analysed 
using Analysis of Covariance, (with treatment as fixed effect, patient as random effect and 
baseline value as covariates) or a repeated measurements model (with treatment, visit and 
treatment-by-visit interaction as fixed effects, baseline as covariate and patient as random 
effect). If an approximation of the variable of interest follows a log-normal distribution rather 
than a normal distribution, a logarithmic transformation of the variable of interest will be 
done. All variables that are transformed will be back transformed for reporting.


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TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
CLINICAL STUDY PROTOCOL SYNOPSIS ....................................................9
TABLE OF CONTENTS................................................................................... 13
1.
INTRODUCTION ............................................................................................. 21
1.1
Background and rationale for conducting this study ........................................... 21
1.2
Rationale for study design, doses and control groups.......................................... 22
1.3
Benefit/risk and ethical assessment .................................................................... 22
1.3.1
Dosing rationale................................................................................................. 24
1.4
Study Design...................................................................................................... 24
2.
STUDY OBJECTIVES...................................................................................... 28
2.1
Primary objective............................................................................................... 28
2.2
Secondary objectives (NA)................................................................................. 28
2.3
Safety objectives (NA)....................................................................................... 28
2.4
Exploratory objectives ....................................................................................... 28
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 29
3.1
Inclusion criteria ................................................................................................ 29
3.2
Exclusion criteria ............................................................................................... 30
3.3
Patient enrolment and randomisation.................................................................. 32
3.4
Procedures for handling incorrectly enrolled or randomized patients.................. 33
3.5
Methods for assigning treatment groups............................................................. 33
3.6
Methods for ensuring blinding ........................................................................... 33
3.7
Methods for unblinding...................................................................................... 34
3.8
Restrictions........................................................................................................ 34
3.8.1
Medications restrictions ..................................................................................... 34
3.8.2
Dietary restrictions............................................................................................. 34
3.8.3
Alcohol, Drugs of abuse, Tobacco and Caffeine Restrictions.............................. 35
3.8.4
Exercise restrictions ........................................................................................... 35
3.8.5
Restrictions for male patients ............................................................................. 35


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3.9
Discontinuation of investigational product ......................................................... 35
3.9.1
Procedures for discontinuation of a patient from investigational product ............ 36
3.10
Criteria for withdrawal....................................................................................... 36
3.10.1
Screen failures ................................................................................................... 36
3.10.2
Withdrawal of the informed consent................................................................... 36
3.10.3
Specific withdrawal criteria between visit 2 and 3.............................................. 37
3.11
Discontinuation of the study............................................................................... 37
3.11.1
Safety Review.................................................................................................... 38
3.11.1.1
Safety Review Board ......................................................................................... 38
3.11.1.2
Safety Review Committee.................................................................................. 38
3.11.1.3
Data Monitoring Group...................................................................................... 39
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 39
4.1
Screening/Enrolment period............................................................................... 48
4.1.1
Pre-study screening............................................................................................ 48
4.1.2
Visit 1 – Screening, enrolment and baseline assessments (Day -90 to -15)..........48
4.1.3
Visit 2 – Randomisation and baseline assessments (Day -35 to -14) ................... 48
4.1.3.1
Pre-operative cardio-thoracic surgery conference to decide individual 
injection map ..................................................................................................... 49
4.2
Treatment period................................................................................................ 50
4.2.1
Visit 3 – CABG surgery and IP administration (Day -1 to Day 4)....................... 50
4.3
Follow-up period................................................................................................ 50
4.3.1
Visit 4 - Telephone contact follow-up (Day 14 ±2 days)..................................... 50
4.3.2
Visit 5 – Follow-up (1 month ±3 days)............................................................... 50
4.3.3
Visit 6 – Follow up (3 months ±14 days)............................................................ 51
4.3.4
Visit 7 – Final follow-up (6 months ±14 days) ................................................... 51
5.
STUDY ASSESSMENTS.................................................................................. 51
5.1
Efficacy assessments (NA)................................................................................. 52
5.2
Safety assessments............................................................................................. 52
5.2.1
Laboratory safety assessments............................................................................ 52
5.2.2
Physical examination ......................................................................................... 54
5.2.3
ECG................................................................................................................... 54
5.2.4
Vital signs.......................................................................................................... 55
5.2.4.1
Pulse, pulse oximetry and blood pressure ........................................................... 55
5.2.5
Other safety assessments.................................................................................... 55
5.2.5.1
Hemopericardium and/or tamponade assessment with echocardiography ........... 55
5.3
Other assessments.............................................................................................. 55
5.3.1
15O PET and CT angiogram.............................................................................. 55
5.3.2
Echocardiography .............................................................................................. 56
5.3.2.1
Stress echocardiography and optional LAD CFVR............................................. 56
5.3.3
Gyrocardiography .............................................................................................. 56
5.3.4
Clinical Outcome Assessments........................................................................... 56


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5.3.4.1
Kansas City Cardiomyopathy Questionnaire ...................................................... 57
5.3.4.2
Seattle Angina Questionnaire ............................................................................. 57
5.3.5
NYHA classification.......................................................................................... 58
5.3.6
Digital 6-minute walk test and Maximum continuously walked steps 
(optional) ........................................................................................................... 58
5.3.7
Filming/photo of injection procedure ................................................................. 58
5.4
Pharmacokinetics ............................................................................................... 58
5.5
Pharmacodynamics ............................................................................................ 59
5.6
Genetics............................................................................................................. 59
5.7
Biomarker analysis............................................................................................. 59
5.7.1
Storage, re-use and destruction of biological samples......................................... 62
5.7.2
Labelling and shipment of biological samples .................................................... 62
5.7.3
Chain of custody of biological samples .............................................................. 62
5.7.4
Withdrawal of Informed Consent for donated biological samples....................... 62
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 63
6.1
Definition of adverse events............................................................................... 63
6.2
Definitions of serious adverse event ................................................................... 63
6.3
Recording of adverse events............................................................................... 64
6.3.1
Time period for collection of adverse events ...................................................... 64
6.3.2
Follow-up of unresolved adverse events............................................................. 64
6.3.3
Variables............................................................................................................ 64
6.3.4
Causality collection............................................................................................ 65
6.3.5
Adverse events based on signs and symptoms.................................................... 66
6.3.6
Adverse events based on examinations and tests ................................................ 66
6.3.7
Hy’s Law ........................................................................................................... 66
6.4
Reporting of serious adverse events ................................................................... 66
6.5
Overdose............................................................................................................ 67
6.6
Pregnancy .......................................................................................................... 67
6.6.1
Maternal exposure.............................................................................................. 68
6.6.2
Paternal exposure............................................................................................... 68
6.7
Medication Error................................................................................................ 68
6.8
Study governance and oversight......................................................................... 69
7.
INVESTIGATIONAL PRODUCT AND OTHER TREATMENTS ................... 70
7.1
Identity of investigational product(s).................................................................. 70
7.2
Dose and treatment regimens ............................................................................. 70
7.3
Labelling............................................................................................................ 70
7.4
Storage............................................................................................................... 71


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Study Code D9150C00003
Version 5.0
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7.5
Compliance........................................................................................................ 71
7.6
Accountability.................................................................................................... 71
7.7
Concomitant and other treatments ...................................................................... 71
7.7.1
Other concomitant treatment .............................................................................. 71
8.
STATISTICAL ANALYSES BY ASTRAZENECA.......................................... 71
8.1
Statistical considerations .................................................................................... 71
8.2
Sample size estimate .......................................................................................... 72
8.3
Definitions of analysis sets................................................................................. 72
8.3.1
Safety analysis set.............................................................................................. 72
8.3.2
Exploratory analysis set ..................................................................................... 72
8.3.3
All Enrolled Patients .......................................................................................... 72
8.3.4
All Randomized Patients.................................................................................... 73
8.4
Outcome measures for analyses.......................................................................... 73
8.4.1
Safety variables.................................................................................................. 73
8.4.2
Exploratory variables ......................................................................................... 73
8.4.3
Exploratory biomarkers...................................................................................... 74
8.5
Methods for statistical analyses.......................................................................... 75
8.5.1
Analysis of the primary variable (s).................................................................... 75
8.5.2
Exploratory analysis........................................................................................... 76
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA......................... 76
9.1
Training of study site staff.................................................................................. 76
9.2
Monitoring of the study...................................................................................... 76
9.2.1
Source data ........................................................................................................ 77
9.2.2
Study agreements............................................................................................... 77
9.2.3
Archiving of study documents............................................................................ 77
9.3
Study timetable and end of study........................................................................ 77
9.4
Data management............................................................................................... 78
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 78
10.1
Ethical conduct of the study ............................................................................... 78
10.2
Patient data protection........................................................................................ 79
10.3
Ethics and regulatory review .............................................................................. 79
10.4
Informed consent ............................................................................................... 79
10.5
Changes to the Clinical Study Protocol and Informed Consent Form.................. 80
10.6
Audits and inspections ....................................................................................... 80
11.
LIST OF REFERENCES ................................................................................... 81


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LIST OF TABLES
Table 1 
Schedule of Assessments: Enrolment and treatment periods..................40
Table 2
Schedule of assessments: Follow-up period...........................................45
Table 3 
Standard Clinical Laboratory Evaluation Panels....................................53
Table 4
Other Clinical Safety Panels..................................................................53
Table 5
Exploratory biomarkers.........................................................................60
Table 6
Investigational products ........................................................................70
Table 7 
Prohibited medication ...........................................................................71
LIST OF FIGURES
Figure 1
Outline of sentinel dosing cohorts .........................................................26
Figure 2
Study flow chart....................................................................................27
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................85
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................87
Appendix C
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ........................................................................88
Appendix D
Kansas City Cardiomyopathy Questionnaire .........................................92
Appendix E
Seattle Angina Questionnaire ................................................................96


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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
15O PET
O-15 Radiowater Positron Emission Tomography
AE
Adverse Event
ACE
Angiotensin Converting Enzyme
ACS
Acute Coronary Syndrome
ALP
Alkaline phosphatase
ALT
Alanine Aminotransferase
ARB
Angiotensin Receptor Blocker
AST
Aspartate aminotransferase
BP
Blood Pressure
CABG
Coronary Artery By-pass Grafting
CAD
Coronary Artery Disease
 
CRF
Case Report Form (electronic/paper)
CRO
Contract Research Organisation
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Event
d6MWT
Digital 6-minute Walking Test
DAE
Discontinuation of Investigational Product due to Adverse Event
DGR
Dangerous Goods Regulations
DILI
Drug Induced Liver Injury
DMG
Data Monitoring Group
DMP
Data Management Plan
DNA
Deoxyribonucleic acid 
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram


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Abbreviation or 
special term
Explanation
eCRF
Electronic Case Report Form
EF
Ejection Fraction
FSH
Follicle Stimulating Hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HIV
Human Immunodeficiency Virus
HR
Heart Rate
hsTNT
High-Sensitivity Troponin T
IATA
International Airline Transportation Association
ICD
Implantable Cardiac Defibrillator
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
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. 
IP
Investigational Product 
ISRB
Investigational Medicines Safety Review Board
KCCQ
Kansas City Cardiomyopathy Questionnaire
LAD
Left Anterior Descending 
LCA
Left Coronary Artery
LCX
Left Circumflex
LH
Luteinizing Hormone
LIMS
Laboratory Information Management System
LPLV
Last Patient Last Visit
LV
Left Ventricular
LVEDV
Left Ventricular End-Diastolic Volume
LVEF
Left Ventricular Ejection Fraction
LVESV
Left Ventricular End-Systolic Volume
MCWS
Maximum Continuously Walked Steps
MedDRA
Medical Dictionary for Regulatory Activities 
modRNA
Modified Ribonucleic Acid
MoP
Manual of Procedures


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Study Code D9150C00003
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Abbreviation or 
special term
Explanation
MPR
Myocardial Perfusion Reserve
NA
Not Applicable
NT-proBNP
N-terminal pro b-type natriuretic peptide
NYHA
New York Heart Association
OAE
Other Significant Adverse Event
PD
Pharmacodynamics
PET
Positron Emission Tomography
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PR
ECG interval measured from the onset of the P wave to the onset of the 
QRS complex
PRO
Patient Reported Outcomes
QRS
ECG interval measured from the onset of the QRS complex to the J point
QT
ECG interval measured from the onset of the QRS complex to the end of 
the T wave
QTcF
QT interval corrected for heart rate using Fridericia’s formula
R&D
Research and Development
RCS
Right Coronary Artery
RR
The time between corresponding points on 2 consecutive R waves on ECG
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SAQ
Seattle Angina Questionnaire
sMBF
Stress Myocardial Blood Flow
SOC
System Organ Class
SRB
Safety Review Board
SRC
Safety Review Committee
TBL
Total Bilirubin
ULN
Upper Limit of Normal
VEGF
Vascular Endothelial Growth Factor
WBDC
Web Based Data Capture


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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Coronary artery disease (CAD) is characterized by obstructive atherosclerotic lesions in the 
arterial wall resulting in limitation in myocardial blood flow, eventually leading to ischemia 
and ventricular dysfunction. In Global Burden of Disease study CAD affected 110 million 
people globally and resulted in 8.9 million deaths in 2015 making CAD the most common 
cause of death in a global scale. (GBD 2015 Disease and Injury Incidence and Prevalence 
Collaborators 2016, GBD 2015 Mortality and Causes of Death Collaborators 2015) Besides 
the apparent acute coronary syndrome (ACS) and myocardial infarction, CAD is the primary 
single cause of left ventricular (LV) systolic dysfunction leading to heart failure, (Task force 
for the diagnosis and treatment of chronic heart failure, European Society of Cardiology 2001) 
with reports suggesting CAD to be the primary cause of heart failure in even close to 70% of 
cases (Medical Advisory Secretariat 2010). According to recent trends in the United States, in 
individuals of 40 years and over, half of healthy men and one third of women develop CAD in 
their life time (Rosamond W et al. 2007). When comparing CAD to heart failure the risk of 
heart failure is lower but with apparently more detrimental progression of disease - in 
population of 40 years and over the lifetime risk of developing heart failure is 20% (Djousse L 
et al. 2009) with approximate survival rate of 50% in 5 years’ time after diagnosis (Go AS et 
al. 2013). Overall, CAD and heart failure are closely linked and left ventricular function 
serves as an important determinant of prognosis and can be used to predict disease outcome. 
(Cohn JN et al 1993, Parameshwar J et al. 1997) Coronary revascularization in many instances 
can relieve symptoms, improve prognosis and left ventricular function and is therefore 
applicable therapy not only in ACS but in symptomatic stable CAD (Stirrup J et al. 2017). 
However, in spite of medical advancements in treatment of especially ischemic heart failure, 
such as revascularizations (Stirrup J et al. 2017), beta-blockers (Packer M et al. 1996), 
angiotensin-converting enzyme (ACE) inhibitors,(The CONSENSUS Trial Study Group 
1987) angiotensin II inhibitors (Pitt B et al. 1997) and aldosterone receptor blockade, as well 
as novel devices such as cardiac resynchronization therapy, (Yancy CW et al. 2013), there is a 
clear unmet medical need in addressing the medical therapies for this patient population.
Through stimulation of angiogenesis, especially arteriogenesis, therapeutic vascular growth is 
emerging as a concept for management of vascular indications such as coronary ischemia, 
critical limb ischemia and chronic wounds. The vascular endothelial growth factor (VEGF) is 
a protein coded by a 7-exon gene localized on chromosome 6 and serves as a major angiogen 
in normal cardiac development (Ferrara N et al. 1991). The VEGF gene is normally spliced 
into 4 different forms; of these, VEGF121 (containing 121 amino acids) and VEGF165 (165 
amino acids) appear to be the most important. 
The VEGF family members are key regulators of vascular growth and the VEGF-A member, 
and especially its 165 amino acid long primary isoform (VEGF165), administered as 
recombinant protein or via naked or adenoviral vector-mediated gene transfer has received 
much attention for its potential beneficial effects in cardiovascular medicine. However, 


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randomized controlled trials have not lived up to expectations and evidence of clinical 
efficacy is inconclusive.
The overall reason(s) for the lack of consistency and conclusive clinical benefit is currently 
somewhat unclear but may include factors such as suboptimal pharmacokinetics (PK) and 
local concentrations of the protein, poor gene transfer efficiency, inappropriate dosing and 
regression of immature vessels, prolonged expression of the paracrine factor as well as growth 
factor-related adverse effects such as oedema and hypotension. To circumvent the issues 
associated with recombinant protein and gene transfer modalities, synthetic and chemically 
modified mRNA (modRNA) has been put forward as a non-immunogenic and non-integrating 
modality for efficient and transient expression of target proteins in mammalian cells. 
AZD8601 is VEGF-A165 modRNA under development as a novel modality for local 
production of human VEGF-A protein and is developed for the treatment of ischemic heart 
disease.
1.2
Rationale for study design, doses and control groups
This study is a randomized, double-blind, placebo-controlled, multicenter, sequential design 
study to assess the safety and tolerability of AZD8601 versus placebo. Placebo has been 
chosen as the comparator to assess safety and tolerability of both injection procedure and 
AZD8601. Parameters for potential efficacy will be addressed under explorative endpoints. 
The study examines the effects of AZD8601 given as epicardial injections in patients with 
stable CAD with decreased left ventricular ejection fraction (LVEF) going through elective 
CABG. Prior to CABG, each patient will undergo a O-15 radio-water positron emission 
tomography (PET)/ Computed Tomography (CT) scan, which generates a combined image of 
coronary angiogram superimposed on a myocardial perfusion map to locate areas of 
myocardial ischemia and dysfunction. Whilst ischemic LV systolic dysfunction may be due to 
myocardial damage, it may also result from the presence of dysfunctional, but viable, 
myocardium. Such viable tissue, associated with reduced perfusion and diminished 
contractility at rest that recovers function upon revascularization, has been commonly referred 
to as hibernating myocardium (Rahimtoola SH 1985, Rahimtoola SH 1989). 
Revascularization can reach and improve function of hibernating myocardium but most often 
it may not be able to recover full physiologic functionality. Primarily the safety and 
tolerability of AZD8601 in increasing doses in patients going through CABG will be assessed. 
In addition, exploratory objectives that address the capabilities of AZD8601 to improve global 
and local myocardial perfusion and/or left ventricle function in the studied patient cohort will 
be explored. For this purpose a PET camera will be utilized to detect changes in myocardial 
perfusion, and ventricular wall motion (Saraste A et el. 2017) will primarily be assessed by 
echocardiography. 
1.3
Benefit/risk and ethical assessment
This is a first time in patient Phase IIa study aiming to show the safety and tolerability of 
epicardial injections of AZD8601 in patients with ischemic heart disease undergoing CABG 
surgery and with moderately impaired systolic function. The study duration with follow-up 


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until 6 months post CABG surgery is expected to be of sufficient length to permit evaluation 
of the drug’s safety and tolerability profile on top of standard of care in CAD patients to 
support further clinical development. As explorative objectives, potential effects of VEGF-A 
RNA (AZD8601) on regional and global stress myocardial blood flow (sMBF) and 
myocardial perfusion reserve (MPR) and cardiac function will be explored.
A prior Phase I study has been conducted investigating AZD8601 induced intradermal VEGF 
production which suggested a well-tolerated safety profile. There were no apparent clinically 
relevant trends in blood pressure, heart rate, ECG or laboratory variables, including liver 
safety parameters. This is in line with prior safety data covering over 10 years’ follow-ups in 
patients with prior treatment with VEGF modalities (Hedman et al. 2009, Muona K et al. 
2012, Rosengart TK et al. 2013). The preclinical safety findings are described in detail in the 
Investigators Brochure. Based on knowledge of the mechanism of action, previous clinical 
experience and the preclinical safety studies the potential risks will be closely monitored. 
No specific harms are anticipated from participating in this trial. Available preclinical and 
clinical data suggest that the patients may benefit from participation in the study as 
administration of VEGF-A 
RNA may improve LVEF. In more detail, functional activity 
of the AZD8601-produced protein was demonstrated as substantial phosphorylation of the 
VEGF receptor 2 was seen in human umbilical vein endothelial cells exposed to conditioned 
medium harvested from cells transfected with AZD8601. Furthermore, AZD8601-produced 
VEGF-A protein was found to induce angiogenesis as evidenced by a trend towards increased 
total tube area and number of branch points to a similar extent as seen in cells exposed to 
human recombinant VEGF-A protein. VEGF-A modRNA given as epicardial injection has 
been shown to improve cardiac function in several animal models of myocardial infarction, 
ranging from mice (Zangi L et al. 2013), rat and pig. Preclinical toxicological study in pig 
model of myocardial infarction did not give rise to any safety concerns (see IB). Further, in an 
ongoing phase I trial where AZD8601 is administered as intradermal injections, AZD8601 
was well tolerated without SAEs. In terms of AEs the most common was local transient 
injection site reaction which is completely reversible (see IB). 
Pharmaceutical therapy administered directly in to myocardium can be administered through 
several different techniques, such as epicardial, endocardial, intracoronary or coronary sinus 
approaches. For accuracy and reliability the epicardial approach has been considered as 
method of choice, although its invasive nature and possible induction of arrhythmias balance 
the scale in comparison to other available administration modalities (Dib N et al. 2011). Due 
to this essential and invasive nature of epicardial injections in this study placebo vehicles will 
be injected to differentiate from possible drug delivery-related effects. To be able to evaluate 
potential beneficial effects of AZD8601 per se, placebo injections are considered to be 
necessary in the study design (Mathiasen A et al. 2015). The selected placebo controlled 
design also enables further differentiation with infrequent but possible adverse effects such as 
pericardial effusion, e.g. for VEGF in individual cases has been associated with pericardial 
effusions (Karatolios et al. 2012).




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Patients suitable for the study will be identified by screening of hospital medical records of 
patients scheduled for elective CABG surgery with an expected waiting time to surgery less 
than 3 months but more than 2 weeks. If a patient is found potentially suitable, he/she will be 
asked about participation in this study and invited to a screening/enrolment visit (Visit 1). 
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). The patients will then 
undergo baseline assessments (Visit 1 and Visit 2). Further details are given in Section 4.
To achieve 7 evaluable patients in each treatment group (low dose, high dose and placebo), 21 
in total – 24 patients will initially be randomized. An evaluable patient is defined as a patient 
who has completed the study.
The study will include two cohorts of 12 patients each, which will receive either a low or high 
dose of AZD8601 (see Section 7.2) in a sequential, dose ascending fashion. Within each 
cohort 8 patients will be randomized to receive AZD8601 and 4 to placebo. 
Each cohort will be divided into 3 sentinel dosing cohorts. See Figure 1. The two first will 
include 2 patients each – 1 patient randomized to placebo and 1 to AZD8601. The third 
sentinel cohort will include the 8 remaining patients on that dose level; 2 placebo, 6 
AZD8601. After each sentinel cohort, before proceeding dosing the next, safety data from up 
to 1 month post dose (Visit 5) from the current cohort and the available data from previous 
cohorts, will be reviewed. The same applies before continuing to the high dose cohort. The 
procedure will be repeated in the same way within the high dose cohort. 
Two parallel safety reviews will be done:

Blinded safety review board (SRB) consisting of study investigators and AZ 
personnel 

Study independent unblinded safety review committee (SRC) consisting of a 
combination of internal AZ expertise and external experts
In addition, to the existing blinded and unblinded safety review after each sentinel cohort, an 
additional unblinded Data Monitoring Group (DMG) will perform data review on emerging 
safety and clinical data. This DMG will consist of internal AstraZeneca employees 
independent of the study team. Internal clinical project and business decision separated from 
the study will be considered for the clinical development program.
This is further described in Section 3.11.1.
For treatment assignment see Section 3.5.


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Figure 1
Outline of sentinel dosing cohorts
Patients will be followed up at 2 weeks, 1 month, 3 months, and 6 months post CABG 
surgery.
The Study flow chart is presented in Figure 2 below. For details and timings of the study 
assessments refer to Table 1 and Table 2 in Section 4.
1 lowdose
1 placebo
1 month
8 patients
(6 lowdose/
2 placebo)
1 high dose
1 placebo
1 high dose
1 placebo
8 patients
(6 high dose/
2 placebo)
Safety review
1 month
Safety review
Safety review
Safety review
Safety review
1 month
1 month
1 lowdose
1 placebo
1 month
Low dose AZD8601 
cohort
High dose AZD8601 
cohort


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Figure 2
Study flow chart
TC = telephone contact; CABG = coronary artery bypass grafting; IP = investigational product, AZD8601 or placebo; m = month
2 week TC
follow-up
Randomization
Enrolment & 
Informed Consent
CABG
& IP 
administration
1 m 
follow-up
3 m 
follow-up
6 m 
follow-up
Visit 1                     Visit 2                 Visit 3            Visit 4            Visit 5                          Visit 6                        Visit 7
Day -90 to -15          Day -35 to -14         Day -1 to 4            2 weeks
1 month
3 months
6 months




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
To determine the VEGF-A protein concentration in plasma in patients undergoing 
CABG surgery, after epicardial injections of AZD8601 or placebo

To collect samples for exploratory research aimed at investigating biomarkers 
including but not limited to VEGF-A downstream biomarkers involved in PK, 
pharmacodynamics (PD), efficacy, safety and tolerability related to AZD8601 
treatment. 

To collect and store samples for future potential exploratory determination of  
plasma concentrations of VEGF-A 
RNA (AZD8601) after epicardial injections 
of AZD8601

To collect and store samples for potential exploration of anti-drug immunogenicity. 

Optional: To assess the effect of AZD8601 on change in digital 6-min walk test  
(d6MWT) and maximum continuously walked steps (MCWS) parameter and to 
explore the relationship between these and echocardiographic or other parameters 
collected here in CAD patients (Not applicable in Germany and any other additional 
country joining the study)
Note: For details regarding exploratory variables, measurements and analyses refer to
Section 5 and subsections, and 8.4.1 to 8.4.3.
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
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.
See Section 3.3 for a description of enrolment procedures.
3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria at Visit 1 and/or 2:
1.
Provision of signed and dated informed consent prior to any study specific 
procedures 
2.
Males and females:
a. Males must be surgically sterile or using an acceptable method of contraception 
(see Section 3.8.5)
b.   Females must be of non-childbearing potential confirmed at screening by 
fulfilling one of the following criteria a) postmenopausal defined as amenorrhoea 


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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
3.
Age >18 years
4.
Indication for elective CABG surgery enrolled at least 15 days before the planned 
surgery
5.
Moderately reduced global LVEF at rest (30% ≤ LVEF ≤ 50%) from medical 
records
6.
If patient is on statin, ACE inhibitor/ARB, and/or beta-blocker, the dose should be 
stable at least 2 weeks prior to Visit 1
7.
Patients who are blood donors should not donate blood during the study and for 3 
months following their last dose of AZD8601.
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site)
2.
Previous randomisation in the present study 
3.
Participation in another clinical study with an investigational product during the last 
3 months
4.
BMI > 35 kg/m2 OR poor image window for echocardiography
5.
Need for CABG emergency operation. (Emergency operation is defined as 
significant symptom status worsening in CAD, such as crescendo angina, unstable 
angina or ACS requiring rescheduling the revascularization. CAD should be stable 
at least 3 months prior to Visit 3.)
6.
History of ventricular arrhythmia (≥ Lown III) without Implantable Cardiac 
Defibrillator (ICD)
7.
History of any clinically significant disease or disorder which, in the opinion of the 
PI, may either put the patient at risk because of participation in the study, or 
influence the results or the patient’s ability to participate in the study


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8.
Severe co-morbidities that can interfere with the execution of the study, 
interpretation of study results or affect the safety of the patient, in judgement of the 
investigator
9.
eGFR ≤ 30 mL/min  (derived from creatinine clearance, calculated by local lab)
10.
For CFVR (Visit 1) and sMBF (Visit 2) measurement:
-
Known severe adverse reactions to adenosine
-
Known elevated intracranial pressure
-
AV block ≥ second degree and/or sick sinus syndrome in patient without 
pacemaker
-
Heart rate < 40 bpm (ECG verified) 
-
Systolic blood pressure < 90 mmHg 
-
Asthma or COPD with strong reactive component in judgement of investigator
-
Treatment with dipyridamole (e.g. Persantin or Asasantin), theophyllamine or 
fluvoxamine that cannot be paused
11.
Inability to comply with the protocol 
12.
History of severe allergy/hypersensitivity or ongoing clinically important 
allergy/hypersensitivity to drugs with a similar chemical structure or class as study 
drugs
13.
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
14.
Positive hepatitis C antibody hepatitis B virus surface antigen or hepatitis B virus 
core antibody or human immunodeficiency virus, at Visit 1
15.
Known history of drug or alcohol abuse
16.
Any concomitant medications that are known to be associated with Torsades de 
Pointes
17.
History of QT prolongation associated with other medications that required 
discontinuation of that medication
18.
Congenital long QT syndrome


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19.
History of arrhythmia (multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment 
(CTCAE Grade 3). 
20.
Current atrial fibrillation as well as paroxysmal atrial fibrillation.
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening. In this study, this will include all patients at the clinic scheduled for elective 
CABG surgery and for whom the medical records were screened to check if they might be 
eligible for the study.
The Investigator(s) will:
1.
Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
2.
Assign potential patient a unique enrolment number, beginning with ‘E#’.
3.
Determine patient eligibility. See Section 3.1 and 3.2.
4.
Assign eligible patient unique randomisation code as obtained from call centre (see 
Section 3.5)
If a patient withdraws from participation in the study, then his/her enrolment/randomization 
code cannot be reused.
Randomization codes will be assigned strictly sequentially as patients become eligible for 
randomization.
It is estimated that 24 patients need to be randomized and receive treatment in order to achieve 
21 evaluable patients who complete safety and tolerability assessments, including 
echocardiography, at baseline and 1, 3 and 6 months follow up. If a patient withdraws 
prematurely (before Visit 7) from the study they will be replaced to achieve 7 evaluable 
patients in each treatment group. Accounting for replacement patients it is estimated that up to 
approximately 33 patients may be randomized. 
If a patient is replaced, then a new enrolment code and randomization code will be assigned. 
The replacement patient will be assigned to the same treatment as the discontinued patient 
using the next available randomization code that corresponds to the specific treatment.


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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. If a patient is 
withdrawn prior to dosing, he/she will be replaced.
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 a discussion should occur between the AstraZeneca study 
physician and the investigator regarding the appropriate follow-up of the patient 
(discontinuation of IP is not an option after Visit 3). The AstraZeneca study physician must 
ensure all decisions are appropriately documented.
3.5
Methods for assigning treatment groups
Upon completion of the randomization requirements specification, the randomization will be 
produced by Parexel using the AstraZeneca randomization solution (AZRand). The study will 
include two dose cohorts which will receive a low or high dose of AZD8601. Dosing for each 
dose cohort will proceed in three sentinel cohorts. In the first and second sentinel cohort 2 
patients will be randomized to placebo or AZD8601 at a ratio of 1:1. In the third sentinel 
cohort 8 patients will be randomized to placebo or AZD8601 at a ratio of 1:3.
For each sentinel cohort an additional set of random numbers will be generated according to 
the same treatment allocation ratio. The replacement patient will receive the lowest available 
randomization code having the same treatment allocation.
AstraZeneca Supply Chain will assign randomisation codes.
3.6
Methods for ensuring blinding
The study will have a double blind design. Placebo solution for injection will match 
appearance of AZD8601 solution for injection. 
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 following exceptions:

AZRand generating the randomization scheme 

AstraZeneca Supply Chain

The AstraZeneca or CRO personnel carrying out the labelling and packaging of 
patient specific treatments

The pharmacy personnel preparing study drug at the site


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
The SRC performing safety evaluation before proceeding with dosing the next 
sentinel cohort and before dose escalation (see 3.11.1.2)

The DMG consisting of internal AstraZeneca employees independent of the study 
team as outlined in the combined SRC and DMG charter, who are reviewing 
unblinded emerging safety data and clinical data for clinical program development 
(see 3.11.1.3)
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 site Investigator(s) or pharmacists.
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 investigational product 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.
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 patient with restriction violation will be allowed to 
continue study participation.
Any restriction mentioned below before Visit 1 and signed ICF are up to the patient upon 
information given per telephone.
3.8.1
Medications 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
Patients should fast overnight from 22:00 hours the evening before Visit 1, 2, 5, 6 and 7. 
Before Visit 1 and signed ICF, fasting is up to the patient upon information given per 
telephone.


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3.8.3
Alcohol, Drugs of abuse, Tobacco and Caffeine Restrictions
Patients should:

abstain from caffeine containing drinks for 24 hours preceding the visits when 
adenosine infusion is given (Visits 1, 2, 5, 6 and 7) 

abstain from smoking for at least 1 hour prior to sMBF measurements, or whenever 
study procedures demand it. No nicotine substitutes will be offered.

abstain from drugs of abuse during the entire study.

abstain from alcohol 72 hours before clinical visits
3.8.4
Exercise restrictions
Patients should avoid intensive endurance training (e.g. running) 48 hours before Visits 2, 5, 6 
and 7. 
3.8.5
Restrictions for male patients 
Male patients 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 administration 
of IP (AZD8601/matching placebo) to prevent pregnancy in partners.
Sperm Donation: Male patients should not donate sperm for the duration of the study and for 
at least 3 months after IP administration. 
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. However, as the study is designed so that the patient 
is administered IP on one occasion during CABG (Visit 3), it is only possible for 
the patient to decide to discontinue IP before any IP is given.

An adverse event that, in the opinion of the Investigator or AstraZeneca, warrants 
discontinuation from further dosing

Patient noncompliance that, in opinion of the Investigator or sponsor, warrants 
withdrawal (e.g. refusal to adhere to scheduled visits)

Risk to the patient as judged by the Investigator and/or AstraZeneca.
If the patient is discontinued from IP (i.e. injections stopped during CABG), the scheduled 
study visits, data collection and procedures should continue according to the Clinical Study 
Protocol (CSP) until study closure (i.e. Visit 7). Alternatively, if the patient does not agree to 


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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 patient and in compliance with local data 
privacy laws/practices. The approach taken should be registered in the CRF.
If patient is required to discontinue the IP, every reasonable effort should be made for the 
patient to remain in the study for appropriate follow-up.
3.9.1
Procedures for discontinuation of a patient from investigational product 
At any time, patients are free to discontinue investigational product or withdraw from the 
study (i.e., investigational product and assessments – see Section 3.10), without prejudice to 
further treatment.  However, as the study is designed so that the patient is administered IP on 
one occasion during CABG (Visit 3), it is only possible for the patient to decide not to receive 
IP before any IP is given. 
After IP has been given, the patient is still free to withdraw from the study (i.e. further 
assessments) although the intention is to keep the patient in the study for follow-up until Visit 
7 has been completed. If a patient is withdrawn from study, see Section 3.10.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screening failures are enrolled patients (i.e. signed ICF) 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 (investigational product 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.  
Any mobile phone that has been provided to the patient for d6MWT and MCWS will be 
returned.
If a patient withdraws from participation in the study, then his/her enrolment/randomisation 
code cannot be reused. Withdrawn patients will be replaced to achieve 7 evaluable patients in 
each treatment group (low dose, high dose and placebo), 21 in total. 


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3.10.3
Specific withdrawal criteria between visit 2 and 3
Between Visit 2 assessments at site and IP administration at visit 3, a pre-operative cardio-
thoracic surgery conference to decide dosing regimen will take place (see Section 4.1.3.1). If 
identified that the patient, according to the PET scan, has a too small ischemic area to 
accommodate the intended 30 injections the patient will not be randomized or receive IP. 
If substantial changes of patient status are identified between visit 2 and 3, that are not 
considered to be consistent with continuation of the study, as judged by the investigator, the 
patient may also be withdrawn before any IP is administered.
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 study drug, 

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, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.
The Sponsor reserves the right to terminate the study at any time. Reasons for terminating the 
study may include, but are not limited to, the following:

Inability to enroll sufficient patients into the study

Good Clinical Practice (GCP) compliance issues that compromise the validity of the 
study

Determination by the SRB or/and SRC (see Section 3.11.1) that the safety of the 
patient is at risk 
The safety and tolerability stopping criteria take into account that each dosing group will have 
8 patients on IP and 4 patients on placebo (i.e., 2:1 ratio). 
Study stopping criteria 
The study can be stopped if 4 or more patients on IP than on placebo, per dose cohort have

intolerable AEs (death or other unexpected SAEs)






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Table 1
Schedule of Assessments: Enrolment and treatment periods
Screening/ 
Enrolment  
Randomization
CABG surgery & IP administration
Notes
Visit
Visit 11
Visit 21
Visit 3
Day
-90 to -15
-35 to -14 
-1 
1
2
3
4
Informed consent
x
Inclusion/exclusion 
criteria
x
x
Demographic data
x
Medical History
x
x
x
Concomitant 
medication 
x
x
x
x
x
x
x
Incl. herbal/ nutritional
supplements
Serology
x
See Table 4, 5.2.1
Nicotine use
x
Previous and current
Height
x
Weight and BMI
x
FSH and LH 
sampling
x
Females only, see Table 3, 
5.2.1
Randomization
x
After the pre-operative cardio-
thoracic surgery conference, 
see 4.1.3.1
IP administration
x
Safety and 
tolerability:


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Screening/ 
Enrolment  
Randomization
CABG surgery & IP administration
Notes
Visit
Visit 11
Visit 21
Visit 3
Day
-90 to -15
-35 to -14 
-1 
1
2
3
4
Adverse event 
review 
x 
(SAE only)
x 
(SAE only)
x 
(SAE 
only)
x
x
x
x
Blood pressure and 
pulse 
x
x
x 
x
x
x 
Supine. 
V3: 4 times/day on Days 1-3 
and at discharge on Day 4. 
Day 1: one assessment done 
pre-surgery and three post-
surgery.
Pulse oximetry 
(saturation)
x
x
x
x
V3: 4 times/day Day 1-4
Day 1, one assessment done 
pre-surgery and three post-
surgery.
See 5.2.4.1
dECG with digital 
source file
x
x
x
x
x
x
x
V3: Once Day -1 as baseline, 2 
times/day Day 1-4. Day 1 both 
timepoints will be post-
surgery.
See 5.2.3
Telemetry 
x
Start on Day -1, pause during 
CABG, re-start post-surgery 
and continue until discharge. 
See 5.2.3
Physical 
examination
x (brief)
x
x
See 5.2.2






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Screening/ 
Enrolment  
Randomization
CABG surgery & IP administration
Notes
Visit
Visit 11
Visit 21
Visit 3
Day
-90 to -15
-35 to -14 
-1 
1
2
3
4
Plasma samples for 
VEGF-A protein 
analysis to be 
stored in biobank 
x
x
x 
x
x
x
V2: 2 samples with at least 15 
min in between.
V3: Pre-surgery Day -1. Post-
surgery 3, 6, 24, 34, 48 and 72 
h after first epicardial 
injection. 2
See 5.7
Plasma samples for 
future exploratory 
analysis of 
AZD8601 (VEGF 
modRNA) to be 
stored in biobank
x
x
x
Pre-surgery Day -1. Post-
surgery 1, 3 and 48 h after first 
epicardial injection. 2
Plasma samples to 
be stored in 
biobank for 
potential 
exploration of anti-
drug 
immunogenicity 
x
See 5.7
Plasma samples to 
be stored in 
biobank for 
potential 
exploratory 
analyses
x
x  
x
x
See 5.7
V3: 6, 48 and 72 hours after 
first epicardial injection. 2


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1
Visit 1 and Visit 2 can be combined, however PET and CFVR (if applicable) assessments should be done on separate days see 4.1.3
2
Post- surgery samples should be taken as close to the specified timepoint as possible, but a time window of ± 1 hour is allowed.
Table 2
Schedule of assessments: Follow-up period
Follow-up
Notes
Visit 
Visit 4 (TC)
Visit 5
Visit 6
Visit 7
Day/month (time 
window)
14 
(±2 days)
1 month 
(±3 days)
3 months
(±14 days)
6 months
(±14 days)
Concomitant 
medication 
x
x
x
Incl herbal/ nutritional 
supplements
Safety and 
tolerability:
Adverse event 
review 
x
x
x
x
Blood pressure and 
pulse 
x
x
x
Supine. See 5.2.4.1
dECG with digital 
source file
x
x
x
See 5.2.3
Physical 
examination
x
x (brief)
x (brief)
See 5.2.2
Blood and urine 
samples for safety 
laboratory 
evaluations 
x
x
x
See 5.2.1
Exploratory 
Assessments




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Follow-up
Notes
Visit 
Visit 4 (TC)
Visit 5
Visit 6
Visit 7
Day/month (time 
window)
14 
(±2 days)
1 month 
(±3 days)
3 months
(±14 days)
6 months
(±14 days)
Plasma samples for 
VEGF-A protein 
analysis 
x
See 5.7
Plasma samples to 
be stored in biobank 
for potential 
exploration of anti-
drug 
immunogenicity 
x
x
x
See 5.7
Plasma samples to 
be stored in biobank 
for potential 
exploratory 
analyses
x
x
x
See 5.7
Order of assessments: 
NB: not all assessments are applicable for all visits but this is the order when they are done:
1. PRO (KCCQ, SAQ) and NYHA classification
2. Supervised d6MWT
3. ECG, AE-review, physical examination, vital signs (BP, pulse, pulse oximetry)
4. Safety laboratory sampling, samples for VEGF, for AZD8601, for hsTnT and NT-proBNP, for anti-drug immunogenicity 
and for biobanking
5. Echo, 
6. 15O PET/CT angiogram
7.
Post-surgery blood samples




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Patients who fulfil all of the inclusion criteria and none of the exclusion criteria will be 
randomized at this visit.
The patient will be fasting on arrival to the clinic.
Baseline assessments of rest and stress MBF by 15O PET will be done. Patients will undergo 
a 15O PET and contrast-enhanced CT scan to generate a combined CT-angiogram and cardiac 
perfusion map. 
Patients will be invited to participate in the optional AZ Activity App component of the study. 
During this visit patients will be provided with a mobile phone (unless they have a suitable 
iPhone already) and given access to a mobile software application (app) that will be used to 
conduct the d6MWT and MCWS. The app will be activated on-site at visit 2 and a supervised 
d6MWT will take place. For further information see Section 5.3.6. (N/A in Germany and any 
other additional country joining the study.)
Randomization will take place after the outcome of the pre-operative cardio-thoracic surgery 
conference is available, as described in 4.1.3.1. This should optimally occur latest Day -10, 
however, this timeframe can be reduced if delivery of investigational product to the site can be 
warranted before the planned date of CABG.
Further assessments during Visit 2 are outlined in Table 1.
4.1.3.1
Pre-operative cardio-thoracic surgery conference to decide individual injection 
map
Based on quantitative coronary angiogram and PET/CT perfusion map available from Visit 2, 
consensus will be reached regarding surgical procedure individualized for each patient. Based 
on the ischemic area (regions with sMBF < 2.3±0.3 mL/g/min or < 80±10% of the segment 
with highest sMBF) identified on PET scan and coronary artery morphology by CT-
angiogram, a tailor-made injection map of approximately 1 cm inter-site distance with 30 
epicardial injections will be determined to guide the injection procedure during CABG to 
target the ischemic but viable (rest perfusion > 60% of normal myocardium resting flow of 1 
mL/g/min) myocardium. 
Treatment will be focused on the LCA territory, starting with the largest ischemic area, i.e. 
either left anterior descending LAD or LCX supply territory. If the number of injections 
remaining after complete treatment of the first largest ischemic area is not sufficient to treat 
the second one as identified by the injection map, the area will be partially treated applying 
the same injection distance.
The individualized injection map will be determined by an expert committee of study site staff 
involved in the study, where the following are mandatory:

Responsible thoracic surgeon, PET physician and cardiologist at the local site


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
PET core lab responsible and at least one more thoracic surgeon from another hospital 
Prior to the meeting, the interpretation of the PET scan will be agreed with the core lab 
responsible person.
If identified that the patient, according to the PET scan, has a too small ischemic area to 
accommodate the intended 30 injections the patient will not be randomized or receive IP.
4.2
Treatment period
4.2.1
Visit 3 – CABG surgery and IP administration (Day -1 to Day 4)
At Visit 3, the patient will come to the clinic and undergo assessments as outlined in Table 1. 
During the operation, following by-pass grafting immediately before reperfusion, patients will 
receive 30 epicardial injections of the treatment they have been randomized to: placebo or any 
of two different doses of AZD8601 (see Section 7.2). The injections will be given under 
cardioplegia into all accessible ischemic border zones according to the individualized injection 
map agreed beforehand (see 4.1.3.1). The actual injection procedure will be documented by 
filming/taking photo during this part of the surgery. After surgery, the surgeon will document 
in the medical records and mark with a pen on a print-out of the injection map where the 
actual injections were placed. Further details will be provided in a separate Manual of 
Procedures (MoP). 
Patients will be required to remain hospitalized at the study site hospital approximately 4 days 
post-surgery for safety and tolerability evaluation with extensive monitoring in line with 
normal clinical routine.
Significant pericardial effusion will be excluded by assessment of hemopericardium and/or 
tamponade using bed-side echocardiography and assessment of maximum thickness of 
pericardial fluid before discharge from the hospital.
4.3
Follow-up period
4.3.1
Visit 4 - Telephone contact follow-up (Day 14 ±2 days) 
Two weeks after the operation, the investigator or research nurse will make a phone call to the 
patient to follow-up on adverse events.
4.3.2
Visit 5 – Follow-up (1 month ±3 days)
The patient will be fasting on arrival to the clinic.
During this visit, rest and stress 15O PET perfusion scan will be performed, and also 
echocardiography including assessment of pericardium, regional/global cardiac function and 
cardiac volumes. If the 15O PET is not available at the hospital where the patient is enrolled, 
the patient will be referred to another hospital for this assessment only; however, the CT scan 
may also be performed at the site of the 15O PET scan if required.


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Before the 15O PET assessment it should be verified that the patient does not have:
-
Heart rate < 40 bpm (ECG verified) 
-
Systolic blood pressure < 90 mmHg
For other assessments, refer to Table 2.
4.3.3
Visit 6 – Follow up (3 months ±14 days)
The patient will be fasting on arrival to the clinic.
A CT angiogram will be performed after PET studies. All other assessments will be identical 
to Visit 5. If the 15O PET is not available at the hospital where the patient is enrolled, the 
patient will be referred to another hospital for this assessment only; however the CT scan may 
also be performed at the site of the 15O PET scan if required.
4.3.4
Visit 7 – Final follow-up (6 months ±14 days)
The patient will be fasting on arrival to the clinic.
Echocardiography, including stress cardiac function, regional/global cardiac function and 
cardiac volumes will be performed. 
Before the stress echocardiography/LAD CFVR assessment it should be verified that the 
 
Any mobile phone that has been provided to the patient for d6MWT and MCWS will be 
returned.
For other assessments, refer to Table 2, Section 4 .
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 (eCRF) as specified in the Clinical Study Protocol and in accordance with the 
instructions provided.
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRF.  A copy of the completed eCRF will be archived at 
the study site.


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5.1
Efficacy assessments (NA)
Efficacy is only evaluated in an exploratory fashion is this study.
5.2
Safety assessments
5.2.1
Laboratory safety assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation, 
and urinalysis will be taken at the times indicated in Table 1 and Table 2, Section 4.
The clinical chemistry, haematology 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 laboratory variables given in Table 3 and Table 4 below will be measured.


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Table 3
Standard Clinical Laboratory Evaluation Panels
Hematology/Hemostasis (whole blood)
Clinical Chemistry* (serum or plasma)
White blood cell (WBC) count
Sodium
Red blood cell (RBC) count
Potassium
Hemoglobin (Hb)
Urea
Hematocrit (HCT)
Creatinine
Mean corpuscular volume (MCV)
Albumin
Mean corpuscular hemoglobin (MCH)
Calcium
Mean corpuscular hemoglobin concentration 
(MCHC)
Phosphate
Neutrophils absolute count 
Alkaline phosphatase (ALP) “LIVER PANEL”
Lymphocytes absolute count 
Alanine aminotransferase (ALT) “LIVER 
PANEL”
Monocytes absolute count 
Aspartate aminotransferase (AST) “LIVER 
PANEL”
Eosinophils absolute count 
Total bilirubin “LIVER PANEL”
Basophils absolute count 
FSH (females only, at screening)
Platelets
LH (females only, at screening)
Reticulocytes absolute count 
Urinalysis 
Coagulation 
Glucose (dipstick)
International normalized ratio (INR)
Albumine (quantification/semi-quantification)
Activated partial thrombin time (APTT)
Protein (dipstick)
Fibrinogen
Blood (dipstick)
WBC (leukocytes) (dipstick)
Creatinine (quantification)
Table 4
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


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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.
NB. In case a patient shows an AST or ALT ≥3xULN or total bilirubin ≥2xULN please refer 
to Appendix C ‘Actions required in cases of combined increase of Aminotransferase and Total 
Bilirubin – Hy’s Law’, for further instructions.
5.2.2
Physical examination
A complete physical examination will be performed at Visits 2, 3 and 5 and 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, 
musculo-skeletal (including spine and extremities) and neurological systems. 
At Visits 1, 6 and 7 a brief physical examination will be performed (general appearance, skin, 
abdomen and musculoskeletal, cardiovascular and respiratory systems).
For handling of AEs based on examinations and tests see Section 6.3.6
5.2.3
ECG
12-lead ECG recordings will be collected using provided ECG machines according to the 
assessments schedule, see Table 1 and Table 2, Section 4 using. On Day 1, Visit 3, the two 
ECG measurements should be done post-surgery with reasonable time interval. 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. Digital ECGs in 
Table 1 and Table 2 refers to the storage of digital Safety ECG source files that are retrievable 
for adjudication if required, e.g. for off-line analysis by experienced ECG readers.
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 available for analysis. Telemetry online ECG surveillance for 
rhythm monitoring and arrhythmia detection will be done at the given time points. Telemetry 
will be initiated the day before operation when the patient arrives to the hospital ward and 
continue until the patient is moved to the operating room (interruptions may be necessary for 
clinical routines and other study assessments). That will provide collection of some pre-


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operative baseline rhythm and heart rate monitoring (preferably at least 6 hours of total 
duration of pre-operative telemetry but will depend on clinical routines). It will then be re-
started when the patient comes back to the ward after the operation and continue as long as the 
patient stays at the ward (approximately 4 days post-operatively). Arrhythmia episodes will be
visually confirmed by the attending physician and printed and if possible stored digitally for 
potential over read by cardiologist. If site has the capability to store telemetry data digitally, 
this should be done.
The following parameters or time intervals will be recorded for each ECG: RR, PR, QRS, QT, 
QTcF and heart rate (HR). A summary of clinically relevant ECG findings from 12-lead ECGs 
and observed arrhythmias during telemetry will be presented and discussed at the SRB/SRC 
meetings (see Section 3.11.1)
5.2.4
Vital signs
Vital signs will include pulse, and systolic and diastolic blood pressure. Vital signs will be 
obtained at time points indicated in Table 1 (and ad- hoc as medically indicated).
For handling of AEs based on examinations and tests see Section 6.3.6
5.2.4.1
Pulse, pulse oximetry 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.
Measurements will be done at the time points indicated in see Table 1 and Table 2, Section 4.
5.2.5
Other safety assessments
5.2.5.1
Hemopericardium and/or tamponade assessment with echocardiography
Hemopericardium and/or tamponade will be assessed by clinical routine echocardiography 
evaluation to assess any postoperative pericardial effusion at Visit 3, day 3 or 4 post CABG.
5.3
Other assessments
A number of exploratory assessments will be performed in the study as described below.
5.3.1
15O PET and CT angiogram
Prior to CABG, each patient will undergo a dynamic oxygen-15 labelled water positron 
emission tomography (15O PET)/CT scan, which generates a combined image of coronary 
angiogram superimposed on a myocardial perfusion map to locate areas of myocardial 
ischemia and dysfunction.




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The PROs in the study are:  Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle 
Angina Questionnaire (SAQ). 
The PRO questionnaires used in this study will all be collected by paper, subject-self completed and do 
not require training. Site personnel or designated data management staff 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 approximately 20 min. The questionnaires to be used are 
further described in Section 5.3.4.1 and 5.3.4.2.
The time points for the below listed PRO assessments are given in Table 1 and Table 2, 
Section 4.
PRO questionnaires should be completed by the patient in private. Appointed site staff should 
remind patients that there are no right or wrong answers and avoid clarifying items in order to 
avoid bias.
Patients must not receive help from relatives, friends, or clinic staff to answer the PRO 
questionnaires. If a patient uses visual aids (e.g., spectacles or contact lenses) for reading and 
does not have them when he attends the clinic, the patient will be exempted from completing 
the PROs.
The patient 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.
5.3.4.1
Kansas City Cardiomyopathy Questionnaire 
The KCCQ is a sensitive, specific, and responsive health-related quality of life measure for 
heart failure. It is a 23-item, self-administered instrument that quantifies physical function, 
symptoms (frequency, severity and recent change), social function, self-efficacy and 
knowledge, and quality of life.
In the KCCQ, an overall summary score can be derived from the physical function, symptom 
(frequency and severity), social function and quality of life domains. For each domain, the 
validity, reproducibility, responsiveness and interpretability have been independently 
established. Scores are transformed to a range of 0-100, in which higher scores reflect better 
health status. 
The master version is enclosed in Appendix D.
5.3.4.2
Seattle Angina Questionnaire
The Seattle Angina Questionnaire is a sensitive, specific, and responsive health-related quality 
of life instrument for coronary artery disease.
The SAQ is a self-administered, disease-specific measure for patients with CAD that is valid, 
reproducible, and sensitive to clinical change. 
The SAQ quantifies patients’ physical limitations caused by angina, the frequency of and 
recent changes in their symptoms, their satisfaction with treatment, and the degree to which 




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5.5
Pharmacodynamics 
For samples taken for analysis of exploratory biomarkers, see Section 5.7. No other 
pharmacodynamics (PD) samples will be taken.
5.6
Genetics
In this study, no genetics samples will be collected. 
5.7
Biomarker analysis 
The patient’s consent to the use of donated biological samples is mandatory to be able to 
participate in the study.  
Biological samples (e.g., blood samples) will be collected for analysis of exploratory biomarkers to 
assess correlations with disease activity, effects of AZD8601, clinical outcomes and toxicity. This 
includes VEGF-A downstream biomarkers. As outlined in Table 5, some exploratory biomarkers will 
be analysed and reported within this study and others may potentially be analysed.  For exploratory 
biomarkers that might be analysed, results will be presented outside the CSR. Samples will be 
collected at the visits and time points listed in Table 1 and Table 2. Post- surgery samples at Visit 3 
should be taken as close to the specified timepoint as possible, but a time window of ± 1 hour is 
allowed.


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Table 5
Exploratory biomarkers
Panel Name
Biomarkers
Analyses
Cardiovascular biomarkers
 (change from baseline 6 
months post CABG)
Analysis will be performed as part of the study 
and done at a local laboratory at or near to the 
Investigator site. 
Sample tubes and sample volumes may vary 
depending on laboratory method used and routine 
practice at the site.
VEGF-A protein
Venous blood samples for the determination of 
plasma concentrations of VEGF-A protein
Analysis will be performed as part of the study. 
Samples to be handled by a central laboratory 
will be collected, labelled stored and shipped as 
detailed in the Laboratory Manual. Samples from 
patients treated with either AZD8601 or placebo 
will be analysed for VEGF-A protein.
Samples will be collected at the time points given 
in Table 1 and Table 2 Section 4.
Potential exploratory analysis of plasma 
concentrations of AZD8601 (VEGF-A modRNA)
Samples will be collected for potential future 
analysis
Any data from these potential analyses will be 
presented outside the CSR.
Samples to be handled by a central laboratory 
will be collected, labelled stored and shipped as 
detailed in the Laboratory Manual.
Plasma samples will potentially be analysed for 
VEGF-A concentrations, by a qualified vendor on 
Potential exploratory biomarker research
Samples will be collected for potential 
exploratory research aimed at investigating 
biomarkers including VEGF-A downstream 
biomarkers involved in PK, PD, efficacy, safety 
and tolerability related to AZD8601 treatment


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Panel Name
Biomarkers
Analyses
Potential Analysis of Anti-drug Immunogenicity
Samples for potential analysis of anti-drug 
immunogenicity will be collected.
behalf of AstraZeneca Research and 
Development (R&D), using an assay that has 
been validated to fit the exploratory purpose of 
the study.
Samples will be collected at the time points given 
in Table 1 and Table 2 Section 4.


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Full details of the analytical method and analyses performed will be described in a separate 
Bioanalytical Report. 
All samples still within the known stability of the analytes of interest (i.e. VEGF-A) at the 
time of receipt by the analytical laboratory will be analysed.
5.7.1
Storage, re-use and destruction of biological 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 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 the study drug 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 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 designated Biobank during 
the entire life cycle.
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.


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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.
6.1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a patient or 
clinical study patient 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. 
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, follow-up), that fulfils one or more of the following criteria:

Results in death


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
Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the patient 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 Clinical Study 
Protocol.
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
Adverse Events will be collected from Visit 3 (CABG surgery) throughout the treatment 
period and including the follow-up period (until Visit 7).
SAEs will be recorded from the time of informed consent (Visit 1).
6.3.2
Follow-up of unresolved adverse events
Any AEs that are unresolved at Visit 6 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 collected for each AE;

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity 

Whether the AE is serious or not

Investigator causality rating against the Investigational Product (yes or no)

Action taken with regard to investigational product

Whether the AE caused patient’s withdrawal from study (yes or no)

Outcome


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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 hospitalisation

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

Causality assessment to drug injection procedure

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 Investigational Product and each 
Adverse Event, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a 
reasonable possibility that the event may have been caused by the investigational product?’
For SAEs causal relationship will also be assessed for other medication and study procedures, 
such as drug injection procedure. 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 Clinical 
Study Protocol.


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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 Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the CSR.  Deterioration as compared to baseline in protocol-mandated 
variables should therefore only be reported as AEs if they fulfil any of the SAE criteria or are 
the reason for discontinuation of treatment with the investigational product.
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information.  Wherever possible the reporting Investigator 
uses the clinical, rather than the laboratory term (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).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE.
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE
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 C 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 investigational 
product, 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.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
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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 AZD8601 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.
6.6
Pregnancy
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
If the pregnancy is discovered before the study patient 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 before Visit 3, the patient will be withdrawn from the study and will not 
receive IP. Should a pregnancy occur after Visit 3, the follow-up assessments will be 
performed as planned until Visit 7, with the exception of PET and CT which will be omitted 
due to radiation. The pregnancy shall be 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. Should a partner, despite precautions, 
become pregnant during this period it should be reported in the same manner as described in 
Section 6.6.1 if the partner consents to this.
Sperm donation
Male patients 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 recognize 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 

Wrong drug administered to patient
Examples of events that do not require reporting as medication errors in clinical studies:

Accidental overdose (will be captured as an overdose)

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ 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.
6.8
Study governance and oversight
Safety of the patients in this clinical trial is closely monitored on an on-going basis by 
AstraZeneca representatives including the study physician. After each sentinel cohort the SRB 
will review the blinded clinical data and AE and SAE data available after the 1 month follow-




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7.4
Storage
All study drugs should be kept in a secure place under appropriate storage conditions.  The 
investigational product label on the vials specifies the appropriate storage.
7.5
Compliance
The administration of all study drugs (including investigational products) should be recorded 
in the appropriate sections of the Case Report Form.
7.6
Accountability
The study drug provided for this study will be used only as directed in the Clinical Study 
Protocol.
The study site staff will account for all study drugs dispensed to the patient.
Study site staff will account for all study drugs received at the site, unused study drugs and for 
appropriate destruction.  Certificates of delivery, destruction should be signed.
7.7
Concomitant and other treatments 
The concomitant medications not allowed at entry and/or during the study are listed below.
Table 7
Prohibited medication
Prohibited Medication/Class of drug:
Persantin or Asasantin.
Dipyridamole, Theophyllamine or 
Fluvoxamine
Ongoing treatment at entry and during the study
7.7.1
Other concomitant treatment
Other medication other 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.
8.
STATISTICAL ANALYSES BY ASTRAZENECA
8.1
Statistical considerations

All personnel involved with the analysis of the study will remain blinded until 
database lock and Clinical Study Protocol violators identified.

Analyses will be performed by AstraZeneca or its representatives.    

Refer to Statistical Analysis Plan (SAP) for details


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A comprehensive Statistical Analysis Plan (SAP) will be prepared prior to the first patient in 
to the study. 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 analysis 
will be fully documented in the SAP.
The statistical methodology below describes the statistical analysis as it is foreseen when the 
study is being planned.
If circumstances should arise during the study rendering the analysis inappropriate, or if in the 
meantime improved methods of analysis should come to light, different analyses may be 
performed.
8.2
Sample size estimate
Due to the exploratory nature of the study, the sample size is not based on formal statistical 
considerations.  The sample size is based on experience from previous studies to obtain 
adequate safety, tolerability and technical feasibility data to achieve the objectives of the study 
while exposing as few patients as possible to study procedures.
It is estimated that 24 patients (8 per arm) need to be randomized and receive treatment in 
order to achieve 21 evaluable patients (7 per arm).
8.3
Definitions of analysis sets
8.3.1
Safety analysis set
The safety analysis set will include all randomized patients who received at least one injection 
of IP. Patients will be analysed according to the treatment which they actually received. Any 
major deviations from randomized treatment will be listed and considered when interpreting 
the safety data.
Unless otherwise stated the safety analysis set will be used for the presentation of all 
demographic and disposition data, as well as all safety analyses.
8.3.2
Exploratory analysis set
The exploratory analysis set will consist of all randomized patients who received at least one 
injection of IP and for whom at least one of the exploratory assessments is available for pre-
dose and at least one post-dose measurement.
The available exploratory data of patients excluded from the exploratory analysis set will be 
listed only.
8.3.3
All Enrolled Patients
All enrolled patients will include patients who have signed the informed consent form. 
Patients will be analysed according to the treatment to which they were randomized.


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8.3.4
All Randomized Patients
All randomized patients will include patients who were randomized. Patients will be analysed 
according to the treatment to which they were randomized.
8.4
Outcome measures for analyses
8.4.1
Safety variables
The primary outcome measures are safety and tolerability variables. They are listed below and 
in Section 5.2. This includes:

Adverse events

Vital signs (blood pressure, pulse, pulse oximetry)

ECG

Physical examination 

Laboratory assessments (hematology, clinical chemistry and urinalysis). See Table 
2 and Table 3, Section 5.2.1

Hemopericardium and/or tamponade assessment, and LVEF with echocardiography

Coagulation and use of concomitant medication
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. 
8.4.2
Exploratory variables

15O PET parameters. The output variables, measured at baseline (pre CABG), 1 
and 3 months post CABG, will be

Regional sMBF in the myocardial region that received injections

Global sMBF

Regional MPR in the myocardial region that received injections

Global MPR 

Echocardiography parameters. The output variables, measured at baseline (pre 
CABG), 1, 3 and 6 months post CABG, will be

Regional wall motion (speckle tracking/vector velocity derived strain) in the 
LV segments where IP was received, measured at baseline (pre CABG), 1, 3 
and 6 months post CABG.




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
Plasma concentration at visit 3 pre-surgery

AUC 0-72 hours post dosing 
8.5
Methods for statistical analyses
Placebo data will be pooled throughout.
Demographic and baseline data will be summarized by treatment and overall.
All statistical analyses and production of tables, figures and listings will be performed using 
SAS version 9.2 or later.
If not otherwise specified, baseline refers to the last measurement prior to IP administration.
8.5.1
Analysis of the primary variable (s)
The analysis and presentation of safety variables will be based on patients in the safety 
analysis set. 
All safety variables will be summarised by treatment group and visit using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum for continuous 
data and absolute and relative frequencies for categorical data). 
AEs will be summarised by treatment group, treatment related and severity by means of 
counts summaries by Medical Dictionary for Regulatory Activities (MedDRA) System 
Organ Class and Preferred Term (PT). 
Laboratory data for haematology and clinical chemistry will be summarized by treatment 
group and visit. The number and percentages of patients with haematology and clinical 
chemistry treatment emergent laboratory of changes with respect to normal ranges between 
baseline and post treatment will be tabulated. 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.
Unless otherwise stated, the following rules will apply to any repeated safety assessments:

If the repeated measurement of a specific parameter occurs prior to IP administration 
(Day 1), the last obtained value prior to dosing will be used in the descriptive statistics 
and in the calculation of changes from baseline.


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8.5.2
Exploratory analysis 
The analysis and presentation of exploratory variables will be based on patients in the 
exploratory analysis set. 
All exploratory variables will be summarised by treatment group and visit using descriptive 
statistics (n, mean, standard deviation [SD], median, minimum, and maximum and geometric 
mean and geometric SD if applicable for continuous data and absolute and relative frequencies 
for categorical data). P-values will be unadjusted and tests will be two-sided.
Mean values per treatment will be plotted against visit.
Geometric mean per treatment and individual plasma levels of VEGF-A will be plotted 
against time after dosing. Calculation of VEGF AUC - Area under the concentration-time 
curve (μmol*h/L)- will be done by linear up/ log down trapezoidal summation. 
Change from baseline will be analysed for all exploratory variables with baseline and post-
dose measurements. Change from baseline for some exploratory variables will be analysed 
using Analysis of Covariance, (with treatment as fixed effect, patient as random effect and 
baseline value as covariates) or a repeated measurements model (with treatment, visit and 
treatment-by-visit interaction as fixed effects, baseline as covariate and patient as random 
effect). If an approximation of the variable of interest follows a log-normal distribution rather 
than a normal distribution, a logarithmic transformation of the variable of interest will be 
done. All variables that are transformed will be back transformed for reporting.
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA
9.1
Training of study site staff
Before the first patient is entered into the study, an AstraZeneca representative will review and 
discuss the requirements of the Clinical Study Protocol and related documents with the 
investigational staff and also train them in any study specific procedures and the WBDC
system(s) utilised.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of these staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.2
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)


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
Confirm that facilities remain acceptable

Confirm that the investigational team is adhering to the Clinical Study Protocol, 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 
patient’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 Clinical Study Agreement for location of source data.
9.2.2
Study agreements
The Principal Investigator at each/the centre should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study.  In the event of any 
inconsistency between this Clinical Study Protocol and the Clinical Study Agreement, the 
terms of Clinical Study Protocol shall prevail with respect to the conduct of the study and the 
treatment of patients and in all other respects, not relating to study conduct or treatment of 
patients, the terms of the Clinical Study Agreement shall prevail.
Agreements between AstraZeneca and the Principal Investigator should be in place before any 
study-related procedures can take place, or patients are enrolled.
9.2.3
Archiving of study documents
The Investigator follows the principles outlined in the Clinical Study Agreement (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 AZD8601.


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9.4
Data management 
Data Management will be performed by a data management vendor per 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 the Medical Dictionary for Regulatory Activities (MedDRA).  Medications 
will be classified according to the WHO Drug Dictionary.  All coding will be performed by 
the Data Management Vendor.
Data queries will be raised for inconsistent, impossible or missing data.  All entries to the 
study database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan.  Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.  The Data Management Plan 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.
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 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.


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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 Clinical Study Protocol, 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.
AstraZeneca should approve any modifications to the ICF that are needed to meet local 
requirements.
If required by local regulations, the Clinical Study Protocol should be re-approved by the 
Ethics Committee annually.
Before enrolment of any patient into the study, the final Clinical Study Protocol, including the 
final version of the ICF, 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. 
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


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
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.
10.5
Changes to the Clinical Study Protocol and Informed Consent 
Form
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca.
If there are any substantial changes to the Clinical Study Protocol, then these changes will be 
documented in a new version of the study protocol.
The new version of the Clinical Study Protocol 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 Clinical Study Protocol to each Principal 
Investigator(s). For distribution to Ethics Committee see Section 10.3.
If a change to a Clinical Study Protocol 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 Clinical Study 
Protocol, Good Clinical Practice (GCP), guidelines of the International Conference on 
Harmonisation (ICH), and any applicable regulatory requirements.  The Investigator will 
contact AstraZeneca immediately if contacted by a regulatory agency about an inspection at 
the centre.


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11.
LIST OF REFERENCES
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Cohn JN, Johnson GR, Shabetai R, Loeb H, Tristani F, Rector T, Smith R, Fletcher R. Ejection 
fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias and 
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The CONSENSUS Trial Study Group 1987
The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe CHF: results 
of CONSENSUS. N Eng J Med 1987;316: 1429–1435
Dib N et al. 2011
Dib N, Khawaja H, Varner S, McCarthy M, Campbell A. Cell Therapy for Cardiovascular 
Disease: A Comparison of Methods of Delivery. J. of Cardiovasc. Trans. Res. 2011; 4:177–
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Djousse L et al. 2009
Djousse L, Driver JA, Gaziano JM. Relation between modifiable lifestyle factors and lifetime 
risk of heart failure. JAMA 2009;302:394-400.
Ferrara N et al. 1991
Ferrara, N., Houck, K. A., Jakeman, L. B., Winer, J. and Leung, D. W. The vascular 
endothelial growth factor family of polypeptides. J. Cell. Biochem. 1991; 47: 211–218.
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators 2016
GBD 2015 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and 
national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 
1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016; 
388: 1545–602
GBD 2015 Mortality and Causes of Death Collaborators 2015
Global, regional, and national life expectancy, all-cause mortality, and cause-specific 
mortality for 249 causes of death, 1980–2015: a systematic analysis for the Global Burden of 
Disease Study 2015, Lancet 2016; 388: 1459–544
Go AS et al. 2013
Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai 
S, Ford ES, Fox CS, Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard 
VJ, Huffman MD, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Magid 
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Clinical Study Protocol 
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Version 5.0
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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 patient 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 patient’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).
Hospitalisation
Outpatient 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 patient 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, hospitalisation, disability or incapacity but may jeopardize the patient 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 hospitalisation
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 patient 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 patient 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.


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Appendix C
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 patient 
meets 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.


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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 pateint 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 patient 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 patient does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the patient 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 patient 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.


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
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.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree 
an approach for the study patients’ follow-up (including any further laboratory testing) 
and the continuous review of data. 

Subsequent to this contact the Investigator will:
Monitor the patient 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


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elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.

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
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDAGuidanceforIndustry(issuedJuly2009)'Drug-inducedliverinjury:Premarketing 
clinicalevaluation'


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Appendix D
Kansas City Cardiomyopathy Questionnaire


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Appendix E
Seattle Angina Questionnaire


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