Conditions: Dyslipidaemia
Keywords: Dose Range Finding AZD8233 Efficacy PK PD Immunogenicity Safety Tolerability
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 119
Healthy volunteers: no

Brief summary:
AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This study aims to evaluate the dose-dependent reduction in LDL-C after SC administration of multiple doses of AZD8233 as well as the associated adverse effects profile. The data generated will be used to guide choice of doses, dosing regimens, and sample sizes, as well as safety and PD monitoring in the further clinical development program.

Detailed description:
This is a randomized parallel, double-blind, placebo-controlled, dose-ranging Phase 2b study in approximately 108 participants with dyslipidemia. The primary objective of the study is to investigate the effect of AZD8233 on LDL-C across different dose levels. The study will be conducted at up to 25 sites in up to 4 countries.

The screening period starts up to 42 days before the randomization visit and ends on Day -1. Eligible participants will attend 7 visits during the treatment period and 7 additional visits during the safety follow up period. Eligible participants are randomized across four different treatment arms in a 1:1:1:1 ratio for a 12-week treatment period. The planned treatment arms are AZD8233 low dose, AZD8233 medium dose, AZD8233 high dose, and Placebo. Participants will be dosed SC on Days 1, 8, 29, and 57.

Arms:
arm 1: Placebo solution for subcutaneous injection. arm 2: AZD8233 high dose for subcutaneous injection. arm 3: AZD8233 medium dose for subcutaneous injection. arm 4: AZD8233 low does for subcutaneous injection.

Interventions: intervention 1: AZD8233 intervention 2: Placebo
Intervention descriptions: intervention 1: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. intervention 2: Placebo solution

Protocol document:
Prot_000.pdf: 
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Clinical Study Protocol 
Study Intervention
AZD8233
Study Code
D7990C00003
Version
2.0
Date
16 Dec 2020
A Randomized, Parallel, Double-blind, Placebo-controlled, Dose-ranging, Phase 2b Study to 
Evaluate the Efficacy, Safety and Tolerability of AZD8233 Treatment in Participants With 
Dyslipidemia
Sponsor Name: AstraZeneca AB
Legal Registered Address: 151 85 Södertälje, Sweden
Regulatory Agency Identifier Number(s): EudraCT number 2020-000767-23
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: 2.0
Amendment Number: 1
Study Intervention: AZD8233
Study Phase: Phase 2b
Short Title: A Phase 2b Study of AZD8233 in Participants With Dyslipidemia
Medical Monitor Name and Contact Information will be provided separately


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TABLE OF CONTENTS
1.
PROTOCOL SUMMARY .................................................................................. 6
1.1
Synopsis ............................................................................................................. 6
1.2
Schema............................................................................................................. 10
1.3
Schedule of Activities ....................................................................................... 11
2.
INTRODUCTION............................................................................................ 19
2.1
Study Rationale ................................................................................................ 19
2.2
Background ...................................................................................................... 19
2.3
Benefit/Risk Assessment................................................................................... 19
2.3.1
Risk Assessment ............................................................................................... 20
2.3.2
Benefit Assessment........................................................................................... 23
2.3.3
Overall Benefit/Risk Conclusion....................................................................... 23
3.
OBJECTIVES AND ENDPOINTS................................................................... 24
4.
STUDY DESIGN ............................................................................................. 26
4.1
Overall Design.................................................................................................. 26
4.2
Scientific Rationale for Study Design ............................................................... 26
4.3
Justification for Dose........................................................................................ 27
4.4
End of Study Definition.................................................................................... 28
5.
STUDY POPULATION.................................................................................... 28
5.1
Inclusion Criteria .............................................................................................. 28
5.2
Exclusion Criteria ............................................................................................. 29
5.3
Lifestyle Considerations ................................................................................... 32
5.3.1
Meals and Dietary Restrictions ......................................................................... 32
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 32
5.3.3
Activity............................................................................................................. 32
5.3.4
Reproductive restrictions .................................................................................. 32
5.3.5
Blood donation ................................................................................................. 33
5.4
Screen Failures ................................................................................................. 33
6.
STUDY INTERVENTION ............................................................................... 34
6.1
Study Intervention(s) Administered................................................................... 34
6.1.1
Investigational Products.................................................................................... 34
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 35
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 35
6.4
Study Intervention Compliance......................................................................... 36
6.5
Concomitant Therapy........................................................................................ 37
6.5.1
Rescue Medicine............................................................................................... 38
6.6
Dose Modification ............................................................................................ 38
6.7
Intervention after the End of the Study.............................................................. 38


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7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 38
7.1
Discontinuation of Study Intervention............................................................... 38
7.2
Participant Withdrawal from the Study.............................................................. 39
7.3
Lost to Follow up.............................................................................................. 40
8.
STUDY ASSESSMENTS AND PROCEDURES.............................................. 41
8.1
Efficacy Assessments........................................................................................ 43
8.2
Safety Assessments........................................................................................... 43
8.2.1
Physical Examinations...................................................................................... 43
8.2.2
Vital Signs ........................................................................................................ 44
8.2.3
Electrocardiograms........................................................................................... 44
8.2.4
Clinical Safety Laboratory Assessments............................................................ 45
8.2.5
Other Screening Assessments............................................................................ 47
8.2.6
Injection Site Reactions .................................................................................... 48
8.3
Adverse Events and Serious Adverse Events..................................................... 48
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 48
8.3.2
Follow-up of AEs and SAEs ............................................................................. 48
8.3.3
Causality Collection.......................................................................................... 49
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 50
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 50
8.3.6
Hy’s Law.......................................................................................................... 50
8.3.7
Reporting of Serious Adverse Events ................................................................ 51
8.3.8
Pregnancy......................................................................................................... 51
8.3.8.1
Maternal Exposure............................................................................................ 51
8.3.8.2
Paternal Exposure............................................................................................. 52
8.3.9
Medication Error............................................................................................... 52
8.4
Overdose .......................................................................................................... 53
8.5
Human Biological Samples............................................................................... 53
8.5.1
Pharmacokinetics.............................................................................................. 54
8.5.1.1
Determination of Drug Concentration ............................................................... 54
8.5.2
Immunogenicity Assessments ........................................................................... 55
8.5.3
Pharmacodynamics........................................................................................... 55
8.5.3.1
Collection of Samples....................................................................................... 55
8.6
Human Biological Sample Biomarkers ............................................................. 56
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 56
8.7
Optional Genomics Initiative Sample................................................................ 56
8.8
Health Economics............................................................................................. 57
9.
STATISTICAL CONSIDERATIONS................................................................ 57
9.1
Statistical Hypotheses....................................................................................... 57
9.2
Sample Size Determination............................................................................... 57
9.3
Populations for Analyses................................................................................... 58
9.4
Statistical Analyses ........................................................................................... 58


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9.4.1
General Considerations..................................................................................... 58
9.4.2
Efficacy ............................................................................................................ 59
9.4.2.1
Primary Endpoint(s).......................................................................................... 59
9.4.2.2
Secondary Endpoint(s)...................................................................................... 59
9.4.3
Safety ............................................................................................................... 60
9.5
Interim Analyses............................................................................................... 61
9.6
Data Monitoring Committee ............................................................................. 61
10.
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 61
11.
REFERENCES................................................................................................. 93
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 10
LIST OF TABLES
Table 1
Schedule of Activities (SoA).................................................................... 12
Table 2
Risk Assessment...................................................................................... 20
Table 3
Objectives and Endpoints......................................................................... 24
Table 4
Investigational Products........................................................................... 34
Table 5
Laboratory safety variables...................................................................... 46
Table 6
Other Screening Assessments .................................................................. 48
Table 7
Pharmacodynamic Laboratory Assessments............................................. 56
Table 8
Populations for Analysis .......................................................................... 58


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LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 62
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 67
Appendix C
Handling of Human Biological Samples .................................................. 72
Appendix D
Optional Genomics Initiative Sample....................................................... 74
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law........................................................................... 78
Appendix F
Actions in Case of Development of Thrombocytopenia or 
Uninterpretable Platelet Counts After Administration of ASOs................ 83
Appendix G
Guidance for Definition of Anaphylactic/Hypersensitivity Reactions and 
Checklist for the Investigator................................................................... 86
Appendix H
High- and Moderate-intensity Statin Therapy........................................... 89
Appendix I
Abbreviations .......................................................................................... 90






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least 80 evaluable participants completed treatment up until and including visit 10 (week 12). 


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Note: "Enrolled" means a participant's, or their legally acceptable representative’s, agreement 
to participate in a clinical study following completion of the informed consent process. 
Potential participants who are screened for the purpose of determining eligibility for the study 
but are not randomly assigned/assigned in the study, are considered “screen failures”, unless 
otherwise specified by the protocol. 
Intervention Groups and Duration:
The screening period starts up to 42 days before the randomization visit and ends on Day -1. 
Eligible participants will attend 7 visits during the treatment period and 7 additional visits 
during the safety follow up period. Eligible participants are randomized across four different 
treatment arms at a 1:1:1:1 ratio for a 12-week treatment period. The planned treatment arms 
are: AZD8233 
, AZD8233
, AZD8233 
, and Placebo. Participants will be 
dosed SC on Days 1, 8, 29, and 57. 
Data Monitoring Committee:
A data monitoring committee will not be used in this study.
Statistical methods
The primary objective of this study is to compare absolute change from baseline in 
log-transformed LDL-C across different dose levels of AZD8233. 
The key secondary objective of this study is to compare absolute change form baseline in 
log-transformed PCSK9 across different dose levels of AZD8233.  
Both log-transformed LDL-C and log-transformed PCSK9 will be analysed by fitting a mixed 
model for repeated measures to the data with baseline as covariate and treatment, time (visit 
number), and interaction between treatment and time as factors.
The participants will be analysed according to the treatment to which the participant was 
randomised. Participants will be analysed with respect to the intention to treat principle using 
the full analysis set which contains data from each participant who received at least one dose 
of placebo or AZD8233.
Key safety objective is overall tolerability, which will be presented with descriptive statistics.
CCI
CCI
CCI




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1.3
Schedule of Activities
Randomization should only proceed if all required assessments have been performed and all 
inclusion/exclusion criteria as well as other protocol restrictions have been evaluated; see 
Sections 5 and 6.5.
Dosing of participants should only be carried out if all required assessments have been 
performed and evaluated. Dosing is not allowed to proceed until the Investigator has 
determined that the results are within acceptable range according to the defined stopping 
criteria; see Section 7.1. Laboratory assessment results should also be reviewed at every visit 
to ensure that stopping criteria have not been met. 
Assessments scheduled at the same time may be initiated based on the sequence below:
1
ECG
2
Vital signs (SBP and diastolic blood pressure [DBP]), pulse rate, and temperature, if 
appropriate)
3
PK and PD blood sampling
4
Dose administration
Pre-dose assessments may be performed up to 60 minutes prior to dosing.


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Informed consent
X
Appendix A 3
Optional Informed 
consent for future genetic 
research sample
X
Appendix D
Verify eligibility criteria
X
Xb
Sections 5.1, 
5.2
Enrolment in RTSM
X
Sections 6.3, 8
Randomisation in RTSM
X
Sections 6.3, 8
Medical history
X
Section 8
Concomitant medication 
review
X
X
X
X
X
X
X
X
X
X
X
X
Section 6.5
Demographics
X
Section 9.4.1
Height
X


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Body weightc
X
X
X
X
X
X
X
Section 8.2.1
BMI
X
X
X
Section 8.2.1
HbA1c
X
Section 8.2.5
Viral serology
X
Section 8.2.5
Pregnancy and 
reproductive status 
(females only, pre-dose)
X
X
Section 8.2.4
Study intervention 
administration 
(AZD8233/Placebo)
X
X
X
X
Section 6.1.1
Safety Assessments
Adverse event review
X (SAE 
only)
X (SAE 
only)
X
X
X
X
X
X
X
X
X
X
Section 8.3


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Injection site reactions d
X
X
X
X
X
X
X
X
X
X
Section 8.2.6
Complete physical 
examination
X
X
X
X
Section 8.2.1
Abbreviated physical 
examination
X
X
X
X
X
X
X
Section 8.2.1
Vital signs (blood 
pressure, pulse and 
temperature) e
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
ECG e
X
X
X
X
X
X
Xf
X
Section 8.2.3
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Hematology
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Coagulation parameters g
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
hs-CRP
X
X
X
X
X
X
Section 8.2.4


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Complement activation 
panel g
X
X
X
X
Section 8.2.4
Urinalysis
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Urine renal safety 
biomarkers
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.4
Pharmacodynamics
LDL-C h
X
X
X
X
X
X
X
X
X
X
X
Section 8.5.3.1
PCSK9 h
X
X
X
X
X
X
X
X
X
X
X
Section 8.5.3.1
Triglycerides h
X
X
X
X
X
X
X
X
X
X
X
Section 8.5.3.1
Other Lipid parameters h
X
X
X
X
X
X
X
X
X
X
Section 8.5.3.1
Lipoprotein profile h
X
X
X
X
X
X
X
X
X
X
Section 8.5.3.1


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Pharmacokinetics
PK plasma sample i
X
X
X
X
X
X
X i
X
Section 8.5.1
Immunogenicity
Samples for anti-
AZD8233 antibodies j
X
X
X
X
X
X j
X
Section 8.5.2
Exploratory biomarker analysis
Biomarker analyses 
(plasma) h
X
X
X
X
X
X
X
X
X
X
X
Section 8.6.1
Biomarker analyses 
(urine) h
X
X
X
X
X
X
X
X
X
X
Section 8.6.1
Genomics Initiative 
optional, exploratory 
genetic sample k
X
Section 8.7


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
Note: Participants are required to fast for at least 8 hours overnight prior to all study visits except for Visit 1; Participants are permitted to drink water during 
this period of fasting until 1 hour before blood sampling. On days where participants attend the clinic in a fasted state, blood and urine samples should be 
obtained prior to administration of IP.
Note: Samples to be obtained from all treatment arms unless specified in the table.
a
Home visits: may be undertaken at the participant’s home or any other appropriate location by site staff or by qualified external service provider. Other 
visits currently not designated as ‘home visits’ may also be undertaken at the participant’s home or any other appropriate location if deemed applicable, 
following consultation with the Investigator and the sponsor. Home visits performed by qualified external service provider (i.e. not by clinical trial site 
personnel) may only be performed starting Visit 5 (D22), excluding dosing visits (Visit 6 (D29) and Visit 8 (D57)).
b
Check screening labs and inclusion/exclusion criteria.
c
Weight should be measured in light indoor clothes, without shoes, after a prior visit to the bathroom.
d
Injection Site Reaction assessments to be collected based on adverse event collection criteria.
e
Vital signs and ECG to be measured pre-dose on dosing days.
f
ECG to be performed during the safety follow up period at Visits 10 (D85), 11 (D99), 13 (D127), and 15 (D155).
g
Blood samples for complement activation panel and coagulation parameters will be taken around Cmax and are to be collected pre-dose and 2 hours post-
dose.
h
Samples to be obtained pre-dose on dosing days.


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Table 1
Schedule of Activities (SoA)
Screening
Treatment Period
EDV
Safety 
Follow-
up 
period
Final 
Follow-
up 
Visit
Details in 
CSP Section 
or Appendix
Visit Number
1
2
3
4
5a
6
7a
8
9a
10, 11a, 
12, 13a, 
14, 15a
16
Study Week
0
1
3
4
6
8
10
12, 14, 
16, 18, 
20, 22
24
Study Day
D-42 to 
D-1l
D-7 to 
D-1
D1
D8
D22
D29
D43
D57
D71
D85, 
D99, 
D113, 
D127, 
D141, 
D155
D169
Visit Window
± 1 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
i
PK sampling to be performed at Visits 4 (D8), 6 (D29), 7 (D43), 8 (D57), 9 (D71), 10 (D85), 12 (D113) and 14 (D141) and final follow-up visit/EDV. 
Schedule of sampling for Visits 4 (D8), 6 (D29), 8 (D57) are shown below.
Visit 4 (Day 8; Loading dose): pre-dose
Visit 6 (Day 29; Dose 3): pre-dose
Visit 8 (Day 57; Final dose): pre-dose
j
ADA sampling to be performed at Visits 3 (D1), 4 (D8), 6 (D29), 8 (D57), 10 (D85), 12 (D113), and 14 (D141), and final follow-up visit/EDV. ADA 
samples to be collected pre-dose on all dosing days.
k
If, for any reason, the sample is not drawn pre-dose on Visit 3 (D1), it may be taken at any visit until the Final follow-up/EDV visit.
l
Visit 1 and visit 2 may be combined. 
BMI = body mass index; CSP = clinical study protocol; D = day; ECG = electrocardiogram; EDV = early discontinuation visit; HbA1c = haemoglobin A1c; 
LDL-C =low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; RTSM = Randomization and Trial Supply Management.


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2.
INTRODUCTION 
2.1
Study Rationale
AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This 
study aims to evaluate the dose-dependent reduction in LDL-C after SC administration of 
multiple doses of AZD8233 as well as the associated adverse effects profile. The data 
generated will be used to guide choice of doses, dosing regimens, and sample sizes, as well as 
safety and PD monitoring in the further clinical development program.
2.2
Background
Dyslipidemia, particularly elevated levels of plasma LDL-C, is a main risk factor for CVD. 
Hypercholesterolemia is typically caused by a combination of environmental and genetic 
factors. Statin therapy is the standard lipid lowering medication for both secondary and 
primary prevention of CVD, as an adjunct to diet. Reduction of LDL-C by statins leads to a 
significant reduction in cardiovascular events (Collins R et al 2016). Statins reduce LDL-C 
by inhibiting HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis. 
However, despite the substantial benefits of statin therapy, many patients do not reach LDL-C 
target goals and some continue to be at residual CVD risk despite maximum doses.
Genetic studies have identified PCSK9 as an important, HMG-CoA-independent circulating 
regulator of LDL-C (Cohen J et al 2005, Cohen J et al 2006). Gain of function mutations in 
PCSK9 cause familial hypercholesterolemia; loss of function is associated with low 
circulating levels of LDL-C and a reduced risk of major vascular events. Molecularly, 
circulating PCSK9 is derived mainly from the liver and increases LDL-C by promoting 
degradation of hepatic LDL receptors. 
Two monoclonal antibodies (evolocumab [Amgen] and alirocumab [Sanofi/Regeneron]) have 
been successfully developed to pharmacologically inhibit circulating PCSK9. Injection of 
these compounds lowers LDL-C levels by approximately 60%, even in clinical study 
participants already receiving maximum dose statin therapy (Sabatine MS et al 2017, Ray 
KK et al 2017). Based on the significant clinical benefit of PCSK9 inhibition, AstraZeneca is 
developing a PCSK9-targeted, N-acetylgalactosamine-conjugated ASO specifically inhibiting 
intracellular PCSK9 expression in the liver (Prakash TP et al 2014). AZD8233 may provide 
novel treatment options for participants with dyslipidemia.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD8233 is 
provided in the Investigator’s Brochure (Investigator’s Brochure 2019).
2.3
Benefit/Risk Assessment
Potential risks of AZD8233 and mitigation strategy are shown in Table 2. More detailed 




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Potential Risk of Clinical 
Significance
Rationale for Risk
Mitigation Strategy (refer to IB 
Section 5.5 for further detail)
in the non-clinical toxicology 
studies.
Anti-drug Antibodies 
There is a potential risk for 
antibody formation. Emergence of 
ADA has been observed in a 
proportion of clinical study 
participants after repeated 
oligonucleotide treatment, leading 
to change in PK profile. To date, 
no apparent association of ADA 
with loss of efficacy or safety 
findings have been observed.
Assessment of ADAs and 
monitoring for immunogenicity 
effects (including hypersensitivity 
reactions and ADA effect on 
PK/PD). Guidance on the 
definition of an anaphylactic 
reaction and the action plan that 
needs to be followed with regards 
to ADA sampling is presented in 
Appendix G.
Injection Site Reactions
As with any exogenous substance, 
injection site reactions may occur 
as a response to the SC injection 
of AZD8233. Possible risks 
associated with SC administration 
are redness, swelling, pain, 
induration, and sometimes 
infection at the administration site. 
Although observed for some 
ASOs, injection site reactions are 
not generally a clinical problem 
for newer generation ASOs.
Monitoring for injection site 
reactions
Complement Activation
This is a known class effect of 
oligonucleotides and appears to be 
directly plasma concentration 
(Cmax) driven. Monkeys are 
considered more sensitive to 
complement activation than 
humans (Crooke ST et al 2016). 
No indication of complement 
activation induced by AZD8233 
have been observed in toxicology 
studies.
Assessment of complement 
activation around Cmax (C3a, C5a, 
Bb)
Increased Bleeding Risk
Increases in aPTT, in the absence 
of clinical or pathological 
sequelae, have been observed with 
ASOs (Burel S et al 2013, Henry 
SP et al 1997). Mechanistically, 
interaction of ASOs with the 
intrinsic tenase complex and 
thrombin results in a selective 
inhibition of the intrinsic clotting 
Assessment of aPTT and PT




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2.3.2 Benefit Assessment
In a previous single ascending dose study, SC administrations of up to 
 AZD8233 have 
been well-tolerated with no particular safety findings. Doses of 
 were efficacious in 
lowering PCSK9 by ≥ 90% and LDL by up to approximately 70% (Study D7990C00001).
A multiple ascending dose study of AZD8233 is ongoing (Study D7990C00002).
Consequently, AZD8233 is expected to lower circulating PCSK9 in this study in all 
participants (see Section 4.3). Pharmacologic inhibition of PCSK9 is known to increases the 
catabolism of LDL-C and reduce circulating LDL-C significantly. Low levels of LDL-C are 
associated with a monotonically lower risk of incident atherosclerotic CVD events, providing 
an important clinical benefit to patients with dyslipidemia.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD8233 is 
provided in the Investigator’s Brochure.
2.3.3 Overall Benefit/Risk Conclusion
Taking into account the measures taken to minimise risk to the participants of this study, the 
potential risks identified in association with AZD8233 are justified by the anticipated benefits 
that may be afforded to participants with dyslipidemia.
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4.
STUDY DESIGN
4.1
Overall Design
For an overview of the study design, see Figure 1. For details on treatment given during the 
study, see Section 6.1.
This is a randomized, parallel, double-blind, placebo-controlled, dose-ranging Phase 2b study 
in approximately 108 participants with dyslipidemia. The primary objective of the study is to 
investigate the effect of AZD8233 on LDL-C across different dose levels. The study will be 
conducted at up to 25 sites in up to 4 countries. 
The screening period starts up to 42 days before the randomization visit and ends on Day -1. 
Some participants routinely come fasting to the clinic. In the event that participants come 
fasting at their own initiative, sites may choose to combine Visit 1 and Visit 2. In case Visit 1 
and Visit 2 are combined, the combined visit must take place between -7 to -1 days prior to 
randomization. Eligible participants will attend 7 visits during the treatment period and 7 
additional visits during the safety follow up period. Eligible participants are randomized 
across four different treatment arms in a 1:1:1:1 ratio for a 12-week treatment period. The 
planned treatment arms are AZD8233 
 SC, AZD8233 
 SC, AZD8233 
 SC, 
and Placebo SC on Days 1, 8, 29, and 57. 
This study is double-blind with regards to treatment (AZD8233 or placebo) at each dose level. 
AZD8233 and placebo will be matched for appearance. Participants randomized to placebo 
will receive a volume of injection that will not differ substantially from participants on active 
drug. From randomization, every second visit is planned to be a site visit and the visits in-
between may be home visits. Home visits are optional, and all visits could be conducted as on-
site visits, if this is preferred. Home visits may be undertaken at the participant’s home or any 
other appropriate location by site staff or qualified external service provider. Other visits that
are currently not designated as ‘home visits’ may also be undertaken at the participant’s home 
or at any other appropriate location if deemed applicable, following consultation with the 
Investigator and the sponsor. Home visits performed by qualified external service provider 
(i.e. not by clinical trial site personnel) may only be performed starting Visit 5 (D22),
excluding dosing visits (Visit 6 (D29) and Visit 8 (D57)).
After the treatment period, participants will continue in a safety follow up period of 12 weeks 
(up to 16 weeks post last dose). 
For detailed information please refer to the SoA (Table 1).
4.2
Scientific Rationale for Study Design
AstraZeneca is developing AZD8233 for the treatment of dyslipidemia. This study aims to 
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evaluate the effect of different doses of AZD8233 on LDL-C at steady state to select a 
therapeutic dose for further clinical development.
The scheduled 12 weeks dosing should be sufficient to reach close to steady state conditions 
in the tissues at the end of the dosing period (estimated terminal half-life of the full length 
ASO in plasma is 2-3 weeks). Based on these data and the expected time course for PCSK9 
and LDL-C reduction, 12 weeks of dosing is predicted to allow for a robust assessment of 
safety, tolerability, PK, as well as PCSK9 and LDL-C reduction to guide dose selection for 
further clinical development of AZD8233.
Dosing and follow up schedule were selected based on the long estimated terminal half-life of 
the full length AZD8233 ASO in plasma as well as the observed time course for PCSK9 levels 
to return to baseline after single dose administration in man. Monthly dosing is predicted to 
result in a low level of fluctuation of PCSK9 levels and tissue exposure during  dose intervals.
Dosing in the current study will only start after AZD8233 is concluded safe and tolerable by 
the Safety Review Committee in Study D7990C00002. The definition of safe and tolerable is 
that none of the pre-specified safety stopping criteria in Study D7990C00002 have been met.
4.3
Justification for Dose
Single SC doses of up to 
 AZD8233 have been well tolerated in participants with 
elevated LDL-C (Study D7990C00001). The doses for the current study have been selected 
based on observed PCSK9 and LDL-C reduction in the single ascending dose study 
(D7990C00001) and the predicted PCSK9 and LDL reduction at steady state of the selected 
doses taking expected accumulation into account for a Q4W dosing regimen that includes a 
loading dose at Day 8. The mid and high dose, planned to 
 and 
 (Days 1, 8, 29, 
and 57) were selected to achieve a PCSK9 reduction of around 90% during the dose interval 
and is expected to result in close to maximum achievable effect in terms of LDL-C reduction, 
with the aim to show that an increase in dose above the mid dose will not result in a clinically 
significant further reduction in LDL-C. The low dose, planned to 
 (Days 1, 8, 29, 
and 57) was selected to reach a PCSK9 reduction of below 80% over the entire dose interval 
and was selected to show that decreasing the dose and PCSK9-reduction to below 80% will 
lead to a clinically significant lower LDL-C reduction as compared to the mid dose. The mid 
dose was thus selected to be in the therapeutic dose range. Prior to the start of dosing in the 
current study, safety data after two repeated doses of AZD8233 
 (in 
Study D7990C00002) as well as safety and potentially PCSK9 and LDL-cholesterol data after 
repeated (Days 1, 8, 29, and 57) dosing of AZD8233 
 (Study D7990C00002) will have 
been evaluated. Based on the results from these cohorts, the planned doses in the current study 
may be slightly adjusted if needed to achieve the intended PCSK9 and LDL-C reduction. 
However, the highest dose will not exceed 
 (Days 1, 8, 29, and 57), which is the highest 
dose planned to be evaluated in Study D7990C00002.
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4.4
End of Study Definition
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the last visit.
The end of the study is defined as the date of the last visit of the last participant in the study. 
5.
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be 18 to 75 years of age, inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2
Participants who have a fasting LDL-C ≥ 70 mg/dL (1.8 mmol/L) but < 190 mg/dL 
(4.9 mmol/L) at screening (Visit 2).
3
Have fasting triglycerides < 400 mg/dL (< 4.52 mmol/L) at screening (Visit 2).
4
Should be receiving moderate- or high-intensity statin therapy (refer to Appendix H) as 
defined by the ACC/AHA guidelines on blood cholesterol management, or according to 
local guidelines.
5
Should be on stable medication for ≥ 3 months prior to screening with no planned 
medication or dose change during study participation. The exception to this restriction is 
for fenofibrate; if the participant is receiving fenofibrate, the therapy must be stable for at 
least 6 weeks prior to randomization at a dose that is appropriate for the duration of the 
study in the judgement of the Investigator. Other fibrate therapy (and derivatives) are 
prohibited.
Weight
6
Body mass index between 19 and 40 kg/m2.
Sex
7
Male or female.
Contraceptive use by men or women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
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
Males must be surgically sterile or using, in conjunction with their female 
partner, a highly effective method of contraception for the duration of the study 
(from the time they sign consent) and for 3 months after the final follow up visit 
to prevent pregnancy in a partner. Acceptable methods of contraception include 
birth control pills, injections, implants, or patches, IUDs, tubal 
ligation/occlusion, and vasectomy. A barrier method is not necessary if the 
female partner is sterilized. Male study participants must not donate or bank 
sperm during this same time period.
(b) Female participants:

Female participants must not be pregnant and must have a negative pregnancy 
test at screening and randomisation or be post-menopausal, must not be 
lactating, and must not be of childbearing potential. Women not of childbearing 
potential are defined as women who are either permanently sterilised 
(hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or who are 
postmenopausal. Women will be considered postmenopausal if they have been 
amenorrhoeic for 12 months prior to the planned date of randomisation without 
an alternative medical cause. The following age-specific requirements apply:

Women < 50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of 
exogenous hormonal treatment and FSH levels in the postmenopausal 
range.

Women ≥50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of all 
exogenous hormonal treatment.
Informed Consent
8
Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the ICF and in this protocol.
9
Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses. Participants who consent only to the 
main study may participate in other components of the main study without participating in 
the optional component of the study. However, to participate in the optional component of 
the study, the participant must sign and date both the consent forms for the main study 
and optional component of the study. If a participant decline to participate in the optional 
component of the study, there will be no penalty or loss of benefit to the participant. The 
participant will not be excluded from other aspects of the study described in this protocol.
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:


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Medical Conditions
1
Estimated glomerular filtration rate < 40 mL/min/1.73m2 using the Chronic Kidney 
Disease-Epidemiology Collaboration equation at Visit 1.
2
History or presence of gastrointestinal, hepatic or renal disease or any other conditions 
known to interfere with absorption, distribution, metabolism, or excretion of drugs.
3
Any uncontrolled or serious disease, or any medical (eg, known major active infection or 
major haematological, renal, metabolic, gastrointestinal, or endocrine dysfunction) or 
surgical condition that, in the opinion of the Investigator, may either interfere with 
participation in the clinical study and/or put the participant at significant risk.
4
Poorly controlled type 2 diabetes mellitus, defined as HbA1c > 10% at Visit 1.
5
Acute ischaemic cardiovascular event in the last 12 months prior to randomization.
6
Heart failure with New York Heart Association (NYHA) Class III-IV.
7
Blood dyscrasias with increased risk of bleeding including idiopathic thrombocytopenic 
purpura and thrombotic thrombocytopenic purpura or symptoms of increased risk of 
bleeding (frequent bleeding gums or nose bleeds).
8
High-risk of bleeding diathesis as judged by the Investigator.
9
Malignancy (except non-melanoma skin cancers, cervical in-situ carcinoma, breast ductal 
carcinoma in-situ, or Stage 1 prostate carcinoma) within the last 10 years.
10 Recipient of any major organ transplant, eg, lung, liver, heart, bone marrow, renal.
11 LDL or plasma apheresis within 12 months prior to randomization.
12 Uncontrolled hypertension defined as average supine SBP > 160 mmHg or DBP > 90 
mmHg at Visit 1 or Visit 3.
13 Heart rate after 10 minutes supine rest < 50 bpm or > 100 bpm at Visit 1 or Visit 3.
14 Any laboratory values with the following deviations at Screening Visit 1; test may be 
repeated at the discretion of the Investigator if abnormal:
(a) Any positive result on screening for hepatitis B, hepatitis C or HIV.
(b) ALT > 1.5 × ULN.
(c) AST > 1.5 × ULN.
(d) TBL > ULN
(e) ALP > 1.5 × ULN
(f) WBC < LLN.
(g) Haemoglobin < 12 g/dL in men or < 11 g/dL in women
(h) Platelet count ≤ LLN.
(i)
aPTT > ULN and PT > ULN.
(j)
UACR > 11.3 mg/mmol (100 mg/g).
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15 Any clinically important abnormalities in rhythm, conduction or morphology of the 
resting ECG and any clinically important abnormalities in the 12-lead ECG as judged by 
the Investigator.
16 QTcF > 470 ms; high degree atrioventricular-block grade II-III and sinus node 
dysfunction with significant sinus pause untreated with pacemaker; and cardiac 
tachyarrhythmias.
17 Known or suspected history of drug abuse as judged by the Investigator.
18 History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.
19 Mipomersen, or lomitapide within 12 months prior to randomization.
20 Previous administration of AZD8233/AZD6615 or other PCSK9 inhibition treatment 
(approved or investigational).
21 History of severe allergy/hypersensitivity or ongoing clinically important 
allergy/hypersensitivity, as judged by the Investigator or history of hypersensitivity to 
drugs with a similar chemical structure or galactosamine-conjugated ASOs.
22 Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of 
the first administration of study intervention. History or evidence of any other clinically 
significant disorder (eg, cognitive impairment), condition, or disease other than those 
outlined above that, in the opinion of the Investigator or AstraZeneca physician, if 
consulted, may compromise the ability of the participant to give written informed 
consent, would pose a risk to participant safety, or interfere with the study evaluation, 
procedures, or completion.
Prior/Concurrent Clinical Study Experience
23 Participation in another clinical study with a study intervention administered in the last 3 
months prior to randomization or 5 half-lives from last dose to first administration of 
study intervention, whichever is the longest. 
24 Received another new chemical entity (defined as a compound which has not been 
approved for marketing) within 30 days of last follow-up to first administration of the 
study intervention of this study or 5 half-lives from last dose to first administration of 
study intervention, whichever is the longest.
25
Use of other investigational products or investigational devices during the course of the 
study.
Other Exclusions
26 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site or their close relatives).
27 Judgement by the Investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements. 
28 As judged by the Investigator, any evidence of disease conditions that, in the 
Investigator’s opinion, makes it undesirable for the participant to participate in the trial.


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29 Previous enrolment or randomisation in the present study. Individuals who do not meet 
the criteria for participation in this study (screen failure) may be rescreened. At the 
Investigator’s discretion, participants may be rescreened a further two times during the 
recruitment period.
30 Participants who cannot communicate reliably with the Investigator.
31 Vulnerable participants, eg, kept in detention, protected adults under guardianship, 
trusteeship, or committed to an institution by governmental or juridical order.
32 Plasma donation within 1 month of the visit at the clinic or any blood donation/blood loss 
> 500 mL during the 3 months prior to screening visit.
Optional Genetic Sampling
Exclusion from this genetic research may be for any of the exclusion criteria specified for the 
main study or any of the following:
33 Previous allogeneic bone marrow transplant.
34 Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample 
collection.
5.3
Lifestyle Considerations
For a list of prohibited medications, see Section 6.5.
5.3.1
Meals and Dietary Restrictions
Except for Visit 1, participants must be fasted for 8 hours prior to blood sampling for LDL-C 
and other lipid parameters, PCSK9, and lipoprotein profile. No fluids will be allowed apart 
from water, which can be given until 1 hour before blood sampling for LDL-C, other lipid 
parameters, PCSK9, and lipoprotein profile.
5.3.2
Caffeine, Alcohol, and Tobacco
Participants with known or suspected history of alcohol abuse, as judged by the Investigator, 
are not allowed to participate in the study.
5.3.3
Activity
Participants should not start any new physical training activities or increase the intensity of 
their usual physical training from 5 days prior to randomization until the end of the study.
5.3.4
Reproductive restrictions
Women of Non-Child Bearing Potential
Women of non-child bearing potential are defined as female participants who are permanently 
surgically sterilized or postmenopausal (see inclusion criteria, Section 5.1).


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Restriction for Male Participants
There is no information about effects that AZD8233 could have on the development of the 
foetus in humans. Therefore, it is important that women of child bearing potential, who are the 
partners of male participants, do not become pregnant during the study and for a total period 
of 3 months after the male participant has attended the Final Follow-Up Visit.
As a precaution, all male participants should avoid fathering a child by either true abstinence 
or by using (together with their female partner/spouse) a highly effective contraception form 
of birth control in combination with a barrier method, starting from the time of study 
intervention administration until 3 months after the Final Follow-Up visit. Acceptable 
methods of preventing pregnancy include birth control pills, injections, implants, or patches, 
IUDs, tubal ligation/occlusion, and vasectomy.
Male participants who have been sterilized are required to use 1 barrier method of 
contraception (condom) from the time of study intervention administration until after the Final 
Follow-Up Visit. A barrier method is not necessary if the female partner is sterilized.
Sperm Donation
Male participants should not donate sperm for the duration of the study and for at least 
3 months after the study Final Follow-up Visit.
Pregnancy
Participants will be instructed that if they or their partner becomes pregnant during the study 
this should be reported to the Investigator. The Investigator should also be notified of 
pregnancy occurring during the study but confirmed after completion of the study. In the event 
that a participant’s partner is subsequently found to be pregnant after the participant is 
included in the study, then consent will be sought from the partner (via the participant’s 
request that their partner contact the study site) and, if granted, any pregnancy will be 
followed, and the status of mother and/or child will be reported to the Sponsor after delivery.
5.3.5
Blood donation
Participants should refrain from blood donation throughout the study, including the follow-up 
period.
5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomized to study intervention. 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 (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, 


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screen failure details, eligibility criteria, and any SAE.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. At the Investigator’s discretion, participants may be rescreened a further two times 
during the recruitment period. Rescreened participants should be assigned the same participant 
number as per their initial screening visit.
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 Intervention(s) Administered
6.1.1
Investigational Products
Details of the identity of the investigational products are presented in Table 4 and in Handling 
Instructions D7990C0003, AZD8233 solution for injection. In case of a change of the planned 
doses (as described in Section 4.3), the investigational product strength/concentrations may be 
used for other cohorts than presented in Table 4, in order to minimize injection volume.
Table 4
Investigational Products
ARM Name
Cohort 1
Cohort 2
Cohort 3
Cohort 4
Intervention Name
AZD8233
AZD8233
AZD8233
Placebo to 
match 
AZD8233
Dose Formulation
AZD8233 solution for injection
Matching 
placebo 
solution for
injection
Strength/Concentrations
Matching 
placebo 
solution for
injection
Dose
Matching 
placebo 
solution for
injection
Regimen
AZD8233/Placebo Days 1, 8, 29, and 57
Route of Administration
Subcutaneous injection 
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Table 4
Investigational Products
Treatment Administration 
Guidelines
Subcutaneous abdominal region injection is the preferred region; 
avoid a 5 cm radius around umbilicus. Other regions might be used if 
needed, as decided by the investigator (thigh or buttock). Slow 
injection of study intervention using gentle pressure (at least 5 
seconds duration is recommended) and rotation of injection sites. 
The anatomical location of each injection site should be documented 
in the eCRF.
Specific device for drug 
administration
Syringes for injection to be provided by Clinical Team
Use
Experimental 
Placebo to 
match 
AZD8233 
IMP and NIMP
IMP 
Sourcing
Provided centrally by the Sponsor 
Packaging and Labelling
Study Intervention will be provided in vials. Each vial will be 
packed in a separate carton. Each vial and carton will be 
labelled as required per country requirement
Special Handling Requirements 
Requirements will be provided in a separate document
Availability of IMP
Will be shipped when approvals are in place
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The Investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the Investigator 
and authorised site staff.
3
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Study Drug Packaging Agreement.
6.3
Measures to Minimise Bias: Randomization and Blinding 
All participants will be centrally assigned to randomized study intervention using a RTSM 


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system. Before the study is initiated, the telephone number and call-in directions and/or the 
log in information & directions for the RTSM will be provided to each site.
To simplify supply of study drug, randomization will be stratified based on the region in 
which the site is located. This will achieve greater balance within each region compared to 
simple randomization. Currently, two regions are planned: Europe and North America.
Study intervention will be dispensed at the study visits summarized in SoA.
The RTSM will provide to the Investigator(s) 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 that will be provided to each centre. 
The randomisation code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment randomisation. 
The Investigator documents and reports the action to AstraZeneca, without revealing the 
treatment given to participant to the AstraZeneca staff. AstraZeneca retains the right to break 
the code for SAEs that are unexpected and are suspected to be causally related to an 
investigational product and that potentially require expedited reporting to regulatory 
authorities. Randomisation 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 (eg, antidote available), the Investigator has the 
sole responsibility for determining if unblinding of a participants’ 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 documents and reports the 
action to AstraZeneca, without revealing the treatment given to participant to the AstraZeneca 
staff.
The laboratory vendor personnel performing the bioanalyses of the plasma samples will have 
access to the randomization list.
6.4
Study Intervention Compliance 
When participants are dosed at the site, they will receive study intervention directly from the 
Investigator or designee, under medical supervision. The date, and time if applicable, of dose 
administered in the clinic, as well as the anatomical location of the injection site, 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 


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study site staff other than the person administering the study intervention.
Dosing visits may be undertaken as home visits by site staff. If participants are dosed at home, 
they will receive study intervention directly from site staff The dose administered at home will 
be recorded in the source documents. 
6.5
Concomitant Therapy
Any medication (including over-the-counter or prescription medicines, vitamins, and/or herbal 
supplements) or vaccine that the participant is receiving at the time of enrolment or receives 
during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate care for participants except for those medications excluded below or listed in 
the exclusion criteria. Specifically, participants should receive full supportive care during the 
study as deemed appropriate, and in accordance with local guidelines.
The following medical restrictions apply:

Medications / therapies specified in the exclusion criteria are prohibited from use for the 
duration of the participant’s involvement in the study. 

All study participants should be receiving moderate-or high-intensity statin therapy as 
defined by the ACC/AHA guidelines on blood cholesterol management, or according to 
local guidelines.

Participants should be on stable medication for ≥ 3 months prior to screening with no 
planned medication or dose change during study participation. The exception to this 
restriction is for fenofibrate; if the participant is receiving fenofibrate, the therapy must be 
stable for at least 6 weeks prior to randomization at a dose that is appropriate for the 
duration of the study in the judgement of the Investigator. Other fibrate therapy (and 
derivatives) are prohibited. 

Participants should not be on any anti-platelet therapy other than low-dose aspirin 
(≤100 mg/day). 

Participants must abstain from making dose changes and taking new prescription or non-
prescription drugs without consultation of the Investigator (including vitamins and dietary 
or herbal supplements) within 7 days (or 14 days if the drug is a potential enzyme 
inducer) or 5 half-lives (whichever is longer) before the start of study intervention (Visit 
3) until completion of the follow-up visits.


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
Paracetamol/acetaminophen, at doses of 2 g/day, is permitted for use any time during 
the study. Other concomitant medication may be considered on a case-by-case basis by 
the Investigator in consultation with the Medical Monitor if required.

The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
6.5.1 Rescue Medicine 
The study will not supply any specific rescue medication. Please see Section 6.5 on 
concomitant therapy for additional instructions.
The date and time of any rescue medication administration or respective dose change must be 
recorded including:

Name of medication;

Reason for use / change;

Dates of administration including start and end dates;

And dosage information including dose and frequency.
6.6
Dose Modification
No dose modification is planned.
6.7
Intervention after the End of the Study
There is no planned intervention following the end of the study.
7.
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
An individual participant will not receive further study treatment if any of the following 
occur in the participant in question:

Confirmed platelet count < 75,000/µL (see Appendix F in case of uninterpretable platelet 
count) 

Hy’s Law defined as ‘an increase in AST or ALT ≥ 3 × ULN and TBL ≥ 2 × ULN’, 
where no other reason, other than the study treatment, can be found to explain the 
combination of increases

ALT or AST > 8 × ULN 

ALT or AST > 5 × ULN for > 2 weeks 

ALT or AST > 3 × ULN and TBL > 2 x ULN or INR > 1.5 


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
ALT or AST > 3 × ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia ( > 5 %)

Confirmed increase in serum creatinine of 0.3 mg/dL from baseline

Confirmed 25% decline in eGFR from baseline

Confirmed new-onset haematuria, albuminuria (UACR ≥ 300 mg/g), or proteinuria 
(UPCR ≥ 500 mg/g)

Hypersensitivity reaction CTCAE grade 3 or higher
Participants may be discontinued from study intervention in the following situations:

Participant decision. The participant is at any time free to discontinue treatment, without 
prejudice to further treatment

Adverse Event

Severe non-compliance with the CSP
If a participant discontinues study treatment, he or she will be encouraged to return to the 
study site for the EDV (see Table 1). Where possible, the EDV should be at the next visit 
according to the original visit schedule, unless consent is withdrawn from further study 
participation. To secure recommended safety follow-up, participants attending an EDV should 
also be asked to continue to return for their originally scheduled visits for a total of three 
months, unless they are unable to or unwilling to return. Note that discontinuation from study 
intervention is NOT the same thing as a withdrawal from the study.
See the SoA for data to be collected at the time of intervention discontinuation and follow-up 
and for any further evaluations that need to be completed.
7.2
Participant Withdrawal from the Study 

A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the Investigator for safety, behavioural, 
compliance, or administrative reasons. This is expected to be uncommon.

A participant who considers withdrawing 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).

At the time of withdrawal from the study, if possible, an EDV should be conducted, as 
shown in the SoA. See SoA for data to be collected at the time of study withdrawal and 
follow-up and for any further evaluations that need to be completed.

The participant will discontinue the study intervention and be withdrawn from the 
study at that time.


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
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 if he/she still agrees for 
existing samples to 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 regulation. The 
Investigator must document the decision on use of existing samples in the site study 
records and inform the Global Study Team/CRA.
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.
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.

Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 

Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. 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 collect vital status information.
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8.
STUDY ASSESSMENTS AND PROCEDURES 

Study procedures and their timing are summarised in the SoA. Protocol waivers or 
exemptions are not allowed. Assessments scheduled at the same time may be initiated 
based on the sequence below
1
ECG
2
Vital signs (SBP and diastolic blood pressure [DBP]), pulse rate, and temperature, if 
appropriate)
3
PK and PD blood sampling
4
Dose administration
Pre-dose assessments may be performed up to 60 minutes prior to dosing.

Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if 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.

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 (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
The study is divided into one treatment period and one safety follow up period. The treatment 
period starts after the screening visits (Visit 1: Day -42 to Day -1; Visit 2: Day -7 to Day -1). 
During Visit 1, the participants will be checked for eligibility and enrolled to the study. 
Additional samples will be collected on Visit 2. Approximately 108 participants will be 
randomized at Visit 3 (Day 1) in a 1:1:1:1 ratio to SC injections of AZD8233 (planned doses 
, 
, and 
) or matching placebo. AZD8233 or placebo will be administered SC 
on Visit 3, 4, 6, and 8. The participants will be treated for 84 days (12 weeks) with AZD8233 
or placebo. Thereafter, the participants will continue in a safety follow up period for 12 weeks; 
the final follow up visit will be performed on Week 24 (16 weeks post last dose of AZD8233 
or placebo).
General description of visits:
Visit 1 (enrolment) and Visit 2: At Visit 1 (Day -42 to Day -1), participants will be asked to 
CCI CCI
CCI


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sign the informed consent and optional informed consent for future genetic research sample. 
Participant demographics, medical history including smoking and alcohol consumption 
history will be recorded in the eCRF. A complete physical examination must be performed. 
Vital signs, height, BMI and ECG must be checked, as well as blood and urine sample 
collection. Enrolment will be performed in RTSM. Visit 2 (Day -7 to Day -1) will include an 
blood sample collection for LDL-C, PCSK9, and triglycerides. 
Visit 3 (randomization): Visit 3 (Day 1) should be performed within 42 days of Visit 1. 
Participants are required to fast for at least 8 hours overnight, prior to the visit; participants are 
permitted to drink water during this period until 1 hour before blood sampling. At Visit 3, 
eligibility criteria must be verified by checking screening labs and inclusion/exclusion criteria. 
A complete physical examination must be performed. Blood and urine samples to be obtained 
prior to administration of study intervention in fasted state. ADA sample will be obtained pre-
dose. Vital signs and ECG to be checked. If the participant fulfils all inclusion criteria and 
none of the exclusion criteria, they will be randomized in RTSM and study intervention will 
be administered as SC injection. 
Visit 4, 6, and 8: Visit 4 (Day 8 ± 1 day), Visit 6 (Day 29 ± 2 days), and Visit 8 
(Day 57 ± 2 days) are planned as clinical visits but may also be undertaken at the participant's 
home or any other appropriate location if deemed applicable, by site staff, following 
consultation with the sponsor. At Visits 4, 6, and 8, study intervention will be administered as 
SC injections. Participants are required to fast for at least 8 hours prior to Visits 4, 6, and 8. 
Participants are permitted to drink water during this period of fasting until 1 hour before blood 
sampling. Blood and urine sampling must be performed prior to administration of study 
intervention. PK sampling to be performed at Visits 4, 6, and 8. On Visits 4, 6, and 8, PK and 
ADA sampling must be done pre-dose. An abbreviated physical examination is required at the 
visits as well as ECG and vital signs examination. 
Visit 5, 7, and 9: For Visit 5 (Day 22 ± 2 days), Visit 7 (Day 43 ± 2 days), and Visit 9 
(Day 71 ± 2 days), are planned as clinical or home visits that may be undertaken at the 
participant's home or any other appropriate location by site staff or by qualified external 
service provider. PK sampling to be performed at Visits 7 and 9. An abbreviated physical 
examination is required at the visits. Vital signs, blood and urine samples to be taken at the 
visits. 
Safety follow up visits (Visit 10-15): ECG must be performed at Visit 10 (Day 85 ± 2 days), 
Visit 11 (Day 99 ± 2 days), Visit 13 (Day 127 ± 2 days) and Visit 15 (Day 155 ± 2 days). At all 
safety follow up visits, an abbreviated physical examination is required, and vital signs, blood, 
and urine samples are to be checked. PK and ADA sampling are to be performed at Visit 10 
(Day 85 ± 2 days), Visit 12 (Day 113 ± 2 days) and Visit 14 (Day 141 ± 2 days). Visit 11, 13, 
and 15 are listed as home visits in the SoA. Those visits may be undertaken at the participant's 


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home or any other appropriate location. Other visits currently not designated as “home visits” 
may also be undertaken at the participant's home or any other appropriate location if deemed 
applicable, following consultation with the sponsor. 
Early Discontinuation Visit: The EDV may take place any time during the study, in case a 
participant discontinues study treatment prior to Visit 8 (where last dose of study treatment is 
administered). The same assessments as during the final follow up visit will be performed. See 
Section 7.1.
Final follow up visit: The final follow up visit will be performed on Day 169 (± 2 days). PK 
and ADA sampling to be performed. A complete physical examination must be performed on 
the visit, and body weight, BMI, vital signs, and ECG to be checked. Blood and urine 
sampling to be obtained.
The maximum blood volume to be drawn from each subject should not exceed 550 mL over 
an 8-week period. Repeat or unscheduled samples may be taken for safety reasons or for 
technical issues with the samples.
8.1
Efficacy Assessments 
Please see Section 8.5.3 for assessments which will be used for primary and key secondary 
efficacy analyses.
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations

A complete physical examination will include assessments of the following; general 
appearance, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, 
eyes, nose and throat), lymph nodes, thyroid, musculoskeletal (including spine and 
extremities), and neurological systems. 

An abbreviated physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). During the home visits, the 
abbreviated physical exam can be conducted via a symptom led assessment.

Body weight should be measured in light indoor clothes without shoes, after a prior visit 
to the bathroom.
Physical examination will be performed at the time points specified in the SoA. BMI will be 
calculated at the time points specified in the SoA.


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8.2.2
Vital Signs
Vital signs (blood pressure, pulse and temperature) will be performed at the time points 
specified in the SoA.

Blood pressure and pulse measurements will be assessed in supine position with a 
completely automated device. Manual techniques will be used only if an automated 
device is not available.

BP and pulse measurements should be preceded by at least 5 minutes of rest for the 
participant in a quiet setting without distractions (eg, television, cell phones).
Vital signs (to be taken before blood collection for laboratory tests) will consist of 1 pulse and 
3 BP measurements (3 consecutive BP readings will be recorded at intervals of at least 
1 minute). The average of the 3 BP readings will be recorded on the eCRF.
8.2.3
Electrocardiograms
ECG will be performed at the time points specified in the SoA.
12-lead ECG will be obtained after the participant has rested in supine position for at least 10 
minutes. The following parameters or time intervals will be recorded for each ECG: RR, PR, 
QRS, QT, QTcF, and HR.
The same recorder should be used for each participant at each time point, if possible.
From the ECG data, the following parameters will be derived: 
- QTcF will be calculated as QTcF=QT*RR^-1/3, where the QT interval is in milliseconds and 
the RR interval is in seconds.
- Heart rate will be calculated, based on the RR interval as HR=60/RR interval, where the RR 
interval is in seconds.
Calculation of derived parameters will be performed after averaging of QT and RR data. 
The ECG data will be averaged on an individual basis before performing the derivations 
above and prior to calculation of any changes from baseline or descriptive statistics. For each 
participant, it will be done as follows: the mean value of all measurements will be taken 
provided that at least 2 measurements are present (and at least 3 consecutive beats were 
analyzable in each ECG) or else, the averaged value at the corresponding target time point will 
be set to missing. 
ECG results will be listed by treatment and dose level of AZD8233 for each participant and 
time point and will include all individual and averaged values of PR, RR, QRS, QT interval, 
and the derived values of QTcF and HR (RR). All averaged and derived parameters will have 


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changes from baseline derived and presented. 
Descriptive statistics will be presented by treatment and dose level of AZD8233, time point 
for averaged values and changes from baseline of averaged values of PR, RR, QRS, QT; 
derived values and changes from baseline for QTcF and HR will also be included. The 
baseline for the dECG measurements will be the pre-dose assessment on Day 1. 
Outliers with respect to QTcF will also be tabulated for the following categories: 
Absolute value > 450 ms and ≤ 480 ms.
Absolute value > 480 ms and ≤ 500 ms.
Absolute value > 500 ms.
Increase from baseline > 30 ms and ≤ 60 ms.
Increase from baseline > 60 ms.
The Investigator (or qualified designee) will make an overall evaluation of the ECG as normal 
or abnormal. If abnormal, it will be decided whether the abnormality is clinically significant 
or not clinically significant, and the reason for the abnormality will be recorded on the eCRF.
Abnormal values shall not be recorded as AEs unless deemed clinically significant. The 
printout of the ECG is to be signed, dated, and filed in the ISF along with a signed and dated 
copy (if the printouts are not on archive-quality paper).
The Investigator may perform additional 12-lead ECG assessments in case of any abnormal 
findings or if considered required by the Investigator for any other safety reason. These 
assessments should be entered as an unscheduled assessment.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples for determination of clinical chemistry, haematology, coagulation
and urinalysis will be taken at the visits indicated in the SoA.
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection and results (values, units and reference ranges) will 
be recorded on the appropriate eCRF.
All laboratory variables will be analysed at Covance central lab. Samples will be collected, 
handled, labelled, stored and shipped as detailed in the laboratory manual. 
The following laboratory variables will be measured.


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Table 5
Laboratory safety variables 
Haematology/Haemostasis (whole blood)
Clinical Chemistry (serum or plasma)
White blood cell (WBC) count
Sodium
Red blood cell (RBC) count
Potassium
Haemoglobin (Hb) 
Blood urea nitrogen (BUN)
Haematocrit (HCT)
Creatinine
Mean-corpuscular volume (MCV)
Calcium
Mean corpuscular haemoglobin concentration 
(MCHC)
Phosphate
Neutrophils absolute count
Creatine kinase (CK)
Lymphocytes absolute count
Direct bilirubin
Monocytes absolute count
Alkaline phosphatase (ALP)
Eosinophils absolute count
Alanine aminotransferase (ALT)
Basophils absolute count
Aspartate aminotransferase (AST)
Platelets absolute count
Gamma glutamyl transpeptidase (GGT)
Reticulocytes absolute count
Total bilirubin (TBL)
Glutamate dehydrogenase (GLDH)
Urinalysis (dipstick)
Bicarbonate
Urinalysis (positive dipstick)
Uric acid
pH
FSH (women only)
Specific gravity
LH (women only)
Glucose
Blood
Coagulation
Colour
Prothrombin time 
Protein
Activated partial thrombin time (aPTT)
Clarity/Appearance
International normalized ratio (INR)
Nitrites
Ketones
Urine renal safety biomarkers
Leukocytes
Albumin
Microscopic analysis (if positive for blood, nitrites or 
protein)
Total protein
Urobilinogen
Creatinine
Urine protein to creatinine ratio (UPCR)
Other Laboratory Assessments
Urine albumin to creatinine ratio (UACR)
Complement activation panel (C3a, Bb, C5a)
Estimated glomerular filtration rate (eGFR; by 
CKD-EPI formula)
High-sensitivity C-reactive protein (hs-CRP)


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NB. In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN 
please refer to Appendix E (Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s Law) for further instructions. 
8.2.5
Other Screening Assessments
Other screening assessments referred to in the SoA (Table 1) are shown in 


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Table 6
Other Screening Assessments
.


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Table 6
Other Screening Assessments
HbA1c
Viral Serology Screen
Human immunodeficiency virus (HIV) I
Hepatitis B surface antigen (HBsAg)
Hepatitis B virus DNA (HBV DNA)
HIV II
Hepatitis C virus antibody
Hepatitis C virus RNA (HCV RNA)
8.2.6
Injection Site Reactions
Injection site reactions (ISR) should be reported using standard AE collection criteria. Details 
regarding the ISRs will be collected in a specific eCRF page.
8.3
Adverse Events and Serious Adverse Events 
The Investigator is responsible for ensuring that all staff involved in the study are familiar 
with the contents of this section
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorised representative). 
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events will be collected from time of first dose throughout the treatment period and 
including the follow-up period.
Serious adverse events will be recorded from the time of signing of the ICF.
If the Investigator becomes aware of an SAE with a suspected causal relationship to the study 
intervention 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 AEs and SAEs
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. AstraZeneca 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.


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Adverse event variables
The following variables will be collected for each AE:

AE (verbatim)

The date and time when the AE started and stopped

Maximum intensity 

Whether the AE is serious or not

Investigator causality rating against the study intervention (yes or no)

Action taken with regard to the study intervention

AE caused participant’s withdrawal from study (yes or no)

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date Investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

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 the study intervention 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 to the CSP.


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8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests 
The results from the CSP mandated laboratory tests and vital signs will be summarised in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the study intervention 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 
study treatment, eg, dose adjustment or drug interruption).
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, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE (see also Section 8.3.7). 
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 ≥ 3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Please refer to Appendix E for further instruction on cases of 
increases in liver biochemistry and evaluation of Hy’s Law.


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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 appropriate AstraZeneca representatives within one day, ie, immediately but no later than 
24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within one 
calendar day, ie, immediately but no later than 24 hours of when he or she becomes aware of 
it.
Once the Investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to the designated AstraZeneca representative.
If the EDC system is not available, then the Investigator or other study site staff reports an 
SAE to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the Investigator/study site staff how to proceed. 
Investigators or other site personnel send relevant CRF modules by fax (+46 317-763-734) or 
email (AEMailboxClinicalTrialTCS@astrazeneca.com) to AstraZeneca Patient Safety Data 
Entry Site, Tata Consultancy Services.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 
drug. 
8.3.8
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study participant has received any study 
drug.
8.3.8.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 


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pregnancy still occur, the investigational product should be discontinued immediately, and the 
pregnancy reported to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study intervention 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs. Elective abortions without complications should not be handled as AEs. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality) should be followed up and documented even if the participant 
was discontinued from the study.
If any pregnancy occurs, then the Investigator or other site personnel informs the appropriate 
AstraZeneca representatives within 1 day, ie, immediately but no later than 24 hours of when 
he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 or 5 
calendar days for SAEs (see Section 8.3.7) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT is 
used to report the outcome of the pregnancy.
8.3.8.2
Paternal Exposure
Male participants should refrain from fathering a child during the study and for 3 months 
following the final follow-up visit (see also Section 5.3.4).
In case of pregnancy of the partner of a male participants, the partner’s pregnancy should be 
reported on the pregnancy form (consent from the partner must be obtained before the 
pregnancy form is completed) following the same timeframe and routing as described for any 
participant’s pregnancy. Pregnancy of the participant's partner is not considered to be an AE. 
These pregnancies will also be followed up, and the outcome of the pregnancy (spontaneous 
miscarriage, elective termination, ectopic pregnancy, normal birth or congenital abnormality) 
should, if possible, be obtained and documented.
8.3.9
Medication Error
If a medication error occurs in the course of the study, then the Investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day, ie, immediately 
but no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 


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relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 
Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error (see Section 8.3.7) and within 30 days for all other 
medication errors.
The definition of a Medication Error can be found in Appendix B. 
8.4
Overdose 
For this study, any dose of AZD8233 greater than the planned dose 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 on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives 
immediately, or no later than 24 hours of when he or she becomes aware of it.
The designated AstraZeneca representative works with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety Data Entry Site.
For overdoses associated with a SAE, the standard reporting timelines apply, see Section 
8.3.7. For other overdoses, reporting must occur within 30 calendar days.
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 
Sample, see Appendix C.
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. 

Pharmacokinetic samples will be disposed of after the Bioanalytical Report finalization or 
six months after issuance of the draft Bioanalytical Report (whichever is earlier), unless 
consented for future analyses. 

Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled, or individual PK samples to 


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further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, 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 
Plasma samples will be collected for measurement of plasma concentrations of AZD8233 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. 
Plasma samples will be used to analyse the PK of AZD8233. Samples collected for analyses 
of AZD8233 concentration may also be used to evaluate safety or efficacy aspects related to 
concerns arising during or after the study.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
8.5.1.1
Determination of Drug Concentration
Samples for determination of drug concentration (AZD8233 full lengths ASOs) in plasma will 
be assayed at bioanalytical test sites operated by or on behalf of AstraZeneca, using an 
appropriately validated bioanalytical method. Full details of the analytical method used will be 
described in a separate bioanalytical report.
Placebo samples will not be analysed, unless there is a need to confirm that correct treatment 
has been given to study participants.
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 or additional assay development/validation work, if 
any, will be performed alongside the bioanalysis of the test samples. 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 immunogenicity assessments (ADA) will be collected according to the SoA 
(Table 1).
The presence or absence of ADAs will be determined in the plasma samples using a validated 
bioanalytical method. A tiered testing scheme will be employed, with the first step being 
screening. Samples found positive in the screening step will be tested in the confirmatory step. 
Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titre 
determination. Full details of the analytical method and analyses performed will be described 
in a separate bioanalytical report.
ADA samples may also be further tested for characterisation of the ADA response. Study 
results may be reported independently to ADA follow-up.
Samples will be collected, labelled, stored, and shipped as detailed in the Laboratory Manual.
Participants with treatment-emerging ADA-positive titres will be asked to return to provide 
another sample 3 months after the first positive sample to evaluate whether ADAs persist. If 
the sample taken 3 months later is ADA-positive, the participant will be asked to return to 
provide a sample in another 3 months. If the sample is ADA-positive at 6 months, the 
Investigator and the medical monitor will discuss additional actions and decide on future 
monitoring frequency. Participants with treatment-induced ADAs are considered 
ADA-positive until levels have returned to baseline or levels have dropped 97% from 
maximum.
8.5.3
Pharmacodynamics
8.5.3.1
Collection of Samples
Blood samples will be collected for the assessment of PCSK9 and dyslipidemia (


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Table 7). Blood samples for the determination of concentrations of PCSK9 and to evaluate the 
lipid parameters and lipoprotein profile (particle size and number) will be collected at the time 
points specified in the SoA (Table 1). 


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Table 7
Pharmacodynamic Laboratory Assessments
LDL-C
PCSK9
Lipoprotein profile (particle size and number)
Biomarkers analyses
Other lipid parameters including:
Total cholesterol 
HDL-C
non-HDL-C
VLDL-C
ApoA1
ApoB
Lp(a)
Triglycerides
Remnants cholesterol
ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-
C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase 
subtilisin/kexin type-9; VLDL-C = very-low-density lipoprotein cholesterol
For storage, re-use and destruction of pharmacodynamic samples see Section 8.5 and 
Appendix C. 
8.6
Human Biological Sample Biomarkers
8.6.1
Collection of Mandatory Samples for Biomarker Analysis
By consenting to take part in the study, the participant consents to take part in the mandatory 
research components of the study. 

Samples for biomarker research are required and will be collected from all participants in 
this study as specified in the SoA. 

Collection and storage of blood (plasma) and urine samples for potential future 
exploratory research aimed at exploring biomarkers involved in PK, PD, safety (including 
anti-platelet antibodies) and tolerability related to AZD8233 treatment or cardiometabolic 
diseases is part of this study.

Biomarkers to be taken:

Blood (plasma) and urine sample analyses

Targeted and unbiased -omics approaches for evaluation of plasma and/or urine 
samples for PD biomarkers and biomarker research relative to safety, tolerability and 
PK profile related to AZD8233 treatment. 
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 and is subject to agreement in the ICF addendum.
6 mL blood sample for DNA isolation will be collected from participants who have consented 
to participate in the genetic analysis component of the study. Participation is optional. 
Participants who do not wish to participate in the genetic research may still participate in the 
study.


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See Appendix D for information regarding the Genomics Initiative genetic sample. Details on 
processes for collection and shipment and destruction of these samples can be found in the 
Laboratory Manual. 
For storage and destruction of genetic samples see Appendix D. 
8.8
Health Economics
Health Economics/Medical Resource Utilization and Health Economics parameters are not 
evaluated in this study.
9.
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
The study hypothesis to test is treatment effect of AZD8233 across different dose levels 
compared to placebo and compared to each other. The null hypotheses for these tests are that 
the absolute change in log-transformed LDL-C for AZD8233 at some dose level is equal to the 
absolute change in log-transformed LDL-C for Placebo or any other dose of AZD8233.
The main statistical test to perform has the null hypothesis that the absolute change in log-
transformed LDL-C for AZD8233 
 dose is equal to the absolute change in log-
transformed LDL-C for AZD8233 
 dose. 
9.2
Sample Size Determination
Approximately 108 participants will be randomly assigned to the four study arms so that at 
least 80 evaluable participants completed treatment up until and including visit 10 (week 12). 
Any participant who receives at least one dose of study intervention is considered evaluable 
and is included in the full analysis set. Participants are randomly assigned to study treatment 
cohorts in a ratio of 1:1:1:1.
The sample size of 20 participants per arm will provide 90% power in a two-sided t-test at 5% 
significance level to detect a difference of 0.33 on the log scale; 0.33 on the log scale is 
considered sufficient to distinguish the effect of the 
 dose from the effect of the 
 
dose. The common SD for log-transformed LDL-C is assumed to be 0.3. 
CCI
CCI
CCI
CCI


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9.3
Populations for Analyses
The following populations are defined:
Table 8
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who sign the ICF.
Randomly assigned to study 
treatment
All participants who were randomized. Participants will be analysed according 
to the treatment to which they were randomized.
Full analysis set
All randomized participants who received at least 1 dose of study intervention, 
in accordance with the intention to treat principle. Participants will be 
included in the analysis according to the treatment to which they were 
randomized. This is the primary analysis set.
Safety analysis set
All participants randomly assigned to study treatment and who take at least 
1 dose of study treatment and for whom any post-dose data are available.
Participants will be analysed according to the treatment which they actually 
received. If a participant received study intervention from the wrong kit for 
only part of the treatment duration and then switched to another, the 
associated treatment group for that participant will be the treatment group that 
participant was randomized to. 
PK analysis set
All participants who received at least one dose of study treatment and who had 
evaluable PK data.
Any important protocol deviations from randomized treatment will be listed and considered 
when interpreting the data. Important protocol deviations will be defined in the Non-
compliance Handling Plan (NHP).
9.4
Statistical Analyses
The statistical analysis plan will be finalised prior to first participant first visit and it will 
include a more technical and detailed description of the statistical analyses described in this 
section. This section is a summary of the planned statistical analyses of the most important 
endpoints including primary and key secondary endpoints. The statistical analysis plan will 
describe the participant populations to be included in the analyses, and procedures for 
accounting for missing, unused, and spurious data.
9.4.1
General Considerations
Unless otherwise stated, the safety analysis set will also be used for the presentation of all 
demographic and disposition data. If not otherwise specified, baseline refers to the last 
measurement prior to study intervention administration.
Statistical tests will be performed using two-sided test at a 5% significance level, if not 
explicitly stated otherwise. The SAS® version 9.3 or higher will be used for the data analysis. 


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A complete set of raw data listings will be appended to the final CSR. All tables, figures and 
listings will be presented in portable document format (PDF) without any manual editing, ie, 
they will appear unmodified as programmed by means of the statistical package.
All results will be presented by treatment with descriptive statistics appropriate to the nature 
of the variables. Demographic and baseline characteristics will be presented as follows; for 
continuous variables, the number of non-missing observations, mean, SD, SEM, 95% CI of 
the mean, median, first and third quartiles, minimum and maximum, will be presented; for 
categorical variables: counts (n) and percentages (%) (where specified) will be presented. 
These summaries will be provided by time point of assessment as appropriate.
9.4.2
Efficacy 
The analysis and presentation of efficacy and exploratory endpoints will be based on 
participants in the full analysis set. 
For selected efficacy variables, if not specified otherwise, a mixed model for repeated 
measures will be fit using log transformed data and results transformed back to geometric 
mean ratios for the purpose of presentation and interpretation. The mixed model for repeated 
measures will include the relevant log transformed baseline biomarker value as a covariate. 
Time point (visit number), treatment, and the interaction between time point and treatment 
will be included as factors. The response variable will be change from baseline in log 
transformed biomarker value. The model will be fit with an unstructured covariance structure, 
and the Kenward-Roger correction applied to obtain the degrees of freedom. Estimation of the 
treatment effect will be done for each visit after baseline. In case of issues when fitting the 
model to the data, a hierarchical model fitting procedure will be described in the statistical 
analysis plan.
9.4.2.1
Primary Endpoint(s)
The primary efficacy endpoint is change from baseline in log-transformed LDL-C at the end 
of Week 12 which will be fitted using a mixed model for repeated measures. 
Comparisons of the change from baseline between the treatment arms will be done using least 
square mean difference between treatment groups as estimated by the fitted model. All 
treatment arms will be compared with each other. 
For active treatment in the study, the geometric mean ratio will be plotted over time.
9.4.2.2
Secondary Endpoint(s)
Percentage change from baseline in LDL-C in the original scale will be calculated for each 
participant and then compared between treatment groups using a mixed model for repeated 
measures. 


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Change from baseline of log-transformed PCSK9 will be fitted using a mixed model for 
repeated measures and least square mean differences between treatment groups estimated 
from the fitted model. Results will be presented on the log scale and as geometric mean ratios.
Levels of other lipid parameters will be summarised using descriptive statistics.
Development of ADA will be monitored for each participant, analysis and reporting of data 
related to ADA will be specified in the statistical analysis plan.
For each treatment, the mean percentage change from baseline of LDL-C and PCSK9 levels 
will be plotted over time.
Pharmacokinetics
If data permits a population PK model will be developed, possibly with the support of PK data 
from studies D7990C00001 and D7990C00002, using nonlinear mixed effects regression 
analysis in NONMEM. Furthermore, if data allows, the population PK model may be coupled 
with separate PD models for PCSK9 and LDL-C.
All PK/PD modelling will be described in a separate data analysis plan. Moreover, the results 
of any such modelling will be provided in a separate population PK/PD report (as an appendix 
to the CSR or as a stand-alone report).
Plasma concentration data of AZD8233 will also be summarized by descriptive statistics per 
sampling time point in the CSR.
9.4.3
Safety
All safety analyses will be performed on the Safety analysis set. Safety variables are AEs, vital 
signs, 12-lead ECGs and laboratory assessments. 
Safety variables will be summarised by treatment group and visit using descriptive statistics 
(n, mean, SD, median, minimum and maximum [and geometric mean and coefficient of 
variation, if applicable]) for continuous data and absolute and relative frequencies for 
categorical data.
Adverse events will be summarised by Preferred Term and System Organ Class using 
MedDRA vocabulary. Adverse events that led to withdrawal, SAEs, AEs by severity and 
causally related AEs will also be presented. All AE summaries will be done by treatment 
group.
Injection site reactions will be considered an AE of special interest and will be listed 
separately. Listing of injection site reactions will include information about size, colour and 
itching status and will be grouped by participant and time point (visit). 


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Clinical laboratory data and ECG parameters will be summarized by treatment group and 
visit.
Use of concomitant medication will be reported.
9.5
Interim Analyses
There are no plans to perform any interim analyses during the study.
9.6
Data Monitoring Committee
A data monitoring committee will not be used in this study.
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS


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Appendix A
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 Council for International Organizations of Medical 
Sciences (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.

AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
CRO but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs

Prompt notification by the Investigator to the sponsor of a 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, IRB/IEC, and Investigators.

For all studies except those utilizing medical devices, Investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) 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 along with the Investigator’s Brochure 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 


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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 1 year after completion of the study.
A 3
Informed Consent Process

The Investigator or his/her representative will explain the nature of the study to the 
participant 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 will be required to sign a statement of informed consent that 
meets the requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance 
Portability and Accountability Act (HIPAA) requirements, where applicable, and the 
IRB/IEC or study centre.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised 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.

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 
authorised designee will explain to each participant the objectives of the analysis to be 
done on the samples and any potential future use. Participants will be told that they are 
free to refuse to participate in any optional samples or the future use 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 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 authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.
A 5
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 main study results when they are 
available. The clinical study and/or summary of main study results may also be available on 
other websites according to the regulations of the countries in which the study is conducted.
A 6
Data Quality Assurance

All participant data relating to the study will be recorded on 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 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the Monitoring Plan.

The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.

The sponsor assumes accountability for actions delegated to other individuals (eg, CRO).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised 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 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 


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records may be transferred to another location or party without written notification to the 
sponsor.
A 7
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.

Definition of what constitutes source data can be found in source data verification plan.
A 8
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 is the first site open and will be the study start date.
The sponsor 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

Discontinuation of further study intervention development
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any CROs used in the study of the 
reason for termination or suspension, as specified by the applicable regulatory requirements. 
The Investigator shall promptly inform the participant and should assure appropriate 
participant therapy and/or follow-up.


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Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 9
Publication Policy

The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to 
provide comments.

The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicentre studies only in their entirety and not as individual site data. In 
this case, a coordinating Investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.


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Appendix B
Adverse 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 unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (ie, run-in, treatment, washout, follow-
up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-participant hospitalisation or prolongation of existing hospitalisation 

Results in persistent or significant disability or incapacity. 

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events for malignant tumours 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 judgement on an individual event basis 
should be applied to clarify that the malignant tumour event should be assessed and reported 
as a Non-Serious AE. For example, if the tumour is included as medical history and 
progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, 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).
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal oedema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the 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 judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardise 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 
judgement must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anaemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalisation

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)


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It is important to distinguish between serious and severe AEs. Severity is a measure of 
intensity whereas seriousness is defined by the criteria in Appendix B 2. An AE of severe 
intensity need not necessarily be considered serious. For example, nausea that persists for 
several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Appendix B 2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Appendix B 2.
B 3
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.

Time Course. Exposure to suspect drug. Has the participant actually received the suspect 
drug? Did the AE occur in a reasonable temporal relationship to the administration of the 
suspect drug?

Consistency with known drug profile. Was the AE consistent with the previous 
knowledge of the suspect drug (pharmacology and toxicology) or drugs of the same 
pharmacological class? Or could the AE be anticipated from its pharmacological 
properties?

De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect drug?

No alternative cause. The AE cannot be reasonably explained by another aetiology such 
as the underlying disease, other drugs, other host or environmental factors.

Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.

Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:

Is this a recognised feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.


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


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
Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the medication 
error.


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Appendix C
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 centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples whilst 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.
AstraZeneca or delegated representatives will keep oversight of the entire life cycle through 
internal procedures, monitoring of study sites, auditing or process checks, and contractual 
requirements of external laboratory providers
Samples retained for further use will be stored in the AstraZeneca-assigned biobanks or other 
sample archive facilities and will be tracked by the appropriate AstraZeneca Team during for
the remainder of the sample life cycle.
If required, AstraZeneca 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 are already 
analysed, AstraZeneca is not obliged to destroy the results of this 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 AstraZeneca or delegate.

Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented

Ensures that the participant and AstraZeneca are informed about the sample disposal.


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AstraZeneca 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 the action documented, and study site notified.
C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (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, for example, 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, for example, 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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Appendix D
Optional Genomics Initiative Sample 
D 1
Use/analysis of DNA
Genetic variation may impact a participant’s response to therapy, susceptibility to, and 
severity and progression of disease. Variable response to therapy may be due to genetic 
determinants that impact drug absorption, distribution, metabolism, and excretion; mechanism 
of action of the drug; disease aetiology; and/or molecular subtype of the disease being treated. 
Therefore, where local regulations and IRB/IEC allow, a blood sample will be collected for 
DNA analysis from consenting participants.
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications.
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies.
Genetic research may consist of the analysis of the structure of the participant´s DNA, ie, the 
entire genome. 
The results of genetic analyses may be reported in the CSR or in a separate study summary. 
The sponsor will store the DNA samples in a secure storage space with adequate measures to 
protect confidentiality. The samples will be retained while research on AZD8233 or other 
AstraZeneca Study treatments of this class or for this indication continues but no longer than 
15 years or other period as per local requirements.
D 2
Genetic Research Plan and Procedures
Selection of genetic research population
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 fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol and: Provide informed consent for 
the Genomics Initiative sampling and analyses.


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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 within 120 days of genetic sample 
collection

Healthy Volunteers and paediatric patient samples will not be collected for the 
Genomics Initiative.
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 of consent are outlined in 
Appendix C 2.
Collection of samples for genetic research
The blood sample for genetic research will preferably be obtained from the participants at 
Visit 3 predose. If, for any reason, the sample is not drawn pre-dose on Visit 3 (D1), it may be 
taken at any visit until the Final follow-up/EDV visit. Although DNA is stable, early sample 
collection is preferred to avoid introducing bias through excluding participants who may 
withdraw due to an adverse event (AE), such participants would be important to include in 
any genetic analysis. If for any reason the sample is not drawn at the screening visit, 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. Samples will be collected, labelled, stored, and shipped as 
detailed in the Laboratory Manual.
Coding and storage of DNA samples
The process adopted for the single coding and storage of samples for genetic analysis are 
important to maintain 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 blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable only by the second, unique number. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organisation. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organisations working with the DNA).


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The link between the participant enrollment/randomization code and the second number will 
be maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organisations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit, 
and permit tracing of samples for destruction in the case of withdrawal of consent.
Ethical and regulatory requirements
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Appendix A.
Informed consent
The genetic component of this study is optional and the 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 centre. The Principal Investigator(s) is responsible for ensuring that 
consent is given freely and that the participant understands that they may freely withdrawal 
from the genetic aspect of the study at any time.
Participant data protection
AstraZeneca will not provide individual genotype results to participants, any insurance 
company, any employer, their family members, general physician unless required to do so by 
law.
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the 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, an AstraZeneca Physician or an Investigator might know a 
participant’s identity and also have access to his or her genetic data. In addition, Regulatory 
authorities may require access to the relevant files, though the participant’s medical 
information and the genetic files would remain physically separate.
Data management
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organisations to analyse the samples.
AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as hospitals, academic organisations or health insurance companies. This can 
be done by placing the results in scientific databases, where they can be combined with the 


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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.
Statistical methods and determination of sample size
The number of participants that will agree to participate in the genetic research is unknown. It 
is therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan may be prepared where appropriate.


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
During the course of the study the Investigator will remain vigilant for increases in liver 
biochemistry. The Investigator is responsible for determining whether a participant meets PHL 
criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The Investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The Investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the study intervention. 
The Investigator is responsible for recording data pertaining to PHL/HL 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 ≥ 3 × ULN together with TBL ≥ 2 × 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 ≥ 3 × ULN together with TBL ≥ 2 × ULN, where no other reason, other than the 
IMP, can be found to explain the combination of increases, eg, elevated ALP indicating 
cholestasis, viral hepatitis, another drug. 
For PHL and HL 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 


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elevations in transaminases and TBL must occur.
E 3
Identification of Potential Hy’s Law Cases
In order to identify cases of PHL it is important to perform a comprehensive review of 
laboratory data for any participant who meets any of the following identification criteria in 
isolation or in combination:

ALT ≥ 3 × ULN

AST ≥ 3 × ULN

TBL ≥ 2 × ULN
Central laboratories being used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the Investigator (also sent to 
AstraZeneca representative). 
The Investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the Investigator will:

Notify the AstraZeneca representative 

Request a repeat of the test (new blood draw) by the central laboratory without 
delay

Complete the appropriate unscheduled laboratory 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 PHL criteria (see Section E 2 for 
definition) by reviewing laboratory reports from all previous visits (including both 
central and local laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the Investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria.


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
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 PHL criteria the Investigator will:

Notify the AstraZeneca representative who will then inform the Global Study Team 

Within 1 day of PHL criteria being met, the Investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the Investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s 
condition

The Study Physician contacts the Investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data

Subsequent to 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. Completes follow-up SAE Form as required.

Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the HL lab kit should be used. 

Complete the three Liver eCRF Modules as information becomes available 
#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 total bilirubin) 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.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the Investigator in order to review available data and agree on whether 


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there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
study treatment, to ensure timely analysis and reporting to health authorities within 15 
calendar days from date PHL criteria was met. The AstraZeneca Global Clinical Lead or 
equivalent and Global Safety Physician will also be involved in this review together with 
other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the Investigator will follow the 
instructions below.
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 a 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 PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the study treatment:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to study 
treatment and seriousness criteria is medically important, according to CSP process for 
SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 


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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
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation


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Appendix F
Actions in Case of Development of Thrombocytopenia or 
Uninterpretable Platelet Counts After Administration of 
ASOs
Recommended actions include reassessment of platelet count, adjustment of monitoring 
frequency (platelet count < 100,000/µL), assessment of additional laboratory parameters 
(platelet count < 75,000/µL), referral to a haematologist (platelet count ≤ 50,000/µL) and start 
of supportive treatment with corticosteroids (platelet count ≤ 30,000/µL). Drug 
discontinuation according to the defined stopping criteria is essential in participants 
with suspected thrombocytopenia.
F 1
Actions in case of uninterpretable platelet count results
Participants with uninterpretable platelet laboratory results due to clumping, haemolysis 
or quantity not sufficient must be reassessed within 2 days. Dosing is not allowed to 
proceed until the Investigator has determined that the results are within acceptable range 
according to the defined stopping criteria. 
In a clinical study with the ASO inotersen diagnosis and treatment of severe thrombocytopenia 
were delayed in some participants because of uninterpretable platelet counts due to clumping 
of platelets in the test tube. Platelet clumping in the test tube was most likely caused by a 
combination of ASO-induced antiplatelet immunoglobulin G (IgG) antibodies and the 
anticoagulant EDTA. If there is suspicion of EDTA-mediated platelet clumping, a repeat 
platelet count using a different anticoagulant, eg, sodium citrate or heparin, should be done as 
soon as possible and always before a new dose is given.
Thrombocyte Monitoring Frequency
Platelet Count (per µL)
Monitoring Frequency
> 100,000
Every 2 weeks
≥75,000 to < 100,000 or more than 50% reduction 
from baseline
Every week
< 75,000
Intensified monitoring; twice weekly to daily 
monitoring dependent of platelet count and rate of 
decline


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Additional Laboratory Assessments (Platelet Count < 75,000/μL)
Peripheral smear 
Fibrinogen split products or D-dimer on fresh blood 
Citrated sample for platelets
Coagulation panel (PT/INR, aPTT)
CBC with reticulocytes and mean platelet volume (MPV)
Serum B12 and folate
Fibrinogen
von Willebrand factor
Total globulins, total IgA, IgG, and IgM
Complement: total C3, total C4, Bb, C5a 
hs-CRP
Serology for:
HBV, HCV, HIV (if not done for screening)
Rubella
CMV
EBV
Parvo B19
Helicobacter pylori (IgG serum test)
Auto-antibody screen:
Antiphospholipid
Rheumatoid factor
Anti-dsDNA
Anti-thyroid
To be performed at specialty lab(s):
Antiplatelet antibodies and Anti-PF4 assay
Anti-drug antibody 
F 2
Referral to Expert Haematologist Care
Participants that develop thrombocytopenia with platelet counts ≤ 50,000/µL should be 
referred to a Haematologist for diagnostic and therapeutic management. This may include the 
additional laboratory tests described in the table above. Additional bone marrow aspiration 
and biopsy should be considered.
Supportive Treatment with Corticosteroids
Treatment of severe thrombocytopenia requires close communication among consulting 
specialists. For major or life-threatening bleeding, platelet transfusions should be administered 


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without delay. Because ASOs have been associated with immune-mediated thrombocytopenia 
it is strongly recommended that participants with platelet counts ≤ 30,000/µl receive 
glucocorticoid therapy (unless contraindicated). High dose steroids have been reported to 
reverse platelet decline and accelerate platelet recovery. Treatment guidelines for immune 
thrombocytopenia recommend: Dexamethasone 40 mg daily for 4 days every 2 to 4 weeks 
for 1 to 4 cycles; Prednis(ol)one 0.5 to 2 mg/kg/day for 2 to 4 weeks then taper; or 
Methylprednisolone 30 mg/kg/day for 7 days (may require continuation with oral steroids 
after methylprednisolone) (Provan et al, 2010). Platelet count should be monitored closely 
during corticosteroid treatment. An increased or normalized platelet count is expected within 
two weeks of therapy. Once the platelet count normalizes or rises significantly and plateaus 
> 50,000/µl, no additional therapy is needed. Participants should be followed until platelet 
count has been > 100,000/µl for 1 month (see above table for monitoring frequency).
F 3
Reference
Provan et al, 2010
Provan D et al. International consensus report on the investigation and management of 
primary immune thrombocytopenia. Blood. 2010;115(2):168-186.


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Appendix G
Guidance for Definition of Anaphylactic/Hypersensitivity 
Reactions and Checklist for the Investigator
The National Institute of Allergy and Infectious Disease and Food Allergy and Anaphylaxis 
Network Guidance for Anaphylaxis Diagnosis define anaphylaxis as a serious allergic reaction 
that is rapid in onset and may cause death. They recognize 3 categories of anaphylaxis, with 
criteria designated to capture from 80% of cases (category 1) to > 95% of all cases of 
anaphylaxis (for all 3 categories). Refer to Sampson et al, 2006.
1
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following:
(a) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(b) Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse], syncope, incontinence).
2
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
participant (minutes to several hours):
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (eg, dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia)
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3
Reduced BP after exposure to known allergen for that participant (minutes to several 
hours):
(a) Infants and children: low SBP (age specific) or greater than 30% decrease in SBP.
(b) Adults: SBP of less than 90 mmHg or greater than 30% decrease from that person’s 
baseline.


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Hypersensitivity Reactions – Checklist for The Investigator 
At least the following should be checked. If “Yes” the diagnosis (preferably not symptoms) should 
be recorded as AE.
Yes
No
Skin and subcutaneous events 
Urticaria 
Erythema 
Pruritus 
Face oedema 
Eye oedema 
Tongue swelling 
Angioedema 
Respiratory compromise 
Bronchospasm 
Dyspnoea 
Cough 
Choking 
Stridor 
Respiratory arrest 
Cardiovascular events 
Cardiac arrest 
Cardiovascular insufficiency 
Hypotension


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Additional Samples to be Collected in Case of an Anaphylactic-like Reaction
In case of anaphylactic-like reaction, the blood samples for tryptase assessments should be 
taken 30, 60, and 120 minutes after the onset of event, if feasible.
In addition, samples for analysis of ADA should be taken at the day of the anaphylactic-like 
reaction, if feasible.
G 1
Reference
Sampson et al, 2006
Sampson HA et al. Second symposium on the definition and management of anaphylaxis: 
Summary report - Second National Institute of Allergy and Infectious Disease/Food Allergy 
and Anaphylaxis Network symposium. J Allergy Clin Immunol. 2006;117:391-397.


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Appendix H
High- and Moderate-intensity Statin Therapy
Participants should be receiving moderate- or high-intensity statin therapy as defined by the 
ACC/AHA guidelines on blood cholesterol management, or according to local guidelines. 
Below are examples of high- and moderate-intensity statin therapy for reference.
High-dose Statin Therapies
Moderate-dose Statin Therapies
•
atorvastatin 40 to 80 mg once daily
•
rosuvastatin 20 to 40 mg once daily
•
atorvastatin 10 to 20 mg once daily
•
lovastatin 40 mg once daily
•
pravastatin 40 mg once daily
•
rosuvastatin 5 mg once daily
•
rosuvastatin 5 to 10 mg daily
•
simvastatin 20 to 40 mg once daily.


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Appendix I
Abbreviations
Abbreviation or special 
term
Explanation
ACC/AHA
American College of Cardiology/American Heart Association
AE
Adverse Event
ADA
Anti-drug antibody
ALP
Alkaline Phosphatase
ALT
Alkaline Aminotransferase
Apo
Apolipoproteins
aPTT
Activated Partial Thromboplastin Time
ASO
Antisense Oligonucleotide
AST
Aspartate Aminotransferase
BMI
Body Mass Index
BP
Blood Pressure
bpm
Beats Per Minute
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CK
Creatine Kinase
CRO
Contract Research Organisation
CSA
Clinical Study Agreement
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CVD
Cardiovascular Disease
DBP
Diastolic Blood Pressure
DILI
Drug Induced Liver Injury
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
ECG
Electrocardiogram
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
EDTA
Ethylenediaminetetraacetic Acid
EDV
Early Discontinuation Visit
eGFR
Estimated Glomerular Filtration Rate
FDA
U.S. Food and Drug Administration
FSH
Follicle-stimulating Hormone
GCP
Good Clinical Practice
GGT
Gamma Glutamyl Transpeptidase


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Abbreviation or special 
term
Explanation
GLDH
Glutamate Dehydrogenase
Hb
Haemoglobin
HbA1c
Haemoglobin A1c
HCT
Haematocrit
HDL-C
High-density Lipoprotein Cholesterol
HIV
Human Immunodeficiency Virus
HL
Hy’s Law
HMG-CoA
3-hydroxy-3-methyl-glutarylcoenzyme A
HR
Heart Rate
hs-CRP
High sensitive C-reactive Protein
IATA
International Airline Transportation Association
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IRB/IEC
Institutional Review Boards/Independent Ethics Committees
ISR
Injection Site Reaction
IUD
Intrauterine Device
LDL
Low-density Lipoprotein Cholesterol
LDL-C 
Low-density Lipoprotein Cholesterol
LH
Luteinizing Hormone
LLN
Lower Limit of Normal
Lp(a)
Lipoprotein(a)
MCH
Mean Corpuscular Haemoglobin
MCHC
Mean Corpuscular Haemaglobin Concentration
MCV
Mean Corpuscular Volume
NHP
Non-compliance Handling Plan
PCSK9
Proprotein Convertase Subtilisin/Kexin type-9
PEF
Peak Expiratory Flow
PD
Pharmacodynamic
PHL
Potential Hy’s Law
PI
Principal Investigator 
PK
Pharmacokinetic
QTcF
Corrected QT Interval by Fredericia
RBC
Red Blood Cell
RTSM
Randomization and Trial Supply Management


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Abbreviation or special 
term
Explanation
SAE
Serious Adverse Event 
SBP
Systolic Blood Pressure
SC
Subcutaneous(ly)
SD
Standard Deviation
SEM
Standard Error of the Mean
SoA
Schedule of Activities
TBL
Total Bilirubin
TC
Total cholesterol
UACR
Urine Albumin to Creatinine Ratio
ULN
Upper Limit of Normal
UPCR
Urine Protein to Creatinine Ratio
VLDL-C
Very-low-density lipoprotein cholesterol
WBC
White Blood Cell


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11.
REFERENCES
Burdick AD et al 2014
Burdick AD et al. Sequence motifs associated with hepatotoxicity of locked nucleic acid 
modified antisense oligonucleotides. Nucleic Acid Res. 2014; 42:4882-4891.
Burel S et al 2013
Burel S et al. Pre-clinical evaluation of the toxicological effects of a novel constrained ethyl 
modified anti sense compound targeting signal transducer and activator of transcription 3 in 
mice and cynomolgus monkeys. Nucleic Acid Ther. 2013; 23:213-227.
Cohen J et al 2005
Cohen J et al. Low LDL cholesterol in individuals of African descent resulting from frequent 
nonsense mutations in PCSK9. Nat Genet. 2005; 37:161-165.
Cohen J et al 2006
Cohen J et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart 
disease. N Engl J Med 2006; 354:1264-1272.
Collins R et al 2016
Collins R et al. Interpretation of the evidence for the efficacy and safety of statin therapy. 
Lancet. 2016; 388:2532-2561.
Crooke ST et al 2016
Crooke ST et al. Integrated safety assessment of 2'-O-methoxyethyl chimeric antisense 
oligonucleotides in non-human primates and healthy human volunteers. Mol Ther. 2016; 
10:1771-1782.
Crooke ST et al 2017
Crooke ST et al. The effects of 2′-O-methoxyethyl containing antisense oligonucleotides on 
platelets in human clinical trials. Nucleic Acid Ther. 2017; 27:121-129.
Hagedorn PH et al 2013
Hagedorn PH et al. Hepatotoxic potential of therapeutic oligonucleotides can be predicted 
from their sequence and modification pattern. Nucleic Acid Ther. 2013; 23(5):302-310.
Henry SP et al 1997
Henry SP et al. Inhibition of coagulation by a phosphorothioate oligonucleotide. Antisense 
Nucleic Drug Dev. 1997; 7(5):503-510.
Henry SP et al 2017
Henry SP et al. Assessment of the effects of 2′-methoxyethyl antisense oligonucleotides on 
platelet count in cynomolgus nonhuman primates. Nucleic Acid Ther. 2017; 27(4):197-208.


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Hildebrandt Eriksen ES et al 2012
Hildebrandt Eriksen ES et al. A locked nucleic acid oligonucleotide targeting microRNA 122 
is well tolerated in cynomolgus monkeys. Nucleic Acid Ther. 2012; 22:152-156.
Hung G et al 2013
Hung G et al. Characterization of target mRNA reduction through in situ RNA hybridization 
in multiple organ systems following systemic antisense treatment in animals. Nucleic Acid 
Ther. 2013; 23(6):369-378.
Investigator’s Brochure 2019
Investigator’s Brochure. AZD8233/AZD6615, Edition 1.1, dated 23 May 2019.
Prakash TP et al 2014
Prakash TP et al. Targeted delivery of antisense oligonucleotides to hepatocytes using 
triantennary N-acetyl galactosamine improves potency 10-fold in mice. Nucleic Acids Res 
2014; 42:8796-8807.
Ray KK et al 2017
Ray KK et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. 
N Engl J Med 2017; 376:1430-1440.
Sabatine MS et al 2017
Sabatine MS et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. 
N Engl J Med. 2017; 376:1713-1722.
Sewell KL et al 2002
Sewell KL et al. Phase 1 trial of ISIS 104838, a 2′-methoxyethyl modified antisense 
oligonucleotide targeting tumor necrosis factor-alpha. J Pharmacol Exp Ther. 2002; 303:1334-
1343.
Sheehan JP, Lan HC 1998
Sheehan JP, Lan HC Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex. 
Blood. 1998; 92:1617-1625.
Sheehan JP, Thao PM 2001
Sheehan JP, Thao PM Phosphorothioate oligonucleotides inhibit the intrinsic tenase complex 
by an allosteric mechanism. Biochemistry. 2001; 40:4980-4989.
Van Meer L et al 2017
Van Meer L et al. Novel SGLT2 inhibitor: first in man studies of antisense compound is 
associated with unexpected renal effects. Pharmacol Res Perspect. 2017; 17:e0029


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Van Poelgeest EP et al 2013
Van Poelgeest EP et al. Acute kidney injury during therapy with an antisense oligonucleotide 
directed against PCSK9. Am J Kidney Dis. 2013; 62:796-800.
Van Poelgeest EP et al 2015
Van Poelgeest EP et al. Antisense mediated reduction of proprotein convertase subtilisin/kexin 
type 9 (PCSK9): a first in human randomized, placebo controlled trial. Br J Clin Pharmacol. 
2015; 80:1350-1361.


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D7990C00003 Clinical Study Protocol version 2
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SAP_001.pdf: 
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Statistical Analysis Plan 
Study Code 
D7990C00003 
Edition Number 
V4.0 
Date 
11/08/2021 
A Randomized, Parallel, Double-blind, Placebo-controlled, Dose-
ranging, Phase 2b Study to Evaluate the Efficacy, Safety and 
Tolerability of AZD8233 Treatment in Participants With 
Dyslipidemia 
 
 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS .......................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................... 5 
AMENDMENT HISTORY ....................................................................................................... 7 
1 
STUDY DETAILS ................................................................................................. 8 
1.1 
Study objectives ...................................................................................................... 8 
1.2 
Study design ........................................................................................................... 9 
1.3 
Number of subjects ............................................................................................... 17 
2 
ANALYSIS SETS ................................................................................................ 17 
2.1 
Definition of analysis sets ..................................................................................... 17 
2.2 
Violations and deviations ..................................................................................... 18 
3 
BASELINE, EFFICACY AND SAFETY EVALUATION ................................. 18 
3.1 
General principles ................................................................................................. 18 
3.1.1 
Handling of missing data ...................................................................................... 18 
3.1.1.1 
Imputation of date of first dose of IP .................................................................... 18 
3.1.1.2 
Imputation of date of last dose of IP ..................................................................... 19 
3.1.1.3 
Imputation of AE end date .................................................................................... 19 
3.1.1.4 
Imputation of AE start date................................................................................... 19 
3.1.1.5 
Imputation of concomitant medications and concomitant procedures end date ... 20 
3.1.1.6 
Imputation of concomitant medication and concomitant procedures start date ... 20 
3.1.2 
Analysis visit windows ......................................................................................... 20 
3.1.3 
Study phase windows ........................................................................................... 22 
3.2 
Baseline assessments and other subject-specific characteristics .......................... 22 
3.2.1 
Demographic and subject characteristics.............................................................. 22 
3.2.2 
Medical history and prior procedures ................................................................... 23 
3.2.3 
Nicotine and alcohol use ....................................................................................... 23 
3.3 
Efficacy, safety and exploratory variables............................................................ 23 
3.3.1 
Primary endpoint .................................................................................................. 24 
3.3.1.1 
Change from baseline in log-transformed dLDL-C.............................................. 24 
3.3.2 
Secondary efficacy endpoints ............................................................................... 24 
3.3.2.1 
Change from baseline in natural logarithm transformed PCSK9 ......................... 24 
3.3.2.2 
Percent change from baseline in LDL-C .............................................................. 25 
3.3.2.3 
LDL-C Friedewald and LDL-C Martin-Hopkins ................................................. 25 
3.3.2.4 
Level of other lipid parameters ............................................................................. 25 
3.3.2.5 
Pharmacokinetic parameters ................................................................................. 26 
3.3.2.6 
Immunogenicity .................................................................................................... 26 
3.3.3 
Safety endpoint ..................................................................................................... 26 
3.3.3.1 
Adverse events ...................................................................................................... 26 


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3.3.3.2 
Safety clinical laboratory parameters ................................................................... 27 
3.3.3.3 
Vital signs ............................................................................................................. 30 
3.3.3.4 
Weight and BMI ................................................................................................... 31 
3.3.3.5 
ECG ...................................................................................................................... 31 
3.3.4 
Exploratory endpoints ........................................................................................... 32 
3.3.4.1 
Lipoprotein profile ................................................................................................ 32 
3.4 
Exposure and treatment compliance ..................................................................... 33 
3.4.1 
Exposure ............................................................................................................... 33 
3.4.2 
Compliance ........................................................................................................... 33 
3.5 
Concomitant medications and procedures ............................................................ 34 
4 
ANALYSIS METHODS ...................................................................................... 34 
4.1 
General principles ................................................................................................. 35 
4.1.1 
MMRM assuming a log-normal distribution ........................................................ 35 
4.1.2 
MMRM assuming a normal distribution .............................................................. 36 
4.1.3 
Sensitivity analysis 1 ............................................................................................ 37 
4.1.4 
Sensitivity analysis 2 ............................................................................................ 37 
4.2 
Analysis of variables............................................................................................. 38 
4.2.1 
Disposition of subjects .......................................................................................... 38 
4.2.2 
Important protocol deviations ............................................................................... 38 
4.2.3 
Baseline assessment and other subject-specific characteristics ............................ 38 
4.2.3.1 
Demographic and subject-specific characteristics ................................................ 38 
4.2.3.2 
Medical history ..................................................................................................... 38 
4.2.3.3 
Nicotine and alcohol use ....................................................................................... 39 
4.2.4 
Primary / Secondary efficacy endpoints ............................................................... 39 
4.2.4.1 
Change from baseline in log-transformed LDL-C and percent change from 
baseline in LDL-C ................................................................................................ 39 
4.2.5 
Secondary efficacy endpoints ............................................................................... 39 
4.2.5.1 
Change from baseline in log-transformed PCSK9 ............................................... 39 
4.2.5.2 
Level of other lipid parameters ............................................................................. 40 
4.2.5.3 
Pharmacokinetic parameters ................................................................................. 40 
4.2.5.4 
Immunogenicity .................................................................................................... 40 
4.2.6 
Safety endpoints.................................................................................................... 42 
4.2.6.1 
Adverse events ...................................................................................................... 42 
4.2.6.2 
Safety clinical laboratory parameters ................................................................... 44 
4.2.6.3 
Vital signs ............................................................................................................. 44 
4.2.6.4 
Weight and BMI ................................................................................................... 45 
4.2.6.5 
ECG ...................................................................................................................... 45 
4.2.7 
Exploratory endpoints ........................................................................................... 45 
4.2.7.1 
Lipoprotein profile ................................................................................................ 45 
4.2.8 
Treatment compliance .......................................................................................... 45 
4.2.8.1 
Exposure ............................................................................................................... 45 
4.2.8.2 
Compliance ........................................................................................................... 45 
4.2.9 
Concomitant medications ..................................................................................... 46 


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5 
INTERIM ANALYSES ........................................................................................ 46 
6 
CHANGES OF ANALYSIS FROM PROTOCOL .............................................. 46 
7 
REFERENCES ..................................................................................................... 47 
8 
APPENDIX .......................................................................................................... 47 
8.1 
Appendix 1 Changes made to the SAP after initial sign-off ................................ 47 
8.1.1 
Version 1.0 ............................................................................................................ 47 
8.1.2 
Version 2.0 ............................................................................................................ 47 
 
LIST OF TABLES 
Table 1     Schedule of assessment .......................................................................................... 11 
Table 2     Populations for Analysis......................................................................................... 17 
Table 3     Analysis visit windows ........................................................................................... 20 
Table 4     Analysis visit windows for unscheduled visits ....................................................... 21 
Table 5     Study phases ........................................................................................................... 22 
Table 6     Vital signs normal reference ranges ....................................................................... 31 
Table 7     ECG normal reference ranges ................................................................................ 32 
 
LIST OF FIGURES 
Figure 1     Study Design ......................................................................................................... 10 
 


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LIST OF ABBREVIATIONS 
Abbreviation or special term 
Explanation  
ADA  
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase  
ALT  
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
ApoA1 
Apolipoprotein A1 
ApoB 
Apolipoprotein B 
AST  
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical  
BMI 
Body mass index 
CI 
Confidence interval 
CS 
Compound symmetry covariance structures 
CSP 
Clinical study protocol 
CSR 
Clinical study report 
CTMS 
Clinical trial management system 
CV 
Coefficient of variation 
D  
Day 
dLDL-C 
Direct low-density lipoprotein cholesterol 
ECG   
Electrocardiogram 
eCRF  
Electronic case report form 
EDV  
Early discontinuation visit 
EXP 
Exponent 
GGT 
Gamma glutamyl transferase 
HbA1c 
Haemoglobin A1c 
HDL-C 
High density lipoprotein cholesterol 
HLT 
High level term 
HR 
Heart rate 
hs-CRP 
High-sensitivity C-reactive protein  
ICF 
Informed consent form 
IDRP 
Integrated data review plan  
IP  
Investigational product 
IPD 
Important protocol deviation 
IRT 
Interactive Response Technology 
LDL-C 
Low density lipoprotein cholesterol 
LLOQ  
Lower limit of quantification 
Lp(a) 
Lipoprotein(a) 
Lsmean 
Least squared mean 
MedDRA  
Medical Dictionary for Regulatory Activities  
MMRM  
Mixed model repeated measures  
NHP 
Non-compliance handling plan 


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PCSK9  
Proprotein convertase subtilisin/kexin type-9 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PT 
Preferred term 
QRS 
QRS wave 
QT 
QT wave 
QTcF 
Corrected QT Interval using Fridericia’s Formula 
REML 
Restricted maximum likelihood  
RR  
Respiratory rate 
RTSM  
Randomization and trial supply management 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SDTM 
Study data tabulation model 
SE 
Standard error 
SI 
International system of units 
SMQ 
Standardized MedDRA queries 
SOC 
System organ class 
SP(POW)  
Power spatial covariance structures 
TBL 
Total bilirubin 
TC 
Total cholesterol 
TE-ADA  
treatment emergent ADA 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
UNS 
Unscheduled 
URC 
Unblinding review committee team  
VLDL-C 
Very-low-density lipoprotein cholesterol 
WHO 
World Health Organization 
WHO-DD  
WHO Drug Dictionary  
 
 
 
 


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AMENDMENT HISTORY 
Version 
number 
Date 
Brief description of change 
V1.0 
18/11/2020 
N/A 
V2.0 
09/04/2021 
Minor amendment: added the IPD list, not available at the time of 
V1.0; reviewed some sections about external data, not available at the 
time of V1.0; added correlation analysis on LDL-c and additional 
figures for ADA parameters as per sponsor late request. All the other 
minor changes are reported in section 8.1.2.  
V3.0 
22/06/2021 
Minor amendment: added “+1” in the calculation of durations for 
ADA measurements 
V4.0 
10/08/2021 
Minor amendment: Rephrased the description of ADA boxplots  
 
 




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Objectives 
Endpoints 
 
To collect and store blood (plasma) and urine 
samples for potential future exploratory 
research aimed at exploring biomarkers 
involved in PK, PD, safety (including anti-
platelet antibodies) and tolerability related to 
AZD8233 treatment or cardiometabolic diseases 
 
Results of potential future exploratory 
biomarker research may be reported outside this 
study’s CSR  
 
Optional: To collect and store DNA from blood 
samples according to each country’s local and 
ethical procedures for future exploratory 
research into genes/genetic variation that may 
influence response to treatment.  
 
Results of possible future genetic research may 
be reported outside this study’s CSR.  
 
Two analyses are planned for this study: 
 
A primary analysis after the treatment period,  
 
A complete analysis after the final follow-up (after final database lock).  
The two analyses will have the same scope, except for  lipoprotein profile which will be included 
only in the complete analysis, as described in sections 2, 3 and 4. With the aim to maintain the 
blinding the primary analysis will be performed by an independent unblinded team. The purpose 
of the primary analysis is to help inform further clinical development; no changes will be made 
to this study unless a safety signal is observed. This analysis will not have any impact on the 
overall type-1 error because no changes will be made to the trial based on the outcome of the 
analysis (all efficacy data is already collected at the point of the primary analysis, no changes 
to the efficacy model will be made). The primary analysis will be done when all patients still in 
study have completed the treatment period (visit 10). Additional details will be given in the 
primary analysis charter and the Unblinded Review Committee (URC) charters (i.e. data cut-
off rules, data cleaning, nomination of the unblinded biometrics team and the URC and the 
operational procedures used to protect the blinding).  
1.2 
Study design 
This is a randomized, parallel, double-blind, placebo-controlled, dose-ranging Phase 2b study 
in approximately 108 participants with dyslipidaemia. The study will be conducted in up to 25 
sites in up to 4 countries.  
The screening period starts up to 42 days before the randomization visit and ends on Day -1. 
Eligible participants will attend 7 visits during the treatment period and 7 additional visits during 
the safety follow up period. Eligible participants are randomized across four different treatment 
arms in a 1:1:1:1 ratio stratified by region (North America vs Europe) for a 12-week treatment 
period. The planned treatment arms are AZD8233 
 SC, AZD8233 
 SC, AZD8233 
 SC, and Placebo SC on Days 1, 8, 29, and 57.  
CCI
CCI
CCI




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Table 1     Schedule of assessment 
 
Screening 
Treatment Period 
EDV 
Safety 
Follow-
up 
period 
Final 
Follow-
up 
Visit 
Visit Number 
1 
2 
3 
4 
5a 
6 
7a 
8 
9a 
 
10, 11a, 
12, 13a, 
14, 15a 
16 
Study Week 
 
 
0 
1 
3 
4 
6 
8 
10 
 
12, 14, 
16, 18, 
20, 22 
24 
Study Day 
D-42 to  
D-1l 
D-7 to  
D-1 
D1 
D8 
D22 
D29 
D43 
D57 
D71 
 
D85, 
D99, 
D113, 
D127, 
D141, 
D155 
D169 
Visit Window 
 
 
 
± 1 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
 
± 2 
days 
± 2 
days 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Optional Informed 
consent for future genetic 
research sample 
X 
 
 
 
 
 
 
 
 
 
 
 
Verify eligibility criteria 
X 
 
Xb 
 
 
 
 
 
 
 
 
 
Enrolment in RTSM 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation in RTSM 
 
 
X 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
X 
X  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 


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Table 1     Schedule of assessment 
 
Screening 
Treatment Period 
EDV 
Safety 
Follow-
up 
period 
Final 
Follow-
up 
Visit 
Visit Number 
1 
2 
3 
4 
5a 
6 
7a 
8 
9a 
 
10, 11a, 
12, 13a, 
14, 15a 
16 
Study Week 
 
 
0 
1 
3 
4 
6 
8 
10 
 
12, 14, 
16, 18, 
20, 22 
24 
Study Day 
D-42 to  
D-1l 
D-7 to  
D-1 
D1 
D8 
D22 
D29 
D43 
D57 
D71 
 
D85, 
D99, 
D113, 
D127, 
D141, 
D155 
D169 
Visit Window 
 
 
 
± 1 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
 
± 2 
days 
± 2 
days 
Body weightc 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
X 
BMI 
X 
 
 
 
 
 
 
 
 
X 
 
X 
HbA1c 
X 
 
 
 
 
 
 
 
 
 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy and 
reproductive status 
(females only, pre-dose) 
X 
 
X 
 
 
 
 
 
 
 
 
 
Study intervention 
administration 
(AZD8233/Placebo) 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Adverse event review 
X (SAE 
only) 
X (SAE 
only) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Injection site reactions d 
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


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Table 1     Schedule of assessment 
 
Screening 
Treatment Period 
EDV 
Safety 
Follow-
up 
period 
Final 
Follow-
up 
Visit 
Visit Number 
1 
2 
3 
4 
5a 
6 
7a 
8 
9a 
 
10, 11a, 
12, 13a, 
14, 15a 
16 
Study Week 
 
 
0 
1 
3 
4 
6 
8 
10 
 
12, 14, 
16, 18, 
20, 22 
24 
Study Day 
D-42 to  
D-1l 
D-7 to  
D-1 
D1 
D8 
D22 
D29 
D43 
D57 
D71 
 
D85, 
D99, 
D113, 
D127, 
D141, 
D155 
D169 
Visit Window 
 
 
 
± 1 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
 
± 2 
days 
± 2 
days 
Complete physical 
examination 
X 
 
X 
 
 
 
 
 
 
X 
 
X 
Abbreviated physical 
examination 
 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs (blood 
pressure, pulse and 
temperature) e 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECG e 
X 
 
X 
X 
 
X 
 
X 
 
X 
Xf 
X 
Serum chemistry 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation parameters g 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
hs-CRP 
X 
 
X 
 
 
 
 
X 
 
X 
X  
X 


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Table 1     Schedule of assessment 
 
Screening 
Treatment Period 
EDV 
Safety 
Follow-
up 
period 
Final 
Follow-
up 
Visit 
Visit Number 
1 
2 
3 
4 
5a 
6 
7a 
8 
9a 
 
10, 11a, 
12, 13a, 
14, 15a 
16 
Study Week 
 
 
0 
1 
3 
4 
6 
8 
10 
 
12, 14, 
16, 18, 
20, 22 
24 
Study Day 
D-42 to  
D-1l 
D-7 to  
D-1 
D1 
D8 
D22 
D29 
D43 
D57 
D71 
 
D85, 
D99, 
D113, 
D127, 
D141, 
D155 
D169 
Visit Window 
 
 
 
± 1 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
 
± 2 
days 
± 2 
days 
Complement activation 
panel g 
 
 
X 
X 
 
X 
 
X 
 
 
 
 
Urinalysis 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine renal safety 
biomarkers 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
LDL-C h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PCSK9 h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Triglycerides h 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Lipid parameters h 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipoprotein profile h 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PK plasma sample i 
 
 
 
X 
 
X 
X 
X 
X 
X 
X i 
X 


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Table 1     Schedule of assessment 
 
Screening 
Treatment Period 
EDV 
Safety 
Follow-
up 
period 
Final 
Follow-
up 
Visit 
Visit Number 
1 
2 
3 
4 
5a 
6 
7a 
8 
9a 
 
10, 11a, 
12, 13a, 
14, 15a 
16 
Study Week 
 
 
0 
1 
3 
4 
6 
8 
10 
 
12, 14, 
16, 18, 
20, 22 
24 
Study Day 
D-42 to  
D-1l 
D-7 to  
D-1 
D1 
D8 
D22 
D29 
D43 
D57 
D71 
 
D85, 
D99, 
D113, 
D127, 
D141, 
D155 
D169 
Visit Window 
 
 
 
± 1 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
± 2 
days 
 
± 2 
days 
± 2 
days 
Samples for anti-
AZD8233 antibodies j 
 
 
X 
X 
 
X 
 
X 
 
X 
X j 
X 
Biomarker analyses 
(plasma) h 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker analyses 
(urine) h 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Genomics Initiative 
optional, exploratory 
genetic sample k 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Note: Participants are required to fast for at least 8 hours overnight prior to all study visits except for Visit 1; Participants are permitted to drink water 
during this period of fasting until 1 hour before blood sampling. On days where participants attend the clinic in a fasted state, blood and urine samples 
should be obtained prior to administration of IP. 


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Note: Samples to be obtained from all treatment arms unless specified in the table. 
a 
Home visits: may be undertaken at the participant’s home or any other appropriate location by site staff or by qualified external service provider. 
Other visits currently not designated as ‘home visits’ may also be undertaken at the participant’s home or any other appropriate location if deemed 
applicable, following consultation with the Investigator and the sponsor. Home visits performed by qualified external service provider (i.e. not by 
clinical trial site personnel) may only be performed starting Visit 5 (D22), excluding dosing visits (Visit 6 (D29) and Visit 8 (D57)). 
b 
Check screening labs and inclusion/exclusion criteria. 
c 
Weight should be measured in light indoor clothes, without shoes, after a prior visit to the bathroom. 
d 
Injection Site Reaction assessments to be collected based on adverse event collection criteria. 
e 
Vital signs and ECG to be measured pre-dose on dosing days. 
f 
ECG to be performed during the safety follow up period at Visits 10 (D85), 11 (D99), 13 (D127), and 15 (D155). 
g 
Blood samples for complement activation panel and coagulation parameters will be taken around Cmax and are to be collected pre-dose and 2 hours 
post-dose. 
h 
Samples to be obtained pre-dose on dosing days. 
i 
PK sampling to be performed at Visits 4 (D8), 6 (D29), 7 (D43), 8 (D57), 9 (D71), 10 (D85), 12 (D113) and 14 (D141) and final follow-up 
visit/EDV. Schedule of sampling for Visits 4 (D8), 6 (D29), 8 (D57) are shown below. 
 
Visit 4 (Day 8; Loading dose): pre-dose 
 
Visit 6 (Day 29; Dose 3): pre-dose 
 
Visit 8 (Day 57; Final dose): pre-dose 
j 
ADA sampling to be performed at Visits 3 (D1), 4 (D8), 6 (D29), 8 (D57), 10 (D85), 12 (D113), and 14 (D141), and final follow-up visit/EDV. ADA 
samples to be collected pre-dose on all dosing days. 
k 
If, for any reason, the sample is not drawn pre-dose on Visit 3 (D1), it may be taken at any visit until the Final follow-up/EDV visit. 
l 
Visit 1 and visit 2 may be combined.  
BMI = body mass index; CSP = clinical study protocol; D = day; ECG = electrocardiogram; EDV = early discontinuation visit; HbA1c = haemoglobin 
A1c; LDL-C =low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9; RTSM = Randomization and Trial Supply 
Management. 


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1.3 
Number of subjects 
Approximately 108 participants will be randomly assigned to study intervention such that at 
least 80 evaluable participants complete the study. Any participant who receives at least one 
dose of study intervention is considered evaluable and is included in the full analysis set. 
Participants are randomly assigned to study treatment in a ratio of 1:1:1:1. 
The sample size of 20 participants per arm will provide 90% power in a two-sided t-test at 5% 
significance level to detect a difference of 0.33 on the logarithmic scale; 0.33 on the logarithmic 
scale is considered sufficient to distinguish the effect of the 
 dose from the effect of the 
 dose. The common SD for log-transformed LDL-C is assumed to be 0.3. 
2 
ANALYSIS SETS 
2.1 
 Definition of analysis sets 
All analysis sets are reported in the table below. 
Table 2     Populations for Analysis 
Population/Analysis set 
Description 
All enrolled subjects 
All participants who sign the ICF. 
All randomized subjects 
All participants who were randomized. Participants will be analysed according 
to the treatment to which they were randomized. 
Full analysis set 
All randomized participants who received at least one dose of IP, in 
accordance with the intention to treat principle. Participants will be included 
in the analysis according to the treatment to which they were randomized. 
This is the primary analysis set. 
Safety analysis set 
All participants randomly assigned to study treatment and who take at least 
1 dose of study treatment and for whom any post-dose data are available. 
Participants will be analysed according to the treatment which they actually 
received. If a participant received study intervention from the wrong kit for 
only part of the treatment duration and then switched to another, the 
associated treatment group for that participant will be the treatment group that 
participant was randomized to.  
ADA analysis set 
All participants randomly assigned to study treatment and who take at least 
1 dose of study treatment and had at least one ADA assessment available. 
Participants will be included in the analysis according to the treatment to 
which they were randomized. 
PK analysis set 
All participants in the full analysis set who have at least one PK sample post 
dose. A patient will be considered as having at least one PK sample post dose 
if he has at least one plasma concentration that is not below LLOQ after the first 
dose. Subjects will be analysed according to the treatment which they actually 
received. However, only samples taken on patients planned to receive active 
CCI
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2.2 
Violations and deviations 
The list of all IPDs is provided in the AstraZeneca NHP. The IPD are classified per the 
AstraZeneca NHP. Refer to this document for all details about protocol deviations. Relevant 
IPDs used to exclude subject from the sensitivity analysis 1 are reported below: 
 
All IPDs included in the category 1 - Inclusion Criteria Deviations (Subject who did not 
meet the below criteria. Those who entered the study even though they did not satisfy the 
entry criteria. If Screen failure, then this is not PD); 
 
All IPDs included in the category 2 - Exclusion Criteria Deviations (Enrolled, even though 
subject fulfilled the below criteria. Those who entered the study even though they did not 
satisfy the entry criteria. If Screen failure, then this is not PD); 
 
All IPDs included in the category 3 - Discontinuation Criteria for study product met but 
patient not withdrawn from study treatment. 
 
All IPDs included in the category 5 - Investigational Product (IP) Deviation, with the except 
of the IPD 5.02 - Subjects who were randomised but did not receive IP which is not 
considered relevant. 
 
All IPDs included in the category 6 - Excluded Medications taken. 
3 
BASELINE, EFFICACY AND SAFETY EVALUATION 
3.1 
General principles 
3.1.1 
Handling of missing data  
Missing data are not replaced unless otherwise specified for the statistical models. Only date of 
first and last dose of IP, AE start and end date and concomitant medications end date are 
imputed. Imputation rules are reported below.  
3.1.1.1 
Imputation of date of first dose of IP 
Date and time of first dose of IP are mandatory eCRF fields recorded in the treatment log. No 
Imputations are expected. In the rare cases of missing date, the date of first dose of IP will be 
imputed if all the following criteria are met: 
 
There is at least one injection (including lot number) recorded in the eCRF treatment log 
 
The first recorded injection has a missing or partial missing date 
If that is the case, the date of first dose of IP is imputed with the date of eCRF visit Day 1. 
Completely missing time and time where only hour is missing is imputed to 00:00. If only 
minutes are missing, then it will be imputed to HH:00.  
treatment are analysed. Thus, patients planned to receive placebo but who 
finally received active treatment will not have any result available. 


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3.1.1.2 
Imputation of date of last dose of IP 
Date and time of last dose of IP are mandatory eCRF fields recorded in the treatment log. No 
Imputations are expected. In the rare cases of missing date, the date of last dose of IP is imputed 
if all the following criteria are met: 
 
There is at least one injection (including lot number) recorded in the eCRF treatment log  
 
The last recorded dose has a missing or partial missing date 
If that is the case, the date of last dose of IP is imputed with the  date in which the subject ended 
the treatment phase recorded in the end of treatment eCRF. 
3.1.1.3 
Imputation of AE end date 
Completely missing AE end dates are not imputed. Partial missing AE end dates are imputed as 
below:  
 
If the AE is ongoing, the end date is stated to missing.  
 
If the AE is not ongoing, and if only the day is missing: Assume the last day of the collected 
month. 
 
If the AE is not ongoing, and both, the day and the month are missing: Assume 31-DEC of 
the collected year. 
After applying these rules, if the imputed AE end date is after the end of study date or the date 
of death, the AE end date is set to the earliest date between the end of study date and the date 
of death. 
3.1.1.4 
Imputation of AE start date 
Before to proceed with the AE start date imputation, the first dose of IP and the AE end date 
are imputed as described in the previous section.  
Only partial AE start dates are imputed; Dates which are completely missing are not imputed. 
Partial dates are imputed as described below:  
If the day is missing and the month and/or the year is different from the month and year of the 
first dose of IP, assume 01-MMM-YYYY. If the month and year are the same as the first dose 
of IP month and year and the end date is on or after (including ongoing / missing) the first dose 
of IP, then assume the date of the first dose of IP. If the month and year are the same as the first 
dose of IP month and year and the end date is prior to the first dose of IP, then assume the end 
date.  
If the month is missing and the year is different from the year of first dose of IP, assume 01-
JAN-YYYY of the collected year. If the year is the same as the first dose of IP year and the end 
date is on or after (including ongoing / missing) the first dose of IP, then assume the date of the 
first dose of IP. If the year is the same as the first dose of IP and the end date is prior to the first 
dose of IP, then assume the end date.  


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After applying these rules, if the imputed AE start date is after a complete AE end date then 
assume the same date as the complete AE end date; if the end date is missing and the imputed 
AE start date is after the end of study date then assume the same date as the study end date. 
3.1.1.5 
Imputation of concomitant medications and concomitant procedures end date 
Completely missing end dates or dates for which the year is missing are not imputed. Partial 
missing concomitant medication end dates are imputed as below:  
 
If the concomitant medication is ongoing, the end date is set to missing.  
 
If the concomitant medication / procedure is not ongoing, and if only the day is missing: 
Assume the last day of the collected month. 
 
If the concomitant medication / procedure is not ongoing, and both, the day and the month 
are missing: Assume 31-DEC of the collected year. 
After applying these rules, if the imputed date is after the end of study date or the date of death, 
the concomitant medication / procedure end date is set to the earliest date between the end of 
study date and the date of death. 
3.1.1.6 
Imputation of concomitant medication and concomitant procedures start date 
Both, completely missing and partially missing start dates are not imputed. 
3.1.2 
Analysis visit windows 
For the purpose of the statistical analysis all parameters, except the adverse event, concomitant 
medication / procedure, medical history, protocol deviations and other non-compliances 
reported in the CTMS and some demographic data (sex, ethic group and race) are allocated to 
the analysis visit as reported in the tables below. The allocation to visit windows is performed 
after the imputation of date of first and last doses of IP as in section 3.1.1. Measurements with 
missing or partially missing dates cannot be imputed to any analysis visit. 
Table 3     Analysis visit windows 
Analysis visit 
(AVISIT) 
Scheduled 
visit day 
Visit Window (Days) 
Days of flexibility 
used to build the 
visit window 
Baseline 
D-42 to D1 
<=1a 
  
Day 1 
1 
1b 
  
Week 1 
8 
6 – 10 
2 
Week 3  
22 
19 – 25 
3 
Week 4 
29 
26 – 32 
3 
Week 6 
43 
39 – 47 
4 
Week 8 
57 
53 – 61 
4 
Week 10 
71 
67 – 75 
4 
Week 12  
85 
80 – 87 
5 - 2 


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Table 3     Analysis visit windows 
Analysis visit 
(AVISIT) 
Scheduled 
visit day 
Visit Window (Days) 
Days of flexibility 
used to build the 
visit window 
Week 14 
99 
92 – 106 
7 
Week 16 
113 
107 – 120 
7 
Week 18 
127 
121 – 134 
7 
Week 20 
141 
135 – 148 
7 
Week 22 
155 
149 – 162 
7 
Week 24 
169 
163 – 176 
7 
a Includes all measurements collected before or on day 1 prior to first dose of IP. If the 
measurement is collected on day 1 but it cannot be determined if it was done before 
or after the first dose of IP (due to missing time and/or planned time point), then it 
will be considered as collected after the first dose of IP. For height, weight, BMI 
and Age if the measurement is collected/derived on day 1, it is always considered 
as collected before the first dose of IP. 
b Includes all measurements collected at day 1 on or after the first dose of IP.  
 
After having assigned the visit windows as described above, if there are measurements which 
have not yet the analysis visit assigned, they are labelled as reported in the table below. 
Table 4     Analysis visit windows for unscheduled visits 
Analysis visit (AVISIT) 
Visit Window (Days) 
UNS 1 
2 – 5 
UNS 2 
11 – 18 
UNS 3 
NA 
UNS 4 
33 – 38 
UNS 5 
48 – 52 
UNS 6 
62 – 66 
UNS 7 
76 – 79 
UNS 8 
88 – 91 
UNS 9 
>=177 
 
The unscheduled visits will be numbered sequentially with an increment of 0.1. For example, if 
two measurements are done in the unscheduled visits that occur between visit Day 29 and Day 
43, then these unscheduled visits will be numbered UNS 4.1 and UNS 4.2 in the order they 
occurred. The unscheduled visits are not summarized in tables but only presented in listing. 
For the purpose of the statistical analysis: 


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 
the baseline value used for statistical analyses is the last available value among those in the 
baseline analysis visit window. If several measurements are collected during the selected 
day, the average (for numeric values)/worst (for categorical values) of the measurements is 
taken. If there are several categorical values corresponding to the worst case, then the last 
measurement registered in eCRF will be taken.  
 
all the other post baseline visit values: If more than one measurement falls in the same visit 
window but in different days, the nearest to the scheduled visit day is taken.  If several 
measurements are collected within the same distance from the scheduled study day, the 
data of the earlier visit after the scheduled study day within that window is used. If several 
measurements are collected during the selected day (selected timepoint within the day for 
PK), the average (for numeric values)/worst (for categorical values) of the measurements 
is taken. If there are several categorical values corresponding to the worst case, then the 
last measurement registered in eCRF will be taken. For coagulation parameters and 
complement activation panel if the selected day is a dosing day (except Day 1),  two 
timepoints within the day need to be considered (pre-dose and 2h post-dose). 
Averages are calculated after LLOQ replacement as reported in the following sections.  
3.1.3 
Study phase windows 
For the purpose of the statistical analysis adverse events, immunogenicity data, LDL-C, PCSK9, 
other lipid parameters, lipoprotein profile, laboratory evaluations, vital sign and ECG are 
allocated to the study phase in which they are collected as reported below. The allocation to the 
study phases is performed after the imputation of date of first and last doses of IP as in section 
3.1.1. The allocation of the AEs to the study phases is performed after the imputation of AE 
start and AE end dates as reported in section 3.1.1.  
Table 5     Study phases 
Study phase 
Phase Window for Analysis (Days) 
Pre-treatment  
before first dose of study IP (day <1a) 
On-treatment  
> day 1b to the end of study date 
a Includes all measurements collected before first dose of IP. If the measurement is collected on day 1 it cannot be 
determined if it was done before or after the first dose of IP (due to missing time and/or planned time point), 
then it will be considered as collected after first dose of IP. 
b Includes all measurements collected on the day of first dose of IP, at the time of IP intake and after. 
3.2 
Baseline assessments and other subject-specific characteristics 
Demographic and subject characteristics, medical history and nicotine and alcohol use are 
collected pre-treatment as per section 1.2.  
3.2.1 
Demographic and subject characteristics 
Demographic and subject characteristics include age, age group (<50; >=50 -<65; >=65), sex, 
race, ethnic group, country, region, height (cm), weight (kg), body mass index (BMI) (kg/m2). 
Age is the age at screening as reported in the eCRF, BMI (kg/m2) is calculated as: weight (kg) 
/ [(height (cm)/100)]^2.  


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Height, weight and BMI are allocated to the concerning analysis visits as per section 3.1.2. 
Evaluations with missing or partially missing dates cannot be imputed to any analysis visit. 
Only baseline values are included in the demographic and subject characteristics. 
3.2.2 
Medical history and prior procedures 
The eCRF collects any relevant medical histories and prior procedures. Medical history and 
prior procedures are coded in MedDRA version 23.0 or higher.  
The procedures are classified as prior as below: 
The imputation method described in section 3.1.1.5 is used in case the procedure end date is 
partially missing. The imputation method described in section 3.1.1.1  is used in case the first 
dose of IP date and time are missing or partially missing.  
After the end date imputation, the procedures will be classified as either prior or concomitant 
(but not both) according to the end date. Prior procedure is defined as any procedure with an 
end date prior to the first dose of IP (exclusive). Concomitant procedure is defined as any 
procedure with an end date on or after the first dose of study drug. Procedures with completely 
missing end date are classified as concomitant. 
3.2.3 
Nicotine and alcohol use  
Nicotine and alcohol use (never-current-former) are collected at screening. 
3.3 
Efficacy, safety and exploratory variables 
The primary efficacy endpoint of the study is  
1. the change from baseline in log-transformed dLDL-C compared with placebo 
descriptively for all visits and within a statistical model at the week 12.  
The secondary efficacy endpoints of the study are: 
2. the change from baseline in log transformed PCSK9 compared with placebo 
descriptively for all visits and within a statistical model at the week 12 
3. the percent change from baseline in dLDL-C compared with placebo descriptively for 
all visits and within a statistical model at the week 12. 
4. Correlation of LDL-C Friedewald and LDL-C Martin-Hopkins with dLDL-C 
5. Level of other lipid parameters compared with placebo descriptively for all visits and 
within a statistical model at the week 12. Other lipid parameters include: 
 
TC 
 
HDL-C 
 
Non-HDL-C 
 
VLDL-C 
 
ApoA1 
 
ApoB 


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 
Lp(a) 
 
Triglycerides 
 
Remnants cholesterol 
6. PK parameters (to be reported in a separate report) 
7. Development of ADA and immunogenicity titre during the on-treatment and follow-up 
analysis phases  
The safety endpoints of the study are: 
8. AE 
9. Vital signs 
10. ECG  
11. Safety clinical laboratory parameters  
The exploratory endpoint of the study is: 
12. Lipoprotein profile 
Efficacy, safety, and exploratory endpoints are collected as reported in section 1.2. 
3.3.1 
Primary endpoint  
3.3.1.1 
Change from baseline in log-transformed dLDL-C 
dLDL-C is assessed in a central laboratory. LDL-C is assigned to the analysis visits and  analysis 
phase as described in section 3.1.2 and 3.1.3. Measurements with missing or partial missing 
dates are not assigned to any analysis visit / analysis phase. dLDL-C below the LLOQ for which 
the exact value cannot be determined, will be replaced with the LLOQ divided by the squared 
root of 2. 
After the LLOQ replacement, change from baseline of the log-transformed variable is calculated 
as the visit value in natural logarithm minus the baseline value in natural logarithm.  The relative 
change from baseline is calculated back transforming the change from baseline of the log-
transformed variable.  
3.3.2 
Secondary efficacy endpoints  
3.3.2.1 
Change from baseline in natural logarithm transformed PCSK9 
PCSK9 is assessed in a central laboratory. PCSK9 is assigned to the analysis visits and analysis 
phases as described in sections 3.1.2 and 3.1.3. Measurements with missing or partial missing 
dates are not assigned to any analysis visit / analysis phase.  PCSK9 below the LLOQ for which 
the exact value cannot be determined, will be replaced with the LLOQ divided by the squared 
root of 2. 
After the LLOQ replacement, change from baseline of the log-transformed variable is calculated 
as the visit value in natural logarithm minus the baseline value in natural logarithm.  The relative 


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change from baseline is calculated back transforming the change from baseline of the log-
transformed variable. Percent change from baseline is also calculated as the visit value minus 
the baseline value divided by the baseline value *100. 
3.3.2.2 
Percent change from baseline in LDL-C 
dLDL-C is assessed in a central laboratory. dLDL-C is assigned to the analysis visits and 
analysis phases as described in sections 3.1.2 and 3.1.3. Measurements with missing or partial 
missing dates are not assigned to any analysis visit / analysis phase. dLDL-C below the LLOQ 
for which the exact value cannot be determined, will be replaced with the LLOQ divided by the 
squared root of 2. 
After the LLOQ replacement, percent change from baseline is calculated as the visit value minus 
the baseline value divided by the baseline value *100.  
3.3.2.3 
LDL-C Friedewald and LDL-C Martin-Hopkins   
LDL-C Friedewald and LDL-C Martin-Hopkins are also derived in a central laboratory. LDL-
C Friedewald and LDL-C Martin-Hopkins are assigned to the analysis visits and  analysis phase 
as described in section 3.1.2 and 3.1.3. Measurements with missing or partial missing dates are 
not assigned to any analysis visit / analysis phase. 
3.3.2.4 
Level of other lipid parameters 
Other lipid parameters include: 
 
TC 
 
HDL-C 
 
Non-HDL-C 
 
VLDL-C 
 
ApoA1 
 
ApoB 
 
Lp(a) 
 
Triglycerides 
 
Remnants cholesterol 
Lipid parameters are assessed in a central laboratory. Lipid parameters are assigned to the 
analysis visits and analysis phases as described in sections 3.1.2 and 3.1.3. Measurements with 
missing or partial missing dates are not assigned to any analysis visit / analysis phase. Lipid 
parameters below the LLOQ for which the exact value cannot be determined, will be replaced 
with the LLOQ divided by the squared root of 2. 
After the LLOQ replacement, change from baseline of the log-transformed variable is calculated 
as the visit value in natural logarithm minus the baseline value in natural logarithm.  The relative 
change from baseline is calculated back transforming the change from baseline of the log-
transformed variable. Percent change from baseline is also calculated for all variables as the 
visit value minus the baseline value divided by the baseline value *100. 


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3.3.2.5 
Pharmacokinetic parameters 
PK concentrations are tested in a central external laboratory as per scheduled timepoints.  
PK concentrations are assigned to the analysis visits as described in section 3.1.2. Measurements 
with missing or partial missing dates are not assigned to any analysis visit. PK concentrations 
below the LLOQ for which the exact value cannot be determined, will be replaced with the 
LLOQ. 
PK parameters are not derived and analysed within this SAP. Details on pharmacokinetic 
parameters are provided in an additional bioanalytical report prepared by a dedicated 
pharmacometrics support group at AstraZeneca.    
3.3.2.6 
Immunogenicity 
Immunogenicity parameters are: 
 ADA 
 Immunogenicity titre 
These parameters are tested in an external laboratory. A validated screening assay will be used 
to determine ADA positive samples. Any positive samples will be tested in a confirmatory assay 
whereby the specificity of the ADA response will be confirmed as either positive or negative 
with respect to AZD8233. Titre evaluation are performed on samples that are confirmed positive 
for ADA.  
All these parameters are assigned to the analysis visits and to the analysis phases as described 
in section 3.1.2 and in section 3.1.3. Measurements with missing or partial missing dates are not 
assigned to any analysis visit / analysis phase. ADA confirmed positive results with titre lower 
than the MRD (<50) will be replaced with titre =50 for the statistical analysis.  
The study day of ADA measurement is calculated as the date of the ADA sample collection – 
the date of first IP +1 for ADA sample collected on or after the day of first IP and as the date of 
the ADA sample collection – the date of first IP for ADA sample collected before the day of 
first IP. 
3.3.3 
Safety endpoint 
3.3.3.1 
Adverse events 
An adverse event is the development of any untoward medical occurrence in a subject or clinical 
study subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended sign 
(e.g., an abnormal laboratory finding), symptom (e.g., nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. The term AE is used to include both serious and non-serious AEs and can 
include a deterioration of a pre-existing medical occurrence. An AE may occur at any time, 
including run-in or washout periods, even if no study treatment has been administered. SAEs 
will be collected from time of signature of informed consent, throughout the treatment period 


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and including the follow-up period. All non-serious AEs will be recorded from time of first dose 
of IP, throughout the treatment period and including the follow-up period. Adverse events (AEs) 
will be coded with MedDRA version 23.0 or higher. For any additional details on AE reporting 
please refer to the study protocol.  
After start and end date imputation as per section 3.1.1 the AEs are assigned to the study phases 
described in section 3.1.3, based on the AE start date and time as follows: 
If both the start date and start time of an AE are known, then: 
 If the AE start datetime is before the first dose of IP datetime, then the AE is assigned 
to the pre-treatment phase.  
 If the AE start datetime is on or after the first dose of IP datetime, then the AE is assigned 
to the on-treatment phase, 
If only the start date of an AE is known, and the start time of the AE is unknown, then: 
 If the AE start date is before the first dose of IP date, then the AE is assigned to the pre-
treatment phase, 
 If the AE start date is on or after the first dose of IP date then the AE is assigned to the 
on-treatment phase, 
If the start date of an AE is completely missing, the AE is assigned as follow:  
 If the AE end date is known and is before the first dose of IP date, then the AE is assigned 
to the pre-treatment phase, 
 If the AE end date is completely missing or if the AE end date is on or after the first dose 
of IP date no assignation can be done. 
All the AE in the on-treatment phase are considered TEAEs.  
The study day of AE is calculated as the start date of the AE – date of first IP +1 for AE started 
on or after the day of first IP and as start date of the AE – date of first IP for AE started before  
the day of first IP. Imputed dates should not be used. If one of the dates is missing or partially 
missing, the study day of the start of the AE is set to missing.  
The duration of AE is calculated as the end date of the AE – start date of the AE +1.  Duration 
is calculated for complete dates only. Imputed dates should not be used. If one of the dates is 
missing or partially missing, the duration is missing.  
3.3.3.2 
Safety clinical laboratory parameters 
Safety clinical laboratory tests are performed in a central clinical laboratory.  
Safety clinical laboratory tests are: 
Haematology 
 White blood cell (WBC) count 
 Red blood cell (RBC) count 


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 Haemoglobin (Hb) 
 Haematocrit (HCT) 
 Mean-corpuscular volume (MCV) 
 Mean corpuscular haemoglobin concentration (MCHC) 
 Neutrophils absolute count 
 Lymphocytes absolute count 
 Monocytes absolute count 
 Eosinophils absolute count 
 Basophils absolute count 
 Platelets absolute count 
 Reticulocytes absolute count 
Coagulation parameters 
 Prothrombin time  
 Activated partial thromboplastin time (aPTT) 
 International normalized ratio (INR) 
Clinical chemistry 
 Sodium 
 Potassium 
 Blood urea nitrogen (BUN) 
 Creatinine  
 Calcium 
 Phosphate 
 Creatine kinase (CK) 
 Direct bilirubin 
 alkaline phosphatase (ALP) 
 alanine aminotransferase (ALT) 
 aspartate aminotransferase (AST)  
 gamma glutamyl transferase (GGT) 
 Total bilirubin (TBL) 
 Glutamate dehydrogenase (GLDH) 
 Bicarbonate 
 Uric acid 
 FSH (women only) 
 LH (women only) 
Urinalysis 
 pH (quantitative) 
 Specific gravity (quantitative) 
 Glucose (qualitative) 
 Blood (qualitative) 
 Colour (qualitative) 
 Protein (qualitative) 
 Appearance (qualitative) 
 Nitrites (qualitative) 
 Ketones (qualitative) 
 Leukocytes (qualitative) 


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 Urobilinogen (qualitative) 
 Microscopic panel (if positive for blood, nitrites or protein): 
- 
Sediment, Leucocytes 
- 
Sediment, Erythrocytes 
- 
White Blood Cell Clumps 
- 
Epithelial Cells, Tubular 
- 
Epithelial Cells, Squamos 
- 
Epithelial Cells, Transitional 
- 
Red Blood Cell Clumps 
- 
Sediment, Hyaline Casts 
- 
Sediment, Granular Casts 
- 
Sediment, Leucocyte Casts 
- 
Sediment, Erythrocyte Casts 
- 
Sediment, Epithelial Casts 
- 
Sediment, Fatty Casts 
- 
Sediment, Cell casts 
- 
Broad Casts 
- 
Sediment, Waxy Casts 
- 
Sediment, Triple Phosph Cryst. 
- 
Sediment, Calcium Ox. Cryst. 
- 
Sediment, Calcium Phosphate 
- 
Sediment, Calcium carbonate Cryst 
- 
Sediment, Uric Acid Cryst. 
- 
Amorphous Crystals 
- 
Sediment, Leucine Cryst. 
- 
Sediment, Cystine Cryst. 
- 
Sediment, Tyrosine Cryst. 
- 
Sediment, Ammonium Urate Crystals 
- 
Sediment, Bilirubin Cryst. 
- 
Sediment, Bacteria 
- 
Yeast, Budding 
- 
Sediment, Trichomonas 
- 
Yeast Hyphae 
- 
Oval Fat Body 
- 
Fat 
- 
Sperm 
- 
Sediment, Mucus 
Urine renal safety biomarkers 
 Albumin 
 Total protein 
 Creatinine 
 Urine protein to creatinine ratio (UPCR) 
 Urine albumin to creatinine ratio (UACR) 
 Estimated glomerular filtration rate (eGFR; by CKD-EPI formula) 
Other Laboratory Assessments 
 Complement activation panel (C3a, Bb, C5a) 


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 hs-CRP 
Safety clinical laboratory parameters are assigned to the analysis visits and the study phases as 
described in section 3.1.2 and section 3.1.3 respectively. Evaluations with missing or partially 
missing dates cannot be imputed to any study phase and analysis visit.  
Safety clinical laboratory results below the LLOQ for which the exact value cannot be 
determined, will be replaced with the LLOQ divided by the squared root of 2. 
After the LLOQ replacement, change from baseline to each post-baseline visit for safety clinical 
laboratory results is defined as the post-baseline visit value minus the baseline visit value; 
percent change from baseline to each post-baseline visit for platelet count is defined as the post-
baseline visit value minus the baseline visit value divided by the baseline visit value *100. 
After the LLOQ replacement, Safety clinical laboratory results except urine renal safety 
biomarkers and other laboratory assessments are also classified as normal (if value is within 
normal reference range), low (if value is below the normal reference range), and high (if value 
is above the normal reference range) based on the reference range indicator.  
After the LLOQ replacement, AST, ALT and TBL are also classified as below: 
AST and ALT: 
 <3xULN (or below the LLOQ) 
 ≥3 - <5xULN 
 ≥5 - < 8xULN 
 ≥8xULN 
TBL: 
 <1 xULN (or below the LLOQ) 
 ≥1 - <2xULN 
 ≥2xULN  
Occurrences of AST or ALT ≥ 3 × ULN together with TBL ≥ 2 × ULN are reported as SAE 
(Potential Hy´s law) as described in the study protocol. 
3.3.3.3 
Vital signs 
Vital signs include: 
 Systolic blood pressure (mmHg) 
 Diastolic blood pressure (mmHg) 
 Pulse rate (bpm) 
 Temperature (C) 


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Vital signs parameters are assigned to the analysis visits and analysis phases as described in 
sections 3.1.2 and 3.1.3. Evaluations with missing or partially missing dates cannot be imputed 
to any analysis visit / analysis phase. 
Change from baseline is defined as the post-baseline visit value minus the baseline value.  
Additionally, vital signs values will be classified as normal (if value is within normal reference 
range), low (if value is below the normal reference range), and high (if value is above the normal 
reference range) according to the normal reference ranges: 
Table 6     Vital signs normal reference ranges 
Parameter 
Normal Reference Ranges 
Systolic blood pressure 
80 - 160 mmHg 
Diastolic blood pressure 
50 -90 mmHg 
Heart rate 
50 - 100 bpm 
Temperature 
 <=37ºC 
 
3.3.3.4 
Weight and BMI 
BMI (kg/m2) is calculated as: weight (kg) / [(height (cm)/100)]^2. Weight (kg) and BMI 
(kg/m2) are assigned to analysis visits as described in section 3.1.2. Evaluations with missing 
or partially missing dates cannot be imputed to any study phase and analysis visit. Change from 
baseline is defined as the post-baseline visit value minus the baseline value. 
3.3.3.5 
ECG 
ECG parameters includes the following: 
 RR (msec) 
 PR (msec) 
 QRS (msec) 
 QT (msec) 
 QTcF (msec) 
 HR (beats/min) 
 Overall evaluation (normal, abnormal). If abnormal also reason and clinically 
significance is collected 
For each participant, RR, PR, QRS and QT will be calculated as follow: the mean value of all 
measurements will be taken provided that at least 2 measurements are present (and at least 3 
consecutive beats were analysable in each ECG) or else, the averaged value at the corresponding 
target time point will be set to missing. QTcF will be calculated as QTcF=QT*RR^-1/3, where 
the QT interval is in milliseconds and the RR interval is in seconds. Heart rate will be calculated, 
based on the RR interval as HR=60/RR interval, where the RR interval is in seconds. 
Calculation of derived parameters will be performed after averaging of QT and RR data. Results 
from these calculations will be reported in the eCRF together with the overall evaluation. 


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ECG parameters are assigned to analysis visits and study phases as described in section 3.1.2 
and section 3.1.3 respectively. Evaluations with missing or partially missing dates cannot be 
imputed to any study phase and analysis visit. 
ECG last observation on treatment is defined as last available value among those in the on-
treatment analysis phase. 
Change from baseline is defined as the post-baseline visit value minus the baseline value. 
Additionally, ECG values will be classified as normal (if value is within normal reference 
range), low (if value is below the normal reference range), and high (if value is above the normal 
reference range) according to the below normal reference ranges: 
Table 7     ECG normal reference ranges 
Parameter 
Normal Reference Ranges 
RR 
600 -1200 msec 
PR  
120 – 200 msec 
QRS  
80 – 120 msec 
QT  
350 – 430 msec 
QTcF  
320 – 470 msec 
Heart rate 
50 – 100 beats/min 
 
QTcF intervals are classified also as: 
 >=450 msec 
 >=480 msec 
 >=500 msec 
QTcF increases respect to baseline are classified as: 
 >=30 msec 
 >=60 msec 
 >=90 msec 
 
3.3.4 
Exploratory endpoints  
3.3.4.1 
Lipoprotein profile 
Lipoprotein profile parameters are: 
 VLDL Subclass >200 nm-Trigl. 
 VLDL, Large-Trigl. 
 VLDL, Medium-Trigl. 
 VLDL, Small-Trigl. 
 Low Density Lipoprotein Particle Conc. 


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 Intermed.Dens. Lipoprot. 25+/-2 nm-Chol* 
 Low Density Lipoprotein, Large-Chol. 
 Low Density Lipoprotein, Small-Chol. 
 HDL Particles 
 High Density Lipoprotein, Large-Chol* 
 Medium HDL 
 High Density Lipoprotein, Small-Chol* 
 Very Low Density Lipoprotein, Mean 
 Low Density Lipoprotein, Mean 
 High Density Lipoprotein, Mean 
 Triglycerides 
 VLDL-Triglycerides 
 HDL-Cholesterol Direct* 
 Lipoprotein Insulin Resistance Score 
 Apolipoprotein A-I 
 Apolipoprotein B 
 Non-HDL-Cholesterol 
Lipoprotein parameters are assessed in a central laboratory and assigned to the analysis visits 
and analysis phases as described in section 3.1.2 and 3.1.3. Measurements with missing or 
partial missing dates are not assigned to any analysis visit / analysis phase.  
Change from baseline is calculated as the visit value minus the baseline value.  
3.4 
Exposure and treatment compliance 
As per study protocol, subjects start the subcutaneous injections of the study IP at day 1. Then 
the subjects will be subcutaneously dosed also on Days 8, 29, and 57. Subcutaneous injections 
should primarily be performed on site. Dosing visits may be undertaken as home visits. If 
participants are dosed at home, they will receive the study intervention directly from the nurse. 
The date, and time if applicable, of dose administered in the clinic and at home, as well as the 
anatomical location of the injection site, will be recorded in the eCRF.  
3.4.1 
Exposure 
Exposure (days) is calculated only for subjects in the full analysis set as the total number of 
days on study drug.  Exposure is calculated as the study drug dose last date minus study drug 
dose first date plus one as reported in the eCRF study treatment log page. If any of the first or 
last dates are missing or partially missing, then imputed dates will not be used, and study drug 
exposure is set to missing.  
3.4.2 
Compliance 
Overall compliance to the IP is calculated only for subjects in the full analysis set. 
The percent compliance is defined as the total number of vials consumed divided by the total 
number of vials that should have been taken where, total number of vials consumed will be 
calculated as number of kits recorded in the IRT system, number of vials that should have been 


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taken is calculated as the number of the scheduled dispensation visits (even if not done) before 
the end of the study.  
No replacement of missing data is used. Therefore, if one of the above factors is missing then 
compliance will be missing.  
Compliance is also categorized as: 
 
< 80% 
 
≥ 80% to < 120% 
 
≥ 120% 
 
3.5 
Concomitant medications and procedures 
Subjects can undergo concomitant medications or procedure deemed necessary to provide 
adequate supportive care except for those medications identified as restricted and prohibited as 
listed in the study protocol and detailed (coding and indication wherever applicable) in the in 
the IDRP.  
The eCRF collects concomitant medications and procedures. The WHO-DD March 2019 B3 
Global or higher is used to classify medications. MedDRA version 23.0 or higher is used to 
classify procedures. 
Medications and procedures are classified as concomitant as below: 
The imputation method described in section 3.1.1.5 is used in case the medication / procedure 
end date is partially missing. The imputation method described in section 3.1.1.1 is used in case 
the first dose of IP date and time are missing or partially missing. 
After the end date imputation, the medications and the procedures will be classified as either 
prior or concomitant (but not both) according to the end date. Prior medication or procedure is 
defined as any medication / procedure with an end date prior to the first dose of study drug 
(exclusive). Concomitant medication / procedure is defined as any medication / procedure with 
an end date on or after the first dose of study drug, or any medication / procedure that is ongoing 
at the end of the study. Medications and procedures with completely missing end date are 
classified as concomitant. 
Prohibited concomitant medications are confirmed and flagged by the study physician in 
accordance with the study protocol. 
4 
ANALYSIS METHODS 
All analyses method described in this section will be applicable to both the analyses, primary 
and final.  


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4.1 
General principles 
Unless otherwise specified, for continuous variables, descriptive statistics will include the 
number of subjects (n), mean, SD, median, minimum and maximum. For log-normal variables 
also the Geometric mean and Geometric CV will be used. 
For categorical variables the number and percentages of subjects by categories will be tabulated. 
Percentages will be calculated based on the number of subjects with no missing data, i.e., will 
add up to 100%. Categories with count of zero will be not displayed. 
Unscheduled analysis visits will not be used in descriptive statistics. Unscheduled analysis visits 
will only be reported in listings and used where explicitly needed.  
For continuous variables, descriptive statistics will be summarized for the observed values, and 
where specified, also for changes from baseline and relative or percent change from baseline.  
Changes from baseline, in certain categorical variables will be summarized using shift tables. 
The number and percent of subjects within each treatment group will be generated for each 
category post-baseline by baseline category.  
If not otherwise specified, all the analyses will include the post IP-discontinuation data for those 
subjects who discontinue from study treatments but are still followed up for their scheduled 
visits. 
The following statistical models will be used: 
4.1.1 
MMRM assuming a log-normal distribution 
An MMRM will be fitted on log-transformed change from baseline. Log-transformed change 
from baseline is calculated as the visit value in natural logarithm minus the baseline value in 
natural logarithm. 
The visit statistically tested within the MMRM model is week 12 (day 85). All previous 
available data on scheduled visits will be used in the model. Fixed factors of the model will be 
treatment, visit and treatment*visit interaction. The natural log-transformed baseline value of 
the outcome variable will be used as a covariate. Visits within subjects will be considered as 
repeated measurements.  
Comparisons derived from the model will be: 
 
AZD8233 
 versus placebo,  
 
AZD8233 
 versus placebo  
 
AZD8233 
 versus placebo 
 
AZD8233 
 versus AZD8233 
  
 
AZD8233 
 versus AZD8233 
 
 
AZD8233 
 versus AZD8233 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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The REML approach will be used for the estimation of the variance and covariance parameters 
of the linear mixed model; two-sided difference test, with alpha level at 5% will be used for the 
comparisons and for the t-type confidence interval calculation. 
The model will be fitted with an unstructured covariance structure and the Kenward-Roger 
correction applied to obtain the degrees of freedom. 
In case the model will not converge for any reason, the following hierarchical model fitting 
procedure will be adopted: 
1. The MMRM will be fitted using a SP(POW) covariance structure; Visit will be expressed 
as scheduled visit days to accomplish the variance-covariance matrix estimation. 
2. The MMRM will be fitted using a CS covariance structure 
3. An ANCOVA model will be used  
The reportable results from the model will be: 
 
The LSmean and their 95% CI for each group for the log-transformed change from baseline 
 
Back transformed LSmean for each group, which correspond to the estimated relative 
change from baseline; back transformed LSmean is derived as [EXP( LSmean)].  
 
95% CI of the back transformed LSmean for each group; 95% CI of the back transformed 
LSmeans is derived as [EXP(lower limit of the 95% CI of the LSmean)]; [EXP(upper limit 
of the 95% CI of the LSmean)]. 
 
The geometric mean ratio between active groups and the control group; the ratio is 
calculated as EXP(of the LSmean of the difference) 
 
The 95% CI of the geometric mean ratio; the 95% CI of the ratio is calculated as 
[EXP(Lower limit of the 95% CI of the LSmean of the difference)]; [EXP(Upper limit of 
the 95% CI of the LSmean of the difference)]. 
 
P-value of the geometric mean ratio 
4.1.2 
MMRM assuming a normal distribution 
An MMRM will be fitted on percent change from baseline. Percent change from baseline is 
calculated as the visit value minus the baseline value divided by the baseline value *100. 
The visit statistically tested within the MMRM is week 12 (day 85). All previous available data 
on scheduled visits will be used in the model. Fixed factors of the model will be treatment, visit 
and treatment*visit interaction. The baseline value of the outcome variable will be used as a 
covariate. Visits within subjects will be considered as repeated measurements.  
Comparisons derived from the model will be: 
 
AZD8233 
 versus placebo,  
 
AZD8233 
 versus placebo  
 
AZD8233 
 versus placebo 
 
AZD8233 
 versus AZD8233 
  
 
AZD8233 
 versus AZD8233 
 
 
AZD8233 
 versus AZD8233 
 
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI
CCI


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The REML approach will be used for the estimation of the variance and covariance parameters 
of the linear mixed model; two-sided difference test, with alpha level at 5% will be used for the 
comparisons and for the t-type confidence interval calculation. 
The model will be fitted with an unstructured covariance structure and the Kenward-Roger 
correction applied to obtain the degrees of freedom. 
In case the model will not converge for any reason, the following hierarchical model fitting 
procedure will be adopted: 
1. The MMRM will be fitted using a SP(POW) covariance structure; Visit will be expressed 
as scheduled visit days to accomplish the variance-covariance matrix estimation.  
2. The MMRM will be fitted using a CS covariance structure. 
3. An ANCOVA model will be used. 
The reportable results from the model will be: 
 
The LSmean and their 95% CI for each group for the percent change from baseline 
 
The LSmean of the difference between active groups and the control group 
 
The 95% CI of the LSmean of the difference 
 
P-value of the LSmean of the difference 
4.1.3 
Sensitivity analysis 1 
The sensitivity analysis 1 will consist of repeating the MMRM assuming a log-normal 
distribution including only subjects who have completed the treatment period as per protocol 
and who have no relevant IPDs. Subjects who have completed the treatment period as per 
protocol are the subjects who reached week 12 and received all four scheduled doses of IP; 
subjects who received wrong dose of IP or wrong treatment will be excluded. Further, relevant 
IPDs are defined in section 2.2.  
4.1.4 
Sensitivity analysis 2 
The sensitivity analysis 2 will consist of repeating MMRM assuming a log-normal distribution 
(without any back-up strategy) using the pattern-mixture model with control-based pattern 
imputation (reference 1). To implement this approach, we firstly use MCMC to impute non 
monotone MAR missing data for subjects who have completed the treatment period as per 
protocol (reached week 12 and received all four doses of IP). Then we use the resulting dataset 
to sequentially impute missing data at each visit using a monotone regression approach. 
Sequential imputation will be done in two ways:  
 
considering only placebo group for the estimations of missing data for placebo patients and 
for active subjects at visits for which the previous scheduled dose of IP is missing or not as 
per protocol (wrong dose of IP or a wrong treatment);   
 
considering only the relevant active group for the estimations of missing data for active 
subjects at visits for which the previous scheduled dose of IP was taken as scheduled. 
The results from each imputation set will be combined using Rubin's formulas 


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4.2 
Analysis of variables 
4.2.1 
Disposition of subjects 
Subject dispositions (number and percentage of subjects enrolled, subjects randomized, subjects 
who received at least one dose of study IP, subjects who completed the treatment and subjects 
who completed the study) will be presented in a summary table for each treatment group and 
overall.  A listing including all standardized disposition terms will also be provided for all 
discontinued subjects. Both, the table and the listing will be based on all enrolled subjects. 
Subjects affected by the COVID-19 pandemic and Subjects with reported issues in the Clinical 
Trial Management System due to COVID-19 pandemic will also be listed.  
The number of subjects belonging to each analysis population will be presented in a separate 
summary table for each treatment group. The table will be based on all enrolled subjects. 
Listings of all subjects excluded from the full analysis set and from the safety analysis set will 
also be provided. The listings will include reason for exclusion from respective population and 
will be based on all enrolled subjects.  
Randomization code and actual kit are also listed. 
4.2.2 
Important protocol deviations 
The number and percentage of subjects with at least one IPD will be summarized following the 
NHP categories, for each treatment group and overall, for the full analysis set. All the IPDs as 
reported in the CTMS (pre-treatment and on treatment) will be included in the table.  All IPDs 
will also be listed for all subjects included in the full analysis set. 
4.2.3 
Baseline assessment and other subject-specific characteristics 
4.2.3.1 
Demographic and subject-specific characteristics 
All demographic and subject-specific characteristics reported in section 3.2.1 will be presented 
in summary tables for each treatment group and overall; Age, height, weight and BMI will be 
summarized descriptively as continuous variable with n, mean, median, SD, minimum, and 
maximum; all the other demographic and subject-specific characteristics will be summarized as 
categorical variables with the number and percentages of subjects by categories. Only the 
baseline measurement for height, weight and BMI will be considered in these tables. Baseline 
and post-baseline definitions are detailed in section 3.1.2. All demographic and subject-specific 
characteristics will also be provided in listings.  The tables and the listings will be based on the 
full analysis set.  
Recruitment by region country and centre will also be summarized.  
4.2.3.2 
Medical history 
Any relevant medical histories and prior procedures as described in section 3.2.2 will be 
presented in summary tables as number and percentages of subjects by SOC and PT for each 
treatment group and overall.  Subjects with multiple medical histories in the same SOC/PT will 


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be counted only once in that SOC/PT. Subjects with medical histories in more than one SOC/PT 
will be counted once in each of those SOC/PT. Tables will be sorted alphabetically by SOC and 
PT. The table will be based on the full analysis set.  
4.2.3.3 
Nicotine and alcohol use 
Nicotine and alcohol use as described in section 3.2.3 will be presented in summary table as 
number and percentages of subjects for each treatment group and overall for  the full analysis 
set. 
4.2.4 
Primary / Secondary efficacy endpoints 
4.2.4.1 
Change from baseline in log-transformed LDL-C and percent change from 
baseline in LDL-C 
dLDL-C is described in section 3.3.1.1 and in section 3.3.2.2. Baseline and post-baseline 
definitions are detailed in section 3.1.2. Tables and listings will be based on the full analysis set 
and presented for each treatment group. 
dLDL-C will be summarized descriptively as a continuous log-normal variable at each analysis 
visit and for relative change and percent change from baseline. Observed values will also be 
presented in figure with geometric mean and 95% CI by visit. Percent changes from baseline 
will be presented in figure with mean and 95% CI by visit.  
An MMRM assuming a log-normal distribution as described in section 4.1 on log-transformed 
change from baseline to week 12 will be presented.  
Additionally, as secondary objective, an MMRM assuming a normal distribution as described 
in section 4.1 on percent change from baseline to week 12 will be presented. 
Sensitivity analyses 1 and2  as per section 4.1 will also be produced. 
Finally, dLDL-C will also be reported in a listing.  
The correlation of LDL-C Friedewald and LDL-C Martin-Hopkins towards dLDL-C will also 
be estimated. The correlations are estimated using the mixed model approach, considering the 
two measurement as random effect in the model, and visits within subject as repeated 
measurements. Data are log-transformed to fulfil normal distribution criteria. Bland-Altman 
scatter plot on log-transformed data will also be shown. 
4.2.5 
Secondary efficacy endpoints  
4.2.5.1 
Change from baseline in log transformed PCSK9 
PCSK9 is described in section 3.3.2.1. Baseline and post-baseline definitions are detailed in 
section 3.1.2. Tables and listings will be based on the full analysis set and presented for each 
treatment group. 


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PCSK9 will be summarized descriptively as a continuous log-normal variable at each analysis 
visit and for relative change and percent change from baseline. Observed values will also be 
presented in figure with geometric mean and 95% CI by visit. Percent changes from baseline 
will be presented in figure with mean and 95% CI by visit.   
An MMRM assuming a log-normal distribution as described in section 4.1 on log-transformed 
change from baseline to week 12 will be presented.  
Finally, PCSK9 will also be reported in a listing.  
4.2.5.2 
Level of other lipid parameters 
The other lipid parameters are listed and described in section 3.3.2.4.Baseline and post baseline 
definitions are detailed in section 3.1.2. Tables and listings will be based on the full analysis set 
and presented for each treatment group. 
All lipid parameters will be summarized descriptively as continuous log-normal variables at 
each analysis visit and for relative change and percent change from baseline.  
An MMRM assuming a normal distribution as described in section 4.1 on percent change from 
baseline to week 12 will also be presented. 
Percent changes from baseline will be presented in figure with mean and 95% CI by visit.   
All other lipid parameters will also be reported in a listing.  
4.2.5.3 
Pharmacokinetic parameters 
The analysis will be based on the PK analysis set. 
Plasma concentrations will be summarized descriptively as a continuous log-normal variable at 
each analysis visit and scheduled time. The geometric mean +/- the geometric standard deviation 
will be also reported together with the number of samples below the limit of quantification. The 
geometric mean +/- the geometric standard deviation is calculated as the exp(mean(variable in 
log) +/- SD(variable in log)). Plasma concentrations will also be listed for all subjects in the PK 
analysis set. Listings of all subjects excluded from the PK analysis set will also be provided. 
The listing will be based on all enrolled subjects.  
PK parameters are not derived and analysed within this SAP. Derivations and results of the 
pharmacokinetic analyses are provided in an additional bioanalytical report prepared by a 
dedicated pharmacometrics support group at AstraZeneca.    
4.2.5.4 
Immunogenicity 
The analysis will be based on the ADA analysis set. 


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Immunogenicity parameters are described in section 3.3.2.5. Baseline and post-baseline 
definitions are detailed in section 3.1.2. Immunogenicity parameters tables and listings will be 
based on the ADA analysis set and presented for each treatment group.  
ADA will be summarized as categorical variables with the number and percentages with a 
positive result at the specific visit. Immunogenicity titre will be summarized descriptively as a 
continuous variable, only for ADA positive tests, with median, interquartile range, minimum, 
and maximum, at each analysis visit.  
ADA will also be summarized including the following: 
 ADA positive at baseline and/or post-baseline (ADA prevalence) 
 TE-ADA positive (ADA incidence)  
 Treatment-induced ADA positive  
 Treatment-boosted ADA positive  
 TE-ADA negative 
 Both baseline and post-baseline positive 
 Only baseline positive 
 ADA persistently positive  
 ADA transiently positive  
 TE-ADA positive with maximum titre > median of maximum titres 
Post baseline coincide with the on-treatment phase as described in section 3.1.3.  
Treatment-induced ADA positive is defined as ADA negative at baseline and post-baseline 
ADA positive 
Treatment-boosted ADA positive is defined as ADA positive at baseline and boosted the pre-
existing titre post-baseline (≥ 4-fold increase). 
TE-ADA positive is defined as the sum of treatment-induced ADA positive and treatment-
boosted ADA positive. 
TE-ADA negative is defined as ADA positive but not fulfilling the definition of TE-ADA 
positive.  
ADA persistently positive is defined as either ADA negative at baseline and ADA positive at ≥ 
2 post-baseline assessments (with ≥ 16 weeks between first and last positive) either ADA 
positive at last post-baseline assessment.  
ADA transiently positive is defined as ADA negative at baseline, having at least one post-
baseline ADA positive assessment and not fulfilling the conditions of ADA persistently 
positive. 
The median of maximum titres is calculated based on the maximum titre for each ADA positive 
subject within each treatment group (including both baseline and post-baseline measurements). 


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Missing ADA results are considered negative for the derivation of the above categories. The 
above categories will be calculated only for subjects in the ADA analysis set. 
All immunogenicity parameters will also be reported in a listing for the full analysis set. Days 
from previous dose of IP will be calculated as the ADA date minus date of previous dose +1. 
Days from previous dose of IP for ADA measured during pre-treatment period will be set to 
missing. Listings of all subjects excluded from the ADA analysis set will also be provided. The 
listing will be based on all enrolled subjects.  
The following figures will be also provided for complete analysis only: 
 A spaghetti plot figure with individual plotted ADA-titres over time in subjects with any 
positive ADA-response, one graph per treatment group (including placebo). 
A boxplot exploring ADA positive vs ADA negatives impact on PK concentrations over time, 
percent change on PCSK9 and percent change on LDL over time, one graph per treatment group 
(including placebo).  
A figure showing the percentage of subjects with positive ADA results over time. 
4.2.6 
Safety endpoints  
4.2.6.1 
Adverse events 
After having assigned the AEs to the corresponding study phase as described in section 3.3.3.1, 
the AEs will be summarized for each treatment group. The AEs tables will be based on the 
safety analysis set. Summary tables will include AEs in the on-treatment phase as described in 
section 3.1.3.  
Summary tables are listed below. 
An overview table containing: 
 
Number and percentage of subjects with any AEs 
 
Number and percentage of subjects with any AEs with outcome of death 
 
Number and percentage of subjects with any SAEs 
 
Number and percentage of subjects with any AEs leading to discontinuation / interruption 
/ reduction of IP 
 
Number and percentage of subjects with any AEs leading to withdrawal from study 
An overview table by ADA category containing: 
 
Number and percentage of subjects with any AEs 
 
Number and percentage of subjects with any AEs with outcome of death 
 
Number and percentage of subjects with any SAEs 
 
Number and percentage of subjects with any AEs leading to discontinuation of IP 


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The following summary tables will be presented by SOC and PT: 
 
The number and percentage of subjects with any AEs  
 
The number of AEs  
 
The number and percentage of subjects with AEs with outcome of death  
 
The number and percentage of subjects with SAEs  
 
The number of SAEs  
 
The number and percentage of subjects with AEs leading to discontinuation.  
The following summary tables will be presented by PT: 
 
The number and percentage of subjects with most common AEs (frequency of >5%)  
 
The number and percentage of subjects with any AEs by maximum reported intensity  
 
The number and percentage of subjects with any AEs and investigator’s causality 
assessment. If a subject has multiple events in the same PT, the event with the strongest 
relationship will be counted.  
Where number of subjects with AEs are summarized by SOC and/or PT , subjects with multiple 
events in the same SOC/PT are counted only once in that SOC/PT. Subjects with events in more 
than 1 SOC/PT are counted once in each of those SOCs/PTs.  
Additionally, the following tables will be presented: 
 
the number of subjects with serious adverse events, by seriousness criteria  
 
number and percentage of subjects with non-serious AEs occurring with a frequency > 
5.0% in any treatment group for each SOC and PT. This table will be produced as a separate 
pdf output to meet clinical trial transparency requirements and not for inclusion in the CSR. 
It will be delivered at the same time as the CSR outputs.  
 
the number of subjects with injection site reactions by HLT and PT  
 
the number of subjects with bleedings by SMQ and PT  
A list of key subject information for subjects with AEs with outcome of death, subjects with 
SAEs, and subjects with AEs leading to discontinuation of IP  will be provided. The durations 
reported in these tables, will be derived only for fully completed dates as below: 
 
Time from first dose of IP to AE (in days) will be calculated as the AE start date minus date 
of first dose of IP +1.  
 
Time from first dose to death (in days) will be calculated as the date of death minus date of 
first dose of IP +1.   
 
The same approach will be used for deriving time from start of treatment to AE becoming 
serious or discontinuation. 
 
Time from last dose prior to AE start and last dose prior to death (in days) will be calculates 
as the date of death minus the date of last dose prior to AE/death +1. 
All the AEs will also be listed for all subjects included in the safety analysis set.  AEs among 
ADA positive and ADA negative subjects will also be listed.  A subject is considered ADA 


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negative if collected samples are tested negative at all timepoints, including baseline and post-
baseline. Regarding ADA positive categories in section 4.2.5.4 are included.  
 
4.2.6.2 
Safety clinical laboratory parameters 
Safety clinical laboratory parameters are described in section 3.3.3.2. Baseline and post-baseline 
definitions are detailed in section 3.1.2.  
Safety clinical laboratory parameters including haematology, coagulation, clinical chemistry, 
urine renal safety biomarkers, other laboratory assessments and urinalysis quantitative 
parameters except for the microscopic panel will be summarized in SI units as continuous 
variables at each visit and for change from baseline; additionally, platelet count will be 
summarized with percent change from baseline. Shifts from baseline to maximum and minimum 
value during the on-treatment phase will also be presented for haematology, coagulation, 
clinical chemistry and urinalysis quantitative parameters except for the microscopic panel. 
Shifts from baseline to maximum value during the on-treatment phase will be presented for 
urinalysis qualitative parameters, except for the microscopic panel.   
All laboratory data for haematology, coagulation, clinical chemistry, urine renal safety 
biomarkers, other laboratory assessments and urinalysis will also be presented in listings.  
In addition to the tables above also the maximum on-treatment ALT and AST by maximum 
total bilirubin for assessing Hy’s law criteria and a list of key subject information for subjects 
with potential Hy’s law will be presented. Potential Hy’s law is defined as AST or ALT ≥ 3 × 
ULN together with TBL ≥ 2 × ULN at any point during the study following the start of study 
medication irrespective of an increase in ALP. For potential Hy’s law the elevation in 
transaminases must precede or be coincident with (i.e., on the same day) the elevation in TBL, 
but there is no specified timeframe within which the elevations in transaminases and TBL must 
occur. Same list is presented for subjects with potential Hy's law adverse event as reported in 
the eCRF. 
Subjects with platelet count <150 (10^9/L) or percent decrease from baseline greater than 30% 
will be also summarized and listed including all platelet count measurements. Individual plots 
of observed data over time and spaghetti plots on percent change from baseline will be also 
represented.  
All tables and listings for laboratory data will be based on the safety analysis set and presented 
for each treatment group. 
4.2.6.3 
Vital signs 
Vital signs parameters are described in section 3.3.3.3. Baseline and post-baseline definitions 
are detailed in section 3.1.2. Vital signs will be summarized descriptively as continuous 
variables at each visit and timepoint within visit and for change from baseline. Vital signs will 


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also be presented in listing. Vital signs tables and listings will be based on the safety analysis 
set and presented for each treatment group. 
4.2.6.4 
Weight and BMI 
Weight and BMI are described in section 3.3.3.4. Baseline and post-baseline definitions are 
detailed in section 3.1.2. Weight and BMI will be presented in listing based on the safety 
analysis set. 
4.2.6.5 
ECG 
ECG parameters are described in section 3.3.3.55. Baseline and post-baseline definitions are 
detailed in section 3.1.2. ECG parameters (except for the overall evaluation) will be summarized 
in SI units as continuous variables, at each visit and for change from baseline. Number and 
percentage of subjects within each QTcF intervals classes at any time during the on-treatment 
phase will also be reported together with number and percentage of subjects within QTcF 
increase classes at any time during the on-treatment phase. Overall evaluation will be analysed 
as shift from baseline to last value in the on-treatment phase. ECG parameters will also be listed.  
Overall evaluation will be listed for subjects with clinically significant abnormalities. ECG 
tables and listings will be based on the safety analysis set and presented for each treatment 
group. 
4.2.7 
Exploratory endpoints  
4.2.7.1 
Lipoprotein profile 
Lipoprotein profile parameters are listed and described in section 3.3.4.1. Baseline and post-
baseline definitions are detailed in section 3.1.2. Tables and listings will be produced only for 
the complete analysis after the final follow-up (after final database lock). They will be based on 
the full analysis set and presented for each treatment group. 
Lipoprotein profile parameters will be summarized descriptively as continuous variables with 
n, mean, median, SD, minimum, maximum, at each analysis visit and for change from baseline. 
Lipoprotein profile parameters will also be reported in a listing.  
4.2.8 
Treatment compliance 
Exposure and compliance are calculated as described in section 3.4. 
4.2.8.1 
Exposure 
The exposure will be presented in a summary table for each treatment group. The table will be 
based on the full analysis set.  Exposure will also be listed for the full analysis set.  
4.2.8.2 
Compliance 
Overall compliance will be presented in a summary table for each treatment group and overall. 
The overall compliance will be summarized descriptively as continuous variable with n, mean, 
median, SD, minimum, and maximum.  


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Compliance will also be listed together with the exposure. Both, the table and the listing will be 
based on the full analysis set.  
4.2.9 
Concomitant medications  
Concomitant medications and procedures are defined in section 3.5. The number and percentage 
of subjects with at least one allowed concomitant medication and the number and percentage of 
subjects by ATC level 4 (therapeutic subgroup) and product name will be provided using the 
full analysis set.  
The number and percentage of subjects with at least one disallowed concomitant medication 
and the number and percentage of subjects by ATC level 4 (therapeutic subgroup) and product 
name will be provided using the full analysis set.  
The concomitant procedures will be presented in summary tables as number and percentages of 
subjects by SOC and PT for each treatment group and overall.  Subjects with multiple events in 
the same SOC/PT will be counted only once in that SOC/PT. Subjects with events in more than 
one SOC/PT will be counted once in each of those SOC/PT. Tables will be sorted alphabetically 
by SOC and PT. The table will be based on the full analysis set.  
5 
INTERIM ANALYSES 
No interim analysis planned for this study.  
6 
CHANGES OF ANALYSIS FROM PROTOCOL 
This SAP is based on study protocol D7990C00003 v2.0 dated 16Dec2020. Any further 
amendment of the study protocol which can have an impact on the SAP will lead to an 
amendment of this document. Changes of analysis from protocol D7990C00003 v2.0 dated 
16Dec2020 are listed here below: 
Section 3 - Objectives and endpoints 
Even if not specified in the protocol, two analyses are planned for this study: 
 
A primary analysis after the treatment period,  
 
A complete analysis after the final follow-up (after final database lock).  
As per additional FDA request, analysis of percent change with MMRM for all lipid parameters 
added. 
Section 4.2.6.1 Adverse event 
Protocol stated that “Injection site reactions will be considered an AE of special interest and 
will be listed separately. Listing of injection site reactions will include information about size, 


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colour and itching status…” however this information is not collected in eCRF so this listing 
cannot be produced. 
 
Section 8.2.3 – Electrocardiograms 
Protocol stated that “ECG results will be listed by treatment and dose level of AZD8233 for 
each participant and time point and will include all individual and averaged values of PR, RR, 
QRS, QT interval, and the derived values of QTcF and HR (RR)”. The investigators are 
supposed to report in the eCRF only 1 result for each parameter (average for PR, RR, QRS, QT 
and derived from averages for QTcF and HR). Due to this, only list of averaged values as 
reported in eCRF can be done. 
Section 9.4 - Statistical analysis 
Protocol stated that “Estimation of the treatment effect will be done for each visit after baseline”, 
however only estimation at visit week 12 are reported in the statistical outputs. 
 
Protocol stated that “All treatment arms will be compared with each other”, however only 
selected comparisons are reported in the statistical outputs. 
7 
REFERENCES 
1 ”Implementation of Pattern-Mixture Models Using Standard SAS/STAT Procedures”, 
PharmaSUG2011 - Paper SP04, Authors: Bohdana Ratitch, Quintiles, Montreal, Quebec, 
Canada and Michael O’Kelly, Quintiles, Dublin, Ireland 
8 
APPENDIX 
8.1 
Appendix 1 Changes made to the SAP after initial sign-off 
8.1.1 
Version 1.0 
NA 
8.1.2 
Version 2.0 
Added the relevant IPD list in section 2.2 and in section 4.1.3. 
Changed the analysis phase, section 3.1.3, consequently change on AE analysis phase 
allocation rules, section 3.3.3.1 and consequently deleted sensitivity analysis 3 on on-
treatment data, section 4.1.5. 
Specified that AE duration is calculated as per AZ standard (xxENDTC – xxSTDTC; If 
ADURN >= 0 then ADURN = ADURN+1). 
Specified derivation of ADA positive measurements in section 3.3.2.5. 


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Deleted lipoprotein profile and added ADA tables at primary analysis, section 1.1. 
Added Coagulation parameters 2h post dose as per CSP v2.0 in the Schedule of assessment: 
(table 1 in section 1.2) and in the analysis visit windows derivation section 3.1.2.  
Added the correlation of LDL-C Friedewald and LDL-C Martin-Hopkins towards dLDL-C 
calculation as secondary objective in section 3.3.2.2 and 4.2.4. 
Added the definition of ADA negative in section 4.2.6.1. 
Urinalysis micro panel parameters updated as per laboratory data transfer specifications in 
section 3.3.3.2.  
Added +1 in the calculation of durations for tables S14, S18 and S20 in section 4.2.6.  
Changed imputation of last dose of IP because there was a typo referring to drug 
accountability form which is not used in this study, section 3.1.1.2. 
Added detail on maintaining the blinding at primary analysis in section 1.1. 
Updated Lipoprotein profile section based on available DTS in sections 3.3.4.1 and 4.2.7.1. 
Updated primary analysis and complete analysis name and details in section 1.1. 
Added figure for complete analysis only in the ADA section. 
8.1.3 
Version 3.0 
Typo in table 1. Added footnotes 
Added +1 in the calculation of durations for ADA measurements in section 4.2.5.4 
8.1.4 
Version 4.0 
Rephrased the description of box-plots in section 4.2.5.4 because was not cristal clear from the 
text. No change in the content but only in the description.