A Phase IIB, Randomized, Double Blinded, Placebo Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants With a Prior Myocardial Infarction and Persistent Inflammation
Phase: PHASE2
Conditions: Coronary Heart Disease (CHD)
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
MEDI6570
Study Code
D4920C00002
Amendment Number
2
Date
09 November 2021
A Phase IIB, Randomized, Double-blinded, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of 
MEDI6570 in Participants with a Prior Myocardial Infarction, 
Persistent Inflammation, and Elevated N-terminal Prohormone 
Brain Natriuretic Peptide
Sponsor Names: 
Global Sponsor: AstraZeneca, AB, 151 85 Södertälje, Sweden
Local Sponsor: AstraZeneca, KK, 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Numbers: IND 139103; EudraCT 2020-000840-75
This 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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Protocol Number: D4920C00002
Amendment Number: 2
Study Intervention: MEDI6570
Study Phase: IIB
Short Title: A Phase IIB Parallel-group Study to Evaluate the Efficacy and Safety of 
MEDI6570 in Participants with a Prior Myocardial Infarction 
Acronym: GOLDILOX-TIMI 69 MitiGating Ox-LDL induced coronary Inflammation, 
Atheroma and Heart Failure via LOX-1 receptor inhibition — Thrombolysis in Myocardial 
Infarction 69
Medical Monitor name and contact information will be provided separately.
TERMS AND CONVENTIONS USED IN THIS DOCUMENT
The list of abbreviations is given in Appendix H.
In addition, the following terms are used interchangeably in this document:

‘Intervention’ and ‘treatment’
‘Intervention’ is used generically in clinical studies to describe the intervention under 
evaluation (eg, medical device, pharmaceutical product, physical or behavioral 
adjustment etc). ‘Intervention’ is used in most sections of this document for MEDI6570 
or its injection/volume-matched placebo; however, ‘treatment’ is used in the statistical 
sections for consistency with standard statistical terminology.

‘Participant’ and ‘subject’
‘Participant’ is used generically to describe healthy volunteers or patients taking part in a 
clinical study. ‘Participant’ is used in most sections of this document; however, ‘subject’ 
is used in the statistical sections for consistency with standard statistical terminology.
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
09Nov2021
Amendment 1
10Mar2021
Original Protocol
22May2020

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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 1.1 Synopsis; Section 1.3
Schedule of Activities, Table 4
Schedule of Activities: 
Intervention Period; Section 3
Objectives and Endpoints; 
 (section 
deleted)
 
 
 
 
 
 
 
Section 1.1 Synopsis; Section 3
Objectives and Endpoints
Randomization to the 
 dose 
group was removed.
•
To reduce the overall sample 
size of the study 
•
The current number of 
participants in the 
mg 
dose group is expected to 
provide sufficient dose-
response information on the 
PK-PD relationship and 
endpoints, and is unlikely to 
be the dose with the optimal 
clinical risk-benefit balance.
Section 1.1 Synopsis; Section 1.2
Schema; Section 4.1 Overall 
Design; Section 4.3 Justification 
for Dose; Section 6.1 Study 
Interventions Administered, Table 
8 Investigational Products; 
Section 6.2.3 Dose Preparation 
Steps, Table 9 Dose Preparation 
for Fixed SC Doses of 
 
and 
 mg MEDI6570 and 
Placebo; Section 6.3.1
Randomization Procedure; 
Section 6.3.2 Blinding Procedure; 
Section 6.3.3 Unblinding for 
Interim Analysis Purposes (section 
deleted); Section 9.2 Sample Size 
Determination; Section 9.5 Interim 
Analyses
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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
The number of participants was 
reduced from 792 to 400. 
 
 
 
 
 
 
 
 
 
 
 
To reduce the overall sample size 
and improve feasibility of 
completion while maintaining 
acceptable power to inform 
development program decisions
Section 1.1 Synopsis; Section 1.2
Schema; Section 4.1 Overall 
Design; Section 9.2 Sample Size 
Determination
The 2 formal interim analyses 
were removed.
The interim analyses were 
administrative in nature. The full 
study results will be used for 
decision making on future 
development options. The study 
was designed to continue to 
completion regardless of the 
results of the interim analyses.
Section 1.1 Synopsis; Section 1.2
Schema; Section 4.1 Overall 
Design; Section 6.3.3 Unblinding 
for Interim Analysis Purposes 
(section deleted); Section 9.4.1
General Considerations; 
Section 9.5 Interim Analyses 
The Day 405 visit (formerly 
Visit 16) was removed and the 
Day 325 visit (Visit 14) (formerly 
Day 334 [Visit 15]) is the new End 
of Study Visit
The safety follow-up visit will be 
performed approximately 
3 months after the last dose 
(shortened from 6 months). 
 
 
 
 
 
 
 
 
 
Section 1.1 Synopsis; Section 1.3
Schedules of Activities, Table 5
Schedule of Activities: Follow-up 
Period; Section 4.1 Overall Design
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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected

Samples for diagnostic 
assay development 
(Screening, Day 29 
[Visit 5], Day 85 
[Visit 7])
Section 1.3 Schedules of 
Activities, Table 3 Schedule of 
Activities: Pre-randomization 
Activities and Table 4 Schedule of 
Activities: Intervention Period

Immunogenicity 
(Day 10 [Visit 4], 
Day 85 [Visit 7], 
Day 141 [Visit 9, 
formerly Visit 10], 
Day 225 [Visit 12, 
formerly Visit 13])
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period

Hematology and clinical 
chemistry (Day 85 
[Visit 7], Day 141 
[Visit 9, formerly 
Visit 10]), Day 197 
[Visit 11, formerly 
Visit 12], and Day 225 
[Visit 12, formerly 
Visit 13])
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period
•
The following blood sample 
collections removed from 
Day 141 [Visit 9, formerly 
Visit 10], were added to 
Day 169 (Visit 10):

PK

ADA

ECG collections were removed for 
the following time points: Day 85 
[Visit 7], Day 141 [Visit 9, 
formerly Visit 10]), Day 197 
[Visit 11, formerly Visit 12], and 
Day 225 [Visit 12, formerly 
Visit 13])
To reduce the patient burden in the 
study
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period
All urine sample collections for 
the evaluation of albumin-to-
creatinine ratio were removed
To reduce the patient burden in the 
study
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period and 
Table 5 Schedule of Activities: 
Follow-up Period; Section 6.3.2
Blinding Procedure 
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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Inclusion criterion 2 was amended 
to state that female participants 
need to be aged ≥ 40 years, but 
male participants need to be aged 
≥21 years.
To broaden the inclusion criteria to 
include younger male patients post 
myocardial infarction given effect 
modification by age is not 
anticipated
Section 4.2.1 Rationale for Study 
Population; Section 5.1 Inclusion 
Criteria
Exclusion criterion 2 was amended 
as follows:
‘Percutaneous coronary 
intervention [PCI] or diagnostic 
angiogram planned after 
screening Visit 1. Eligible 
participants who have a PCI
diagnostic angiogram performed
after screening Visit 1 in the 
absence of undergoing a new 
PCI may continue screening 
after the diagnostic angiogram 
has been performed or may be 
rescreened after the PCI has been 
performed (Section 5.4).’
and
To reduce the likelihood of 
recruiting patients who need 
further investigation that may 
confound study results
Section 5.2 Exclusion Criteria

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Description of Change
Brief Rationale
Sections Affected
‘•
Eligible participants who 
exceed the 42-day pre-
randomization window may be 
rescreened to determine eligibility 
before randomization and the 
Medical Monitor will decide 
whether screening laboratory 
evaluations should be repeated. 
If the screening assessments are 
not considered to be representative 
of the usual status of the health of 
the participant by the investigator, 
or if ≥ 1 exclusion criteria are 
considered temporary (eg, planned
PCI diagnostic angiogram) or 
from a reversible condition, repeat 
screening assessments to establish 
eligibility will generally be 
permitted once, at the discretion of 
the investigator.’
and
‘Eligible participants who have a 
PCI diagnostic angiogram
performed planned after 
screening Visit 1 in the absence 
of undergoing a new PCI may be 
rescreened continue screening
after the PCI diagnostic 
angiogram has been performed 
(Exclusion Criterion 2). If they 
exceed the 42-day pre-
randomization window, the 
Medical Monitor will decide 
whether the participant is 
required to be rescreened and 
whether screening laboratory 
evaluations should be repeated. 
Participants who have a PCI 
performed between screening 
Visit 1 and Randomization 
Visit 3 may not be rescreened.’
Section 5.4 Screen Failures

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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Exclusion criterion 6(b) was 
amended as follows:
(b)
Active bleeding or high 
risk for major bleeding (eg, 
gastrointestinal pathology,
malignancy with high risk of 
bleeding, active peptic ulcer).
Signs of ongoing bleeding at 
screening (eg, identified 
macroscopic bleeding, low 
hemoglobin presumed to be 
caused by bleeding) or high risk 
for major bleeding in 
accordance with the 
Investigator’s assessment.
Exclusion criteria updated for 
clarity and with the aim to avoid 
unnecessary exclusion of 
participants due to the theoretical 
risk of bleeding, by introducing 
some flexibility for medical 
assessment by the Investigator
Section 5.2 Exclusion Criteria
Exclusion criterion 6(c) was 
amended as follows:
(c)
Need for chronic 
therapeutic anticoagulation 
therapy anticipated to be 
required throughout the course 
of the study (short-term 
treatment with prophylactic doses 
of heparin/low molecular weight 
heparin are allowed).
Exclusion criteria updated for 
clarity
Section 5.2 Exclusion Criteria
Exclusion criterion 12 was
amended as follows:
‘Planned participation in an 
additional investigational study of 
an intervention or biologic before 
the end of the follow-up period.
Participation in observational 
studies or studies without 
investigational drugs or devices 
is allowed.’
To allow patients who are 
participating in observational 
studies of devices to participate in 
this study
Section 5.2 Exclusion Criteria

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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Text was amended as follows:
‘Participants with a need for 
chronic therapeutic
anticoagulation therapy are 
excluded from study participation; 
however, prophylactic doses of 
heparin are allowed short-term 
treatment with prophylactic 
doses of heparin/low molecular 
weight heparin are allowed’
Text updated for clarity and to 
align with updated wording in 
exclusion criterion 6(c). with the 
aim to avoid unnecessary 
discontinuation of participants due 
to the theoretical risk of bleeding, 
by introducing some flexibility for 
medical assessment by the 
Investigator
Section 6.5.1 Permitted 
Concomitant Medications
Text on discontinuation of study 
intervention was amended as 
follows:
‘(a)
Providers should consider 
temporary or permanent 
discontinuation of study 
intervention in participants who: 
(i)
In participants Develop a 
condition that requires the use of 
chronic therapeutic
anticoagulation therapy.
(ii)
Experience severe 
bleeding that is not readily 
explained by a reversible alternate 
etiology. All bleeding events 
should be treated and followed up 
according to local clinical practice. 
Study intervention may be 
resumed when the risk of bleeding 
is deemed low in the judgment of 
the investigator.’
Text updated for clarity and to 
align with updated wording in 
exclusion criterion 6(c). with the 
aim to avoid unnecessary 
discontinuation of participants due 
to the theoretical risk of bleeding, 
by introducing some flexibility for 
medical assessment by the 
Investigator
Section 7.1 Discontinuation of 
Study Intervention

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Table 1
Substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
The following new text was added 
to the Pregnancy section: 
‘Nonsterilized male study 
participants should be advised to 
use a condom for all sexual 
intercourse with a female partner 
of childbearing potential from 
Day 1 through the end of the study 
follow-up period. All male 
participants should refrain from 
fathering a child or donating sperm 
during the study and for 190 days 
following the last dose. If the 
partner becomes pregnant, the 
partner will be asked (under a 
separate consent) to provide 
information about the pregnancy 
and newborn baby.’
In addition, the order of 
paragraphs in the section was 
re-arranged to match the template.
AstraZeneca has reassessed the 
theoretical risk to women of 
childbearing potential of exposure 
to semen from male participants 
receiving MEDI6570. The 
reassessment confirms that semen 
from male participants exposed to 
MEDI6570 poses low to no risk to 
the fetus of pregnant sexual 
partners or the potential fetus of 
sexual partners who may become 
pregnant. However, as a 
conservative and cautionary 
approach, following the 
AstraZeneca and Clinical Trial 
Facilitation Group guidelines, 
AstraZeneca has decided to update 
the clinical study protocol 
accordingly.
Section 8.3.8 Pregnancy; 
Section 8.3.8.1 Maternal Exposure 
(new section created with existing 
text); Section 8.3.8.2 Paternal 
Exposure (new text added to new 
section)
The following text was removed: 
‘For the biomarker samples 
collected at Day 1 (Visit 3), Day 
29 (Visit 5) and Day 85 (Visit 7) 
for
 NT-
proBNP, 
 part of each 
sample will be reserved for 
exploratory subgroup analysis for 
predicting response to therapy in 
primary, secondary, and 
exploratory endpoints’
Analyses will not be performed
Section 8.6.1 Collection of 
Mandatory Samples for Biomarker 
Analysis
The wording of the alternative 
hypothesis was amended as 
follows:
‘The alternative hypothesis is that 
there is a difference in this 
endpoint in participants given 
MEDI6570 compared with 
placebo the change from baseline 
in NCPVMD reduction is larger 
in the MEDI6570 
mg group 
compared with the pooled 
placebo group.’
To reflect the change from 2-sided 
analyses to 1-sided analyses
Section 9.1 Statistical Hypotheses
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ADA, anti-drug antibody(ies); CTA, computed tomography angiography; CV, cardiovascular; 
ECG, electrocardiogram; 
 hs-CRP, high sensitivity 
C-reactive protein;
 MVPA,  
moderate-to-vigorous physical activity; NCPVMD, Non-calcified plaque volume in the most diseased coronary 
segment; NT-proBNP, N-terminal prohormone brain natriuretic peptide; PCI, percutaneous coronary 
intervention; PK, pharmacokinetic;
; ULN 
upper limit of normal
Table 2
Non-substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Rationale text was amended as 
follows: ‘The results of the 
Phase IIB study will may inform 
future clinical development 
options and precision medicine 
strategy for future clinical studies.’
For clarification
Section 1.1 Synopsis
The time window for the Baseline 
Imaging visit was extended
from 21 - 1 day before 
randomization to 30 - 1 day before 
randomization
To align with Section 8.1.1.3
language and to provide sites with 
more flexibility to obtain baseline 
image without affecting study 
endpoint
Section 1.2 Schema; Section 1.3
Schedules of Activities, Table 3
Schedule of Activities: Pre-
randomization Activities; 
Section 8.1.1.3 Radiation 
Exposure from CTA Imaging, 
Including Rules for Repeating 
CTA Scans and Conducting the 
Interim CTA
The rows for weeks were removed 
from the schedules of activities
To add clarity because the weeks 
did not always correspond directly 
with visit days
Section 1.3 Schedules of 
Activities, Table 3 Schedule of 
Activities: Pre-randomization 
Activities, Table 4 Schedule of 
Activities: Intervention Period, 
and Table 5 Schedule of 
Activities: Follow-up Period
Text was added to indicate that a 
local laboratory sample for 
coagulation may be used to assess 
eligibility
To allow flexibility if the central 
laboratory sample does not 
provide a valid result; the result 
from a central sample would be 
required to establish the baseline 
value before dosing
Section 1.3 Schedules of 
Activities, Table 3 Schedule of 
Activities: Pre-randomization 
Activities
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Table 2
Non-substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Text was added to clarify that the 
visit window is ± 7 days for dosing 
visits and ± 3 days for non-dosing 
visits (ie, Day 10 [Visit 4]), and 
that if a participant is dosed 
outside of the visit window, he or 
she should return to the initial 
planned schedule for subsequent 
visits.
For clarification
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period
Text was modified to reflect that 
blood and urine samples will be 
drawn before dosing, not before 
randomization.
For clarification
Section 1.3 Schedules of 
Activities, Table 4 Schedule of 
Activities: Intervention Period
The terms ‘alanine transaminase’ 
and ‘aspartate transaminase’ were 
amended to ‘alanine 
aminotransferase’ and ‘aspartate 
aminotransferase’, respectively
For consistency with other study 
documents
Section 5.2 Exclusion Criteria; 
Section 8.2.4 Clinical Safety 
Laboratory Assessments; Table 10
Laboratory Safety Variables; 
Appendix H Abbreviations
Text requiring permission from the 
Medical Monitor for additional 
repeat screening was removed.
To reduce participant burden, 
participants will not be asked to 
rescreen more than once
Section 5.4 Screen Failures
Superscript ‘a’ was corrected
Incorrect original footnote ‘a’ was 
deleted and newly required 
footnote ‘a’ was added
Section 6.1 Study Interventions 
Administered, Table 8
Investigational Products
Text relating to re-allocation of 
dosing volumes was amended to 
past tense
To clarify that the re-allocation 
applied under Protocol 
Amendment 1 only
Section 6.3.1 Randomization 
Procedure
The following text was added: ‘A  
full coronary CTA interpretation 
will not be performed locally.’
For clarification
Section 8.1.1.4 CTA Image 
Analysis

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Table 2
Non-substantial Changes to the Protocol
Description of Change
Brief Rationale
Sections Affected
Text was amended as follows:
‘…The investigator or authorized 
designee will explain to each 
participant the objectives of the 
analysis to be done on the samples 
and images (CTA and 
echocardiogram) and any 
potential future use. Participants 
will be told that they are free to 
refuse to participate in any 
optional samples or have their 
unused samples and images 
(CTA and echocardiogram) used 
in future use research and may 
withdraw their consent at any time 
and for any reason during the 
retention period.  …’
For clarification
Appendix A 3 Informed Consent 
Process
Minor formatting and 
capitalization changes
For consistency
Throughout
CTA, computed tomography angiography

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TERMS AND CONVENTIONS USED IN THIS DOCUMENT........................................... 2
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE.................................... 2
TABLE OF CONTENTS.................................................................................................... 16
LIST OF TABLES.............................................................................................................. 18
LIST OF FIGURES ............................................................................................................ 19
LIST OF APPENDICES..................................................................................................... 19
1
PROTOCOL SUMMARY................................................................................ 20
1.1
Synopsis ........................................................................................................... 20
1.2
Schema............................................................................................................. 25
1.3
Schedules of Activities ..................................................................................... 26
2
INTRODUCTION............................................................................................ 36
2.1
Study Rationale ................................................................................................ 36
2.2
Background ...................................................................................................... 36
2.3
Benefit/Risk Assessment................................................................................... 38
2.3.1
Risk Assessment............................................................................................... 38
2.3.2
Benefit Assessment........................................................................................... 40
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 41
3
OBJECTIVES AND ENDPOINTS................................................................... 42
4
STUDY DESIGN ............................................................................................. 43
4.1
Overall Design.................................................................................................. 43
4.2
Scientific Rationale for Study Design ............................................................... 45
4.2.1
Rationale for Study Population ......................................................................... 45
4.2.2
Rationale for Endpoints .................................................................................... 46
4.2.2.1
Primary Endpoint.............................................................................................. 46
4.2.2.2
Secondary Endpoints ........................................................................................ 46
4.2.2.3
Exploratory Endpoints ...................................................................................... 48
4.3
Justification for Dose........................................................................................ 49
4.4
End of Study Definition.................................................................................... 50
5
STUDY POPULATION ................................................................................... 50
5.1
Inclusion Criteria .............................................................................................. 50
5.2
Exclusion Criteria ............................................................................................. 51
5.3
Lifestyle Considerations ................................................................................... 53
5.4
Screen Failures ................................................................................................. 53
6
STUDY INTERVENTION............................................................................... 54
6.1
Study Interventions Administered..................................................................... 54

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6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 56
6.2.1
Study Intervention Inspection ........................................................................... 56
6.2.2
Storage ............................................................................................................. 56
6.2.3
Dose Preparation Steps ..................................................................................... 56
6.2.4
Treatment Administration................................................................................. 57
6.2.5
Accountability .................................................................................................. 58
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 58
6.3.1
Randomization Procedure................................................................................. 58
6.3.2
Blinding Procedure........................................................................................... 59
6.4
Study Intervention Compliance......................................................................... 60
6.5
Concomitant Therapy........................................................................................ 60
6.5.1
Permitted Concomitant Medications ................................................................. 61
6.5.2
Prohibited Concomitant Medications ................................................................ 61
6.6
Dose Modification ............................................................................................ 61
6.7
Intervention after the End of the Study.............................................................. 61
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL.......................................................... 62
7.1
Discontinuation of Study Intervention............................................................... 62
7.2
Participant Withdrawal from the Study ............................................................. 63
7.3
Lost to Follow-up ............................................................................................. 63
8
STUDY ASSESSMENTS AND PROCEDURES ............................................. 64
8.1
Efficacy Assessments........................................................................................ 64
8.1.1
CTA Imaging.................................................................................................... 64
8.1.1.1
Timing of CTA Imaging Relative to Echocardiogram....................................... 64
8.1.1.2
Criteria for CTA Imaging.................................................................................. 65
8.1.1.3
Radiation Exposure from CTA Imaging, Including Rules for Repeating CTA 
Scans ................................................................................................................ 65
8.1.1.4
CTA Image Analysis ........................................................................................ 66
8.1.2
Echocardiography............................................................................................. 67
8.2
Safety Assessments........................................................................................... 67
8.2.1
Physical Examinations...................................................................................... 67
8.2.2
Vital Signs........................................................................................................ 68
8.2.3
Electrocardiogram............................................................................................. 68
8.2.4
Clinical Safety Laboratory Assessments............................................................ 68
8.2.5
Other Safety Assessments................................................................................. 69
8.2.5.1
Bleeding ........................................................................................................... 69
8.2.5.2
Monitoring for Hypersensitivity Reactions........................................................ 69
8.2.5.3
Injection Site Reactions .................................................................................... 69
8.3
Adverse Events and Serious Adverse Events..................................................... 69
8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information............................................................................................. 70
8.3.2
Follow-up of Adverse Events and Serious Adverse Events................................ 70
8.3.3
Causality Collection.......................................................................................... 71

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8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 71
8.3.5
Adverse Events Based on Examinations and Tests............................................ 71
8.3.6
Hy’s Law.......................................................................................................... 72
8.3.7
Reporting of Serious Adverse Events................................................................ 72
8.3.8
Pregnancy......................................................................................................... 73
8.3.8.1
Maternal Exposure............................................................................................ 73
8.3.8.2
Paternal Exposure............................................................................................. 73
8.3.9
Study Intervention Error ................................................................................... 74
8.4
Overdose .......................................................................................................... 74
8.5
Human Biological Samples............................................................................... 74
8.5.1
Pharmacokinetics.............................................................................................. 75
8.5.2
Immunogenicity Assessments ........................................................................... 76
8.5.3
Pharmacodynamics........................................................................................... 76
8.6
Human Biological Sample Biomarkers ............................................................. 76
8.6.1
Collection of Mandatory Samples for Biomarker Analysis................................ 76
8.6.2
Collection of Optional Samples for Biomarker Analysis ................................... 77
8.7
Optional Genomics Initiative Sample................................................................ 77
8.8
Medical Resource Utilization and Health Economics........................................ 77
9
STATISTICAL CONSIDERATIONS............................................................... 77
9.1
Statistical Hypotheses....................................................................................... 77
9.2
Sample Size Determination............................................................................... 77
9.3
Populations for Analyses .................................................................................. 78
9.4
Statistical Analyses........................................................................................... 79
9.4.1
General Considerations..................................................................................... 79
9.4.2
Efficacy ............................................................................................................ 79
9.4.2.1
Primary Endpoint.............................................................................................. 79
9.4.2.2
Secondary Endpoints ........................................................................................ 79
9.4.2.3
Exploratory Endpoints ...................................................................................... 80
9.4.2.4
Subgroup Analyses ........................................................................................... 80
9.4.3
Safety ............................................................................................................... 81
9.5
Interim Analyses............................................................................................... 81
9.6
Data Monitoring Committee ............................................................................. 81
10
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS........................................................................................ 81
11
REFERENCES............................................................................................... 124
LIST OF TABLES
Table 1
Substantial Changes to the Protocol........................................................... 3
Table 2
Non-substantial Changes to the Protocol.................................................. 13
Table 3
Schedule of Activities: Pre-randomization Activities ............................... 26

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Table 4
Schedule of Activities: Intervention Period.............................................. 30
Table 5
Schedule of Activities: Follow-up Period................................................. 33
Table 6
Risk Assessment...................................................................................... 38
Table 7
Objectives and Endpoints......................................................................... 42
Table 8
Investigational Products........................................................................... 55
 
.......................................................................... 57
Table 10
Laboratory Safety Variables..................................................................... 68
Table 11
Populations for Analyses ......................................................................... 78
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 25
LIST OF APPENDICES
Regulatory, Ethical, and Study Oversight Considerations......................... 82
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 87
Handling of Human Biological Samples .................................................. 91
Optional Genomics Initiative Sample....................................................... 93
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 96
Intensity Categories for Statin Therapy.................................................. 102
Risk Assessment for COVID-19 Pandemic ............................................ 103
Abbreviations ........................................................................................ 108
Protocol Amendment History................................................................. 111
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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase IIB, Randomized, Double-blinded, Placebo-controlled, 
Parallel-group Study to Evaluate the Efficacy and Safety of MEDI6570 in Participants with a 
Prior Myocardial Infarction, Persistent Inflammation, and Elevated N-terminal Prohormone 
Brain Natriuretic Peptide
Short Title: A Phase IIB Parallel-group Study to Evaluate the Efficacy and Safety of 
MEDI6570 in Participants with a Prior Myocardial Infarction 
Rationale: This Phase IIB, proof-of-concept, dose-range finding clinical study is being 
conducted to evaluate the anti-inflammatory potential of MEDI6570 and its effect on 
surrogates for atherosclerotic and heart failure (HF) events in patients with a history of 
myocardial infarction (MI). The results of the Phase IIB study may inform future clinical 
development options and precision medicine strategy for future clinical studies.
Objectives and Endpoints:
Objectives
Endpoints
Primary
To evaluate the effect of MEDI6570 on non-calcified 
coronary atherosclerotic plaques compared with 
placebo
Change from baseline to Day 253 in non-calcified 
plaque volume in the most diseased coronary segment 
(NCPVMD), as measured by CTA imaging
Secondary
To evaluate the effect of MEDI6570 on a surrogate 
biomarker of HF compared with placebo
Relative change from baseline to Day 253 in 
NT-proBNP.
To evaluate the effect of MEDI6570 on left ventricular 
systolic function compared with placebo
Change from baseline to Day 253 in:
•
LVEF
•
GLS
as measured by echocardiography
To evaluate the effect of MEDI6570 on left ventricular 
systolic function among participants with reduced
ejection fraction (defined as < 50%) compared with 
placebo
Change from baseline to Day 253 in:
•
LVEF
•
GLS
as measured by echocardiography
To evaluate the effect of MEDI6570 on other measures 
of non-calcified coronary atherosclerotic plaque 
compared with placebo
Change from baseline to Day 253 in:
•
Global non-calcified plaque volume
•
Low attenuation plaque volume
as measured by CTA imaging
To evaluate the immunogenicity of MEDI6570
•
ADA incidence
•
Titer 
as measured in serum during the intervention and 
follow-up periods

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Overall Design:
This is a randomized, double-blinded, placebo-controlled, parallel-group, multicenter 
(approximately 70 to 100), international study in participants who have recently (within the 
previous 30 to 365 days) had an MI (either ST segment elevation MI or non-ST segment 
elevation MI), with persistent inflammation (high sensitivity C-reactive protein [hs-CRP] 
≥1 mg/L). Participants will be randomized in a 2:2:1:1 ratio to receive
in an injection 
volume of 1.5 mL) or 
 (in an injection volume of 4.0 mL) MEDI6570, or an
injection/volume-matched placebo, subcutaneously (SC), every 4 weeks (Q4W) for 32 weeks 
(9 doses in total). Participants who were randomized to a study intervention under Protocol 
Version 1.0 or Amendment 1 (when there was also a 
 dose group) and were allocated a 
dosing volume of 0.5 mL will continue on their randomized study intervention (
 
MEDI6570, or its injection/volume-matched placebo) to the end of the study, and the study 
blind will be maintained with regard to active versus placebo.
The randomization will be stratified by geographic region (Asia, North America and Rest of 
World) and by statin therapy intensity at screening (no, low- or moderate-intensity statin 
therapy vs high-intensity statin therapy). 
Participants will undergo an echocardiogram and computed tomography angiography (CTA)
scan before randomization and administration of study intervention. During the follow-up 
period, participants will also undergo an echocardiogram and CTA scan.
Disclosure Statement: This is a parallel-group, treatment study with 6 intervention groups 
(including the legacy 
 mg dose group and matched placebo) that is participant- and 
investigator-blinded.
Number of Participants: Approximately 400 participants will be randomly assigned to a 
study intervention, with an anticipated 369 participants being randomized to receive active
study intervention (123 participants in each of the 2 MEDI6570 groups), and 123 participants 
being randomized across the 3 placebo groups (ie, including participants already randomized 
to the legacy dose/volume-matched placebo group for the 
 mg dose). It is estimated that 
approximately 360 evaluable participants (111 evaluable participants in each of the 2 
MEDI6570 groups [
 and 
mg], plus 27 evaluable participants in the legacy 
mg 
MEDI6570 group, plus 111 participants across the 3 placebo groups) will complete the study.
Evaluable participants are defined as those with an evaluable CTA at baseline and follow-up 
(Day 253; Visit 13).
Intervention Groups and Duration: The study intervention is MEDI6570, a human
Immunoglobulin G1 lambda (IgG1λ) triple mutation antibody that binds to 
 
 Going forward from Amendment 2, the
study will include 4 intervention groups: 
and 
mg MEDI6570, and 2 
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Statistical methods for primary endpoint: The primary endpoint is change from baseline in 
NCPVMD. An analysis of covariance (ANCOVA) model on change from baseline adjusted for 
treatment group, baseline, and randomization strata will be used for the primary analysis.
Statistical methods for secondary efficacy endpoints: Secondary endpoint of relative 
change from baseline in NT-proBNP will be analyzed with a mixed model with repeated 
measures analysis on change from baseline for the log-transformed value of NT-proBNP. The 
results will be back-transformed to the original scale. The model will include fixed effects of 
treatment group, visit, treatment group-by-visit interaction, and randomization strata, with 
baseline NT-proBNP as a covariate. Repeated measures for the model will be visit within 
subjects; an unstructured covariance structure will be used for the repeated measures. In case 
the model does not converge, back-up covariance structures and other analysis solutions will 
be detailed in the statistical analysis plan.
Secondary endpoints that are measured by echocardiogram or CTA will be analyzed based on 
the Echocardiogram or CTA Analysis Population, respectively. ANCOVA analyses similar to 
the primary endpoint will be performed; the model will adjust for treatment group, respective 
baseline value, and randomization strata.
Statistical methods for safety variables: Type, incidence, severity, and relationship of 
adverse events (AEs) and serious adverse events to study intervention will be summarized by 
MedDRA System Organ Class and Preferred Term and by study intervention. Specific AEs 
will be counted once for each participant for calculating percentages. If the same AE occurs 
multiple times within a participant, the highest severity and level of relationship to study 
intervention observed will be reported. Vital signs and safety laboratory data will be 
summarized descriptively at each time point by study intervention.
Interim analysis: No formal interim analysis is planned. 
An analysis restricted to PK (serum MEDI6570 concentration) 
 
 
 Non-study personnel who have no other 
involvement in the study will perform this evaluation. These PK and PD data will be reviewed 
in conjunction with the safety data by the independent DMC.
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1.3
Schedules of Activities
Activities for the pre-randomization, intervention, and follow-up periods are given in Table 3, Table 4, and Table 5, respectively. 
Table 3
Schedule of Activities: Pre-randomization Activities
Procedure
Pre-
screening 
(Optional)
Screening
Baseline 
Imaging
Notes
Details in CSP 
section or 
appendix
Optional 
visit
Visit 1
Visit 2
o
Enrollment occurs at time of first consent (ie, pre-screening 
or full consent). Optional pre-screening may begin 31 days 
post myocardial infarction and up to 42 days before 
screening. Screening may not occur more than 42 days 
before randomization. Baseline imaging may not occur 
until after screening visit and no more than 30 days before 
randomization.  
o
The screening period from Day -42 to Day -30 may be 
shortened if all results support moving to the pre-
randomization period.
Day -84 to 
Screening
Day -42 to -1
Day -30 to -1
Informed consent(s) 
X a
X
o
Brief informed consent for local laboratory sample 
collection at pre-screening only - optional a
o
Informed consent for main protocol at screening - required
o
Informed consent for future use at screening - optional
o
Informed consent for Genomics Initiative at screening -
optional
Appendix A 3
Appendix D 2
Med. history; Con. 
meds.
X
Section 5.2
Full physical 
examination
X
Including height and weight
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Table 3
Schedule of Activities: Pre-randomization Activities
Procedure
Pre-
screening 
(Optional)
Screening
Baseline 
Imaging
Notes
Details in CSP 
section or 
appendix
Optional 
visit
Visit 1
Visit 2
o
Enrollment occurs at time of first consent (ie, pre-screening 
or full consent). Optional pre-screening may begin 31 days 
post myocardial infarction and up to 42 days before 
screening. Screening may not occur more than 42 days 
before randomization. Baseline imaging may not occur 
until after screening visit and no more than 30 days before 
randomization.  
o
The screening period from Day -42 to Day -30 may be 
shortened if all results support moving to the pre-
randomization period.
Day -84 to 
Screening
Day -42 to -1
Day -30 to -1
Vital signs and 
ECGs
X
When vital signs and blood draws are scheduled for the same 
nominal time, blood draws should occur last. The timing of 
vital signs and ECGs should allow the blood draw (eg, PK 
blood sample) to occur at the assigned nominal time. ECGs can 
occur at any time relative to dosing and will be interpreted 
locally.
Sections 8.2.2
and 8.2.3
Assessment of 
SAEs
X 
X
X
SAE collection will start from enrollment (ie, when the 
participant signs the first informed consent form, at either pre-
screening or screening) a
Section 8.3
Collect blood for:
Clinical safety
X
Samples for clinical chemistry, hematology, coagulation panel
(a local sample may be used to assess eligibility; if central 
laboratory screening sample is not resulted because of a
technical issue, a central laboratory sample would be redrawn 
before dosing), LH and FSH (female participants only), 
Hepatitis B and C, HIV
Sections 5.1, 
8.2.4

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Table 3
Schedule of Activities: Pre-randomization Activities
Procedure
Pre-
screening 
(Optional)
Screening
Baseline 
Imaging
Notes
Details in CSP 
section or 
appendix
Optional 
visit
Visit 1
Visit 2
o
Enrollment occurs at time of first consent (ie, pre-screening 
or full consent). Optional pre-screening may begin 31 days 
post myocardial infarction and up to 42 days before 
screening. Screening may not occur more than 42 days 
before randomization. Baseline imaging may not occur 
until after screening visit and no more than 30 days before 
randomization.  
o
The screening period from Day -42 to Day -30 may be 
shortened if all results support moving to the pre-
randomization period.
Day -84 to 
Screening
Day -42 to -1
Day -30 to -1
hs-CRP
X a
X
A sample for hs-CRP may be collected at pre-screening. The 
sample must be collected again at screening and processed at 
the central laboratory to determine eligibility. 
Section 8.6.1
NT-proBNP
X a
X
If randomization of participants with NT-proBNP < 125 pg/mL 
is capped, a sample for NT-proBNP (or BNP if NT-proBNP is 
not available) may be collected at pre-screening.
Sections 5.1
and 8.6.1
Creatinine for 
calculating eGFR
X a
X
o
A sample for creatinine may be collected at pre-screening 
using the local laboratory. The sample must be collected 
again at screening and processed at the central laboratory to 
determine eligibility.a
o
CTA: sample is required within 30 days before CTA scan 
(if the CTA sample is not the same sample that was used to 
determine eligibility, then the central laboratory or local 
laboratory or point of care testing may be used (according 
to local standard of care [plasma or serum]). 
Sections 5.2, 
8.1.1.2 and 8.2.4
Verify eligibility 
X
X
Participants must meet the study eligibility criteria before 
undergoing the echocardiogram and CTA scan.
Sections 5.1 and 
5.2

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Table 3
Schedule of Activities: Pre-randomization Activities
Procedure
Pre-
screening 
(Optional)
Screening
Baseline 
Imaging
Notes
Details in CSP 
section or 
appendix
Optional 
visit
Visit 1
Visit 2
o
Enrollment occurs at time of first consent (ie, pre-screening 
or full consent). Optional pre-screening may begin 31 days 
post myocardial infarction and up to 42 days before 
screening. Screening may not occur more than 42 days 
before randomization. Baseline imaging may not occur 
until after screening visit and no more than 30 days before 
randomization.  
o
The screening period from Day -42 to Day -30 may be 
shortened if all results support moving to the pre-
randomization period.
Day -84 to 
Screening
Day -42 to -1
Day -30 to -1
Echocardiogram and 
CTA scan
X
Participants must meet the study eligibility criteria before 
undergoing the echocardiogram and CTA scan. In addition, 
participants must meet CTA scan eligibility criteria before CTA 
scan imaging. If the echocardiogram and CTA scan are 
performed on the same day, the echocardiogram must always 
occur before the CTA scan and before any additional beta-
blocker is given for the CTA scan.
Sections 8.1.1
and 8.1.2
(including 
instructions for 
repeating 
uninterpretable 
echocardiogram
s and CTA 
scans)
a
An optional, pre-screening visit may occur before screening Visit 1 to collect blood for evaluating (using the local laboratory) hs-CRP and creatinine (for 
calculating e[GFR]), and, if randomization of participants with NT-proBNP < 125 pg/mL is capped, NT-proBNP (or BNP) (Section 5.1). Participants must 
sign a brief ICF for pre-screening before any pre-screen evaluations may be performed. If pre-screen evaluations are performed, written, informed consent 
for the full screening evaluations must still be given, and the full screening assessments (including hs-CRP and creatinine, and NT-proBNP if applicable) 
must still be performed for the participant to progress in the study. The pre-screening ICF must be signed not more than 42 days before the full ICF is 
signed. Participants who undergo pre-screening will be considered to have enrolled in the study.
BNP, brain natriuretic peptide; CSP, Clinical Study Protocol; CTA, computed tomography angiography; CV, cardiovascular; ECG, electrocardiogram; eGFR, 
estimated glomerular filtration rate; FSH, follicle stimulating hormone; hs-CRP, high sensitivity C-reactive protein; LH, luteinizing hormone; NT-proBNP,
N-terminal prohormone brain natriuretic peptide; SAE, serious adverse event.

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Table 4
Schedule of Activities: Intervention Period
Procedure
Visit:
3
4
5
6
7
8
9
10
11
12
Notes
Details in 
CSP section 
or appendix
Day (± 7): a
1
10a
29
57
85
113
141
169
197
225
Physical examination
X
Abbreviated; 
includes weight
Section 8.2.1
Vital signs
X
X
X
X
X
X
X
X
X
X
When vital signs 
and blood draws are 
scheduled for the 
same nominal time, 
blood draws should 
occur last. The 
timing of vital signs 
should allow the 
blood draw (eg, PK 
blood sample) to 
occur at the assigned 
nominal time. 
Section 8.2.2
ECG
X
X
X
X
X
X
The timing of ECGs 
should allow the 
blood draw (eg, PK 
blood sample) to 
occur at the assigned 
nominal time. ECGs 
can occur at any 
time relative to 
dosing and will be 
interpreted locally.
Section 8.2.3

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Table 4
Schedule of Activities: Intervention Period
Procedure
Visit:
3
4
5
6
7
8
9
10
11
12
Notes
Details in 
CSP section 
or appendix
Day (± 7): a
1
10a
29
57
85
113
141
169
197
225
Collect blood for:
Clinical safety (hematology and 
clinical chemistry) 
X
X
X
X
X
X
Must be collected 
before dosing study 
intervention.
Section 8.2.4
PK
X
X
X
X
X
X
Must be collected 
before dosing study 
intervention.
Section 8.5.1
X
X
X
X
X
X
Must be collected 
before dosing study 
intervention. 
Section 8.6.1
 NT-proBNP 
X
X
Section 8.6.1
Circulating biomarkers of 
inflammation and CV disease
X
X
Section 8.6.1
Genomics Initiative
X
•
Optional; 
collect sample 
if participant 
signed 
informed 
consent
•
Samples will 
be collected 
before dosing, 
and stored.
•
If for any 
reason the 
sample is not 
drawn at Visit 
3, it may be 
Section 8.7
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Table 4
Schedule of Activities: Intervention Period
Procedure
Visit:
3
4
5
6
7
8
9
10
11
12
Notes
Details in 
CSP section 
or appendix
Day (± 7): a
1
10a
29
57
85
113
141
169
197
225
taken at any 
visit until the 
last study visit
Samples for diagnostic assay 
development 
X
X
Must be collected 
before study 
intervention. 
Samples will be 
collected and stored. 
Section 8.6.1
Immunogenicity
X
X
X
X
X
On dosing visits, 
must be collected 
before dosing study 
intervention.
Section 8.5.2
Collect urine for:
Future use (optional)
X
Sample will be 
collected and stored
Section 8.6.2
Randomization
X
To be randomized, 
baseline CTA must 
be interpretable.
Section 6.3.1
Study intervention administration
X
X
X
X
X
X
X
X
X
Dosing will occur 
after blood and
optional urine 
samples have been 
collected
Sections 6.2.3
and 6.2.4

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Table 4
Schedule of Activities: Intervention Period
Procedure
Visit:
3
4
5
6
7
8
9
10
11
12
Notes
Details in 
CSP section 
or appendix
Day (± 7): a
1
10a
29
57
85
113
141
169
197
225
Observational period
X
X
Participant must be 
in clinic for 2 hours 
after dosing.
Section 8.2.5.2
Assessment of AEs/SAEs
X
X
X
X
X
X
X
X
X
X
Section 8.3
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Section 6.5
Assess for injection site reactions
X
X
X
X
X
X
X
X
X
Section 8.2.5.3
a
The visit window is ± 7 days for dosing visits and ± 3 days for non-dosing visits (ie, Day 10 [Visit 4]). If a participant is dosed outside of the visit window, 
he or she should return to the initial planned schedule for subsequent visits.
AE, adverse event; CSP, Clinical Study Protocol; CV, cardiovascular; ECG, electrocardiogram; HIV, human immunodeficiency virus;
 
 NT-proBNP, N-terminal prohormone brain natriuretic peptide; PK, pharmacokinetic(s); SAE serious adverse event; 
Table 5
Schedule of Activities: Follow-up Period
Procedure
Visit:
13
14
Notes
Details in CSP 
section or 
appendix
Day:
253
(- 4 to + 11 days)
325
(± 7 days)
End of study visit
X
Section 4.3
Full physical examination
X
Section 8.2.1
Weight
X
Section 8.2.1
Vital signs
X
X
Whenever vital signs and blood draws are 
scheduled for the same nominal time, the 
blood draws should occur last. 
Section 8.2.2
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Table 5
Schedule of Activities: Follow-up Period
Procedure
Visit:
13
14
Notes
Details in CSP 
section or 
appendix
Day:
253
(- 4 to + 11 days)
325
(± 7 days)
ECGs
X
X
Section 8.2.3
Assessment of AEs/SAEs
X
X
Section 8.3
Concomitant medications
X
X
Section 6.5
Collect blood for:
Clinical safety (clinical chemistry and 
hematology)
X
X
Section 8.2.4
PK
X
X
Section 8.5.1
X
X
Sample collected on Day 325 will be stored.
Section 8.6.1
 NT-proBNP 
X
Section 8.6.1
Circulating biomarkers of inflammation CV 
disease
X
Section 8.6.1
Immunogenicity 
X
X
Section 8.5.2
Creatinine for calculating eGFR
X
should occur within 30 days before the CTA; 
either local laboratory or point of care testing 
can be used. 
Section 8.2.4
Collect urine for:
Future use (optional)
X
Sample will be collected and stored.
Section 8.6.2
Echocardiogram
X
Section 8.1.1
and 8.1.2
(including 
instructions for 
repeating 
uninterpretable 
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Table 5
Schedule of Activities: Follow-up Period
Procedure
Visit:
13
14
Notes
Details in CSP 
section or 
appendix
Day:
253
(- 4 to + 11 days)
325
(± 7 days)
echocardiograms 
scans)
Verify criteria for CTA scan imaging
X
Participants must meet CTA scan eligibility 
criteria before CTA scan imaging.
Section 8.1.1
CTA scan
X
If the echocardiogram and CTA scan are 
performed on the same day, the 
echocardiogram must always occur before the 
CTA scan and before any additional beta-
blocker is given for the CTA scan. If the end 
of study CTA is determined to be of 
inadequate image quality by the CTA core 
laboratory, the participant may return for a 
repeat CTA up to 274 days after Dose 1.
Section 8.1.1
(including 
instructions for 
repeating 
uninterpretable 
CTA scans)
AE, adverse event; CSP, Clinical Study Protocol; CTA, computed tomography angiography; CV, cardiovascular; ECG, electrocardiogram; 
 
; NT-proBNP, N-terminal prohormone brain natriuretic peptide; eGFR, estimated glomerular filtration rate; 
SAE, serious adverse event; 
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2
INTRODUCTION
MEDI6570 is an IgG1λ triple mutation antibody that is being developed as an adjunct therapy 
to standard of care to reduce the rate of CV outcomes in patients with a history of MI.
2.1
Study Rationale
This Phase IIB, proof-of-concept, dose-range finding clinical study will evaluate the 
anti-inflammatory potential of MEDI6570 and its effect on surrogates for atherosclerotic and 
HF events in patients with a history of MI. The results of the Phase IIB study will inform the 
future clinical development options and precision medicine strategy for future clinical studies.
2.2
Background
Despite marked improved adherence to medical and lifestyle changes for secondary 
prevention, CHD remains the leading cause of mortality worldwide with a recorded 
8930369 deaths attributed to it in 2018. Of those deaths 2110562 occurred in Europe (87019 
in the United Kingdom and 18317 in Sweden), 581645 occurred in North America (533166 in 
the United States and 48381 in Canada), 4929141 in Asia, 728511 in Africa, 33667 in 
Australia and 477308 in Latin America and the Caribbean (BHF-CVD-Statistics 2019). The 
economic burden is also substantial with an estimated cost of $218.7 billion for the year 2014
to 2015 in the United States alone.
CHD is a product of CAD, the latter being defined as the presence of atherosclerosis in the 
coronary arteries. CAD can lead to CHD in the form of stable angina, ACS, a syndrome of 
unstable angina, NSTEMI, and STEMI. 
Atherosclerosis develops as a result of 2 interrelated primary mechanisms: lipid deposition
and coronary inflammation (Ross 1999, Linton et al 2000). Patients with a prior MI are at 
increased risk of MACE from atherosclerosis, including CV death, MI, and stroke. Treatment 
with statins, which decrease low-density lipoprotein concentration, forms part of the current 
standard of care for patients with a prior MI. While statins decrease the residual lipid risk and 
partially decrease the inflammatory risk in patients with a prior MI, a clinically significant risk 
of MACE remains, indicating a possible need to reconsider whether background statin use 
should be mandated. CANTOS demonstrated that targeting the inflammatory risk with 
canakinumab, a monoclonal antibody against interleukin-1 β, reduces MACE compared with 
placebo (Ridker et al 2017). Natriuretic peptides were not evaluated in this study; therefore, it 
is not known whether canakinumab affected natriuretic peptide levels. To the sponsor’s
knowledge, there are no plans to develop canakinumab for the CHD indication.
Furthermore, ischemic CHD is the most common cause of HF (Crespo-Leiro et al 2016), a 
global epidemic affecting > 37.7 million people worldwide (Ziaeian and Fonarow 2016), with 
a projected 46% increase in the prevalence by the year 2030 (Savarese and Lund 2017). In 

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addition to its considerable impact on mortality and morbidity (Crespo-Leiro et al 2016), HF 
accounts for 1% to 2% of the total healthcare expenditure in Europe and North America
(Cowie et al 2014). Despite the increasing availability of therapies for HF, there is a need for 
additional therapies as the prevalence and costs of HF increase.
 
 
 
 
 
MEDI6570 is 
anticipated to reduce the following in patients with a prior MI, residual inflammation, and 
elevated NT-proBNP:

Reduce the lipid and inflammatory risks that cause atherosclerosis, and thus reduce the 
incidence of MACE 

Reduce the inflammatory risk and endothelial dysfunction that contribute to HF, and thus 
reduce the incidence of HF hospitalization 
A detailed description of the chemistry, pharmacology, efficacy, and safety of MEDI6570 is 
provided in the IB.
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Table 6
Risk Assessment
Potential Risk of Clinical 
Significance
Summary of Data and/or 
Rationale for Risk
Mitigation Strategy
CTA scan
Potential clinical consequences of 
undergoing a CTA scan include, as 
follows:
•
Radiation exposure
•
Reactions to iodinated 
contrast
•
Renal impairment due to 
contrast administration
•
Detection of incidental 
findings that may require 
assessment
•
Radiation reduction 
technologies, including 
prospective ECG-triggering 
and iterative reconstruction, 
allow CTA scans to be 
performed at low radiation 
doses (Chen et al 2013, Hou 
et al 2014, Meyersohn et al
2017, Schmermund et al
2017). Radiation reducing 
image acquisition techniques 
will be used (Section 8.1.1)
and the anticipated median 
(range) radiation exposure 
per CTA imaging time point
is 6 (3-10) mSv.
•
Risks of renal impairment 
will be minimized by 
excluding participants with 
clinically significant renal 
disease from CTA scanning
(Section 8.1.1).
•
For each CTA scan, critical 
alert findings of clinical 
importance will be 
interpreted locally at the site 
to permit appropriate 
assessment and treatment 
(Section 8.1.1).
ADA, anti-drug antibody(ies); AE, adverse event; CTA, computed tomography angiography; 
ECG, electrocardiogram; Ig, immunoglobulin;
 
mAb, monoclonal antibody; mSv, millisievert; NSAID, Non-steroidal anti-inflammatory drug; PPI, Proton Pump 
Inhibitors; SC, subcutaneous(ly)
More detailed information about the potential risks of MEDI6570 can be found in the IB.
This study is being conducted during the COVID-19 global pandemic. As a result, a risk 
assessment evaluation for COVID-19 has been prepared to protect study participants and site 
staff, including COVID-19 vaccination guidance and recommendations (Appendix G).
2.3.2 Benefit Assessment
Despite improvements made over the last decades in the prevention of secondary MIs, a 
clinically significant risk of mortality and morbidity remains for up to 5 years post-MI, with 
the highest risk in the first months post-MI (Fox et al 2010). Plaque progression has also been 
shown to predict ACS independently (Ridker et al 2017, Tardif et al 2019). Furthermore, 
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treating the inflammatory pathways associated with MIs results in improved outcomes (Ridker
et al 2017, Tardif et al 2019). In preclinical models of atherosclerosis and HF, deletion of the 
 has demonstrated decreased atherosclerosis, reductions in myocardial 
fibrosis, improvements in left ventricular function, and improvements in adverse remodeling
of the heart following MI (Lu et al 2012, Hu et al 2008, Mehta et al 2007, Yokoyama et al
2016). 
 
 
More extreme inflammatory 
phenotypes, such as patients with psoriasis, who have an increased risk of CHD also have 
elevated 
 levels. A recent study demonstrated that treatment with anti-inflammatory 
therapies in psoriasis decreased 
levels and non-calcified plaque burden. Moreover,
levels during treatment predicted regression of non-calcified plaque burden (Dey et al
2020). 
 Given 
the preclinical and clinical data, MEDI6570 may decrease the severity of atherosclerosis and 
HF and is a potential future therapy for the secondary prevention of CV death, MI, stroke, HF, 
and revascularization. 
However, as the efficacy of MEDI6570 in patients with a prior MI is yet to be determined, 
participants might receive limited or no efficacy benefits from participating in this study. 
Participants might also benefit from receiving close monitoring and follow-up of their disease 
status post-MI.
2.3.3 Overall Benefit: Risk Conclusion
Given the measures taken to minimize risk to participants enrolled in this study, the potential 
risks identified in association with MEDI6570 are justified by the potential benefits of reduced 
severity of atherosclerosis and HF that are anticipated for participants with a prior MI.
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3
OBJECTIVES AND ENDPOINTS
In participants with a prior MI, persistent inflammation and elevated NT-proBNP, the 
following endpoints in Table 7 will be evaluated in order to meet the objectives of the study.
Table 7
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the effect of MEDI6570 on non-calcified 
coronary atherosclerotic plaques compared with 
placebo
Change from baseline to Day 253 in non-calcified
plaque volume in the most diseased coronary segment 
(NCPVMD), as measured by CTA imaging
Secondary
To evaluate the effect of MEDI6570 on a surrogate 
biomarker of HF compared with placebo
Relative change from baseline to Day 253 in 
NT-proBNP.
To evaluate the effect of MEDI6570 on left ventricular 
systolic function compared with placebo
Change from baseline to Day 253 in:
•
LVEF
•
GLS
as measured by echocardiography
To evaluate the effect of MEDI6570 on left ventricular 
systolic function among participants with reduced
ejection fraction (defined as < 50%) compared with 
placebo
Change from baseline to Day 253 in:
•
LVEF
•
GLS
as measured by echocardiography
To evaluate the effect of MEDI6570 on other measures 
of non-calcified coronary atherosclerotic plaque 
compared with placebo
Change from baseline to Day 253 in:
•
Global non-calcified plaque volume
•
Low attenuation plaque volume
as measured by CTA imaging
To evaluate the immunogenicity of MEDI6570
•
ADA incidence
•
Titer
as measured in serum during the intervention and 
follow-up periods
To evaluate the PK of MEDI6570
MEDI6570 concentrations as measured in serum 
during the intervention and follow-up periods
Safety
To assess the safety and tolerability of MEDI6570 
compared with placebo
During the intervention and follow-up periods:
•
AEs
•
Clinically important changes in:
Vital signs
ECGs
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injection volume of 4.0 mL) MEDI6570, or injection/volume-matched placebo (1.5 or 
4.0 mL), subcutaneously (SC), every 4 weeks (Q4W) for 32 weeks (9 doses in total). 
Approximately 400 participants will be randomly assigned to a study intervention, with an 
anticipated 369 participants being randomized to receive active study intervention 
(123 participants in each of the 2 MEDI6570 groups), and 123 participants being randomized 
across the 3 placebo groups (ie, including participants already randomized to the legacy 
dose/volume-matched placebo group for the 
 mg dose). It is estimated that approximately 
360 evaluable participants (111 evaluable participants in each of the 2 MEDI6570 groups 
[
and 
mg], plus 27 evaluable participants in the legacy 
mg MEDI6570 group, plus 
111 participants across the 3 placebo groups) will complete the study. The randomization will 
be stratified by geographic region (Asia, North America and Rest of World) and by statin 
therapy status (no, low- or moderate-intensity statin therapy vs high-intensity statin therapy; 
refer to Appendix F) at baseline.
Participants who were randomized to a study intervention under Protocol Version 1.0 or 
Amendment 1 (when there was also a 
mg dose group) and were allocated a dosing volume 
of 0.5 mL will continue on their randomized study intervention (
 mg MEDI6570, or its 
injection/volume-matched placebo) to the end of the study, and the study blind will be 
maintained with regard to active versus placebo.
In accordance with the ESC/EAS and ACC/AHA guidelines regarding lipid modification and 
the reduction of residual CV risk, the use of high-dose statins in secondary prevention is a 
Class I recommendation with Level A evidence to support it (Mach et al 2020, Grundy et al
2019). As such, and in keeping with the expected standard of care, the implementation and 
maintenance of the highest tolerated dose of statins (although not mandated) is strongly 
encouraged in this study population.
The study will be conducted at approximately 70 to 100 study sites globally. The COVID-19 
pandemic may continue to affect different geographic regions differently, having an 
unpredictable impact on study enrollment; therefore, a more accurate estimation of the number 
of countries and study sites that may be included globally is challenging.
Participants will be enrolled in the study for up to approximately 12 months, comprising an 
optional, pre-screening period of up to 42 days (6 weeks), a screening and baseline imaging
period of up to 42 days (6 weeks), an intervention period of 225 days (31 to 32 weeks), and a 
follow-up period of 100 days (approximately 14 weeks; Figure 1). Following screening and 
confirmation of eligibility, participants will undergo an echocardiogram and CTA scan before 
randomization. The first dose of study intervention will be administered on Day 1 (Visit 3), 
after randomization. During the follow-up period, participants will undergo an 
echocardiogram and CTA scan.
An independent DMC will review safety data from this study (Section 9.6 and Appendix A 5).
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No formal interim analysis is planned. An analysis restricted to PK (serum MEDI6570 
concentration) and 
 data will be performed after approximately 80 participants 
have completed the Day 57 visit (Visit 6), to evaluate the PK data and the PK-PD relationship. 
Non-study personnel who have no other involvement in the study will perform this evaluation. 
These PK and PD data will be reviewed in conjunction with the safety data by the independent 
DMC.
4.2
Scientific Rationale for Study Design
4.2.1
Rationale for Study Population
A study population comprising participants with a prior MI and persistent inflammation was 
chosen because it reflects the population proposed for subsequent clinical development. A 
majority of participants will also have elevated NT-proBNP.
Patients surviving an MI remain at high risk of mortality and morbidity with the greatest risk 
occurring within the first 30 days post event (Abu-Assi et al 2016, Jernberg et al 2015,
Johansson et al 2017). This increased risk is partially driven by the presence of significant 
atherosclerosis in the non-infarct related vessels (Momiyama et al 2012, Park 2014, Kato et al 
2012), which may become more susceptible to rupture due to the intense inflammatory 
response, a prerequisite for healing and scar formation triggered by the MI (Frangogiannis et 
al 2002). This post-infarction inflammatory process peaks within the first and second weeks 
post-ischemic event and resolves by the third or fourth week (Sun et al 2009). Moreover, 
evidence from clinical studies suggests that patients with persistent elevation of serum 
inflammatory biomarkers 4 weeks after an ACS have worse outcomes (de Lemos et al 2007).
NCPV and total plaque volume have been shown to be significant predictors of cardiac events 
in ACS, with NCPV being a better predictor of a MACE than total plaque volume or calcium 
score (Kristensen et al 2011). These different components of coronary atherosclerosis during 
CTA have been shown to be of incremental value for prognostication (Radosavljevic-
Radovanovic et al 2016). 
In addition, NT-proBNP has been shown to be a strong predictor of future AEs in the post-MI 
population (Lindahl et al 2005), being more reliable when measured in the relatively stable 
phase (Kurtul et al 2016). Furthermore, the levels of NT-proBNP were associated with the 
severity and complexity of the underlying CAD (Kurtul et al 2016). 
The lower limit of 30 days post-MI was selected both to refrain from suppressing the 
necessary inflammatory response and because the expected elevated levels in hs-CRP,
cytokines and NT-proBNP during this window may not persist long-term. In addition, this 
period would allow patients’ standard of care medical therapy to be optimized and stabilized 
before being enrolled in the study. An upper limit of 365 days after the MI was selected to 
include patients who have a high residual risk of MACE and may derive benefit from 
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Left Ventricular Function: Ejection Fraction and Global Longitudinal Strain
Complimenting NT-proBNP for the evaluation of MEDI6570 in HF, LVEF and GLS will be 
secondary endpoints in the study. Change in LVEF and change in GLS by echocardiography 
imaging from baseline to Day 253 will be measured and compared with placebo. 
LVEF is a well-established measurement of the systolic function of the left ventricle that 
predicts prognosis in post-MI patients (Multicenter Postinfarction Research Group 1983). In 
addition, changes in LVEF following MI are predictive of sudden cardiac arrest and death 
(Chew et al 2018). Furthermore, pharmacologic improvements in LVEF have been linked to 
decreases in mortality and HF hospitalizations (Breathett et al 2016, Kramer et al 2010). 
Improvements in LVEF can occur with anti-inflammatory therapies. The CANTOS study 
demonstrated an improvement in the exercise capacity (measured by peak oxygen 
consumption) and LVEF in a subgroup analysis (Trankle et al 2018). LVEF will be calculated 
as the ratio of stroke volume divided by end-diastolic volume. 
Although LVEF is the most extensively used and investigated assessment of left ventricular 
function, GLS is a new, emerging technique that may have a more significant predictive value 
pertaining to outcomes in the HF population when compared with LVEF (Kalam et al 2014). 
In a study of 4172 patients with acute HF and varying degrees of LVEF, 1% improvement in 
GLS was associated with a 5% reduction in mortality risk irrespective of the ejection fraction
(Park et al 2018). Furthermore, it has been shown that the reproducibility of GLS as a 
measurement of left ventricular function surpasses that of LVEF, regardless of the level of 
echocardiographic training (Karlsen et al 2019).
Global Non-calcified Plaque Volume and Low Attenuation Plaque Volume
Two further measurements of plaque burden will be used in this study as a secondary 
endpoint. NCPV is the total volume of plaque in the coronary arteries that lacks calcification. 
A subset of NCPV is LAPV.
Previous studies have shown increased NCPV and LAPV in patients with ACS when 
compared with patients with stable angina (Motoyama et al 2015, Dey et al 2014). This 
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finding is consistent with low attenuation plaque being a lipid-rich plaque, laden with 
lipid-rich foam cells, at the core of an atheroma. These lipid-rich foam cells are the target of 
MEDI6570. Due to the spatial resolution of CTA, it is important to measure NCPV and LAPV 
to evaluate the effect of MEDI6570 on modifiable plaque volume in the coronary arteries
comprehensively. Computed tomography angiography measurements of NCPV and LAPV are 
highly reproducible (Andelius et al 2018). Change in NCPV and LAPV in the coronary 
arteries will be measured from baseline to Day 253 and compared with placebo. NCPV and 
LAPV were selected as secondary endpoints over calcified and total plaque volume for several 
reasons. First, when studied in ACS, specifically non-STEMI, NCPV is a better predictor of 
MACE when compared with Agatston calcium score and total plaque volume (Kristensen et al
2011). 
 
 
 In studies evaluating plaque regression with statin use, regression of both 
NCPV and LAPV have been observed. LAPV reduction has been associated with decrease in 
CV events (Andelius et al 2018). NCPV and LAPV will be measured in all vessels ≥2 mm in 
diameter and expressed in mm3. Coronary segments with stents or otherwise deemed 
uninterpretable on the baseline or follow-up scan will be excluded from analysis.
4.2.2.3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.3
Justification for Dose
Doses for this study have been selected based on analysis of final PK-PD data for single and 
multiple ascending doses of MEDI6570 in Phase I clinical study, D4920C00001. In that study, 
single doses of
 mg to 
mg SC and multiple doses of
mg to
 mg Q4W SC were 
administered to participants with Type 2 Diabetes Mellitus.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
As MEDI6570 is a monoclonal antibody that is being developed as a chronic therapy, only SC 
dosing will be used. Injection/volume-matched placebo groups are included for detecting an 
efficacy response.
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4.4
End of Study Definition
A participant is considered to have completed the study if he or she has completed all periods 
of the study through to the final protocol-specified visit/assessment (including telephone 
contact) or death, regardless of the number of doses of study intervention that was received.
The end of the study is defined as the date of the last visit/assessment (including telephone 
contact) of the last participant in the study globally.
5
STUDY POPULATION
Prospective approvals of protocol deviations to recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, are not permitted.
Participants may undergo an optional pre-screening visit upon providing written, informed 
consent for pre-screening. The optional pre-screening visit is for the purpose of collecting 
blood samples to assess qualifying biomarker values (Table 3). The local laboratory may be 
used for analyzing pre-screening samples. The optional pre-screening visit will not replace the 
screening visit; all screening visit laboratory samples must be collected and will be used to 
determine eligibility.
Participants are considered to have enrolled in the study from the time they (or their legally 
acceptable representatives) sign the first ICF (either the ICF for the optional pre-screening 
evaluations, or the ICF for the full screening evaluations).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1
Participant must provide informed consent before any study-specific activities are 
performed (Appendix A 3), must be able and willing to meet all requirements for 
randomization within 42 days after signing the full ICF, and must adhere to the schedules 
of activities.
2
Women must be ≥40 years of age at the time of signing the ICF. Men must be ≥ 21 years 
of age at the time of signing the ICF.
3
Participant must:
(a) be 30 to 365 days after presumed type-1 (ie, due to plaque rupture or erosion) MI 
(either STEMI or NSTEMI) at the time of enrollment.
(b) have persistent inflammation, defined as hs-CRP ≥1 mg/L, as measured centrally at 
screening Visit 1.
4
Participant must have body mass index within the range 18 to 40 kg/m2 inclusive.

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5
For female participants, the participant must not be pregnant or lactating and must be of 
non-childbearing potential, confirmed at screening Visit 1 by one of the following:
(a) Postmenopausal, defined as amenorrhea for ≥12 months following cessation of all 
exogenous hormonal treatments, and with luteinizing hormone and follicle 
stimulating hormone levels in the postmenopausal range.
(b) Documentation of irreversible surgical sterilization by hysterectomy, bilateral 
oophorectomy, or bilateral salpingectomy. Tubal ligation is not considered as 
irreversible surgical sterilization.
6
Participant must have an evaluable, pre-randomization CTA with quantifiable, 
non-calcified plaque, as confirmed by the core laboratory.
Participants will be reassessed for study eligibility before study intervention is administered
on Day 1 (Visit 3). Participants should be considered for a high-intensity statin based on 
existing guidelines for long-term management of patients after an MI. Participants should 
ideally be on a stable dose of lipid-lowering therapy throughout the treatment period of the 
study; therefore, efforts should be made to maximize statin intensity before randomization. 
The proportion of participants with an NT-proBNP value < 125 pg/mL at screening who can 
be randomized to a study intervention may be capped. If this proportion is capped, a baseline 
NT-proBNP value of ≥ 125 pg/mL will be required for inclusion in the study. During the 
study, randomization to an intervention group may also be capped within other specific 
participant subgroups.
In addition to the inclusion criteria specified above, study participants may elect to take part in 
the Genomics Initiative; participants who chose to do this must provide written informed 
consent before samples are collected for the optional genetic research that supports the 
Genomics Initiative (Appendix D 2).
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
1
History of any clinically important disease or disorder which, in the opinion of the 
investigator, may either put the participant at risk because of participation in the study, or 
influence the results or the participant’s ability to participate in the study.
2
Percutaneous coronary intervention or diagnostic angiogram planned after screening 
Visit 1. Eligible participants who have a diagnostic angiogram performed in the absence 
of undergoing a new PCI may continue screening after the diagnostic angiogram has been 
performed or may be rescreened (Section 5.4).
3
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4
Documented episode of post-MI pericarditis (eg, Dressler’s Syndrome) in the 3 months
before enrollment.
5
Ongoing New York Heart Association Class IV (severe) HF.
6
Increased risk of bleeding
(a) Patients with history or presence of any bleeding disorder.
(b) Signs of ongoing bleeding at screening (eg, identified macroscopic bleeding, low 
hemoglobin presumed to be caused by bleeding) or high risk for major bleeding in 
accordance with the Investigator’s assessment.
(c) Need for chronic therapeutic anticoagulation therapy anticipated to be required 
throughout the course of the study (short-term treatment with prophylactic doses of 
heparin/low molecular weight heparin are allowed).
(d) Known severe liver disease (eg, ascites and/or clinical signs of coagulopathy).
7
History or presence of any of the following:
(a) Ongoing infection or febrile illness that in the opinion of the investigator may be the 
cause of elevated hs-CRP on screening (Visit 1).
(b) Ongoing atrial fibrillation or flutter.
(c) Cancer within 5 years before randomization (Day 1; Visit 3), with the exception of 
non-melanoma skin cancer.
(d) Alcohol or substance abuse within 6 months before randomization (Day 1; Visit 3), 
as judged by the investigator. 
(e) Known history of hypersensitivity reactions to other biologics, to human IgG 
preparations, or to any component of MEDI6570, or ongoing severe allergy as judged 
by the investigator.
(f) Patients with active positive results on screening for serum hepatitis B surface 
antigen, hepatitis C antibody, or HIV.
8
Any clinically important abnormalities in clinical chemistry, hematology, coagulation 
parameters, as judged by the investigator, including but not limited to:
(a) AST > 2.0 × ULN.
(b) ALT > 2.0 × ULN.
(c) TBL > 1.5 x ULN (unless due to Gilbert’s syndrome).
(d) Platelet count < 100000 platelets/μl.
9
BP values at screening Visit 1:
(a) Systolic BP < 90 mmHg or > 180 mmHg.
(b) Diastolic BP > 100 mmHg.
(c) Participants who are excluded based on elevated BP may be rescreened following 
adequate treatment.

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The eligibility assessment is based on measurements taken starting from after 5 minutes 
of rest; if the result is outside these limits, additional BP measurements can be taken over 
the following 5 minutes, ie, up to a total of 10 minutes of rest (repeated a maximum of 
3 times). If the result is outside these limits during this period, the participant is 
considered a screen fail.
10 Participants with any of the following contraindications to CTA:
(a) eGFR < 50 mL/min/1.73 m2 by the Chronic Kidney Disease Epidemiology 
Collaboration equation, or end stage renal disease treated with kidney transplant or 
renal replacement therapy.
(b) Allergy to iodinated contrast.
(c) History of contrast-induced nephropathy.
(d) Contraindication to nitroglycerin.
(e) Rapid heart rate that is uncontrolled by medical therapy.
(f) Inability to hold breath for at least 6 seconds.
11 Receipt of any investigational device or therapy within 6 months or 5 half-lives before 
screening (whichever is longer).
This criterion does NOT apply for inactive, non-replicating COVID-19 vaccines approved 
by Health Authorities or under emergency use authorization.
12 Planned participation in an additional investigational study of an intervention or biologic 
before the end of the follow-up period. Participation in observational studies or studies 
without investigational drugs or devices is allowed.
13 Participants who are legally institutionalized.
14 An employee or close relative of an employee of the sponsor, the CRO, or the study site, 
regardless of the employee or close relative’s role.
5.3
Lifestyle Considerations
Not applicable.
5.4
Screen Failures
Potential participants who are pre-screened and/or screened for the purpose of determining 
eligibility for the study, but are not randomly assigned in the study, are considered screen 
failures.
A minimal set of screen failure information is required to ensure transparent reporting of 
screen failure participants to meet the Consolidated Standards of Reporting Trials publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
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Rescreening
Participants who fail screening may be rescreened under the following circumstances:

Eligible participants who exceed the 42-day pre-randomization window may be 
rescreened to determine eligibility before randomization and the Medical Monitor will 
decide whether screening laboratory evaluations should be repeated. If the screening 
assessments are not considered to be representative of the usual status of the health of the 
participant by the investigator, or if ≥1 exclusion criteria are considered temporary (eg, 
diagnostic angiogram) or from a reversible condition, repeat screening assessments to 
establish eligibility will generally be permitted once, at the discretion of the investigator. 

Eligible participants who have a diagnostic angiogram performed after screening Visit 1 
in the absence of undergoing a new PCI may continue screening after the diagnostic 
angiogram has been performed (Exclusion Criterion 2). If they exceed the 42-day 
pre-randomization window, the Medical Monitor will decide whether the participant is 
required to be rescreened and whether screening laboratory evaluations should be 
repeated. Participants who have a PCI performed between Screening Visit 1 and 
Randomization Visit 3 may not be rescreened.

Participants who are excluded based on elevated BP may be rescreened following 
adequate treatment (Exclusion Criterion 9(c)).
For eligible participants who are rescreened, the rescreen date must also be within the MI 
window of not more than 365 days since MI.
Rescreened participants should be assigned the same enrollment code as for the initial 
screening.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Interventions Administered
In this study, the study intervention is an IMP, and the IMP is a biologic or its matching 
placebo (Table 8). The study intervention/IMP is MEDI6570, a human IgG1λ triple mutation
antibody that binds to human
MEDI6570 is supplied as a lyophilized powder that needs to be reconstituted; whereas, the 
placebo is supplied in liquid form.
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Table 8
Investigational Products
Group name
MEDI6570
Placebo
Intervention 
name
MEDI6570
Placebo
Type
Biologic
Placebo
Supplied as
A sterile, white to off-white, lyophilized product in a 6R 
glass vial stoppered with a 20 mm rubber stopper, and 
sealed with a flip-off cap overseal
A sterile, clear to slightly 
opalescent, colorless to 
slightly yellow liquid, free 
from visible particles in a 6R 
glass vial at a nominal volume 
of 5.3 mL, stoppered with a 20 
mm rubber stopper, and sealed 
with a flip-off cap overseal. 
Dose 
formulation
(after 
reconstitution)
After reconstitution, the vial contains a nominal volume 
of 1.0 mL, at concentrations of 
mg/mL MEDI6570, 
20 mM L-histidine/L-histidine hydrochloride, 240 mM 
sucrose, 0.04% (w/v) polysorbate 80, and at pH 6.0.
The supplied vial contains 
20 mM L-histidine/L-histidine 
hydrochloride, 240 mM 
sucrose, 0.02% (w/v) 
polysorbate 80, at pH 6.0.
Unit dose 
strength
mg MEDI6570 per vial
NA
Dosage levels
mg Q4W for 
32 weeks (9 
doses in total) a
 mg Q4W for 
32 weeks 
(9 doses in total)
mg Q4W for 
32 weeks 
(9 doses in total)
Q4W for 32 weeks (9 doses in 
total) dependent on 
intervention group
Route of 
administration
SC injection
SC injection
Use
Experimental
Placebo comparator
IMP or NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor.
Provided centrally by the 
sponsor.
Packaging and 
labeling
Study intervention will be provided in 6R vials 
packaged into single vial kits. Each 6R vial and outer 
carton will be labeled as required per country 
requirement.
Study intervention will be 
provided in 6R vials packaged 
into single vial kits. Each 6R 
vial and outer carton will be 
labeled as required per country 
requirement.
a
Under Protocol Amendment 2, no new participants will be randomized to the 
 mg dose group or its 
injection/volumed matched placebo (0.5 mL); participants who were randomized to 
mg MEDI6570 or its 
injection/volume-matched placebo will continue on their randomized intervention until the end of the study. 
For participants enrolled under Amendment 2, there will be 2 placebo groups to match the dosing volumes 
of the 2 active groups: 1.5 and 4.0 mL.
IMP, investigational medicinal product; NA, not applicable; NIMP, non-investigational medicinal product; Q4W, 
every 4 weeks; SC, subcutaneous; w/v, weight per volume.
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6.2
Preparation/Handling/Storage/Accountability of Interventions
6.2.1
Study Intervention Inspection
MEDI6570 is supplied in 6R vials as a sterile white to off-white lyophilized product. Placebo 
is supplied in 6R vials as a sterile liquid. 
If there are any defects noted with the study intervention, the investigator and site monitor 
should be notified immediately.
6.2.2
Storage
The study intervention should be stored at 2°C to 8°C (36°F to 46°F). The investigator or 
designee must confirm that appropriate temperature conditions have been maintained during 
transit for all study intervention received and that any discrepancies are reported and resolved 
before the study intervention is used. 
All study intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions and with access 
limited to authorized, unblinded site staff.
6.2.3
Dose Preparation Steps
The MEDI6570 and placebo doses must be prepared by the site’s designated unblinded study 
intervention manager using aseptic technique.
The total time from needle puncture of the MEDI6570 vial or placebo vial to SC 
administration should not exceed:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature
If the preparation time exceeds the time limits, a new dose must be prepared from new vials. 
MEDI6570 and placebo do not contain preservatives and any unused portion must be 
discarded.
Reconstitution Procedure
Each vial of MEDI6570 must be reconstituted with 1.3 mL of sterile water for injection to 
achieve 
 mg/mL MEDI6570. Slowly add 1.3 mL of sterile water for injection by tilting the 
vial to one side such that the liquid stream is directed along the vial wall and not directly onto 
the lyophilized product. Gently swirl the solution until all solids are dissolved. Do not shake 
or vigorously agitate the vial. Visually inspect the solution to ensure that the entire content of 
the lyophilized product is completely reconstituted. The reconstituted solution should appear 
clear to opalescent. A thin layer of bubbles on the surface of the liquid is normal.
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Study intervention will be dispensed at the study visits as summarized in the SoA 
(Section 1.3). The first day of dosing is considered Day 1.
The study intervention administrator should be experienced in performing SC injections. The 
skin surface of the anterolateral thigh, upper outer tricep area, upper buttocks, or abdomen 
(avoid a 2-inch [5 cm]) radius around the umbilicus) should be prepared with an alcohol wipe 
and allowed to air dry. The skin will be pinched to isolate SC tissue from the muscle. The 
needle will be inserted at a 90-degree angle to the skin surface approximately halfway into the 
SC tissue. The study intervention will be injected slowly (at an appropriate speed in 
accordance with local procedures) into the SC tissue using gentle pressure. The area should 
not be massaged after injection.
Study intervention should NOT be administered if it is not fully reconstituted, if it has been at 
room temperature for more than 4 hours, or if it has been at 2°C to 8°C (36°F to 46°F) for 
more than 24 hours.
6.2.5
Accountability
The site’s designated unblinded study intervention manager is required to maintain accurate 
study intervention accountability records. Upon completion of the study, copies of 
investigational product accountability records will be returned to the sponsor. All unused 
study intervention will be destroyed locally, in accordance with local standard operating 
procedures, after full accountability by the site has been performed. Destruction can be 
outsourced to a third party. Certificates of destruction must be collected.
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Randomization Procedure
Participants will be randomized to an intervention group to minimize bias. 
Randomization will be performed after the blood and urine samples are collected on Day 1
(Visit 3).
A 3-stage randomization procedure will be implemented:
1
Participants will first be grouped into strata according to geographic region (Asia, North 
America and Rest of World). 
2
Then, within each geographic region, participants will be grouped into strata according to 
the status of their statin therapy intensity at baseline (no, low- or moderate-intensity statin 
therapy, vs high-intensity statin therapy; refer to Appendix F).
3
Then, within each stratum, participants will be assigned randomly to an intervention 
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Before the study starts, the instructions for the RTSM will be provided to each site.
Re-allocation of participants to a dosing volume (Protocol Amendment 1): As a result of 
removing the 
 mg dose and introducing the 
mg dose in Amendment 1, all participants 
enrolled under Protocol Version 1.0 were re-allocated to the appropriate dosing volume for 
their randomized intervention group under Amendment 1. Participants originally randomized 
to the 
mg MEDI6570 group under Protocol Version 1.0 who had not completed treatment 
were switched to the 
 mg MEDI6570 group under Amendment 1. Participants originally 
randomized to the placebo group and who had not completed study treatment were
re-randomized to one of the 3 injection/volume-matched placebo groups under Amendment 1.
6.3.2
Blinding Procedure
The participant, the investigator, and the site staff performing study-related procedures will all 
be blinded to the participant’s intervention group, with respect to active treatment versus 
placebo, to minimize bias.
The RTSM will provide to the investigators or pharmacists the kit identification number to be 
allocated to the participant at the dispensing visit. Routines for this will be described in the 
RTSM user manual provided to each study site.
The sponsor retains the right to break the code for SAEs that are unexpected and are suspected 
to be causally related to the study intervention 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 participant have 
been made and documented.
The RTSM will be programmed with blind-breaking instructions. In case of an emergency, in 
which the knowledge of the specific blinded study treatment will affect the immediate 
management of the participant’s condition, the investigator has the sole responsibility for 
determining whether unblinding of a participant’s intervention assignment is warranted. 
Participant safety must always be the first consideration in making such a determination. If a 
participant’s intervention assignment is unblinded, the sponsor must be notified within 
24 hours after breaking the blind. The investigator must document and report the action to the 
sponsor, without revealing the participant’s treatment to the sponsor’s staff.
Participants enrolled under Protocol Amendment 2 will be randomly assigned to one of 4 
possible intervention groups in a 2:2:1:1 ratio: 
 mg (with an injection volume of 1.5 mL) 
or 
mg (with an injection volume of 4.0 mL) MEDI6570, or an injection/volume-matched 
placebo (1.5 or 4.0 mL). Investigators will remain blinded to each participant’s assigned study 
intervention, with respect to active treatment versus placebo, throughout the course of the 
study. 
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Participants who were randomized to a study intervention under Protocol Version 1.0 or 
Amendment 1 and were allocated a dosing volume of 0.5 mL will continue on their 
randomized study intervention (
 mg MEDI6570, or its injection/volume-matched placebo) 
to the end of the study, and the study blind will be maintained with regard to active versus 
placebo.
To maintain the study blind, an otherwise uninvolved third party will be responsible for the 
reconstitution and dispensation of all study intervention and will endeavor to ensure that there 
are no differences in the times taken to dispense the study interventions following 
randomization.
Areas of the pharmacy where the study intervention is being stored and prepared must be
accessed only by unblinded team members. 
In the event of a Quality Assurance audit, the auditor(s) will be allowed access to unblinded 
study intervention records at the site(s) to verify that randomization and/or dispensing has 
been done accurately.
Laboratory results
The participant, investigator and study site staff will remain blinded to the following 
post-randomization laboratory results:

 

NT-proBNP



Concentrations of MEDI6570 in serum

ADAs
6.4
Study Intervention Compliance
Participants will receive study intervention directly from the investigator or designee, under 
medical supervision, at the clinic. The date, and time if applicable, of dose administration will 
be recorded in the source documents and recorded in the eCRF. The dose of study intervention 
and study participant identification will be confirmed at the time of dosing by a member of the 
study site staff other than the person administering the study intervention.
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines and/or 
vitamins) that the participant is receiving at the time of enrollment, or receives during the 
study, must be recorded along with:

Reason for use
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
Dates of administration including start and end dates

Dosage information, including dose and frequency
The Medical Monitor should be contacted if there are any questions regarding concomitant or 
prior therapy. 
6.5.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to provide 
adequate supportive care. Specifically, participants should receive standard of care during the 
study in accordance with their institutional guidelines. Participants should be considered for a 
high-intensity statin and for anti-platelet therapies based on existing guidelines for long-term 
management of patients after a myocardial infarction. Participants with a need for chronic 
therapeutic anticoagulation therapy are excluded from study participation; however, short-term 
treatment with prophylactic doses of heparin/low molecular weight heparin are allowed
(Section 6.5.2 and Section 7.1).
In view of the use of anti-platelet therapy in this population, the use of PPIs is encouraged, to 
confer gastric protection in the event that the concomitant use of NSAIDs is required. This is 
of special consideration in this study population because of a theoretical risk of bleeding 
highlighted in Table 6.
If the participant requires concomitant NSAID therapy, Investigators are encouraged to 
prescribe PPIs in order to minimize the theoretical risk of bleeding events.
Guidance for participants undergoing COVID-19 vaccination during the study is provided in 
Appendix G 4.
6.5.2
Prohibited Concomitant Medications
The need for chronic therapeutic anticoagulation therapy is an exclusion criterion. If the 
participant develops a condition that requires the use of chronic therapeutic anticoagulation 
therapy during dosing, temporary or permanent discontinuation of study intervention should be 
considered by the investigator, based on assessment of bleeding risk.
6.6
Dose Modification
Not applicable.
6.7
Intervention after the End of the Study
No study intervention will be provided to participants following the end of the study.

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7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to discontinue study intervention temporarily or 
permanently. An individual participant will discontinue study intervention (either temporarily 
or permanently) if any of the following occurs in the participant in question:
1
An AE that in the opinion of the investigator or the sponsor contraindicates dosing.
2
Clinical symptoms of spontaneous bleeding so that the PI judges further administration of 
study intervention should be paused or stopped.
(a) Providers should consider temporary or permanent discontinuation of study 
intervention in participants who: 
(i)
Develop a condition that requires the use of chronic therapeutic anticoagulation 
therapy.
(ii) Experience severe bleeding that is not readily explained by a reversible alternate 
etiology. All bleeding events should be treated and followed up according to 
local clinical practice. Study intervention may be resumed when the risk of 
bleeding is deemed low in the judgment of the investigator.
(b) Study intervention must be stopped in the event of severe thrombocytopenia (platelet 
count < 50000 platelets/µL) which does not resolve, or if after resolution the 
investigator thinks it is not appropriate to restart study intervention because it may 
put the participant at undue risk.
3
A generalized hypersensitivity reaction occurring which, in the opinion of the PI and/or 
the Medical Monitor, would warrant discontinuation.
4
After initial dosing, there exists a clinically significant safety issue based on information 
not known or not disclosed before randomization.
5
Participant non-compliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal (eg, refusal or inability to adhere to scheduled visits).
6
Withdrawal of consent.
If study intervention is permanently discontinued, the participant will remain in the study to be 
evaluated for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation (Section 7.2) or the participant is lost to follow-up
(Section 7.3).
Note that discontinuation from study intervention is NOT the same as a withdrawal from the 
study.

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7.2
Participant Withdrawal from the Study

A participant may withdraw from the study at any time at his/her own request
(withdrawal of consent).

A participant who considers withdrawing consent from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records). If the participant 
agrees to any of these methods of follow-up, then he/she will not be considered to have 
withdrawn consent.

If the participant 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 participant withdraws from the study, it should be confirmed whether he/she still 
agrees that existing samples may be used in line with the original consent. If he/she 
requests withdrawal of consent for use of samples, destruction of any samples taken and 
not tested should be carried in line with what was stated in the informed consent and local 
regulations. The investigator must document the decision on use of existing samples in 
the site study records and inform the Global Study Team.
7.3
Lost to Follow-up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site by the end of the study. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:

The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.

Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.

If the participant’s final health status can be determined by contact with a relative or 
personal doctor, then the participant will not be deemed to be lost to follow-up.

Site personnel will attempt to collect the vital status of the participant within legal and 
ethical boundaries for all participants randomized, including those who did not receive 
study intervention. Public sources may be searched for vital status information. If vital 
status is determined as deceased, this will be documented and the participant will not be 
considered lost to follow-up. Sponsor personnel will not be involved in any attempts to 
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
Patients will only be designated as “Lost to Follow-up” at the time of database lock when 
all attempts to contact or gain vital status for the participant have failed.
Discontinuation of specific sites or of the study as a whole is described in Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol
waivers or exemptions are not allowed.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine whether the participant should continue or 
discontinue study intervention.

Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct.

An optional pre-screening visit to collect local laboratory values for hs-CRP and 
creatinine (for eGFR calculation) may occur upon completing the pre-screening informed 
consent within 42 days before signing the screening ICF (screening Visit 1). If 
randomization of participants with NT-proBNP < 125 pg/mL is capped, NT-proBNP (or 
BNP if NT-proBNP is not available) may also be collected during pre-screening.

All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable.

Procedures conducted as part of the participant’s routine clinical management and 
obtained before signing of the ICF may be used 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 participant over the duration of the 
study, including any extra assessments that may be required, will not exceed 630 mL. 
Repeat or unscheduled samples may be taken for safety reasons or if there are technical 
issues with the samples.
8.1
Efficacy Assessments
8.1.1
CTA Imaging
8.1.1.1
Timing of CTA Imaging Relative to Echocardiogram
If echocardiogram (Section 8.1.2) and CTA imaging are performed on the same day, 
echocardiogram imaging must always occur before CTA imaging, and before any additional 
beta-blocker administration above the daily dose used by the participant, to avoid large doses 
of a beta-blocker affecting echocardiogram measurements. This only applies to a beta-blocker 
given for the purposes of heart rate control for coronary CTA. Participants should continue 
taking their clinically prescribed dose of beta-blocker as scheduled.

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8.1.1.2
Criteria for CTA Imaging
For the pre-randomization period, CTA imaging requirements are included in the inclusion 
criteria (Section 5.1). 
For the follow-up period, participants must meet the following criteria before CTA imaging:
1
Using creatinine samples for the calculations, eGFR must be ≥45 mL/min/1.73m2 (within 
30 days before the CTA scan). Sites are permitted to test for an additional creatinine 
(local or central), if needed for the purposes of CTA imaging.
2
No known allergy to iodinated contrast or known history of contrast-induced 
nephropathy.
3
No history of coronary bypass surgery.
4
No active arrhythmia including atrial fibrillation or atrial flutter on the day of CTA 
imaging that would likely interfere with quality of CTA imaging. Participants can return 
for CTA imaging on another day, if necessary.
5
No contraindication to nitroglycerin.
6
Not have rapid heart rate that is uncontrolled by medical therapy.
7
Participants who have any condition that, in the opinion of the investigator, would 
increase the risk associated with having CTA imaging (eg, clinically significant renal 
disease) will not undergo CTA imaging.
8.1.1.3
Radiation Exposure from CTA Imaging, Including Rules for Repeating CTA 
Scans 
The overarching principle for CTA imaging will be to maximize high-quality CTA imaging 
for endpoint ascertainment while minimizing radiation exposure to participants. 
The anticipated median (range) radiation exposure per CTA imaging time point is 
6 (3-10) mSv. A maximum cumulative radiation exposure of 30 mSv is anticipated in this 
study and will be monitored by the CTA core laboratory through a radiation monitoring 
escalation plan. Radiation dose will be estimated based on dose length product using a 
K (conversion) factor of 0.014. Dose-saving image acquisition techniques will be used where 
applicable. 
The baseline and follow-up CTA scans may be repeated under certain circumstances. 
In order to ensure that the overall radiation exposure remains within the specified limit, rules 
for CTA scans are detailed by time point below:
1
Baseline CTA (Day -30 to -1; Visit 2):
(a) If the baseline CTA scan is obtained but randomization does not occur within the 
prespecified screening window, there is a 30-day window to repeat screening and 
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The CTA images will be analyzed in the core laboratory. The CTA imaging manual describes 
the CTA imaging protocol, which will accommodate differences in imaging platforms across 
sites.
8.1.2
Echocardiography
Participants must meet the study eligibility criteria (Sections 5.1 and 5.2) before undergoing 
echocardiogram imaging. If echocardiogram and CTA imaging are performed on the same 
day, echocardiogram imaging must always occur before CTA imaging, and before any 
additional beta-blocker is administered above the daily dose used by the participant.
Imaging personnel and equipment will undergo certification by a separate, blinded, 
independent core laboratory. Echocardiography will be performed at time points specified in 
the SoA (Section 1.3).
Planned measurements include, as follows:

Left Ventricular Ejection Fraction

Left Ventricular GLS


Any additional measurements as described in the echo imaging manual/protocol
The echocardiogram images will be analyzed in the core laboratory. The echocardiography 
imaging manual describes the imaging protocol, which will accommodate differences in 
imaging platforms across sites.
If for any reason an echocardiogram image is deemed uninterpretable for any planned 
measurements by the core laboratory, then echocardiography may be repeated at the discretion 
of the investigator, participant, and Medical Monitor. The repeat echocardiogram must be 
obtained within the time specified for the visit window in the SoA (Section 1.3).
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations
A complete physical examination will be performed and will include assessments of the 
following: general appearance; the respiratory, CV, thyroid, muscular-skeletal (including 
spine and extremities) and neurological systems; the abdomen, skin, head and neck (including 
ears, eyes, nose and throat), and lymph nodes; weight and height. 
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An abbreviated physical examination will include, at a minimum, assessments of the skin, the 
respiratory and CV systems, the abdomen (liver and spleen), and any type of bleeding.
Physical examination will be performed at timelines as specified in the SoA (Section 1.3).
8.2.2
Vital Signs
Vital signs (BP and heart rate) will be measured at the time points specified in the SoA
(Section 1.3). Measurements will be taken after the patient has rested for at least 5 minutes in 
a sitting position. If multiple vital signs measurements are taken, the last measurement is the 
one that should be recorded.
8.2.3
Electrocardiogram
Electrocardiogram will be performed at the time points specified in the SoA (Section 1.3).
Participants will have 12-lead ECG recordings taken as specified in SoA, recorded after a 
5-minute rest with the participant in the supine position. Analysis of the ECG results will be 
performed locally and results recorded using electronic data capture. 
8.2.4
Clinical Safety Laboratory Assessments
Blood samples for determination of clinical chemistry, hematology, and coagulation variables
will be collected at the visits indicated in the SoA (Section 1.3).
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date, time of collection, and type of sample will be recorded on the 
appropriate eCRF.
The clinical chemistry and hematology safety laboratory samples will be analyzed at a central 
core laboratory. Laboratory safety variables are listed in Table 10.
Table 10
Laboratory Safety Variables
Hematology
(whole blood)
Clinical chemistry 
(serum)
Eligibility
B-Hemoglobin
S/P-Creatinine
Luteinizing Hormone
B-Leukocyte count
S/P-Bilirubin, total
Follicle Stimulating Hormone
B-Leukocyte differential count (absolute count)
S/P-ALP
HIV
B-Platelet count
S/P-AST
Hepatitis B
Coagulation panel including INR, and aPTT
(screening only)
S/P-ALT
Hepatitis C
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S/P-Potassium
S/P-Calcium, total
S/P-Sodium
S/P-CK
If a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN refer to Appendix E.
ALP, alkaline phosphatase; ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; AST, 
aspartate aminotransferase; CK, creatine kinase; HIV, human immunodeficiency virus; INR, international 
normalized ratio; S/P, serum/plasma; TBL, total bilirubin; ULN, upper limit of normal
8.2.5
Other Safety Assessments
8.2.5.1
Bleeding
Study participants will be monitored for AEs related to bleeding by reviewing AEs and SAEs 
assessed at time points specified in the SoA (Section 1.3). All bleeding events will be reported 
as AEs and characterized further, allowing for their classification according to bleeding type.
8.2.5.2
Monitoring for Hypersensitivity Reactions
Participants will be closely monitored during and after administration of study intervention 
during the observation period as specified in the SoA (Section 1.3) for hypersensitivity 
reactions, including monitoring for signs and symptoms of immune complex disease. Severe 
hypersensitivity reactions should be managed according to standard clinical practice, and 
medical equipment and staff trained to treat acute anaphylactic reactions must be available at 
all sites. If a hypersensitivity reaction occurs, dosing of the participant will be stopped.
Hypersensitivity reactions will be recorded as AEs or SAEs, as appropriate.
8.2.5.3
Injection Site Reactions
Study participants will be monitored for injection site reactions. All injection site reactions 
will be recorded as AEs and further characterized.
8.3
Adverse Events and Serious Adverse Events
The PI 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 are given in Appendix B.
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant's legally authorized representative).
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.

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8.3.1
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
Non-serious AEs will be collected from the time of randomization throughout the treatment 
period and including the follow-up period.
Serious adverse events will be recorded from the time of signing of the first ICF (either the 
brief, pre-screening ICF or the full, screening ICF) throughout the treatment period and 
including the follow-up period.
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational product that occurs after the end of the clinical study in a participant treated by 
him or her, the investigator shall, without undue delay, report the SAE to the sponsor.
8.3.2
Follow-up of Adverse Events and Serious Adverse Events
Any AEs that are unresolved at the participant’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. The sponsor retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The date when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Whether the AE is an injection site reaction

Investigator causality rating against the investigational product (yes or no)

Action taken with regard to investigational product

AE caused participant’s discontinuation of IP administration (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

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
Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between investigational product and each 
AE, 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 should 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.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or care provider, reported in response to an 
open question from the study site staff (ie, Have you had any health problems since the 
previous visit/you were previously asked?), 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.
In addition, the recording of CV events (in this study to include CV death, MI, stroke, 
coronary revascularization, and heart failure hospitalization) are important efficacy measures 
in CV clinical trials. All CV events will be recorded as AEs to allow for further 
characterization. Although this study will not be powered for these endpoints, the study will 
explore the effect of MEDI6570 on these important parameters.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP-mandated laboratory tests and vital signs will be summarized in the 
CSR.
Deterioration from baseline in protocol-mandated laboratory values or vital signs should 
therefore only be reported as AEs if they fulfill any of the SAE criteria, are the reason for 
discontinuation of treatment with the investigational product or are considered to be clinically 
relevant as judged by the investigator (which may include but not limited to consideration as 
to whether treatment or non-planned visits were required or other action was taken with the 
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If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible, the reporting investigator
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
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.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3x ULN together with TBL ≥2x ULN may need 
to be reported as SAEs. Further instruction on cases of increases in liver biochemistry and 
evaluation of Hy’s Law is given in Appendix E.
8.3.7
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 inform 
the sponsor’s appropriate representatives within 1 day, ie, immediately but no later than 
24 hours after 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 sponsor’s 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 AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. investigators or other site personnel inform the 
sponsor’s representatives of any follow-up information on a previously reported SAE within 
1 calendar day, ie, immediately but no later than 24 hours after he or she becomes aware of 
it.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture system, an automated email alert is sent to the sponsor’s designated representative.
If the electronic data capture system is not available, then the investigator or other study site 
staff reports an SAE to the appropriate sponsor representative by telephone.

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The sponsor’s representative will advise the investigator/study site staff how to proceed. 
For further guidance on the definition of an SAE, see Appendix B.
The reference document for definition of expectedness/listedness is the IB for the study 
intervention.
8.3.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to the sponsor except if the 
pregnancy is discovered before the study participant has received any study intervention.
8.3.8.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately, and the 
pregnancy reported to the sponsor.
Pregnancy itself is not regarded as an AE. 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 participant was discontinued from the 
study.
If any pregnancy occurs during the study, then the investigator or other site personnel informs 
the appropriate sponsor representatives within 1 day, ie, immediately but no later than 
24 hours after he or she becomes aware of it.
The sponsor’s designated representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site within 1 or 5 calendar 
days for SAEs (Section 8.3.7) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
8.3.8.2
Paternal Exposure
Nonsterilized male study participants should be advised to use a condom for all sexual 
intercourse with a female partner of childbearing potential from Day 1 through the end of the 
study follow-up period. All male participants should refrain from fathering a child or donating 
sperm during the study and for 190 days following the last dose. If the partner becomes 
pregnant, the partner will be asked (under a separate consent) to provide information about the 
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8.3.9
Study Intervention Error
If a study intervention error occurs during the study, then the investigator or other site 
personnel informs the sponsor’s appropriate representatives within 1 day, ie, immediately but 
no later than 24 hours of when he or she becomes aware of it.
The sponsor’s designated 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 study intervention error (Section 8.3.7) and within 30 days for all other 
study intervention errors.
The definition of a study intervention error can be found in Appendix B.
8.4
Overdose
For this study, any dose of MEDI6570 greater than the intended maximum investigated dose 
per participant will be considered an overdose.
In cases of known or suspected overdose:

Symptomatic treatment and monitoring of vital functions should be performed according 
to routine clinical practice. 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 of a study intervention occurs during the study, the investigator or other site 
personnel inform the appropriate sponsor representatives immediately, but no later than 
24 hours after he or she becomes aware of it.
The sponsor’s designated representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site within 1 (Initial 
Fatal/Life-Threatening or follow-up Fatal/Life-Threatening) or 5 (other serious initial and 
follow-up) calendar days for overdoses associated with an SAE (Section 8.3.7) and within 
30 days for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the 
study-specific laboratory manual. Samples should be stored in a secure storage space with 
adequate measures to protect confidentiality. For further details on Handling of Human 
Biological Samples (Appendix C).

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Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

PK samples will be disposed of after the Bioanalytical Report is finalized, unless 
participants provided consent for their use in future analyses. 

PK samples may be disposed of or anonymized by pooling. Additional analyses may 
be conducted on the PK samples to evaluate and validate the analytical method
further. Any results from such analyses may be reported separately from the CSR.

Remaining ADA sample aliquots will be retained by the sponsor or its designee for up to 
2 years after registration. If the program is terminated, samples may be disposed of 
sooner. Additional use includes but is not limited to further characterization of any ADAs, 
and confirmation and/or requalification of the assay, as well as additional assay 
development work. The results from future analysis will not be reported in the CSR.
8.5.1
Pharmacokinetics

Serum samples will be collected for measurement of serum concentrations of MEDI6570
as specified in the SoA.

Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor (eg, for safety reasons). The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring.

PK samples from participants receiving placebo will be analyzed at minimum to 
demonstrate lack of dosing.

Serum samples will be used to analyze the PK of MEDI6570. Samples collected for 
analyses of MEDI6570 serum concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study.

Samples will be collected, labeled, stored, and shipped as detailed in the laboratory 
manual.
Determination of Drug Concentration
Samples for determination of drug concentration in serum will be assayed by a bioanalytical 
test site operated by or on behalf of the sponsor, using an appropriately validated bioanalytical 
method. Full details of the analytical method used will be described in a separate bioanalytical 
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.
Incurred sample reproducibility analysis may be performed. The results from the evaluation, if 
performed, will be reported in a separate Bioanalytical Report.

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8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of the sponsor, using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report.
ADA samples may also be tested further for characterization of the ADA response.
Samples may be collected at additional time points during the study if warranted and agreed 
upon between the investigator and the sponsor (eg, for safety reasons). The timing of sampling 
may be altered during the course of the study based on newly available data to ensure 
appropriate monitoring.
Samples will be collected, labeled, stored, and shipped as detailed in the laboratory manual.
8.5.3
Pharmacodynamics
8.6
Human Biological Sample Biomarkers
Blood will be collected to evaluate:


Known inflammatory markers in atherogenesis (
and HF biomarker 
(NT-proBNP) in serum, using validated clinical assays. 
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to take part in the study, the participant consents to the mandatory research 
components of the study.
The following blood sample collections are mandatory; the time points for their collection are 
given in the SoA (Section 1.3), and instructions for collecting, handling, labeling, storing, and 
shipping samples are given in the laboratory manual:

Samples for circulating biomarkers, including:


NT-proBNP (HF biomarker)

 
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
Samples for additional evaluation of circulating biomarkers of inflammation and 
biomarkers of CV disease pathogenesis and related disease states.

Samples for diagnostic assay development; these will be stored and may be used for 
commercial diagnostic assay development.
8.6.2
Collection of Optional Samples for Biomarker Analysis
Collection of urine samples and unused plasma and serum samples for future use is also part 
of this study and is subject to the participant’s optional consent. 
8.7
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA (Section 1.3) and is subject to agreement in the ICF addendum.
For storage and destruction of genetic samples see Appendix D.
8.8
Medical Resource Utilization and Health Economics
Not applicable.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The primary efficacy variable is NCPVMD, which is defined as the coronary segment with the 
largest NCPV on the baseline scan. The null hypothesis is that there is no difference in change 
from baseline in NCPVMD between a MEDI6570 dose group and the placebo group. The 
alternative hypothesis is that the change from baseline in NCPVMD reduction is larger in the 
MEDI6570
mg group compared with the pooled placebo group.
9.2
Sample Size Determination
The 3 injection/volume-matched placebo groups will be pooled for the analyses.
 
 
 
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9.3
Populations for Analyses
There are 7 populations defined for this study (Table 11).
Table 11
Populations for Analyses
Population
Description
ITT
All randomized participants will be included in the ITT Population. 
Participants will be analyzed according to their randomized intervention 
group. Participants randomized to the 
mg group that switch dose to 
mg during the trial will be analyzed according to the 
 mg group.
As-treated
Randomized participants who receive any study intervention will be 
included in the As-treated Population. Participants will be analyzed 
according to the actual intervention they receive, regardless of their 
randomized intervention group. Participants randomized to the 
 mg 
group that receive at least one 
mg dose during the study will be 
analyzed according to the 
 mg group. Participants that only receive 
mg will be analyzed as a separate 
mg group.
CTA Analysis
Participants within the ITT population who have interpretable CTA scans at 
baseline and at least one post-baseline time point will be included in the 
CTA Analysis Population. 
Per-protocol CTA analysis
Participants in the CTA Analysis Population who receive at least 3 doses of 
study intervention will be included in the Per-protocol CTA Analysis 
Population. 
Participants will be analyzed according to the actual intervention they 
receive.
Echocardiogram Analysis
Participants within the ITT population who have interpretable 
echocardiograms in the baseline and follow-up periods will be included in 
the Echocardiogram Analysis Population.
PK
All participants who receive ≥1 dose of MEDI6570 per protocol and 
have ≥one post-dose, evaluable, MEDI6570 serum concentration 
determination will be included in the PK analysis set. 
Immunogenicity
Participants included in the As-treated Population who 
have ≥1 immunogenicity sample will be included in the Immunogenicity 
Population.
CTA, computed tomography angiography; ITT, Intent-to-treat; PK, pharmacokinetic.
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9.4
Statistical Analyses
This section summarizes the planned statistical analyses of the endpoints, including primary 
and secondary endpoints.
A comprehensive SAP will be finalized within one month of the first participant being dosed.
The SAP will include a more technical and detailed description of the statistical analyses 
described in this section. Any subsequent amendments to the SAP will be documented, with 
final amendments completed before unblinding of the data for the analysis. Details of all 
analyses will be documented fully in the SAP. 
9.4.1
General Considerations
All primary, secondary, and exploratory efficacy endpoints will be summarized descriptively. 
Categorical data will be summarized by the number and percentage of participants in each 
category. Continuous variables will be summarized by descriptive statistics, eg, n, mean,
geometric mean, SD, coefficient of variation, median, interquartile range, minimum, and 
maximum. Baseline values will be defined as the last assessment before the first 
administration of study intervention. 
P-values will be presented as 1-sided without multiplicity adjustments. Confidence intervals 
will be presented as 90%, 2-sided, without multiplicity adjustments.
9.4.2
Efficacy
9.4.2.1
Primary Endpoint
The primary endpoint is change from baseline in NCPVMD. An ANCOVA model on change 
from baseline adjusted for treatment group, baseline, and randomization strata will be used for 
the primary analysis. The CTA analysis population will be used for the primary analysis.
Per-protocol analysis for the primary endpoint will be performed on the per-protocol CTA
analysis population. Additional sensitivity analysis may also be done for the primary endpoint, 
and baseline-by-treatment interaction effect will be evaluated; further details will be provided 
in the SAP. 
9.4.2.2
Secondary Endpoints
NT-proBNP
Secondary endpoint of relative change from baseline in NT-proBNP will be analyzed based on 
the ITT population. Relative change from baseline is defined as the ratio of the post-baseline 
visit value over the baseline value, expressed as a percentage. A MMRM analysis will be 
performed. The dependent variable is change from baseline for the log-transformed value of 
NT-proBNP, ie log(post-baseline visit value) minus log(baseline value). The results will be 
back-transformed to the original scale. The model will include fixed effects of treatment 
group, visit, treatment group-by-visit interaction, and randomization strata, with baseline 

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NT-proBNP as a covariate. Repeated measures for the model will be visit within subjects. An 
unstructured covariance structure will be used for the repeated measures. In case the model 
does not converge, back-up covariance structures and other analysis solutions will be detailed 
in the SAP.
Secondary Endpoints Derived from Echocardiogram and CTA
Secondary endpoints that are measured by echocardiogram or CTA will be analyzed based on 
the Echocardiogram or CTA Analysis Population, respectively. ANCOVA analyses similar to
the primary endpoint will be performed; the model will adjust for treatment group, respective 
baseline value, and randomization strata.
Immunogenicity Analyses
The Immunogenicity Population will be used for the immunogenicity analyses.
The number and percentage of participants with confirmed positive serum ADA to MEDI6570 
will be reported by dose level. Titer data will be summarized descriptively.
The potential impact of ADA on MEDI6570 PK, efficacy, and safety will be evaluated as data 
allow.
PK Analyses
The PK Population will be used for the PK analyses.
MEDI6570 serum concentration data will be summarized descriptively, tabulated and plotted. 
9.4.2.3
 
 
 
 
 
 
9.4.2.4
Subgroup Analyses
Subgroups planned for analysis include but are not limited to those defined by randomization 
stratification factors. Further details will be provided in the SAP.
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9.4.3
Safety
The As-treated Population will be used for the safety analyses.
AEs and SAEs will be coded using the most up-to-date version of MedDRA. Type, incidence, 
severity, and relationship to study intervention will be summarized by MedDRA System 
Organ Class and Preferred Term and by study intervention. Specific AEs will be counted once 
for each participant for calculating percentages. If the same AE occurs multiple times within a 
participant, the highest severity and level of relationship to study intervention observed will be 
reported.
Vital signs and safety laboratory data will be summarized descriptively at each time point by 
study intervention.
9.5
Interim Analyses
No formal interim analysis is planned.
An analysis restricted to PK and PD data will be performed after approximately 
80 participants have completed the Day 57 visit (Visit 6). The purpose of this evaluation will 
be to confirm the predicted PK and exposure-response relationship, based on data in 
participants with Type 2 Diabetes Mellitus in the post-MI study population. Non-study 
personnel who have no other involvement in the study will perform this evaluation. This 
analysis will be based on serum MEDI6570 concentration and 
data. These PK and 
PD data will be reviewed in conjunction with safety data by the independent DMC; full details 
are provided in the independent DMC charter.
9.6
Data Monitoring Committee
For details on the independent DMC, refer to Appendix A 5.
10
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS
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Regulatory, Ethical, and Study Oversight Considerations
A 1
Regulatory and Ethical Considerations

This study will be conducted in accordance with the protocol and with the following:

Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and CIOMS International Ethical Guidelines

Applicable ICH GCP Guidelines

Applicable laws and regulations

The protocol, 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 and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

The sponsor will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with the sponsor.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.

For all studies, except those using medical devices, investigator safety reports must be 
prepared for SUSARs according to local regulatory requirements and sponsor policy and 
forwarded to investigators as necessary.

An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it, and will notify the IRB/IEC, if appropriate according to local 
requirements.
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 
are responsible for providing information on financial interests during the course of the study 
and for one year after completion of the study.

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A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, HIPAA requirements, where applicable, and the IRB/IEC or 
study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants 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 participant or the participant’s legally 
authorized representative.

The ICF may be an electronic form or a paper consent form.
In this study, participants may take part in optional, pre-screening evaluations, and a separate, 
brief ICF will be used to obtain informed consent for any pre-screening evaluations. 
Participants who are pre-screened and then progress to the full screening phase of the study 
must sign the full ICF before any of the full screening evaluations can occur.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and images (CTA and echocardiogram) and any potential future use. Participants will 
be told that they are free to refuse to participate in any optional samples or have their unused 
samples and images (CTA and echocardiogram) used in future use research and may withdraw 
their consent at any time and for any reason during the retention period. 
A 4
Data Protection

Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor, or its delegate, will contain the identifier only; 
participant names or any information which would make the participant identifiable will 
not be transferred.

The participant 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 and use 
of their data must also be explained to the participant in the informed consent 

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
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
Committees Structure
An independent DMC will be appointed. The DMC will be responsible for safeguarding the 
interests of the participants, by assessing the safety of the intervention during the study and for 
reviewing the overall conduct of the study. The DMC will have access to the individual 
treatment codes and allocated doses and will be able to merge these with the collected study 
data while the study is ongoing. The DMC will review prespecified data (including the effects 
of the increased dose from
mg MEDI6570) periodically to ensure participant safety 
and make recommendations to the sponsor regarding further conduct of the study. This 
recommendation will be relayed to the sponsor’s safety review committee and appropriate 
action will be taken. The DMC will have scheduled meetings at study initiation and at 
predefined study milestones with greater frequency during the initial part of the study. A 
separate charter will establish the rules, meeting frequency, and scope of responsibilities of the 
DMC.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of 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 participant data relating to the study will be recorded on an eCRF 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 eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
non-compliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan or contracts.

The sponsor or designee is responsible for the data management of this study, including 
quality checking of the data.
CCI

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
The sponsor assumes accountability for actions delegated to other individuals (eg, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants 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 the periods of time specified by the sponsor’s 
policies, 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 participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data reported on the eCRF or entered in the eCRF 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.
A 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment will be the study start date.
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines

Inadequate recruitment of participants by the investigator

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
Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall inform the investigators, 
the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the reason for 
termination or suspension promptly, as specified by the applicable regulatory requirements. 
The investigator shall inform the participant promptly and should assure appropriate 
participant therapy and/or follow-up.
Participants from terminated sites may have the opportunity to be transferred to another site to 
continue the study.
A 10
Publication Policy

The results of this study will 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 multicenter studies only in their entirety and not as individual site data. The 
coordinating investigator will lead the multicenter publication.

Authorship will be in accordance with International Committee of Medical Journal 
Editors authorship requirements.

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Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of Adverse Events
An AE is the development of any untoward medical occurrence in a participant or clinical 
study participant administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (eg, an abnormal laboratory finding), symptom (eg, 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 intervention has been administered.
B 2
Definitions of Serious Adverse Event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-up) 
that fulfills one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalization or prolongation of existing hospitalization 

Results in persistent or significant disability or incapacity

Is a congenital abnormality or birth defect

Is an Important Medical Event that may jeopardize the participant or may require medical 
treatment to prevent one of the outcomes listed above
AEs for malignant tumors reported during a study should generally be assessed as serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. In certain situations, however, medical judgment on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
non-serious AE. For example, if the tumor is included as medical history and progression 
occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as non-serious; examples in adults include 
Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy.

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Life-threatening
‘Life-threatening’ means that the participant 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 
participant’s death. ‘Life-threatening’ does not mean that, had an AE occurred in a more 
severe form, it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where Important Medical Events may not be immediately life-threatening or result 
in death, hospitalization, disability or incapacity but may jeopardize the participant 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 judgment 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 (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Intensity Rating Scale

mild (awareness of sign or symptom, but easily tolerated)

moderate (discomfort sufficient to cause interference with normal activities)

severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 

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several hours may be considered severe nausea, but not an 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 an SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality, consider the following factors when deciding 
whether there is a ‘reasonable possibility’ that an AE may have been caused by the study 
intervention.

Time Course. Exposure to study intervention. Has the participant actually received the 
study intervention? Did the AE occur in a reasonable temporal relationship to the 
administration of the study intervention?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the study intervention (pharmacology and toxicology) or interventions of 
the same pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE re-occur if the study intervention was reintroduced
after having been stopped? The sponsor 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 study intervention?

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 no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.

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B 4
Study Intervention Error
For the purposes of this clinical study, a study intervention error is an unintended failure or 
mistake in the process for administering a study intervention that either causes harm to the 
participant or has the potential to cause harm to the participant. 
A study intervention error is not lack of efficacy of the study intervention, but rather a human 
or process related failure while the study intervention is in the control of the study site staff or 
participant.
Study intervention error includes situations where an error:

occurred

was identified and intercepted before the participant received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as study intervention errors:

Study intervention name confusion

Dispensing error, eg, study intervention prepared incorrectly, even if it was not actually 
given to the participant

Study intervention not administered as indicated, for example, wrong route or wrong site 
of administration

Study intervention not taken as indicated eg, tablet dissolved in water when it should be 
taken as a solid tablet 

Study intervention not stored as instructed eg, kept in the fridge when it should be at room 
temperature 

Wrong participant received the study intervention (excluding RTSM errors)

Wrong study intervention administered to participant (excluding RTSM errors)
Examples of events that do not require reporting as study intervention errors in clinical 
studies:

Errors related to or resulting from RTSM - including those which lead to one of the 
events listed above that would otherwise have been a study intervention error 

Participant accidentally missed study intervention dose(s) eg, forgot to take study 
intervention

Accidental overdose (will be captured as an overdose)

Participant failed to return unused study intervention or empty packaging
Study intervention errors are not regarded as AEs, but AEs may occur as a consequence of the 
medication error.

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Handling of Human Biological Samples
C 1
Chain of Custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each center keeps full traceability of collected biological samples from the 
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
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 record of receipt of arrival and onward 
shipment or disposal.
The sponsor or delegated representatives will keep oversight of the entire lifecycle 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 sponsor’s assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate staff during for the remainder 
of the sample lifecycle.
If required, the sponsor will ensure that remaining biological samples are returned to the site 
according to local regulations or at the end of the retention period, whichever is the sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples have already been 
analyzed, the sponsor is not obliged to destroy the results of the research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:

Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to the sponsor or delegate

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are identified immediately, disposed of appropriately, and that the action is 
documented

Ensures that the participant and the sponsor are informed about the sample disposal

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The sponsor ensures the organization(s) holding the samples is/are informed about the 
withdrawn consent immediately, and that samples are disposed of or repatriated as 
appropriate, and that the action is documented and study site is notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELING AND SHIPMENT OF BIOHAZARD SAMPLES
IATA (https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies 
infectious substances into 3 categories: Category A, Category B or Exempt
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. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900.
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, C, D, and E viruses. 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 - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these Regulations unless they 
meet the criteria for inclusion in another class.

Clinical study samples will fall into Category B or exempt under IATA regulations

Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).

Biological samples transported in dry ice require additional dangerous goods specification 
for the dry ice content

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Optional Genomics Initiative Sample
D 1
Use/Analysis of DNA

The sponsor 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. This genetic research may lead to better understanding of diseases, better 
diagnosis of diseases or other improvements in healthcare and to the discovery of new 
diagnostics, treatments or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported 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 for up to 15 years after the end of the study.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population
All participants will be asked to participate in this genetic research. Participation is voluntary 
and if a participant declines to participate there will be no penalty or loss of benefit. The 
participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfill all of the inclusion criteria 
described in Section 5.1 and provide informed consent for the Genomics Initiative 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

Participants 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 7.2.

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Collection of Samples for Genetic Research
The blood sample for this genetic research will be obtained from the participants at Day 1, 
Visit 3 (before dosing). Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding participants who may withdraw due to an AE. If for any 
reason the sample is not drawn at Day 1, Visit 3, it may be taken at any visit until the last 
study visit. Only one sample should be collected per participant for genetics during the study.
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years from the date of last participant 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 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 sponsor’s genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(sponsor employee or designated organizations working with the DNA).

The link between the participant enrollment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at sponsor or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory 
audit, and 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 participant may participate in other 
components of the main study without participating in this genetic component. To participate 
in the genetic component of the study, the participant must sign and date both the consent 
form for the main study and the addendum for the Genomics Initiative component of the 
study. Copies of both signed and dated consent forms must be given to the participant and the 
original filed at the study center. The Principal investigator(s) is responsible for ensuring that 
consent is given freely and that the participant understands that they may freely withdraw
from the genetic aspect of the study at any time.

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Participant Data Protection

The sponsor will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, or 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 participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, a sponsor physician or an investigator 
might know a participant’s identity and also have access to his or her genetic data. 
Regulatory authorities may require access to the relevant files, though the participant’s 
medical information and the genetic files would remain physically separate.
Data Management

Any genetic data generated in this study will be stored at a secure system by the sponsor
and/or designated organizations to analyze the samples.

The sponsor and its designated organizations 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 organizations 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 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.

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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 cases and Hy’s Law cases. It is not intended to be a comprehensive 
guide to the management of elevated liver biochemistries. 
Specific guidance on managing liver abnormalities can be found in Section 8.3.6.
During the study the investigator will remain vigilant for increases in liver biochemistry. The 
investigator is responsible for determining whether a participant meets potential Potential 
Hy’s Law criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of Potential Hy’s Law and 
Hy’s Law 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, Potential Hy’s Law 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 AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible Potential Hy’s Law events.
The investigator participates, together with the sponsor’s clinical project representatives, in 
review and assessment of cases meeting Potential Hy’s Law criteria to agree whether Hy’s 
Law criteria are met. HL criteria are met if there is no alternative explanation for the 
elevations in liver biochemistry other than DILI caused by the investigational product.
The investigator is responsible for recording data pertaining to Potential Hy’s Law/Hy’s Law 
cases and for reporting SAEs and AEs according to the outcome of the review and assessment 
in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law
AST or ALT ≥3x ULN together with TBL ≥2x ULN at any point during the study following 
the start of study medication irrespective of an increase in ALP.
Hy’s Law
AST or ALT ≥3x ULN together with TBL ≥2x ULN, where no other reason, other than the 
investigational product, can be found to explain the combination of increases, eg, elevated 
ALP indicating cholestasis, viral hepatitis, another drug. 

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For Potential Hy’s Law and Hy’s Law, the elevation in transaminases must precede or be 
coincident with (ie, 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 Potential Hy’s Law, it is important to perform a comprehensive 
review of laboratory data for any participant who meets any of the following identification 
criteria in isolation or in combination:

ALT ≥3x ULN

AST ≥3x ULN

TBL ≥2x ULN
Central Laboratories Being Used:
When a participant meets any of the Potential Hy’s Law identification criteria, in isolation or 
in combination, the central laboratory will immediately send an alert to the investigator (also 
sent to the sponsor’s representative). 
The investigator will also remain vigilant for any local laboratory reports where the Potential 
Hy’s Law identification criteria are met; where this is the case, the investigator will:

Notify the sponsor’s representative.

Request a repeat of the test (new blood draw) by the central laboratory without delay.

Complete the appropriate unscheduled laboratory eCRF 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 participant meets Potential Hy’s Law criteria (refer to
Appendix E 2 for definition) by reviewing laboratory reports from all previous visits 
(including both central and local laboratory results).
Local Laboratories Being Used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:

Notify the sponsor’s representative.

Determine whether the participant meets Potential Hy’s Law criteria (refer to
Appendix E 2 for definition) by reviewing laboratory reports from all previous visits.

Promptly enter the laboratory data into the laboratory eCRF.

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E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria Not Met
If the participant does not meet Potential Hy’s Law criteria the investigator will:

Inform the sponsor’s representative that the participant has not met Potential Hy’s Law 
criteria.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the CSP.
E 4.2
Potential Hy’s Law Criteria Met
If the participant does meet Potential Hy’s Law criteria the investigator will:

Determine whether Potential Hy’s Law criteria were met at any study visit before starting 
study treatment (refer to Section 8.3.6).

Notify the sponsor’s representative who will then inform the central Study Team 

Within 1 day of Potential Hy’s Law 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 participants that met Potential Hy’s Law criteria before starting the study 
intervention, the investigator is not required to submit a Potential Hy’s Law SAE unless 
there is a significant change1 in the participant’s condition.

The Study Physician contacts the investigator to provide guidance, discuss, and agree on 
an approach for the study participants’ follow-up (including any further laboratory 
testing) and the continuous review of data

After this contact, the investigator will:

Monitor the participant 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 etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the Hy’s Law lab kit should be used.

Complete the 3 Liver eCRF Modules as information becomes available.
                                               
1 A ‘significant’ change in the participant’s condition refers to a clinically relevant change in any of the 
individual liver biochemistry parameters (ALT, AST or TBL) in isolation or in combination, or a clinically 
relevant change in associated symptoms. The determination of whether there has been a significant change will 
be at the discretion of the investigator, this may be in consultation with the Study Physician if there is any 
uncertainty.

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E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this section should be followed for all cases where Potential Hy’s Law 
criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator to review available data and agree on whether there is an 
alternative explanation for meeting Potential Hy’s Law criteria other than DILI caused by the 
investigational product, to ensure timely analysis and reporting to health authorities within 
15 calendar days from date Potential Hy’s Law criteria was met. The sponsor’s 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.
Where 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 an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the sponsor’s standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational product:

Send updated SAE (report term ‘Hy’s Law’) according to the sponsor’s standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the Hy’s Law case, a causality 
assessment of ‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for Hy’s Law, 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 
investigational product and seriousness criteria is medically important, according to CSP 
process for SAE reporting.

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
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether Hy’s Law criteria are still met. Update the previously submitted Potential Hy’s 
Law 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.
E 6
Laboratory Tests
Hy’s Law lab kit for central laboratories
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNA a
IgG anti-HCV
HCV RNA a
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin
Autoimmune hepatitis
Antinuclear antibody
Anti-Liver/Kidney Microsomal Ab
Anti-Smooth Muscle Ab
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HCV RNA; HBV DNA are only tested when IgG anti-HCV is positive or inconclusive
Ab, antibody; anti-CMV, antibody to the cytomegalovirus; anti-EBV, antibody to the Epstein-Barr virus; anti-
HAV, antibody to the hepatitis A virus; anti-HBc, antibody to the hepatitis B core antigen; anti-HCV, antibody to 
the hepatitis C virus; anti-HEV, antibody to the hepatitis E virus; anti-HSV, antibody to the herpes simplex virus; 
GGT, Gamma-glutamyltransferase; HBV DNA, hepatitis B virus deoxyribonucleic acid; HBsAg, hepatitis B 
surface antigen; HCV RNA, hepatitis C virus ribonucleic acid; HEV RNA, hepatitis E virus ribonucleic acid; 
INR, international normalized ratio; IgG, immunoglobulin G; IgM, immunoglobulin M; LDH, lactic acid 
dehydrogenase

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E 7
References
Aithal et al 2011
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case 
definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther.
2011;89(6):806-15.
FDA Guidance for Industry 2009
FDA Guidance for Industry (issued July 2009). Drug-induced liver injury: Premarketing 
clinical evaluation. [cited 28Oct2021]. Available from https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/drug-induced-liver-injury-premarketing-clinical-
evaluation.

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Intensity Categories for Statin Therapy
2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce 
Atherosclerotic Cardiovascular Risk in Adults
A Report of the American College of Cardiology/American Heart Association Task Force on 
Practice Guidelines
Endorsed by the American Academy of Physician Assistants, American Association of 
Cardiovascular and Pulmonary Rehabilitation, American Pharmacists Association, American 
Society for Preventive Cardiology, Association of Black Cardiologists, Preventive 
Cardiovascular Nurses Association, and WomenHeart: The National Coalition for Women 
With Heart Disease.
High-, Moderate-, and Low-Intensity Statin Therapy (Used in the RCTs Reviewed by 
the Expert Panel) a
High-Intensity Statin Therapy
Moderate-Intensity Statin 
Therapy
Low-Intensity Statin Therapy
Daily dose lowers LDL-C, on 
average, by approximately ≥50%
Daily dose lowers LDL-C, on 
average, by approximately 30% to 
< 50%
Daily dose lowers LDL-C, on 
average, by < 30%
Atorvastatin (40 b)–80 mg
Atorvastatin 10 (20) mg
Simvastatin 10 mg
Rosuvastatin 20 (40) mg
Rosuvastatin (5) 10 mg
Pravastatin 10–20 mg
Simvastatin 20–40 mg c
Lovastatin 20 mg
Pravastatin 40 (80) mg
Fluvastatin 20–40 mg
Lovastatin 40 mg
Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg BID
Pitavastatin 2–4 mg
a
Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice. 
There might be a biological basis for a less-than-average response.
b
Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in the IDEAL 
(Incremental Decrease through Aggressive Lipid Lowering) study.
c
Although simvastatin 80 mg was evaluated in RCTs, initiation of simvastatin 80 mg or titration to 80 mg is 
not recommended by the FDA because of the increased risk of myopathy, including rhabdomyolysis.
Boldface type indicates speciﬁc statins and doses that were evaluated in RCTs included in CQ1, CQ2, and the 
Cholesterol Treatment Trialists 2010 meta-analysis included in CQ3. All of these RCTs demonstrated a reduction 
in major cardiovascular events. Italic type indicates statins and doses that have been approved by the FDA but 
were not tested in the RCTs reviewed.
BID, twice daily; CQ, critical question; FDA, Food and Drug Administration; LDL-C, low-density lipoprotein 
cholesterol; RCTs, randomized controlled trials.

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Risk Assessment for COVID-19 Pandemic
G 1
Background to COVID-19
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel severe 
acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that was first detected in Wuhan 
City, Hubei Province, China in 2019. This new virus spread across the globe rapidly, and 
caused the WHO to declare a pandemic situation on 12 March 2020. The countermeasures 
initiated by national and local governments worldwide and the recommendations issued by the 
health authorities have affected current and new clinical studies. As the threat of the pandemic 
burden, including new outbreaks, locally or globally, will affect the conduct of clinical
studies, appropriate risk assessments and mitigation measures need to be considered in all 
clinical studies to protect participants, site staff, and society as a whole.
Both EMA and FDA, as well as national health authorities in Europe, have issued new 
guidelines that aim to provide recommendations for actions for conduct of clinical studies of 
medical products during the COVID-19 pandemic. Since the pandemic situation is evolving, 
guidelines, recommendations, national laws, and local restrictions may change at a high pace. 
Given the circumstances of a potentially relapsing pandemic or epidemic situation with regard 
to the spread of COVID-19 in the future, special attention will be paid to protect study 
participants and site staff against infection with COVID-19 as requested by the EMA 
guideline.
G 2
Risk Assessment for COVID-19 Pandemic
G 2.1
Risk versus Benefit Assessment for MEDI6570
 
 
 
 
 
 
 
Furthermore, in a recent study conducted in severe and critical COVID-19-infected patients, 
researchers reported that the expression of
 by immature neutrophils positively 
correlated with clinical severity and with the cytokine storm (IL-1b, IL-6, IL-8, TNFα), 
(Combadiere et al 2020). Moreover, it was associated with intravascular coagulation and 
higher risks of severe thrombosis (Combadiere et al 2020). These data suggest that treatment 
with MEDI6570, 
, may offer benefit for those infected with COVID-19.
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G 2.2
Measures to Mitigate Risks of Infection with COVID-19
Participation in the study might increase the likelihood of COVID-19 infection among study 
participants and staff as a result of increased travel (to and from study sites) and interaction 
between participants and study site staff to conduct protocol-specified procedures.
Measures to mitigate the additional risks caused by COVID-19 are as follows:

Enrollment to the study will only start when the sponsor and CRO in collaboration deem 
it is safe to start the study. In addition, the study will not start until the local confinement 
measures or other safety restrictions linked to the COVID-19 pandemic imposed by the 
local authorities are compatible with safe conduct of the study.

The sponsor and CRO will perform continual risk assessments throughout the study, 
paying attention to evolving local infection rates and adapting as required, for example,
by temporarily pausing screening at a site if required. Current national laws and local 
recommendations for prevention of pandemic will be adhered to strictly.

Participants will be monitored closely throughout the study during the pandemic for any 
of the signs and symptoms currently recognized by the WHO and local guidelines to 
indicate possible COVID-19 infection. If clinical signs of COVID-19 infection are 
reported by participants, the investigator will determine whether protocol-specified study 
samples can be collected, and whether safety data can be recorded on site. If not, adverse 
events and concomitant medications will be obtained via phone calls. If a participant 
shows symptoms of COVID-19 infection, the investigator will have discretion (with 
support and guidance from the Medical Monitor if required) to determine whether the 
participant should continue with dosing. 

The probability of virus transmission will be controlled as much as possible by:

Advising the participant to adhere to local requirements for reducing the public 
exposure while ambulatory.

Study site staff will monitor themselves for COVID-19 symptoms, and in the event 
of developing symptoms or having a positive COVID-19 test result, should not attend 
the site or come into person-to-person contact with any participants; this may also 
extend to other scenarios of potential infection risk as defined by local guidance and 
laws.

Participants may be contacted by telephone before a visit to enquire whether 
COVID-19 symptoms and signs are present, and they should be asked not to attend 
the site if they are suspected to be infected with COVID-19. In addition, participants 
may be asked whether they have been in contact with a person who has tested 
positive for COVID-19. If applicable, participants will be referred to the local health 
care system for further follow-up and treatment.

Physical distancing and person-to-person contact restrictions will apply during site 
visits and in-house confinement.

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
Where physical distancing is not possible, personal protective equipment will be used 
by study participants (face masks, gloves) and staff (for example but not limited to: 
face masks, gloves, protectors, medical suits) if deemed appropriate by the 
investigators and site staff and guided by local requirements.

Logistical improvements of the site and structural measures of the study site building 
will be implemented to improve physical distancing further.
G 2.3
Restrictions Related to COVID-19
During the COVID-19 pandemic, participants are advised to adhere to local requirements for 
reduction of the public COVID-19 exposure while ambulatory. If applicable, before Screening 
Visit 1, potential participants should be called to confirm they are not experiencing any 
COVID-19 symptoms and signs and are asked not to attend the site in case of suspected 
infection. If appropriate, participants will be referred to the local health care system. Physical 
distancing and person-to-person contact restrictions will be applied and explained to 
participants while staying at the study site. Where physical distancing is not possible, study 
participants will be asked to use face masks and/or gloves if deemed appropriate by the 
investigator and site staff and guided by local requirements.
G 3
Data Quality Assurance Related to COVID-19
Monitoring visits at site will be limited to the minimum required as deemed appropriate 
during the COVID-19 pandemic in accordance with local regulations.
In addition, where possible, other measures for carrying out protocol-related activities, such as 
but not limited to home-nursing, may be employed as required.
G 4
COVID-19 Vaccination Guidance and Recommendations
The COVID-19 pandemic continues to have a profound impact on society as a whole, and 
global mass vaccination to prevent infection, disease, and transmission is underway and 
expected to persist beyond 2021. For AstraZeneca, the safety and well-being of study 
participants is of primary importance and this includes vaccination in the current pandemic 
situation.
Currently, inactive/non-replicating COVID-19 vaccines are being approved across the globe 
as emergency use products. AstraZeneca has no data on the co-administration of MEDI6570 
and respective COVID-19 vaccines. Potential MEDI6570/vaccine interactions affecting 
patient safety or IP and vaccine efficacy are therefore unclear. In addition, vaccine-related 
AEs may confound the AE profile of the MEDI6570 investigational drug.

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Current local guidelines, vaccine availability, and a benefit-risk assessment should all be 
considered when determining whether a participant should be vaccinated. Ultimately, the 
decision to vaccinate will be based on the judgment of the treating physician taking into 
account the participant’s best interest.
Patients enrolled in studies with MEDI6570 can be vaccinated against Covid-19 particularly 
since many patients are likely to belong to one of the risk groups targeted for vaccination).
G 4.1
Considerations to Facilitate COVID-19 Vaccination 
Covid-19 vaccination may be administered before, during or after enrollment in the study. If 
administered during the study it should be recorded as a concomitant medication. .
G 4.1.1
COVID-19 Vaccination before Entering Clinical Study/Randomization
For study participants with flexibility as to when to start in the study and if COVID-19 
vaccination is planned, complete vaccination (both doses of vaccine, where applicable) before 
the first dose may be advisable. If possible, the first dose of MEDI6570 should be given at 
least 14 days after the last dose of vaccine.
G 4.1.2
COVID-19 Vaccination during the Ongoing Study (Dosing Period)
For study participants already receiving treatment with MEDI6570, Covid-19 vaccination is 
acceptable if the benefit/risk assessment does not indicate otherwise. 
In order to understand whether a potential reaction is caused by administration of a vaccine or 
by MEDI6570 consider administering IP and vaccine 7 days apart. 
G 4.1.3
End of Study
For participants approaching the end of study, Covid-19 vaccination could be delayed, if 
possible, until after the last dose of study drug is given. 
G 4.2
CRF
To better assess the overall impact of COVID-19 vaccination on a particular study and study 
population, COVID-19 vaccines should be recorded in the CRF as concomitant medications 
(including date and type of vaccine). 
G 4.3
AE Monitoring
Vaccinated study participants should be monitored according to local guidelines and the 
guidance within this study protocol. 

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For AEs with an onset date near the time of administration of a COVID-19 vaccination, the 
investigator should adhere to the standard practice in judging whether there is a reasonable 
possibility that an AE is considered related to MEDI6570.

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Abbreviations
Abbreviation or special 
term
Explanation
ACS
acute coronary syndrome
ACC
American College of Cardiology
ADA
Anti-drug antibody(ies)
AE
Adverse event
AHA
American Heart Association
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANCOVA
Analysis of covariance
AST
Aspartate aminotransferase
AUC0-tau
Area under the curve from time 0 over the dosing interval
BNP
Brain natriuretic peptide
BP
Blood pressure
CAD
Coronary artery disease
CANTOS
Canakinumab Anti-inflammatory Thrombosis Outcome Study
CHD
Coronary heart disease
CIOMS
Council for International Organizations of Medical Sciences
Cmax 
Maximum observed concentration
COVID-19
Coronavirus disease caused by the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2)
CRO
Contract research organization
CRP
C-reactive protein
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTA
(Coronary) computed tomography angiography
CV
Cardiovascular
DILI
Drug Induced Liver Injury
DMC
Data monitoring committee
DNA
deoxyribonucleic acid 
EAS
European Atherosclerosis Society
ECG
Electrocardiogram
eCRF
electronic Case Report Form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency
ESC
European Society of Cardiology

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Abbreviation or special 
term
Explanation
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GLS
Global longitudinal strain
HED
Human equivalent dose
HF
Heart failure
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human immunodeficiency virus
hs-CRP
high sensitivity C-reactive protein
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
ICF
Informed consent form
ICH
International Council for Harmonisation (of Technical Requirements for 
Pharmaceuticals for Human Use)
IgG1λ
Immunoglobulin G1 lambda
IRB
Institutional Review Board
IMP
Investigational medicinal product
ITT
Intent-to-treat (population)
LAPV
low attenuation plaque volume
LVEF
Left ventricular ejection fraction
MACE
Major adverse cardiovascular events
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MMRM
Mixed model with repeated measures 
mRNA
Messenger RNA
mSv
millisievert
NCPV
Non-calcified plaque volume
NCPVMD
Non-calcified plaque volume in the most diseased coronary segment
NOAEL
No observed adverse effect level
NSAID
Non-steroidal anti-inflammatory drug
NSTEMI
Non-ST segment elevation myocardial infarction
NT-proBNP
N-terminal prohormone brain natriuretic peptide
PBMC
Peripheral blood mononuclear cell
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Abbreviation or special 
term
Explanation
PCI
Percutaneous coronary intervention
PD
Pharmacodynamic
PI
Principal Investigator 
PK
Pharmacokinetics
PPI
Proton pump inhibitor
Q1W
Every week
Q4W
Every 4 weeks
RTSM
Randomization and Trial Supply Management
SAE
Serious adverse event 
SAP
Statistical Analysis Plan
SC
Subcutaneous(ly)
SD
Standard deviation
SoA
Schedule(s) of Activities
STEMI
ST segment elevation myocardial infarction
SUSAR
Suspected unexpected serious adverse reaction
TBL
Total bilirubin
ULN
Upper limit of normal
WHO
World Health Organization
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Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located 
directly before the Table of Contents.
Amendment 1 (10Mar2021)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union.
Overall Rationale for the Amendment: 

to change the dose strength in the high dose group from 
 to 
mg MEDI6570 to 
achieve full 
 suppression in a majority of participants

to modify the participant population to widen eligibility to the study by increasing the 
post-infarction eligibility window, reducing the threshold for hs-CRP, and not requiring 
all participants to have elevated NT-proBNP at baseline
In addition, the following other substantial changes were made: to minimize the theoretical 
risk of bleeding events; to minimize the number of injections required; to introduce an 
optional pre-screening visit; to provide guidance on conducting the study during the 
COVID-19 pandemic; to clarify permitted and prohibited concomitant medications; to clarify 
that participants who discontinue investigational product because of an AE may remain in the 
study; and to remove the requirement that a participant who develops ADAs should be 
followed up until the value returns to baseline. All of the changes and their rationale are 
summarized below. 
Substantial changes:
Description of Change
Brief Rationale
Sections Affected
Upper limit of allowable time after 
MI before enrollment in the study 
was extended from 180 to 365 days
To allow a pragmatic approach for 
identifying suitable candidates who 
may still be at risk of MACE and may 
derive benefit from treatment with 
MEDI6570 when added to standard 
of care
Section 1.1 Synopsis; 
Section 4.1 Overall Design; 
Section 4.2.1 Rationale for 
Study Population; 
Section 5.1 Inclusion 
Criteria; Section 5.4 Screen 
Failures
Definition of persistent inflammation 
was changed from hs-CRP ≥ 2 to 
hs-CRP ≥ 1 mg/L
The study has witnessed a high screen 
fail rate secondary, in part, to the 
hs-CRP requirement.  Furthermore, 
emerging data have demonstrated that 
an hs-CRP of ≥2 mg/L is not required 
for anti-inflammatory studies (Tardif 
et al 2019 and Nidorf et al 2020), 
inflammatory risk rises linearly 
between 1 and 2 mg/L, and there are 
Section 1.1 Synopsis; 
Section 4.1 Overall Design; 
Section 5.1 Inclusion Criteria
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Description of Change
Brief Rationale
Sections Affected
intervention were changed, from 3 
injections (totalling 2.5 mL, for all 
interventions), to 1 injection (of 
0.5 mL for the 
mg group and 
1.5 mL for the 
mg group) or 2 
injections (totalling 4 mL for the 
mg group).
Consequential changes are outlined 
below:
required and to make the study more 
patient-centric.
Section 1.1 Synopsis; 
Section 6.2.3 Dose 
Preparation Steps, text and 
Table 9; Section 6.2.4
Treatment Administration
•
The placebo intervention now 
comprises 3 injection/volume-
matched placebo groups, and 
the randomization ratio has 
changed (from 1:1:1:1 for 3 
MEDI6570 dose groups and 1 
placebo group to 3:3:3:1:1:1 for 
3 MEDI6570 dose groups and 3 
injection/volume-matched 
placebo groups.
•
To maintain the study blind 
between active treatment and 
placebo
•
Terms and Conventions 
Used in this Document; 
Section 4.1 Overall 
Design; Section 4.3
Justification for Dose; 
Section 6.2.3 Dose 
Preparation Steps, text 
and Table 9; 
Section 6.2.4 Treatment 
Administration; 
Section 6.3.1
Randomization 
Procedure; 
Section 6.3.2 Blinding 
Procedure 
•
Text was amended to clarify 
that the study is blinded with 
respect to active treatment 
versus placebo.
•
In minimizing the numbers of 
injections required at each dose 
level to make the study more 
patient-centric, is no longer 
blinded with regard to dose 
level, but it remains blinded to 
active versus placebo. 
•
Section 6.3.2 Blinding 
Procedure
•
Text was added to explain that 
participants enrolled under 
Protocol Version 1.0 will be 
re-allocated to the appropriate 
dosing volume for their 
randomized intervention group, 
and that participants originally 
randomized to receive placebo 
will be re-randomized to a 
placebo group that is 
injection/volume-matched to a 
MEDI6570 treatment group.
•
To transition participants from 
Protocol Version 1.0 to 
Amendment 1 while 
maintaining the integrity of the 
randomization schedule and the 
study blind (with regard to 
active versus placebo)
•
Section 6.3.1
Randomization 
Procedure; 
Section 6.3.2 Blinding 
Procedure
•
Text was added to explain that 
the 3 injection/volume-matched 
placebo groups would be pooled 
for the analyses.
•
For clarification
•
Section 1.1 Synopsis; 
Section 9.2 Sample 
Size Determination
An optional pre-screening visit and 
associated brief ICF have been 
introduced to allow local laboratory 
assessment of hs-CRP and creatinine 
To allow a pragmatic approach to 
identifying suitable candidates for 
screening.
Section 1.2 Schema; 
Section 1.3 Schedule of 
Activities, Table 3; Section 5
Study Population; 
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Description of Change
Brief Rationale
Sections Affected
(and NT-proBNP [or BNP] if 
randomization of participants with 
NT-proBNP < 125 pg/mL is capped). 
The pre-screening visit does not 
replace the full screening visit. 
Participants who sign the brief, 
pre-screen, ICF are considered to 
have enrolled in the study.
Section 5.1 Inclusion 
Criteria; Section 5.4 Screen 
Failures; Section 8 Study 
Assessments and Procedures; 
Section 8.3.1 Time Period 
and Frequency for Collecting 
Adverse Event and Serious 
Adverse Event Information; 
Appendix A 3 Informed 
Consent Process
Changes to participant population 
with regard to NT-proBNP profile:
•
A screening NT-proBNP value 
≥125 pg/mL was removed as an 
inclusion criterion and replaced 
with an option to cap the 
proportion of participants with 
an NT-proBNP value of 
< 125 pg/mL who are 
randomized.
•
To widen eligibility for 
participation in the study
•
Section 4.1 Overall 
Design; Section 4.2.2.2
Secondary Endpoints; 
Section 5.1 Inclusion 
Criteria
•
Removal of statement ‘The 
proposed sample size in this 
Phase IIB clinical study is 
powered to detect a 25% 
reduction in NT-proBNP.’
•
No longer applicable
•
Section 4.2.2.2
Instruction to encourage the use of 
PPIs if concomitant NSAID therapy 
is required
To minimize the theoretical risk of 
bleeding events
Section 2.3.1 Risk 
Assessment, Table 6
Changes caused by COVID-19 
global pandemic:
•
Change to eligibility criteria to 
include participants who have 
had inactive, non-replicating 
COVID-19 vaccines approved 
by Health Authorities or under 
emergency use authorization
•
To allow inclusion of 
participants who have been 
vaccinated against COVID-19
•
Section 2.3.1 Risk 
Assessment; 
Section 5.2  Exclusion 
Criteria; Section 6.5.1
Permitted Concomitant 
Medications
•
Addition of new appendix
•
To provide details on the 
additional risk and risk-
mitigating measures for study 
participants related to 
COVID-19 and COVID-19 
vaccination
•
Appendix G Risk 
Assessment for 
COVID-19 Pandemic
Addition of Subsections 6.5.1 and 
6.5.2 for permitted and prohibited 
concomitant medications; reiteration 
of the encouragement to use PPI if 
concomitant NSAID therapy is 
required.
To provide clarity on permitted and 
prohibited concomitant medications; 
to minimize the theoretical risk of 
bleeding events
Section 6.5 Concomitant 
Therapy

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Description of Change
Brief Rationale
Sections Affected
Addition of guidance text on 
spontaneous severe bleeding events 
including development of conditions 
requiring anticoagulation therapy as a 
reason for considering temporary or 
permanent discontinuation of study 
intervention
To minimize the theoretical risk of 
exacerbating bleeding events
Section 7.1 Discontinuation 
of Study Intervention
Text updated to capture whether an 
AE caused the participant to 
discontinue investigational product 
administration, rather than whether 
an AE caused the participant to 
withdraw from the study
To clarify that a participant may wish 
to discontinue investigational product
administration and still remain in the 
study
Section 8.3.2 Follow-up of 
Adverse Events and Serious 
Adverse Events
Changes related to collecting ADA 
samples:
•
Removal of the statement, ‘Any 
participants who develop ADAs 
will be followed until the value 
returns to baseline’
•
Removed because of the Phase 1 
safety profile and because 
participants are already followed 
for 6 months after their last dose 
in current study design.
•
Section 8.5.2
Immunogenicity 
Assessments
•
The statement ‘Samples may be 
collected at additional time 
points during the study if 
warranted and agreed upon 
between the investigator and the 
sponsor (eg, for safety reasons). 
The timing of sampling may be 
altered during the course of the 
study based on newly available 
data to ensure appropriate
monitoring’ was added.
•
This situation may apply if 
samples were required during an 
AE and outside the pre-specified 
sampling visit.
•
Section 8.5.2
Immunogenicity 
Assessments
ADA(s), anti-drug antibody(ies); AE, adverse event; BNP, brain natriuretic peptide; COVID-19, coronavirus 
disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); DMC, data 
monitoring committee; hs-CRP, high sensitivity C-reactive protein; ICF, informed consent form; ITT, intent-to-
treat; MACE, major adverse cardiovascular events; MI, myocardial infarction; NT-proBNP, N-terminal 
prohormone brain natriuretic peptide; NSAID, non-steroidal anti-inflammatory drug; PD, pharmacodynamic; PK, 
pharmacokinetic; PPI, proton pump inhibitor; 
 
Non-substantial changes:
Description of Change
Brief Rationale
Sections Affected
Minor PK changes:
•
The PK endpoints were 
changed from Cmax and 
terminal t1/2 in serum to 
MEDI6570 concentrations in 
•
To align the PK endpoint and 
analyses sections with the 
sparse PK sampling schedule, 
which does not allow for 
accurate estimation of Cmax
and terminal t1/2.
•
Section 1.1 Synopsis; 
Section 3 Objectives and 
Endpoints; Section 9.4.2.2
Secondary Endpoints
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Description of Change
Brief Rationale
Sections Affected
serum; the planned PK 
analyses were amended from 
PK parameter determinations 
to descriptive summaries, 
tabulations and plots of 
MEDI6570 serum 
concentration data
•
The PK Population definition 
was changed from 
‘participants who receive ≥ 1 
dose of MEDI6570 per 
protocol and have at least one 
post-dose, evaluable, 
MEDI6570 PK
determination’ to ‘… at least 
one post-dose, evaluable, 
MEDI6570 serum 
concentration determination’
•
To reflect the changes in the 
PK endpoints
•
Section 1.1 Synopsis; 
Section 9.3 (Table 11) 
Populations for Analysis
Clarification footnotes added to 
Objectives and Endpoints table:
•
to explain that physical 
activity monitor results will 
be reported separately from 
the clinical study report
•
to include the Day 253 study 
visit window
For clarification
Section 1.1 Synopsis; Section 3
Objectives and Endpoints
The number of participants 
undergoing the interim CTA 
between the fifth and sixth doses 
was amended from 50 
participants/intervention group to 
200 participants overall.
To simplify the presentation
Section 1.1 Synopsis
Notes were added the Schedule of 
Activities for vital signs and ECG.
To clarify the timing of vital signs 
relative to blood draws
Section 1.3 Schedule of Activities, 
Table 3
The table notes and text for 
creatinine for calculating eGFR 
were all amended to clarify that 
the collection should occur within 
30 days before the CTA, and that a 
local laboratory or point of care 
could be used
For clarification
Section 1.3 Schedule of Activities, 
Table 3, Table 4 and Table 5; 
Section 8.1.1.2 Criteria for CTA 
Imaging
Changes in sample collection 
timepoints in the Schedules of 
Activities:
•
Urine collections for 
albumin-to-creatinine ratio 
analyses at Visits 2, 5, 7, 10 
and 12 were removed.
•
The number of collections 
was reduced to correct an 
error; the change from 
baseline will only be 
evaluated at one time point 
•
Section 1.3 Schedule of 
Activities, Table 3 and 
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Description of Change
Brief Rationale
Sections Affected
•
The planned number of study 
sites was amended from 60 to 
85 to approximately 70 to 
100, and the following text 
was added: ‘The COVID-19 
pandemic may continue to 
affect different geographic 
regions differently, having an 
unpredictable impact on 
study enrollment; therefore, a 
more accurate estimation of 
the number of countries and 
study sites that may be 
included globally is 
challenging.’
•
To allow more flexibility in 
the number of sites and 
countries participating in the 
study
•
Section 1.1 Synopsis; 
Section 4.1 Overall Design
•
The 3 geographic regions 
used for the randomization 
strata were amended from 
‘North America, Europe and 
Japan’ to ‘Asia, North 
America and Rest of World’
•
To better reflect the likely 
global distribution of study 
sites
•
Section 1.1 Synopsis; 
Section 4.1 Overall Design; 
Section 6.3.1 Randomization 
Procedure
Changes caused by change in 
definition of persistent 
inflammation:
•
Deletion of ‘with ongoing 
inflammation reflected by a 
hs-CRP > 2 mg/L present in 
> 60% of patients post-MI 
being a strong predictor of 
ongoing risk of MACE 
(Carrero et al 2019)’
•
Deletion of ‘Multiple studies 
have suggested various cut-
off points for the upper limit 
of a clinically meaningful 
value of NT-proBNP 
(McCullough and Kluger 
2018). Both the FDA and the 
European Society of 
Cardiology have proposed an 
exclusion cut-off of 
< 125 pg/mL (McCullough 
and Kluger 2018); as such, 
this was the threshold that 
was selected. This allows for 
the investigation of the 
efficacy of MEDI6570 in a 
population with a wide range 
of NT-proBNP and 
corresponding degrees of 
HF.’
•
Discussion of CRP > 2 mg/L 
no longer required
•
Section 4.2.1 Rational for 
Study Population; 
•
Section 11 References

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Description of Change
Brief Rationale
Sections Affected
•
Deletion of Carrero et al 
2019 and McCullough and 
Kluger 2018 references
The type of myocardial infarction 
participants must have had to take 
part in the study was added 
(presumed Type-I)
For clarification
Section 5.1 Inclusion Criterion 
3(a)
The wording of Exclusion 
Criterion 7a was amended from:
‘History or presence of any of the 
following: Ongoing infection or 
febrile illness within 30 days 
before randomization (Day 1; Visit 
3),’
to:
‘…Ongoing infection or febrile 
illness that in the opinion of the 
investigator may be the cause of 
elevated hs-CRP on screening  
(Visit 1)’
For clarification
Section 5.2 Exclusion Criterion 
7(a)
The time window for measuring 
BP, and the number of 
measurements allowed, at 
Screening was added
For clarification
Section 5.2 Exclusion Criterion 9
The equation used to calculate 
eGFR was changed from the 
Modification in Diet in Renal 
Disease to the Chronic Kidney 
Disease Epidemiology 
Collaboration equation
For calculating eGFR, the Chronic 
Kidney Disease Epidemiology 
Collaboration equation has an 
improved performance over the 
Modification in Diet in Renal 
Disease calculation
Section 5.2 Exclusion Criterion 
10(a)
A new subsection was added 
(‘Rescreening’)
To consolidate the different 
circumstances that could warrant 
rescreening
Section 5.4 Screen Failures
Additional information was 
included on the study intervention 
supplied
To describe the appearance, 
packaging and formulation in 
greater detail.
Section 6.1 Study Interventions 
Administered, text and Table 8
Serum concentrations of 
MEDI6570, albumin-to-creatinine
ratios in urine and ADAs were 
added to the list of variables that 
will remain blinded to the 
participant, investigator and site 
staff
For clarification
Section 6.3.2 Blinding Procedure

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Description of Change
Brief Rationale
Sections Affected
concentration and
 
data.’
•
Text was added explaining 
that the exposure-response 
relationship will be evaluated 
before the first interim 
analysis.
•
For clarification 
•
Section 1.1 Synopsis; 
Section 9.5 Interim Analyses
Paragraph removed:
•
‘In the event of positive 
outcome at the interim 
analyses, an evaluation of 
exposure-response 
relationship may be 
performed. This analysis has 
the intention to guide the 
dose selection for the next 
study. This will be performed 
by non-study personnel with 
no other involvement in the 
study. Data for this analysis 
will be based on PK and 
primary, secondary, and 
exploratory efficacy and 
biomarker endpoints.’
•
Text was consolidated for 
brevity.
•
Section 1.1 Synopsis; 
Section 9.5 Interim Analyses
Paragraph removed:
•
‘A separate analysis plan 
will also be prepared for the 
evaluation of exposure-
response relationship and it 
should be finalized before the 
first interim analysis.’ were 
removed.
And replaced with:
•
An exposure-response 
analysis plan may not be 
prepared.
•
Section 1.1 Synopsis; 
Section 9.5 Interim Analyses
•
‘In addition, an analysis 
restricted to PK and PD data, 
will be performed before the 
first formal interim analysis, 
after approximately 80 
participants have completed 
the Day 57 visit (Visit 6). 
The purpose of this 
evaluation will be to confirm 
the predicted PK and 
exposure-response 
relationship, based on data in 
participants with Type 2 
Diabetes Mellitus in the 
post-MI study population. 
Non-study personnel who 
have no other involvement in 
the study will perform this 
evaluation. This analysis will 
•
For clarification
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Description of Change
Brief Rationale
Sections Affected
•
‘neutrophils’ was replaced 
with ‘buffy coat’
•
To correct the terminology
•
Section 8.6 Human 
Biological Sample 
Biomarkers
•
Updated footer text table for 
abbreviation for HCV DNA 
to HBV DNA
•
Corrected typo in footer text
•
Appendix E 6 Laboratory 
Tests
•
Added italic font to table 
•
Italic type was missing from 
the table. Updated to align 
with table footer.
•
Appendix F Intensity 
Categories for Statin Therapy
•
The year of the Zhang et al 
reference was corrected from 
2008 to 2009 in the hyperlink
•
Correction of typo
•
Section 11 Reference List
•
In-text definitions of 
abbreviations at first use 
were removed
•
For consistency with style 
conventions
•
Throughout
ADA(s), anti-drug antibody(ies); AE, adverse event; BP, blood pressure; Cmax, maximum observed 
concentration; COVID-19, Coronavirus disease caused by the novel severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2); CTA, computed tomography angiography; CV, cardiovascular; ECG, 
electrocardiogram; DMC, data monitoring committee; eGFR, estimated glomerular filtration rate; FDA, Food 
and Drug Administration; HBV DNA, hepatitis B virus deoxyribonucleic acid; HF, heart failure;
 
 IMP, investigational medicinal product; MACE, major adverse 
cardiovascular events; MI, myocardial infarction;
No, number; NT-proBNP: N-terminal prohormone brain natriuretic peptide; NSAID, non-steroidal anti-
inflammatory drug; PK, pharmacokinetic; PPI, proton pump inhibitor; 
 
 t1/2, half-life
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11
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