Clinical trial NCT03756285
Conditions: Heart Failure
Keywords: Heart Failure with Ejection Fraction
Sponsor: AstraZeneca
Start date: 2018-12-11; Completion date: 2020-05-07
Enrollment: 41 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, placebo-controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF). The study will be conducted at approximately 15 sites in 5 countries. Approximately 96 patients will be randomized to AZD4831 or placebo (treatment duration 90 days).

Detailed description:
This is a randomized, double-blind, placebo controlled, parallel group, multicentre study in patients with Heart Failure with preserved Ejection Fraction (HFpEF) and mid-range Ejection Fraction (HRmrEF). The study will be conducted at approximately 15 sites in 5 countries (USA, Sweden, Denmark, Finland, Netherlands). Patients suitable for the study will be checked for eligibility, signing the informed consent and enrolled to the study at visit 1. The study will be divided into two parts, Part A and Part B. In part A 37 patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo for approximately 90 days. After approximately 30 days of treatment, an interim analysis will be done to analyse the safety, tolerability and target engagement. After the evaluation, the randomization to Part B may proceed. In Part B the approximate 59 remaining patients will be randomized and treated for approximately 90 days.

Arms: arm 1: AZD4831 tablets taken orally for for 90 days. arm 2: Placebo tablets taken orally for 90 days.
Interventions: intervention 1: AZD4831 intervention 2: Placebo
Intervention descriptions: intervention 1: AZD4831 tablet taken orally for 90 days. intervention 2: Placebo tablet taken orally for 90 days.

Protocol documents:
Prot_000.pdf: 
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Clinical Study Protocol 
Drug Substance
AZD4831
Study Code
D6580C00003
Version
4.0
Date
9 January 2020
A randomized, double blind, placebo-controlled, parallel group, multicentre, phase 2a study to 
assess target engagement, safety and tolerability of AZD4831 in patients with Heart Failure with 
preserved Ejection Fraction (HFpEF) 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Regulatory Agency Identifying Number(s):
EudraCT number: 2018-002895-42




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The inclusion criteria 5 was updated to BMI 18- 40kg/m2 to increase the potential 
population to be included. 
The following section of the CSP have been updated to reflect this change: 5.1 Inclusion 
criteria
Exclusion criteria 23 is updated to clarify this relates to patients with known positive HIV, 
hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody, at 
screening visit. The following section of the CSP have been updated to reflect this change: 
5.2 Exclusion Criteria
Clarification regarding PK analysis. PK concentrations may be assessed during the study for 
evaluation of the exposure levels.
The following sections of the CSP have been updated to reflect this change: 8.5.1 
Determination of drug concentration
Clarification that PK samples at visit 7 should be taken at predose, 0.5 -1h, 1-3h and >3 h 
after dose, not to limit the last sample to be taken within 5 hours as previously stated. 
The following section of the CSP have been updated to reflect this change: 1.1 Schedule of
Activities
The blood volume for genetic sample is updated to be aligned with the Laboratory Manual 
and the Informed Consent Form. Volume decreased from 10mL to 6mL.
The following section of the CSP have been updated to reflect this change: 8.7.1 Optional
exploratory genetic sample
Clarification added to the hypothesis for the first secondary efficacy endpoint CFVR to 
reflect the sample size calculation for CFVR.
The following sections of the CSP have been updated to reflect this change: 1.2 Synopsis, 
9.4.1 Efficacy analyses
Clarification added regarding analysis of TE Biomarker as requested from the authorities in 
the Netherlands.
The following section of the CSP have been updated to reflect this change: 9.2 Sample size 
determination
Clarification is added regarding analysis of prematurely discontinued patients.
The following section of the CSP have been updated to reflect this change: 9.3.1 Full 
analysis set
Clarification that the primary and secondary efficacy variables are measured as percent 
change from baseline to end of treatment, and not to end of study. 




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5.2 Exclusion criteria. Justification of change: Clinical safety margins have been calculated based on 
exposures at the NOELs for changes in TSH levels in the 3-month rat and dog toxicology studies. At the 
NOELs, the mean AUC values for total AZD4831 achieved in the 3-month dog and rat 
toxicology studies were 69 umol*h/L and 173 umol*h/L, respectively. After repeated 
dosing in the MAD study, the mean AUC for the 
 dose level was 1.45 umol*h/L, 
which is approximately 48 and 119 times lower than the respective toxicology study NOEL 
exposures.
In addition, blinded data for the TSH, T3, T4 hormone level dynamics was assessed for 26 
patients. There were no clinically significant changes, meaningful deviations or trends 
identified. Therefore, the established nonclinical safety margins in conjunction with the 
ability to readily monitor for thyroid function in the clinic support the revised 
inclusion/exclusion criteria for thyroid function.
Exclusion criteria 3 is updated with a clarification: Any ongoing skin disorder, history of or 
ongoing clinically significant allergy/hypersensitivity. The following section of the CSP has 
been updated to reflect this change: 5.2 Exclusion criteria.
Table 6 - Safety laboratory assessments is updated with the addition of TSH, T3 and T4 
sampling at visit 7.
Clarification that approximately 96 randomized patients will be included in the study and 
addition of approximate 59 remaining patients in Part B.
Section 4.1, Overall design, general description of visits. Visit 1 (enrollment) and Visit 2 
(randomization) are updated to clarify in case visit 1 and visit 2 occur at the same day, local 
lab results will enroll the patient, in case they meet the inclusion criteria. In case the central 
lab results are returned and do not meet the inclusion criteria, the patient will not be 
withdrawn.
This Clinical Study Protocol (CSP) has been subject to a peer review according to 
AstraZeneca Standard procedures. The CSP 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.
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TABLE OF CONTENTS
1
PROTOCOL SUMMARY................................................................................ 10
1.1
Schedule of Activities (SoA)............................................................................. 10
1.2
Synopsis ........................................................................................................... 15
1.3
Scheme............................................................................................................. 22
5
2
INTRODUCTION............................................................................................ 23
2.1
Study rationale.................................................................................................. 23
2.2
Background ...................................................................................................... 24
2.3
Benefit/risk assessment..................................................................................... 26
3
OBJECTIVES AND ENDPOINTS................................................................... 28
10
4
STUDY DESIGN ............................................................................................. 30
4.1
Overall design................................................................................................... 30
4.2
Scientific rationale for study design .................................................................. 34
4.3
Justification for dose......................................................................................... 35
4.4
End of study definition...................................................................................... 36
15
5
STUDY POPULATION ................................................................................... 36
5.1
Inclusion criteria............................................................................................... 36
5.2
Exclusion criteria.............................................................................................. 38
5.3
Prevalence of Atrial Fibrillation in study population ......................................... 41
5.4
Lifestyle restrictions ......................................................................................... 41
20
5.4.1
Meals and dietary restrictions............................................................................ 41
5.4.2
Caffeine, alcohol, and tobacco .......................................................................... 41
5.4.3
Activity............................................................................................................. 41
5.4.4
Reproductive restrictions .................................................................................. 41
5.5
Screen failures .................................................................................................. 43
25
6
STUDY TREATMENTS.................................................................................. 43
6.1
Treatments administered................................................................................... 44
6.1.1
Investigational products.................................................................................... 44
6.2
Preparation/handling/storage/accountability...................................................... 44
6.3
Measures to minimise bias: randomization and blinding ................................... 45
30
6.3.1
Stratification..................................................................................................... 46
6.4
Treatment compliance....................................................................................... 46
6.5
Concomitant therapy......................................................................................... 46
6.5.1
Background medication .................................................................................... 47
6.5.2
Other concomitant treatment............................................................................. 47
35
6.5.3
Rescue medication............................................................................................ 47
6.6
Dose modification - Not Applicable.................................................................. 48
7
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL . 48


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7.1
Discontinuation of study treatment.................................................................... 48
7.1.1
Temporary discontinuation ............................................................................... 48
7.1.2
Rechallenge ...................................................................................................... 49
7.1.3
Procedures for discontinuation of study treatment............................................. 49
7.2
Lost to follow-up .............................................................................................. 49
5
7.3
Withdrawal from the study................................................................................ 50
7.4
Study termination ............................................................................................. 50
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 51
8.1
Efficacy assessments......................................................................................... 52
8.1.1
Target engagement assessment.......................................................................... 52
10
8.1.2
Clinical outcome assessments ........................................................................... 52
8.1.2.1
Echocardiography............................................................................................. 52
8.1.2.2
Transthoracic Doppler echocardiography (TDE) with coronary flow velocity 
reserve (CFVR) measurement........................................................................... 52
8.1.2.3
Carotid-femoral Pulse Wave Velocity (cfPWV) and brachial Pulse Wave 
15
Analysis (bPWA).............................................................................................. 52
8.1.2.4
Endothelial function measurement - EndoPAT™.............................................. 53
8.1.2.5
6 Minute Walk Test (6MWT) ........................................................................... 53
8.1.2.6
Laboratory assessments..................................................................................... 53
8.2
Safety assessments............................................................................................ 53
20
8.2.1
Clinical safety laboratory assessments............................................................... 54
8.2.2
Physical examinations....................................................................................... 56
8.2.3
Skin Rash ......................................................................................................... 56
8.2.4
Vital signs......................................................................................................... 56
8.2.5
Electrocardiograms........................................................................................... 57
25
8.3
Collection of adverse events ............................................................................. 57
8.3.1
Method of detecting AEs and SAEs .................................................................. 57
8.3.2
Time period and frequency for collecting AE and SAE information.................. 57
8.3.3
Follow-up of AEs and SAEs ............................................................................. 58
8.3.4
Adverse event data collection............................................................................ 58
30
8.3.5
Causality collection........................................................................................... 59
8.3.6
Adverse events based on signs and symptoms................................................... 59
8.3.7
Adverse events based on examinations and tests ............................................... 59
8.3.8
Hy’s law ........................................................................................................... 60
8.4
Safety reporting and medical management........................................................ 60
35
8.4.1
Reporting of serious adverse events .................................................................. 60
8.4.2
Pregnancy......................................................................................................... 61
8.4.2.1
Maternal exposure ............................................................................................ 61
8.4.2.2
Paternal exposure.............................................................................................. 61
8.4.2.3
Overdose .......................................................................................................... 62
40
8.4.3
Medication error ............................................................................................... 62
8.5
Pharmacokinetics.............................................................................................. 62
8.5.1
Determination of drug concentration................................................................. 63
8.5.2
Storage and destruction of pharmacokinetic samples......................................... 63


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8.6
Pharmacodynamics........................................................................................... 63
8.7
Genetics............................................................................................................ 64
8.7.1
Optional exploratory genetic sample ................................................................. 64
8.7.2
Storage and destruction of genetic samples ....................................................... 64
8.8
Exploratory Biomarkers.................................................................................... 64
5
8.8.1
Storage, re-use and destruction of biomarker samples ....................................... 64
8.9
Patient Reported Outcome Questionnaires ........................................................ 65
8.9.1
The Kansas City Cardiomyopathy Questionnaire (KCCQ)................................ 65
8.10
Health Economics............................................................................................. 65
9
STATISTICAL CONSIDERATIONS............................................................... 65
10
9.1
Statistical hypotheses........................................................................................ 65
9.2
Sample size determination ................................................................................ 65
9.3
Populations for analyses.................................................................................... 66
9.3.1
Full analysis set ................................................................................................ 66
9.3.2
Safety analysis set............................................................................................. 66
15
9.3.3
PK analysis set.................................................................................................. 66
9.4
Statistical analyses............................................................................................ 67
9.4.1
Efficacy analyses .............................................................................................. 68
9.4.2
Safety analyses ................................................................................................. 68
9.4.3
Exploratory analysis ......................................................................................... 69
20
9.4.4
Other analyses .................................................................................................. 69
9.5
Interim analyses................................................................................................ 69
9.6
Safety Review Committee................................................................................. 70
9.7
Data Review Committee ................................................................................... 70
10
REFERENCES................................................................................................. 71
25
11
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS........................................................................................ 74
LIST OF TABLES
Table 1
Study of Assessments .............................................................................. 10
30
Table 2
Study objectives....................................................................................... 28
Table 3
Study Treatments..................................................................................... 44
Table 4
Prohibited medications............................................................................. 47
Table 5
Laboratory assessments ........................................................................... 53
Table 6
Safety Laboratory Assessments................................................................ 55
35
Table 7
Other Clinical Safety Panels .................................................................... 56


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LIST OF FIGURES
Figure 1
Study design............................................................................................ 22
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................. 74
5
Appendix B
Adverse event definitions and additional safety information .................... 78
Appendix C
Handling of Human Biological Samples .................................................. 86
Appendix D
Genetics................................................................................................... 88
Appendix E
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law............................................................................ 92
10
Appendix F
Medical device incidents: definition and procedures for recording, 
evaluating, follow-up, and reporting – Not Applicable............................. 96
Appendix G
The Kansas City Cardiomyopathy Questionnaire (KCCQ)....................... 97
Appendix H
Abbreviations ........................................................................................ 101
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h
For inclusion at visit 1 NT-proBNP or BNP can be used. For all other visits NT-proBNP should be analysed centrally. 
i
If echocardiography data is available in medical records from within 1 year before enrollment it may be used for inclusion/exclusion. If not available a 
simplified echo screen protocol needs to be performed at visit 1 focusing on EF, LAVi, E/e’, LVM and image analysis will be performed by local echo lab. 
In case visit 1 and 2 occur the same day the simplified echo screen will be performed first to judge if patient is eligible, thereafter the full echo screen 
protocol for visit 2 should follow.
j
Subjects may enter a screening period up to 28 days prior to visit 2. If visit 1 is performed more than 14 days prior to visit 2, all assessments except blood 
and urine sampling should be completed at that visit. Blood and urine samples related to visit 1 must be taken within 14 to 0 days prior to visit 2 to ensure 
patient eligibility


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1.2
Synopsis
Protocol Title: 
A randomized, double blind, placebo-controlled, parallel group, multicentre, phase 2a study to 
assess target engagement, safety and tolerability of AZD4831 in patients with Heart Failure 
with preserved Ejection Fraction (HFpEF) 
Short Title: 
A phase 2a study to assess target engagement, safety and tolerability of AZD4831 in patients 
with HFpEF.
Rationale: 
The primary objective of this study is to evaluate the target engagement of AZD4831 by 
measuring myeloperoxidase (MPO) specific activity in plasma following ex vivo stimulation 
of fresh blood samples with zymosan, in patients with heart failure with mid-range ejection 
fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF). Secondly, to 
evaluate the safety and tolerability of AZD4831 in patients with HFpEF and HFmrEF and the 
incidence of maculopapular rash grade 3. In addition, the effect of AZD4831 on Coronary 
Flow Velocity Reserve (CFVR) as a measure of myocardial microvascular function will be 
evaluated. 
For the current moment, there are no available point of care assays for the on-site screen 
testing enabling the selection of patients with high levels of MPO. There are no known 
potential surrogate markers offer enough evidence of linkage with the MPO levels. 
Consequently, separate exploratory objective will be focused on the assessment of all 
secondary/exploratory outcomes in the sub-group of patients with elevated MPO-pathway 
biomarkers. 
The study will be conducted in adaptive design manner.  Part A will establish if the safety and 
tolerability profile, and target engagement are acceptable to continue into Part B of the study. 
Pending observed target engagement in Part A, there is also a possibility to adjust the dose for 
patients randomized in Part B which will mainly focus on efficacy and effect on target 
engagement versus placebo. The result of the study treatment will provide a more complete 
AZD4831 safety and tolerability profile and will facilitate the scientific and clinical basis for 
further investigation of AZD4831 in improving cardiovascular mortality and morbidity on top 
of standard of care (SoC) in HFmrEF and HFpEF population. The treatment duration for this 
study is 90 days, which should be sufficient for the reliable assessment of secondary objective.




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To explore the effect of AZD4831 on right 
ventricular free wall longitudinal strain 
compared to placebo
Change from baseline in right ventricular 
free wall longitudinal strain measured by 
strain imaging echocardiography
To explore the effect of AZD4831 on left 
atrium reservoir strain compared to placebo
Change from baseline in left atrium reservoir 
strain measured by strain imaging 
echocardiography
To explore the effect of AZD4831 on 
diastolic function (measured as ratio between 
early mitral inflow velocity and mitral 
annular early diastolic velocity (E/e’)) 
compared to placebo
Change from baseline in E/e’ as measured 
by standard echocardiography
To explore the effect of AZD4831 on 
peripheral endothelial function compared to 
placebo
Change from baseline in Reactive hyperemic 
index (RHI)
To explore the effect of AZD4831 on pulse 
wave velocity (PWV) and Pulse Wave 
Analysis (PWA) compared to placebo
Change from baseline in PWV and PWA
To explore the effect of AZD4831 on NT-
proBNP compared to placebo
Change from baseline in NT-proBNP values 
To explore the effect of AZD4831 on 
changes in health-related Quality of Life 
(QoL) compared to placebo
Change from baseline in the Kansas City 
Cardiomyopathy Questionnaire (KCCQ) 
overall summary score, with specific focus 
on physical function domain
To explore the effect of AZD4831 on left 
atrium volume index (LAVI) compared to 
placebo 
Change from baseline in LAVI
To explore the effect of AZD4831 on MPO-
related biomarkers compared to placebo
Change from baseline in MPO- related 
biomarkers  
To collect and store samples for potential 
future 
exploratory 
research 
aimed 
at 
exploring biomarkers involved in PK, 
pharmacodynamic (PD), efficacy, safety and 
tolerability related to HFpEF and AZD4831 
treatment. 
Exploratory biomarker analysis in plasma,
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To explore all secondary and exploratory 
objectives in patients with elevated MPO-
pathway biomarkers
Corresponding variables for secondary and 
exploratory endpoints
Optional:  To collect and store samples for 
potential future exploratory genetic research 
aimed at e.g. identifying/exploring genetic 
variations that may affect PK, PD, efficacy, 
safety and tolerability related to AZD4831 
treatment
Overall design:
This is a randomized, double blind, placebo controlled study including approximately 96 
randomized patients with HFpEF. Patients with HFmrEF will also be included in the study 
and will hereafter be included in the definition of HFpEF, if not otherwise specified. The 
study will be conducted at approximately 10 sites in 5 countries. All patients will be treated 
once daily with AZD4831 or placebo for approximately 90 days. The study will be divided 
into two parts, Part A and Part B. In part A 37 patients will be randomized and treated for 90 
days with an interim analysis after approximately 30 days of treatment. The safety, tolerability 
and target engagement will be evaluated in the interim analysis and after the evaluation the 
randomization to Part B may proceed. In part B the approximate 59 remaining patients will be 
randomized and treated for approximately 90 days.
Part A:
At visit 1 the patients will be checked for eligibility and enrolled to the study. 37 patients will 
be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo. 
The patients will be dosed the first 10 days (until visit 3) with a starting dose of 
 once 
daily AZD4831 or matching placebo. After 10 days, at visit 3, the dose will be increased to  
 AZD4831 or matching placebo and patients will be treated for another 20 days (visit 4 and 
visit 5). When all 37 patients have been treated for approximately 30 days an interim analysis 
will follow but the 37 patients included in part A will continue the treatment at 
 
AZD4831 or matching placebo once daily for another 60 days until stop of treatment and 
complete the next visit approximately every 30 days for visit 6 and visit 7. After the stop of 
treatment patients will be followed-up (visit 8) after approximately 30 days. 
After evaluation of the interim analysis patients may be randomized to Part B of the study, see 
section 9.5 for information regarding the interim analysis.


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Part B: 
At visit 1 patients will be checked for eligibility and enrolled into study. Approximately 59 
patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or 
matching placebo. Patients in part B will be dosed the first 10 days (until visit 3) with a 
starting dose of 
 AZD4831 or matching placebo once daily. At Visit 3, further level of 
dosing for all patients will depend on the Interim Analysis results (it can be 
 or 
 
depending on safety profile and target engagement). Treatment will continue for 
approximately 80 days more to achieve 90 days in total in Part B. Following visit 3 patients 
will complete the next visit in 20 days, (visit 4), 30 days (visit 5), 60 days (visit 6) and 90 days 
(visit 7) after randomization. After the stop of treatment patients will be followed-up (visit 8) 
for approximately 30 days.
NB: At all visits, patients will be instructed to contact the investigator immediately, if rash has 
developed at any time point of the study. Patients will be recommended to make an acceptable 
quality self-photo of skin affected with rash. If any patient develops a confirmed generalised 
maculopapular rash grade 3, throat tightness or angioedema at any time during the study, the 
relevant site investigator should immediately stop the study drug and arrange appropriate 
medical consultation to provide relevant treatment. Patient should visit the site for an un-
scheduled visit (End-of Treatment visit = Visit 7).
During visit at site, if generalised maculopapular rash grade 3 is suspected, Investigator will 
make a quality photo(s) of patient’s skin affected with rash, acceptable for the evaluation of 
rash according to guidance provided in Appendix B9. These photo(s) should be also provided 
to the AstraZeneca Safety Committee.
If the prespecified number of patients discontinues due to maculopapular rash grade 3 during 
Part A the dose for all the subsequently randomized patients in Part A may be adjusted or 
study may be stopped. 
Study Period:
Estimated date of first patient enrolled: November 2018
Estimated date of last patient completed: Q2 2020
Number of Patients: 
Approximately 150 patients will be enrolled to achieve approximately 96 randomized patients. 
Treatments and treatment duration:
All patients will be treated once daily with AZD4831 or placebo for in total approximately 90 
days. 


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In part A the first 37 patients will be treated for approximately 10 days with a starting dose at 
 AZD4831 or matching placebo once daily. After 10 days the dose will be increased to 
 AZD4831 or matching placebo once daily for approximately 80 days. When all patients 
in part A have been treated for approximately 30 days (visit 5) an interim analysis will be 
performed. 
In part B the approximate 59 remaining patients will be treated for approximately 10 days 
with a starting dose at 
 AZD4831 or matching placebo once daily. After 10 days the 
dose may be maintained at 
 or increased to 
 or 
 AZD4831 or matching 
placebo once daily depending on the outcome of the interim analysis. 
Safety Review Committee
A blinded Safety Review Committee (SRC) consisting of internal AstraZeneca (AZ) expertise 
will review safety data related to rash on an ongoing basis throughout the study and give input 
and recommendations to a Data Review Committee (DRC). For more information refer to 
SRC/DRC charter.
Data Review Committee
The number of patients who discontinue the study due to generalised maculopapular rash 
CTCAE grade 3 or higher will be continuously monitored by a Data Review Committee 
(DRC) and the study will be stopped if at any time the proportion of discontinued patients on 
AZD4831 is above a prespecified level. The DRC consists of internal AZ expertise. 
The statistical monitoring will be described in the SRC/DRC charter that must be finalised 
before first patient in.
Statistical methods
The primary efficacy variable TE biomarker measure percent change from baseline to end of 
treatment in target engagement marker. The primary efficacy variable TE biomarker will test 
the null hypothesis of equality in TE biomarker comparing AZD4831 to placebo versus the 
alternative hypothesis of non-equality comparing AZD4831 to placebo at 5% two-sided 
significance level.
The first secondary efficacy variable CFVR measure percent change from baseline to end of 
treatment in CFVR. The first secondary efficacy variable CFVR will test the null hypothesis 
of no increase in CFVR comparing AZD4831 to placebo versus the alternative hypothesis of 
an increase in CFVR in favor of AZD4831 compared to placebo at 5% one-sided significance 
level. 
The primary efficacy variable TE biomarker and the first secondary efficacy variable CFVR 
will be analyzed using an ANCOVA model.


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An interim analysis is planned after 37 patients, 25 on AZD4831 and 12 on placebo, have 
been treated for approximately 30 days in Part A. The interim analysis results will be used to 
decide on dose for Part B or to stop the study. Only patients treated with AZD4831 will be 
included in the analysis.




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2
INTRODUCTION
2.1
Study rationale
The primary objective of this study is to evaluate the target engagement of AZD4831, MPO 
inhibitor by measuring MPO specific activity in plasma following ex vivo stimulation of fresh
blood samples with zymosan, in patients with HFpEF. MPO is known to influence vascular 
reactivity through consumption of endothelial Nitric Oxide (NO) under inflammatory 
conditions. Removing vascular MPO by using heparin and achieving a 45% reduction in MPO 
circulating levels has shown to significantly improve vascular function measured by Flow 
Mediated Dilation (Baldus et al 2006). 
The objectives of this study are also to evaluate the safety and tolerability of AZD4831 in 
patients with HFpEF and HFmrEF and the incidence of maculopapular rash grade 3. In 
addition, to assess the effect of AZD4831 on CFVR as a measure of myocardial microvascular 
function. Impaired CFVR is known to reflect both macro and microvascular dysfunction and 
endothelial dysfunction. CFVR is defined as the ratio of maximal (stimulated) to baseline 
(resting) coronary blood flow (Gan et al 2013). While fractional flow reserve (FFR) reflects 
severity of focal coronary artery lesions, CFVR is a measure of the global coronary vascular 
function. Reduced CFVR has been shown to confer prognostic information for cardiovascular 
outcome in various conditions. Reduced CFVR is seen in patients with systemic inflammation 
and improves after immunomodulatory treatment. CFVR is also reduced in co-morbidities 
associated with HFpEF like diabetes, left ventricular hypertrophy (LVH) and hypertension. 
CFVR can be measured through a variety of invasive and non-invasive methods. TDE 
provides reliable measurements of CFVR in the distal or middle segment of the LAD coronary 
artery, using pulse wave Doppler. Compared to other methods it is relatively inexpensive, 
non-invasive and does not expose to radiation. The increase in blood flow can be induced with 
adenosine or dipyridamole, where adenosine has the advantage of being short-acting. 
Recently, this protocol has been successfully used in PROMIS-HFpEF study. The study 
provided evidences that coronary microvascular dysfunction is highly prevalent in HFpEF and 
it correlates with several key features of HFpEF, including disease severity, systemic 
endothelial dysfunction, as well as diastolic dysfunction (Shah SJ et al, 2018) For the current 
moment, there are no available point of care assays for the on-site screen testing enabling the 
selection of patients with high levels of MPO. There are no known potential surrogate markers 
offer enough evidence of linkage with the MPO levels. Consequently, separate exploratory 
objective will be focused on the assessment of all secondary/exploratory outcomes in the sub-
group of patients with elevated MPO-pathway biomarkers.
Current study will evaluate safety and tolerability, efficacy and effect on target engagement in 
an adaptive design. Part A will establish if there is a satisfactory safety, tolerability and target 
engagement to continue into Part B of the study. Pending observed target engagement in Part 
A, there is also a possibility to adjust the dose for patients randomized in Part B. In Part B the 


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focus will mainly be on efficacy and effect on target engagement versus placebo. A placebo 
control arm in the trial will enable placebo-corrected analysis of safety and efficacy. In 
addition, the treatment duration of 3 months is expected to be of sufficient length to allow 
assessment of AZD4831 effect on CFVR and echocardiography parameters in HFpEF patients 
on top of long-term Standard of Care (SoC). The result of the study treatment will provide a 
more complete AZD4831 safety and tolerability profile and will facilitate the scientific and 
clinical basis for further investigation of AZD4831 in improving CV mortality and morbidity 
on top of SoC in HFpEF population.
Medical comorbidities including renal impairment, hypertension and diabetes mellitus are 
common in patients with HFpEF, consequently patients with these conditions will be included 
into this study. AZD4831 has not been studied in patients with renal impairment. AZD4831 is 
predominantly cleared via renal route, consequently, only patients with normal renal function 
and mild-moderate renal impairment (eGFR ≥30mL/min/1.73m2) will be included in the 
study, presuming that they have acceptable risk/benefit profile.
2.2
Background
Heart failure (HF) affects 2% of the Western population, increases to 10% over the age of 65 
years and up to 20% over the age of 75 years (Go et al 2014). The proportion of the Western 
population over the age of 65 years is expected to increase to over 30% by year 2050 and the 
costs of HF to society are expected to triple between years 2010 and 2030. HF is currently
broadly divided into three categories based on the systolic function of the left ventricle: (1) HF 
with reduced ejection fraction (HFrEF; Left ventricle ejection fraction (LVEF) <40%), (2) HF 
with mid-range ejection fraction (HFmrEF; LVEF 40-49%); and (3) HF with preserved 
ejection fraction (HFpEF; LVEF ≥50%). 
HFmrEF and HFpEF together account for 55% of HF cases. HFpEF and HFrEF are distinct 
clinical phenotypes with differing underlying pathophysiology, while HFmrEF appears to 
share some features of both HFrEF and HFpEF whilst remaining a possible independent 
category. Over recent years there has been a drive to include HFmrEF patients into future HF 
studies in order to learn more about this category while evaluating new therapies for the 
treatment of either HFpEF or HFrEF. To further increase knowledge about this condition, 
patients with HFmrEF will be included in the current study. 


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HFpEF is overrepresented in elderly and in women. Mortality in the community approaches 
25% at one year. In a comparison of trial populations, the prognosis in HFpEF is 50-75 deaths 
and 40-75 HF hospitalizations per 1000 patient-years whereas in stable coronary disease it is 
10-30 deaths and 5-10 hospitalizations per 1000 patient-years and has improved further with 
modern therapy. Thus, novel interventions for coronary artery disease have little potential 
whereas for HFpEF novel treatment is both a critical unmet need and if successful of great 
public health impact (Kannan et al. 2018
Kannan L., Shaw P.A., Morley M.P., Brandimarto J, Fang J.C., Sweitzer N.K., Cappola T.P., 
Cappola A.R. Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circ Heart 
Fail. 2018;11:e005266. 
McMurray et al. 2012, Butler at al 2014).
In patients with heart failure, low T3 levels have been associated with myocardial fibrosis and 
abnormalities in myocardial perfusion and metabolism. The low T3 syndrome, defined as a 
low T3 level with levels of TSH and FT4 in the reference range, is present in 20% to 30% of 
patients with heart failure (Kannan et al. 2018).
A novel paradigm for HFpEF pathophysiology states that co-morbidities (age, renal disease, 
hypertension, obesity, diabetes) lead to a global inflammatory state, leading to immune cell 
recruitment and endothelial and coronary microvascular dysfunction, with distinct 
pathophysiology different from macrovascular coronary disease (Paulus et al. 2013). This, in 
turn, can lead to both extracellular fibrosis and myocardial stiffness and reduced myocardial 
nitric oxide (NO) bioavailability and cyclic guanosine monophosphate (cGMP) content and 
impaired myocyte relaxation. Numerous clinical data support this hypothesis.
Coronary endothelial dysfunction is associated with diastolic dysfunction and with worse 
outcomes in HFpEF. Exercise studies implicate vascular stiffness and impaired exercise 
vasodilation and suggest that impaired diastolic reserve may be related to endothelial and 
microvascular dysfunction. Angina and false positive stress tests are common in HFpEF. 
Further, recent autopsy studies have provided convincing evidence of coronary microvascular 
rarefaction in HFpEF (Mohammed et al. 2015). Using TDE-CFVR approach, Shah SJ et al 
provided recently the first robust evidence that coronary microvascular dysfunction is highly 
prevalent in HFpEF, diagnosed according to guidelines. 
MPO is a highly abundant protein mainly present in azurophilic granules of neutrophils, 
constituting 5% of the dry weight of the cells. In addition to neutrophils, there are also data 
suggesting the presence of MPO in monocytes and macrophages. MPO can be secreted, and is 
unique in its ability to generate reactive chlorinating species such as hypochlorous acid, the 
active component of bleach, which possesses potent bactericidal and viricidal activities. In 


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addition, hypochlorous acid reacts with electron-rich moieties of a large range of biomolecules 
(Nicholls and Hazen 2005).
Multiple lines of evidence suggest that MPO may play a role in atherogenesis in humans 
(Brennan et al 2003; Baldus et al 2003; Zhang R et al 2001) and MPO plasma levels predict 
outcome of cardiovascular disease. In chronic heart failure (HF), elevated plasma MPO levels 
are associated with more advanced HF. Additionally, elevated plasma MPO levels can predict 
increased adverse clinical outcomes in HF patients (Tang et al 2007).
Individuals with inherited low MPO activity were protected from leukocyte activation induced 
deterioration of vascular function (Rudolph et al 2012). Direct MPO administration in 
anaesthetized pigs increased the tone of conductance and resistance vessels and adversely 
affected myocardial blood flow, thereby strengthening the concept that MPO indeed acts as a 
modulator of vascular tone in vivo and identifying MPO as a systemic regulator of 
vasomotion in humans and thus a potential therapeutic target (Rudolph et al 2012). As 
published by Rudolph V et al 2010, MPO is also involved in structural remodelling of the 
myocardium, leading to an increased vulnerability to atrial fibrillation (Rudolph V et al 2010). 
Furthermore, in humans systemic MPO was increased in patients with established HFpEF and 
correlated with diastolic dysfunction independent of age and plasma B-type natriuretic peptide 
(Tang WH et al 2006).
Overall, recent evidence suggests that MPO may provide a mechanistic link between 
inflammation, oxidative stress, vascular dysfunction and impaired cardiac remodelling. It is 
thus hypothesized that the MPO inhibitor AZD4831 will improve coronary microvascular 
status as well as systemic endothelial function, leading to improved diastolic function and 
overall status of HFpEF patients.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD4831 is 
provided in the Investigator’s Brochure.
2.3
Benefit/risk assessment
AZD4831 is a first in class MPO inhibitor in development as a novel treatment for heart 
failure with preserved ejection fraction (HFpEF). Patients involved in the proposed study may 
derive some benefits from given treatment even though the duration of the treatment is limited 
up to 90 days. HFpEF is a common condition with rising prevalence associated with poor 
quality of life and adverse prognosis for which there are no approved therapies therefore 
information acquired from this study could be of benefit to patients in the future.
AZD4831 has been administered to 59 healthy subjects in completed studies in single doses 
up to 
 
, and in repeated doses up to 
 for up to 14 days. There were no deaths or 
SAEs and all subjects except one completed the studies. The most common adverse events 
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were headache and generalized maculopapular rash. Dosing in 
 cohort in the Multiple 
Ascending Dose (MAD) study was stopped because of self-reported throat tightness in one 
subject that was considered intolerable by the Principal Investigator (PI) and SRC. This 
subject also had a more long-lasting rash of moderate intensity. Otherwise AZD4831has been 
well tolerated in healthy subjects. No clinically meaningful differences for changes over time 
in clinical laboratory tests, vital signs or ECGs were observed between subjects who received 
AZD4831 and those who received placebo. Preclinical safety studies have identified several 
potential risks including increment in liver enzymes and liver weights, elevation in thyroid 
stimulating hormone (TSH) and reduction in thyroxine (T4) levels, slight body weight loss 
and potential effects on heart rate and blood pressure. None of these findings were observed in 
the clinical studies performed to date. More detailed information about the known and 
expected benefits and risks and reasonably expected adverse events of AZD4831 may be 
found in the Investigator’s Brochure.
Based on knowledge of the mechanism of action, previous clinical experience and the 
preclinical safety studies the potential risks will be closely monitored and the patients will be 
withdrawn from Investigational Product (IP) if they present with rash grade 3, for definition of 
rash grade 3 see 7.1 No specific harms are anticipated from participating to this trial. 
Available preclinical and clinical data suggest that the subjects may benefit from participation 
in the study as inhibition of MPO activity may improve both coronary microvascular function 
and peripheral vascular function.
The essential imaging modality in the trial is cardiac ultrasound. The TDE with CFVR 
measurement has the advantage of being non-radioactive, non-invasive and utilizing 
equipment readily available in the departments of cardiology. The cardiac ultrasound 
examination itself does not involve any discomfort. To measure the ability to increase blood 
flow, intravenous adenosine will be used in connection to the ultrasound examination. 
Adenosine is approved as tool for cardiovascular examinations. It can provide a fast and 
transient (one minute) heat sensation and a slight chest discomfort. The most common adverse 
reactions are warmth, shortness of breath, flushing and headache. In rare cases, heart 
palpitations, nausea, anxiety or blurred vision may occur. Another rare condition is the risk for 
transient high degree Atrioventricular (AV) block and this risk is potentially higher in patients 
with bradycardia (heart rate< 50 beats/minute (bpm) and ongoing medication with e.g. beta-
blocker and calcium-channel antagonist. Therefore, patients with AV block of second degree 
or higher or heart rate of less than 50bpm will be excluded from the present study. Under the 
medical attention provided in this trial, ultrasound CFVR measurement with adenosine 
infusion is not considered to pose a risk for the patients.






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To collect and store samples for potential 
future exploratory research aimed at 
exploring biomarkers involved in PK, 
pharmacodynamic (PD), efficacy, safety and 
tolerability related to HFpEF and AZD4831 
treatment. 
Exploratory biomarker analysis in plasma, 
serum and urine
To explore all secondary and exploratory 
objectives in patients with elevated MPO-
pathway biomarkers
Corresponding variables for secondary and 
exploratory endpoints
Optional:  To collect and store samples for 
potential future exploratory genetic research 
aimed at e.g. identifying/exploring genetic 
variations that may affect PK, PD, efficacy, 
safety and tolerability related to AZD4831 
treatment
4
STUDY DESIGN
4.1
Overall design
For an overview of the study design see Figure 1. For details on treatments given during the 
study, see Section 6.1. For details on what is included in the efficacy and safety endpoints, see 
Section 3.
This is a randomized, double blind, placebo controlled study including approximately 96 
randomized patients with HFpEF. Patients with HFmrEF will also be included in the study 
and will hereafter be included in the definition of HFpEF, if not otherwise specified. The 
study will be conducted at approximately 10 sites and 5 countries. All patients will be treated 
once daily with AZD4831 or placebo for approximately 90 days. The study will be divided 
into two parts, Part A and Part B. In part A 37 patients will be randomized and treated for 
approximately 90 days. An interim analysis will take place when all patients in part A has 
been treated for approximately 30 days. The safety, tolerability and target engagement will be 
evaluated in the interim analysis and after the evaluation the randomization to Part B may 
proceed. In part B the approximate 59 remaining patients will be randomized and treated for 
approximately 90 days.


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Part A: 
At visit 1 the patients will be checked for eligibility and enrolled to the study. 37 patients will 
be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or matching placebo. 
The patients will be dosed the first 10 days (until visit 3) with a starting dose of 
 once 
daily AZD4831 or matching placebo. After 10 days, at visit 3, the dose will be increased to  
 AZD4831 or matching placebo and patients will be treated for another 20 days (visit 4 and 
visit 5). When all 37 patients have been treated for approximately 30 days an interim analysis 
will follow but the 37 patients included in part A will continue the treatment at 
 
AZD4831 or matching placebo once daily for another 60 days until stop of treatment and 
complete the following visits approximately every 30 days for visit 6 and visit 7. After the 
stop of treatment patients will be followed-up (visit 8) after approximately 30 days. 
After evaluation of the interim analysis patients may be randomized to Part B of the study, see 
section 9.5 for information regarding the interim analysis.
Part B: 
At visit 1 patients will be checked for eligibility and enrolled into study. Approximately 59 
patients will be randomized at visit 2 in a 2:1 ratio to once daily dosing of AZD4831 or 
matching placebo. Patients in part B will be dosed the first 10 days (until visit 3) with a 
starting dose of 
 AZD4831 or matching placebo once daily. At Visit 3, further level of 
dosing for all patients will depend on the Interim Analysis results (it can be 
 or 
 
depending on safety profile and target engagement). Treatment will continue for 
approximately 80 days more to achieve 90 days in total in Part B. Following visit 3 patients 
will complete the next visit in 20 days, (visit 4), 30 days (visit 5), 60 days (visit 6) and 90 days 
(visit 7) after randomization. After the stop of treatment patients will be followed-up (visit 8) 
for approximately 30 days.
NB: At all visits, patients will be instructed to contact the investigator immediately, if rash has 
developed at any time point of the study. Patients will be recommended to make an acceptable 
quality self-photo of skin affected with rash. If any patient develops a confirmed generalised 
maculopapular rash grade 3, throat tightness or angioedema at any time during the study, the 
relevant site investigator should immediately stop the study drug and arrange appropriate 
medical consultation to provide relevant treatment. Patient should visit the site for an un-
scheduled visit (End-of Treatment visit = Visit 7).
During visit at site, if generalised maculopapular rash grade 3 is suspected, Investigator will 
make quality photo(s) of patient’s skin affected with rash, acceptable for the evaluation of rash 


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according to guidance provided in Appendix B9. These photo(s) will be also provided to the 
AstraZeneca Safety Committee. 
If the prespecified number of patients discontinues due to maculopapular rash grade 3 during 
Part A the dose for all the subsequently randomized patients in Part A may be adjusted or 
study may be stopped. For more information see SRC/DRC charter. 
General description of visits: 
Visit 1 (enrollment): At visit 1 patients will be asked to sign informed consent. Patients 
demography, medical and surgical history will be recorded in the electronic Case Report Form 
(eCRF). To check the patients for eligibility an echocardiography evaluation performed within 
1 year and documented in medical records may be used, but if no echocardiography is 
available a simplified echo screen protocol needs to be performed at visit 1. This 
echocardiography will focus on Ejection Fraction (EF), LAVI, E/e’, Left ventricular mass
(LVM) and image analysis will be performed by local echo lab. 
Preferably any non-invasive assessments (physical examinations assessments, Blood Pressure 
(BP) and pulse, weight etc.) will be performed before the echocardiography assessments, if 
applicable. Blood samples should preferably be taken thereafter, and patient may leave the site 
after completion of all assessments. 
Visit 1 may take place up to 28 days before Visit 2. Subjects may enter a screening period up 
to 28 days prior to visit 2. If visit 1 is performed more than 14 days prior to visit 2, all 
assessments except blood and urine sampling should be completed at that visit. Blood and 
urine samples related to visit 1 must be taken within 14 to 0 days prior to visit 2 to ensure 
patient eligibility. Visit 1 may occur on the same day as visit 2 if deemed operationally 
feasible. If so, laboratory sampling for inclusion/exclusion criteria will be analyzed locally but 
the lab-samples deriving from visit 2 should still be sent to central lab for analysis. If the lab 
samples analyzed locally meet the inclusion criteria, the patient can be enrolled into the study. 
In the event that the central lab results are returned and do not meet the inclusion criteria, the 
patient will not be withdrawn. Other assessments that co-occur at visit 1 and 2 need to be 
performed only once and recorded in the eCRF according to Completion Guidelines.
For detailed information regarding visits, see SoA
Visit 2 (randomization): Visit 2 should be performed within 28 days (blood and urine 
samples related to visit 1 must be taken within 14 days to visit 2) from visit 1. Visit 2 could be 
performed on the same day as visit 1 if deemed operational feasible by site. If the lab samples 
analyzed locally meet the inclusion criteria, the patient can be enrolled into the study. In the 
event that the central lab results are returned and do not meet the inclusion criteria, the patient 
will not be withdrawn.


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At visit 2 patients should be asked to arrive to site fasting, see section 5.4.1. Patient should be 
fasting until CFVR and Endothelial function measurement (EndoPAT™) assessments are 
performed and laboratory samples are taken.
If patient fulfils all inclusion and none of the exclusion criteria they will be randomized into 
the study. Preferably any the non-invasive assessments like physical examination, vital signs, 
KCCQ, ECG, weight, height and body temperature should be performed first, thereafter 
EndoPAT, and PVW/PWA will follow. Blood sampling is preferably taken before assessment 
of echocardiography and CFVR and 6MWT. When all assessments are completed the IP will 
be dispensed and taken at site. 
For detailed information regarding visits, see SoA
Visit 3 (Part A): Visit 3 will be performed 10 (±2) days after visit 2. Patients will be asked 
not to take IP at home on the same day as the visit. At visit 3, treatment will be increased to  
 once daily or matching placebo. IP should be administered at site and assessments 
performed as outlined in SoA. 
Visit 3 (Part B): Visit 3 will be performed 10 (±2) days after visit 2. Patients will be asked 
not to take IP at home on the same day as the visit. At visit 3 treatment may be 
 
or 
 AZD4831 or matching placebo once daily depending on the results from the interim 
analysis, see section 9.5. IP should be administered at site and assessments performed as 
outlined in SoA.
Visits 4 and 6 (Part A and Part B): Visit 4 will be performed 20 (±2) days after visit 2, visit 
6 will be performed 60 (±4) days after visit 2. At visit 4 and 6 patients should be instructed not 
to take the IP at home on the same day as the visit. Preferably any non-invasive assessments 
(physical examination, vital signs, etc.) should be performed before blood sampling. When all 
assessments are completed the IP will be administered and taken at site. For detailed 
information regarding visits, see SoA.
Visit 4 and 6 may be performed as home visits if operationally feasible, for assessments 
performed at home see SoA.
After interim analysis AstraZeneca may decide to make visit 4 and visit 6 in part B to a visit
that could optionally be performed as a telephone contact with the patient if judged
appropriate by the investigator. In such cases any on-site examinations or laboratory samples
will be eliminated and patient will only be asked for any health concerns and/or AEs.  
Visit 5 and visit 7 (Part A and Part B): Visit 5 shall be performed 30 (±3) days after visit 2 
and visit 7 shall be performed 90 (+2/-7) days after visit 2. 


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At visits 5 and 7 patients should be asked to arrive to site fasting, see section 5.4.1. Patient 
should be fasting until CFVR (visit 7) and EndoPAT assessments are performed and 
laboratory samples are taken. At visit 5 and 7 the patients should be instructed not to take the 
dose of IP at home before the visit. 
For detailed information regarding visits, see SoA
Visit 8 (Part A and Part B): Visit 8 will be performed 120 (±4 days) after visit 2 and will 
serve as the follow-up visit. Assessments will be performed as outlined in SoA. 
4.2
Scientific rationale for study design
Pathophysiology of HFpEF suggests that comorbidities lead to a systemic inflammation, 
which triggers endothelial and microvascular dysfunction. This results in diastolic stiffness as 
well as concentric LV remodelling and fibrosis. Presence of diastolic and vascular dysfunction 
out of proportion to comorbidities and the lack of neurohormonal antagonism benefitting 
HFpEF patients might suggest a different pathophysiology of HFpEF compared to HFrEF. 
The microvascular inflammation and dysfunction is the key driver of HFpEF disease 
progression and leads to excessive mortality and hospitalization. MPO and related biomarkers 
are significantly elevated in HFpEF patients and studies have shown that MPO genetically and 
phenotypically is linked to microvascular dysfunction (Mäkelä R et al. 2004).
MPO inhibition is a novel mechanism of action with the intention to become an established 
treatment option for patients with HFpEF aiming to reduce inflammation and oxidative stress. 
The rationale for this study is that MPO inhibition through AZD4831 will improve vascular 
function and this will subsequently lead to increased organ perfusion. Based on evidence 
discussed above on impact of MPO inhibition on microvascular function, a study treatment of 
90 days is considered sufficient to decrease the level of MPO-mediated inflammation and 
improve myocardial microvascular function, which will be reflected in measurements of 
inhibition of ex vivo zymosan stimulated MPO specific activity and CFVR. In addition, the 
study duration is expected to be of sufficient length to permit evaluation of the drug’s safety 
and tolerability profile on top of SoC in HFpEF patients to support further clinical 
development. To best evaluate the potential effect of AZD4831 the Phase 2a Proof-of-
Principle study will be conducted in a randomized, double blind, placebo-controlled design on 
top of SoC.
Since reproduction toxicology studies have not yet been conducted with AZD4831, females of 
child-bearing potential are excluded from the study and males are required to abstain from 
fathering a child or donating sperm for the same reason.
Collection of blood samples for potential future exploratory research into biomarkers related 
to HFpEF or that may influence drug response to AZD4831, has been included in the study. In 


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addition, blood samples for potential current and future exploratory genetic research will be 
collected in patients who have given a separate consent for genetic research.
4.3
Justification for dose
Single doses of up to 
 AZD4831 and once daily repeated doses of 
 and 
 mg 
for 10 days (14 days for the 
 dose) have been well tolerated in healthy patients except for 
incidences of rash on higher doses (Single Ascending Dose (SAD) study, D6580C00001: 
 
 (1 patient out of 6 treated), 
 (1/6) and 
 (2/6); MAD: 
 (2/6) 
 
(2/4)). Dosing will start by giving 
 once daily for 10 days. The dose will then be 
increased to 
 once daily. The dose of 
 is anticipated to give similar exposure in 
patients as the 
 dose in healthy volunteers, since renal clearance is close to total 
clearance and patients have approximately half the level of eGFR seen in healthy volunteers. 
At a dose of 
 in healthy volunteers, no rash was observed in the MAD study. The 
procedure of starting with a somewhat lower dose is an attempt to mitigate occurrence of rash 
by desensitizing the patients to AZD4831. The choice of 10 days of dosing with the lower 
dose is because all incidences of rash observed in the SAD and MAD (D6580C00001) studies 
appeared around day 7-9 after the first dose. 
The 
 dose in healthy volunteers resulted in around 50% inhibition of ex vivo zymosan 
stimulated MPO specific activity (MPO activity divided by MPO protein mass) at steady state 
when normalizing for the maximum detectable MPO inhibition (subtraction of the ex vivo 
zymosan stimulated MPO specific activity obtained in a pre-dose blood sample in presence of 
excess AZD4831). Published data support a 50% inhibition of MPO activity to result in 
clinically relevant improvement in vascular function. Releasing MPO from the vessel wall 
using heparin resulted in improvement in Flow Mediated Dilatation (FMD) (Baldus et al 
2006). Furthermore, patients with low MPO activity levels had no deterioration in FMD 
following nicotine challenge, as compared to patients with normal MPO activity levels where 
nicotine challenge resulted in a deterioration in FMD (Rudolph et al 2012).
At the interim analysis target engagement, in form of level of MPO inhibition as measured by 
normalised ex vivo zymosan stimulated specific MPO activity, will be evaluated. The 
intention is to use the 
 dose throughout the study (after a starting dose of 
 for the 
first 10 days). However, pending outcome of the interim analysis, there is a possibility to 
either increase the dose to 
 for the following patients in the study should there be too 
low target engagement and minimal rash, or to lower the dose to 
 should there be good 
target engagement but too high incidence of rash. For both the 
 and the 
 
alternatives, dosing will start by 10 days with 
 once daily followed by either 
 or 
 
 once daily.


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4.4
End of study definition
The end of study is defined as the last expected visit/contact of the last patient undergoing the 
study.
A patient is considered to have completed the study when he/she has completed his/her last 
scheduled visit.
See Appendix A 6 for guidelines for the dissemination of study results.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
Each patient should meet all the inclusion criteria and none of the exclusion criteria to be 
assigned/randomized to a study intervention. Under no circumstances can there be exceptions 
to this rule. Patients who do not meet the entry requirements are screen failures, refer to 
section 5.4.
In this protocol, “enrolled” patients are defined as those who sign informed consent. 
“Randomized” patients are defined as those who undergo randomization and receive a 
randomization number.
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3.
5.1
Inclusion criteria
Patients are eligible to be included in the study only if all of the following inclusion criteria 
and none of the exclusion criteria apply:
Informed consent
1.
Capable of giving signed informed consent which includes compliance with the 
requirements and restrictions listed in the informed consent form (ICF) and in this 
CSP
2.
Provision of signed and dated, written informed consent form prior to any 
mandatory study specific procedures, sampling, and analyses
The ICF process is described in Appendix A 3
Age
3.
Patient must be 45 to 85 years of age inclusive, at the time of signing the informed 
consent form


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Type of patient and disease characteristics
4.
Signs and symptoms of HF in judgement of Investigator AND
a. Stable NYHA II-IV and
b. EF ≥ 40 % and
c.  Elevated NT-proBNP or BNP in the last 1 year defined as: 

Measured as out-patient: NT-proBNP ≥125 ng/L or BNP≥35 ng/L with sinus 
rhythm, NT-proBNP ≥750 ng/L or BNP ≥200 ng/L with atrial fibrillation (AF), 
or

Measured when hospitalized acutely: NT-proBNP ≥500 (ng/L) or BNP ≥125 
ng/L with sinus rhythm, NT-proBNP ≥1250 (ng/L) or BNP ≥350 ng/L with AF
d. And at least one of the following: 

Hospitalization with HF as primary cause in last 12 months 

Structural heart disease on echo according to ESC guidelines i.e. either enlarged 
Left atrial volume index (LAVI > 34 ml/m2) or increased LVM (LVM index > 
95 g/m2 in women and > 115 g/m2 in men)

Pulmonary capillary wedge pressure (PCWP) at rest >15 mmHg or >25 mmHg 
at exercise

Spectral tissue Doppler echocardiography - E/e’ ratio ≥13 at rest
Weight
5.
Body Mass Index (BMI) range 18- 40kg/m2
Sex
6.
Male or female of nonchildbearing potential
Reproduction
7.
Female patients must be 1 year post-menopausal or surgically sterile 
8.
Male patients must be surgically sterile or using an acceptable method of 
contraception (defined as barrier methods in conjunction with spermicides) for the 
duration of the study (from the time they sign consent) and for 3 months after the 
last dose of AZD4831/matching placebo to prevent pregnancy in a partner. Male 
patients must not donate or bank sperm during this same time period
Genetic sampling


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9.
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria 
described above and provide informed consent for the genetic sampling and 
analysis
5.2
Exclusion criteria 
Medical conditions
1.
Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) eGFR <30 ml/min/1.73m2 or dialysis
2.
Life expectancy < 3 years due to other reasons than cardiovascular disease
3.
Any ongoing skin disorder, history of or ongoing clinically significant 
allergy/hypersensitivity
Remove extra spacing
4.
Current decompensated HF
5.
Primary cardiomyopathy (e.g. constrictive, restrictive, infiltrative, toxic, 
hypertrophic, congenital or any primary cardiomyopathy) in judgment of 
investigator
6.
Current hemodynamically significant valve disease in opinion of investigator
7.
Any condition with indication for cardiac surgery or catheter intervention
8.
EF ever documented < 40%
9.
Any event (e.g. acute myocardial infarction) that may have reduced EF, that 
occurred after the echocardiogram used for inclusion, unless repeat echocardiogram 
confirms EF ≥ 40%
10.
Tachycardia > 110 bpm
11.
Any current life-threatening dysrhythmia
12.
Probable alternative primary reason for patient’s symptoms in judgment of 
investigator, including but not limited to:
a. Isolated pulmonary arterial hypertension or right ventricular (RV) failure; in the 
absence of left-sided HF
b. Anaemia: Hb <100 mg/L (10g/dL)


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c. Severe chronic obstructive pulmonary disease (COPD) or lung disease (chronic 
O2, nebulizer or oral steroid therapy)
13.
Cardiac surgery, acute coronary syndrome (ACS), or non-elective percutaneous 
coronary intervention (PCI) < 3 months
14.
Known or clinically judged significant macrovascular coronary artery disease 
(CAD) that has not been revascularized
15.
Any non-elective hospitalization < 2weeks
16.
Current significant major or unstable respiratory disease, haematological disease, 
hepatic disease, renal disease, gastrointestinal (GI) disease, or other major treatment 
required disease as judged by the investigator.
17.
Stroke, transient ischemic attack, carotid surgery or angioplasty within 3 months
18.
Heart transplantation or left ventricular assist device ever
19.
Patients with hypertension (unstable or untreated) or symptomatic hypotension (that 
in the opinion of the investigator requires treatment)
20.
Patients with uncontrolled or clinically significant thyroid disease as judged by the 
investigator
21.
History of any clinically significant disease or disorder other than HFpEF which, in 
the opinion of the investigator, may either put the patient at risk on participation in 
the study, or influence the results or the patient’s ability to participate in the study.
22.
Alanine transaminase (ALT) or aspartate aminotransferase (AST) ≥2 x upper limit 
of normal (ULN). Resampling will not be allowed during the same screening period 
if detected abnormal values do not have reasonable explanation and are not 
expected to return to normal level within few days.
23.
Known positive HIV, hepatitis C antibody, hepatitis B virus surface antigen or 
hepatitis B virus core antibody, at screening
24.
Plasma donation within 1 month of enrollment or any blood donation/blood loss 
>500 mL during the 3 months prior to enrollment.
25.
For CFVR:
a. Known allergy to adenosine
b. Known elevated intracranial pressure


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c. AV block ≥ second degree and/or sick sinus syndrome in patient without 
pacemaker
d. Heart rate < 50 bpm
e. Systolic blood pressure < 90 mmHg
f. Asthma or COPD with strong reactive component in judgment of investigator
g. Treatment with dipyridamole, theophylline or fluvoxamine within 24 h or 
caffeine containing beverages within 12 h
26.
Any circumstances in which in the investigator’s opinion makes it undesirable for 
the patient to participate in the trial.
27.
Known history of drug or alcohol abuse within 1 year of screening
28.
History of QT prolongation associated with other medications that required 
discontinuation of that medication.
29.
Congenital long QT syndrome.
30.
History of arrhythmia (multifocal premature ventricular contractions, bigeminy, 
trigeminy, ventricular tachycardia), which is symptomatic or requires treatment, 
uncontrolled atrial fibrillation despite treatment, or asymptomatic sustained 
ventricular tachycardia.  Patients with atrial fibrillation controlled by medication are 
permitted.
Prior/concomitant therapy
31.
Any concomitant medications known to be associated with Torsades de Pointes or 
potent cytochrome P450 3A4 (CYP3A4) inducers or inhibitors e.g. itraconazole, 
rifampicin, clarithromycin
Prior/concurrent clinical study experience
32.
Participation in another clinical study with an investigational product administered 
in the last 3 months (or 5 half-lives). 
Other exclusions
33.
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
34.
Any condition, e.g. ongoing drug abuse, which may interfere with participation or 
safety of investigations or interferes with participation, in the opinion of the 
investigator


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35.
Judgment by the investigator that the patient should not participate in the study if 
the patient is unlikely to comply with study procedures, restrictions and 
requirements.
36.
Previous randomization in the present study
5.3
Prevalence of Atrial Fibrillation in study population
Prevalence of AF in the study population should not exceed 50%. 
Interactive voice/web response system (IxRS) will be preset accordingly. 
Whenever possible, it is recommended to keep the difference in prevalence HFmrEF and 
HFpEF between the groups on a reasonably comparable level. 
5.4
Lifestyle restrictions
5.4.1
Meals and dietary restrictions
Patient should arrive to the clinic after fasting overnight (no food or liquid [except for water] 
intake permitted 12 hours before the visit) for Visits 2, 5, 7 for sampling of safety laboratory 
samples, CFVR and EndoPAT measurements.
In case patient has not been fasted for 12 hours prior the visit it should be rescheduled. 
5.4.2
Caffeine, alcohol, and tobacco
Prior to Visits 2, 5 and 7 avoid intake of coffee or other caffeine containing beverages 12 hours 
before and until after completion of the study specific clinical assessments (CFVR, Echo).
Abstain from tobacco/nicotine for at least 120 minutes prior to CFVR measurements, or 
whenever study procedures demand it. Nicotine substitutes will be offered at the discretion of 
the Investigator
Abstain from excessive intake of alcohol for 48 hours preceding all the clinical visits.
Abstain from drugs of abuse during the entire study.
5.4.3
Activity
In conjunction with visit 2, 5 and 7 patients should avoid excessive physical activity 24h prior 
visit. 
5.4.4
Reproductive restrictions
There is no information about effects that AZD4831 could have on the development of the 
foetus in humans. Pre-clinical studies have shown that AZD4831 is not genotoxic, however 
formal pre-clinical reproductive toxicology studies have not yet been completed. Women of 
child-bearing potential will not be included in this study (for definition see inclusion criteria). 
In addition, it is important that women of childbearing potential, who are the partners of male 
patients, do not become pregnant during the study and for a total period of 3 months after the 
male study patient has received his last dose of IP.


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All male patients should avoid fathering a child by either true abstinence or use together with 
their female partner/spouse a highly effective method of contraception (see definition below), 
starting from the time of IP administration until 3 months after the last dose of IP. For male 
patients whose partner is pregnant, the man should use a condom for the duration of the study 
and for 1 week afterwards.
Methods that can achieve a failure rate of less than 1% per year when used consistently and 
correctly are considered highly effective birth control methods. Such methods include:

Combined (estrogen and progesterone containing) hormonal contraception associated with 
inhibition of ovulation:

oral

intravaginal

transdermal

Progesterone-only hormonal contraception associated with inhibition of ovulation:

oral

injectable

implantable

Intrauterine device (IUD)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion of female partner

Male vasectomy

True sexual abstinence
True abstinence refers to: When this is in line with the preferred and usual lifestyle of the 
patient.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation 
methods), declaration of abstinence for the duration of a trial, and withdrawal are not 
acceptable methods of contraception.
Sperm Donation
Male patients should not donate sperm for the duration of the study and for at least 3 months 
after his last dose of IP. 
Pregnancy
Male patients will be instructed that if their partner becomes pregnant during the study this 
should be reported to the Investigator.  The Investigator should also be notified of pregnancy 
occurring during the study but confirmed after completion of the study.  In the event that a 
patient’s partner is subsequently found to be pregnant after the study patient is included in the 
study, then consent will be sought from the partner and if granted any pregnancy will be 
followed and the status of mother and/or child will be reported to the Sponsor after delivery.


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A pregnancy notification form and follow-up will be completed.
5.5
Screen failures
Screen failures are defined as patients who signed the informed consent form to participate in 
the clinical study but are not subsequently randomized into the study. A minimal set of screen 
failure information is required to ensure transparent reporting of screen failure patients to meet 
the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 
screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one time after 1 month if they fulfil the inclusion/exclusion criteria then. The 
patient should sign a new informed consent if rescreened. 
These patients should have the reason for study withdrawal recorded in the eCRF.
6
STUDY TREATMENTS
Study treatment is defined as any investigational product(s) (including marketed product 
comparator and placebo) or medical device(s) intended to be administered to a study 
participant according to the CSP. Study treatment in this study refers to AZD4831 or matching 
placebo.




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The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for IP accountability, reconciliation, and record maintenance (i.e., receipt, 
reconciliation, and final disposition records).
The investigator will retain the returned IP until the AZ representative or delegate collects it, 
along with any IP not dispensed. The AZ representative or delegate is responsible for confirming 
the investigator or delegate has recorded the quantities of returned and unused tablets at a patient 
level before IP is destroyed. The AZ representative or delegate will advise on the appropriate 
method for destruction of unused IP.
6.3
Measures to minimise bias: randomization and blinding
All patients will be blinded with respect to active or placebo treatment, but not the dose that is 
selected for the active treatment after the interim analysis. 
All patients will be centrally assigned to randomized IP using an interactive voice/web 
response system (IxRS). Randomization to IP will be performed in balanced blocks to ensure 
approximate balance between the treatment groups (2:1). The randomization codes will be 
computer generated and loaded into the IxRS database. Before the study is initiated, the 
telephone number and call-in directions for the IxRS and/or the log-in information and 
directions for the IxRS will be provided to each site. 
If a patient withdraws from the study, then his/her enrollment/randomization code cannot be 
reused. Withdrawn patients will not be replaced. 
The IxRS will provide to the Investigator or pharmacist the kit identification number to be 
allocated to the patient at the dispensing visit. At all visits where IP is dispensed, site 
personnel will do a kit verification in IxRS before providing the IP bottle to the patient. 
Routines for this will be described in the IxRS user manual that will be provided to each 
centre.
The IxRS will be programmed with blind-breaking instructions. The randomization 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 within 24 hours after breaking the blind, without revealing 
the treatment given to the patient to the AstraZeneca staff. The date and reason that the blind 
was broken must be recorded in the source documentation and eCRF, as applicable. 
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. Randomization codes will not be broken for the 
planned analyses of data until all decisions on the evaluability of the data from each individual 
patient have been made and documented.


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The randomization list should be sent to the personnel analysing the PK samples.
6.3.1
Stratification
The randomisation will be stratified by Atrial Fibrillation (Yes vs No). 
6.4
Treatment compliance
The administration of IP should be recorded in the appropriate sections of the eCRF. Any 
change from the dosing schedule should be recorded in the eCRF.
Patients will be asked to bring the IP bottle to the clinic at all site visits (except at visit 4 and 
visit 6) to check IP compliance. At each visit, any patient found to be non-compliant will be 
counselled on the importance of taking their IP as prescribed. The investigator or delegate will 
enter the number of returned tablets in the eCRF. 
The Investigational Product Storage Manager is responsible for managing the IP from receipt 
by the study site until the destruction or return of all unused IP. The Investigator(s) is 
responsible for ensuring that the patient has returned all unused IP.
Diary Cards will be given to the patients at the randomization visit and the patients will be 
asked to fill in the dose intake information for each dose (date and time) at home. The diary 
cards will be checked by study site personnel at the study visits and data transferred to the 
eCRF.
6.5
Concomitant therapy
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Concomitant medication not allowed within 24 h prior to visits including CFVR examinations 
are listed in the exclusion criteria (last bullet), Section 5.2.


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Remove extra spacing
Table 4
Prohibited medications
Prohibited medication/class of drug:
- Cyclosporin or Tacrolimus
- Potent Inhibitors CYP3A4
1) protease inhibitors: ritonavir, indinavir, nelfinavir, saquinavir, atazanavir, darunavir, 
lopinavir, tipranavir
2) macrolide antibiotics: clarithromycin, telithromycin
3) chloramphenicol (antibiotic)
4) azole antifungals: ketoconazole, itraconazole, posaconazole, voriconazole
5) nefazodone (antidepressant)
6) cobicistat
- Potent Inducers CYP3A4
Nevirapine, Rifampicin, Carbamazepine, Fosphenytoin, Pentobarbital, Phenobarbital, 
Phenytoin, Primidone, Rifapentine, Enzalutamide, Lumacaftor, St. John's Wort, Mitotane, 
Apalutamide, Quinine, Rimexolone, Rifaximin, Rifamycin, Topiramate, Qsymia, 
Oxcarbazepine, Midostaurin
Table 4 is not a complete list of potent CYP3A4 inhibitors/inducers. Please refer to 
concomitant medications SmPCs for further information and clarification
6.5.1
Background medication
The patients should be on stable background treatment and have no intended dose change of 
the background therapy within the period of the study treatment. 
6.5.2
Other concomitant treatment
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 eCRF. If this is one of the prohibited medications listed above, the 
study drug must be discontinued, and the patient withdrawn from the study.
6.5.3
Rescue medication
If any study patient develops a confirmed generalised maculopapular rash grade 3, throat 
tightness or angioedema at any time during the study, the investigator should immediately 
stop the study drug and arrange for the patient to receive the appropriate medical treatment 
relevant to this situation.


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6.6
Dose modification - Not Applicable
7
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL 
7.1
Discontinuation of study treatment 
At each visit patients will be instructed to contact the investigator immediately, if rash has 
developed. If maculopapular rash grade 1 and/or grade 2 has developed, the decision to 
continue treatment will be made by investigator in discussion with patient and AstraZeneca 
medical staff. If maculopapular rash grade 3 has developed, patient must be discontinued from 
IP and AstraZeneca medical staff should be informed. 

Grade 1: Macules/papules covering < 10% Body Surface Area with or without 
symptoms (e.g., pruritus, burning, tightness).

Grade 2: Macules/papules covering 10 - 30% Body Surface Area, with or without 
symptoms (e.g., pruritus, burning, tightness); limiting Instrumental Activities of Daily 
Living (refer to preparing meals, shopping for groceries or clothes, using the 
telephone, managing money, etc); rash covering > 30% Body Surface Area with or 
without mild symptoms. 

Grade 3: Macules/papules covering > 30% Body Surface Area, with moderate or 
severe symptoms; limiting Self-care Activities of Daily Living (refer to bathing, 
dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden).
For further information and rash evaluation guidance see Appendix B9. 
Patients may be discontinued from investigational product (IP) in the following situations: 

Patient decision. The patient is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse Event

Severe non-compliance with the CSP 
Note that discontinuation from study treatment is NOT the same thing as a complete 
withdrawal from the study.
See section 7.1.3 for data to be collected at the time of treatment discontinuation and follow-
up and for any further evaluations that need to be completed.
7.1.1
Temporary discontinuation 
Temporary discontinuation of study medication is NOT permitted in this study.


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7.1.2
Rechallenge
Rechallenge of study medication is NOT permitted in this study.
7.1.3
Procedures for discontinuation of study treatment
The investigator should instruct the patient to contact the site before or at the time if IP is 
stopped. A patient that decides to discontinue IP will always be asked about the reason(s) and 
the presence of any AEs.  The date of last intake of IP should be documented in the eCRF. All 
IP should be returned by the patient at their next on-site study visit or unscheduled visit.  
Patients permanently discontinuing IP should be given locally available standard of care 
therapy, at the discretion of the Investigator.
Discontinuation of IP for any reason, does not impact on the patient´s participation in the 
study. The patient should continue attending subsequent study visits and data collection 
should continue according to the CSP. If the patient does not agree to continue in-person study 
visits, a modified follow-up must be arranged to ensure the collection of endpoints and safety 
information. Preferably the patient will be seen for an end-of treatment visit (visit 7). This 
could be a telephone contact with the patient, a contact with a relative or treating physician, or 
information from medical records. The approach taken should be recorded in the medical 
records. A patient that agrees to modified follow-up is not considered to have withdrawn 
consent or to have withdrawn from the study.
7.2
Lost to follow-up
A patient will be considered potentially lost to follow-up if he or she fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a patient fails to return to the clinic for a required study 
visit:

The site must attempt to contact the patient and reschedule the missed visit as soon as 
possible and counsel the patient on the importance of maintaining the assigned visit 
schedule.

Before a patient is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the patient or next of kin by e.g. repeat telephone 
calls, certified letter to the patient´s last known mailing address or local equivalent 
methods. These contact attempts should be documented in the patient’s medical 
record.

Should the patient be unreachable at the end of the study the patient should be 
considered to be lost to follow up with unknown vital status at end of study and 
censored at latest follow up contact.


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
AstraZeneca or its delegate will request investigators to collect information on 
patients’ vital status (dead or alive; date of death when applicable) at the end of the 
study from publicly available sources, in accordance with local regulations. 
Knowledge of the vital status at study end in all patients is crucial for the integrity of 
the study.
7.3
Withdrawal from the study
A patient may withdraw from the study (e.g., withdraw consent), at any time (investigational 
product and assessments) at his/her own request, without prejudice to further treatment.
A patient who considers withdrawing from the study must be informed by the Investigator 
about modified follow-up options (e.g., telephone contact, a contact with a relative or treating 
physician, or information from medical records).
If the patient withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent.
If a patient withdraws from the study, he/she may request destruction of any samples taken, 
and the investigator must document this in the site study records.  
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 patients as medically indicated. 
See SoA, Table 1, for data to be collected at the time of study discontinuation and follow-up 
and for any further evaluations that need to be completed. All IP should be returned by the 
patient.
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 eCRF. All reasons for discontinuation of 
the treatment must be documented.
7.4
Study termination
The sponsor reserves the right to temporarily suspend or terminate this study at any time. The 
reasons for temporarily suspending or terminating the study may include but are not limited to 
the following:

The study may be terminated if, in the judgement of the sponsor, trial patients are 
placed at undue risk. 

Patient enrollment is unsatisfactory


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
Non-compliance that might significantly jeopardize the validity or integrity of the 
study

Sponsor decision to terminate development
Premature termination of the study must be mutually agreed upon by the PI and the sponsor and 
must be documented. However, study results will be reported according to the requirements 
outlined in this clinical study protocol as far as applicable.
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests. 
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarised in the SoA.  
The investigator will ensure that data are recorded in the eCRF. A Web Based Data Capture 
(WBDC) system will be used for data collection and query handling. 
The investigator ensures the accuracy, completeness, legibility and timeliness of the data 
recorded and of the provision of answers to data queries according to the Clinical Study 
Agreement. The investigator will sign the completed eCRF copy of the completed eCase 
Report Forms, and it will be archived at the study site.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue IP.
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The investigator will maintain a screening log to record details of 
all patients screened and to confirm eligibility or record reasons for screening failure, as 
applicable.  
Procedures conducted as part of the patient’s routine clinical management (e.g., blood count)
and obtained before signing of the ICF may be utilised for screening or baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA.
The maximum amount of blood collected from each patient over the duration of the study, 
including any extra assessments that may be required, will not exceed 250 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.


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8.1
Efficacy assessments 
8.1.1
Target engagement assessment
Target engagement will be assessed through measuring ex vivo zymosan stimulated MPO 
specific activity (MPO activity divided by MPO protein mass), normalised.
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual at timepoints described in the SoA
8.1.2
Clinical outcome assessments
8.1.2.1
Echocardiography
Comprehensive echocardiographic examination will be performed with patients in the left 
recumbent position at rest. Standard clinical cardiac transducers will be used for B-mode, 
colour Doppler, and tissue Doppler imaging. CINE-loops1 of the parasternal long- and short-
axis views, apical 4-, 2-, and 3-chamber views, and subcostal views will be obtained and 
stored for off-line analysis of cardiac structure and function, as detailed in the Manual of 
Procedures (MoP) for Echocardiography (detailed echocardiography protocol) that will be 
supplied to all study sites. Doppler and tissue Doppler echocardiography will be performed to 
obtain indices necessary for comprehensive assessment of LV diastolic function and non-
invasive hemodynamic measurements, as detailed in MoP.
If echocardiography data from examination within 1 year is available in medical records that
may be used for incl./excl. criteria. If not available a simplified echo screen protocol needs to 
be performed at visit 1. For screening echocardiography focus will be on EF, LAVI, E/e’, 
LVM and image analysis will be performed by local echo lab.
8.1.2.2
Transthoracic Doppler echocardiography (TDE) with coronary flow velocity 
reserve (CFVR) measurement 
Coronary flow velocity reserve is measured in the LAD coronary artery before, and during 
constant adenosine infusion at a rate of 140 µg/kg/min for 10 minutes using conventional 
colour Doppler ultrasound equipped with coronary imaging protocol. For details see MoP. 
8.1.2.3
Carotid-femoral Pulse Wave Velocity (cfPWV) and brachial Pulse Wave 
Analysis (bPWA)
Carotid-femoral pulse wave velocity (cfPWV) is measured in a single step with a 
simultaneous measurement by femoral cuff and carotid placed tonometer. Brachial pulse wave 
analysis (bPWA) is conducted with a brachial cuff recording. For details see MoP.
                                               
1 A CINE-loop is a period of images, stored digitally as a sequence of individual frames. CINE-loops recorded at 
high frame rates may contain more frames than were displayed during the examination




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8.2.1
Clinical safety laboratory assessments
See Table 6 for the list of clinical safety laboratory tests to be performed and to the SoA for 
the timing and frequency. All protocol-required laboratory assessments, as defined in the 
tables, must be conducted in accordance with the laboratory manual and the SoA.  
The Investigator should make 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 8.3.7
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date and time of collection will be recorded on the appropriate eCRF.
The clinical chemistry, haematology and urinalysis will be performed at a central laboratory.




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Table 7
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
8.2.2
Physical examinations
A complete physical examination will be performed at enrolment (visit 1), visit 4 and at 
Follow-up (visit 8) and will include an assessment of the following: general appearance, 
respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose and 
throat), lymph nodes, thyroid, abdomen, musculoskeletal (including spine and extremities) 
and neurological systems. On the other occasions a brief physical examination (general 
appearance, skin, abdomen and musculoskeletal, cardiovascular and respiratory systems) will 
be conducted. 
Physical examination will be performed at timelines as specified in the SoA, Investigators 
should pay special attention to clinical signs related to previous serious illnesses, new or 
worsening abnormalities may qualify as adverse events, see Section 8.3.7
8.2.3
Skin Rash
Skin rash (if any) will be documented as follows: start date, severity, body surface area, 
anatomical site, symptoms, signs, effect on patient, medication administered. Photos 
(overview and detailed) should be taken. All skin rash reactions should be recorded as AEs, 
with the evaluation of severity as Grade 1, 2 or 3. Corresponding rash related eCRF page 
should be filled out as soon as possible. 
Please refer to Appendix B9 for further guidance in rash assessment and reporting.     
Upon PI discretion, clinical dermatologist can be asked for consultation, and providing patient 
with the treatment of skin rash, according to clinical management standards.
8.2.4
Vital signs
Blood pressure and pulse measurements will be assessed prior to collection of laboratory tests 
with patient in resting semi-supine position with a completely automated device. Manual 
techniques will be used only if an automated device is not available.
Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for 
the patient in a quiet setting without distractions (e.g. television, cell phones).


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Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 blood pressure measurements (3 consecutive blood pressure readings will be recorded at 
intervals of at least 1 minute). The average of the 3 blood pressure readings will be recorded 
in the eCRF.
Weight, height and body temperature will be assessed as outlined in SoA. 
8.2.5
Electrocardiograms
Single 12-lead ECG will be obtained after the patient has been resting in a supine position for 
at least 10 minutes, at the visits outlined in the SoA. A digital ECG machine that 
automatically calculates the heart rate and measures PR, QRS, QT, and QTc intervals will be 
used. Interpretation of the clinical safety digital ECG findings will be reviewed and confirmed 
by the Investigator and recorded in the eCRF. 
8.3
Collection of adverse events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
AE will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient's legally authorized representative).  
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs 
see section 8.3.3.  
8.3.1
Method of detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2
Time period and frequency for collecting AE and SAE information 
Adverse Events will be collected from the time of the first dose throughout the treatment 
period and including the follow-up period.
SAEs will be recorded from the time of signing the informed consent form.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as 
indicated in Appendix B. The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.


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Investigators are not obligated to actively seek AE or SAE in former study patients. However, 
if the investigator learns of any SAE, including a death, at any time after a patient’s last visit 
and he/she considers the event to be reasonably related to the Study treatment or study 
participation, the investigator may notify the sponsor.
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix B.
8.3.3
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow each patient 
at subsequent visits/contacts. All SAEs/non- serious AEs will be followed until resolution, 
stabilization, the event is otherwise explained, or the patient is lost to follow-up. 
Any AEs that are unresolved at the patient’s last AE assessment in the study are followed up
by the Investigator for as long as medically indicated, but without further recording in the 
eCRF. 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.
8.3.4
Adverse event data collection
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 IP (yes or no)

Action taken with regard to IP

AE caused patient’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

In case of fatality: 
o
Probable cause of death


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o
Date of death
o
Autopsy performed

Causality assessment in relation to Study procedure(s)

Causality assessment to other medication
8.3.5
Causality collection
The Investigator will assess causal relationship between IP and each Adverse Event, and
answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable possibility that 
the event may have been caused by the investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures. 
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the CSP.
8.3.6
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?’, or 
revealed by observation will be collected and recorded in the eCRF. 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.
8.3.7
Adverse events based on examinations and tests
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
Clinical Study Report (CSR). Deterioration as compared to baseline in protocol-mandated 
measurements 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).
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 unless unequivocally 
related to the disease under study.


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8.3.8
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 E for further instruction on cases of increases 
in liver biochemistry and evaluation of Hy’s Law.
8.4
Safety reporting and medical management
8.4.1
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 eCRF.
If any SAE occurs in the course of the study, then Investigators or other site personnel should 
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 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day i.e., immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AstraZeneca representative.
If the WBDC system is not available, then the Investigator or other study site staff reports a 
SAE to the appropriate AstraZeneca representative by fax (+46 31 776 37 34) or E-mail
(AEMailboxWBDCTCS@astrazeneca.com).
The AstraZeneca representative will advise the Investigator/study site staff how to proceed.  
Investigators or other site personnel send relevant eCRF modules by fax to the designated 
AstraZeneca representative.
For further guidance on the definition of a SAE, see Appendix B of the CSP. 


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8.4.2
Pregnancy
Women of child-bearing potential are not permitted to participate in this study. Male study 
patients with female partners of child-bearing potential must adhere to the reproductive 
restrictions provided in Section 5.4.4. 
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for if 
the female partner of a male study participant discovers she is pregnant before the study 
patient has received any study drug.
If a pregnancy is reported, the Investigator should inform the sponsor within 24 hours of 
learning of the pregnancy.
8.4.2.1
Maternal exposure
Women of childbearing potential are not permitted to participate in this study (see inclusion 
criteria for definition of women not of child-bearing potential). Should a pregnancy still occur, 
the investigational product should be discontinued immediately and the pregnancy reported to 
AstraZeneca.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital abnormalities/birth defects and spontaneous 
miscarriages should be reported and handled as SAEs. Elective abortions without 
complications should not be handled as AEs. The outcome of all pregnancies (spontaneous 
miscarriage, elective 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, 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.4.2.2
Paternal exposure 
See section 5.4.4


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8.4.2.3
Overdose
For this study, any dose of AZD4831 greater than specified in the CSP will be considered an 
overdose. There is no recommended specific treatment for an overdose.

An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module

An overdose without associated symptoms is only reported on the Overdose eCRF 
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 
8.4.1.  For other overdoses, reporting must occur within 30 days.
8.4.3
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 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.2) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B8.
8.5
Pharmacokinetics
Blood samples of approximately 2 mL will be collected for measurement for plasma 
concentrations of AZD4831 as specified in the SoA. Samples will be collected, handled, 
labelled, stored and shipped as detailed in the Laboratory Manual. Samples may be collected 
at additional time points during the study if warranted and agreed upon between the 
Investigator and the sponsor. Instructions for the collection and handling of biological samples 
will be provided by the sponsor or analytical test site. Diary Cards will be given to the patients 
at the randomization visit and the patients will be asked to fill in the dose intake information 
(date and time) at home. 


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If data permits, a population PK model will be developed, possibly with support of PK data 
from previous studies with AZD4831, using non-linear mixed effect regression analysis in 
NONMEM. All PK, and PK/PD, modelling work will be described in a separate data analysis 
plan. Moreover, the results of such modelling will be provided in a separate population PK, or 
PK/PD, report (as an appendix to the CSR or as a stand-alone report). 
Drug concentration information that would unblind the study will not be reported to 
investigative sites or blinded personnel until the study has been unblinded. 
Any changes in the timing or addition of time points for any planned study assessments must 
be documented and approved by the relevant study team member and then archived in the 
sponsor and site study files, but will not constitute a protocol amendment. The IRB/IEC will 
be informed of any safety issues that require alteration of the safety monitoring scheme or 
amendment of the ICF.
8.5.1
Determination of drug concentration
Samples for determination of drug concentration will be analysed by Covance on behalf of 
AstraZeneca, using an appropriate bioanalytical method. Full details of the analytical method 
used will be described in a separate bioanalytical report.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a bioanalytical report. PK concentrations may be assessed during the study for 
evaluation of the exposure levels.
Placebo samples will not be analysed unless there is a need to confirm that correct treatment 
has been given to study patients.
8.5.2
Storage and destruction of pharmacokinetic samples
Pharmacokinetic (PK) samples will be disposed of after the Bioanalytical Report finalization 
or six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
requested for future analyses.  
Pharmacokinetic samples may be disposed of or destroyed and anonymised by pooling. 
Additional analyses may be conducted on the anonymised, pooled pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.


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8.7
Genetics
8.7.1
Optional exploratory genetic sample
Approximately 6mL blood sample for DNA isolation will be collected from patients who have 
consented to participate in the genetic analysis component of the study.  Participation is 
optional.  Patients who do not wish to participate in the genetic research may still participate 
in the study.
In the event of DNA extraction failure, a replacement genetic blood sample may be requested 
from the patient.  Signed informed consent will be required to obtain a replacement sample 
unless it was included in the original consent.
See Appendix D for Information regarding genetic research.  Details on processes for 
collection and shipment and destruction of these samples can be found in the Laboratory 
Manual.
8.7.2
Storage and destruction of genetic samples
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality. Samples may be stored for a maximum of 15 
years or as per local regulations from the date of the Last Patient’s Last Visit, after which they 
will be destroyed. DNA is a finite resource that may be used up during analyses. The results of 
any further analyses will be reported either in the CSR itself or as an addendum, or separately 
in a scientific report or publication.
No personal details identifying the individual will be available to AstraZeneca or designated 
organizations working with the DNA.
8.8
Exploratory Biomarkers
Mandatory collection of samples for endogenous MPO activity and other exploratory 
biomarker research is also part of this study. Plasma/serum/urine samples for exploratory 
analysis of biomarkers that may be related to PK, metabolites, PD, efficacy, response to 
treatment or safety and tolerability of AZD4831 or related to HFpEF will be collected from all 
patients in this study as specified in the SoA.
Samples will be collected, labelled, stored and shipped according to the details outlined in the 
laboratory manual.
8.8.1
Storage, re-use and destruction of biomarker 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 


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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.
8.9
Patient Reported Outcome Questionnaires
8.9.1
The Kansas City Cardiomyopathy Questionnaire (KCCQ)
The KCCQ is a psychometrically validated questionnaire developed for patients with 
congestive heart failure (Green et al 2000). It is a 23-item, self-administered health status 
measure that quantifies physical limitations, symptoms, social interference, self-efficacy and 
quality of life. Results for each domain are summarised and transformed to a score of 0 to 
100; higher scores indicate better health status. To summarise the multiple domains of health 
status quantified by KCCQ, an overall summary score (KCCQ-os) has been developed that 
includes the physical limitation, symptoms, quality of life and social interference domains of 
KCCQ. The KCCQ English US Master version is enclosed in Appendix G
KCCQ will be answered by patients on paper at visits as outlined in SoA, Table 1 and 
recorded in the eCRF by site staff. 
8.10
Health Economics 
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9
STATISTICAL CONSIDERATIONS 
9.1
Statistical hypotheses
Statistical hypotheses are described in section 9.4 and further details will be provided in the 
Statistical Analysis Plan (SAP).
9.2
Sample size determination 
The study has been powered to show a statistically significant result for the primary endpoint, 
and first secondary endpoint. To preserve the overall type1-error at 5% when testing these two 
endpoints a closed test procedure will be used where the first secondary endpoint will be 
tested only if the primary endpoint is significant. That is, the primary endpoint will be tested 
at 5% significant level and if the test is positive the first secondary endpoint will also be tested 
on a significant level of 5%. If the primary objective is not significant the first secondary 
objective will also be declared non-significant.
In addition, to get information about incidence rate of Generalised Maculopapular Rash Grade 
3 in the AZD4831 arm a randomisation allocation ratio of 2:1 (active versus placebo) will be 
used. With approximately 96 randomized patients, this will give at most 64 patients on active 
drug for rash evaluation and about 53 patients on AZD4831 versus 27 patients on placebo for 


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evaluation of the first primary endpoint and the first secondary endpoint. It has been deemed 
that about 64 patients provide sufficient information about the incidence rate of rash when 
treated with AZD4831.
A relative change in TE biomarker to end of treatment comparing AZD4831 to placebo is 
assumed to be log-normal distributed with a CV of 60% (based on data from the MAD study). 
An expected reduction of 15% from baseline to end of treatment in TE biomarker in placebo, 
and an expected reduction of 50% from baseline to end of treatment in TE biomarker in 
AZD4831 are assumed (based on data from the MAD study, Baldus et al 2006). A foldchange 
of at least 1.7 in TE biomarker comparing AZD4831 to placebo will give more than 95% 
power for a two-sided test on a 5% significant level with 53 patients on AZD4831 versus 27 
patients on placebo, accounting for patient drop out. If the dose level is adjusted after the 
interim analysis the power will still be at least 90% for testing the primary endpoint 
hypothesis with the assumption of 25 patients on AZD4831 and 25 patients on placebo. 
Assuming a log-normal distribution of the CFVR and an expected 20% increase in CFVR in 
the AZD4831 group compared to placebo with a coefficient of variation (CV) of 30%, 53 
versus 27 patients in the treatment group and placebo respectively is required to achieve 80% 
power with a one-sided confidence interval of 95%.
9.3
Populations for analyses
9.3.1
Full analysis set
All patients who have been randomized to investigational product (IP) will be included in the 
full analysis set irrespective of their protocol adherence and continued participation in the 
study. Patients will be analysed according to their randomized IP irrespective of whether or 
not they have prematurely discontinued. Patients who withdraw consent to participate in the 
study are included up to the date of their study termination.
9.3.2
Safety analysis set
All patients who received at least 1 dose of randomized AZD4831 or placebo, will be included 
in the safety analysis set. Throughout the safety results sections, erroneously treated patients 
(e.g. those randomized to AZD4831 but actually given placebo) will be accounted for in the 
actual treatment group.
9.3.3
PK analysis set
The PK analysis set will consist of all patients in the full analysis set who has received at least 
one dose of AZD4831, and who has at least one PK sample post dose.


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9.4
Statistical analyses
This section provides a summary of the planned statistical analyses. Further details will be 
provided in a SAP. All study personnel involved with the analysis of the study will remain 
blinded until database lock and Clinical Study Protocol deviations identified. The only 
exception are study independent personnel who are involved in the interim analyses.  
Analyses will be performed by AstraZeneca or its representatives. A comprehensive SAP will 
be developed and finalised before database lock and will describe the patient populations to be 
included in the analyses, and procedures for accounting for missing, unused, and spurious 
data. This section is a summary of the planned statistical analyses of the primary and 
secondary endpoints. Any deviations from this plan will be reported in the CSR.
All efficacy and safety variables will be summarised by treatment groups using descriptive 
statistics (n, mean, geometric mean, standard deviation [SD], median, minimum, maximum, 
and coefficient of variation [CV] where applicable for continuous data and absolute and 
relative frequencies for categorical data). Data will be summarised for baseline, endpoint and 
by visit (if applicable). P-values will be unadjusted and tests will be two-sided. For the 
primary efficacy variable TE biomarker a two-sided test will be used and first secondary 
efficacy variable CFVR a one-sided test will be used. A closed test procedure will be applied 
to control the overall type 1-error rate due to multiplicity for the primary endpoint and the first 
secondary endpoint. All tests, unless otherwise stated, will be performed between the 
AZD4831 group versus placebo. The analyses will be done separately for each dose level if 
the dose has been changed at the interim analysis. 
Results from data that have been transformed, e.g. log-transformed, during the analysis will be 
back transformed to original scale. 
Descriptive statistics will be presented to assess the distribution of the baseline variables 
across treatment groups.
The analysis and presentation of efficacy variables, exploratory variables and exploratory 
biomarkers will be based on patients in the full analysis set. All efficacy variables will be 
summarised descriptively displaying parameter values at visits where they were measured. 
The analysis and presentation of safety variables will be based on patients in the safety 
analysis set.
Baseline measurement is defined as last measurement obtained before or at the randomization 
visit if nothing else is specified.
Change from baseline is defined as change from baseline to end of treatment if nothing else is 
specified.


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9.4.1
Efficacy analyses
The primary efficacy variable TE biomarker and first secondary efficacy variable CFVR are 
measured as percent change from baseline to end of treatment comparing AZD4831 to 
placebo.
The primary efficacy variable TE biomarker will test the null hypothesis of equality in TE 
biomarker comparing AZD4831 to placebo versus the alternative hypothesis of non-equality 
comparing AZD4831 to placebo at 5% two-sided significance level.
The first secondary efficacy variable CFVR will test the null hypothesis of no increase in 
CFVR comparing AZD4831 to placebo versus the alternative hypothesis of an increase in 
CFVR in favour of AZD4831 compared to placebo at 5% one-sided significance level.
Change from baseline for the primary and first secondary efficacy variables will be analysed 
using an ANCOVA model. The result will be presented as point estimate with 95% 
confidence intervals together with p-values.
All other secondary variables measuring change from baseline will be analysed using an 
ANCOVA model. If the distribution of the variable of interest can be better approximated by a 
log-normal distribution than with a normal distribution, a logarithmic transformation of the 
variable of interest will be done.
9.4.2
Safety analyses
AEs will be summarised by treatment group by means of counts summaries by Medical 
Dictionary for Regulatory Activities (MedDRA) System Organ Class and Preferred Term 
(PT). All AEs will be listed and assigned to treatment period as:
•
Baseline period: The time before first administration of IP.
•
On treatment: The time from first administration of IP until 14 days after last dose of IP.
•
Off treatment: More than 14 days after last dose of IP. 
AEs will be assigned to the period where they start. 
Clinical laboratory, physical examination and vital signs measurements will be summarized 
by treatment group.
Laboratory data for haematology and clinical chemistry will be summarized by treatment 
group. The frequency of changes with respect to normal ranges between baseline and end of
treatment will be tabulated. Shifts from normal to abnormal between baseline and end of 
treatment time point will be evaluated for urinalysis. The incidence of markedly abnormal 
values and changes from baseline in the ECG parameters will be summarised by treatment 


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group. Categorical outliers may be presented by numbers but need to be considered in context 
of inclusion/exclusion criteria. Vital signs variables will be summarised by treatment group.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator.
The patients who discontinue due to generalised maculopapular rash grade 3 will be presented 
as point estimate of incidence rate by treatment group together with 95% confidence interval.   
Other safety variables will be summarised as appropriate. Further details will be provided in 
the SAP.
9.4.3
Exploratory analysis
All exploratory variables and exploratory biomarkers measuring change from baseline will be 
analysed using an ANCOVA model.
Patients with elevated MPO-pathway biomarkers will be identified and for all secondary 
variables and exploratory variables change from baseline will be analysed using an ANCOVA 
model.
9.4.4
Other analyses 
If data permits, a population PK model will be developed, possibly with the support of PK 
data from earlier AZD4831 studies, using nonlinear mixed effects regression analysis in 
NONMEM. Furthermore, if data allows, the population PK model may be coupled with 
separate PD models for spike normalised ex vivo zymosan stimulated specific MPO activity 
and for CFVR.
All PK and PK/PD modelling will be described in a separate data analysis plan. Moreover, the 
results of any such modelling will be provided in a separate population PK/PD report (as an 
appendix to the CSR or as a stand-alone report).
9.5
Interim analyses 
An interim analysis will be performed after 37 patients, 25 on AZD4831 and 12 on placebo, 
have been treated for approximately 30 days in Part A. The interim analysis will be used for 
selecting dose for Part B or to stop the study. The decision on dose adjustment or whether to 
stop the study will be based on the level of TE biomarker and the number of patients 
discontinued due to generalised maculopapular rash grade 3. Only patients treated with 
AZD4831 will be included in the analysis. The possible outcomes of the interim analysis are 
continuing with 
 decrease the dose to 
, increase the dose to 
 or stop the 
study. The interim analysis will be performed by study independent personnel. The Interim 
Analysis Plan will describe the planned interim analyses in detail. 


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9.6
Safety Review Committee
A blinded Safety Review Committee (SRC) consisting of internal AstraZeneca (AZ) expertise 
will review safety data related to rash on an ongoing basis throughout the study and give input 
and recommendations to a Data Review Committee (DRC). For more information refer to 
SRC/DRC charter. 
9.7
Data Review Committee
The number of patients who discontinue the study due to generalised maculopapular rash 
CTCAE grade 3 or higher will be continuously monitored by a Data Review Committee 
(DRC) and the study will be stopped if at any time the proportion of discontinued patients on 
AZD4831 is above a prespecified level. The DRC consists of internal AZ expertise. 
The statistical monitoring will be described in the SRC/DRC charter that must be finalised 
before first patient in.


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10
REFERENCES
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’
Baldus et al 2006
Baldus S, Rudolph V, Roiss M, Ito WD, Rudolph TK, Eiserich JP, Sydow K, Lau D, Szocs K, 
Klinke A, Kubala L, Berglund L, Schrepfer S, Deuse T, Haddad M, Risius T, Klemm H, 
Reichenspurner HC, Meinertz T, Heitzer T. Heparins increase endothelial nitric oxide 
bioavailability by liberating vessel-immobilized myeloperoxidase. Circulation. 
2006;113:1871-1878
Baldus et al 2003
Baldus S, Heeschen C, Meinertz T, Zeiher AM, Eiserich JP, Munzel T et al. Myeloperoxidase 
Serum Levels Predict Risk in Patients With Acute Coronary Syndromes. 
Circulation 2003;108(12):1440-5. 
Brennan et al 2003
Brennan ML, Penn MS, Van Lente F, Nambi V, Shishehbor MH, Aviles RJ et al. Prognostic 
Value of Myeloperoxidase in Patients with Chest Pain. 
N Engl J Med 2003;349(17):1595-604
Butler at al 2014
Developing therapies for heart failure with preserved ejection fraction:
current state and future directions. JACC Heart Fail. 2014 Apr;2(2):97-112
Gan et al 2013
Rudolph TK, Wipper S, Reiter B, Rudolph V, Coym A, Detter C et al. Myeloperoxidase 
deficiency preserves vasomotorfunction in humans. European Heart Journal 2012 
33,16251634
Green et al 2000
C.Patrick Green MD, Charles B.PorterMD, FACC, Dennis R.BresnahanMD, FACC, John 
A.Spertus MD, MPH, FACC. Development and evaluation of the Kansas City 
Cardiomyopathy Questionnaire: a new health status measure for heart failure
Go et al 2014
Heart Disease and Stroke Statistics--2014 Update: A Report From the American Heart 
Association 2014 129(3):e28-e292


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Kannan et al. 2018
Kannan L., Shaw P.A., Morley M.P., Brandimarto J, Fang J.C., Sweitzer N.K., Cappola T.P., 
Cappola A.R. Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circ Heart 
Fail. 2018;11:e005266. 
McMurray et al. 2012 
ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The 
Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the 
European Society of Cardiology. Developed in collaboration with the Heart Failure 
Association (HFA) of the ESC. Eur Heart J. 2012 Jul;33(14):1787-847
Mohammed et al. 2015
Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM. 
Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved 
ejection fraction. Circulation. 2015;131:550-9
Mäkelä R et al. 2004
Myeloperoxidase gene variation and coronary flow reserve in young healthy men. Journal of 
Biomedical Science January 2004, Volume 11, Issue 1, pp 59–64
Nicholls and Hazen 2005
Nicholls S and Hazen S. Myeloperoxidase and Cardiovascular Disease. 
Arterioscler Thromb Vasc Biol 2005;25(6):1102-11. 
Paulus et al. 2013
Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: 
comorbidities drive myocardial dysfunction and remodeling through coronary microvascular 
endothelial inflammation. JACC 2013;62(4):263-
Rudolph V et al 2010
Rudolph V, Andrie RP, Rudolph TK, Friedrichs K, Klinke A, Hirsch-Hoffmann B et al. 
Myeloperoxidase acts as a profibrotic mediator ofatrial fibrillation. Nature Medicine 
2010;16(4):470-4
Rudolph et al 2012
Rudolph TK, Wipper S, Reiter B, Rudolph V, Coym A, Detter C et al. Myeloperoxidase 
deficiency preserves vasomotor function in humans. Eur Heart J 2012;33(13):1625-34.
Shah SJ et al 2018
Shah SJ, Lam CSP, Svedlund S, Saraste A, Hage C, Tan RS, Beussink-Nelson L, Fermer ML, Broberg 
MA, Gan LM, Lund LH. Prevalence and correlates of coronary microvascular dysfunction in heart 
failure with preserved ejection fraction: PROMIS-HFpEF. Eur Heart J. 2018 Aug 27.


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Tang WH et al 2006
Plasma myeloperoxidase levels in patients with chronic heart failure. Am J Cardiol. 2006 Sep 
15;98(6):796-9. Epub 2006 Jul 28
Tang et al 2007
Tang WH, Tong W, Troughton RW, Martin MG, Shrestha K, Borowski A et al. Prognostic 
Value and Echocardiographic Determinants of Plasma Myeloperoxidase Levels in Chronic 
Heart Failure. J Am Coll Cardiol 2007;49(24):2364-70. 
Zhang R et al 2001
Zhang R, Brennan ML, Fu X, Avilies RJ, Pearce GI, Penn MS et al. Association Between 
Myeloperoxidase Levels and Risk of Coronary Artery Disease. JAMA 2001;286(17):2136-42. 


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11
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONSREGULATORY, ETHICAL AND STUDY 
OVERSIGHT CONSIDERATIONS
A 1
Regulatory and ethical considerations
This study will be conducted in accordance with the CSP and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines

Applicable ICH Good Clinical Practice (GCP) Guidelines

Applicable laws and regulations
The CSP, protocol amendments, ICF, Investigator Brochure, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.  
Any amendments to the protocol will require IRB/IEC approval before implementation of
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study patients.  
The investigator will be responsible for the following:

Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC

Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures

Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations
The study will be performed in accordance with the AstraZeneca policy on Bioethics and 
Human Biological Samples.
A 2
Financial disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities.  Investigators 


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are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed consent process
The investigator or his/her representative will explain the nature of the study to the patient or 
his/her legally authorised representative and answer all questions regarding the study.  
Patients must be informed that their participation is voluntary.  Patients or their legally 
authorised representative will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
centre.  
The medical record must include a statement that written informed consent was obtained 
before the patient was enrolled in the study and the date and time the written consent was 
obtained.  The authorised person obtaining the informed consent must also sign the ICF.
Patients must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
A copy of the ICF(s) must be provided to the patient or the patient’s legally authorised 
representative.  
If a patient declines to participate in any voluntary exploratory genetic research component of 
the study, there will be no penalty or loss of benefit to the patient and he/she will not be 
excluded from other aspects of the study.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened one time after 1 month if they fulfil the inclusion/exclusion criteria then. The 
patient should sign a new informed consent if rescreened. 
The ICF will contain a separate section that addresses the use of remaining mandatory 
samples for optional exploratory research.  The investigator or authorised designee will 
explain to each patient the objectives of the further genetic and exploratory research.  Patients 
will be told that they are free to refuse to participate and may withdraw their consent at any 
time and for any reason during the storage period.  The patient will give separate agreements 
to allow any remaining specimens to be used for exploratory research.  Patients who decline to 
participate in this optional research will indicate this in the ICF.  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 already have been analysed at the time of the request,
AstraZeneca will not be obliged to destroy the results of this research. The response to these 
separate agreements will be recorded in the eCRF.


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A 4
Data protection
Each patient will be assigned a unique identifier by the sponsor.  Any patient records or data 
sets transferred to the sponsor will contain only the identifier; patient names or any 
information which would make the patient identifiable will not be transferred.  
The patient must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law.  The level of disclosure must also be 
explained to the patient.  
The patient must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorised personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees structure
SRC and DRC is described in separate SRC/DRC charter. 
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca representatives in consultation with Patient Safety.  Issues identified will be 
addressed; for instance, this could involve amendments to the CSP and letters to Investigators.
A 6
Dissemination of clinical study data
A description of this clinical trial will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study main results when they are 
available. The clinical trial and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the study is conducted.
A 7
Data quality assurance
All patient data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data).  The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF.  
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  


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The sponsor or designee is responsible for the data management of this study including quality 
checking of the data.  
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorised site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of patients are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator for 15 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during 
the retention period without the written approval of the sponsor.  No records may be 
transferred to another location or party without written notification to the sponsor. 
A 8
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected.  Source documents are filed at the investigator’s site.
Data reported on the CRF that are transcribed from source documents must be consistent with 
the source documents or the discrepancies must be explained.  The investigator may need to 
request previous medical records or transfer records, depending on the study.  Also, current 
medical records must be available.
Definitions of what constitutes source data can be found in source data verification plan.
A 9
Publication policy
The results of this study may be published or presented at scientific meetings.  If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor before 
submission.  This allows the sponsor to protect proprietary information and to provide 
comments.  
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicentre studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements.


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Appendix B
Adverse event definitions and additional safety information
B 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.
B 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

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 
treatment to prevent one of the outcomes listed above.
B 3
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).
B 4
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.
B 5
Important medical event or medical treatment


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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 treatment 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
B 6
Intensity rating scale:
1
mild (awareness of sign or symptom, but easily tolerated)
2
moderate (discomfort sufficient to cause interference with normal activities)
3
severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 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 Appendix B 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 Appendix B 2.
B 7
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.

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 


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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.
B 8
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 participant 
or has the potential to cause harm to the participant.  
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 participant.
Medication error includes situations where an error.  

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognize that could have led to an error


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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 participant

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 participant received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to participant (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of the 
above listed events that would otherwise have been a medication error 

Participant accidentally missed drug dose(s) e.g.  forgot to take medication

Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
B 9
Guide to skin rash severity assessment
This Appendix describes the process to be followed to appropriately identify, assess and 
report cases of skin rash. All skin rash reactions should be recorded and reported as AEs, with 
the evaluation of severity as Grade 1, 2 or 3.
If maculopapular rash Grade 1 or Grade 2 has developed, the decision to continue treatment 
will be done by investigator in discussion with patient and AstraZeneca medical staff. 
If maculopapular rash Grade 3 has developed, patient must be discontinued from IP, and 
AstraZeneca medical staff should be informed. Investigator should make quality photo(s) of 
patient’s skin affected with rash, that will allow the evaluation of rash according to the 
guidance given in this section. These photo(s) should be also provided to the Astra Zeneca 
Safety Committee.


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The Common Terminology Criteria for AEs is a descriptive terminology used for Adverse 
Event (AE) reporting. A grading (severity) scale is provided for each AE term. 
In general, CTCAE Guideline describes the Grades of AE severity from 1 to 5: 
Grade 1:  
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only;
intervention not indicated 
Grade 2:  
Moderate; minimal, local or noninvasive intervention indicated; limiting
age-appropriate instrumental ADL* 
Grade 3:  
Severe or medically significant, but Not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL** 
Grade 4:  
Life-threatening consequences; urgent intervention indicated
Grade 5: 
Death related to AE
*Instrumental Activities of Daily Living (ADL) refer to preparing meals, shopping for
groceries or clothes, using the telephone, managing money, etc. 
**Self-care Activities of Daily Living (ADL) refer to bathing, dressing and undressing,
feeding self, using the toilet, taking medications, and not bedridden.
NB! : for Maculo-Papular rash, only 3 CTC Grades exist:
Maculo-Papular Rash
Definition: A disorder characterized by the presence of macules (flat) and papules (elevated). 
Also known as morbilliform rash, it is one of the most common cutaneous adverse events, 
frequently affecting the upper trunk, spreading centripetally and associated with pruritis.
Grade 1
Macules/papules covering < 10% Body Surface Area with or without symptoms 
(e.g., pruritus, burning, tightness)
Grade 2
Macules/papules covering 10 - 30% Body Surface Area, with or without 
symptoms (e.g., pruritus, burning, tightness); limiting Instrumental Activities of 
Daily Living*; rash covering > 30% Body Surface Area with or without mild 
symptoms
Grade 3
Macules/papules covering > 30% Body Surface Area, with moderate or severe 
symptoms; limiting Self-care Activities of Daily Living **
Ref. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. 
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Publish Date  November 27, 2017. 


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To assess the Body Surface Area (BSA) affected by rash, please follow the algorithm 
described below:
Area
Number of palms
Percent area
Whole body
100
100%
Head and Neck
10
10%
Upper extremities
20
20%
Trunk
30
30%
Lower extremities
40
40%
The patient’s palm is defined as ”1”, representing 1% of total Body Surface Area (BSA). 
Total BSA = 100% (100 palms). 


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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The 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).
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 will keep oversight of the entire life cycle through internal procedures, 
monitoring of study sites, auditing or process checks, and contractual requirements of external 
laboratory providers
Samples retained for further use will be stored in the AZ-assigned biobanks and will be 
registered by the AstraZeneca Biobank Team during the entire life cycle.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed,
AstraZeneca is not obliged to destroy the results of this research.
As collection of the biological sample(s) is an integral part of the study, then the patient is 
withdrawn from further study participation.
The 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.


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C 3
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 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm). For 
transport purposes the classification of infectious substances according to risk groups was 
removed from the Dangerous Goods Regulations 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 eg, 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 eg, Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus 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 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.htm)

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 D
Genetics
D 1
Use/analysis of DNA
Genetic variation may impact a patient’s response to therapy, susceptibility to, and severity 
and progression of disease.  Variable response to therapy may be due to genetic determinants 
that impact drug absorption, distribution, metabolism, and excretion; mechanism of action of 
the drug; disease aetiology; and/or molecular subtype of the disease being treated.  Therefore, 
where local regulations and IRB/IEC allow, a blood sample will be collected for DNA 
analysis from consenting patients.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications.  Genetic research may lead to better understanding of diseases, better diagnosis 
of diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.  
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the patient´s DNA, i.e. the 
entire genome. 
The results of genetic analyses may be reported in the clinical study report (CSR) or in a 
separate study summary.
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality.
The samples will be retained while research on AZD4831 or other AstraZeneca Study 
treatments of this class or for this indication continues but no longer than 15 years or other 
period as per local requirements.
D 2
Genetic research plan and procedures
Selection of genetic research population
Study selection record
All patients will be asked to participate in this genetic research.  Participation is voluntary and 
if a patient declines to participate there will be no penalty or loss of benefit.  The patient will 
not be excluded from any aspect of the main study.


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Inclusion criteria
For inclusion in this genetic research, patients must fulfil all of the inclusion criteria described 
in the main body of the CSP and: Provide informed consent for the genetic sampling and 
analyses.
Exclusion criteria
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection
Withdrawal of consent for genetic research:  
Patients may withdraw from this genetic research at any time, independent of any decision 
concerning participation in other aspects of the main study.  Voluntary withdrawal will not 
prejudice further treatment.  Procedures for withdrawal are outlined in Section 7 of the main 
Clinical Study Protocol.
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the patients at Visit 2 
randomization.  Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding patients who may withdraw due to an adverse event (AE), 
such patients would be important to include in any genetic analysis.  If for any reason the 
sample is not drawn at Visit 2, it may be taken at any visit until the last study visit.  Only one 
sample should be collected per patient for genetics during the study.  Samples will be 
collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Coding and storage of DNA samples
The process adopted for the single coding and storage of samples for genetic analysis are 
important to maintain patient confidentiality.  Samples will be stored for a maximum of 15
years, from the date of last patient last visit, after which they will be destroyed.  DNA is a 
finite resource that is used up during analyses.  Samples will be stored and used until no 
further analyses are possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable only by the second, unique number.  This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation.  No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).


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The link between the patient enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations.  The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A
Informed consent
The genetic component of this study is optional and the patient may participate in other 
components of the main study without participating in the genetic component.  To participate 
in the genetic component of the study the patient must sign and date both the consent form for 
the main study and the genetic component of the study.  Copies of both signed and dated 
consent forms must be given to the patient and the original filed at the study centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
patient understands that they may freely withdrawal from the genetic aspect of the study at 
any time.
Patient data protection
AstraZeneca will not provide individual genotype results to patients, any insurance company, 
any employer, their family members, general physician unless required to do so by law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient.  In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a patient.  For example, in the case of 
a medical emergency, an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her genetic data.  In addition, Regulatory authorities 
may require access to the relevant files, though the patient’s medical information and the 
genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies.  This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease.  The researchers can 
only use this information for health related research purposes.  Researchers may see summary 
results but they will not be able to see individual patient data or any personal identifiers.  


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Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database.
Statistical methods and determination of sample size
The number of patients that will agree to participate in the genetic research is unknown.  It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated.  A Statistical 
Analysis Plan may be prepared where appropriate.


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Appendix E
Actions required in cases of increases in liver biochemistry 
and evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases.  It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries.
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry.  The Investigator is responsible for determining whether a subject meets 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory.  
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than Drug Induced Liver Injury (DILI) caused by the Investigational Medicinal Product 
(IMP).
The Investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting Serious Adverse Events (SAE) and Adverse Events (AE) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 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.
E 3
Identification of potential Hy’s Law cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any subject who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
When a subject meets any of the PHL identification criteria, in isolation or in combination, the 
central laboratory will immediately send an alert to the Investigator (also sent to AstraZeneca 
representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will::

Notify the AstraZeneca representative

Request a repeat of the test (new blood draw) by the central laboratory without delay

Complete the appropriate unscheduled laboratory CRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the Investigator 
will without delay:

Determine whether the subject meets PHL criteria (see Section 2 within this Appendix for 
definition) by reviewing laboratory reports from all previous visits (including both central 
and local laboratory results)
E 4
Follow-up
E 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.


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E 4.2
Potential Hy’s Law criteria met
If the subject does meet PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to CSP process for SAE reporting.

For subjects that met PHL criteria prior to starting IMP, the investigator is not required to 
submit a PHL SAE unless there is a significant change in the subject’s condition.

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data.

Subsequent to this contact the Investigator will:

Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically indicated. 
Complete follow-up SAE Form as required. 

Investigate the aetiology of the event and perform diagnostic investigations as discussed 
with the Study Physician. 

Complete the three Liver CRF Modules as information becomes available 
E 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


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
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the AZ standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  

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 days in obtaining the information necessary to 
assess whether or not the case meets the criteria for HL, then it is assumed that there is no 
alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.  
References
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’


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Appendix F
Medical device incidents: definition and procedures for 
recording, evaluating, follow-up, and reporting – Not 
Applicable


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Appendix G
The Kansas City Cardiomyopathy Questionnaire (KCCQ)


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Appendix H
Abbreviations 
Abbreviation or special 
term
Explanation
6MWT
6 Minutes Walking Test
AE
adverse event
ACS
Acute Coronary Syndrome
ALT
Alanine transaminase
AST
Aspartate aminotransferase
AV
Atrioventricular
AZ
AstraZeneca
BMI
Body Mass Index
BP
Blood Pressure
bpm
Beats/minute
CAD
Coronary Artery Disease
CFVR
Coronary Flow Velocity Reserve
cGMP
Cyclic Guanosine Monophosphate
CKD-EPI
Creatinine clearance by Chronic Kidney Disease Epidemiology Collaboration 
COPD
Chronic Obstructive Pulmonary Disease
CSP
Clinical study protocol
CSA
Clinical Study Agreement
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Event
CYP3A4
Cytochrome P450 SA4
DNA
Deoxyribonucleic acid 
DRC
Data Review Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EF
Ejection Fraction
eGFR
Estimated Glomerular filtration rate
EndoPAT
A method for Endothelial function measurement
ESC
European Society of Cardiology
FFR
Fractional Flow Reserve
FMD
Flow Mediated Dilatation
GCP
Good Clinical Practice
GI
Gastrointestinal
GLS
Global longitudinal strain


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Abbreviation or special 
term
Explanation
HF
Heart Failure
HFmrEF
Heart Failure with mid-range Ejection Fraction
HFpEF
Heart Failure with preserved Ejection Fraction
HIPAA
Health Insurance Portability and Accountability Act
HL
Hy´s Law
ICH
International Conference on Harmonisation
IUD
Intrauterine device
IUS
Intruuterine hormone-releasing system
IP
Investigational Product
IRB/IEC
Institutional review board (IRB) and independent ethics committee (IEC)
IxRS
Intractive voice/web response system
KCCQ
The Kansas City Cardiomyopathy Questionnaire
LAD
Left anterior descending
LAVI
Left atrium volume index
LVEF
Left ventricle Ejection Fraction
LVH
Left ventricular hypertrophy
LVM
Left ventricular mass
MAD
Multiple Ascending Dose
MoP
Manual of Procedures
MPO
Myeloperoxidase
NB
Nota Bene
NO
Nitric Oxide
NYHA
New York Heart Association
o.d
Omni Die (latin that refers to dosing once daily)
OAE
other significant adverse event
PCI
Percutaneous Coronary Intervention
PCWP
Pulmonary Capillary Wedge Pressure
PHL
Potential Hy´s Law
PI
Principal Investigator 
PK
Pharmacokinetics
PWA
Pulse Wave Analysis
PWV
Pulse Wave Velocity
QoL
Quality of Life
RHI
Reactive hyperemic index
SAD
Single Ascending Dose


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Abbreviation or special 
term
Explanation
SAE
Serious Adverse Event 
SAP
Statistical Analysis Plan
SmPC
Summary of product characteristics
SoA
Schedule of Activities
SoC
Standard of Care
SRC
Safety Review Committee
TBL
Total Bilirubin
TC
Telephone Contact
TDE
Transthoracic Doppler Echocardiography
TE
Target Engagement 
TSH
Thyroid Stimulating Hormone
ULN
Upper Limit of Normal
WBDC
Web Based Data Capture


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d6580c00003-csp-v4
Document Title:
D6580C00003 Clinical Study Protocol version 4
Document ID:
Doc ID-003862640
Version Label:
4.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
13-Jan-2020 18:42 UTC
Management Approval
13-Jan-2020 08:50 UTC
Content Approval
12-Jan-2020 14:38 UTC
Author Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.

SAP_001.pdf: