Clinical trial NCT04823611
Conditions: Dyslipidemia
Keywords: AZD8233 Efficacy PK PD Immunogenicity Safety Tolerability
Sponsor: AstraZeneca
Start date: 2021-01-20; Completion date: 2022-09-10
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 1 and 2 Study of AZD8233 in Participants with Dyslipidemia and this study consists of Part A , Part B and Part C. Part A is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study. Part B is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Part C is designed as a randomized , single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Detailed description:
Part A: This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 high dose or placebo. Participants will be dosed SC on Days 1, 8, 29, and 57.

Part B:This is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study. Approximately 60 Japanese participants will be randomized in a 1:1:1 ratio into 1 of the 4 double-blinded treatment arms; AZD8233 low dose, AZD8233 medium dose, or placebo. Participants will be dosed SC on Days 1, 29, and 57.

Part C:This is designed as a randomized, single-blind (blinding of participants and sites), placebo-controlled, multiple dose, phase 1 study.

Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 single-blinded treatment arms; AZD8233 medium dose or placebo. Participants will be dosed SC on Days 1, 29, and 57.

Arms: arm 1: Placebo solution for subcutaneous injection. arm 2: AZD8233 for subcutaneous injection. arm 3: Placebo solution for subcutaneous injection. arm 4: AZD8233 medium dose for subcutaneous injection. arm 5: AZD8233 low dose for subcutaneous injection. arm 6: Placebo solution for subcutaneous injection. arm 7: AZD8233 medium dose for subcutaneous injection.
Interventions: intervention 1: Part A:Placebo intervention 2: Part A:AZD8233 intervention 3: Part B:Placebo intervention 4: Part B:AZD8233 intervention 5: Part C: Placebo intervention 6: Part C: AZD8233
Intervention descriptions: intervention 1: Placebo solution intervention 2: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. intervention 3: Placebo solution intervention 4: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. intervention 5: Placebo solution intervention 6: PCSK9-targeted ASO for the reduction of circulating levels of LDL-C.

Protocol documents:
Prot_008.pdf: 
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Clinical Study Protocol 
Study Intervention
AZD8233
Study Code
D7990C00006
Version
5.0
Date
16Jun2022
A Phase 1 and 2 study to evaluate the safety, tolerability, efficacy, 
pharmacokinetics and pharmacodynamics of AZD8233 
following a multiple subcutaneous dose administration 
in Japanese participants with dyslipidemia
( HAYATE )
Sponsor Name: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s): Not applicable
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.


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Protocol Number: D7990C00006
Amendment Number: N/A
Study Intervention: AZD8233Study Phase: Ph 1/Ph 2
Short Title: A Phase 1/2 Study of AZD8233 in Participants with Dyslipidemia
Study Physician Name and Contact Information will be provided separately.


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Document History
Document
Date
Version1.0
20-Oct-2020
Amendment 1
13-Nov-2020
Amendment 2
10-May-2021
Amendment 3
02-Nov-2021
Amendment 4
16-Jun-2022
Amendment 1 ( 13-Nov-2020)
Overall Rationale for the Amendment:
The original CSP, Version 1.0, dated 20 Oct 2020, was updated following the PMDA’s review 
(dated 30 Oct 2020), and updates were made to correct errors and further clarify the contents 
in this Version 2.0.
Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria: Criterion 4
(Part A)
Added patients on anti-coagulation 
therapy as an exclusion criterion for Part 
A.
To exclude the patients with high 
risks in bleeding.
Section 5.2 Exclusion 
Criteria: Criterion 6
(Part A)
Specified the relevant risk classification 
(subjects in high risk class)  based on the 
Suita Score.
To specify the risk classification.
Section 5.2 Exclusion 
Criteria: Criterion 7
(Part B)
Added “patients on anti-coagulation 
therapy” as an exclusion criterion for Part 
B.
To exclude the patients with high 
risks in bleeding.
Section 5.3.4
Reproductive 
Restrictions
Added 
the contraceptives approved/certified
and those not approved/certified in Japan.
To explain the concrete conditions of 
contraception. in Japan
Section 8.5.3.1
Collection of Samples
Specified the other lipid assessments, in 
addition to PCSK9 and LDL-C, to be 
masked.
Clarification
Table 1
Schedule of Activities 
(Part A)
Corrected the date for the pregnancy test 
from Day -1 to Day 1.
To correct the erroneous description.
Table 1
Schedule of Activities 
(Part A)
Pregnancy and reproductive status will 
not assessed at Visit 2; therefore the 
assessment at Visit 2 was deleted.
To correct the erroneous description.


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Section # and Name
Description of Change
Brief Rationale
Table 1Schedule of 
Activities (Part A)
Added the concrete date and timing for 
the pregnancy test in Footnote p
To update the description.
Table 1 Schedule of 
Activities (Part A)
Added footnote q
Clarification
Table 2 Schedule of 
Activities (Part B)
Added footnote m
Clarification
Amendment 2 ( 10-May-2021)
Overall Rationale for the Amendment: The highest dose 
 and a loading dose have 
been removed from Part B based on the emerging pharmacodynamic data after repeated (Days 
1, 8, 29, and 57) dosing of AZD8233 up to 
 in other AZD8233 studies (Study 
D7990C00002 and Study D7990C00003). Safety descriptions has been updated based on the 
emerging safety data. Changes to Clinical Study Protocol version 2.0 [13- Nov-2020] are 
summarised
Section # and Name
Description of Change
Brief Rationale
Section 1.1
Synopsis (Part B)
Overall Design:
Intervention Groups and Duration:
Corrected the date for the end of 
screening period / Removed the dosing 
on Day8 / Removed the highest 
dose
/ Revised number of 
randomized participants / Added the 
explanation of SRC
To correct the erroneous description / 
Not applicable to this study. / Revised 
number of randomized participants 
due to removal the highest dose. / 
SRC wording has been updated.
Section 1.2 Schema (Part 
B)
Removed the 
 arm / Added the 
footnote 
Not applicable to this study/ Added 
the information in case of a change of 
the planned dose
Table 1 Schedule of 
Activities (Part A)
Corrected the participants of the 
pregnancy tests
All the women participants should 
have pregnancy tests ,irrespective of 
childbearing potential.
Table 1 Schedule of 
Activities (Part A)
Deleted measurement position of BP and 
pulse rate, and added the description of 
measurement position of BP and pulse 
rate in Footnote f
Clarification
Table 1 Schedule of 
Activities (Part A)
Footnote h:
Added the allowance of blood samples.
Clarification
Table 1 Schedule of 
Activities (Part A)
Footnote o, p:
Corrected the participants of the 
pregnancy tests 
All the women participants should 
have pregnancy tests ,irrespective of 
childbearing potential.
CCI
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Section # and Name
Description of Change
Brief Rationale
Table 2 Schedule of 
Activities (Part B)
Corrected the Screening period 
To correct the erroneous description.
Table 2 Schedule of 
Activities (Part B)
Corrected the participants of the 
pregnancy tests
All the women participants should 
have pregnancy tests ,irrespective of 
childbearing potential.
Table 2 Schedule of 
Activities (Part B)
Removed the dosing on Day8 
Not applicable to this study
Table 2 Schedule of 
Activities (Part B)
Added description about PK sample
Clarification
Table 2 Schedule of 
Activities (Part B)
Revised required the fasting hours
Adapted the standard of care 
treatment in Japan in accordance with 
the guideline for clinical evaluation of 
Dyslipidemia
Table 2 Schedule of 
Activities (Part B)
Footnote d:
Specified the allowance of blood samples
Clarification
Table 2 Schedule pf 
Activities (Part B)
Footnote f:
Removed description of “Visit 4(Day8)” 
and “Visit 4(Day8 ; Loading dose):pre-
dose” from the schedule of sampling due 
to no administration on Day8/Removed 
description of Dose3 and Final Dose
Improvement of 
description/Improvement of 
description
Table 2 Schedule of 
Activities (Part B)
Footnote k , l:
Corrected the participants of the 
pregnancy tests.
All the women participants should 
have pregnancy tests ,irrespective of 
childbearing potential.
Table 2 Schedule of 
Activities (Part B)
Added Footnote n
Clarification
Section 2.2 Background
Added the safety information from 
ongoing studies
Updated information


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Section # and Name
Description of Change
Brief Rationale
Section 2.3.1 Risk 
Assessment (Table 3)
Liver Toxicity - Transaminase Elevation: 
Updated the result of toxicology study / 
added the safety data from ongoing 
studies
Injection Site Reactions: Updated
information
Complement Activation: Added finding 
from the 9-month monkey study / 
Corrected as C3a (Part A only )
Inhibition of Intrinsic Coagulation 
Pathway: Title of potential risk changed 
from
‘Impaired Coagulation’ to ‘Inhibition of
Intrinsic Coagulation Pathway’ / Updated  
information
Hypersensitivity and Anaphylactic 
Reaction: Newly added
Flu-like Reactions: Title of potential risk 
changed from ‘Systemic Inflammatory 
Effects’ to ‘Flu-like Reactions’/ 
Improvement of description
Updated information / Improvement 
of description / C3a assessment will 
be conducted in Part A only / Newly 
added 
Section 2.3.2 Benefit 
Assessment
Removed the description of  
D7990C00002 andD7990C00003 studies
Removed
Section 3 Objectives and 
Endpoints Table 4 (Part 
A)
Exploratory: Removed ‘serum’ 
Not applicable to this study
Section 4.1 Overall 
Design 
(Part B)
Removed the loading dose on Day8 and 
AZD8233 
 SC
Not applicable to this study
Section 4.2 Scientific 
Rationale for Study 
Ddesign
Clarified the dosing schedule on Day8  
Dosing on Day8 will be conducted in 
Part A only
Section4.3 Justification 
for Dose
Part A:Added the explanation of SRC 
Part B: Added the information of 
ongoing studies / Removed the loading 
dose on Day8
Part A: SRC wording has been 
updated.
Part B: Updated information / Not 
applicable to this study
Section 5.1 Inclusion 
Criteria: Criterion 5
(Part A)
Improvement description
Unified description with Part B
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Section # and Name
Description of Change
Brief Rationale
Section 5.2 Exclusion 
Criteria: Criterion 13
(Part A)
Deleted the description of dECG 
parameters
Not applicable to this study
Section 5.2 Exclusion 
Criteria: Criterion 12, 13 
(Part B)
Modified the measurement position of 
BP and pulse
Modified in accordance with 
procedure
Section 5.3.1 Meals and 
Dietary Restriction
( Part B )
Revised required the fasting hours
Adapted the standard of care 
treatment in Japan in accordance with 
the guideline for clinical evaluation of 
Dyslipidemia
Section 6.1.1
Investigational Products
Added the description in case of a change 
of the planned dose
Added
Section 6.1.1
Investigational Products 
Table 5 ( Part B)
Removed Day8 from Regimen / 
Removed 
 dose cohort and added 
footnote in cohort 1
Not applicable to this study / Added 
the information in case of a change of 
the planned dose
Section 6.5 Concomitant 
Therapy
（Part A / Part B）
Added a note of administration of 
COVID-19 vaccines
Added guideline for participants on 
administrating COVID-19 vaccines
Section 7.1
Discontinuation of Study 
Intervention (Part A)
Added the explanation of SRC
SRC wording has been updated.
Section 8 Study 
Assessments and 
Procedures
（Part B）
Corrected the screening period/Removed 
SC injection at Visit 4/Revised required 
the fasting hours/ Change the amount of 
blood
To correct the screening period/This 
is not applicable to Part B/Adapted 
the standard of care treatment in 
Japan in accordance with the 
guideline for clinical evaluation of 
Dyslipidemia/To update the latest 
information
Section 8 Study 
Assessments and 
Procedures
（Part A）
General description of visits: 
Change the amount of blood
To update the latest information 
Section 8.2.2 Vital Sings
Modified the description of measurement 
position of BP and pulse
Added the description of procedure for 
pulse
Added the description of resting 
conditions for measurement of BP and 
pulse
Clarification
Section 8.2.3
Electrocardiograms
( Part A )
Corrected procedures for measurement 
when the 12-lead safety ECG time points  
coincide with the telemetry time points 
Improvement of description
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Section # and Name
Description of Change
Brief Rationale
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
（Part A）
Added indirect bilirubin to Clinical 
Chemistry / Corrected the participants of 
the pregnancy tests ( β-hCG and hCG)
Newly added / All the women 
participants should have pregnancy 
tests ,irrespective of childbearing 
potential
Section 8.2.4
Safety Laboratory 
Assessments
（Part B）
Added indirect bilirubin LDH to Clinical 
Chemistry
Unified laboratory variable with Part 
A
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
（Part B）
Corrected the participants of the 
pregnancy tests (β-hCG and hCG) 
All the women participants should 
have pregnancy tests ,irrespective of 
childbearing potential.
Section 8.2.4 Clinical 
Safety Laboratory 
Assessments
（Part B）
Other laboratory assessments
Deleted C3a
Not applicable to Part B
Section 8.3.2 Follow-up 
of AEs and SAEs
SAEs: Added ‘Description of AE’
Added
Section 8.5.1.1
Determination of Drug 
Concentration
（Part B）
Urine sample for determination of 
AZD8233 of total full length ASOs 
concentrations is deleted
Correction
Section 8.5.2
Immunogenicity 
Assessments
Improvement of description
Improvement of description
Section9.2 Sample Size 
Determination (Part B)
Revised number of randomized 
participants
Revised number of randomized 
participants due to removal the 
highest dose
9.4.2.1 Primary Endpoint 
(s) (Part B)
Regarding pair-wise comparisons, 
revised the description from ‘high’ to 
‘mid’
Not applicable to Part B
Appendix A 3
Informed Consent 
Process
Clearly stated the timing of requirement 
to sign a new ICF for Part B study
Clarification
Appendix I
Abbreviations
Added ‘ ISR ‘
Newly added
Section11 References
Improvement of description / Added 
‘Jacqmin P et al 2007’
Updated information / Newly added


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Amendment 3 ( 02-Nov-2021)
Overall Rationale for the Amendment: Part C is planned to investigate the safety and 
tolerability of AZD8233
 , following SC administration of multiple dose in a limited 
number of Japanese patients with dyslipiddemia before progressing to Ph3. Changes to 
Clinical Study Protocol version 3.0 [10- May-2021] are summarized.
Section # and Name
Description of Change
Brief Rationale
Throughout
Minor editorial changes
To ensure consistency with the latest 
protocol template
1.1 Synopsis
Added “Part C” and “Part B”
Short Title / Rationale / Objectives and 
Endpoints / Overall Design / Disclosure 
Statement / Number of Participants / 
Study Period / Intervention Groups and 
Duration /Data Monitoring Committee/ 
Safety Review Committee / Statistical 
Methods
Newly added “Part C study” / Added 
Data Monitoring Committee in Part B 
study
1.2 Schema
Figure 1 Study Design：Added “Part C”
Newly added “Part C study”
1.3 Schedule of 
Activities (Part B)
Pre-dose assessments time changed from 
within 30 minutes to 60 minutes.
Adapted the turnaround time
Table 2 Schedule pf 
Activities (Part B)
Complement activation panel: Removed Day8
Not applicable to Part B
1.3Schedule of Activities
Added “Part C”
Newly added “Part C study”
2.1 Study Rationale
Added “Part C”
Newly added “Part C study”
3 Objectives and 
Endpoints (Table 5)
Added “Part C”
Newly added “Part C study”
4.1 Overall Design
Added “Part C”
Newly added “Part C study”
4.2 Scientific Rationale 
for Study Design
Added “Part C”
Newly added “Part C study”
4.3 Justification for Dose
Added “Part C”
Newly added “Part C study”
4.4 End of Study 
Definition
Added “Part C”
Newly added “Part C study”
5 Study Population 
Added description of procedure for 
handling incorrectly randomized 
participants
Clarification
5.1 Inclusion Criteria
Added “Part C”
Newly added “Part C study”
5.2 Exclusion Criteria
Added “Part C”
Newly added “Part C study”
5.3.1 Meals and Dietary 
Restrictions
Added “Part C”
Newly added “Part C study”
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Section # and Name
Description of Change
Brief Rationale
5.3.2 Caffeine, Alcohol, 
and Tobacco
Added “Part C”
Newly added “Part C study”
6.1.1 Investigational 
Products（Table 6）
Added “Part C”
Newly added “Part C study”
6.3 Measures to 
Minimise Bias: 
Randomization and 
Blinding
Added “Part C”
Newly added “Part C study”
6.5Concomitant Therapy
Added “Part C”
Newly added “Part C study”
7.1 Discontinuation of 
Study Intervention
Added “Part C” / Added the explanation 
of iSMC for Part B
Newly added “Part C study” / Added 
iSMC in Part B study
8 Study Assessments and 
Procedures
Added “Part C” / Pre-dose assessments 
time changed from within 30 minutes to 
60 minutes for Part B.
Newly added “Part C study” /
Adapted the turnaround time
8.2.3 Electrocardiograms
Added “Part C”
Newly added “Part C study”
8.2.4 Clinical Safety 
Laboratory Assessments
Added “Part C”
Newly added “Part C study”
8.2.5 Other Screening 
Assessments
Added “Part C”
Newly added “Part C study”
8.5.1 Pharmacokinetics
Added “Part C”
Newly added “Part C study”
8.5.1.1 Determination of 
Drug Concentration
Added “Part C”
Newly added “Part C study”
8.5.2 Immunogenicity 
Assessments
Added “Part C”
Newly added “Part C study”
8.5.3.1 Collection of 
Samples
（Table 7）
Added “Part C”
Newly added “Part C study”
8.7 Optional Genomics 
Initiative Sample
Added “Part C”
Newly added “Part C study”
9.1 Statistical Hypotheses
Added “Part C”
Newly added “Part C study”
9.2 Sample Size 
Determination
Added “Part C”
Newly added “Part C study”
9.4.2.2 Secondary 
Endpoint(s)
Added “Part C”
Newly added “Part C study”
9.4.3 Safety
Added “Part C”
Newly added “Part C study”
9.5 Interim Analyses
Deleted: CSR for Part B-IA
Not applicable to Part B-IA
9.6Data Monitoring 
Committee
Added “iSMC”
Newly added in Part B study


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Section # and Name
Description of Change
Brief Rationale
Appendix A 3
Informed Consent 
Process
Added “Part C”
Newly added “Part C study”
Appendix A 5
Committees Structure
Added "Part B" and  “Part C”
Added iSMC in Part B study and 
newly added “Part C study”
Amendment 4 ( 16-Jun-2022)
Overall Rationale for the Amendment: Deleted all mentions of SRC (Safety Review 
Committee) for Part C. Changes to Clinical Study Protocol version 4.0 [02- Nov-2021] are 
summarized.
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis
Study Period:
Estimated date of last patient completed 
was extended.
To consider the period of  ADA 
positive participants follow-up
1.1 Synopsis
Safety Review Committee (SRC):
Removed SRC from Part C.
Not applicable to Part C
Table 1 Schedule of 
Activities (Part A)
Corrected the corresponding section 
number of Medical History.
Correction
Table 3 Schedule of 
Activities (Part C)
Corrected a duplicate visit number 
(English version only) / 
Corrected the corresponding section 
number of Medical History.
Correction
6.1.1 Investigational 
Products Table 6 (Part B)
Footnote *: Corrected a unit of the 
strength (Japanese version only)
Correction
6.3 Measures to 
Minimise Bias: 
Randomization and 
Blinding
[Part A/Part B]
Corrected as the SRC(Part A only)
Not applicable to Part C
7.1 Discontinuation of 
Study Intervention
Removed Part C from SRC
Not applicable to Part C
8.2.4 Clinical Safety 
Laboratory Assessments
Central Laboratory name changed from 
COVANCE to Labcorp
To keep consistency as vendor legal 
name changed during course of the 
study
8.5.1.1 Determination of 
Drug Concentration
Central Laboratory name changed from 
COVANCE to Labcorp
To keep consistency as vendor legal 
name changed during course of the 
study


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Section # and Name
Description of Change
Brief Rationale
9.6 Data Monitoring 
Committee
Appendix reference letter that was 
missing has been included  (English 
version only)
Typo correction
Appendix A 5
Committees Structure
Removed Part C from SRC
Not applicable to Part C


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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
TABLE OF CONTENTS .................................................................................................... 13
1
PROTOCOL SUMMARY ................................................................................ 17
1.1
Synopsis ........................................................................................................... 17
1.2
Schema............................................................................................................. 24
1.3
Schedule of Activities ....................................................................................... 25
2
INTRODUCTION............................................................................................ 54
2.1
Study Rationale ................................................................................................ 54
2.2
Background ...................................................................................................... 55
2.3
Benefit/Risk Assessment................................................................................... 56
2.3.1
Risk Assessment ............................................................................................... 57
2.3.2
Benefit Assessment........................................................................................... 60
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 60
3
OBJECTIVES AND ENDPOINTS................................................................... 60
4
STUDY DESIGN ............................................................................................. 63
4.1
Overall Design.................................................................................................. 63
4.2
Scientific Rationale for Study Design ............................................................... 64
4.3
Justification for Dose........................................................................................ 65
4.4
End of Study Definition.................................................................................... 67
5
STUDY POPULATION.................................................................................... 67
5.1
Inclusion Criteria .............................................................................................. 68
5.2
Exclusion Criteria ............................................................................................. 71
5.3
Lifestyle Considerations ................................................................................... 76
5.3.1
Meals and Dietary Restrictions ......................................................................... 77
5.3.2
Caffeine, Alcohol, and Tobacco......................................................................... 77
5.3.3
Activity............................................................................................................. 77
5.3.4
Reproductive Restrictions ................................................................................. 77
5.4
Screen Failures ................................................................................................. 78
6
STUDY INTERVENTION ............................................................................... 79
6.1
Study Intervention(s) Administered................................................................... 79
6.1.1
Investigational Products.................................................................................... 79
6.2
Preparation/Handling/Storage/Accountability ................................................... 82
6.3
Measures to Minimise Bias: Randomization and Blinding ................................ 82
6.4
Study Intervention Compliance......................................................................... 84
6.5
Concomitant Therapy........................................................................................ 85
6.5.1
Rescue Medicine............................................................................................... 86
6.6
Dose Modification ............................................................................................ 86


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6.7
Intervention After the End of the Study............................................................. 86
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 86
7.1
Discontinuation of Study Intervention............................................................... 86
7.2
Participant Withdrawal from the Study.............................................................. 89
7.3
Lost to Follow up.............................................................................................. 90
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 91
8.1
Efficacy Assessments........................................................................................ 96
8.2
Safety Assessments........................................................................................... 96
8.2.1
Physical Examinations...................................................................................... 96
8.2.2
Vital Signs ........................................................................................................ 96
8.2.3
Electrocardiograms........................................................................................... 97
8.2.4
Clinical Safety Laboratory Assessments............................................................ 99
8.2.5
Other Screening Assessments.......................................................................... 103
8.2.6
Injection Site Reactions .................................................................................. 103
8.3
Adverse Events and Serious Adverse Events................................................... 103
8.3.1
Time Period and Frequency for Collecting AE and SAE Information.............. 104
8.3.2
Follow-up of AEs and SAEs ........................................................................... 104
8.3.3
Causality Collection........................................................................................ 105
8.3.4
Adverse Events Based on Signs and Symptoms .............................................. 105
8.3.5
Adverse Events Based on Examinations and Tests .......................................... 105
8.3.6
Hy’s Law........................................................................................................ 106
8.3.7
Reporting of Serious Adverse Events .............................................................. 106
8.3.8
Pregnancy....................................................................................................... 107
8.3.8.1
Maternal Exposure.......................................................................................... 107
8.3.8.2
Paternal Exposure........................................................................................... 107
8.3.9
Medication Error............................................................................................. 108
8.4
Overdose ........................................................................................................ 108
8.5
Human Biological Samples............................................................................. 109
8.5.1
Pharmacokinetics............................................................................................ 109
8.5.1.1
Determination of Drug Concentration ............................................................. 110
8.5.2
Immunogenicity Assessments ......................................................................... 110
8.5.3
Pharmacodynamics..........................................................................................111
8.5.3.1
Collection of Samples......................................................................................111
8.6
Human Biological Sample Biomarkers ........................................................... 112
8.6.1
Collection of mandatory samples for biomarker analysis................................. 112
8.6.2
Collection of Optional Biomarker Samples ..................................................... 113
8.6.3
Other Study Related Biomarker Research ....................................................... 113
8.7
Optional Genomics Initiative Sample.............................................................. 113
8.8
Health Economics........................................................................................... 113
9
STATISTICAL CONSIDERATIONS.............................................................. 113
9.1
Statistical Hypotheses..................................................................................... 113


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9.2
Sample Size Determination............................................................................. 114
9.3
Populations for Analyses................................................................................. 114
9.4
Statistical Analyses ......................................................................................... 115
9.4.1
General Considerations................................................................................... 115
9.4.2
Efficacy .......................................................................................................... 116
9.4.2.1
Primary Endpoint(s)........................................................................................ 116
9.4.2.2
Secondary Endpoint(s).................................................................................... 117
9.4.3
Safety ............................................................................................................. 118
9.4.4
Other Analyses................................................................................................ 118
9.5
Interim Analyses............................................................................................. 118
9.6
Data Monitoring Committee ........................................................................... 119
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ...................................................................................... 119
11
REFERENCES............................................................................................... 150
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 24
LIST OF TABLES
Table 1
Schedule of Activities (Part A) ................................................................ 27
Table 2
Schedule of Activities (Part B)................................................................. 38
Table 3
Schedule of Activities (Part C)................................................................. 44
Table 4
Risk Assessment...................................................................................... 57
Table 5
Objectives and Endpoints......................................................................... 60
Table 6
Investigational Products........................................................................... 80
Table 7
Pharmacodynamic Laboratory Assessments........................................... 111
Table 8
Populations for Analysis ........................................................................ 115
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations....................... 120
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ...................................................................... 126
Appendix C
Handling of Human Biological Samples ................................................ 131
Appendix D
Optional Genomics Initiative Sample..................................................... 133


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 136
Appendix F
Actions in Case of Development of Thrombocytopenia or 
Uninterpretable Platelet Counts After Administration of ASOs.............. 141
Appendix G
Guidance for Definition of Anaphylactic/Hypersensitivity Reactions and 
Checklist for the Investigator................................................................. 144
Appendix H
Statin Therapy ....................................................................................... 146
Appendix I
Abbreviations ........................................................................................ 147


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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title:
A Phase 1 and 2 study to evaluate the safety, tolerability, efficacy, pharmacokinetics and 
pharmacodynamics of AZD8233 following a multiple subcutaneous dose administration  in 
Japanese participants with dyslipidemia
Short Title:
A Phase 1/2 Study of AZD8233 in Participants with Dyslipidemia
This study consists of Part A ,Part B and Part C.
[Part A]
Part A is designed as a randomized, single-blind (blinding of participants and sites), placebo-
controlled, multiple dose, phase 1 study.
Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 
single-blinded treatment arms; AZD8233 
 or placebo.
[Part B]
Part B is designed as a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 
study.
Approximately 60 Japanese participants will be randomized in a 1:1:1 ratio into 1 of the 3 
double-blinded treatment arms; AZD8233 
, AZD8233 
, or placebo.
[Part C]
Part C is designed as a randomized, single-blind (blinding of participants and sites), placebo-
controlled, multiple dose, phase 1 study.
Approximately 11 Japanese participants will be randomized in an 8:3 ratio into 1 of the 2 
single-blinded treatment arms; AZD8233 
 or placebo.
Rationale: 
[Part A] 
In the Phase 1, a single ascending dose (SAD) study that has been conducted in the US, single 
subcutaneous (SC) doses of up to 
 AZD8233 have been well tolerated in healthy male 
participants with moderately elevated Low-density Lipoprotein Cholesterol (LDL-C).  A 
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single SC dose of 
 AZD8233 has been administered to healthy subjects of Japanese 
origin, and no clinically important safety findings have been reported.
In the US, the Phase 1, a multiple ascending dose (MAD) study, is being conducted to assess 
the safety and tolerability of AZD8233 and to characterize the pharmacokinetic (PK) profile of 
AZD8233, following SC administration of multiple ascending doses of AZD8233 in 
33 participants with dyslipidemia. The study is also assessing the pharmacodynamics (PD) of 
AZD8233 by investigating the effect of AZD8233 on levels of LDL-C and proprotein 
convertase subtilisin/kexin type 9 (PCSK9) following SC administration of ascending doses of 
AZD8233.
The dose to be evaluated in Part A is 
 This is the highest dose that has been evaluated in 
the MAD study conducted in the US. A dose of 
 monthly is expected to result in close to 
the maximum achievable reduction in PCSK9 as well as LDL-C levels over the dose interval 
with AZD8233.
According to the Japanese Guideline for General Considerations for Clinical Trials 
(International Council for Harmonisation [ICH]-E8, June 1995), patients who have mild 
hyperlipidaemia alone are permitted to be included in phase I studies of investigational 
products for hyperlipidaemia.
Therefore, dyslipidaemic patients with a moderately increased LDL-C will be selected for Part 
A of the study.
The objective of the study is to investigate the safety and tolerability of AZD8233, following 
SC administration of multiple doses in a limited number of Japanese participants with 
dyslipidemia before progressing to Part B, where a larger number of participants will be 
exposed. The study will also investigate the PK and the PD of AZD8233.
[Part B] 
Part B is planned to evaluate LDL-C reduction at steady state at different doses of AZD8233.
[Part C]
The objective of the study is to investigate the safety and tolerability of AZD8233 with dosing 
regimen to be used in phase 3 study, following SC administration of multiple doses in a 
limited number of Japanese participants with dyslipidemia before progressing to Ph3. The 
study will also investigate the PK and the PD of AZD8233.
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Objectives and Endpoints
[Part A/Part C]
Objectives
Estimands descriptions/Endpoints
Primary
To assess the safety and tolerability of AZD8233 
following SC administration of multiple doses.
Adverse events; vital signs, ECG, cardiac 
telemetry, injection site reaction examinations and 
clinical laboratory evaluations including platelet 
count
Secondary
To characterize the PK of AZD8233 following SC 
administration of multiple doses.
Plasma parameters (tlag, tmax, Cmax, AUC(0-last), 
AUC(0-24), AUC(0-48), AUC, AUCτ, Ctrough, CL/F, 
Vz/F, t1/2, MRT); urine parameters (Ae, Fe, CLR)
To assess the effect of AZD8233 on levels of PCSK9 
following SC administration of multiple doses.
Absolute change from baseline in log-transformed 
PCSK9 in plasma
Percent change from baseline in PCSK9 in plasma
To assess the effect of AZD8233 on levels of LDL-C 
following SC administration of multiple doses.
Percent change from baseline in levels of LDL-C 
in serum
To assess the effects of AZD8233 on other lipid 
parameters following SC administration of multiple 
doses.
Levels of other lipid parameters, including:
•
Total cholesterol (TC)
•
High-density lipoprotein cholesterol (HDL-
C)
•
Non-HDL-C
•
Very-low-density lipoprotein cholesterol 
(VLDL-C)
•
Apolipoproteins (Apo) A1
•
ApoB
•
Lp(a)
•
Triglycerides
Ae = amount excreted in urine; apoB = apolipoprotein B; AUC = area under the plasma concentration-time curve 
from time zero extrapolated to infinity; AUC(0-last) =  area under the plasma concentration-curve from time zero to 
time last value above the limit of quantification; AUC(0-48) =  area under the plasma concentration-time curve 
from time zero to 48 hours after dosing; AUCτ = area under the plasma concentration-time curve from time 
during the dosing interval; CLR = renal clearance; CL/F = apparent total body clearance of drug from plasma 
after extravascular administration; Cmax = Observed maximum plasma concentration; Ctrough = observed trough 
plasma drug concentration; Fe = fraction excreted unchanged in urine; LDL-C = low-density lipoprotein 
cholesterol; Lp(a) = lipoprotein (a); MRT = mean residence time of the unchanged drug in the systemic 
circulation; PCSK9 = proprotein convertase subtilisin/kexin type 9; PK = pharmacokinetics; SC = subcutaneous; 
tmax = time to reach peak or maximum observed concentration or response following drug administration; tlag = 
time delay between drug administration and the first observed concentration in plasma; Vz/F = apparent volume 
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[Part B]
Objectives
Estimands descriptions/Endpoints
Primary
To assess the effect of different doses of AZD8233 on 
LDL-C versus placebo
Absolute change from baseline in log-transformed 
LDL-C in serum
Secondary
To assess the effect of different doses of AZD8233 on 
PCSK9 versus placebo.
Absolute change from baseline in log-transformed 
PCSK9 in plasma
Percent change from baseline in PCSK9 in plasma
To assess the effect of different doses of AZD8233 on 
LDL-C versus placebo.
Percent change from baseline in levels of LDL-C 
in serum
To assess the effect of AZD8233 on other lipid 
parameters versus placebo
Levels of other lipid parameters including:
•
TC
•
HDL-C
•
Non-HDL-C
•
VLDL-C
•
ApoA1
•
ApoB
•
Lp(a)
•
Triglycerides
•
Remnants cholesterol
To evaluate PK of AZD8233.
Population PK parameters
To evaluate the immunogenicity of AZD8233.
Development of antidrug antibodies (ADA) and 
ADA titer (if subjects are ADA positive) during 
treatment and follow-up.
Safety
To assess the safety and tolerability of AZD8233.
Safety and tolerability will be evaluated in terms 
of AEs, vital signs, ECG, injection site reactions,
and clinical laboratory evaluations, including 
platelet count.
AE = adverse event; ApoA1=  apolipoprotein A1; ApoB = apolipoprotein B; ECG = electrocardiogram; HDL-C
= high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = Lipoprotein(a); PK 
= pharmacokinetics; TC = Total cholesterol; VLDL-C = Very-low-density lipoprotein cholesterol
For Exploratory objectives and estimands descriptions/endpoints, see Section 3 of the 
protocol. 


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Overall Design
This study is composed of three parts, two for the preliminary safety assessment (Part A/Part 
C) and the other for the main randomized dose ranging study (Part B).
[Part A/Part C] 
These are each randomized, single-blind, placebo-controlled, multiple dose Phase 1 study 
parts, including approximately 11 participants with dyslipidemia in each part. The primary 
objective of the study is to assess the safety and tolerability of AZD8233 following a multiple 
SC administration in Japanese patients with dyslipidemia. The study will be conducted at up 
to 2 sites in Japan.
The Screening Period starts within 28 days before the randomization visit and ends on 
Day −4. Eligible participants will make 8 visits during the treatment period and 8 additional 
visits during the follow-up period. They are randomized across 2 different treatment arms in 
an 8:3 ratio for a 58-day (up to Visit 9) treatment period. The planned treatment arms are 
AZD8233 
 (Part A) / AZD8233 
 (Part C) and placebo. Participants will be dosed 
subcutaneously on Days 1, 8 (Part A only) , 29, and 57.
[Part B]
This is a randomized parallel, double-blind, placebo-controlled, dose-ranging Phase 2 study 
part in approximately 60 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 approximately 6 sites in Japan. 
The screening period starts within 28 days before the randomization visit and ends on Day −4. 
Eligible participants will make 7 visits during the treatment period and 7 additional visits 
during the follow-up period. They are randomized across 3 different treatment arms in a 1:1:1 
ratio for a 12-week treatment period. The planned treatment arms are AZD8233 
 
AZD8233 
, and placebo. Participants will be dosed subcutaneously on Days 1, 29, and 
57. 
Disclosure Statement:
[Part A/Part C] 
This study is single-blind with regards to treatment (AZD8233 or placebo), and blinded to the 
participants, site investigators, and site staff. The Sponsor will be unblinded to treatment 
allocation.
[Part B] 
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This is a parallel group treatment study in 3 arms with participants, investigators and the 
sponsor blinded.
Number of Participants:
[Part A/Part C] 
Approximately 11 participants will be randomly assigned to the 2 study arms in each part. 
[Part B] 
Approximately 60 participants will be randomly assigned to the 3 study arms.
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. 
Study Period:
[Part A/Part B/Part C]
Estimated date of first patient enrolled: Q4 2020
Estimated date of last patient completed: Q4 2023
Intervention Groups and Duration:
[Part A/Part C] 
The screening period starts up to 28 days before the randomization visit and ends on Day −4. 
Eligible participants will make 8 visits during the treatment period and 8 additional visits 
during the follow-up period. They are randomized across 2 different treatment arms at an 8:3 
ratio for a 58-day (up to Visit 9) treatment period. The planned treatment arms are AZD8233 
 (Part A) / AZD8233 
 (Part C)  and placebo. Participants will be dosed 
subcutaneously on Days 1, 8 (Part A only), 29, and 57.
[Part B] 
The screening period starts up to 28 days before the randomization visit and ends on Day −4. 
Eligible participants will make 7 visits during the treatment period and 7 additional visits 
during the follow-up period. They are randomized across 3 different treatment arms at a 1:1:1 
ratio for a 12-week treatment period. The planned treatment arms are: AZD8233 
 
AZD8233 
, and placebo. Participants will be dosed subcutaneously on Days 1, 29, and 
57. 
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Data Monitoring Committee: 
An internal Safety Monitoring Committee will be used for monitoring of unblinded safety data 
in Part B.
Safety Review Committee (SRC):
After data are collected from all the participants in Part A until Day 64 (7 days after the last 
dose), the Safety Review Committee (SRC) will be held to make a decision to initiate the Part 
B. The data from all participants must be reviewed before that. Data later than Day 64 (if 
available) may be reviewed by the SRC as needed. Depending on the results, the SRC may 
decide not to proceed with the Part B.
The SRC meetings will be prepared and conducted in a blinded manner to keep all attendees 
blinded prior to and during the meetings. Required personnel involved in PD and PK 
evaluations of data (if available) may be unblinded for the evaluation of these data. 
Alternatively, PK and PD data will be provided in a blinded manner for the SRC review. 
Separate unblinded SRC meetings may also be held as needed.
The Part B will be put on temporary hold if any of the following criteria occurs in participants 
receiving AZD8233:

At least one serious adverse event (SAE) considered at least possibly related to the 
Investigational Medicinal Product (IMP) administration. 

At least one severe non-serious AEs considered as, at least, possibly related to the IMP 
administration) in ≥ 2 participants, independent of within or not within the same system 
organ class.
The SRC will carefully review the totality of data, taking into account moderate non-serious 
AEs at least possibly related to the IMP administration and their relations to PD effects (if 
available), the number of subjects in whom the non-serious AEs occur, concurrency of more 
than 1 AE within the same subject and potential safety signals identified with the other IMPs 
in the same class (mechanistic and/or chemical). The SRC will also consider differences 
between Part A and Part B, including but not limited to dosing regimen, as well as available 
overall safety and PK/PD conclusions from other AZD8233 studies (including Study 
D7990C00002 and Study D7990C00003).
Further information on blinding, SRC data review requirements, and SRC process will be 
included in a separate SRC Charter document.
Statistical Methods
[Part A/Part C]


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The primary objective of Parts A and C is to assess safety in Japanese dyslipidaemic 
participants after multiple dosing of AZD8233. Safety data will be descriptively summarized 
with regard to AEs (including SAEs), laboratory parameters, vital signs and ECGs, cardiac 
telemetry, and injection site reactions.
[Part B]
The primary objective of Part B is to compare absolute changes from baseline in log-
transformed LDL-C across different dose levels of AZD8233. The key secondary objective of 
this study is to compare absolute changes from 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 participants 
were 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 receives at least one 
dose of placebo or AZD8233.
Key safety objective is overall tolerability, which will be presented with descriptive statistics.
1.2
Schema
Figure 1
Study Design
[Part A]
Screening
Residential period
Follow-up
Residential period
Informed 
consent
Check-in
Check-in
Check-out
Check-out
≦-28 days
Day-1
Randomization,
Dosing
Day 1
Day 3
Day 8,29
Day 56
Day 57
Day 59 Day 64
Telephone 
contact
Weeks 
2,4,6,8,10,12,14 and 
16
Dosing
Dosing
Visit 1
Visit 2
Visit 3,6
Visit 9
Visit 10-17
Visit days:15(Visit 4), 22(Visit 5), 
36(Visit 7), 44(Visit 8)


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[Part B]
R = randomisation
*In case of a change of the planned dose, the investigational product dose may be used 
 (not 
exceeding 
 )
[Part C]
1.3
Schedule of Activities
[Part A] 
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 should only be carried out for participants 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. Laboratory assessment results should also be reviewed at every visit to ensure that 
stopping criteria have not been met.
Screening
(up to 4 
weeks)
R
AZD8233
（n=20)
AZD8233
（n=20)
Placebo（n=20)
Follow up
(up to 16 weeks 
post last dose)
Treatment period (12 weeks )
Screening
Residential period
Follow-up
Residential period
Informed 
consent
Check-in
Check-in
Check-out
Check-out
≦-28 days
Day-1
Randomization,
Dosing
Day1
Day3
Day29
Day56
Day57
Day59
Week2,4,6,8,10,12
,14 and 16
Dosing
Dosing
Visit 1
Visit 2
Visit 6
Visit 9
Visit 10-17
Visit days:8(Visit 3), 15(Visit 4), 22(Visit 5), 36(Visit 7), 44(Visit 8)
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Assessments scheduled to be done at the same time may be initiated based on the sequence 
below:
1
ECGs
2
Vital signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]), pulse 
rate, and temperature, if appropriate
3
Blood sampling
4
Dose administration
Pre-dose assessments may be performed within 30 minutes prior to dosing.


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Informed consent
X
Appendix 
A 3
Inclusion/exclusio
n criteriab
X
X
Sections
5.1, 5.2
Demographic data
X
Section
9.4.1
Weight and height 
(BMI) c
X
X
X
(Day 57)
X
Section
8.2.1
Medical history
X
Section
8
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
Section 6.5
Drug abuse and 
alcohol screen d
X
X
Section 
5.3.2, 5.2
Smoking history
X
Section 
5.3.2


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Viral serology e
X
Section
8.2.5
Pregnancy test
(females only)
X o
X p
Section
8.2.4
Pregnancy and 
reproductive 
status (females 
onlyq) 
X
Section
8.2.4
Randomisation
X
(Day 1)
Section 6.3
Study residency
Check-in
X
X
Figure 1
Check-out
X
(Day 3 l)
X
(Day 59)
Figure 1


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
IMP 
administration
X
(Day 1)
X
X
(Day 57)
Figure 1, 
Section
6.1.1
Safety and 
tolerability
Adverse event 
questioning 
(including 
collection of data 
for injection site 
reactions)
X
(only SAEs)
X
(only 
SAEs)
X
X
X
X
X
X
X
X
Section 8.3
Physical 
examination 
X
(complete)
X
(abbre-
viated)
X
(abbreviated; pre-
dose and then 24 
and 48 h post-
dose)
X
(abbre-
viated; 
pre-
dose)
X
(abbreviated; 24 h 
post-dose)
X
(abbreviated)
X
(complete)
Section 
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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Blood pressure 
and pulse rate f
X
X
X
(pre-dose and then 
0.25, 0.5, 1, 1.5, 2, 
2.5, 3, 4, 6, 8, 12, 
24, 36 and 48 h 
post-dose)
X
(pre-
dose)
X
(pre-dose and then 
0.5, 1, 2, 3, 4, 6, 8, 
12, 24, 36 and 48 h 
post-dose)
X
X
Section 
8.2.2
Body temperature
X
X
(pre-dose)
X
(pre-
dose)
X
(pre-dose)
X
X
Section 
8.2.2
12-lead safety 
ECG g
X
X
(pre-dose and then 
0.5, 1, 2, 3, 4, 6, 8, 
12, 24, 36 and 48 h 
post-dose)
X
(pre-
dose)
X
(pre-dose and then 0.5, 
1, 2, 3, 4, 6, 8, 12, 24, 
36 and 48 h post-dose)
X
X
Section 
8.2.3


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Cardiac telemetry 
X
(for at 
least 4 
h)
X
(pre-dose to 24 h 
post-dose)
X
(pre-dose to 24 h post-
dose)
Section 
8.2.3
Hematology, 
Chemistry and 
Coagulation 
including hs-CRP) 
X
X
X
(24 h post-dose)
X
(pre-
dose)
X
(pre-dose)
X
(Week 2, 4, 
8 and 12 
after last 
dose)
X
Section 
8.2.4
Sampling for renal 
safety biomarkers 
X
X
(pre-dose and then 
24 and 48 h post-
dose)
X
(pre-
dose)
X
(pre-dose)
Section 
8.2.4


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Sampling for 
dipstick urinalysis 
for hematuria
X
X
(pre-dose and then 
24 and 48 h post-
dose)
X
(pre-
dose)
X
(pre-dose)
Section
8.2.4
Sampling for 
platelet count
X
X
X
(24 and 48 h post-
dose)
X
(pre-
dose)
X
(Days 
22, 44)
X
X
X
Section
8.2.4
Complement 
activation panel h
X
(pre-dose and then 
1, 2 and 4 h post-
dose)
X
(pre-dose and then 
1, 2 and 4 h post-
dose)
Section 
8.2.4


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Immunogenicity
Samples for anti-
AZD8233 
antibodies 
X
(pre-dose)
X
(Day 29 
pre-
dose)
X
(pre-dose)
X
(Week 2 
after last 
dose)
X
Section 
8.5.2
Pharmacodynamics
Blood sampling for 
LDL-C and PCSK9 
X m,
X m
X m
(pre-dose and then 
48 h post-dose)
X m, n
(pre-
dose)
X m, n
X m
(pre-dose and then 
24 h post-dose)
X m
X n
Section 
8.5.3.1
Blood sampling 
for other lipid 
parameters
X m
X m
X m
(pre-dose and then 
48 h post-dose)
X m, n
(pre-
dose)
X m, n
X m
(pre-dose and then 
24 h post-dose)
X m
X m
Section 
8.5.3.1


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Exploratory 
biomarker 
sampling
Plasma and urine 
samples to be 
stored in the 
Biobank until 
further analysis i
X
(pre-dose)
X
(pre-
dose)
X
(pre-dose)
X
(Weeks 2 
and 4 after 
last dose)
X
Section 
8.6.1
Pharmacokinetics
Plasma for 
AZD8233 and 
total full length 
ASOs of 
AZD8233 j
X
(pre-dose and then 
0.5, 1, 1.5, 2, 2.5, 
3, 4, 5, 6, 8, 10, 
12, 24, 36 and 48 
h post dose)
X
(pre-
dose)
X
X
(pre-dose and then 
0.5, 1, 1.5, 2, 2.5, 3, 
4, 5, 6, 8, 10, 12, 
24, 36 and 
48 h post dose)
X
X
Section
8.5.1


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Table 1
Schedule of Activities (Part A)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section 
in 
Protocol
Visit Number
1
2
3, 6
4, 5, 
7, 8
9
Telephone 
contact k
10 to 16
17
(Final 
Follow-
up Visit/ 
ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 3
Days 
8a, 29
Days 
15, 
22, 
36, 44
Day 
56
Days 57 to 59
Day 64
Weeks 2, 
4, 6, 8, 10, 
12, 14
(after last 
dose)
Week 16
(after 
last 
dose)
Visit Window
-
-
-
± 1 day
± 1 
day
± 1 day
+2 days
± 2 days
± 2 days
Urine for total full 
length ASOs of 
AZD8233 
X
(pre-dose and 
intervals 0-6, 6-12, 
12-24 h post-dose)
X
(pre-dose and intervals 
0-6, 6-12, 12-24 h 
post-dose)
Section
8.5.1
ASO: Antisense oligonucleotides; BMI = body mass index; ET = early termination; FSH = follicle-stimulating hormone; hs-CRP = high sensitive C-reactive 
protein; IMP: Investigational medicinal product; LDL-C = low-density lipoprotein cholesterol; LH = luteinizing hormone; PCSK9 = proprotein convertase 
subtilisin/kexin type-9; SAE: Serious adverse event
Participants are required to be fasted for at least 10 hours overnight prior to all study visits except for Visit 1 (only for the purpose of signing his/her informed 
consent); subjects are permitted to drink water during this period of fasting until 1 hour before blood sampling. On days when subjects attend the clinic in a 
fasting state, blood and urine samples should be obtained prior to administration of IMP.
a
Day 8: no allowances.
b
The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (Visit1).
c
At Visit 1 and on Day −1, BMI be calculated. For Day −1, the height measured on Visit 1 will be utilised. At all other time points, only weight will be 
measured.
d
Drugs of abuse and alcohol screen: Investigator will interview participants regarding their use of drugs and alcohol.
e
Samples for HIV should be tested at a local laboratory. 


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f
Allowances: pre-dose (up to 30 minutes prior to dosing)  and then 0.25 h (± 2 minutes), 0.5 h (± 10 minutes), 1 h (± 10 minutes), 1.5 h (± 10 minutes), 2 h 
(± 15 minutes), 2.5 h ( ±15 minutes), 3 h (±15 minutes), 4 h  (± 15 minutes), 6 h (± 15 minutes) , 8 h (± 15 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 
36 h (± 1 hour) and 48 h (±1 hour) post-dose. Screening and Day-1: Sitting position, Day1 to Follow-up Period (Final Follow-up Visit / EDV ); Supine 
position.
g
Allowances: pre-dose (up to 30 minutes prior to dosing) and then 0.5 h (±10 minutes), 1 h (± 10 minutes), 2 h (±15 minutes), 3 h (±15 minutes), 4 h (±15 
minutes),  6h (±15 minutes), 8 h (±15 minutes), 12 h (±30 minutes),  24 h (± 1 hour), 36 h (±1 hour) and 48 h (±1 hour) post-dose
h
Blood samples for complement activation panel will be collected pre-dose(up to 30 minutes prior to dosing), and 1(±5 minutes), 2(±5 minutes) and 4 h (±10 
minutes) post-dose so that the samples can be taken around Cmax.
i
Plasma and urine samples for biobanking must be collected at the same hour every morning after an overnight (10-hour) fast.
j
allowance; pre-dose (up to 30 minutes prior to dosing) and then 0.5 h (±2 minutes), 1 h (±5 minutes), 1.5 h (±5 minutes), 2 h (±5 minutes), 2.5 h (±5 
minutes), 3 h (±10 minutes), 4 h (±10 minutes), 5 h (±10 minutes), 6 h (± 10 minutes), 8 h (±10 minutes), 10 h (± 30 minutes), 12 h (± 30 minutes), 24 h 
(± 1 hour), 36 h (± 1hour)  and 48 h (± 1 hour) post dose
k
Telephone contact: A site or investigator will call participants to assess AEs.
l
Participants will be discharged after the results from the 48 h post-dose assessments have been reviewed by the Investigator.
m
The sample should be taken in a fasting state in the morning (after a 10 hour fasting) at approximately the same time point as the pre-dose sample on Day 1
n
Sampling to be done at approximately the same time points on the days of dosing (pre-dose) as on the non-dosing days (in the morning).
o
Pregnancy test: Serum β-human chorionic gonadotropin (β-hCG) will be performed on all the women participants , irrespective of childbearing potential.
p
Pregnancy test (Day1): Urine pregnancy test using dipstick will be performed before randomization on all the women participants , irrespective of  
childbearing potential at a local laboratory
q
All the women participants should have FSH and LH levels determined, irrespective of childbearing potential.


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[Part B] 
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 should only be carried out for participants 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. Laboratory assessment results should also be reviewed at every visit to ensure that 
stopping criteria have not been met.
Assessments scheduled to be done at the same time may be initiated based on the sequence 
below:
1
Electrocardiogram (ECG)
2
Vital signs (SBP and DBP), pulse rate, and temperature, if appropriate
3
Blood sampling
4
Dose administration
Pre-dose assessments may be performed within 60 minutes prior to dosing.


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Table 2
Schedule of Activities (Part B)
Screening
Treatment Period
EDV
Follow-up 
periodn
Final 
Follow-
up 
Visitn
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
4
5
6
7
8
9
10, 11, 12, 13, 
14, 15
16
Study Week
0
1
3
4
6
8
10
12, 14, 16, 18, 
20, 22
24
Study Day
Days 
−28 
to
−10
Days 
−7 to
−4
Day 1
Day 8
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Days 85, 99, 
113, 127, 141, 
155
Day 169
Visit Window
± 1 
day
± 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
X i
Sections 
5.1, 5.2
Enrolment
X
Sections 
6.3, 8
Randomisation
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
Body weight a
X
X
X
X
X
X
X
Section 8.2.1
BMI
X
X
X
Section 8.2.1


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Table 2
Schedule of Activities (Part B)
Screening
Treatment Period
EDV
Follow-up 
periodn
Final 
Follow-
up 
Visitn
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
4
5
6
7
8
9
10, 11, 12, 13, 
14, 15
16
Study Week
0
1
3
4
6
8
10
12, 14, 16, 18, 
20, 22
24
Study Day
Days 
−28 
to
−10
Days 
−7 to
−4
Day 1
Day 8
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Days 85, 99, 
113, 127, 141, 
155
Day 169
Visit Window
± 1 
day
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 days
± 2 days
HbA1c
X
Section 8.2.5
Alcohol and smoking history
X
X
Viral serology
X
Section 8.2.5
Pregnancy test (females only)
X k
X l
Section 8.2.4
Pregnancy and reproductive 
status (females onlym)
X
Section 8.2.4
IMP administration 
(AZD8233/Placebo)
X
X
X
Section 6.1.1
Safety Assessments
Adverse event review
X
(SAEs 
Only)
X
(SAEs 
Only)
X
X
X
X
X
X
X
X
X
X
Section 8.3
Injection site reactions b
X
X
X
X
X
X
X
X
X
X
Section 8.2.6
Physical examination (complete)
X
X
X
X
Section 8.2.1
Physical examination 
(abbreviated)
X
X
X
X
X
X
X
Section 8.2.1


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Table 2
Schedule of Activities (Part B)
Screening
Treatment Period
EDV
Follow-up 
periodn
Final 
Follow-
up 
Visitn
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
4
5
6
7
8
9
10, 11, 12, 13, 
14, 15
16
Study Week
0
1
3
4
6
8
10
12, 14, 16, 18, 
20, 22
24
Study Day
Days 
−28 
to
−10
Days 
−7 to
−4
Day 1
Day 8
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Days 85, 99, 
113, 127, 141, 
155
Day 169
Visit Window
± 1 
day
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 days
± 2 days
Vital signs (blood pressure, 
pulse and temperature) c
X
X
X
X
X
X
X
X
X
X
X
Section 8.2.2
12-lead ECG c
X
X
X
X
X
X
X j
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
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
Complement activation panel d
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 e
X
X
X
X
X
X
X
X
X
X
X
Section 
8.5.3.1
PCSK9 e
X
X
X
X
X
X
X
X
X
X
X
Section 
8.5.3.1


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Table 2
Schedule of Activities (Part B)
Screening
Treatment Period
EDV
Follow-up 
periodn
Final 
Follow-
up 
Visitn
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
4
5
6
7
8
9
10, 11, 12, 13, 
14, 15
16
Study Week
0
1
3
4
6
8
10
12, 14, 16, 18, 
20, 22
24
Study Day
Days 
−28 
to
−10
Days 
−7 to
−4
Day 1
Day 8
Day 
22
Day 
29
Day 
43
Day 
57
Day 
71
Days 85, 99, 
113, 127, 141, 
155
Day 169
Visit Window
± 1 
day
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 
days
± 2 days
± 2 days
Triglycerides e
X
X
X
X
X
X
X
X
X
X
X
Section 
8.5.3.1
Other lipid parameters e
X
X
X
X
X
X
X
X
X
X
Section 
8.5.3.1
Pharmacokinetics
Plasma sample for total full 
length ASOs of AZD8233 f
X
X
X
X
X
X
X f
X
Section 8.5.1
Immunogenicity
Samples for anti-AZD8233 
antibodies g
X
X
X
X
X
X g
X
Section 8.5.2
Exploratory biomarker analysis
Biomarker analyses (plasma) e
X
X
X
X
X
X
X
X
X
X
X
Section 8.6.1
Biomarker analyses (urine) e
X
X
X
X
X
X
X
X
X
X
Section 8.6.1
Genomics Initiative optional, 
exploratory genetic sample h
X
Section 8.7


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ADA = antidrug antibody; BMI = body mass index; D = day; ECG = electrocardiogram; EDV = early discontinuation visit; FSH = follicle-stimulating hormone; 
HbA1c = haemoglobin A1c; hs-CRP = high sensitive C-reactive protein; LDL-C = low-density lipoprotein cholesterol; LH = luteinizing hormone; PCSK9 = 
proprotein convertase subtilisin/kexin type-9; PK = pharmacokinetic; IMP = Investigational medicinal product
Subjects are required to be fasted for at least 10 hours overnight prior to all study visits except for Visit 1; subjects are permitted to drink water during this period 
of fasting until 1 hour before blood sampling. On days when subjects attend the clinic in a fasting state, blood and urine samples should be obtained prior to 
administration of the IMP.
Samples to be obtained from all treatment arms unless specified in the table.
a
Weight should be measured in light indoor clothes, without shoes, after using the bathroom. Otherwise, follow the local standard procedure.
b
Injection Site Reaction assessments to be collected based on adverse event collection criteria.
c
Vital signs and ECG to be measured pre-dose on dosing days.
d
Blood samples for complement activation panel will be taken around Cmax and are to be collected pre-dose and 2 hours (±5 minutes) post-dose.
e
Samples to be obtained pre-dose on dosing days.
f
PK sampling to be performed at Visits 4 (Day 8), 6 (Day 29), 7 (Day 43), 8 (Day 57), 9 (Day 71), 10 (Day 85), 12 (Day 113), 14 (Day 141), and final 
follow-up visit/EDV. Schedule of sampling for Visit 6 (Day 29), 8 (Day 57) is shown below.
Visit 6 (Day 29): pre-dose, Visit 8 (Day 57): pre-dose.
g
ADA sampling to be performed at Visits 3 (D 1), 4 (D 8), 6 (D 29), 8 (D 57), 10 (D 85), 12 (D 113), 14 (D 141), and final follow-up visit/EDV. ADA 
samples to be collected pre-dose on all dosing days.
h
If, for any reason, the sample is not drawn pre-dose on Visit 3 (Day 1), it may be taken at any visit until the final follow-up/EDV visit.
i
Check screening labs and inclusion/exclusion criteria.
j
ECG to be performed during the follow-up period at Visits 10 (Day 85), 11 (Day 99), 13 (Day 127), and 15 (Day 155).
k
Pregnancy test: Serum β-human chorionic gonadotropin (β-hCG) will be performed on all the women participants , irrespective of childbearing potential. 
l
Pregnancy test ( Day1 ): Urine pregnancy test using dipstick will be performed before randomization on all the women participants , irrespective of 
childbearing potential. at a local laboratory.
m
All the women participants should have FSH and LH levels determined, irrespective of childbearing potential.
n
In the case of early discontinuation, follow-up visit will be performed every 2 weeks after last dose.


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[Part C] 
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 should only be carried out for participants 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. Laboratory assessment results should also be reviewed at every visit to ensure that 
stopping criteria have not been met.
Assessments scheduled to be done at the same time may be initiated based on the sequence 
below:
1
ECGs
2
Vital signs (Systolic Blood Pressure [SBP] and Diastolic Blood Pressure [DBP]), pulse 
rate, and temperature, if appropriate
3
Blood sampling
4
Dose administration
Pre-dose assessments may be performed within 30 minutes prior to dosing.


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Table 3
Schedule of Activities (Part C)
Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Informed 
consent
X
Appendix 
A 3
Inclusion/exclus
ion criteriab
X
X
Sections
5.1, 5.2
Demographic 
data
X
Section
9.4.1
Weight and 
height (BMI) c
X
X
X
(Day 57)
X
Section
8.2.1
Medical history
X
Section
8
Concomitant 
medication
X
X
X
X
X
X
X
X
X
X
Section 6.5
Drug abuse and 
alcohol screen d
X
X
Section 
5.3.2, 5.2
Smoking history
X
Section 
5.3.2


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Viral serology e
X
Section
8.2.5
Pregnancy test
(females only)
X n
X o
Section
8.2.4
Pregnancy and 
reproductive 
status (females 
onlyp) 
X
Section
8.2.4
Randomisation
X
(Day 1)
Section 6.3
Study residency
Check-in
X
X
Figure 1
Check-out
X
(Day 3 k)
X
(Day 59)
Figure 1
IMP 
administration
X
(Day 1)
X
X
(Day 57)
Figure 1, 
Section
6.1.1


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Safety and 
tolerability
Adverse event 
questioning 
(including 
collection of 
data for 
injection site 
reactions)
X
(only 
SAEs)
X
(only 
SAEs)
X
X
X
X
X
X
X
X
Section 8.3
Physical 
examination 
X
(complete)
X
(abbre
-
viated
)
X
(abbreviate
d; pre-dose 
and then 
24 and 48 
h post-
dose)
X
(abbre-
viated)
X
(abbre-
viated; pre-
dose)
X
(abbreviate
d; 24 h 
post-dose)
X
(abbreviated)
X
(complete)
Section 
8.2.1


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Blood pressure 
and pulse rate f
X
X
X
(pre-dose 
and then 
0.25, 0.5, 1, 
1.5, 2, 2.5, 
3, 4, 6, 8, 
12, 24, 36
and 48 h 
post-dose)
X
X
(pre-dose)
X
(pre-dose 
and then 0.5, 
1, 2, 3, 4, 6, 
8, 12, 24, 36 
and 48 h 
post-dose)
X
X
Section 
8.2.2
Body 
temperature
X
X
(pre-dose)
X
X
(pre-dose)
X
(pre-dose)
X
X
Section 
8.2.2
12-lead safety 
ECG g
X
X
(pre-dose and 
then 0.5, 1, 2, 
3, 4, 6, 8, 12, 
24, 36 and 48 
h post-dose)
X
X
(pre-dose)
X
(pre-dose and 
then 0.5, 1, 2, 
3, 4, 6, 8, 12, 
24, 36 and 48 
h post-dose)
X
X
Section 
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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Cardiac 
telemetry 
X
(for at 
least 4 
h)
X
(pre-dose to 
24 h post-
dose)
X
(pre-dose to 
24 h post-
dose)
Section 
8.2.3
Hematology, 
Chemistry and 
Coagulation 
including hs-
CRP) 
X
X
X
(24 h post-
dose)
X
X
(pre-dose)
X
(pre-dose)
X
(Week 2, 4, 8 
and 12 after last 
dose)
X
Section 
8.2.4
Sampling for 
renal safety 
biomarkers 
X
X
(pre-dose 
and then 
24 and 48 
h post-
dose)
X
X
(pre-dose)
X
(pre-dose)
Section 
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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Sampling for 
dipstick 
urinalysis for 
hematuria
X
X
(pre-dose 
and then 
24 and 48 
h post-
dose)
X
X
(pre-dose)
X
(pre-dose)
Section
8.2.4
Sampling for 
platelet count
X
X
X
(24 and 48 
h post-
dose)
X
X
(pre-dose)
X
(Days 22, 
44)
X
X
X
Section
8.2.4
Complement 
activation panel
h
X
(pre-dose 
and then 1, 
2 and 4 h 
post-dose)
X
(pre-dose 
and then 1, 
2 and 4 h 
post-dose)
Section 
8.2.4
Immunogenicity
Samples for 
anti-AZD8233 
antibodies 
X
(pre-dose)
X
(pre-dose)
X
(pre-dose)
X
(Week 2 after 
last dose)
X
Section 
8.5.2


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Pharmacodynami
cs
Blood sampling 
for LDL-C and 
PCSK9 
X l
X l
X l
(pre-dose 
and then 
48 h post-
dose)
Xl,m
X l, m
(pre-dose)
X l, m
X l
(pre-dose 
and then 
24 h post-
dose)
X l
X m
Section 
8.5.3.1
Blood sampling 
for other lipid 
parameters
X l
X l
X l
(pre-dose 
and then 
48 h post-
dose)
Xl,m
X l, m
(pre-dose)
X l, m
X l
(pre-dose 
and then 
24 h post-
dose)
X l
X l
Section 
8.5.3.1


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Exploratory 
biomarker 
sampling
Plasma and 
urine samples to 
be stored in the 
Biobank until 
further analysis i
X
(pre-dose)
X
X
(pre-dose)
X
(pre-dose)
X
(Weeks 2 and 4 
after last dose)
X
Section 
8.6.1
Pharmacokinetic
s


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Screening
Treatment Period
Follow-up Period
Corre-
sponding 
Section in 
Protocol
Visit Number
1
2
3
6
4, 5, 7, 8
9
10 to 16
17
(Final 
Follow-up 
Visit/ ED 
Visit)
Study 
Day/Week
Days 
−28 to 
−4
Day 
−1
Days 1 to 
3
Day 8a
Day 29
Days 15, 
22, 36, 44
Day 
56
Days 57 
to 59
Weeks 2, 4, 6, 
8, 10, 12, 14
(after last 
dose)
Week 16
(after last 
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Plasma for 
AZD8233 and 
total full length 
ASOs of 
AZD8233 j
X
(pre-dose 
and then 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
5, 6, 8, 10, 
12, 24, 36 
and 48 h 
post dose)
X
X
(pre-dose)
X
X
(pre-dose 
and then 
0.5, 1, 1.5, 
2, 2.5, 3, 4, 
5, 6, 8, 10, 
12, 24, 36 
and 
48 h post 
dose)
X
X
Section
8.5.1
Urine for total 
full length ASOs 
of AZD8233 
X
(pre-dose and 
intervals 0-6, 
6-12, 12-24 h 
post-dose)
X
(pre-dose and 
intervals 0-6, 
6-12, 12-24 h 
post-dose)
Section
8.5.1
ASO: Antisense oligonucleotides; BMI = body mass index; ET = early termination; FSH = follicle-stimulating hormone; hs-CRP = high sensitive C-reactive 
protein; IMP: Investigational medicinal product; LDL-C = low-density lipoprotein cholesterol; LH = luteinizing hormone; PCSK9 = proprotein convertase 
subtilisin/kexin type-9; SAE: Serious adverse event
Participants are required to be fasted for at least 10 hours overnight prior to all study visits except for Visit 1 (only for the purpose of signing his/her informed 
consent); subjects are permitted to drink water during this period of fasting until 1 hour before blood sampling. On days when subjects attend the clinic in a 
fasting state, blood and urine samples should be obtained prior to administration of IMP.


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a
Day 8: no allowances.
b
The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (Visit1).
c
At Visit 1 and on Day −1, BMI be calculated. For Day −1, the height measured on Visit 1 will be utilised. At all other time points, only weight will be 
measured.
d
Drugs of abuse and alcohol screen: Investigator will interview participants regarding their use of drugs and alcohol.
e
Samples for HIV should be tested at a local laboratory. 
f
Allowances: pre-dose and then 0.25 h (± 2 minutes), 0.5 h (± 10 minutes), 1 h (± 10 minutes), 1.5 h (± 10 minutes), 2 h (± 15 minutes), 2.5 h ( ±15 minutes), 
3 h (±15 minutes), 4 h  (± 15 minutes), 6 h (± 15 minutes) , 8 h (± 15 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 36 h (± 1 hour) and 48 h (±1 hour) 
post-dose. Screening and Day-1: Sitting position, Day1 to Follow-up Period (Final Follow-up Visit / EDV ); Supine position
g
Allowances: pre-dose and then 0.5 h (±10 minutes), 1 h (± 10 minutes), 2 h (±15 minutes), 3 h (±15 minutes), 4 h (±15 minutes),  6h (±15 minutes), 8 h 
(±15 minutes), 12 h (±30 minutes),  24 h (± 1 hour), 36 h (±1 hour) and 48 h (±1 hour) post-dose
h
Blood samples for complement activation panel will be collected pre-dose and 1(±5 minutes), 2(±5 minutes) and 4 h (±10 minutes) post-dose so that the 
samples can be taken around Cmax.
i
Plasma and urine samples for biobanking must be collected at the same hour every morning after an overnight (10-hour) fast.
j
allowance; pre-dose and then 0.5 h (±2 minutes), 1 h (±5 minutes), 1.5 h (±5 minutes), 2 h (±5 minutes), 2.5 h (±5 minutes), 3 h (±10 minutes), 4 h (±10 
minutes), 5 h (±10 minutes), 6 h (± 10 minutes), 8 h (±10 minutes), 10 h (± 30 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 36 h (± 1hour)  and 48 h (± 1 
hour) post dose
k
Participants will be discharged after the results from the 48 h post-dose assessments have been reviewed by the Investigator.
l
The sample should be taken in a fasting state in the morning (after a 10 hour fasting) at approximately the same time point as the pre-dose sample on Day 1
m
Sampling to be done at approximately the same time points on the days of dosing (pre-dose) as on the non-dosing days (in the morning).
n
Pregnancy test: Serum β-human chorionic gonadotropin (β-hCG) will be performed on all the women participants , irrespective of childbearing potential.
o
Pregnancy test (Day1): Urine pregnancy test using dipstick will be performed before randomization on all the women participants , irrespective of  
childbearing potential at a local laboratory.
p
All the women participants should have FSH and LH levels determined, irrespective of childbearing potential.


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2
INTRODUCTION
2.1
Study Rationale
[Part A]
AstraZeneca is developing AZD8233, a PCSK9 targeted antisense oligonucleotide (ASO) for 
the reduction of circulating levels of LDLs, a major cardiovascular disease (CVD) risk factor. 
Patients with dyslipidemia have increased risks of CVD events compared with the general 
population. Low levels of LDL-C are associated with a monotonically lower risk of incident 
atherosclerotic CVD events. The blood level of LDL-C is decreased by inhibiting PCSK9 
from binding to LDL receptors (LDLRs) and by promoting the uptake of LDL-C into 
hepatocytes.
In the US, the Phase 1, MAD study, is being conducted to assess the safety and tolerability of 
AZD8233 and to characterize its PK following SC administration of multiple ascending doses. 
The study is also assessing the PD of AZD8233 by investigating its effect on levels of LDL-C 
and PCSK9 following SC administration of ascending doses.
According to the Japanese Guideline for General Considerations for Clinical Trials (ICH-E8, 
June 1995), patients who have mild hyperlipidaemia alone are permitted to be included in the 
phase I studies of investigational products for hyperlipidaemia.
Therefore, dyslipidaemic patients with a moderately increased LDL-C will be selected for the 
study.
The objective of Part A of the study is to investigate the safety and tolerability of AZD8233, 
following SC administration of multiple doses in a limited number of Japanese patients with 
dyslipidemia before progressing to part B of the study. Part A of the study will also investigate 
the PK and the PD of AZD8233.
 is the highest repeated administered dose that has been evaluated in a multiple dosing 
study conducted in the US (Study D7990C00002) and is also the highest planned dose to be 
evaluated in dose finding studies in Western populations. A dose of 
 per month is 
expected to result in close to the maximum achievable reduction in PCSK9 as well as LDL-C 
levels over the dose interval with AZD8233.
[Part B] 
AZD8233 is a PCSK9-targeted ASO for the reduction of circulating levels of LDL-C. This 
study part 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 
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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. 
[Part C]
The objective of Part C of the study is to investigate the safety and tolerability of AZD8233 
 
, following SC administration of multiple doses (QM dosing) in a limited number of 
Japanese patients with dyslipidemia before progressing to Ph3. Part C of the study will also 
investigate the PK and the PD of AZD8233. This dose has been evaluated in the ongoing 
D7990C00004 study (SOLANO) , and is also the planned dose to be evaluated in Ph3.
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 preventions 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 3 hydroxy 3 methyl glutaryl coenzyme A (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 targets and some continue to be at residual risk 
despite maximum doses; for others, side effects such as myalgia and myositis may preclude 
statin use.
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 causes familiar dominant hypercholesterolemia; loss of function is associated with 
low circulating levels of LDL-C and a reduced risk of major vascular events. 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 subjects 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). The potential risks identified for 
AZD8233 based on ASO class are presented in Table 4. AZD8233 may provide novel 
treatment options to patients with dyslipidemia.
In the ongoing SAD (Study D7990C00001), global MAD (Study D7990C00002), this study 
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(Study D7990C00006), and global dose ranging (Study D7990C00003 [ETESIAN]) studies,  
> 120 participants have been exposed to multiple doses of subcutaneous administration of 
AZD8233.
The majority of the AEs reported have been mild or moderate. Injection site reactions (ISRs) 
have been reported in some participants, of which one was discontinued from treatment.
A total of six participants presented treatment-emergent ALT increases between 3 × ULN and 
< 6 × ULN (max = 268 U/L). No increase in total bilirubin has been observed in any of these 
participants, and no clinical signs or symptoms have been associated. In all 6 participants, the 
elevation in ALT was transient, and all participants recovered while still in the study (3 on 
continued treatment, and 3 that had discontinued).
Except for these findings, there have been no indications of ASO-related platform risks, 
including thrombocytopenia (platelet counts have remained stable in all participants), renal 
injury, impaired blood coagulation, complement activation, hypersensitivity/anaphylactic 
reaction, and flu-like reactions. Results on ADA from ongoing studies are not yet available. 
Overall, AZD8233 has been generally well tolerated at all doses studied with no significant 
safety findings on vital signs, ECG, body temperature, haematological, or clinical chemistry 
safety lab parameters.
Preliminary data from Study D7990C00001 showed that AZD8233 doses of ≥ 
 reduced 
PCSK9 by ≥ 90% and LDL-C by as much as 70%.
A detailed description of the chemistry, pharmacology, efficacy, and safety of AZD8233 is 
provided in the Investigator’s Brochure (Investigator’s Brochure 2021).
2.3
Benefit/Risk Assessment
Potential risks of AZD8233 and mitigation strategy are shown in Table 4. More detailed 
information about the known and expected benefits and potential risks of AZD8233 may be 
found in the Investigator’s Brochure.
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2.3.1
Risk Assessment
Table 4
Risk Assessment
Potential risk of clinical 
significance
Rationale for risk
Mitigation Strategy 
Study intervention
Thrombocytopenia
Severe thrombocytopenia has been 
observed in some ASO programs 
and it is not known whether other 
members of the class may be 
affected (Crooke ST et al 2017). 
One case of severe 
thrombocytopenia was observed in 
a non-human primate toxicology 
study with AZD8233.
Monitoring of platelet count. In 
case of severe thrombocytopenia, 
the action plan detailed in 
Appendix F will be followed.
Kidney injury
The kidney is an oligonucleotide 
high-uptake tissue. Tubular 
necrosis has been observed with 
ASOs including an ASO inhibiting 
PCSK9. This was not observed in 
toxicology studies with AZD8233 
(Van Poelgeest EP et al 2013, Van 
Poelgeest EP et al 2015, Van Meer 
L et al 2017).
Monitoring of S-creatinine, BUN, 
urine albumin, and urine total 
protein as well as calculation of 
eGFR.
Liver Toxicity - Transaminase 
Elevation
The liver is an oligonucleotide 
high-uptake tissue (Hung G et al 
2013). Oligonucleotide treatment 
may cause transient transaminase 
elevations in mice, monkeys, and 
humans at therapeutic exposures 
(Burdick AD et al 2014, Hagedorn 
PH et al 2013, Hildebrandt Eriksen 
ES et al 2012). AZD8233 is a 
GalNAc conjugated 
oligonucleotide, utilizing the 
ASGP-R to enhance the uptake by 
hepatocytes.  In the 6-month 
mouse chronic toxicology study, 
higher levels in liver enzymes 
(AST and ALT) in males and/or in 
females was observed and minimal 
to mild histopathological changes 
in few animals at high doses, 
however deemed not to be 
adverse. 
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Potential risk of clinical 
significance
Rationale for risk
Mitigation Strategy 
In ongoing clinical studies with 
AZD8233, transient increases in 
transaminases have been seen in 6 
participants (see Section 2.2 for 
details).
Antidrug 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 the PK profile. To 
date, no apparent association of 
ADA with loss of efficacy or 
safety findings has 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 are 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. 
There have been reports in some 
ASO programs of a few cases of 
severe ISRs with a high incidence 
of discomfort to the patient that 
have led to withdrawal from 
treatment.
In the ongoing clinical programme 
for AZD8233, mild ISRs have 
been observed in a few 
participants (see Section2.2for 
details).
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). 
In the 9-month monkey study, 
minimal to mild higher 
complement Bb was observed at ≥ 
6 mg/kg/occasion at the end of the 
Assessment of complement 
activation around Cmax (C3a [Part 
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Potential risk of clinical 
significance
Rationale for risk
Mitigation Strategy 
study and correlated 
microscopically with mononuclear 
cell (predominantly lymphocytic) 
infiltration/inflammation observed 
in multiple tissues, including the 
administration site.
Inhibition of Intrinsic Coagulation 
Pathway
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 
cascade and hence aPTT was 
prolonged. (Henry SP et al 2017, 
Sheehan JP, Lan HC 1998, 
Sheehan JP, Thao PM 2001). 
Changes in activity of the intrinsic 
clotting pathway reverse when 
ASOs are cleared from plasma. 
Transient prolongation of aPTT 
has been described in man and was 
observed to correlate in a linear 
manner with the Cmax at the end of 
infusion (Sewell KL et al 2002).
There were no treatment related 
changes in any coagulation 
parameters in the nonclinical 
toxicology studies
Assessment of aPTT and PT
Hypersensitivity and Anaphylactic 
Reaction
Similar to any foreign biological 
agent, administration of AZD8233 
may induce hypersensitivity 
reactions. These acute reactions 
are important because they may be 
severe but are considered rare.
Monitoring for immunogenicity 
effects (severe allergy and 
hypersensitivity reactions and 
ADA), see Appendix G
Flu-like Reactions
Flu-like symptoms (chills, 
myalgia, arthralgia, feeling hot, 
and body temperature increase) are 
rather common for some ASOs No 
indications of systemic 
inflammatory effects induced by 
Monitoring for any flu-like 
symptoms and assessment of hs-
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Potential risk of clinical 
significance
Rationale for risk
Mitigation Strategy 
AZD8233 have been seen in the 
toxicology studies.
Study procedures
Subcutaneous Injection 
Pain near the injection site (for 1 
or 2 days) is the most common 
complication of subcutaneous 
injections.
Slow injection of AZD8233 using 
gentle pressure (at least 5 seconds 
duration is recommended) and 
rotation of injection sites.
ADA = antidrug antibody; aPTT = activated partial thromboplastin time; ASGP-R = asialoglycoprotein 
receptor; ASO = antisense oligonucleotide; BUN = blood urea nitrogen; Cmax = maximum plasma concentration; 
eGFR = estimated glomerular filtration rate; hsCRP high sensitive C reactive protein; IB = Investigator’s 
Brochure; ISR = injection site reaction; PCSK9 = proprotein convertase subtilisin/kexin type-9; PT = 
prothrombin time; PD = pharmacodynamics; PK = pharmacokinetics; SC = subcutaneous
2.3.2 Benefit Assessment
In a previous single ascending dose study, SC administrations of up to 
 of 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).
Consequently, AZD8233 is expected to lower circulating PCSK9 in Study D7990C00006 in 
all participants (see Section 4.3). Pharmacologic inhibition of PCSK9 is known to increase 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 in this study, the 
potential risks identified in association with AZD8233 are justified by the anticipated benefits 
that may be afforded to participants with dyslipidemia.
3
OBJECTIVES AND ENDPOINTS
Table 5
Objectives and Endpoints
[Part A/Part C]
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Objectives
Estimands descriptions/Endpoints
Primary
To assess the safety and tolerability of AZD8233 
following SC administration of multiple doses.
Adverse events; vital signs, ECG, cardiac telemetry, 
injection site reaction examinations and clinical 
laboratory evaluations including platelet count
Secondary
To characterize the PK of AZD8233 following 
SC administration of multiple doses.
Plasma parameters (tlag, tmax, Cmax, AUC(0-last), AUC(0-24), 
AUC(0-48), AUC, AUCτ, Ctrough, CL/F, Vz/F, t1/2, MRT); 
urine parameters (Ae, Fe, CLR).
To assess the effect of AZD8233 on levels of 
PCSK9 following SC administration of multiple 
doses.
Absolute change from baseline in log-transformed 
PCSK9 in plasma
Percent change from baseline in PCSK9 in plasma
To assess the effect of AZD8233 on levels of 
LDL-C following SC administration of multiple 
doses.
Percent change in levels of LDL-C in serum
To assess the effects of AZD8233 on other lipid 
parameters following SC administration of 
multiple doses.
Levels of other lipid parameters, including:
•
TC
•
HDL-C
•
Non-HDL-C
•
VLDL-C
•
ApoA1
•
ApoB
•
Lp(a)
•
Triglycerides
Exploratory
To collect and store plasma and urine samples for 
potential future exploratory research aimed at 
exploring biomarkers involved in PK, PD, safety 
(including antiplatelet antibodies), and tolerability 
related to AZD8233 treatment or cardiometabolic 
diseases.
The biomarkers to be analyzed may include but not 
limited to Apo CIII (3), ANGPTL3, ANGPTL4, 
ANGPTL8, and ProC3.
The result will not form part of the CSR for this study.
To collect and analyse samples for exploration of 
antidrug immunogenicity
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Ae = amount excreted in urine; ANGPLT3 = angiopoietin-like protein 3; ANGPLT4 = angiopoietin-like protein 4; 
ANGPLT8 = angiopoietin-like protein 8; apoB = apolipoprotein B; apoCIII (3) = apolipoprotein CIII (3); AUC = area under 
the plasma concentration-time curve from time zero extrapolated to infinity; AUC(0-last) =  area under the plasma 
concentration-curve from time zero to time last value above the limit of quantification; AUC(0-48) =  area under the plasma 
concentration-time curve from time zero to 48 hours after dosing; AUCτ = area under the plasma concentration-time curve 
from time during the dosing interval; CLR = renal clearance; Cmax =  Observed maximum plasma concentration; CL/F = 
apparent total body clearance of drug from plasma after extravascular administration; CSR = clinical study report; Ctrough = 
observed trough plasma drug concentration; Fe = fraction excreted unchanged in urine; HDL-C = high-density lipoprotein 
cholesterol; LDL-C = low-density lipoprotein cholesterol; Lp(a) = lipoprotein (a); MRT = mean residence time of the 
unchanged drug in the systemic circulation; PCSK9 = proprotein convertase subtilisin/kexin type 9; PD = pharmacodynamics; 
PK = pharmacokinetics; ProC3 = propeptide of type III collagen; SC = subcutaneous; tmax = time to reach peak or maximum 
observed concentration or response following drug administration; tlag = time delay between drug administration and the first 
observed concentration in plasma; Vz/F = apparent volume of distribution during the terminal phase after extravascular 
administration 
[Part B]
Objectives
Estimands descriptions/Endpoints
Primary
To assess the effect of different doses of AZD8233 
on LDL-C versus placebo
Absolute change from baseline in log-transformed 
LDL-C in serum
Secondary
To assess the effect of different doses of AZD8233 
on PCSK9 versus placebo.
Absolute change from baseline in log-transformed 
PCSK9 in plasma
Percent change from baseline in PCSK9 in plasma
To assess the effect of different doses of AZD8233 
on LDL-C versus placebo.
Percent change in levels of LDL-C in serum
To assess the effect of AZD8233 on other lipid 
parameters versus placebo
Levels of other lipid parameters including:
•
TC
•
HDL-C
•
Non-HDL-C
•
VLDL-C
•
ApoA1
•
ApoB
•
Lp(a)
•
Triglycerides
•
Remnants cholesterol
To evaluate the pharmacokinetics (PK) of 
AZD8233.
Population PK parameters
To evaluate the immunogenicity of AZD8233.
Development of ADA and ADA titer (if subjects are 
ADA positive) during treatment and follow-up.
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Objectives
Estimands descriptions/Endpoints
To assess the safety and tolerability of AZD8233.
Safety and tolerability will be evaluated in terms of 
AEs, vital signs, ECG, injection site reactions, and 
clinical laboratory evaluations, including platelet count.
Exploratory
To collect and store blood (plasma) and urine 
samples for potential future exploratory research 
aimed at exploring biomarkers involved in PK, PD, 
safety (including antiplatelet antibodies) and 
tolerability related to AZD8233 treatment or 
cardiometabolic diseases.
Evaluation of changes in biomarkers.
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 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.
AE = adverse event; ApoA1=  Apolipoproteins A1; ApoB = apolipoprotein B; CSR = clinical study report;
ECG = electrocardiogram; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein 
cholesterol; Lp(a) = Lipoprotein(a); PK = pharmacokinetics; TC = Total cholesterol; VLDL-C = Very-low-
density lipoprotein cholesterol
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.
[Part A/Part C]
These are each randomized, single-blind, placebo-controlled, multiple dose Phase 1 study 
parts, including approximately 11 participants with dyslipidemia in each part. The primary 
objective of the study is to assess the safety and tolerability of AZD8233 following a multiple 
subcutaneous dose administration in Japanese patients with dyslipidemia. The study will be 
conducted at up to 2 sites in Japan.
The Screening Period starts within 28 days before the randomization visit and ends on 
Day −4. Eligible participants will make 8 visits during the treatment period, 1 telephone 
contact and 8 additional visits during the follow-up period. They are randomized across 2 
different treatment arms in an 8:3 ratio for a 58-day (up to Visit 9) treatment period. The 
planned treatment arms are AZD8233 
 (Part A) / AZD8233 
 (Part C)  and placebo. 
Participants will be dosed subcutaneously on Days 1, 8(Part A only), 29, and 57.
These studies are each single-blind with regards to treatment (AZD8233 or placebo). 
AZD8233 and placebo should be matched in appearance. Participants randomized to placebo 
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will receive the same volume of injection as that of AZD8233. 
After the treatment period, participants will continue in a follow-up period of 14 weeks (up to 
16 weeks after the last dose).
For detailed information, please refer to the Schedule of Activities (SoA) (Table 1:Part A, 
Table 3: Part C).
[Part B] 
This is a randomized, parallel, double-blind, placebo-controlled, dose-ranging phase 2 study in 
approximately 60 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 approximately 6 sites in Japan. 
Eligible participants will make 7 visits during the treatment period and 7 additional visits 
during the follow-up period. They are randomized across 3 different treatment arms in a 1:1:1 
ratio for a 12-week treatment period. The planned treatment arms are AZD8233 
 SC, 
AZD8233 
 SC, and placebo SC to be dosed on Days 1, 29, and 57.
This is a double-blind study with regards to treatment (AZD8233 or placebo) at each dose 
level. AZD8233 and placebo should be matched in appearance. Participants randomized to 
placebo will receive a volume of injection that does not differ visually from the active drug. 
After the treatment period, participants will continue in a follow-up period of 12 weeks (up to 
16 weeks after the last dose).
For detailed information, please refer to the SoA (Table 2).
4.2
Scientific Rationale for Study Design
AstraZeneca is developing AZD8233 for the treatment of dyslipidemia. This study consists of 
Part A, Part B and Part C. The objective of Part A is to investigate the safety and tolerability of 
AZD8233 following SC administration of multiple doses in a limited number of Japanese 
participants with dyslipidemia before progressing to Part B where a larger number of 
participants will be exposed. The study will also investigate the PK and the PD of AZD8233.   
Part B aims to evaluate the effect of different doses of AZD8233 on LDL-C at steady state to 
select a therapeutic dose for further clinical development. The objective of Part C is  to 
investigate the safety and tolerability of 
 AZD8233 following SC administration of 
multiple dose (QM dosing) in a limited number of Japanese participants with dyslipidemia 
before progressing to Ph3. The study will also investigate the PK and the PD of AZD8233.
The dosing schedule (dosing on Days 1, 8 [Part A only], 29, and 57) should be sufficient to 
closely reach steady state conditions in the tissues at the end of the dosing period (the 
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estimated terminal half-life of the full length ASO in plasma is 2 to 3 weeks). Based on these 
data and the expected time course for PCSK9 and LDL-C reduction, the dosing schedule 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.
The dosing and follow-up schedule are 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 humans. Monthly dosing is 
predicted to result in a low level of fluctuation of PCSK9 levels and tissue exposure during a 
dose interval.
4.3
Justification for Dose
[Part A]
In the Phase 1 SAD study (Study D7990C00001), which has been conducted in the US, single 
SC doses of AZD8233 up to 
 have been well tolerated in participants with elevated 
LDL-C.
The dose to be evaluated in Part A is 
.
This is the highest dose that has been evaluated in the MAD study (Study D7990C00002) 
conducted in the US, and is also the highest planned dose to be evaluated in Part B. A dose of 
 monthly is expected to result in close to the maximum achievable reduction in PCSK9 
and hence LDL-C levels over the dose interval with AZD8233.
One extra dose (loading dose) is planned to be administered one week after the first dose with 
the purpose to reach steady state conditions more quickly in trough concentrations (assumed 
to reflect tissue concentrations). As the loading dose is administered after the initial large 
decline in plasma concentrations of the first dose, the loading dose is predicted to result in 
minimally higher Cmax or AUC0-48 as compared to the first single dose. Thus, a total of 4 doses 
are planned to be administered to each subject, i.e., dosing on Days 1, 8, 29, and 57.
A dose of 
 monthly is expected to result in a mean Cmax and AUC0-48 at steady state at 
approximately half the exposure limits defined from the NOAEL dose in a 3-month toxicity 
study in cynomolgus monkeys. From a safety perspective, risks observed in other ASO 
development programs can be divided into acute and chronic risks. Acute risks, as those 
related to Cmax, including transient increase in activated partial thromboplastin time (aPTT), 
are expected to occur very soon after dosing. Chronic risks, like reduction of platelet count 
and development of ADAs have, if at all, most often appeared after more than 3 months of 
dosing.
Taken together, the benign safety profile observed for single doses of AZD8233 up to 
 
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support initiation of Part B after the SRC will review safety data up to 7 days after last dose 
administration in Part A. Data later than Day 64 (if available) may be reviewed by the SRC as 
needed. 
The SRC will review safety and tolerability data (AEs, vital signs [SBP], pulse rate and body 
temperature, cardiac telemetry, physical examination, laboratory assessments [hematology, 
clinical chemistry, coagulation, renal safety biomarkers, and dipstick urinalysis for 
hematuria]) collected up to 7 days after last dose. The SRC will also consider differences 
between Part A and Part B, including but not limited to dosing regimen, as well as available 
overall safety and PK/PD conclusions from other AZD8233 studies (including Study 
D7990C00002 and Study D7990C00003).
[Part B]
The doses of Part B are selected based on observed PCSK9 and LDL-C reduction in the SAD 
study (Study D7990C00001) and MAD study (Study D7990C00002). The original plan was to 
include three doses, mid and high doses planned to be 
 and 
 Both of these 
monthly doses were planned to achieve a PCSK9 reduction of around 90% during the dose 
interval and were selected to result in close to the maximum achievable effect in terms of 
LDL-C reduction, with the aim to show that an increase in the dose above the mid dose will 
not result in a clinically significant further reduction in LDL-C. The low dose, planned to be 
 was selected so as to reach a PCSK9 reduction of below 80% over the entire dose 
interval and was selected so as 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 is thus selected so as to be in the therapeutic dose range. However data 
from the ongoing MAD study have shown that dose vs PCSK9 reduction after repeated dosing 
is very predictable with a consistently high PCSK9 reduction observed in the patients that 
received the highest dose, 
 ie the same dose that is evaluated in Part A of this study, 
indicating no need to include 
 in part B. Thus, sufficient data on PCSK9 and LDL-C 
reduction have already been generated on the high dose 
 in the ongoing MAD study 
(with additional data to be collected in Part A of this study and the ongoing dose-range-finding 
study [Study D7990C00003]), and such data is expected to show that increasing the dose 
above the mid dose 
 will not result in a clinically significant further reduction in LDL-
C. The revised design of Part B will therefore instead include 2 active doses: the original mid 
dose (planned to 
) and low dose (planned to 
). Together with the data on the 
 
dose generated in Part A (with support of data from other studies, as relevant), data from the 
two active doses selected for Part B is expected to be sufficient for therapeutic dose selection.
In Part B of this study, a loading dose on Day 8 has been removed. A Kinetic-
Pharmacodynamic-model (Jacqmin et al 2007) was fitted to the observed PCSK9 data over 
time in the SAD and MAD studies. The model predicts a similar PCSK9-reduction at the end 
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of Week 12 with or without inclusion of the loading dose, ie for a once monthly dosing 
regimen. This is in line with preliminary estimates of the terminal half-life of AZD8233 full 
length ASOs in plasma (2-3 weeks) that indicate that close to pharmacokinetic steady state 
should have been reached 12 weeks after start of dosing. Thus the effect of a loading dose will 
be marginal, and therefore there will be no additional dose one week after the initial dose of 
AZD8233 in Part B.
The safety data and potentially the PCSK9 and LDL-C data after repeated (Days 1, 8, 29, and 
57) dosing of AZD8233 up to 
 from other AZD8233 studies (including the ongoing 
D7990C00002 and D7990C00003 studies) will have been evaluated before the doses of Part B 
will be finally selected. Based on such emerging data of AZD8233, the planned doses in Part 
B may be slightly adjusted if needed to achieve the intended PCSK9 and LDL-C reduction. 
However, the highest dose will not exceed 
 (Days 1, 29, and 57), which is lower than 
the highest dose in the ongoing MAD study and the dose in Part A.
[Part C]
AZD8233 
 will be assessed in Part C. The efficacy and safety of 
 and 
 were 
assessed in global phase 2 study (D7990C00003) with 3 months treatment and 
 is 
evaluated in an ongoing phase 2 study with 6 months treatment (D7990C00004). Based on the 
results from the global phase 2 study, the 
 dose resulted in a larger mean LDL-C 
reduction (-79% (95% CI; -83, -74)) than the 
 dose (-72% (95% CI; -78, -65) indicating 
that 
 dose is not fully on the plateau of the max achievable effect.  Therefore, if the 
 
 dose is confirmed as well tolerated and no significant safety concerns are raised, the 
 
is the dose planned to be selected for the phase 3 study program. The safety and tolerability of 
 is therefore planned to be assessed in Part C.
4.4
End of Study Definition
[Part A/Part B/Part C] 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.
Each participant should meet all of the inclusion criteria and none of the exclusion criteria for 
this study in order to be randomized to a study intervention. Participants who are enrolled but 
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subsequently found not to meet all the eligibility criteria must not be randomized or initiated 
on treatment and must be withdrawn from the study.
Where a participant does not meet all the eligibility criteria but is randomized in error, or 
incorrectly started on treatment, the Investigator should inform the AstraZeneca Physician 
immediately, and a discussion should occur between the AstraZeneca Physician and the 
Investigator regarding whether to continue or discontinue the participant from treatment, The 
AstraZeneca Physician must ensure all decisions are appropriately documented and that the 
potential benefit/risk profile remains positive for the participant.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
[Part A/Part C]
Age
1
Participants must be 20 to 60 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 but < 140 mg/dL at screening.
3
Participants who have fasting triglycerides < 400 mg/dL at screening.
4
Participants who should be receiving statin therapy.
5
LDL-lowering medications should be on stable dosing 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 therapies (and 
derivatives) are prohibited. Non-LDL-lowering medications should be on stable dosing 
for ≥ 3 months prior to screening with no planned medication or dose change during 
treatment period.
6
Participants who have suitable veins for cannulation or repeated venepuncture.
Weight
7
Body mass index (BMI) between 19 and 40 kg/m2.
Sex
8
Male or female
Reproduction
9
Females must not be pregnant and must have a negative pregnancy test at screening and 
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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:
(a)
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 follicle-stimulating hormone (FSH) levels in the postmenopausal 
range.
(b) 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. 
10 Males must be surgically sterile or using, in conjunction with their female partners, 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, intrauterine devices (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. 
Rationale for LDL-C upper limit:
Based on the reference value of LDL hypercholesterolemia, as proposed by the Japan 
Atherosclerosis Society (JAS) guidelines.
Informed consent
11 Capable of giving signed informed consent as described in Appendix A which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol.
12 Provision of signed and dated, written informed consent form prior to any mandatory 
study specific procedures, sampling, and analyses.
[Part B]
Age
1
Participants must be 20 to 75 years of age inclusive, at the time of signing the informed 
consent.
Type of Participant and Disease Characteristics
2
Have a fasting LDL-C ≥ 70 mg/dL but < 190 mg/dL at screening (Visit 2).
3
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4
Should be receiving statin therapy as defined in Appendix H, in accordance with the 
Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic 
cardiovascular diseases.
5
LDL-lowering medications should be on stable dosing 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 therapies (and 
derivatives) are prohibited. Non-LDL-lowering medications should be on stable dosing 
for ≥ 3 months prior to screening with no planned medication or dose change during 
treatment period.
6
Have suitable veins for cannulation or repeated venepuncture.
Weight
7
BMI between 19 and 40 kg/m2
Sex
8
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.
9
Female participants
Female participants must not be pregnant and must have a negative pregnancy
test at screening and randomisation, 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:
(a) 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.
(b) 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.
10 Males participants
Males must be surgically sterile or using, in conjunction with their female partners, 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 their 
partners. Acceptable methods of contraception include birth control pills, injections, 
implants, or patches, IUDs, tubal ligation/occlusion, and vasectomy. A barrier method is 


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not necessary if the female partner is sterilized. Male study participants must not donate 
or bank sperm during this same time period.
Informed consent
11 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.
12 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 subject must sign and date both the consent forms for the main study and 
optional component of the study. If a participant declines to participate in the optional 
component of the study, there will be no penalty or loss of benefit to the subject. 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:
[Part A/Part C]
Medical Conditions
1
Estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2 using the Japanese 
equation. (eGFR = 194 × sCr (mg/dL) − 1.094 × Age − 0.287 × α, where α is 1 for males and 
0.739 for females)
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 (e.g., 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
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). Or participants receiving anti-
coagulation therapy.
5
History of major bleed or high-risk of bleeding diathesis.
6
Subjects with a high 10-year risk of coronary heart disease as calculated using the Suita 
score  (Participants classified in high risk class).
7
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.
8
Recipient of any major organ transplant, e.g., lung, liver, heart, bone marrow, kidney.


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9
LDL or plasma apheresis within 12 months prior to randomization.
10 Heart rate after 10 minutes of sitting rest < 50 or > 100 beats per minute (bpm).
11 Uncontrolled hypertension defined as sitting SBP > 140 mmHg or DBP > 90 mmHg.
12 Any laboratory values with the following deviations at the Screening Visit; test may be 
repeated at the discretion of the Investigator if abnormal: 

Any positive result on screening for hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV).

Alanine aminotransferase/transaminase (ALT) > 1.5 × upper limit of normal (ULN).

Aspartate aminotransferase/transaminase (AST) > 1.5 × ULN.

Creatinine > 1.5 mg/dL.

White blood cell (WBC) < lower limit of normal (LLN).

Hemoglobin < 12 g/dL in men or < 11 g/dL in women

Platelet count ≤LLN.

Activated partial thromboplastin time (aPTT) > ULN and PT > ULN.

Urinary albumin creatinine ratio (UACR) > 11 mg/mmol (100 mg/g).
13 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 that may interfere with the interpretation of QTc interval (Corrected QT 
Interval by Fridericia [QTcF] > 450 ms) changes, including abnormal ST-T-wave 
morphology, left ventricular hypertrophy, test may be repeated at the discretion of the 
Investigator if abnormal. 
14 Known or suspected history of drug abuse as judged by the Investigator.
15 Smokers with > 10 cigarettes/day and unable to comply with the nicotine restriction 
during the study.
16 History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.
17 Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate,) as 
judged by the Investigator.
18 Use of drugs with cytochrome P450 enzyme inducing properties such as St John's Wort 
within 3 weeks before the first administration of IMP.
19 Antiplatelet therapy, other than low-dose aspirin ≤100 mg/day, within 1 month prior to 
randomization.
20 Mipomersen (not approved in Japan), or lomitapide within 12 months prior to 
randomization.
21
Previous administration of AZD8233 or other PCSK9 inhibition treatment (approved or 
IMP).


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22 Use of any herbal remedies, megadose vitamins (intake of 20 to 600 times the 
recommended daily dose) and minerals during the 2 weeks prior to the first administration 
of IMP or 5 half-lives, whichever is longer.
23 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 antisense 
oligonucleotides.
24
Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of 
the first administration of IMP. History or evidence of any other clinically significant 
disorder (e.g., 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 subject to give written informed consent, would pose a risk 
to subject safety, or interfere with the study evaluation, procedures, or completion.
Prior/concurrent clinical study experience
25 Participation in another clinical study with an investigational product administered in the 
last 3 months prior to randomisation or 5 half-lives from last dose to first administration 
of study intervention, whichever is the longest.
26 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 
IMP of this study or 5 half-lives from last dose to first administration of IMP, whichever 
is the longest.
27 Use of other IMP or devices during the course of the study.
Other exclusions
28 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).
29 Judgment by the Investigator that the patient should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions and requirements.
30 Previous enrolment or randomisation into the present study.
31 Participants who cannot communicate reliably with the Investigator.
32 Vulnerable participants, e.g., kept in detention, protected adults under guardianship, 
trusteeship, or committed to an institution by governmental or juridical order.
33 Plasma donation within 1 month of the Screening Visit. For male participants, donation of 
whole blood or significant blood loss in excess of 400 mL within 3 months prior to 
screening visit and for female participants, donation of whole blood or significant blood 
loss in excess 400 mL within 4 months prior to screening visit.
References for eGFR and SBP threshold, and The Suita score (J Atheroscler Thromb, 2018): 


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
eGFR - based on the mildly-decreased levels proposed by the Japanese Society of 
Nephrology. 

SBP - based on the hypertension criterion proposed by the Japanese Society of 
Hypertension.
[Part B]
Medical conditions
1
eGFR < 40 mL/min/1.73m2 using the Japanese equation at Visit 1. (eGFR = 194 × sCr 
(mg/dL) − 1.094 × Age − 0.287 × α, where α is 1 for males and 0.739 for females)
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 (e.g., 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 (T2DM), defined as Haemoglobin A1c
(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). Or participants receiving anti-
coagulation therapy.
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, e.g., 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 the Screening Visit; test may be 
repeated at the discretion of the Investigator if abnormal:

Any positive result on screening for hepatitis B, hepatitis C, or HIV

ALT > 1.5 ×ULN

AST > 1.5 × ULN


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
Total bilirubin (TBL) > ULN

Alkaline phosphatase (ALP) > 1.5 × ULN

WBC < LLN

Hemoglobin < 12 g/dL in men or < 11 g/dL in women

Platelet count ≤LLN

aPTT > ULN and PT > ULN

UACR > 11.3 mg/mmol (100 mg/g)

Urine protein/creatinine (UPCR) > 300 mg/g
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 (AV)-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 (not approved in Japan), or lomitapide within 12 months prior to 
randomization.
20 Previous administration of AZD8233 or other PCSK9 inhibition treatment (approved or 
IMP).
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 antisense 
oligonucleotides.
22 Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of 
the first administration of IP. History or evidence of any other clinically significant 
disorder (e.g., 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 subject to give written informed consent, would pose a risk 
to subject safety, or interfere with the study evaluation, procedures, or completion.
Prior/Concurrent Clinical Study Experience
23 Participation in another clinical study with an investigational product administered in the 
last 3 months prior to randomisation 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 


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IMP of this study or 5 half-lives from last dose to first administration of IMP, whichever 
is the longest.
25 Use of other IMP or 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 Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions and requirements.
28 As judged by the Investigator, any evidence of disease conditions that, in the 
Investigator's opinion, make it undesirable for the participant to participate in the trial.
29 Previous enrolment or randomisation in the present study.
30 Participants who cannot communicate reliably with the Investigator.
31 Vulnerable participants, e.g., 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 screening visit. For male participants, donation of 
whole blood or significant blood loss in excess of 400 mL within 3 months prior to 
screening visit. For female participants, donation of whole blood or significant blood loss 
in excess of 400 mL within 4 months prior to screening visit.
Optional Genetic Sampling
[Part A/Part C] 
Not applicable
[Part B] 
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.


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5.3.1
Meals and Dietary Restrictions
[Part A/Part B/Part C]
Participants must be fasted for 10 hours prior to blood sampling for LDL-C, PCSK9, and other 
lipid parameters. No fluids will be allowed apart from water, which can be given until 1 hour 
before blood sampling for LDL-C, PCSK9, and other lipid parameters.
5.3.2
Caffeine, Alcohol, and Tobacco
[Part A/Part C]
Smokers with >10 cigarettes/day (or using any other nicotine products) who are unable to 
comply with the nicotine restriction during the study are not allowed to participate in the 
study.
Participants with known or suspected history of alcohol abuse, as judged by the Investigator, 
are not allowed to participate in the study.
[Part B]
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-childbearing potential are defined as female participants who are permanently 
surgically sterilized or postmenopausal.
Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral 
salpingectomy, but excludes bilateral tubal ligation.
Females are considered postmenopausal if they have had amenorrhea for at least 12 months or 
more, following cessation of all exogenous hormonal treatments, and FSH levels are in the 
postmenopausal range.
Restriction for Male Participants
There is no information about effects that AZD8233 could have on the development of the 


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fetus in humans. Therefore, it is important that women of childbearing potential who are the 
partners of male subjects do not become pregnant during the study and for a total period of 3 
months after the male participants have attended the final follow-up visit.
As a precaution, all male participants should avoid fathering a child by either true abstinence
or use (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 IMP 
administration until 3 months after the final follow-up visit. Approved/Certified measurements 
in Japan are combined pill, vasectomy, tubal occlusion, intrauterine device (provided coils are 
copper banded),and levonorgestrel intrauterine system (eg, Mirena®). Not Approved/Certified 
measurements in Japan are Cerazette® (desogestrel) pills , Medroxyprogesterone injections 
(eg, Depo-Provera®), etonogestrel implants (eg, Implanon®, Norplan®), normal and low dose 
combined oral pills, norelgestromin / ethinylestradiol transdermal system (eg Evra® Patch), 
Intravaginal device (eg, NuvaRing®)
Male participants who have been sterilized are required to use 1 barrier method of 
contraception (condom) from the time of IMP 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 or for at least 3 
months after the study follow-up visit.
Pregnancy
Participants will be instructed that if they or their partners become pregnant during the study 
this should be reported to the Principal investigator (PI). The PI 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 volunteer is included 
in the study, then consent will be sought from the partner (via the subject’s request that his 
partner contacts 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.
A pregnancy notification form and follow-up will be completed.
Blood Donation
Subject 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 


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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, 
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) or 
placebo intended to be administered to or medical device(s) utilised by 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 6 and in IMP 
instructions (D7990C00006) on AZD8233 solution for injection.
For Part B, an unblinded pharmacist will be assigned in case of a change of the planned doses 
(as described in Section 4.3).The strength of 
/mL will be applied when a mid dose is 
adjusted above 
 ( not exceeding 
 ).
CCI
CCI
CCI


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Table 6
Investigational Products
[Part A]
Arm Name
MAD Cohort 1
MAD Cohort 2
Intervention Name
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
Treatment Administration 
Guidelines
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 electronic Case 
Report Form (eCRF).
Specific device for drug 
administration
Syringes for injection to be provided by study site
IMP and NIMP
IMP
Sourcing
Provided by the Sponsor
Packaging and Labeling
Study intervention will be provided in vials. Each vial will be labeled 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
eCRF = electric case report form
[Part B]
ARM Name
Cohort 1
Cohort 2
Cohort 3
Intervention Name
AZD8233
AZD8233
Placebo to match 
AZD8233
Dose Formulation
AZD8233 solution for injection
Matching placebo 
solution for injection
Strength/Concentration
s
 *
Matching placebo 
solution for injection
Dose
Matching placebo 
solution for injection
Regimen
AZD8233/placebo Days 1, 29, and 57 
CCI
CCI
CCI
CCI
CCI
CCI


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ARM Name
Cohort 1
Cohort 2
Cohort 3
Route of 
Administration
Subcutaneous injection 
Treatment 
Administration 
Guidelines
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 study site
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 labeled 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
eCRF = electric case report form
* The strength of 
 will be applied when a mid dose is adjusted above 
 (not exceeding 
 )
[Part C]
Arm Name
MAD Cohort 1
MAD Cohort 2
Intervention Name
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, 29 and 57
Route of Administration
Subcutaneous injection
Treatment Administration 
Guidelines
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 electronic Case 
Report Form (eCRF).
Specific device for drug 
administration
Syringes for injection to be provided by study site
IMP and NIMP
IMP
Sourcing
Provided by the Sponsor
Packaging and Labeling
Study intervention will be provided in vials. Each vial will be labeled as 
required per country requirement
CCI
CCI
CCI
CCI
CCI


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Arm Name
MAD Cohort 1
MAD Cohort 2
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
1
The head of the medical institution can delegate the control of and accountability for the 
study drug to an investigational product storage manager. The head of the medical 
institution or the investigational product storage manager 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 head of the 
medical institution and authorised site staff.
3
The head of the medical institution 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 Pharmacy manual or specified handling instructions.
6.3
Measures to Minimise Bias: Randomization and Blinding
[Part A/Part C]
This study is single-blind with regards to treatment (AZD8233 or placebo), and blinded to 
participants, site investigators, and site staff. The Sponsor will be unblinded to treatment 
allocation. Detailed blinding procedure of the SRC (Part A only) is described in Appendix 
A 5.
The following personnel may have access to the study randomization list or may be unblinded 
to treatment assignment in another way:

AstraZeneca personnel carrying out labeling and packaging of subject-specific treatments

AstraZeneca personnel involved in analyses and preparation of outputs for the SRC(Part 
A Only) and project decisions
The Investigator will ensure that all eligible subjects in accordance with the inclusion and 
exclusion criteria have signed the ICF. Participants who have signed the ICF will undergo 


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randomization to receive AZD8233 or placebo in a ratio of 8:3. All participants will be 
assigned to randomized study treatment using an Interactive Voice/Web Response System 
(IXRS). A randomization number will be provided to the randomized participants. Before the 
study is initiated, the log-in information and directions for the IXRS will be provided to each 
site.
A participant who fails to meet the inclusion criteria and meets any exclusion criterion should 
not, under any circumstances, be randomized into the study. There can be no exceptions to this 
rule.
Where a participant, who does not meet the selection criteria, is randomized in error and this 
is identified before dosing, he/she should be withdrawn from the study. 
If a participant who does not meet the selection criteria has been dosed before the error is 
identified, he/she should be advised to continue safety assessments to ensure his/her safety. 
The PI will inform the AZ Lead Physician of the error and a joint decision will be made as to 
whether the participant may continue to be dosed.
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. This single blinded study is blinded to the participants and investigative site 
personnel until all dosing, follow-up, and SRC review for all cohorts have been completed. 
AstraZeneca and personnel involved in PD and PK evaluation of data (to be reviewed only at 
select SRC meetings) may be unblinded to the evaluation of these data. Alternatively, PK and 
PD data will be provided in a blinded manner for the SRC review.
AstraZeneca retains the right to break the code for SAEs that are unexpected and are 
suspected to be causally related to the investigational product and that potentially require 
expedited reporting to regulatory authorities.
The IXRS will be programmed with blind-breaking instructions. The blind may be broken if, 
in the opinion of the Investigator, it is in the participant’s best interest for the Investigator to 
know the study treatment assignment. The sponsor must be notified before the blind is broken 
unless identification of the study treatment is required for a medical emergency in which the 
knowledge of the specific blinded study treatment will affect the immediate management of 
the participant’s condition (e.g., antidote available). In this case, the Sponsor must be notified 
within 24 hours after breaking the blinding. The date when and reasons why the blinding was 
broken must be recorded in the site source documents and electronic Case Report Form
(eCRF).
The laboratory vendor personnel performing the bioanalyses of the plasma/urine samples will 
have access to the randomization list.


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[Part B]
All participants will be centrally assigned to randomized study intervention using an IXRS 
system. Before the study is initiated, the telephone number and call-in directions and/or the 
log in information & directions for the IXRS will be provided to each site. Study intervention 
will be dispensed at the study visits summarised in the SoA.
The IXRS 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 
IXRS 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 IXRS 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 a participant’s condition (e.g., antidote available), the Investigator has the sole 
responsibility for determining if unblinding of the participant's intervention assignment is 
warranted. Participant safety must always be the first consideration in making such a 
determination. If the participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blinding. The Investigator documents and report 
the action to AstraZeneca, without revealing the treatment given to the 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 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 study site 
staff other than the person administering the study intervention.


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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
The Study Physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
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:
[Part A/Part C]

Participants should be receiving statin therapy.
[Part B]

Participants should be receiving statin therapy as defined in Appendix H in accordance 
with the JAS guidelines for prevention of atherosclerotic cardiovascular diseases.

Participants must abstain from taking prescription or non-prescription drugs without 
consultation with 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 until completion of the follow-
up visit.
[Part A/Part B/Part C]

Medications/therapies specified in the exclusion criteria are prohibited from use for the 
duration of the subject's involvement in the study.

Participants who are receiving LDL-lowering medications should be on stable dosing 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 


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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  
who are receiving non-LDL-lowering medications should be on stable dosing for ≥ 3 
months prior to screening with no planned medication or dose change during treatment 
period.

Participants should not be on any antiplatelet therapy other than low-dose aspirin 
(≤100 mg/day).

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 study physician if required.

COVID-19 vaccines are allowed to be administered as a concomitant medication during 
study participation. The Sponsor has no data on the co-administration of AZD8233 and 
respective COVID-19 vaccines. The participants should be encouraged to inform the 
investigator whether COVID-19 vaccination is planned and study participants become 
eligible for COVID-19 vaccination.

COVID-19 vaccination (all doses) prior to the first dose may be advisable. If 
possible, the first dose of AZD8233 should be given at least 14 days after the last 
dose of vaccine.

Patients should not receive COVID-19 vaccines on dosing days (+/- 7 days).

Ultimately, the decision to vaccinate will be based on the judgement of the treating 
physician taking into account the participants best interest. Any deviation from the 
recommendation above should be agreed with the Study Physician.
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.
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 IMP if any of the following occurs in the 


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participant in question:
[Part A/Part C]
Dosing for any individual participant will be stopped if he/she experiences a possible drug 
related SAE or a possibly drug-related significant non-serious AE, which in the opinion of the 
PI warrants discontinuation of the participant from the active protocol for his or her well-
being. Dosing of the individual participants will also be stopped if any significant change in 
safety parameters as listed in stopping rules is met. The decision to hold or discontinue study 
treatment may be also based on lesser changes in these parameters observed in isolation or in 
association with other safety-related abnormalities. Sponsor must be informed immediately if 
dosing for individual participants is stopped or put on hold.
Stopping Rules 
Stopping rules are applicable for the following situations if there are any safety concerns 
found in terms of general, cardiovascular, and laboratory criteria:

Part A:SRC may decide not to proceed with the Part B

Part B: iSMC may recommend not to proceed with the Part C
The following are the detailed criteria:
General Criteria
The study will be put on temporary hold (Part A: defined as cessation of Part B initiation) 
pending further safety data analysis if any of the following criteria occurs in participants 
receiving AZD8233:

At least one SAE considered at least possibly related to the IMP administration.

At least one severe non-serious AEs considered as, at least, possibly related to the IMP 
administration) in ≥ 2 participants, independent of within or not within the same System 
Organ Class (SOC).
The SRC will carefully review the totality of data, taking into account moderate non SAEs at 
least possibly related to the IMP administration in unblinded fashion and their relations to PD 
effects (if available), the number of participants in whom they occur, concurrency of more 
than one within the same participant, and potential safety signals identified for other IMPs in 
the same class (mechanistic and/or chemical). The SRC will also consider differences between 
Part A and Part B, including but not limited to dosing regimen, as well as available overall 
safety and PK/PD conclusions from other AZD8233 studies (including Study D7990C00002 
and Study D7990C00003).


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Cardiovascular Criteria

Two or more participants who receive AZD8233, have QT (ECG interval measured from 
the onset of the QRS complex to the end of the T wave) interval corrected (QTc) 
prolongation, defined as the QT interval corrected for heart rate using Fridericia's formula 
(QTcF) > 500 ms, or a prolongation from baseline of > 60 ms, confirmed (persistent for at 
least 5 min) and determined post-dose either during continuous 12-lead ECG monitoring 
or on a repeat 12-lead ECG.

Two or more participants who receive AZD8233, have tachycardia defined as resting 
supine heart rate > 125 bpm persisting for at least 10 minutes.

Two or more participants who receive AZD8233, have symptomatic bradycardia defined 
as resting supine heart rate < 45 bpm or asymptomatic bradycardia defined as resting 
supine heart rate < 30 bpm while awake persisting for at least 10 minutes.

Two or more participants who receive AZD8233, develop hypertension, defined as an 
increase by > 40 mmHg from baseline or in resting supine SBP above 180 mmHg and 
persisting for at least 10 minutes.

Two or more participants who receive AZD8233 develop hypotension, defined as an 
asymptomatic decrease of > 20 mmHg for SBP to below 70 mmHg persisting at least 10 
minutes, or a symptomatic SBP decrease of > 20 mmHg (excluding vasovagal reaction).
Laboratory Findings

One or more participants who receive AZD8233 fulfill Hy’s Law (HL) defined as an 
increase in AST or ALT ≥ 3 ×ULN and TBL ≥ 2 × ULN, where no other reason can be 
found to explain the combination of increases, e.g., elevated serum ALP indicating 
cholestasis, viral hepatitis, or another drug. The elevations do not have to be at the same 
time or within a specified time frame (see Appendix E for follow-up procedures).

Two or more participants who receive AZD8233 have confirmed > 3 × ULN of either 
ALT or AST or > 2 × ULN for TBL or ALP.

Two or more participants who receive AZD8233 have confirmed leukocyte count < 2.0 × 
109/L.

Two or more participants who receive AZD8233 have confirmed neutrophil count < 1.0 × 
109/L.

Two or more participants who receive AZD8233 have confirmed platelet count < 75 × 
109/L. 

Two or more participants who receive AZD8233 have a platelet count reduction of 50% 
or more from baseline.

Two or more participants treated with AZD8233 have confirmed increase in serum 
creatinine (SCr) > 0.3 mg/dL (26.5 μmol/L) from baseline.


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
Two or more participants who receive AZD8233 have confirmed SCr > 2 × baseline, 
when there is no other reason to explain the increase.
[Part B]

Confirmed platelet count < 75 × 109/L

HL, defined as an increase in AST or ALT ≥3 × ULN and TBL ≥2 × ULN, where no 
other reason, other than the IMP, can be found to explain the combination of increases

Confirmed > 3 × ULN of either ALT or AST or > 2 × ULN for TBLor ALP

Confirmed increase in serum creatinine of 0.3 mg/dL from baseline

Confirmed 25% decline in eGFR from baseline

Confirmed new-onset hematuria, albuminuria (UACR ≥300 mg/g), or proteinuria 
(UPCR ≥500 mg/g)

Hypersensitivity reaction CTCAE grade 3 or higher
If a participant discontinues study treatment, he or she will be encouraged to return to the 
study site for the Early Discontinuation Visit (EDV) (see the SoA). 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 Early Study Intervention 
Discontinuation visit 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 
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
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.

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 out 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 Study Team.
7.3
Lost to Follow up
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
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.
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.


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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 DBP), pulse rate, and temperature, if appropriate
3
Blood sampling
4
Dose administration
Pre-dose assessments may be performed within 30 minutes prior to dosing for Part A 
and Part C, and 60 minutes prior to dosing for Part B.

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.
[Part A]
The study is divided into a treatment period and a follow-up period. The treatment period 
starts after the screening visits (Visit 1: Day −28 to Day −4; Visit 2: Day −1 to Day 3). During 
Visit 1, the participants will be checked for eligibility and enrolled in the study. Additional 
samples will be collected at Visit 2. Approximately 11 participants will be randomized at 
Visit 2 (Day 1) in an 8:3 ratio to SC injections of AZD8233 (planned doses of 
) or 
matching placebo. AZD8233 or placebo will be administered subcutaneously on Days 1, 8, 29, 
and 57. The treatment phase will be 58 days (8 weeks) with AZD8233 or placebo. Thereafter, 
the participants will continue in a follow-up period for 14 weeks; the final follow-up visit will 
be performed on Week 24 (16 weeks after the last dose of AZD8233 or placebo).
[Part B]
The study is divided into a treatment period and a follow-up period. The treatment period 
starts after the screening visits (Visit 1: Day −28 to Day −10; Visit 2: Day −7 to Day −4). 
During Visit 1, the participants will be checked for eligibility and enrolled to the study. 
Additional samples will be collected at Visit 2. Approximately 60 participants will be 
randomized at Visit 3 (Day 1) in a 1:1:1 ratio to SC injections of AZD8233 (planned doses of 
CCI


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, and 
) or matching placebo. AZD8233 or placebo will be administered 
subcutaneously on Visits 3, 6, and 8. The treatment phase will be 84 days (12 weeks). 
Thereafter, the participants will continue in a follow-up period for 12 weeks; the final follow-
up visit will be performed on Week 24 (up to 16 weeks after the last dose of AZD8233 or 
placebo).
[Part C]
The study is divided into a treatment period and a follow-up period. The treatment period 
starts after the screening visits (Visit 1: Day −28 to Day −4; Visit 2: Day −1 to Day 3). During 
Visit 1, the participants will be checked for eligibility and enrolled in the study. Additional 
samples will be collected at Visit 2. Approximately 11 participants will be randomized at Visit 
2 (Day 1) in an 8:3 ratio to SC injections of AZD8233 (planned doses of 
) or matching 
placebo. AZD8233 or placebo will be administered subcutaneously on Days 1, 29, and 57. 
The treatment phase will be 58 days (8 weeks) with AZD8233 or placebo. Thereafter, the 
participants will continue in a follow-up period for 14 weeks; the final follow-up visit will be 
performed on Week 24 (16 weeks after the last dose of AZD8233 or placebo).
General description of visits:
[Part A/Part C] 
Visit 1 (enrollment): At Visit 1 (Day −28 to Day −4), participants will be asked to sign the 
informed consent. The participants’ demographics and medical history, including smoking and 
alcohol consumption history, will be recorded in an 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. 
Visit 2 (randomization): Visit 2 (Day −1 to Day 3) should be performed within 28 days of 
Visit 1. Participants should be admitted on Day −1 and will be discharged after the results 
from the 48 hours post-dose assessments have been reviewed by the Principal Investigator.
Blood sampling for LDL-C, PCSK9 and other lipid parameters should be taken in the morning 
after a 10 hour fasting. No fluids will be allowed apart from water, which can be given until 1 
hour before blood sampling for LDL-C, PCSK9, and other lipid parameters. 
On Day −1, eligibility criteria must be verified by checking screening labs and 
inclusion/exclusion criteria. An abbreviated physical examination must be performed. Blood 
and urine samples will be obtained prior to administration of study intervention in fasted state. 
Vital signs and BMI will be checked. Cardiac telemetry should be performed for at least 4 
hours.
On Day 1, he/she will be randomized in IXRS, and the study intervention will be administered 
CCI
CCI
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as an SC injection.
An abbreviated physical examination must be performed. Blood and urine samples will be 
obtained prior to administration of study intervention in fasted state. An ADA sample will be 
obtained pre-dose. Vital signs, ECG, and cardiac telemetry will be performed.
On Day 3, the participant will be discharged after the results from the 48 hours post-dose 
assessments have been reviewed by the Principal Investigator.
Visits 3 and 6 (Part A:treatment visit): Visit 3 (Day 8) and Visit 6 (Day 29 ± 1 day) are 
planned as clinical visits. At Visit 3 and Visit 6, the study intervention will be administered as 
an SC injection. Blood sampling for LDL-C, PCSK9, and other lipid parameters should be 
taken in the morning after a 10-hour fast. No fluids will be allowed apart from water, which 
can be given until 1 hour before blood sampling for LDL-C, PCSK9, and other lipid 
parameters. Blood and urine sampling must be performed prior to administration of study 
intervention. PK
sampling must be done pre-dose. An abbreviated physical examination, 
ECG, and vital signs examination must be performed prior to administration of study 
intervention. At Visit 6, the ADA sampling must be done pre-dose.
Visits 3 (Part C:non-treatment visit): Visit 3 (Day 8) is planned as clinical visits. Blood 
sampling for LDL-C, PCSK9, and other lipid parameters should be taken in the morning after 
a 10-hour fast. No fluids will be allowed apart from water, which can be given until 1 hour 
before blood sampling for LDL-C, PCSK9, and other lipid parameters. Blood and urine 
sampling must be performed. PK sampling must be done. An abbreviated physical 
examination, ECG, and vital signs examination must be performed. 
Visits 6 (Part C:treatment visit): Visit 6 (Day 29 ± 1 day) is planned as clinical visits. At 
Visit 6, the study intervention will be administered as an SC injection. Blood sampling for 
LDL-C, PCSK9, and other lipid parameters should be taken in the morning after a 10-hour 
fast. No fluids will be allowed apart from water, which can be given until 1 hour before blood 
sampling for LDL-C, PCSK9, and other lipid parameters. Blood and urine sampling must be 
performed prior to administration of study intervention. PK sampling must be done pre-dose. 
An abbreviated physical examination, ECG, and vital signs examination must be performed 
prior to administration of study intervention. The ADA sampling must be done pre-dose.
Visits 4, 5, 7, and 8 (non-treatment visit): Visit 4 (Day 15 ± 1 day), Visit 5 (Day 22 ± 1 day), 
Visit 7 (Day 36 ± 1 day), and Visit 8 (Day 44 ± 1 day) are planned as clinical visits. At Visit 5 
and Visit 8, blood sampling for platelet count must be done. Blood sampling for LDL-C, 
PCSK9, and other lipid parameters should be taken in the morning after a 10-hour fast. No 
fluids will be allowed apart from water, which can be given until 1 hour before blood 
sampling for LDL-C, PCSK9 and other lipid parameters. PK sampling must be done.


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Visit 9 (treatment visit): Visit 9 (Days 56-59; ± 1 day) is planned for hospitalization. 
Participants should be admitted on Day 56 and will be discharged after the results from the 
48 h post-dose assessments have been reviewed by the Principal Investigator.
On Day 56, blood sampling for platelet count must be done. 
On Day 57, the study intervention will be administered as an SC injection. Weight will be 
checked. ADA, blood, and urine sampling must be performed prior to administration of study 
intervention. Blood sampling for LDL-C, PCSK9, and other lipid parameters should be taken 
in the morning after a 10-hour fasting. No fluids will be allowed apart from water, which can 
be given until 1 hour before blood sampling for LDL-C, PCSK9, and other lipid parameters. 
Vital signs, ECG, and cardiac telemetry to be performed. An abbreviated physical examination 
must be performed 24 hours post-dose. PK sampling must be done.
Follow-up contact (Part A: Day 64 + 2 days): One telephone contact from a participant’s 
site (or an investigator) to assess AEs.
Follow-up visits (Visits 10-16): At all follow-up visits, ECG and an abbreviated physical 
examination are required, and vital signs, blood, and urine samples are to be checked.
An ADA sampling is to be performed at Visit 10 (Week 2 after last dose; ± 2 days). At all 
follow-up visit PK sampling is to be performed.
Early Discontinuation Visit: The EDV may take place any time during the study, in case a 
participant discontinues study treatment prior to Visit 9 (where last dose of study treatment is 
administered). The same assessments as done during the final follow-up visit will be 
performed. See Section 7.1.
Final follow-up visit (Visit 17): The final follow-up visit will be performed in Week 16 after 
last dose (± 2 days). PK and ADA sampling is to be performed. A complete physical 
examination must be performed on the visit, and body weight, BMI, vital signs, body 
temperature, and ECG are to be checked. Blood and urine sampling is to be obtained.
The maximum blood volume to be drawn from each participant will not exceed 800 mL over 
the duration of the study period. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.
[Part B] 
Visit 1 (enrollment) and Visit 2: At Visit 1 (Day −28 to Day −10), participants will be asked 
to sign the informed consent and optional informed consent for future genetic research 
sample. Participant demographics and medical history, including smoking and alcohol 
consumption history, will be recorded in the eCRF. A complete physical examination must be 


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performed. Vital signs, height, weight, BMI, and ECG must be checked, as well as blood and 
urine sample collection. Visit 2 (Day −7 to Day −4) will include an additional blood sample 
collection for LDL-C, PCSK9, and triglycerides. 
Visit 3 (randomization): Visit 3 (Day 1) should be performed within 28 days of Visit 1. 
Participants are required to fast for at least 10 hours overnight prior to the visit; participants 
are permitted to drink water during this period of fasting until 1 hour before blood sampling. 
At Visit 3, the eligibility criteria must be verified by checking screening labs and 
inclusion/exclusion criteria. A complete physical examination must be performed. Blood and 
urine samples are to be obtained prior to administration of study intervention in fasted state. 
An ADA sample will be obtained pre-dose. Vital signs and ECG are to be checked. If the 
participant fulfills all inclusion criteria and none of the exclusion criteria, he/she will be 
randomized in IXRS, and the study intervention will be administered as an SC injection. 
Treatment visits (Visits 4- 9): Visit 4 (Day 8 ± 1 day), Visit 5 (Day 22 ± 2 days), Visit 6 
(Day 29 ± 2 days), Visit 7 (Day 43 ± 2 days), Visit 8 (Day 57 ± 2 days) and Visit 9 (Day 71 ± 
2 days) are planned as clinical visits. At Visits 6 and 8, the study intervention will be 
administered as an SC injection. Participants are required to fast for at least 10 hours prior to 
Visits 4, 6, and 8. They 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, 7, 8, and 9. At Visits 4, 6, 
and 8, PK and ADA sampling must be done pre-dose when the study intervention will be 
administered. An abbreviated physical examination is required at the visits. Vital signs and 
blood and urine samples are to be taken at the visits. ECG must be performed at Visits 4, 6 and 
8.
Follow-up visits (Visits 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 follow-up visits, an abbreviated physical examination is required, and vital signs, blood, 
and urine samples are to be checked. PK and ADA sampling is to be performed at Visit 10, 
Visit 12 (Day 113 ± 2 days), and Visit 14 (Day 141 ± 2 days). 
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 the 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 is to be performed. A complete physical examination must be performed at 
the visit, and body weight, BMI, vital signs, and ECG are to be checked. Blood and urine 
sampling is to be obtained.


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The maximum blood volume to be drawn from each participant will not exceed 650 mL over 
the duration of the study period. Repeat or unscheduled samples may be taken for safety 
reasons or for technical issues with the samples.
Include the maximum amount of blood collected from each participant over the duration of 
the study and if any repeat or unscheduled samples may be taken, as appropriate.
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).

Body weight should be measured in light indoor clothes without shoes, after using the 
bathroom.
The physical examination will be performed at timepoints as specified in the SoA. BMI will 
be calculated at the time points specified in the SoA.
8.2.2
Vital Signs
Vital signs (blood pressure, pulse, and temperature) will be performed at timelines as 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.

Blood pressure (BP) and pulse measurements should be preceded by at least 5 minutes of
rest for the participant in a quiet setting without distractions (e.g., 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. If the result of the 


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pulse is obtained automatically when BP assessed with automated device, 3 consecutive pulse 
readings will be recorded at intervals of at least 1 minute.  For time points where ECG 
recording precedes vital sign measurement, the 10-minute rest in the supine position prior to 
the ECG suffices for the rest prior to vital sign measurement.
8.2.3
Electrocardiograms
An electrocardiogram will be performed at timepoints as specified in the SoA.
12-lead Safety Electrocardiogram 
[Part A/Part C]
At the time points indicated in the SoA (Table 1 and Table 3), 12-lead safety ECGs will be 
obtained after the participant has rested in supine position for at least 10 minutes (can be 
reduced to 5 minutes at collection time points). The following parameters or time intervals 
will be recorded for each ECG: RR, PR, QRS, QT, QTcF, and heart rate (HR). When the 12-
lead safety ECG time points coincide with the telemetry time points, the 12-lead safety ECG 
should be measured at the same time.
The Investigator will judge the overall interpretation as normal or abnormal. If abnormal, it 
will be decided whether the abnormality is clinically significant, and the reason for the 
abnormality will be recorded. Throughout the study, clinically relevant new findings or 
worsening of a preexisting finding in the ECGs (parameters or abnormal findings in the 
tracing) must be considered an AE and must be recorded. The Investigator may add additional 
12-lead safety 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.
[Part B]
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.


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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 
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 ECG 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 will make an overall evaluation of the ECG as normal or abnormal. If 
abnormal, it will be decided whether the abnormality is 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.
Cardiac Telemetry


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[Part A/Part C]
Real-time cardiac telemetry will be performed for 4 hours on Day −1 and from 30 minutes 
pre-dose until 24 hours post dose on Days 1 and 57. The telemetry monitoring system will be 
reviewed by the Investigator and paper printouts of any clinically important events will be 
stored as source data.
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 Labcorp central lab. Samples will be collected, 
handled, labelled, stored, and shipped as detailed in the laboratory manual.
The following laboratory variables will be measured.
[Part A/Part C]
Hematology
WBC count
Neutrophils absolute count
Red blood cell (RBC) count
Lymphocytes absolute count
Hemoglobin (Hb)
Monocytes absolute count
Hematocrit (HCT)
Eosinophils absolute count
Mean corpuscular volume (MCV)
Basophils absolute count
Mean corpuscular haemoglobin (MCH)
Platelets absolute count
Mean corpuscular haemoglobin concentration (MCHC)
Reticulocytes absolute count
Clinical Chemistry
Sodium
ALP
Potassium
ALT
Blood urea nitrogen (BUN)
AST
Creatinine
Gamma glutamyl transpeptidase (GGT)
Calcium
Total bilirubin
Phosphate
Direct bilirubin
Glucose (fasting)
Indirect bilirubin


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Creatine kinase (CK)
Glutamate dehydrogenase (GLDH)
Bicarbonate
Lactate dehydrogenase (LDH)
HbA1c
Uric acid
Serum β-human chorionic gonadotropin (β-
hCG)(women only)
FSH (women only)
Luteinizing hormone (LH) (women only)
Subject’s eGFR will be calculated from serum creatinine (SCr) concentration, according to the Japanese equation 
as follows:
eGFR = 194 × SCr (mg/dL) −1.094 × Age −0.287 × α, where α is 1 for males and 0.739 for females.
Liver Panel: ALP, ALT, AST, GGT, Total bilirubin, Direct bilirubin and Indirect bilirubin 
Coagulation
aPTT
Prothrombin time 
International normalized ratio (INR)
Urine renal safety biomarkers
Albumin
N-acetyl-beta-D-glucosaminidase (NAG)
Total protein 
Kidney Injury Molecule-1 (KIM-1) 
Creatinine
Neutrophil gelatinase-associated lipocalin (NGAL) 
Clusterina
Osteopontin
Cystatin-C
UACR 
a
PFC index. Refer PFC Index and Composite for details.
Other laboratory assessments
Complement activation panel (C3a [Part A only], Bb, 
C5a)
High-sensitive C-reactive protein (hs-CRP)
Dipstick urinalysis for hematuria 
Dipstick urinalysis for human chorionic 
gonadotropin (hCG)(women only)
PFC Index and Composite Measure
The renal safety biomarker panel (called PFC index) will be monitored in healthy volunteers 
and explored in subjects with dyslipidemia. The PFC index is a Food and Drug Administration 
(FDA) qualified safety composite biomarker panel to be used in conjunction with traditional 
measures to aid in the detection of kidney tubular injury in Phase 1 trials in healthy volunteers 
when there is an a priori concern that a drug may cause renal tubular injury in humans. The 
PFC index was developed by The Foundation for the National Institutes of Health (FNIH) 
Biomarkers Consortium Kidney Safety Biomarker Project Team and the Critical Path 
Institute’s (C-Path) Predictive Safety Testing Consortium Nephrotoxicity Working Group 


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(FNIH BC/PSTC NWG). The PFC index includes clusterin, cystatin-C, osteopontin, N-acetyl-
beta-D-glucosaminidase (NAG), kidney injury molecule 1 (KIM-1), and neutrophil gelatinase-
associated lipocalin (NGAL).
Composite Measure
The composite measure (CM) is a geometric mean (GM) of the fold changes from baseline of 
the uCr-normalised 6 urine biomarkers (called PFC index): clusterin, cystatin C, KIM 1, 
NAG, NGAL, and osteopontin.
The CM and the ratio between IMP and control will be calculated as follows:

For each subject, calculate the (uCr)-normalised fold-change from baseline for each 
biomarker. Define this as FCij for subject i and biomarker j, where j = 1, 2,…,6.

For each subject i, calculate CM:

Calculate the GM of CM for cohort k (k = Drug, Control):

Calculate the ratio of the GMs for the two cohorts:
 
[Part B]
Hematology
WBC count
Neutrophils absolute count
RBC count
Lymphocytes absolute count
Hb
Monocytes absolute count
HCT
Eosinophils absolute count
MCV
Basophils absolute count
MCHC
Platelets absolute count


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Reticulocytes absolute count
Clinical Chemistry
Sodium
GGT
Potassium
Total bilirubin
BUN
GLDH
Creatinine
LDH
Calcium
Bicarbonate
Phosphate
Uric acid
CK
AST
Direct bilirubin
ALT
Indirect bilirubin
FSH (women only)
ALP
LH (women only)
β-hCG (women only)
Liver Panel: ALP, ALT, AST, GGT, Total bilirubin, Direct bilirubin and Indirect bilirubin
Coagulation
Prothrombin time 
INR
aPTT
Urinalysis
Urine human chorionic gonadotropin (hCG) (Women only)
Urinalysis dipstick test
Urinalysis (positive dipstick)
pH
Clarity/Appearance
Specific gravity
Nitrites
Glucose
Ketones
Blood
Leukocytes
Colour
Microscopic analysis (if positive for blood, nitrates 
or protein)
Protein
Urobilinogen


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Urine renal safety biomarkers
Albumin
UPCR
Total protein
UACR
Creatinine
Estimated glomerular filtration rate (eGFR; by the 
Japanese equation)
Other laboratory assessments
hs-CRP
Complement activation panel (Bb, C5a)
HbA1c
NB. In case a participant shows an AST or ALT ≥3 × ULN together with total bilirubin ≥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 ,Table 2 and Table 3) are shown below.
Viral serology (screening only)
[Part A/Part B/Part C]
HIV I
Hepatitis B surface antigen (HBsAg) 
HIV II
Hepatitis C virus antibody
8.2.6
Injection Site Reactions
Injection site reactions 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 PI is responsible for ensuring that all staff involved in the study are familiar with the 
content of this section
The definitions of an AE or SAE 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.


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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.
SAEs will be recorded from the time of signing of the informed consent form.
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.
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 Investigational Product(s) (yes or no)

Action taken with regard to Investigational Product(s)

AE caused participant's withdrawal from study (yes or no)

Outcome

Whether the AE is an injection site reaction or not
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death


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
Date of death

Autopsy performed

Causality assessment in relation to study procedure(s)

Causality assessment to other medication

Description of AE
8.3.3 Causality Collection
The investigator should assess causal relationship between Investigational Product and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B to the Clinical 
Study Protocol.
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 Clinical Study Protocol mandated laboratory tests and vital signs will be 
summarised in the Clinical Study Report (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 investigational product or are considered to be 
clinically relevant as judged by the investigator (which may include but not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study intervention, 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 


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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.
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 total bilirubin ≥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.
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, investigators or other site personnel will 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 will work with the investigator to ensure that all 
the necessary information is provided to the AstraZeneca Patient Safety data entry site within 
one 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 will be undertaken immediately. Investigators or other site personnel will 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 Electronic Data 
Capture (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 a SAE 


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to the appropriate AstraZeneca representative by telephone.
The AstraZeneca representative will advise the investigator/study site staff how to proceed. 
The reference document for definition of expectedness/listedness is the Investigator’s 
Brochure (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 
intervention
8.3.8.1
Maternal Exposure
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur, the investigational product should be discontinued immediately and the 
pregnancy reported to AstraZeneca.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital anomalies/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 anomaly/birth defect) 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.
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 


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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. The pregnancy will also be followed up, 
and the outcome of the pregnancy (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital anomaly/birth defect) 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 
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 4. 
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 intervention occurs in the course of the study, the 
investigator or other site personnel inform appropriate AstraZeneca representatives 
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 one 
or 5 calendar days for overdoses associated with an SAE (see section 8.3.7) and within 
30 days for all other overdoses.


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8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Samples 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 (PK) samples will be disposed of after the Bioanalytical Report 
finalization or 6 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 pharmacokinetic samples to 
further evaluate and validate the analytical method. Any results from such analyses 
may be reported separately from the CSR.

Remaining anti-drug antibody (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
[Part A/Part C]
Blood samples for the determination of plasma concentrations of AZD8233 and AZD8233 
total full lengths ASOs will be collected for each treatment period as specified in the SoA. The 
concentration levels of AZD8233 total full lengths ASOs will be used to assess all the primary 
PK-parameters. Blood samples for a potential exploration of the plasma concentrations levels 
of unchanged AZD8233 will also collected as specified in the SoA.
Urine samples for the determination of urine concentrations of AZD8233 total full length 
ASOs will be collected for each treatment period as specified in the SoA.
Samples will be collected, handled, labelled, stored and shipped as detailed in the Laboratory 
Manual.
[Part B]
Plasma samples will be collected for measurement of plasma concentrations of total full-
length ASOs 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 


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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 this PK 
purpose may also be used to evaluate safety and 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
[Part A/Part C]
Blood and urine samples will be analyzed by Labcorp on behalf of AstraZeneca Research, 
using validated (plasma)/qualified (urine) assays, for determination of AZD8233 and 
AZD8233 total full lengths ASOs concentrations in plasma and AZD8233 total full lengths 
ASOs concentrations in urine. Full details of the analytical methods used will be described in 
a separate bioanalytical report.
[Part B]
Blood samples for determination of AZD8233 total full lengths ASOs concentrations in 
plasma will be analyzed by Labcorp on behalf of AstraZeneca Research, using validated 
(plasma)/qualified (urine) assays. Full details of the analytical methods used will be described 
in a separate bioanalytical report.
[Part A/Part B/Part C]
Placebo samples will not be analyzed, unless there is a need to confirm that correct treatment 
has been given to study participants.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation will not be reported in the CSR but 
separately in a Bioanalytical Report. In the event of safety concerns, blood samples collected 
for PK or PD analysis may be used for safety laboratory analysis at the discretion of the 
Investigator.
8.5.2
Immunogenicity Assessments
Blood samples for immunogenicity assessments (ADA) will be collected according to the SoA 
(Table 1, Table 2 and Table 3).
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. 


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Samples confirmed positive for ADA in the confirmatory step will undergo endpoint titer 
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, labeled, stored, and shipped as detailed in the Laboratory Manual.
Participants that are ADA positive at the end of the study and that has more than 2-fold higher 
titers than at baseline with multiple dosing of AZD8233 will be asked to return to provide 
another sample after 3 months to evaluate whether or not ADAs persist. If positive ADA-
results, and more than 2-fold higher titers than at baseline, subjects will be asked to return 
after an additional 3 months (i.e., 6 months after the end of study visit). If the sample is ADA 
positive at 6 months, the Investigator and AstraZeneca Physician will discuss additional 
actions and decide on future monitoring frequency. If 3 months (and 6months) have already 
passed at the time AstraZeneca confirmed a participant’s sample of Visit 17 for Part A and Part 
C or Visit 16 for Part B was ADA positive, the investigator will ask the participant to return to 
the study site as soon as possible to provide ADA sample. Results of ADA at 3 months and 6 
months after the end of study will not be recorded in the eCRF module or in the database. 
Participants with treatment-induced ADAs are considered ADA positive until levels have 
returned to within 2-fold of 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 measurement of PCSK9 and dyslipidemia (Table 7). 
Blood samples for the determination of concentrations of PCSK9 and to evaluate the lipid 
parameters will be collected at the time points specified in the SoA (Table 1, Table 2 and 
Table 3). The results of PCSK9, LDL-C and other lipid assessments except during screening 
period will be masked to the subjects and sites.
Table 7
Pharmacodynamic Laboratory Assessments
[Part A/Part C]
LDL-C
PCSK9
Levels of other lipid parameters including;
TC
ApoA1
HDL-C
ApoB


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Non-HDL-C
Lipoprotein(a) [Lp(a)]
VLDL-C
Triglycerides
[Part B]
LDL-C
Biomarkers analyses
PCSK9
Levels of other lipid parameters including;
TC
ApoB
HDL-C
Lipoprotein(a) (Lp[a])
Non-HDL-C
Triglycerides
VLDL-C
Remnants cholesterol
ApoA1
For storage, reuse, 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 participate in the study the participant consents to 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 
antiplatelet antibodies), and tolerability related to AZD8233 treatment or cardiometabolic 
diseases are 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.


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8.6.2
Collection of Optional Biomarker Samples
Not applicable.
8.6.3
Other Study Related Biomarker Research
Not applicable.
8.7
Optional Genomics Initiative Sample
[Part A/Part C] 
Not applicable
[Part B] 
The collection of optional samples for biomarker research is also part of this study as specified 
in the SoA and is subject to agreement to optional ICF.
Six 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.
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
[Part A]
No formal statistical hypothesis will be set. However, the safety and tolerability after multiple 
dosing of AZD8233 
 will be descriptively evaluated.
CCI


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[Part B] 
The study hypothesis to be tested is treatment effect of AZD8233 across different dose levels 
compared to placebo. 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. 
[Part C]
No formal statistical hypothesis will be set. However, the safety and tolerability after multiple 
dosing of AZD8233 
 will be descriptively evaluated.
9.2
Sample Size Determination
[Part A / Part C] 
Due to the exploratory nature of the study, the sample size is not based on formal statistical 
considerations, but on experience from similar Phase I studies previously conducted with 
other compounds. Eight Japanese subjects on active drug are considered to be sufficient to 
confirm a tendency for safety, PK, and PD data.
[Part B] 
The primary endpoint is assumed to follow a log-normal distribution with a standard deviation 
of 0.3. Under these assumptions, at least 18 evaluable patients per arm yield more than 95% 
power to detect a difference of 0.693 on the log-scale (corresponding to 50% relative 
reduction) compared to placebo in a two-sided t-test at a 5% significance level. The same 
number of evaluable patients would provide approximately 89% power to detect a difference 
of 0.33 between the 
 group and 
 group. Accounting for 10% drop-out, 60 patients 
in total will be randomized.
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. 
9.3
Populations for Analyses
The following populations are defined:
CCI
CCI
CCI


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Table 8
Populations for Analysis
Population/Analysis set
Description
Enrolled 
All participants who signed the ICF. 
Randomly assigned to study 
intervention
All participants who were randomized. Participants will be analyzed 
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 who took 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 would 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 Data Base Lock 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.
9.4.1
General Considerations
Unless otherwise stated, the safety analysis set will also be used for the presentation of all 
demographic  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. 
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, Standard Deviation
(SD), Standard Error of the Mean (SEM), 95% Confidence Interval (CI) of the mean, median, 


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first and third quartiles, minimum and maximum as appropriate ; for categorical variables, 
counts (n) and percentages (%) (where specified) will be presented. These summaries will be 
provided by time point of assessment as appropriate.
Baseline for efficacy assessments refers to the last measurements obtained before 
randomization. Baseline for safety assessments refers to the last measurements obtained 
before the first dose of IMP.
Primary estimand is hypothetical estimand, if all the patients had continued treatment until 
Week 12. The primary analysis will be carried out with likelihood based repeated measure 
model, which would provide unbiased treatment effect under the assumption of Missing At 
Random. Sensitivity analyses including different type of estimands will be detailed in the 
statistical analysis plan.
9.4.2
Efficacy 
[Part B] 
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 fitted 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 fitted 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)
[Part B] 
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 the 
least square mean difference between treatment groups as estimated by the fitted model. 
Pair-wise comparisons will be done between each AZD8233 dose (mid and low) vs. placebo. 


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In addition, pair-wise comparisons between AZD8233 dose groups will also be done for 
reference.
The geometric mean ratio will be plotted over time by treatment group.
9.4.2.2
Secondary Endpoint(s)
[Part B] 
Percent 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. 
The 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 will be 
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 summarized 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
[Part A/Part C]
The PK analysis set will consist of all subjects in the safety analysis set who received 
AZD8233 and who have evaluable PK data, with no important protocol deviations thought to 
impact on the analysis of the PK data.
The exclusion of any subjects or time points from the calculation of the PK parameters will be 
documented by the PK scientist, including the reason(s) for exclusion.
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only. Concentration data for subjects excluded from the PK 
analysis set will be presented in the individual figures of concentration versus time plots.
[Part B]
If data permits, a population PK model will be developed, possibly with the support of PK 
data from studies D7990C00001 and D7990C00002 and additional clinical studies with 


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AZD8233, 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
[Part A/Part B/Part C] 
All safety analyses will be performed on the safety analysis set. Safety variables are AEs, vital 
signs, 12-lead ECGs, and laboratory assessments. All safety data (scheduled and unscheduled) 
will be presented in the data listings.
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 terminology. 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.
Clinical laboratory data and ECG parameters will be summarized by treatment group and 
visit.
Use of concomitant medication will be reported.
9.4.4
Other Analyses 
Not applicable.
9.5
Interim Analyses 
In Part B, an interim analysis is planned. An interim analysis will include all participants’ data 
available until data cut-off, including the primary/secondary analysis at Week 12. The Sponsor 
will be unblinded at the time of interim analysis, but investigators, participants and site-staff 


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will not be informed of assigned treatment in order to maintain integrity as much as possible. 
The data cut-off date is defined as a day when all participants have completed 12 weeks of 
treatment (Visit 10). 
9.6
Data Monitoring Committee
An iSMC will be used for monitoring of unblinded safety data in the Part B. For details on the 
iSMC to be used in this study, please refer to Appendix A 5.
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 Good Clinical Practice (GCP) Guidelines

Standards stipulated in Article 14, Paragraph 3 and Article 80-2 of the Law on 
Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and 
Medical Devices

Japan Ministerial Ordinance on Good Clinical Practice for drugs No. 28 of March 27, 
1997 (in this Protocol called J-GCP) and the notification of amendments to the J-
GCP

Applicable laws and regulations

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant
documents (eg, advertisements) must be submitted to an Institutional Review Board 
(IRB)/ Independent Ethics Committee (IEC) by the head of the medical institution 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 
Contract Research Organisation (CRO) but the accountability remains with AstraZeneca.

The investigator will be responsible for providing oversight of the conduct of the study at 
the site and adherence to requirements of 21 CFR, ICH guidelines, the IRB/IEC, 
European Regulation 536/2014 for clinical studies (if applicable), European Medical 
Device Regulation 2017/745 for clinical device research (if applicable), and all other 
applicable local regulations
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 


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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.

European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations

An investigator who receives an investigator safety report describing a 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 or state other documents]. The 
head of the medical institution will also receive the safety report from the sponsor and 
will notify the IRB/IEC, if appropriate according to local requirements.
A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 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 or his/her legally authorised representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorised representative will be required to 
sign a statement of informed consent that meets the requirements of J-GCP in addition to 
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 or the participant’s legally 
authorised representative.


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
[Part A] Participants who are rescreened are required to sign a new ICF.

[Part B/Part C] When participants will be rescreened more than 28 days from the initial 
informed  consent, participants 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. 

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
Committees Structure
The safety of all AstraZeneca clinical studies is closely monitored on an on-going basis by 
AstraZeneca in consultation with AstraZeneca Patient Safety representatives. Issues identified 
will be addressed; for instance this could involve amendments to the Clinical Study Protocol 
and letters to Investigators.
[Part A]
The SRC meetings will be prepared and conducted in a blinded manner to keep all attendees 
blinded prior and during the meeting. All personnel involved in PD and PK evaluation of data 
(if available) may be unblinded for the evaluation of these data. Alternatively, PK and PD data 
will be provided in a blinded manner for the SRC review. Separate unblinded SRC meetings 
may also be held as needed.
The SRC will carefully review the totality of data, taking into account moderate non-serious 
AEs at least possibly related to the IMP administration and their relation to PD effects (if 
available), the number of subjects in whom these AEs occur, concurrency of more than 1 
within the same subject and potential safety signals identified for other IMPs in the same class 


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(mechanistic and/or chemical).
The committee will be operated in accordance with the SRC Charter.
[Part B]
An iSMC comprised of independent experts will be conducted to review the unblinded safety 
study data and ensure that study subjects are not exposed to undue risk. The iSMC is 
responsible for assessing unblinded study safety data according to an agreed upon schedule 
and making a recommendation to the study team. An iSMC charter gives details of precise 
roles and responsibilities and procedures and the committee will be operated in accordance 
with the iSMC Charter.
A 6
Dissemination of Clinical Study Data
A description of this clinical study will be available on 
http://astrazenecagrouptrials.pharmacm.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 main study is conducted.
A 7
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 electronically 
signing the eCRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator and the head of the medical institution 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, 
Contract Research Organizations).


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
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, J-GCP, 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. For Japan the 
investigator, the study site, IRB and the sponsor should retain the records according to J-
GCP. No records may be destroyed during the retention period without the written 
approval of the sponsor. No records may be transferred to another location or party 
without written notification to the sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data 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 9
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment 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


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
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 contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. For Japan, AstraZeneca will promptly inform the head 
of the medical institute, and the head of the medical institute will inform the investigators and 
the IECs/IRBs. The investigator shall promptly inform the participant and should assure 
appropriate participant therapy and/or follow-up.
Participants from terminated sites will have the opportunity to be transferred to another site to 
continue the study.
A 10
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 adverse event is the development of any untoward medical occurrence in a patient 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 intervention has been administered.
B 2
Definition of Serious Adverse Events
A serious adverse event 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 anomaly 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 (AEs) 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)
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 


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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.
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 


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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 intervention 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 Interactive Response Technology 
[IRT]/ Randomisation and Trial Supply Management [RTSM] errors)

Wrong drug administered to participant (excluding IRT/RTSM errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IRT/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

Accidental overdose (will be captured as an overdose)


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
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.
AstraZeneca ensures the organization(s) holding the samples is/are informed about the 


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withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action is documented and study site is notified.
C 3
International Airline Transportation Association 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, eg, Ebola, Lassa fever virus. Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to 
UN 2814. Infectious substances which cause disease only in animals must be assigned to
UN 2900.
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are, eg, Hepatitis A, C, D, and E viruses. They 
are assigned the following UN number and proper shipping name:

UN 3373 – Biological Substance, Category B

are to be packed in accordance with UN 3373 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

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. This 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. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA, ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
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.
Exclusion Criteria

Exclusion from this genetic research may be for any of the exclusion criteria specified in 
the main study or any of the following:

Previous allogeneic bone marrow transplant

Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample 
collection

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 


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withdrawal will not prejudice further treatment. Procedures for withdrawal are outlined in 
Section 7.2 of the main Clinical Study Protocol.
Collection of Samples for Genetic Research

The blood sample for this genetic research will be obtained from the participants at Visit
3 pre-dose. 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 AE. If for any reason the sample is not drawn at 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 processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years, from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the 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).

The link between the participant enrolment/randomisation 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.


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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. Regulatory authorities may require access to the relevant files, though the 
participant’s medical information and the genetic files would remain physically separate.
Data management

Any genetic data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyse the samples.

AstraZeneca and its designated organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organisations or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.


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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and 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 
potential PHL criteria at any point during the study.
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than Drug Induced Liver Injury (DILI) caused by the IMP. 
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.

Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.


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E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Determine whether PHL criteria were met at any study visit prior to starting study 
intervention. 

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to Clinical Study Protocol (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. For studies using a central laboratory add: This 
includes deciding which the tests available in the Hy’s law 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 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
IMP, to ensure timely analysis and reporting to health authorities within 15 calendar days from 
date PHL criteria was met. The AstraZeneca Global Clinical Lead or equivalent and Global 


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Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for an SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF

If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE eCRFs accordingly with the new information (reassessing event 
term; causality and seriousness criteria) following the 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 IMP:

Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes. 

The ‘Medically Important’ serious criterion should be used if no other serious 
criteria apply

As there is no alternative explanation for the HL case, a causality assessment of 
‘related’ should be assigned.
If, there is an unavoidable delay, of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made:

Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to IMP and 
seriousness criteria is medically important, according to CSP process for SAE reporting.

Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 
amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined.


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E 6
Laboratory Tests
Hy’s Law Lab Kit for Central Laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
HBsAg
IgM and IgG anti-HBc
HBV DNA a
IgG anti-HCV
HCV RNA b
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) 
Autoimmune hepatitis
Antinuclear antibody (ANA)
Anti-Liver/Kidney Microsomal Ab (Anti-LKM)
Anti-Smooth Muscle Ab (ASMA)
Metabolic diseases
alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrin
Transferrin saturation
a
HBV DNA is only recommended when IgG anti-HBc is positive
b
HCV RNA is only recommended when IgG anti-HCV is positive or inconclusive 
E 7
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 Ethylenediaminetetraacetic Acid (EDTA). If there is suspicion of EDTA 
mediated platelet clumping, a repeat platelet count using a different anticoagulant, e.g., 
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
Antithyroid
To be performed at specialty lab(s):
Antiplatelet antibodies and Anti-PF4 assay
Antidrug 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 


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specialists. For major or life-threatening bleeding, platelet transfusions should be administered 
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 (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula)
and at least one of the following:
(a) Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, reduced 
Peak Expiratory Flow [PEF], hypoxemia)
(b) Reduced BP or associated symptoms of end-organ dysfunction (e.g., 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 (e.g., generalized hives, itch-flush, swollen 
lips-tongue-uvula)
(b) Respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia)
(c) Reduced BP or associated symptoms (e.g., hypotonia [collapse], syncope, 
incontinence)
(d) Persistent gastrointestinal symptoms (e.g., 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.
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 


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Yes
No
Pruritus 
Face oedema 
Eye oedema 
Tongue swelling 
Angioedema 
Respiratory compromise 
Bronchospasm 
Dyspnoea 
Cough 
Choking 
Stridor 
Respiratory arrest 
Cardiovascular events 
Cardiac arrest 
Cardiovascular insufficiency 
Hypotension
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
Statin Therapy
•
atorvastatin 10 to 40 mg once daily
•
rosuvastatin 2.5 to 20 mg once daily
•
simvastatin 10 to 20 mg once daily
•
pitavastatin 1 to 4 mg once daily
•
fluvastatin 60 mg once daily
These statin therapies are selected by referring to moderate- or high-intensity statin therapy in the American 
College of Cardiology/American Heart Association (ACC/AHA) 2018 Guideline on the Management of Blood 
Cholesterol, and expected to lower LDL-C levels by ≥30% in Japanese patients.


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Appendix I
Abbreviations
Abbreviation or special 
term
Explanation
ADA
Antidrug antibody
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase/transaminase
Apo
Apolipoproteins
aPTT
Activated partial thromboplastin time
ASO
Antisense oligonucleotide
AST
Aspartate aminotransferase/transaminase
BMI
Body mass index
BP
Blood pressure
bpm
Beats per minute
BUN
Blood urea nitrogen
CK
Creatine kinase
CSP
Clinical study protocol
CSR
Clinical study report
CVD
Cardiovascular disease
DBP
Diastolic blood pressure
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid 
ECG
Electrocardiogram
eCRF
Electronic case report form
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
EDV
Early discontinuation visit
eGFR
Estimated glomerular filtration rate
FDA
United States Food and Drug Administration
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma glutamyl transpeptidase
GLDH
Glutamate dehydrogenase
Hb
Haemoglobin
HbA1c
Haemoglobin A1c
HCT
Haematocrit


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Abbreviation or special 
term
Explanation
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 sensitivity C-reactive protein
IB
Investigator’s Brochure
IATA
International Airline Transportation Association
ICF
Informed consent form
ICH
International Council for Harmonisation
IEC
Independent ethics committee
IMP
Investigational medicinal product
IRB
Institutional Review Board
IRT
Interactive response technology
ISR
Injection Site Reaction
iSMC
internal Safety Monitoring Committee
IUD
Intrauterine device
IXRS
Interactive Voice/Web Response System
LDL
Low-density lipoprotein 
LDL C 
Low-density lipoprotein cholesterol
LH
Luteinizing hormone
LLN
Lower limit of normal
Lp(a)
Lipoprotein(a)
MCHC
Mean corpuscular haemoglobin concentration
MCV
Mean corpuscular volume
PCSK9
Proprotein convertase subtilisin/kexin type 9
PEF
Peak expiratory flow
PD
Pharmacodynamic(s)
PHL
Potential Hy’s Law
PI
Principal investigator 
PK
Pharmacokinetic(s)
QTcF
Corrected QT interval by Fredericia
RBC
Red blood cell
RTSM
Randomization and trial supply management
SAE
Serious adverse event 


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Abbreviation or special 
term
Explanation
SBP
Systolic blood pressure
SC
Subcutaneous(ly)
SD
Standard deviation
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 2021
Investigator’s Brochure. AZD8233, Edition 1.3, dated 22 April 2021.
Jacqmin et al 2007
Jacqmin P, Snoeck E, van Schaick EA, Gieschke R, Pillai P, Steimer JL, et al. Modelling 
response time profiles in the absence of drug concentrations: definition and performance 
evaluation of the K-PD model. J Pharmacokinet Pharmacodyn. 2007 Feb;34(1):57-85.
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.


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The Suita score
J Atheroscler Thromb, 2018; 25: 846-984 "Japan Atherosclerosis Society (JAS) Guidelines for 
Prevention of Atherosclerotic Cardiovascular Diseases 2017"
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
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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Document Name: d7990c00006-csp-v5
Document Title:
D7990C00006 Clinical Study Protocol version 5
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SAP_009.pdf: 
STATISTICAL ANALYSIS PLAN 
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STATISTICAL ANALYSIS PLAN 
Study Code 
D7990C00006 (Part A) 
Edition Number 
4.0 
Date 
4-Jul-2022
Statistical Analysis Plan for D7990C00006, A Phase 1 and 2 
study to evaluate the safety, tolerability, efficacy, 
pharmacokinetics and pharmacodynamics of AZD8233 
following a multiple subcutaneous dose administration in 
Japanese participants with dyslipidemia (HAYATE) – Part A 


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TABLE OF CONTENTS 
TITLE PAGE .................................................................................................................... 1 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF ABBREVIATIONS .......................................................................................... 5 
AMENDMENT HISTORY .............................................................................................. 7 
1 
INTRODUCTION ......................................................................................... 9 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................. 9 
3 
DATA ANALYSIS CONSIDERATIONS .................................................... 9 
3.1 
Timing of Analyses ........................................................................................ 9 
3.2 
Analysis Populations ..................................................................................... 9 
3.2.1 
Enrolled Set ................................................................................................... 9 
3.2.2 
Randomly Assigned to Study Intervention .................................................... 9 
3.2.3 
Safety Analysis Set ........................................................................................ 9 
3.2.4 
Pharmacokinetic Analysis Set ..................................................................... 10 
3.2.5 
Pharmacodynamic Analysis Set .................................................................. 10 
3.3 
General Considerations ................................................................................ 10 
3.3.1 
General Study Level Definitions ................................................................. 11 
3.3.1.1 
Definition of Baseline .................................................................................. 11 
3.3.1.2 
Handling of Missing Data ............................................................................ 11 
3.3.1.3 
Study Periods ............................................................................................... 12 
3.3.2 
Visit Window ............................................................................................... 13 
3.3.3 
Handling of Unscheduled Visits .................................................................. 18 
3.3.4 
Multiplicity/Multiple Comparisons ............................................................. 18 
3.3.5 
Handling of Protocol Deviations in Study Analysis .................................... 18 
4 
STATISTICAL ANALYSIS ....................................................................... 19 
4.1 
Study Population .......................................................................................... 19 
4.1.1 
Subject Disposition and Completion Status ................................................ 19 
4.1.1.1 
Definitions and Derivations ......................................................................... 19 
4.1.1.2 
Presentation .................................................................................................. 19 
4.1.2 
Analysis Sets ................................................................................................ 19 
4.1.2.1 
Definitions and Derivations ......................................................................... 19 
4.1.2.2 
Presentation .................................................................................................. 19 
4.1.3 
Protocol Deviations ..................................................................................... 20 
4.1.3.1 
Definitions and Derivations ......................................................................... 20 
4.1.3.2 
Presentation .................................................................................................. 20 
4.1.4 
Demographics .............................................................................................. 20 
4.1.4.1 
Definitions and Derivations ......................................................................... 20 
4.1.4.2 
Presentation .................................................................................................. 20 
4.1.5 
Baseline Characteristics ............................................................................... 20 
4.1.5.1 
Definitions and Derivations ......................................................................... 20 
4.1.5.2 
Presentation .................................................................................................. 20 
4.1.6 
Disease Characteristics ................................................................................ 20 


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4.1.6.1 
Definition and Derivations .......................................................................... 20 
4.1.6.2 
Presentation .................................................................................................. 21 
4.1.7 
Medical History and Concomitant Disease ................................................. 21 
4.1.7.1 
Definitions and Derivations ......................................................................... 21 
4.1.7.2 
Presentation .................................................................................................. 21 
4.1.8 
Prior and Concomitant Medications ............................................................ 21 
4.1.8.1 
Definitions and Derivations ......................................................................... 21 
4.1.8.2 
Presentation .................................................................................................. 22 
4.1.9 
Study Drug Compliance .............................................................................. 22 
4.1.9.1 
Definitions and Derivations ......................................................................... 22 
4.1.9.2 
Presentation .................................................................................................. 22 
4.2 
Endpoint Analyses ....................................................................................... 22 
4.2.1 
Primary Endpoint – Adverse Events ............................................................ 23 
4.2.1.1 
Definition ..................................................................................................... 23 
4.2.1.2 
Derivations ................................................................................................... 24 
4.2.1.3 
Handling of Dropouts and Missing Data ..................................................... 24 
4.2.1.4 
Primary Analysis of Primary Endpoint ........................................................ 24 
4.2.2 
Primary Endpoint – Injection Site Reactions............................................... 25 
4.2.2.1 
Definition ..................................................................................................... 25 
4.2.2.2 
Derivations ................................................................................................... 25 
4.2.2.3 
Handling of Dropouts and Missing Data ..................................................... 25 
4.2.2.4 
Primary Analysis of Primary Endpoint ........................................................ 25 
4.2.3 
Primary Endpoint – Clinical Laboratory Assessments ................................ 25 
4.2.3.1 
Definition ..................................................................................................... 25 
4.2.3.2 
Derivations ................................................................................................... 26 
4.2.3.3 
Handling of Dropouts and Missing Data ..................................................... 27 
4.2.3.4 
Primary Analysis of Primary Endpoint ........................................................ 28 
4.2.4 
Primary Endpoint – Vital Signs, ECG and Cardiac Telemetry ................... 28 
4.2.4.1 
Definition ..................................................................................................... 28 
4.2.4.2 
Derivations ................................................................................................... 29 
4.2.4.3 
Handling of Dropouts and Missing Data ..................................................... 29 
4.2.4.4 
Primary Analysis of Primary Endpoint ........................................................ 30 
4.2.5 
Secondary Endpoint - Pharmacokinetics ..................................................... 30 
4.2.5.1 
Definition ..................................................................................................... 30 
4.2.5.2 
Derivations ................................................................................................... 31 
4.2.5.3 
Handling of Dropouts and Missing Data ..................................................... 32 
4.2.5.4 
Primary Analysis of Secondary Endpoint .................................................... 32 
4.2.6 
Secondary Endpoint – Change from baseline in log-transformed PCSK9 in 
plasma .......................................................................................................... 36 
4.2.6.1 
Definition ..................................................................................................... 36 
4.2.6.2 
Derivations ................................................................................................... 36 
4.2.6.3 
Handling of Dropouts and Missing Data ..................................................... 37 
4.2.6.4 
Primary Analysis of Secondary Endpoint .................................................... 37 
4.2.7 
Secondary Endpoint – Percent change from baseline in LDL-C ................. 37 
4.2.7.1 
Definition ..................................................................................................... 37 
4.2.7.2 
Derivations ................................................................................................... 37 


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4.2.7.3 
Handling of Dropouts and Missing Data ..................................................... 38 
4.2.7.4 
Primary Analysis of Secondary Endpoint .................................................... 38 
4.2.8 
Secondary Endpoint – Other Lipid Parameters ........................................... 38 
4.2.8.1 
Definition ..................................................................................................... 38 
4.2.8.2 
Derivations ................................................................................................... 38 
4.2.8.3 
Handling of Dropouts and Missing Data ..................................................... 39 
4.2.8.4 
Primary Analysis of Secondary Endpoint .................................................... 39 
4.2.9 
Exploratory Endpoint - Immunogenicity ..................................................... 39 
4.2.9.1 
Definition ..................................................................................................... 39 
4.2.9.2 
Derivations ................................................................................................... 39 
4.2.9.3 
Handling of Dropouts and Missing Data ..................................................... 39 
4.2.9.4 
Primary Analysis of Other Endpoint ........................................................... 39 
4.3 
Pharmacodynamic Endpoint(s) .................................................................... 39 
4.4 
Pharmacokinetics ......................................................................................... 39 
4.5 
Immunogenicity ........................................................................................... 39 
4.6 
Safety Analyses ........................................................................................... 39 
4.6.1 
Exposure ...................................................................................................... 40 
4.6.1.1 
Definitions and Derivations ......................................................................... 40 
4.6.1.2 
Presentation .................................................................................................. 40 
4.6.2 
Overdose ...................................................................................................... 40 
4.6.2.1 
Definitions and Derivations ......................................................................... 40 
4.6.2.2 
Presentation .................................................................................................. 40 
4.6.3 
Physical Examinations ................................................................................. 40 
4.6.3.1 
Definitions and Derivations ......................................................................... 40 
4.6.3.2 
Presentation .................................................................................................. 40 
5 
INTERIM ANALYSIS ................................................................................ 40 
6 
REFERENCES ............................................................................................ 41 
7 
APPENDIX.................................................................................................. 42 
7.1 
Schedule of Activities .................................................................................. 42 
7.2 
Clinical Laboratory Assessments ................................................................ 49 


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LIST OF ABBREVIATIONS 
 
Abbreviation or 
Specialized Term 
Definition 
ADA  
Anti-drug antibody 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical therapeutic chemical 
BLQ 
Below limits of quantification 
BMI 
Body mass index 
CI 
Confidence interval 
CM 
Composite measure 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV  
Coefficient of variation 
DBL 
Database lock 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
HLT 
High level term 
IPD 
Important Protocol Deviation 
LDL-C 
Low density lipoprotein cholesterol 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical dictionary for regulatory activities 
PCSK9 
Proprotein convertase subtilisin/kexin type-9 
PD 
Pharmacodynamics 
PK 
Pharmacokinetics 
PR 
PR interval 
PT 
Preferred term 
QRS 
QRS wave 
QT 
QT wave 
QTcF 
Corrected QT Interval using Fridericia’s Formula 
RR 
Respiratory rate 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 


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Abbreviation or 
Specialized Term 
Definition 
SD 
Standard deviation 
SOC 
System organ class 
TBL 
Total bilirubin  
TEAE 
Treatment-emergent adverse event 
UNS 
Unscheduled 
ULN 
Upper limit of normal 
WHO-DD 
World Health Organisation drug dictionary  
 
 
 


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AMENDMENT HISTORY 
CATEGORY 
Change refers to: 
Date 
Description of change 
In line with 
CSP? 
Rationale 
N/A 
27-Apr-2021 
Initial approved SAP 
N/A 
N/A 
Derivation of primary 
endpoint(s) 
30-Jun-2021 
4.2.1.4/ 1st bullet: Any 
AE → All AE 
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.5.4:  
- summarized by dose 
level → summarized by 
analytes and timepoints 
- presented by dose level 
→ presented by analytes 
and timepoints 
- Figures for the 
arithmetic mean (SD) 
concentration → remove 
“(SD)” 
- (SD only on the linear 
scale) → (SD on the 
linear scale and gSD on 
the semi-logarithmic 
scale) 
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.6.4/ L2: Safety 
Analysis Set → PD 
Analysis Set for lipid 
parameters 
Y(V1) 
Correction 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.6.4/ L3: delete 
“alongside the individual 
value of the respective 
visit”.  
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.6.4/ L6: 95% Cis → 
gSD  
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.7.4/ L2: Safety 
Analysis Set → PD 
Analysis Set  
Y(V1) 
Correction 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.8.4/ L2: Safety 
Analysis Set → PD 
Analysis Set  
Y(V1) 
Correction 
Statistical analysis 
method for secondary 
endpoint(s) 
30-Jun-2021 
4.2.8.4/ L3: delete 
“alongside the individual 
value of the respective 
visit”.  
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Other 
30-Jun-2021 
4.1.7:  
- prior disease → past 
disease 
- concomitant disease → 
current disease 
Y(V1) 
Change as the result 
of Mock Shell 
review. 


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Other 
30-Jun-2021 
4.6.2.2:  
- All overdose data will 
be listed → All overdose 
data will not be listed 
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Other 
30-Jun-2021 
4.6.3.2:  
- Any recorded 
abnormalities will be 
presented in the listings. 
→ Any recorded 
abnormalities will not be 
presented in the listings 
Y(V1) 
Change as the result 
of Mock Shell 
review. 
Other 
15-Sep-21 
Updated the analysis 
visits windows to 
coincide with the visits 
in the CSP 
Y 
Change requested.  
Data presentation 
15-Sep-21 
Included analysis of the 
composite measure 
Y 
Change requested 
Other 
26-Oct-21 
Summarised the lab and 
anti-AZD8233 antibodies 
analysis visit windows in 
a separate table 
Y 
Change as a result of 
BDR1 
Data presentation 
26-Oct-21 
Additional summary for 
the liver enzyme 
abnormalities 
Y 
Change as a result of 
BDR1. 
Other 
05-Nov-21 
Added detail that pre-
treatment phase can be 
up to 28 days prior to IP 
administration 
Y 
Change requested. 
Other 
05-Nov-21 
Added that Part C will be 
summarised in a separate 
SAP. 
Y 
Change requested. 
Statistical analysis 
method for secondary 
endpoint(s) 
23-May-22 
(post-DBL) 
Updated derivation of 
LDL-C derived by the 
Friedewald or 
Martin/Hopkins formula 
and added the 
corresponding reference 
Y 
To replace missing 
values which were 
negative due to 
formula. 
Other 
01-Jun-22 
(post-DBL) 
RAC (AUD) and RAC 
(Cmax) added to list of 
PK parameters 
Y 
To be in line with the 
parameters collected 
during study. 
Other 
04-Jul-22 
(post-DBL) 
Analysis visit numbers 
updated in Tables 1-4 
Y 
Updated to be in line 
with the CSP. 
 


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1 
INTRODUCTION 
The purpose of this document is to give details for the statistical analysis of study 
D7990C00006 – Part A, supporting the clinical study report (CSR). Additional statistical 
analysis plans (SAP) will be created detailing the analysis of Part B and Part C of the study. 
The reader is referred to the clinical study protocol (CSP) and the electronic case report form 
(eCRF) for details of study conduct and data collection. This SAP is based on Version 2.0 of 
the CSP dated 13 November 2020 and Version 2.0 of the eCRFs dated 18 January 2021.  
2 
CHANGES TO PROTOCOL PLANNED ANALYSES 
The Enrolled Set will be used for the summary of subject disposition instead of the Safety 
Analysis Set. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
Timing of Analyses 
A single analysis of all data from Part A will be conducted after database lock (DBL) and all 
results will be included in the CSR. DBL will occur after completion of all follow up visits, 
approximately 16 weeks after last administration of study intervention to the last ongoing 
subject.  
3.2 
Analysis Populations 
3.2.1 
Enrolled Set 
All participants who signed the informed consent form. The Enrolled Set will be used to 
summarize patient disposition. 
3.2.2 
Randomly Assigned to Study Intervention 
All participants who were randomized. Participants will be analyzed according to the 
treatment to which they were randomized.  
3.2.3 
Safety Analysis Set 
All participants randomly assigned to study treatment who took at least one dose of AZD8233 
or placebo and for whom any post-dose data are available. Participants will be analyzed 
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 would be the treatment group that 
participant was randomized to. The Safety Analysis Set will be used as the analysis set for 
all summaries for safety evaluation unless stated otherwise and for the analysis of the 
immunogenicity data.  


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3.2.4 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set will consist of all subjects in the Safety Analysis Set 
who received AZD8233 and who have evaluable PK data, with no important protocol 
deviations thought to impact on the analysis of the PK data. 
The exclusion of any subjects or time points from the calculation of the PK parameters will 
be documented by the PK scientist, including the reasons for exclusion. 
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only. Concentration data for subjects excluded from the PK 
analysis set will be presented in the individual figures of concentration versus time plots. 
The PK Analysis Set will be used to summarize the PK data. 
3.2.5 
Pharmacodynamic Analysis Set 
The Pharmacodynamic (PD) Analysis Set will consist of all patients who received AZD8233 
or placebo, who have at least one baseline and one post-baseline measurement for either the 
level of PCSK9 in plasma or the level of LDL-C in plasma, and who have no important 
protocol deviations thought to impact on the analysis of the data.  
The available PD data for any subjects excluded from the PD analysis set will be listed only, 
together with a flag indicating patients excluded from the PD analysis set. Only subjects or 
samples in the PD analysis set will be included in the descriptive summary tables. 
The PD analysis set will be used to analyse the lipid parameters (PCSK9, LDL-C and other 
lipids).  
3.3 
General Considerations 
There is no formal statistical hypothesis testing in this study. Safety and tolerability after 
multiple dosing of AZD8233 
 (or placebo) will be descriptively evaluated. The 
following principles will be followed throughout the study: 
• Continuous variables will be summarized by the number of non-missing observations, 
mean, standard deviation (SD), median, first and third quartiles, and the minimum 
and maximum as appropriate. 
• Log-transformed continuous variables will be summarized in a similar manner. In 
addition, the relative change from baseline will be calculated by back-transforming 
the change from baseline of the logarithmic variable as necessary.  


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• Categorical variables will be summarized as counts (n) and percentages (%). Unless 
otherwise stated, percentages will be calculated using the relevant analysis set 
population total as the denominator. Percentages will not be presented for zero counts. 
• Mean and medians will be rounded to one additional decimal place relative to the 
original data, the SD will be rounded to two additional decimal places, and the 
maximum, minimum and quartiles will be displayed with the same accuracy as the 
original data. 95% confidence intervals (CIs) will be presented to one more decimal 
place than the raw data. Percentages (proportion) will be rounded to one decimal 
place.  
• Summaries will be provided by time point of assessment where appropriate. Where 
summaries are over time, study day will be calculated in relation to the date of first 
dose of study treatment. 
• Corresponding listings will be provided for all tabulated results unless stated 
otherwise. Any additional listings that are required will be described in the 
appropriate sections of the SAP. 
• SAS® version 9.3 or higher will be used for all data analyses. 
3.3.1 
General Study Level Definitions 
3.3.1.1 
Definition of Baseline 
Unless otherwise specified, ‘baseline’ refers to the last measurement obtained before the first 
dose of study intervention. For lipid parameters (PCSK9, LDL-C, etc), the geometric mean 
of the two measures taken pre-dose at Visit 2 (Day -1 and pre-dose Day 1) will be considered 
as baseline.  
3.3.1.2 
Handling of Missing Data 
In general, missing data will not be imputed and will be treated as missing unless specifically 
described in an analysis section. The following considerations are made for missing safety 
data, adverse event (AE) dates, and concomitant medication/diseases dates: 
• Safety assessment values of the form ‘<x’ or ‘>x’ (i.e., above or below the limits of 
quantifications) will be imputed as ‘x’ in the calculation of summary statistics but 
displayed as ‘<x’ or ‘>x’ in the listings. 
• Adverse events that have missing causality after data querying will be assumed to be 
related to study drug.  
• For missing AE/concomitant medication/disease start dates, the following will be 
applied: 


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o Missing day: Impute 1st of the month unless the month is the same as that of 
the first dose of study drug in which case impute first dose date. 
o Missing day and month: Impute 1st January unless the year is the same as that 
of the first dose date in which case impute first dose date.   
o Missing year: Impute the year of dosing. 
o Completely missing: Impute first dose date unless the end date suggests it 
could have started prior to this in which case impute 1st January of the same 
year as the end date. 
• For missing AE/concomitant medication/disease end dates, the following will be 
applied: 
o Missing day: Impute the last day of the month unless the month is the same 
as that of the last dose of the study drug in which case impute the date of last 
dose. 
o Missing day and month: Impute 31st December unless the year is the same as 
that of the last dose of study drug in which case impute date of last dose. 
o Missing year: Impute the year of dosing. 
o Completely missing: Do not impute a date i.e., assume that AE/concomitant 
medication/disease is ongoing. 
For all missing start/end dates, flags will be retained in the analysis datasets indicating where 
any programmatic imputation has been applied, and in such cases, any durations would not 
be calculated. 
If a subject is known to have died where only a partial death date is available, then the date 
of death will be imputed as the latest of the last known date to be alive + 1 from the database 
and the death date using the available information provided: 
• Missing day only: Use the 1st of the month. 
• Missing day and month: Use 1st January. 
• Missing year: Impute the year of dosing. 
3.3.1.3 
Study Periods 
For listings of adverse events, lipid levels, laboratory values, vital signs and ECG, values will 
be allocated to a study period. The allocation to the study periods will be performed after any 


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imputation of missing dates (for AEs only) as described in Section 3.3.1.2. The study periods 
are defined as follows: 
• Pre-treatment: Up to 28 days prior to administration of study drug (Day <1). 
• Treatment Period: From Day 1 to date of last dose + 2 days (from visit 2 up to visit 
9). 
• Follow-up Period: From day of last dose + 3 days onwards (visit 10 to visit 17). 
 
3.3.2 
Visit Window 
Study visits windows are defined in the table below. 
 
Analysis Visit Windows 
Analysis visit windows will be defined for the lipid parameters, ECG, anti-AZD8233 
antibodies, laboratory results and vital signs which summarize values by visit. These analysis 
visit windows will be exhaustive so that data recorded at any time point has the potential to 
be summarized. Inclusion within the window will be based on the actual date and not the 
intended date of visit.  
Analysis visit windows will be constructed such that the upper limit of the window interval 
falls halfway between the two scheduled visits, where the number of days between visits is 
odd, the additional day will be applied to the lower interval of the later date.  
 
 










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For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used, regardless of where it falls in an interval. For summaries 
at a subject level (i.e., the maximum) all values will be included regardless of whether they 
appear in a corresponding visit-based summary. 
3.3.3 
Handling of Unscheduled Visits  
Visits that fall outside the visit windows defined in the CSP will be classified as Unscheduled 
Visits. Unscheduled visits will be numbered sequentially with an increment of 0.1. For 
example, if two measurements are done in an unscheduled visit that occurs between Day 3 
and Day 8, then these visits will be numbered UNS 2.1 and 2.2 in the order they occurred. 
The values measured at unscheduled visits will not be included in the by-visit summary 
tables, they will be included in the overall summary tables (for abnormalities, 
minimum/maximums etc.) and will be presented in the listings.  
3.3.4 
Multiplicity/Multiple Comparisons 
Not applicable. 
3.3.5 
Handling of Protocol Deviations in Study Analysis 
Important protocol deviations are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments. The impact of 
important protocol deviations on the safety results will be investigated by assessing the 
robustness of the study results and conclusions to the choice of analysis set, both including 
and excluding data potentially affected by important protocol deviations. 
This estimation will be performed on a Data Review Meeting (DRM) shortly before database 
lock. Results and population assignments will be summarized in a DRM report which will be 
agreed up on  by all relevant scientific experts. 
During the study, a list of important protocol deviations (IPD) will be developed, which will 
include inclusion/exclusion/discontinuation criteria deviations, investigational product 
deviations and excluded medication taken. These will be taken into consideration when 
interpreting the data.  Patients with an IPD may be excluded from the analysis of the PK data.  
 
 
 


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4 
STATISTICAL ANALYSIS 
This section provides information on definitions, derivations and analysis/data presentation 
per domain. 
4.1 
Study Population 
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics medical and surgical history, prior and concomitant 
medication and study drug compliance.  
4.1.1 
Subject Disposition and Completion Status 
4.1.1.1 
Definitions and Derivations 
Not applicable.  
4.1.1.2 
Presentation 
Subject disposition will be summarized based on the Enrolled Set and will include the 
following information: the number of subjects enrolled, randomized and who received at least 
one dose of study drug, the number and percentage of subjects who completed 
treatment/discontinued treatment (including reasons for IP discontinuation), and the number 
and percentage of subjects who completed or discontinued study (including reason for early 
withdrawal). Summaries will be by treatment group and overall.  
A randomization listing will be presented and will include the following information: 
randomization number, full enrolment number, date of randomization and randomized 
treatment group. 
Subjects affected by the COVID-19 pandemic and subjects with reported issues in the 
Clinical Trial Management System due to COVID-19 pandemic will be listed. 
4.1.2 
Analysis Sets 
4.1.2.1 
Definitions and Derivations 
Analysis sets are defined in Section 3.2. 
4.1.2.2 
Presentation 
Analysis sets will be summarized based on the Enrolled Set. The number of subjects included 
and excluded (including reason for exclusion) in each analysis population will be presented 
by treatment group.  


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4.1.3 
Protocol Deviations 
4.1.3.1 
Definitions and Derivations 
Important protocol deviations (IPDs) will be defined in the Non-compliance Handling Plan 
and are considered as those deviations from the protocol likely to have an impact on the 
perceived efficacy or safety of study treatment. The final list of IPDs will be determined 
before DBL. 
4.1.3.2 
Presentation 
IPDs will be summarized based on the Randomized set. The number and percentage of 
subjects meeting each IPD criterion will be summarized by treatment group. Subjects who 
deviate from a given criterion more than once will be counted once for that criterion. Any 
subjects with more than one IPD will be counted once in the overall summary. 
4.1.4 
Demographics 
4.1.4.1 
Definitions and Derivations 
Age is measured in years and calculated as: 
Age (years) = (Date of randomization – date of birth + 1) / 365.25 
4.1.4.2 
Presentation 
Demographics (age, sex, race, ethnicity) will be summarized based on the Safety Analysis 
Set. Summaries will be presented by treatment group and according to the principles outlined 
in Section 3.3.   
4.1.5 
Baseline Characteristics 
4.1.5.1 
Definitions and Derivations 
Body mass index (BMI) is calculated as: 
BMI (kg/m2) = weight (kg) / height2 (m) 
4.1.5.2 
Presentation 
Baseline characteristics (height, weight, BMI, nicotine use and alcohol use) will be 
summarized based on the Safety Analysis Set. Summaries will be presented by treatment 
group and according to the principles outlined in Section 3.3.   
4.1.6 
Disease Characteristics 
4.1.6.1 
Definition and Derivations 
Disease characteristics are defined as the following lipid related parameters measured at 
baseline: 
• LDL-C derived by the Friedewald formula. 


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• LDL-C derived by the Martin/Hopkins formula. 
• Direct LDL-C. 
• HDL-C and Non-HDL-C. 
• VLDL-C. 
• ApoA1 and ApoB. 
• Lp(a). 
• TG. 
4.1.6.2 
Presentation 
Disease characteristics will be summarized based on the Safety Analysis set. Summaries will 
be presented by treatment group and according to the principles outlined in Section 3.3.   
4.1.7 
Medical History and Concomitant Disease 
4.1.7.1 
Definitions and Derivations 
Medical and surgical history, and concomitant (called “current”) diseases are coded using 
MedDRA version 23.1 or higher. The imputation method described in Section 3.3.1.2 will 
be used in the instance that partial or missing dates are recorded. After imputation of dates, 
concomitant diseases will be classified as prior (called “past”) or current.  
A past disease is defined as any disease with a start and end date prior to the first dose date 
(exclusive). A current disease is defined as any disease with an end date on or after the first 
dose date. A disease with a completely missing end date will be considered as current.  
4.1.7.2 
Presentation 
Medical/surgical history and current diseases will be summarized based on the Safety 
Analysis Set. The number and percentage of subjects with relevant medical/surgical 
history/current diseases will be presented by treatment group and summarized by System 
Organ Class (SOC) and Preferred Term (PT). Subjects with histories in more than one 
SOC/PT will be counted only once in that SOC/PT. Tables will be sorted alphabetically by 
SOC and PT. 
4.1.8 
Prior and Concomitant Medications 
4.1.8.1 
Definitions and Derivations 
Prior and concomitant medications are coded using the WHO-DD. The imputation method 
described in Section 3.3.1.2 will be used in the instance that partial or missing dates are 
recorded. 






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The term AE is used to include both serious (SAE) and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset date on or 
after the first dose date.  
4.2.1.2 
Derivations 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) version 23.1 or higher. 
4.2.1.3 
Handling of Dropouts and Missing Data 
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2. 
4.2.1.4 
Primary Analysis of Primary Endpoint 
All summaries of adverse event data will be based on the Safety Analysis Set and will be 
presented by treatment group. Summary tables will include TEAEs only whereas listings will 
include all reported AEs. 
A subject-level overview of AEs (the number and percent of subjects and the number of 
events) will be tabulated in a single table for: 
• All AE. 
• AEs possibly related to study treatment. 
• AEs with an outcome of death. 
• AEs with outcome of death possibly related to study treatment. 
• All serious adverse events (SAE). 
• SAEs possibly related to study treatment. 
• AEs leading to discontinuation of study treatment. 
• AEs leading to discontinuation of study treatment, possibly related to study treatment. 
• AEs leading to dose interruption and reduction (separately). 
• AEs leading to withdrawal from the study. 


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Separate AE summary tables of the number and percentage of subjects with AEs and the 
number of events in each of the categories above will be produced by SOC and PT.  
Additionally, the following tables will be presented by SOC and PT: 
• AEs by the maximum reported intensity. 
• AEs by causality assessment. 
Subjects with multiple events in the same category are counted once in that category. Subjects 
with events in more than one category are counted once in each of those categories.  
4.2.2 
Primary Endpoint – Injection Site Reactions 
4.2.2.1 
Definition 
Injection site reactions (ISRs) are reported using standard AE collection criteria. 
4.2.2.2 
Derivations 
Injection site criteria will be coded using the MedDRA version 23.1 or higher. 
4.2.2.3 
Handling of Dropouts and Missing Data 
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2. 
4.2.2.4 
Primary Analysis of Primary Endpoint 
All summaries of injection site reactions will be based on the Safety Analysis Set and will be 
summarized by treatment group. The number and percentage of subjects with an injection 
site reaction and the number of events will be summarized by High Level Term (HLT) and 
preferred term.  
Subjects with multiple events in the same category are counted once in that category. Subjects 
with events in more than one category are counted once in each of those categories.  
4.2.3 
Primary Endpoint – Clinical Laboratory Assessments 
4.2.3.1 
Definition 
Clinical laboratory assessments consist of hematology parameters, clinical chemistry, 
coagulation, urine renal safety biomarkers (called PFC Index) and composite measure (CM), 
and other laboratory assessments. The parameters to be summarized are listed in Appendix 
7.2.  
The composite measure (CM) is a geometric mean of the fold changes from baseline of the 
uCr-normalised 6 urine biomarkers (the PFC index): clusterin, cystatin C, KIM 1,NAG, 
NGAL, and osteopontin. 


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4.2.3.2 
Derivations 
Clinical laboratory results will be assigned to analysis visits as described in Section 3.3.2. 
Except for lipids (section 4.2.6.2, 4.2.7.2 and 4.2.8.2) – safety clinical laboratory results 
below the lower limit of quantification (LLOQ) for which the exact value cannot be 
determined will be replaced with the LLOQ.  
After replacements of LLOQ, the change from baseline will be calculated for all post-baseline 
timepoints as the respective timepoint value minus the baseline value.  
Based on the respective reference range indicators, the following flags will be applied to all 
laboratory assessments; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 
(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range).  
eGFR 
Subject’s eGFR will be calculated from serum creatinine (SCr) concentration, according to 
the Japanese equation as follows: 
eGFR = 194 × SCr(mg/dL)−1.094 × Age−0.287 × α  
where α is 1 for males and 0.739 for females. 
Composite measure 
The CM and the ratio between treatment and placebo will be calculated as follows. 
1. For each subject, calculate the (uCr)-normalised fold-change from baseline for each 
biomarker in the PFC index. The (uCr)-normalised concentration at a given timepoint 
is calculated as the concentration of the biomarker at that timepoint, divided by the 
concentration of urinary creatinine (uCr) at the same timepoint. The fold change from 
baseline is then calculated as the uCr-normalised concentration at a given timepoint, 
divided by the uCr-normalised concentration at baseline. Define the fold-change as 
FCij for subject i and biomarker j, where j = 1, 2,…,6. 
2. For each subject i, calculate CM: 
 
3. Calculate the GM of CM for cohort k (k = Treatment, Placebo): 


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4. Calculate the ratio of the GMs for the two cohorts: 
 
Liver enzyme abnormalities 
AST, ALT and TBL will be classified as follows: 
AST and ALT: 
• <3×ULN (or below the LLOQ). 
• ≥3 to <5×ULN. 
• ≥5 to < 8×ULN. 
• ≥8×ULN. 
TBL: 
• <1×ULN (or below the LLOQ). 
• ≥1 to <2×ULN. 
• ≥2×ULN. 
Occurrences of AST or ALT ≥3×ULN together with TBL ≥ 2×ULN are reported as SAE 
(Potential Hy’s Law). 
Reduced platelet count 
Platelet count <150 (10^9/L) or percent decrease from baseline greater than 30%. 
4.2.3.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 


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4.2.3.4 
Primary Analysis of Primary Endpoint 
Laboratory data will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. The number and proportion of patients 
with liver enzyme abnormalities and reduced platelet counts will summarized by treatment 
group and visit, including a summary of the maximum (for AST,ALT and TBL) or minimum 
value (for  platelet count) recorded post-baseline.   
The composite measure of the PFC index and corresponding ratio of AZD8233 to placebo 
will be presented by treatment group and visit. Box plots over time will be produced by 
treatment group for the composite measure and for the fold-change of the six individual 
biomarkers. A spaghetti plot over time of the fold-change of the six individual biomarkers 
will also be produced for each subject. 
Shift tables will be presented for select laboratory parameters (clinical chemistry and 
hematology). Spaghetti plots over time will be produced for ALT, AST, TBIL and gamma 
GPT, with the corresponding reference range overlaid on top.  
Clinical laboratory data will be reported in standard international units. 
4.2.4 
Primary Endpoint – Vital Signs, ECG and Cardiac Telemetry 
4.2.4.1 
Definition 
Vital Signs 
The vital sign measurements to be summarized are:  
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Body temperature (oral) (ºC). 
ECG 
The following parameters or time intervals will be recorded for each ECG: RR, PR interval, 
QRS duration, QT interval, QTcF interval, and ECG mean heart rate (HR). The Investigator 
will judge whether the overall interpretation is ‘normal’ or ‘abnormal’.  
 
 


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Cardiac Telemetry 
Cardiac telemetry results will be reviewed by the Investigator and clinically important results 
are stored. 
4.2.4.2 
Derivations 
Vital sign measurements, ECG and cardiac telemetry results will be assigned to analysis visits 
as described in Section 3.3.2. 
Change from baseline for vital sign measurements and ECG parameters (where applicable) 
will be calculated for all post-baseline visits as the respective visit value minus the baseline 
value. 
Vital Signs 
Based on the respective reference range indicators, the following flags will be applied to all 
vital sign measurements; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 
(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range).  
Parameter  
Normal Reference Ranges 
Systolic blood pressure  
80 - 140 mmHg 
Diastolic blood pressure  
50 -90 mmHg 
Heart rate  
50 - 100 bpm 
Temperature  
<=37ºC 
 
ECG 
Outlier categories with respect to QTcF will be defined as follows: 
• 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   
4.2.4.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 


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4.2.4.4 
Primary Analysis of Primary Endpoint 
Vital Signs 
Vital signs will be summarized based on the Safety Analysis Set. Summaries of the individual 
values and change from baseline will be presented by treatment group and visit according to 
the principles outlined in section 3.3.1.  
ECG 
ECG parameters will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. Outliers with respect to QTcF will be 
tabulated using the categories defined in Section 4.2.4.2. 
Cardiac Telemetry 
Results for 12-lead ECG real-time cardiac telemetry will be listed based on the Safety 
Analysis Set including the overall assessment, specifics of abnormalities and the start and 
stop date/time. 
4.2.5 
Secondary Endpoint - Pharmacokinetics 
4.2.5.1 
Definition 
Where possible, the following PK parameters will be determined. 
AUC  
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity. AUC is estimated by AUC(0-last) + 
Clast/λz where Clast is the last observed quantifiable concentration. 
AUC(0-last)  
Area under the plasma concentration-curve from time zero to the 
time of last quantifiable analyte concentration. 
AUC(0-24)  
Area under the concentration-time curve from time zero to 24 hours 
post-dose. 
AUC(0-48)  
Area under the concentration-time curve from time zero to 48 hours 
post-dose. 
AUCτ 
Area under the plasma concentration-time curve during the dosing 
interval 
CL/F  
Apparent total body clearance of drug from plasma after 
extravascular administration. 
Cmax  
Maximum observed plasma concentration. 
Ctrough 
Observed trough plasma concentration 
λz  
Terminal rate constant, estimated by log-linear least-squares 
regression of the terminal part of the concentration-time curve. 
MRT 
Mean residence time of the unchanged drug in the systemic 
circulation. 


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RAC (AUC) 
Accumulation ratio based on AUC 
RAC (Cmax) 
Accumulation ratio based on Cmax 
t1/2z  
Half-life associated with the terminal slope (λz) of a semi-
logarithmic concentration-time curve 
tlag 
Time delay between drug administration and the first observed 
concentration in plasma 
tlast  
Time of last quantifiable concentration. 
tmax  
Time to reach peak or maximum observed concentration following 
drug 
Vz/F 
Apparent volume of distribution during the terminal phase after 
extravascular administration. 
 
The following PK parameters will be determined, where possible, from urine concentrations. 
  
Ae(t1-t2) 
Amount of analyte excreted unchanged in urine from time t1 to t2 
fe(t1-t2) 
Percentage of analyte excreted unchanged in urine from t1 to t2 
Ae(0-last) 
Cumulative amount of analyte excreted at the last sampling 
interval 
fe(0-last)  
Cumulative percentage of dose excreted unchanged into the urine 
from time zero to the last measured time point for an analyte, 
estimated by dividing Ae(0-last) by dose 
CLR  
Renal clearance of drug from plasma, estimated by dividing Ae(0-
24) by AUC(0-24) 
Additional PK parameters may be determined where appropriate. 
4.2.5.2 
Derivations 
The geometric mean is calculated as the exponential of the arithmetic mean calculated from 
the data on the natural log scale. 
The percent coefficient of variation is calculated as: CV (%) = √(exp(𝑠2) −1 where s is 
the standard deviation of the data on a log scale. 
Handling of values below the lower limit of quantification (BLQ) 
Plasma concentrations below the limit of quantification (BLQ) from the time of pre dose 
sampling (t = 0) up to the time of the first quantifiable concentration will be set to a value of 
0. After the first quantifiable concentration, BLQ plasma concentrations will be set to missing 
for the calculation of PK parameters unless it is considered to be a true characteristic of the 
profile of the drug.  
If two or more consecutive BLQ concentrations are followed by quantifiable concentrations 
in the terminal portion of the concentration curve, the profile will be deemed to have 
terminated and therefore these quantifiable values will be set to missing for the calculation 


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of the PK parameters unless there is a scientific rationale not to do so, which will be 
documented in the CSR.  
Any embedded BLQ value (between two quantifiable concentrations) will be set to missing 
for the PK analysis. 
If an entire concentration-time profile is BLQ, the profile is excluded from the PK analysis. 
For descriptive statistics plasma concentrations that are below the LLOQ will be handled as 
follows:  
• At a time point where less than or equal to 50% of the values are BLQ, all BLQ values 
will be set to LLOQ, and all descriptive statistics will be calculated. 
• At a time point where more than half of the values are BLQ, the mean, SD, geometric 
mean and CV% will be set to Not Determined (ND). The max value will be reported 
from the individual data, and the min and median will be set to BLQ. 
• If all values are BLQ at a time point, no descriptive statistics will be calculated for 
that time point. Not applicable (NA) will be written in the field for SD and CV% and 
BLQ will be written in fields for mean, geometric mean, min, median, and max. 
• The number of BLQ values (n below LLOQ) will be reported for each time point. 
• Where there is no result, these will be set to missing.  
Urine concentrations that are below the LLOQ will be handled as follows: 
• BLQ values should be set to zero for the calculation of individual Ae. 
• Any resulting Ae values equal to zero should be set to missing for the calculation of 
the summary statistics. 
4.2.5.3 
Handling of Dropouts and Missing Data 
Not applicable  
4.2.5.4 
Primary Analysis of Secondary Endpoint 
A listing of PK blood sample collection times as well as derived sampling time deviations 
will be provided. A listing of urine sample collection start and stop times will be provided. 
Urine amount and fraction of dose excreted (by interval and cumulative) will be listed. 
 
 


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Pharmacokinetic Concentrations 
Plasma concentrations, amount excreted in urine (Ae), and fraction of dose excreted (per 
collection interval and cumulative) and PK parameters will be summarized by analytes and 
timepoints using descriptive statistic, number of non-missing observations, n below LLOQ, 
arithmetic mean, SD, geometric mean, geometric coefficient of variation (CV%), min, 
median, max and based upon the PK analysis set. 
Where the actual time that a sample was taken deviates by more than the specified time 
allowances from the nominal time then concentration will be excluded from the summary 
statistics and statistical analysis.  
Nominal Time 
Time allowance 
Pre-dose 
Up to 30 minutes prior to dosing 
0.5 h post dose 
± 2 minutes 
1 h post dose 
± 5 minutes 
1.5 h post dose 
± 5 minutes 
2 h post dose 
± 5 minutes 
2.5 h post dose 
± 5 minutes 
3 h post dose 
± 10 minutes 
4 h post dose 
± 10 minutes 
5 h post dose 
± 10 minutes 
6 h post dose 
± 10 minutes 
8 h post dose 
± 10 minutes 
10 h post dose 
± 30 minutes 
12 h post dose 
± 30 minutes 
24 h post dose 
± 1 hour 
36 h post dose 
± 1 hour 
48 h post dose 
± 1 hour 
 
Data from subjects excluded from the PK population will be included in the data listings, but 
not in the summaries or in the inferential statistics. 
For tmax and time of last quantifiable plasma concentration (tlast) only n, median, minimum 
and maximum will be used.  
Pharmacokinetic parameters will be rounded for reporting purposes in the summary tables 
and subject listings, as per the PK order form provided by AZ. 


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Individual plasma concentrations versus actual time will be plotted in linear and semi-
logarithmic scale, with separate plots for each subject. Plots will be based on the PK analysis 
set. 
Combined individual plasma concentration versus actual times will be plotted in linear and 
semilogarithmic scale. Plots will be grouped by dose level and based on the PK analysis.  
Figures for the arithmetic mean concentration-time data will be presented for all groups (pool 
data from all treatment groups and for placebo) overlaid on the same plot, in both a linear 
and semi-logarithmic scale (SD on the linear scale and gSD on the semi-logarithmic scale). 
Additional graphical presentations of PK data may be added at the discretion of the PK 
scientist. 
Pharmacokinetic data will be presented by analytes and  timepoints. A listing of all 
concentration-time data will be presented by dose level.  
The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of concentration data:  
1. Source data shall be used in all derived PK concentrations without prior rounding. 
2. The mean, standard deviation (SD), geometric mean and median will be tabulated to 
one more significant digit compared to the source data, but with a maximum of four 
significant digits. 
3. Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four significant digits. 
4. Geometric coefficient of variation (CV) % and coefficient of variation (CV%) will be 
presented to one decimal place. 
Graphical Presentation  
For individual figures, concentrations that are BLQ will be regarded as missing, with the 
exception of pre-dose BLQ values which will be set to zero for linear scale plots.  
For mean plots, BLQ values will be handled as described for the summary tabulations so that 
the same plasma concentration values are used in the mean data graphs as those given in the 
descriptive statistics summary table for each time point. All mean plots will be based on the 
PK analysis set. 
 


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Pharmacokinetic Parameters 
Pharmacokinetic parameters will be derived using noncompartmental methods with 
WinNonlin® Professional Version 6.4, or higher, (Certara) and/or SAS® Version 9.3, or 
higher (SAS Institute, Inc., Cary, North Carolina). All descriptive and inferential statistical 
computations will be performed using SAS® Version 9.3, or higher. 
The actual sampling times, recorded in the raw data, will be used in the final plasma PK 
parameter calculations. If actual times are missing, nominal times may be used. 
Nominal sampling times will be used for interim plasma PK parameter calculations. 
Nominal times will be used for the calculation of urine PK parameters. 
Concentration data will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with amount and concentration units, 
will be presented as they are received from the analytical laboratory. 
Dose normalized parameters for AUClast, AUC and Cmax will be calculated by dividing the 
original parameter by dose.  
The Cmax and time to reach peak or maximum observed concentration or response following 
drug administration (tmax) will be derived directly from the plasma concentration-time 
profiles. For multiple peaks the highest post dose concentration will be reported as Cmax. In 
the case that the multiple peaks are of equal magnitude, the earliest tmax will be reported. 
Terminal elimination half-life, estimated as (ln2)/λz, where λz refers to the terminal 
elimination rate constant, will be estimated by log linear least squares regression of the 
terminal part of the concentration-time curve. 
The choice of data points used to estimate λz should follow the general guidelines: 
• If there is more than 1 phase, use only observations from the terminal phase. 
• In general, the minimum data requirements are 3 measured concentrations spanning 
three half-lives. Where t1/2 is estimated over less than three half-lives, the values will 
be flagged in the data listings. 
• Should include the last measurable concentration. 
• Include only observations after Cmax. 
• The adjusted correlation coefficient (regression coefficient adjusted for λz, N, 
goodness of fit statistic for calculation of λz; Rsq adj) should be ≥ 0.80.  


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Area under the plasma concentration-curve will be calculated using trapezoidal methods 
when concentration is increasing and logarithmic trapezoidal method when concentrations 
are decreasing (linear up log down). 
Three concentrations higher than the lower limit of quantification (LLOQ) are required as a 
minimum for the AUC parameter to be calculated.  
If the pre-dose concentration prior to the first dose is missing it will be set to zero by default. 
If the pre-dose sample on Day 57 is missing it may be set equal to the concentration at the 
end of the dosing interval for the calculation of area under the plasma concentration-time 
curve in the dosing interval (AUC) assuming linear PK and steady state conditions apply. 
If the sample at the end of the profile is missing on Day 57 the concentration may be set equal 
to the pre-dose value for the calculation of AUC assuming linear PK and steady state 
conditions apply.  
If a plasma or urine concentration value is considered anomalous due to being inconsistent 
with the expected pharmaceutical profile it may be appropriate to exclude this data point from 
the PK analysis. However, the exclusion of any data must have strong justification and will 
be documented in the study report. Embedded BLQs may be considered anomalous 
depending on the characteristics of the drug.  
Urine PK parameters will be calculated based on measurements with the ECL assay. In case 
of an incomplete urine collection in any of the specified collection intervals (eg, spilled 
sample), the calculation of the fraction of dose excreted into urine as well as renal clearance 
will be subject to discretion of the AZ study pharmacokineticist. 
The amount excreted in urine (Ae) will be calculated using a urine density of 1.0 g/mL. Urine 
concentrations below LLOQ will be treated as numerical zero.  
The amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)] and percentage 
excreted unchanged in urine from t1 to t2 [fe(t1-t2)] will be calculated by collection interval 
and cumulatively for all collection intervals. 
4.2.6 
Secondary Endpoint – Change from baseline in log-transformed 
PCSK9 in plasma 
4.2.6.1 
Definition 
Not applicable. 
4.2.6.2 
Derivations 
PCSK9 measurement will be assigned to analysis visits as described in Section 3.3.2. 
Measurements below the LLOQ for which the exact value cannot be determined will be 


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replaced by the LLOQ divided by the square root of 2. After replacement of LLOQ, PCSK9 
the absolute change and percent change from baseline are calculated for each study visit.  
Change from baseline of the log-transformed variable is calculated as the visit value in natural 
logarithm minus the baseline value in natural logarithm. Percent change from baseline is 
calculated using the raw values as the visit value minus the baseline value divided by the 
baseline value *100. 
Baseline values for PCSK9 are defined as the geometric mean of the two measures taken pre-
dose at Visit 2 (Day -1 and pre-dose Day1). 
4.2.6.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.  
4.2.6.4 
Primary Analysis of Secondary Endpoint 
PCSK9 endpoints will be summarized as continuous log-normal variables and based on the 
PD Analysis Set. The absolute change and percent change from baseline will presented. 
Summaries of the log-transformed variables will be presented by visit and treatment group 
using the principles defined in Section 3.3.  
A plot of geometric means and corresponding gSD at each post-treatment visit, by treatment 
group will be generated. 
4.2.7 
Secondary Endpoint – Percent change from baseline in LDL-C 
4.2.7.1 
Definition 
Three measures of LDL-C will be assessed; LDL-C derived by Friedewald formula, LDL-C 
derived by the Martin/Hopkins formula and direct LDL-C. 
4.2.7.2 
Derivations 
LDL-C values will be assigned to analysis visits as defined in Section 3.3.2. Measurements 
below the LLOQ for which the exact value cannot be determined will be replaced by the 
LLOQ divided by the square root of 2.  
LDL-C derived by Friedewald or Martin/Hopkins formula are indirectly calculated and hence 
may take 0 mg/dL or negative values (reported as ‘Unable to Calculate’ by Central lab)  
(Sampson et al, 2020). LLOQs will not be defined for these indirectly calculated 
measurements according to Central lab. These data will be replaced by 1/square root of 2 
mg/dL for the analysis and displayed as reported from Central lab in the listings. After 
replacement of LLOQ, the percent change from baseline is calculated as the visit value minus 
the baseline value divided by the baseline value * 100. 


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Baseline values for LDL-C are defined as the geometric mean of the two measures taken pre-
dose at Visit 2 (Day -1 and pre-dose Day1). 
4.2.7.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.  
4.2.7.4 
Primary Analysis of Secondary Endpoint 
LDL-C values will be summarized based on the PD Analysis Set. Summaries of the percent 
change from baseline and individual values will be presented by visit and treatment group 
using the principles defined in Section 3.3. 
4.2.8 
Secondary Endpoint – Other Lipid Parameters 
4.2.8.1 
Definition 
The following lipid parameters will be summarized: 
• Total cholesterol (TC). 
• High-density lipoprotein cholesterol (HDL-C). 
• Non-HDL-C. 
• Very low density lipoprotein cholesterol (VLDL-C). 
• Apolipoproteins (Apo) A1. 
• ApoB. 
• Lp(a) 
• Triglycerides. 
4.2.8.2 
Derivations 
Lipid parameters will be assigned to analysis visits as defined in Section 3.3.2. Measurements 
below the LLOQ for which the exact value cannot be determined will be replaced by the 
LLOQ divided by the square root of 2.  After replacement of LLOQ, lipid values will be log-
transformed and the change from baseline, and the percent change from baseline will be 
calculated for each study visit.  
Change from baseline of the log-transformed variable is calculated as the visit value in natural 
logarithm minus the baseline value in natural logarithm. Percent change from baseline is 
calculated as the visit value minus the baseline value divided by the baseline value * 100. 


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4.2.8.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.2.8.4 
Primary Analysis of Secondary Endpoint 
Other lipid endpoints will be summarized as continuous log-normal variables and based on 
the PD Analysis Set. The absolute change and the percent change from baseline will 
presented. Summaries of the log-transformed variables will be presented by visit and 
treatment group using the principles defined in Section 3.3.  
4.2.9 
Exploratory Endpoint - Immunogenicity 
4.2.9.1 
Definition 
Development of anti-drug antibodies (ADA) and ADA titre will be used to evaluate the 
immunogenicity of AZD8233. Titre evaluations are conducted only on those samples that are 
confirmed positive for ADA.  
4.2.9.2 
Derivations 
ADA parameters will be assigned to an analysis visit as defined in Section 3.3.2.  
4.2.9.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2 
4.2.9.4 
Primary Analysis of Other Endpoint 
ADA endpoints will be analyzed based on the Safety Analysis Set. The number and 
percentage of subjects with a positive result will be tabulated for: any time in study, baseline, 
any time post-baseline, and by visit and treatment group along with a summary of ADA titre 
using the principles defined in Section 3.3. 
4.3 
Pharmacodynamic Endpoint(s)  
Refer to Sections 4.2.6, 4.2.7 and 4.2.8. 
4.4 
Pharmacokinetics  
Refer to Section 4.2.5. 
4.5 
Immunogenicity  
Refer to Section 4.2.9.Safety Analyses  
The domain safety covers exposure, overdoses and physical examinations. Adverse events, 
clinical laboratory, vital signs, and ECG have been summarized in previous sections. 


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4.6.1 
Exposure 
4.6.1.1 
Definitions and Derivations 
Treatment exposure will be calculated in days as the treatment duration from date of first 
dose to date of last dose, inclusive. 
Duration of exposure (days) = last dose date – first dose date + 1 
4.6.1.2 
Presentation 
Duration of exposure will be summarized based on the Safety Analysis Set. Summaries will 
be presented by treatment group using the principles outlined in Section 3.3 for continuous 
variables. 
4.6.2 
Overdose 
4.6.2.1 
Definitions and Derivations 
An overdose is considered as any dose of AZD8233 greater than the planned dose.  
4.6.2.2 
Presentation 
All overdose data will be listed, including randomized treatment, total dose and unit, 
date/time overdose started and stopped, whether it was intentional and association with AE.  
4.6.3 
Physical Examinations 
4.6.3.1 
Definitions and Derivations 
The full physical examination includes an assessment of general appearance and a review 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. 
Abbreviated physical examinations will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen). 
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.     
4.6.3.2 
Presentation 
Physical Examination data will not be solely collected and not presented in CSR. 
5 
INTERIM ANALYSIS 
No planned interim analyses. 


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6 
REFERENCES 
Sampson, Maureen, Clarence Ling, Qian Sun, Roa Harb, Mohmed Ashmaig, Russell 
Warnick, Amar Sethi et al. "A new equation for calculation of low-density lipoprotein 
cholesterol in patients with normolipidemia and/or hypertriglyceridemia." JAMA 
cardiology 5, no. 5 (2020): 540-548.


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7 
APPENDIX 
7.1 
Schedule of Activities 
 
Screening 
Treatment Period 
Follow-up Period 
Visit Number  
1 
2 
3, 6 
4, 5, 7, 8 
9 
Telephone 
contact k 
10 to 16 
17 
(Final 
Follow up 
Visit/ ED 
Visit) 
Study 
Day/Week 
Days 
-28 to -4 
Day -1 
Days 1 to 3 
Day 8a, 29 
Days 
15, 22, 36, 44 
Day 56 
Days  
57 to 59 
Day 64 
Weeks 2, 
4, 6, 8, 10, 
12, 14 (after 
last dose) 
Week 16 
(after last 
dose) 
Visit Window  
- 
- 
- 
± 1 day 
± 1 day 
± 1 day 
± 2 days 
± 2 days 
+2 days 
Informed consent  
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria b 
X 
X 
 
 
 
 
 
 
 
 
Demographic data  
X 
 
 
 
 
 
 
 
 
 
Weight and height 
(BMI)c  
X 
X 
 
 
 
 
X 
(Day 57) 
 
 
X 
Medical history  
X 
 
 
 
 
 
 
 
 
 
Concomitant 
medication  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Drug abuse and 
alcohol screen d 
X 
 
 
 
 
X 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
 
 
Viral serology e 
X  
 
 
 
 
 
 
 
 
 
Pregnancy test  
XO 
 
XP 
 
 
 
 
 
 
 




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Screening 
Treatment Period 
Follow-up Period 
Visit Number  
1 
2 
3, 6 
4, 5, 7, 8 
9 
Telephone 
contact k 
10 to 16 
17 
(Final 
Follow up 
Visit/ ED 
Visit) 
Study 
Day/Week 
Days 
-28 to -4 
Day -1 
Days 1 to 3 
Day 8a, 29 
Days 
15, 22, 36, 44 
Day 56 
Days  
57 to 59 
Day 64 
Weeks 2, 
4, 6, 8, 10, 
12, 14 (after 
last dose) 
Week 16 
(after last 
dose) 
Visit Window  
- 
- 
- 
± 1 day 
± 1 day 
± 1 day 
± 2 days 
± 2 days 
+2 days 
Physical 
examination 
X 
(complete) 
X 
(abbreviated) 
X 
(abbreviated; 
pre-dose and 
then 24 and 
48 h post- 
dose) 
X 
(abbreviated; 
pre-dose) 
 
 
X 
(abbreviated; 
24 h post-
dose) 
 
X 
(abbreviated) 
X 
(complete) 
Blood pressure and 
pulse rate (sitting)f 
X  
X 
X 
(pre-dose 
and then 
0.25, 0.5, 1, 
1.5, 2, 2.5, 3, 
4, 6, 8, 12, 
24, 36 and 
48h post-
dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose 
and then 0.5, 
1, 2, 3, 4, 6, 
8, 12, 24, 36 
and 48h 
post-dose) 
 
X  
X  
Body temperature  
 
X 
X 
(pre-dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose) 
 
X 
X 
12-lead safety 
ECG g 
X 
 
X 
(pre-dose 
and then 0.5, 
1, 2, 3, 4, 6, 
8, 12, 24, 36 
and 48h 
post-dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose 
and then 0.5, 
1, 2, 3, 4, 6, 
8, 12, 24, 
36 and 48 h 
post-dose) 
 
X 
X 


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Screening 
Treatment Period 
Follow-up Period 
Visit Number  
1 
2 
3, 6 
4, 5, 7, 8 
9 
Telephone 
contact k 
10 to 16 
17 
(Final 
Follow up 
Visit/ ED 
Visit) 
Study 
Day/Week 
Days 
-28 to -4 
Day -1 
Days 1 to 3 
Day 8a, 29 
Days 
15, 22, 36, 44 
Day 56 
Days  
57 to 59 
Day 64 
Weeks 2, 
4, 6, 8, 10, 
12, 14 (after 
last dose) 
Week 16 
(after last 
dose) 
Visit Window  
- 
- 
- 
± 1 day 
± 1 day 
± 1 day 
± 2 days 
± 2 days 
+2 days 
Cardiac telemetry 
 
X 
(for at least 
4h) 
X 
(pre-dose to 
24 h post-
dose) 
 
 
 
X 
(pre-dose to 
24 h post 
dose) 
 
 
 
Hematology, 
Chemistry and 
Coagulation 
including hs-CRP) 
X  
X 
X 
(24 h post-
dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose) 
 
X 
(Week 2, 4, 
8 and 12 
after last 
dose) 
X  
Sampling for renal 
safety biomarkers  
X 
 
X 
(pre-dose 
and then 24 
and 48 h post 
dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose) 
 
 
 
Sampling for 
dipstick urinalysis 
for hematuria 
X 
 
X 
(pre-dose 
and then 24 
and 48 h post 
dose) 
X 
(pre-dose) 
 
 
X 
(pre-dose) 
 
 
 
Sampling for 
platelet count  
X  
X 
X 
(24 and 48 h 
post dose) 
X 
(pre-dose) 
X 
(Days 22, 44) 
X  
 
 
X  
X  
Complement 
activation panel h 
 
 
X 
(pre-dose 
 
 
 
X 
(pre-dose 
 
 
 






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a Day 8: no allowances. 
b The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (Visit1). 
c At Visit 1 and on Day -1, BMI be calculated. For Day -1, the height measured on Visit 1 will be utilised. At all other time points, only weight will be measured. 
d Drugs of abuse and alcohol screen: Investigator will interview participants regarding their use of drugs and alcohol. 
e Samples for HIV should be tested at a local laboratory. 
f Allowances: pre-dose (up to 30 minutes prior to dosing) and then 0.25 h (± 2 minutes), 0.5 h (± 10 minutes), 1 h (± 10 minutes), 1.5 h (± 10 minutes), 2 h (± 15 
minutes), 2.5 h ( ±15 minutes), 3 h (±15 minutes), 4 h (± 15 minutes), 6 h (± 15 minutes) , 8 h (± 15 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 36 h (± 1 hour) 
and 48 h (±1 hour) post-dose 
g Allowances: pre-dose (up to 30 minutes prior to dosing) and then 0.5 h (±10 minutes), 1 h (± 10 minutes), 2 h (±15 minutes), 3 h (±15 minutes), 4 h (±15 minutes), 
6h (±15 minutes), 8 h (±15 minutes), 12 h (±30 minutes), 24 h (± 1 hour), 36 h (±1 hour) and 48 h (±1 hour) post-dose. 
h Blood samples for complement activation panel will be collected pre-dose, and 1, 2 and 4 h post-dose so that the samples can be taken around Cmax. 
I Plasma and urine samples for biobanking must be collected at the same hour every morning after an overnight (10-hour) fast. 
j Allowance; pre-dose (up to 30 minutes prior to dosing) and then 0.5 h (±2 minutes), 1 h (±5 minutes), 1.5 h (±5 minutes), 2 h (±5 minutes), 2.5 h (±5 
minutes), 3 h (±10 minutes), 4 h (±10 minutes), 5 h (±10 minutes), 6 h (± 10 minutes), 8 h (±10 minutes), 10 h (± 30 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 
36 h (± 1hour) and 48 h (± 1 hour) post dose. 
k Telephone contact: A site or investigator will call participants to assess AEs. 
l Participants will be discharged after the results from the 48 h post-dose assessments have been reviewed by the Investigator. 
m The sample should be taken in a fasting state in the morning (after a 10 hour fasting) at approximately the same time point as the pre-dose sample on Day 1 
n Sampling to be done at approximately the same time points on the days of dosing (pre-dose) as on the non-dosing days (in the morning). 
o Pregnancy test: Serum β-human chorionic gonadotropin (β-hCG) will be performed on women of childbearing potential. 
p Pregnancy test (Day1): Urine pregnancy test using dipstick will be performed before randomization on women childbearing potential at a local laboratory. 
q All the women participants should have FSH and LH levels determined, irrespective of childbearing potential. 
 


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7.2 
Clinical Laboratory Assessments 
Hematology 
 
WBC count  
Neutrophils absolute count 
Red blood cell (RBC) count  
Lymphocytes absolute count 
Hemoglobin (Hb)  
Monocytes absolute count 
Hematocrit (HCT)  
Eosinophils absolute count 
Mean corpuscular volume (MCV)  
Basophils absolute count 
Mean corpuscular haemoglobin (MCH)  
Platelets absolute count 
Mean corpuscular haemoglobin concentration 
(MCHC)  
Reticulocytes absolute count 
 
Clinical Chemistry 
Sodium  
ALP 
Potassium  
ALT 
Blood urea nitrogen (BUN)  
AST 
Creatinine  
Gamma glutamyl transpeptidase (GGT) 
Calcium  
Total bilirubin 
Phosphate  
Direct bilirubin 
Glucose (fasting)  
Glutamate dehydrogenase (GLDH) 
Creatine kinase (CK)  
Lactate dehydrogenase (LDH) 
Bicarbonate  
Uric acid 
HbA1c  
FSH (women only) 
Serum β-human chorionic gonadotropin (β- 
hCG)(women of childbearing potential only) 
Luteinizing hormone (LH) (women only) 
eGFR 
 
 
Coagulation 
aPTT  
Prothrombin time 
International normalized ratio (INR) 
 
 
 
 


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Urine renal safety biomarkers 
Albumin  
N-acetyl-beta-D-glucosaminidase (NAG) 
Total protein  
Kidney Injury Molecule-1 (KIM-1) 
Creatinine  
Neutrophil gelatinase-associated lipocalin (NGAL) 
Clusterin 
Osteopontin 
Cystatin-C  
UACR 
Composite Measure 
 
 
 
Other laboratory assessments 
Complement activation panel (C3a, Bb, C5a)  
High-sensitive C-reactive protein (hs-CRP) 
Dipstick urinalysis for hematuria  
Dipstick urinalysis for human chorionic 
gonadotropin (hCG)(women of childbearing 
potential only) 
 
 
 
 


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7990c00006-sap-part-a-ed-4
Document Title:
D7990C00006 Statistical Analysis Plan Part A Edition 4 (post-
DBL)
Document ID:
Version Label:
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
Content Approval
Author Approval
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.


STATISTICAL ANALYSIS PLAN 
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D7990C00006 (Part B) – ed. 2.0 
11-May-2022 
CONFIDENTIAL AND PROPRIETARY 
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STATISTICAL ANALYSIS PLAN 
Study Code 
D7990C00006 (Part B) 
Edition Number 
2.0 
Date 
11-May-2022 
A Phase 1 and 2 study to evaluate the safety, tolerability, 
efficacy, pharmacokinetics and pharmacodynamics of AZD8233 
following a multiple subcutaneous dose administration in 
Japanese participants with dyslipidemia (HAYATE) – Part B 
 


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11-May-2022 
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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................. 2 
LIST OF ABBREVIATIONS .......................................................................................... 5 
AMENDMENT HISTORY .............................................................................................. 7 
1 
INTRODUCTION ......................................................................................... 8 
2 
CHANGES TO PROTOCOL PLANNED ANALYSES .............................. 8 
3 
DATA ANALYSIS CONSIDERATIONS .................................................... 8 
3.1 
Timing of Analyses ........................................................................................ 8 
3.2 
Analysis Populations ..................................................................................... 9 
3.2.1 
Enrolled Set ................................................................................................... 9 
3.2.2 
Randomly Assigned to Study Intervention .................................................... 9 
3.2.3 
Full Analysis Set (FAS) ................................................................................. 9 
3.2.4 
Safety Analysis Set ........................................................................................ 9 
3.2.5 
Pharmacokinetic Analysis Set ..................................................................... 10 
3.3 
General Considerations ................................................................................ 10 
3.3.1 
General Study Level Definitions ................................................................. 11 
3.3.1.1 
Definition of Baseline .................................................................................. 11 
3.3.1.2 
Handling of Missing Data ............................................................................ 11 
3.3.1.3 
Study Periods ............................................................................................... 13 
3.3.2 
Visit Window ............................................................................................... 13 
3.3.3 
Handling of Unscheduled Visits .................................................................. 17 
3.3.4 
Multiplicity/Multiple Comparisons ............................................................. 17 
3.3.5 
Handling of Protocol Deviations in Study Analysis .................................... 17 
4 
STATISTICAL ANALYSIS ....................................................................... 18 
4.1 
Study Population .......................................................................................... 18 
4.1.1 
Subject Disposition and Completion Status ................................................ 18 
4.1.1.1 
Definitions and Derivations ......................................................................... 18 
4.1.1.2 
Presentation .................................................................................................. 18 
4.1.2 
Analysis Sets ................................................................................................ 19 
4.1.2.1 
Definitions and Derivations ......................................................................... 19 
4.1.2.2 
Presentation .................................................................................................. 19 
4.1.3 
Protocol Deviations ..................................................................................... 19 
4.1.3.1 
Definitions and Derivations ......................................................................... 19 
4.1.3.2 
Presentation .................................................................................................. 19 
4.1.4 
Demographics .............................................................................................. 19 
4.1.4.1 
Definitions and Derivations ......................................................................... 19 
4.1.4.2 
Presentation .................................................................................................. 20 
4.1.5 
Baseline Characteristics ............................................................................... 20 
4.1.5.1 
Definitions and Derivations ......................................................................... 20 
4.1.5.2 
Presentation .................................................................................................. 20 
4.1.6 
Disease Characteristics ................................................................................ 20 
4.1.6.1 
Definitions and Derivations ......................................................................... 20 


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4.1.6.2 
Presentation .................................................................................................. 21 
4.1.7 
Medical History and Concomitant Disease ................................................. 21 
4.1.7.1 
Definitions and Derivations ......................................................................... 21 
4.1.7.2 
Presentation .................................................................................................. 21 
4.1.8 
Prior and Concomitant Medications ............................................................ 21 
4.1.8.1 
Definitions and Derivations ......................................................................... 21 
4.1.8.2 
Presentation .................................................................................................. 21 
4.1.9 
Study Drug Compliance .............................................................................. 22 
4.1.9.1 
Definitions and Derivations ......................................................................... 22 
4.1.9.2 
Presentation .................................................................................................. 22 
4.2 
Endpoint Analyses ....................................................................................... 22 
4.2.1 
Primary Endpoint ......................................................................................... 24 
4.2.1.1 
Definition ..................................................................................................... 24 
4.2.1.2 
Derivations ................................................................................................... 24 
4.2.1.3 
Handling of Dropouts and Missing Data ..................................................... 25 
4.2.1.4 
Primary Analysis of Primary Endpoint ........................................................ 25 
4.2.1.5 
Sensitivity Analyses of the Primary Endpoint ............................................. 26 
4.2.1.6 
Supplementary Analyses of the Primary Endpoint ...................................... 27 
4.2.1.7 
Subgroup Analyses ...................................................................................... 27 
4.2.2 
Secondary Endpoint- Absolute change from baseline in log-transformed 
PCSK9 in plasma and percent change from baseline in PCSK9 in plasma . 27 
4.2.2.1 
Definition ..................................................................................................... 27 
4.2.2.2 
Derivations ................................................................................................... 27 
4.2.2.3 
Handling of Dropouts and Missing Data ..................................................... 27 
4.2.2.4 
Primary Analysis of Secondary Endpoint .................................................... 27 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint ......................................... 28 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint .................................. 28 
4.2.2.7 
Subgroup Analyses ...................................................................................... 28 
4.2.3 
Secondary Endpoint- Percent change in levels of LDL-C in serum ............ 28 
4.2.3.1 
Definition ..................................................................................................... 28 
4.2.3.2 
Derivations ................................................................................................... 28 
4.2.3.3 
Handling of Dropouts and Missing Data ..................................................... 29 
4.2.3.4 
Analysis of Secondary Endpoint ................................................................. 29 
4.2.4 
Secondary Endpoint- Levels of other lipid parameters ............................... 29 
4.2.4.1 
Definition ..................................................................................................... 29 
4.2.4.2 
Derivations ................................................................................................... 29 
4.2.4.3 
Handling of Dropouts and Missing Data ..................................................... 29 
4.2.4.4 
Analysis of Secondary Endpoint ................................................................. 30 
4.2.5 
Secondary Endpoint- PK ............................................................................. 30 
4.2.5.1 
Definition ..................................................................................................... 30 
4.2.5.2 
Derivations ................................................................................................... 30 
4.2.5.3 
Handlings of Dropouts and Missing Data ................................................... 30 
4.2.5.4 
Analysis of Secondary Outcome ................................................................. 30 
4.2.6 
Secondary Endpoint- Development of ADA and ADA titer (if subjects are 
ADA positive) during treatment and follow-up. .......................................... 31 
4.2.6.1 
Definition ..................................................................................................... 31 


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4.2.6.2 
Derivations ................................................................................................... 31 
4.2.6.3 
Handling of Dropouts and Missing Data ..................................................... 31 
4.2.6.4 
Analysis of Secondary Endpoint ................................................................. 32 
4.2.7 
Other Endpoint – Injection Site Reactions .................................................. 33 
4.2.7.1 
Definition ..................................................................................................... 33 
4.2.7.2 
Derivations ................................................................................................... 33 
4.2.7.3 
Handling of Dropouts and Missing Data ..................................................... 33 
4.2.7.4 
Analysis of Other Endpoint ......................................................................... 33 
4.3 
Safety Analyses ........................................................................................... 33 
4.3.1 
Exposure ...................................................................................................... 33 
4.3.1.1 
Definitions and Derivations ......................................................................... 33 
4.3.1.2 
Presentation .................................................................................................. 33 
4.3.2 
Adverse Events ............................................................................................ 34 
4.3.2.1 
Definitions and Derivations ......................................................................... 34 
4.3.2.2 
Presentation .................................................................................................. 34 
4.3.3 
Clinical Laboratory, Blood Sample ............................................................. 35 
4.3.3.1 
Definitions and Derivations ......................................................................... 35 
4.3.3.2 
Presentation .................................................................................................. 37 
4.3.4 
Clinical Laboratory, Urinalysis ................................................................... 38 
4.3.4.1 
Definitions and Derivations ......................................................................... 38 
4.3.4.2 
Presentation .................................................................................................. 38 
4.3.5 
Other Laboratory Evaluations ...................................................................... 38 
4.3.5.1 
Definitions and Derivations ......................................................................... 38 
4.3.5.2 
Presentation .................................................................................................. 39 
4.3.6 
Vital Signs ................................................................................................... 39 
4.3.6.1 
Definitions and Derivations ......................................................................... 39 
4.3.6.2 
Presentation .................................................................................................. 39 
4.3.7 
Electrocardiogram ........................................................................................ 40 
4.3.7.1 
Definitions and Derivations ......................................................................... 40 
4.3.7.2 
Presentation .................................................................................................. 40 
4.3.8 
Other Safety Assessments ............................................................................ 41 
5 
INTERIM ANALYSIS ................................................................................ 41 
6 
REFERENCES ............................................................................................ 41 
7 
APPENDIX.................................................................................................. 42 
7.1 
Schedule of Activities .................................................................................. 42 
7.2 
Clinical Laboratory Assessments ................................................................ 47 
 
 
 
 
 


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11-May-2022 
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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialized Term 
Definition 
ADA 
Antidrug antibody 
AE 
Adverse event 
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 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CV 
Coefficient of variation 
DBL 
Database Lock 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDV 
Early discontinuation visit 
eGFR 
Estimated glomerular filtration rate 
FAS 
Full Analysis Set 
FUP 
Follow Up Period 
HDL-C 
High density lipoprotein cholesterol 
HLT 
High level term 
HR 
Heart rate 
IP 
Investigational Product 
IPD 
Important Protocol Deviation 
IV 
intravenous 
LDL-C 
Low density lipoprotein cholesterol 
LLOQ 
Lower limit of quantification 
Lp(a) 
Lipoprotein(a) 
LSM 
Least Squares Mean 
LSMD 
Least Squares Mean Difference 
MAR 
Missing at Random 
MCMC  
Monte-Carlo Markov Chain 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model with repeated measures 
NHP 
Non-compliance Handling Plan 
PCSK9 
Proprotein convertase subtilisin/kexin type-9 
PK 
Pharmacokinetics 
PT 
Preferred Term 
QTcF 
Corrected QT Interval using Fridericia’s Formula 
RR 
Respiratory rate 
SAE 
Serious adverse event 


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SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
TBL 
Total bilirubin 
TC 
Total cholesterol 
TEAE 
Treatment emergent adverse event 
TG 
Triglycerides  
ULN 
Upper limit of normal 
VLDL-C 
Very-low-density lipoprotein cholesterol 
WHO 
World Health Organization 
WHO-DD 
WHO Drug Dictionary 
 


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11-May-2022 
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AMENDMENT HISTORY 
CATEGORY 
Change refers to: 
Date 
Description of 
change 
In line with CSP? 
Rationale 
N/A 
Click or tap here 
to enter text. 
Initial approved SAP 
N/A 
N/A 
Data presentation 
18-Nov-21 
Update analysis visit 
windows in line with 
schedule of activities 
in CSP 
Y 
Ease of programming.  
NA 
12-Apr-22 
Added that an 
additional SAP will 
be produced for Part 
C 
Y 
NA 
Data presentation 
12-Apr-22 
Removed LSM (SE) 
plots from primary 
analysis 
Y 
Not required. 
Data presentation 
12-Apr-22 
Percent change 
derived from MMRM 
model, definition and 
summary.  
Y 
Ease of interpretation of 
the results.  
Data presentation 
12-Apr-22 
Added additional 
analyses for Bleeding 
AEs 
Y 
To give more detailed 
summary of AEs 
Data presentation 
12-Apr-22 
Added additional 
analyses for platelet 
counts 
Y 
To give more detailed 
summary of platelet 
counts 
Data presentation 
12-Apr-22 
Added additional 
analyses for 
hematology results 
Y 
To give more detailed 
summary of hematology 
results 
 




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• Investigators, other site personnel and study subjects will remain blinded to treatment 
assignment until the final DBL.  
• The final analysis will be conducted after all randomized patients have completed the 
entire 24-week study period (including safety follow-up) or been withdrawn from the 
study.    
The two analyses will have the same scope, except for PK analysis which will be included 
only in the final analysis.  
3.2 
Analysis Populations 
3.2.1 
Enrolled Set 
All participants who signed the informed consent form. The Enrolled Set will be used to 
summarize patient disposition. 
3.2.2 
Randomly Assigned to Study Intervention 
All participants who were randomized. Participants will be analyzed according to the 
treatment to which they were randomized.  
3.2.3 
Full Analysis Set (FAS) 
All randomized participants who received at least one 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. For all efficacy analyses, FAS 
will be used. 
3.2.4 
Safety Analysis Set 
All participants randomly assigned to study treatment who took at least one dose of study 
intervention and for whom any post-dose data are available. Participants will be analyzed 
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 
would be the treatment group that participant was randomized to.  
The Safety Analysis Set will be used as the analysis set for all summaries for safety evaluation 
unless stated otherwise and for the analysis of the immunogenicity data.  


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3.2.5 
Pharmacokinetic Analysis Set 
The Pharmacokinetic (PK) Analysis Set will consist of all subjects in the FAS who received 
at least one dose of AZD8233 and who have evaluable PK data, with no important protocol 
deviations thought to impact on the analysis of the PK data.  
The exclusion of any subjects or time points will be documented by the PK scientist, 
including the reasons for exclusion. The available concentration data for any participants 
excluded from the PK analysis set will be listed only. Concentration data for participants 
excluded from the PK analysis set will not be presented in the individual figures of 
concentration versus time plots. 
The PK Analysis Set will be used to summarize the PK data and will be presented in 
accordance with the actual treatment received.  
3.3 
General Considerations 
The following principles will be followed throughout the study: 
• Continuous variables will be summarized by the number of non-missing observations, 
mean, standard deviation (SD), median, first and third quartiles, and the minimum 
and maximum as appropriate. 
• Log-transformed continuous variables will be summarized in a similar manner. In 
addition, the relative change from baseline will be calculated by back-transforming 
the change from baseline of the logarithmic variable as necessary.  
• Categorical variables will be summarized as counts (n) and percentages (%). Unless 
otherwise stated, percentages will be calculated using the relevant analysis set 
population total as the denominator. Percentages will not be presented for zero counts. 
• Mean and medians will be rounded to one additional decimal place relative to the 
original data, the SD will be rounded to two additional decimal places, and the 
maximum, minimum and quartiles will be displayed with the same accuracy as the 
original data. 95% confidence intervals (CIs) will be presented to one more decimal 
place than the raw data. Percentages (proportion) will be rounded to one decimal 
place.  
• Summaries will be provided by time point of assessment where appropriate. Where 
summaries are over time, study day will be calculated in relation to Day 1, the date 
of first dose of study treatment. 


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• Corresponding listings will be provided for all tabulated results unless stated 
otherwise. Any additional listings that are required will be described in the 
appropriate sections of the SAP. 
• Statistical tests will be performed using two-sided test at a 5% significance level, if 
not explicitly stated otherwise. 
• 
SAS® version 9.3 or higher will be used for all data analyses. 
3.3.1 
General Study Level Definitions 
3.3.1.1 
Definition of Baseline 
Unless otherwise specified, ‘baseline’ refers to the last measurement obtained before the first 
dose of study intervention. For lipid parameters (PCSK9, LDL-C, etc), the measure taken 
pre-dose at Visit 3 (Day 1) will be typically considered as baseline.  
3.3.1.2 
Handling of Missing Data 
In general, missing data will not be imputed and will be treated as missing unless specifically 
described in an analysis section. The following considerations are made for missing safety 
data, adverse event (AE) dates, and concomitant medication/diseases dates: 
• Safety assessment values of the form ‘<x’ or ‘>x’ (i.e., above or below the limits of 
quantifications) will be imputed as ‘x’ divided by the square root of 2 in the 
calculation of summary statistics but displayed as ‘<x’ or ‘>x’ in the listings. 
• AEs that have missing causality after data querying will be assumed to be related to 
study drug.  
• For missing AE start dates, the following will be applied: 
o Only partial AE start dates are imputed. Dates which are completely missing 
are not imputed.  
o If only the day is missing and the month and/or the year is different from the 
month and year of the first dose of investigational product (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. 


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o 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. 
o 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. 
• For missing AE end dates, the following will be applied: 
o Completely missing AE end dates are not imputed. 
o If the AE is ongoing, the end date is set to missing. 
o If the AE is not ongoing, and if only the day is missing them assume the last 
day of the collected month. 
o If the AE is not ongoing, and both, the day and the month are missing then 
assume 31-DEC of the collected year. 
o 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. 
• For missing concomitant medication and concomitant procedures start dates, neither 
partially nor completely missing dates are imputed.  
• For missing concomitant medication and concomitant procedures end dates, the 
following will be applied: 
o Completely missing end dates or dates for which the year is missing are not 
imputed. 
o If the concomitant medication is ongoing, the end date is set to missing. 
o If the concomitant medication / procedure is not ongoing, and if only the day 
is missing then assume the last day of the collected month. 


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o If the concomitant medication / procedure is not ongoing, and both, the day 
and the month are missing then assume 31-DEC of the collected year. 
o 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. 
• If a subject is known to have died where only a partial death date is available, then 
the date of death will be imputed as the latest of the last known date to be alive + 1 
from the database and the death date using the available information provided: 
o Missing day only: Use the 1st of the month. 
o Missing day and month: Use 1st January. 
o Missing year: Impute the year of dosing. 
For all missing start/end dates, flags will be retained in the analysis datasets indicating where 
any programmatic imputation has been applied, and in such cases, any durations would not 
be calculated. 
3.3.1.3 
Study Periods 
For listings of adverse events, lipid levels, laboratory values, vital signs and ECG, values will 
be allocated to a study period. The allocation to the study periods will be performed after any 
imputation of missing dates (for AEs only) as described in Section 3.3.1.2. The study periods 
are defined as follows: 
• Pre-treatment: Before first date of study drug (Day <1). 
• On-treatment: From Day 1 to date of end of study. 
3.3.2 
Visit Window 
Study visits windows are defined in the table below: 








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at a subject level (i.e., the maximum) all values will be included regardless of whether they 
appear in a corresponding visit-based summary. 
3.3.3 
Handling of Unscheduled Visits  
Visits that fall outside the visit windows defined in the CSP will be classified as Unscheduled 
Visits. Unscheduled visits will be numbered sequentially with an increment of 0.1. For 
example, if two measurements are done in an unscheduled visit that occurs between Day 3 
and Day 8, then these visits will be numbered UNS 2.1 and 2.2 in the order they occurred.  
The values measured at unscheduled visits will not be included in the by-visit summary 
tables, they will be included in the overall summary tables (for abnormalities, 
minimum/maximums etc.) and will be presented in the listings. 
3.3.4 
Multiplicity/Multiple Comparisons 
Not applicable. 
3.3.5 
Handling of Protocol Deviations in Study Analysis 
Important protocol deviations (IPD) are defined as those deviations from the protocol likely 
to have an impact on the perceived efficacy and/or safety of study treatments. The impact of 
IPDs on the safety results will be investigated by assessing the robustness of the study results 
and conclusions to the choice of analysis set, both including and excluding data potentially 
affected by IPDs.  
This estimation will be performed on a Data Review Meeting (DRM) shortly before database 
lock. Results and population assignments will be summarized in a DRM report which will be 
signed off by all relevant scientific experts. 
The list of all IPDs is provided in the AstraZeneca Non-compliance Handling Plan (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 
(section 4.2.1.5) 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 a protocol deviation). 
• 
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 a protocol 
deviation). 


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• 
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. 
4 
STATISTICAL ANALYSIS 
This section provides information on definitions, derivation, and analysis/data presentation 
per domain. 
4.1 
Study Population 
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics medical history, prior and concomitant medication, 
and study drug compliance.  
4.1.1 
Subject Disposition and Completion Status 
4.1.1.1 
Definitions and Derivations 
Not applicable. 
4.1.1.2 
Presentation 
Subject disposition will be summarized based on the Enrolled Set and will include the 
following information:  
• 
Number of subjects enrolled. 
• 
Number of subjects randomized, 
• 
 Number and percentage of subjects who received at least one dose of study drug,  
• 
Number of subjects not randomized. 
• 
Number and percentage of subjects who completed treatment/discontinued 
treatment (including reasons for IP discontinuation).  
• 
Number and percentage of subjects who completed or discontinued study (including 
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Summaries will be by treatment group and overall. Percentages will be calculated using 
"Subjects randomized" as denominator. A randomization listing will be presented and will 
include the following information: randomization number, full enrolment number, date of 
randomization and randomized treatment group. 
Subjects affected by the COVID-19 pandemic and subjects with reported issues in the 
Clinical Trial Management System due to COVID-19 pandemic will be listed. 
4.1.2 
Analysis Sets 
4.1.2.1 
Definitions and Derivations 
Analysis sets are defined in Section 3.2. 
4.1.2.2 
Presentation 
Analysis sets will be summarized based on the Enrolled Set. The number of subjects included 
and excluded (including reason for exclusion) in each analysis population will be presented 
by treatment group. 
4.1.3 
Protocol Deviations 
4.1.3.1 
Definitions and Derivations 
Important protocol deviations (IPDs) will be defined in the NHP (refer to Section 3.3.5) and 
are considered as those deviations from the protocol likely to have an impact on the perceived 
efficacy or safety of study treatment. The final list of IPDs will be determined before each 
DBL. 
4.1.3.2 
Presentation 
IPDs will be summarized based on the Randomized set. The number and percentage of 
subjects meeting each IPD criterion will be summarized by treatment group. Subjects who 
deviate from a given criterion more than once will be counted once for that criterion. Any 
subjects with more than one IPD will be counted once in the overall summary. 
4.1.4 
Demographics 
4.1.4.1 
Definitions and Derivations 
Age is measured in years and calculated as: 
Age (years) = (Date of randomization – date of birth + 1) / 365.25 


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4.1.4.2 
Presentation 
Demographics (age, sex, ethnicity, race) will be summarized based on the Full Analysis Set. 
Summaries will be presented by treatment group and according to the principles outlined in 
Section 3.3. 
4.1.5 
Baseline Characteristics 
4.1.5.1 
Definitions and Derivations 
Body mass index (BMI) is calculated as: 
BMI (kg/m2) = weight (kg) / height2 (m) 
4.1.5.2 
Presentation 
Baseline characteristics (height, weight, BMI, nicotine use and alcohol use) will be 
summarized based on the Full Analysis Set. Summaries will be presented by treatment group 
and according to the principles outlined in Section 3.3. 
4.1.6 
Disease Characteristics 
4.1.6.1 
Definitions and Derivations 
Disease characteristics are defined as the following lipid related parameters measured at 
baseline: 
• LDL-C with reflex to PUC/beta-Quantification equals to:  
o LDL-C derived by Friedewald formula if LDL-C (Friedewald) ≥ 40mg/dL 
and Triglycerides (TG) < 400mg/dL. 
o LDL-C (PUC/beta-Quantification) if LDL-C (Friedewald) < 40mg/dL or TG 
≥ 400mg/dL. 
• LDL-C derived by Friedewald formula, without reflex, LDL-C derived by 
Martin/Hopkins formula and Direct LDL-C. 
• HDL-C and Non-HDL-C. 
• VLDL-C. 
• ApoA1 and ApoB. 
• Lipoprotein(a) (Lp(a)). 
• Triglycerides (TG). 


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• Remnant cholesterol 
4.1.6.2 
Presentation 
Disease characteristics will be summarized based on the Full Analysis set. Summaries will 
be presented by treatment group and according to the principles outlined in Section 3.3. 
4.1.7 
Medical History and Concomitant Disease 
4.1.7.1 
Definitions and Derivations 
Medical/surgical history, and concomitant (called “current”) diseases are coded using 
MedDRA version 24.0 or higher. The imputation method described in Section 3.3.1.2 will 
be used in the instance that partial or missing dates are recorded. After imputation of dates, 
current diseases will be classified as prior (called “past”) or current.  
A past disease is defined as any disease with a start and end date prior to the first dose date 
(exclusive). A current disease is defined as any disease with an end date on or after the first 
dose date. A disease with a completely missing end date will be considered as current. 
4.1.7.2 
Presentation 
Medical/surgical history, and current diseases will be summarized based on the Full Analysis 
Set. The number and percentage of subjects with relevant medical/surgical history/current 
diseases will be presented by treatment group and summarized by System Organ Class (SOC) 
and Preferred Term (PT). Subjects with histories in more than one SOC/PT will be counted 
only once in that SOC/PT. Tables will be sorted alphabetically by SOC and PT. 
4.1.8 
Prior and Concomitant Medications 
4.1.8.1 
Definitions and Derivations 
Prior (called “past”) and concomitant (called “current”) medications are coded using the 
WHO-DD. The imputation method described in Section 3.3.1.2 will be used in the instance 
that partial or missing dates are recorded. 
Past medications are defined as those that stopped and started prior to the first dose date. All 
medications on or after the first dose date are considered as current, this includes those 
medications that started prior to date of first dose but continued after. 
4.1.8.2 
Presentation 
Past and current medications will be summarized based on the Full Analysis Set. The number 
and percentage of subjects will be presented by treatment group and summarized by 
Anatomical Therapeutic Chemical (ATC) Class and Preferred Term (PT). Subjects with 
medications in more than one ATC class/PT will be counted only once in that ATC class/PT. 
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Change from baseline of the log-transformed variable will be calculated as the visit value in 
the natural logarithm minus the baseline value in natural logarithm. 
Percent change will be derived from the MMRM estimates as: 
Mean percent change = 100*(exp(LSMean) – 1) 
4.2.1.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.2.1.4 
Primary Analysis of Primary Endpoint 
The analysis and presentation will be based on subjects in the Full Analysis Set. 
The study hypothesis to be tested is treatment effect of AZD8233 across different dose levels 
 compared to placebo. 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. 
A mixed model with repeated measures will be fitted using the log-transformed LDL-C data. 
The model will include the log-transformed LDL-C baseline value as a covariate and 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 
LDL-C. The model will be fitted with an unstructured covariance structure, and the Kenward-
Roger correction applied to obtain the degrees of freedom. The primary model will include 
data up to and including Week 12 as a response variable.  
Estimation of the treatment effect will be calculated for each visit after baseline and presented 
alongside the corresponding 95% confidence interval. In case of issues when fitting the model 
to the data, the following hierarchical model fitting procedure will be adopted: 
1. The MMRM will be fitted using a spatial power 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 compound symmetry covariance structure. 
3. An ANCOVA model for Week 12 only will be used. 
Comparisons of the change from baseline between the treatment groups will be conducted 
using the least square mean difference (LSMD) between treatment groups as estimated by 




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2. Considering only the relevant AZD8233 group for the estimations of missing data 
for AZD8233 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 (reference 1). 
4.2.1.6 
Supplementary Analyses of the Primary Endpoint 
LDL-C derived by the Friedewald formula without reflex, LDL-C derived by the 
Martin/Hopkins formula and direct LDL-C will be analysed as described in section 4.2.1.4 
above and presented as a supplementary analysis of the primary endpoint.  
4.2.1.7 
Subgroup Analyses 
Not applicable. 
4.2.2 
Secondary Endpoint- Absolute change from baseline in log-
transformed PCSK9 in plasma and percent change from baseline in 
PCSK9 in plasma 
4.2.2.1 
Definition 
Not applicable. 
4.2.2.2 
Derivations 
PCSK9 measurement will be assigned to analysis visits as described in Section 3.3.2. 
Measurements below the LLOQ for which the exact value cannot be determined will be 
replaced by the LLOQ divided by the square root of 2. After replacement of LLOQ, the 
absolute change and percent change from baseline are calculated for each study visit.  
Change from baseline of the log-transformed variable is calculated as the visit value in natural 
logarithm minus the baseline value in natural logarithm. Percent change from baseline is 
calculated using the raw values as the visit value minus the baseline value divided by the 
baseline value *100. 
4.2.2.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.2.2.4 
Primary Analysis of Secondary Endpoint 
The absolute change from baseline in the log-transformed PCSK9 will be fitted using the 
mixed model for repeated measures as described for the primary endpoint (refer to section 
4.2.1.4), such that the model includes the log-transformed baseline value as a covariate, time 
point (visit number), treatment, and the interaction between time point and treatment as 


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factors. The least square mean differences between treatment groups will be estimated from 
the fitted model and presented alongside the corresponding 95% confidence interval. In 
addition, LSMs and 95% CIs will be back-transformed to present as relative (geometric) 
difference among treatment groups and the relative change will also be presented as the 
percent change from baseline. 
The summary and corresponding plot of the absolute change from baseline will be generated 
using the same method described for the primary endpoint (refer to Section 4.2.1.4). 
The percent change from baseline in PCSK9 will be analyzed using the same model as 
described previously without log-transformation. In addition, the summary and plot will be 
made using the same method. 
4.2.2.5 
Sensitivity Analyses of the Secondary Endpoint 
Not applicable. 
4.2.2.6 
Supplementary Analyses of the Secondary Endpoint 
Not applicable. 
4.2.2.7 
Subgroup Analyses 
Not applicable. 
4.2.3 
Secondary Endpoint- Percent change in levels of LDL-C in serum 
4.2.3.1 
Definition 
Percent change from baseline in LDL-C will be calculated on the raw scale for each subject.  
Reflex LDL-C will be primarily assessed and the direct LDL-C or other quantification may 
be considered in sensitivity analyses (refer to Section 4.2.1.1). 
4.2.3.2 
Derivations 
LDL-C values will be assigned to analysis visits as defined in Section 3.3.2. Measurements 
below the LLOQ for which the exact value cannot be determined will be replaced by the 
LLOQ divided by the square root of 2.  
LDL-C derived by Friedewald or Martin/Hopkins formula are indirectly calculated and hence 
may take 0 mg/dL or negative values (reported as ‘Unable to Calculate’ by Central lab)  
(Sampson et al, 2020). LLOQs will not be defined for these indirectly calculated 
measurements according to Central lab. These data will be replaced by 1/square root of 2 
mg/dL for the analysis and displayed as reported from Central lab in the listings. After 
replacement of LLOQ, the percent change from baseline is calculated as the visit value minus 
the baseline value divided by the baseline value * 100. 


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4.2.3.3 
Handling of Dropouts and Missing Data 
Refer to Sections 4.2.1.3. 
4.2.3.4 
 Analysis of Secondary Endpoint 
LDL-C will be analyzed using the statistical model described for the primary endpoint (refer 
to Section 4.2.1.4). 
LDL-C endpoints will be summarized by visit and treatment group using descriptive statistics 
(arithmetic mean, SD, minimum, median, maximum) using the principles defined in Section 
3.3.  
The plot of LSMean (95% CI) based on the MMRM estimates will be produced. 
Percent change from baseline for direct LDL-C will be analysed similarly. 
4.2.4 
Secondary Endpoint- Levels of other lipid parameters 
4.2.4.1 
Definition 
The following lipid parameters will be summarized: 
• Total cholesterol (TC). 
• High-density lipoprotein cholesterol (HDL-C). 
• Non-HDL-C. 
• Very low density lipoprotein cholesterol (VLDL-C). 
• Apolipoproteins (Apo) A1. 
• ApoB. 
• Lp(a) 
• Triglycerides. 
• Remnants cholesterol. 
4.2.4.2 
Derivations 
Refer to Section 4.2.2.2. 
4.2.4.3 
Handling of Dropouts and Missing Data 
Refer to Section 4.2.2.3. 


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4.2.4.4 
 Analysis of Secondary Endpoint 
Other lipid endpoints will be summarized as continuous log-normal variables and based on 
the Full Analysis Set.  
Change from baseline and percent change from baseline will be summarized by visit and 
treatment group using descriptive statistics (arithmetic mean, SD, minimum, median, 
maximum) using the principles defined in Section 3.3. 
An MMRM assuming a normal distribution on percent change from baseline to week 12 will 
also be presented for each lipid endpoint. 
The following plots by visit will be created by treatment group: 
• Mean (SD) for absolute value. 
• LSMean (95% CI) for percent change from baseline based on MMRM estimates. 
4.2.5 
Secondary Endpoint- PK 
4.2.5.1 
Definition 
Not applicable. 
4.2.5.2 
Derivations 
Population PK parameters are not derived and analysed within this SAP. Details on 
population PK analysis are provided in a separate report prepared by a dedicated 
pharmacometrics support group at AstraZeneca. Plasma concentrations are evaluated 
descriptively. 
4.2.5.3 
Handlings of Dropouts and Missing Data 
PK concentrations will be assigned to analysis visits as defined in Section 3.3.2. PK 
concentrations below the LLOQ for which the exact value cannot be determined, will be 
replaced with the LLOQ. 
4.2.5.4 
Analysis of Secondary Outcome 
Plasma concentrations will be summarized by each analysis visit and scheduled time using 
descriptive statistic, number of non-missing observations, n below LLOQ, arithmetic mean, 
SD, geometric mean, geometric coefficient of variation (CV%), min, median and max. 
Plasma concentrations will also be listed for all subjects in the PK analysis set. 


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4.2.6 
Secondary Endpoint- Development of ADA and ADA titer (if subjects 
are ADA positive) during treatment and follow-up. 
4.2.6.1 
Definition 
Development of anti-drug antibodies (ADA) and ADA titre will be used to evaluate the 
immunogenicity of AZD8233. Titre evaluations are conducted only on those samples that are 
confirmed positive for ADA. 
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 
postbaseline ADA positive assessment and not fulfilling the conditions of ADA persistently 
positive. 
4.2.6.2 
Derivations 
ADA parameters will be assigned to an analysis visit as defined in Section 3.3.2. 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). 
Missing ADA results are considered negative for the derivation of the ADA categories. The 
above categories will be calculated only for subjects in the ADA analysis set. 
4.2.6.3 
Handling of Dropouts and Missing Data 
Missing data will not be imputed and only observed values will be reported in the summary 
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4.2.6.4 
Analysis of Secondary Endpoint 
ADA endpoints will be analyzed based on the Safety Analysis Set. The number and 
percentage of subjects with a positive result will be tabulated for: any time in study, baseline, 
any time post-baseline, and by visit and treatment group.  ADA titre will be summarized 
descriptively as a continuous variable, only for ADA positive tests, with median, interquartile 
range, minimum, and maximum, at each 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 
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). 


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• A boxplot on log-transformed data exploring ADA positive vs ADA negatives impact 
on PK concentrations, PCSK9 and LDL over time one graph per treatment group 
(including placebo). 
• A figure showing the percentage of subjects with positive ADA results over time. 
4.2.7 
Other Endpoint – Injection Site Reactions 
4.2.7.1 
Definition 
Injection site reactions (ISRs) are reported using standard AE collection criteria. 
4.2.7.2 
Derivations 
Injection site criteria will be coded using the MedDRA version 24.0 or higher. 
4.2.7.3 
Handling of Dropouts and Missing Data 
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2. 
4.2.7.4 
Analysis of Other Endpoint 
All summaries of injection site reactions will be based on the Safety Analysis Set and will be 
summarized by treatment group. The number and percentage of subjects with an injection 
site reaction and the number of events will be summarized by High Level Term (HLT) and 
preferred term.  
Subjects with multiple events in the same category are counted once in that category. Subjects 
with events in more than one category are counted once in each of those categories. 
4.3 
Safety Analyses 
The domain safety covers exposure, adverse events, clinical laboratory, vital signs, and ECG.  
4.3.1 
Exposure 
4.3.1.1 
Definitions and Derivations 
Treatment exposure will be calculated in days as the treatment duration from date of first 
dose to date of last dose, inclusive. 
Duration of exposure (days) = last dose date – first dose date + 1 
4.3.1.2 
Presentation 
Duration of exposure will be summarized based on the Safety Analysis Set. Summaries will 
be presented by treatment group using the principles outlined in Section 3.3 for continuous 
variables. 


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4.3.2 
Adverse Events 
4.3.2.1 
Definitions and Derivations 
An adverse event (AE) is the development of any untoward medical occurrence in a patient 
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 (SAE) and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered. 
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset date on or 
after the first dose date. 
Adverse events will be coded using the MedDRA version 24.0 or higher. 
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2. 
4.3.2.2 
Presentation 
All summaries of adverse event data will be based on the Safety Analysis Set and will be 
presented by treatment group. Summary tables will include TEAEs only whereas listings will 
include all reported AEs. 
A subject-level overview of AEs (the number and percent of subjects and the number of 
events) will be tabulated by the treatment groups in a single table for: 
• Any AE. 
• AEs possibly related to study treatment. 
• AEs with an outcome of death. 
• AEs with outcome of death possibly related to study treatment. 
• All serious adverse events (SAE). 
• SAEs possibly related to study treatment. 


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• AEs leading to discontinuation of study treatment. 
• AEs leading to discontinuation of study treatment, possibly related to study treatment. 
• AEs leading to dose interruption. 
• AEs leading to withdrawal from the study. 
Separate AE summary tables of the number and percentage of subjects with AEs and the 
number of events in each of the categories above will be produced by SOC and PT.  
Additionally, the following tables will be presented by SOC and PT: 
• AEs by the maximum reported intensity. 
• AEs by causality assessment. 
• Bleeding AEs (Haemorrhages (SMQ) including both "Haemorrhage laboratory terms 
(SMQ)" &  "Haemorrhage terms (excluding laboratory terms) (SMQ)"). 
Subjects with multiple events in the same category are counted once in that category. 
Subjects with events in more than one category are counted once in each of those 
categories. 
4.3.3 
Clinical Laboratory, Blood Sample 
4.3.3.1 
Definitions and Derivations 
In the assessments of hematology parameters, clinical chemistry and coagulation, the 
parameters to be summarized are listed in Appendix 7.2.  
Clinical laboratory results will be assigned to analysis visits as described in Section 3.3.2. 
Safety clinical laboratory results below the lower limit of quantification (LLOQ) for which 
the exact value cannot be determined will be replaced with the LLOQ.  
After replacements of LLOQ, the change from baseline will be calculated for all post-baseline 
timepoints as the respective timepoint value minus the baseline value.  
Based on the respective reference range indicators, the following flags will be applied to all 
laboratory assessments; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 
(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range).  


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eGFR 
Subject’s eGFR will be calculated from serum creatinine (SCr) concentration, according to 
the Japanese equation as follows: 
eGFR = 194 × SCr(mg/dL)−1.094 × Age−0.287 × α  
where α is 1 for males and 0.739 for females. 
Liver enzyme abnormalities 
AST, ALT and TBL will be classified as follows: 
AST and ALT: 
• <1.5×ULN (or below the LLOQ). 
• ≥1.5 to <3×ULN. 
• ≥3 to <5×ULN. 
• ≥5 to < 8×ULN. 
• ≥8×ULN. 
TBL: 
• <1×ULN (or below the LLOQ). 
• ≥1 to <2×ULN. 
• ≥2×ULN. 
Occurrences of AST or ALT ≥3×ULN together with TBL ≥ 2×ULN are reported as SAE 
(Potential Hy’s Law). 
Platelet count 
Platelet count will be classified as follows: 
• < LLN 
• > ULN 


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• < 50 (10^9/L) 
• < 75 (10^9/L)  
• < 100 (10^9/L) 
• <150 (10^9/L)  
• > 30% decrease from baseline  
• <150 (10^9/L) and >30% decrease from baseline 
Shift to minimum value on-treatment value for platelet count will be classified as follows: 
• <50 (10^9/L) 
• ≥ 50 and < 75 (10^9/L) 
• ≥ 75 and < 100 (10^9/L) 
• ≥ 100 and < 150 (10^9/L) 
• ≥ 150 (10^9/L) 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.3.3.2 
Presentation 
Laboratory data will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. The number and proportion of patients 
with liver enzyme abnormalities will summarized by treatment group and visit including a 
summary of the maximum recorded post-baseline value. Treatment-emergent platelet count 
abnormalities will be summarised by treatment group and visit, including the shift to 
minimum value and key subject information will be presented. 
Shift tables will be presented for select laboratory parameters (clinical chemistry and 
hematology). An additional shift table will be presented for hematology results, displaying 
the percent change from baseline (i.e. the relative change). Spaghetti plots over time will be 
produced for platelet count, ALT, AST, and TBL, with the corresponding reference range 
overlaid on top. The following additional plots will be presented for platelet count only: 


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• Empirical cumulative distribution function curves for the absolute change from 
baseline to minimum value.  
• A spaghetti plot of the relative change from baseline in subjects with platelet count 
<150 (10^9/L) or > 30% decrease from baseline.  
• A spaghetti plot of the absolute change from baseline in subjects with platelet count 
<150 (10^9/L) or > 30% decrease from baseline.  
4.3.4 
Clinical Laboratory, Urinalysis 
4.3.4.1 
Definitions and Derivations 
In the assessments of urinalysis, and urinalysis (positive dipstick), the parameters to be 
summarized are listed in Appendix 7.2.  
Clinical laboratory results will be assigned to analysis visits as described in Section 3.3.2. 
Safety clinical laboratory results below the lower limit of quantification (LLOQ) for which 
the exact value cannot be determined will be replaced with the LLOQ.  
After replacements of LLOQ, the change from baseline will be calculated for all post-baseline 
timepoints as the respective timepoint value minus the baseline value.  
4.3.4.2 
Presentation  
Laboratory data will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. 
4.3.5 
Other Laboratory Evaluations 
4.3.5.1 
Definitions and Derivations 
The parameters to be summarized are listed in Appendix 7.2.  
Clinical laboratory results will be assigned to analysis visits as described in Section 3.3.2. 
Safety clinical laboratory results below the lower limit of quantification (LLOQ) for which 
the exact value cannot be determined will be replaced with the LLOQ.  
After replacements of LLOQ, the change from baseline will be calculated for all post-baseline 
timepoints as the respective timepoint value minus the baseline value.  


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4.3.5.2 
Presentation  
Laboratory data will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. 
4.3.6 
Vital Signs 
4.3.6.1 
Definitions and Derivations 
The vital sign measurements to be summarized are:  
• Systolic blood pressure (mmHg) 
• Diastolic blood pressure (mmHg) 
• Pulse rate (bpm) 
• Body temperature (oral) (ºC). 
Vital sign measurements will be assigned to analysis visits as described in Section 3.3.2. 
Change from baseline for vital sign measurements (where applicable) will be calculated for 
all post-baseline visits as the respective visit value minus the baseline value. 
Based on the respective reference range indicators, the following flags will be applied to all 
vital sign measurements; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 
(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range).  
Parameter  
Normal Reference Ranges 
Systolic blood pressure  
80 - 140 mmHg 
Diastolic blood pressure  
50 -90 mmHg 
Heart rate  
50 - 100 bpm 
Temperature  
<=37ºC 
 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.3.6.2 
Presentation 
Vital signs will be summarized based on the Safety Analysis Set. Summaries of the individual 
values and change from baseline will be presented by treatment group and visit according to 
the principles outlined in section 3.3.1. 


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4.3.7 
Electrocardiogram 
4.3.7.1 
Definitions and Derivations 
The following parameters or time intervals will be recorded for each ECG: RR, PR interval, 
QRS duration, QT interval, QTcF interval, and ECG mean heart rate (HR).  
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 Investigator will judge whether the overall interpretation is ‘normal’ or ‘abnormal’. 
ECG results will be assigned to analysis visits as described in Section 3.3.2. 
Change from baseline for ECG parameters (where applicable) will be calculated for all post-
baseline visits as the respective visit value minus the baseline value. 
Outlier categories with respect to QTcF will be defined as follows: 
• 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 
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.3.7.2 
Presentation 
ECG parameters will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. Outliers with respect to QTcF will be 
tabulated using the categories defined in Section 4.3.7.1. 


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4.3.8 
Other Safety Assessments 
Not applicable. 
5 
INTERIM ANALYSIS 
After all randomized patients have completed (or discontinued from) the treatment period, 
an interim analysis will be performed for all endpoints except for PK variables. Efficacy 
outputs will display visits up to and including the Week 12 time point, all visits will be 
displayed for the safety outputs.  
A limited number of Sponsor personnel will be unblinded at the time of interim analysis. 
Investigators, participants and site-staff will not be informed of assigned treatment or the 
results of the interim analysis in order to maintain study integrity. A Confidentiality 
List/Communication Plan will be prepared documenting unblinded personnel.  
This interim analysis will be documented as an interim clinical study report. 
6 
REFERENCES 
1. Rubin, D. B. (1987) Multiple Imputation for Nonresponse in Surveys. New York: 
Wiley 
2. Sampson, Maureen, Clarence Ling, Qian Sun, Roa Harb, Mohmed Ashmaig, Russell 
Warnick, Amar Sethi et al. "A new equation for calculation of low-density lipoprotein 
cholesterol in patients with normolipidemia and/or hypertriglyceridemia." JAMA 
cardiology 5, no. 5 (2020): 540-548.


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7 
APPENDIX 
7.1 
Schedule of Activities 
 


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7.2 
Clinical Laboratory Assessments 
Hematology 
 
WBC count  
Neutrophils absolute count 
Red blood cell (RBC) count  
Lymphocytes absolute count 
Hemoglobin (Hb)  
Monocytes absolute count 
Hematocrit (HCT)  
Eosinophils absolute count 
Mean corpuscular volume (MCV)  
Basophils absolute count 
Mean corpuscular haemoglobin concentration (MCHC)  
Platelets absolute count 
 
Reticulocytes absolute count 
 
Clinical Chemistry 
Sodium  
ALP 
Potassium  
ALT 
Blood urea nitrogen (BUN)  
AST 
Creatinine  
Gamma glutamyl transpeptidase (GGT) 
Calcium  
Total bilirubin 
Phosphate  
Direct bilirubin 
Creatine kinase (CK)  
Glutamate dehydrogenase (GLDH) 
Bicarbonate  
Lactate dehydrogenase (LDH) 
Serum β-human chorionic gonadotropin (β- 
hCG)(women only) 
Uric acid 
Luteinizing hormone (LH) (women only) 
FSH (women only) 
Indirect bilirubin 
 
 
Coagulation 
aPTT  
Prothrombin time 
International normalized ratio (INR) 
 
 
Urinalysis 
Urine human chorionic gonadotropin (hCG) (Women only) 
Urinalysis dipstick test 
 


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Urinalysis (positive dipstick) 
pH 
Clarity/Appearance 
Specific gravity 
Nitrites 
Glucose 
Ketones 
Blood 
Leukocytes 
Colour 
Microscopic analysis (if positive for blood, nitrates 
or protein) 
Protein 
Urobilinogen 
 
Urine renal safety biomarkers 
Albumin  
UPCR 
Total protein  
UACR 
Creatinine  
Estimated glomerular filtration rate (eGFR; by the 
Japanese equation) 
 
Other laboratory assessments 
Complement activation panel (Bb, C5a)  
High-sensitive C-reactive protein (hs-CRP) 
 
HbA1c 
 
 
 
 
 


SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d7990c00006-sap-part-b-ed-1
Document Title:
Statistical Analysis Plan Part B Edition 1
Document ID:
Version Label:
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
Content Approval
Author Approval
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.


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STATISTICAL ANALYSIS PLAN
Study Code
D7990C00006 (Part C)
Edition Number
2.0
Date
3-Nov-2022
Statistical Analysis Plan for D7990C00006, A Phase 1 and 2 
study to evaluate the safety, tolerability, efficacy, 
pharmacokinetics and pharmacodynamics of AZD8233 
following a multiple subcutaneous dose administration in 
Japanese participants with dyslipidemia (HAYATE) – Part C


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TABLE OF CONTENTS
TITLE PAGE................................................................................................................1
TABLE OF CONTENTS..............................................................................................2
LIST OF ABBREVIATIONS .......................................................................................5
AMENDMENT HISTORY...........................................................................................7
1
INTRODUCTION......................................................................................8
2
CHANGES TO PROTOCOL PLANNED ANALYSES..............................8
3
DATA ANALYSIS CONSIDERATIONS ..................................................8
3.1
Timing of Analyses.....................................................................................8
3.2
Analysis Populations...................................................................................8
3.2.1
Enrolled Set................................................................................................8
3.2.2
Randomized Set..........................................................................................8
3.2.3
Safety Analysis Set.....................................................................................9
3.2.4
Pharmacokinetic Analysis Set.....................................................................9
3.2.5
Pharmacodynamic Analysis Set ..................................................................9
3.3
General Considerations...............................................................................9
3.3.1
General Study Level Definitions ...............................................................10
3.3.1.1
Definition of Baseline...............................................................................10
3.3.1.2
Handling of Missing Data.........................................................................10
3.3.1.3
Study Periods............................................................................................12
3.3.2
Visit Window ...........................................................................................12
3.3.3
Handling of Unscheduled Visits................................................................17
3.3.4
Multiplicity/Multiple Comparisons ...........................................................17
3.3.5
Handling of Protocol Deviations in Study Analysis...................................17
4
STATISTICAL ANALYSIS.....................................................................17
4.1
Study Population.......................................................................................18
4.1.1
Subject Disposition and Completion Status...............................................18
4.1.1.1
Definitions and Derivations ......................................................................18
4.1.1.2
Presentation ..............................................................................................18
4.1.2
Analysis Sets ............................................................................................18
4.1.2.1
Definitions and Derivations ......................................................................18
4.1.2.2
Presentation ..............................................................................................18
4.1.3
Protocol Deviations...................................................................................18
4.1.3.1
Definitions and Derivations ......................................................................18
4.1.3.2
Presentation ..............................................................................................19
4.1.4
Demographics...........................................................................................19
4.1.4.1
Definitions and Derivations ......................................................................19
4.1.4.2
Presentation ..............................................................................................19
4.1.5
Baseline Characteristics ............................................................................19
4.1.5.1
Definitions and Derivations ......................................................................19
4.1.5.2
Presentation ..............................................................................................19
4.1.6
Disease Characteristics .............................................................................19


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4.1.6.1
Definition and Derivations........................................................................19
4.1.6.2
Presentation ..............................................................................................20
4.1.7
Medical History and Concomitant Disease................................................20
4.1.7.1
Definitions and Derivations ......................................................................20
4.1.7.2
Presentation ..............................................................................................20
4.1.8
Prior and Concomitant Medications ..........................................................20
4.1.8.1
Definitions and Derivations ......................................................................20
4.1.8.2
Presentation ..............................................................................................21
4.1.9
Study Drug Compliance............................................................................21
4.1.9.1
Definitions and Derivations ......................................................................21
4.1.9.2
Presentation ..............................................................................................21
4.2
Endpoint Analyses....................................................................................21
4.2.1
Primary Endpoint – Adverse Events..........................................................22
4.2.1.1
Definition .................................................................................................22
4.2.1.2
Derivations ...............................................................................................23
4.2.1.3
Handling of Dropouts and Missing Data ...................................................23
4.2.1.4
Primary Analysis of Primary Endpoint......................................................23
4.2.2
Primary Endpoint – Injection Site Reactions .............................................24
4.2.2.1
Definition .................................................................................................24
4.2.2.2
Derivations ...............................................................................................24
4.2.2.3
Handling of Dropouts and Missing Data ...................................................24
4.2.2.4
Primary Analysis of Primary Endpoint......................................................24
4.2.3
Primary Endpoint – Clinical Laboratory Assessments...............................24
4.2.3.1
Definition .................................................................................................24
4.2.3.2
Derivations ...............................................................................................25
4.2.3.3
Handling of Dropouts and Missing Data ...................................................27
4.2.3.4
Primary Analysis of Primary Endpoint......................................................27
4.2.4
Primary Endpoint – Vital Signs, ECG and Cardiac Telemetry...................28
4.2.4.1
Definition .................................................................................................28
4.2.4.2
Derivations ...............................................................................................28
4.2.4.3
Handling of Dropouts and Missing Data ...................................................29
4.2.4.4
Primary Analysis of Primary Endpoint......................................................29
4.2.5
Secondary Endpoint - Pharmacokinetics ...................................................30
4.2.5.1
Definition .................................................................................................30
4.2.5.2
Derivations ...............................................................................................31
4.2.5.3
Handling of Dropouts and Missing Data ...................................................32
4.2.5.4
Primary Analysis of Secondary Endpoint..................................................32
4.2.6
Secondary Endpoint – Change from baseline in log-transformed PCSK9 in 
plasma ......................................................................................................36
4.2.6.1
Definition .................................................................................................36
4.2.6.2
Derivations ...............................................................................................36
4.2.6.3
Handling of Dropouts and Missing Data ...................................................36
4.2.6.4
Primary Analysis of Secondary Endpoint..................................................36
4.2.7
Secondary Endpoint – Percent change from baseline in LDL-C ................37
4.2.7.1
Definition .................................................................................................37
4.2.7.2
Derivations ...............................................................................................37


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4.2.7.3
Handling of Dropouts and Missing Data ...................................................37
4.2.7.4
Primary Analysis of Secondary Endpoint..................................................37
4.2.8
Secondary Endpoint – Other Lipid Parameters..........................................38
4.2.8.1
Definition .................................................................................................38
4.2.8.2
Derivations ...............................................................................................38
4.2.8.3
Handling of Dropouts and Missing Data ...................................................38
4.2.8.4
Primary Analysis of Secondary Endpoint..................................................38
4.2.9
Exploratory Endpoint - Immunogenicity...................................................39
4.2.9.1
Definition .................................................................................................39
4.2.9.2
Derivations ...............................................................................................39
4.2.9.3
Handling of Dropouts and Missing Data ...................................................39
4.2.9.4
Primary Analysis of Other Endpoint .........................................................39
4.3
Pharmacodynamic Endpoint(s) .................................................................39
4.4
Pharmacokinetics......................................................................................39
4.5
Immunogenicity........................................................................................39
4.6
Safety Analyses ........................................................................................39
4.6.1
Exposure...................................................................................................40
4.6.1.1
Definitions and Derivations ......................................................................40
4.6.1.2
Presentation ..............................................................................................40
4.6.2
Overdose and Medication Error ................................................................40
4.6.2.1
Definitions and Derivations ......................................................................40
4.6.2.2
Presentation ..............................................................................................40
4.6.3
Physical Examinations..............................................................................40
4.6.3.1
Definitions and Derivations ......................................................................40
4.6.3.2
Presentation ..............................................................................................40
5
INTERIM ANALYSIS .............................................................................40
6
REFERENCES.........................................................................................41
7
APPENDIX ..............................................................................................42
7.1
Schedule of Activities...............................................................................42
7.2
Clinical Laboratory Assessments ..............................................................49


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LIST OF ABBREVIATIONS
Abbreviation or 
Specialized Term
Definition
ADA 
Anti-drug antibody
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical therapeutic chemical
BLQ
Below limits of quantification
BMI
Body mass index
CI
Confidence interval
CM
Composite measure
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV 
Coefficient of variation
DBL
Database lock
DRM
Data review meeting 
ECG
Electrocardiogram
eCRF
Electronic case report form
EDV
Early discontinuation visit
eGFR
Estimated glomerular filtration rate
gSD
Geometric standard deviation
HLT
High level term
HR 
Heart Rate
ICF
Informed consent form.
IMP
Investigational medicinal product 
IPD
Important protocol deviation
ISR
Injection site reaction
LDL-C
Low density lipoprotein cholesterol
LLOQ
Lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
PCSK9
Proprotein convertase subtilisin/kexin type-9
PD
Pharmacodynamics
PK
Pharmacokinetics
PT
Preferred term
QTcF
Corrected QT Interval using Fridericia’s Formula
SAE
Serious adverse event


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Abbreviation or 
Specialized Term
Definition
SAP
Statistical Analysis Plan
SC
Subcutaneous
SCr
Serum creatinine
SD
Standard deviation
SOC
System organ class
TBL
Total bilirubin 
TEAE
Treatment-emergent adverse event
UNS
Unscheduled
ULN
Upper limit of normal
WHO-DD
World Health Organisation drug dictionary 


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AMENDMENT HISTORY
CATEGORY
Change refers to:
Date
Description of change
In line with 
CSP?
Rationale
N/A
02-May-2022
Initial approved SAP
N/A
N/A
Data presentation
12-Sep-2022
Added additional 
analyses for 
hematology results
Y
To give more detailed 
summary of 
hematology results
Data presentation
12-Sep-2022
Added additional 
analyses for platelet 
counts
Y
To give more detailed 
summary of platelet 
counts
Data presentation
12-Sep-2022
Added plots of mean 
(SD) over time for 
pharmacodynamic 
endpoints
Y
To give a graphical 
presentation of the 
results. 
Data presentation
12-Sep-2022
Added additional 
analyses for Bleeding 
AEs
Y
To give more detailed 
summary of AEs
Data presentation
03-Nov-2022
Added plots and 
summary of geometric 
mean (gSD) for LDL-C 
parameters
Y
To give a graphical 
presentation.




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3.2.3
Safety Analysis Set
All participants randomly assigned to study treatment who took at least one dose of AZD8233 
or placebo and for whom any post-dose data are available. Participants will be analyzed 
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 would be the treatment group that 
participant was randomized to. The Safety Analysis Set will be used as the analysis set for 
all summaries of baseline demographics and disease characteristics, safety evaluations unless 
stated otherwise and for the analysis of the immunogenicity data. 
3.2.4
Pharmacokinetic Analysis Set
The Pharmacokinetic (PK) Analysis Set will consist of all subjects in the Safety Analysis Set
who received AZD8233 and who have evaluable PK data, with no important protocol 
deviations thought to impact on the analysis of the PK data.
The exclusion of any subjects or time points from the calculation of the PK parameters will 
be documented by the PK scientist, including the reasons for exclusion.
The available concentration data and PK parameter data for any subjects excluded from the 
PK analysis set will be listed only. Concentration data for subjects excluded from the PK 
analysis set will be presented in the individual figures of concentration versus time plots.
The PK Analysis Set will be used to summarize the PK data.
3.2.5
Pharmacodynamic Analysis Set
The Pharmacodynamic (PD) Analysis Set will consist of all subjects who received AZD8233 
or placebo, who have at least one baseline and one post-baseline measurement for either the 
level of PCSK9 in plasma or the level of LDL-C in plasma, and who have no important 
protocol deviations thought to impact on the analysis of the data. 
The available PD data for any subjects excluded from the PD analysis set will be listed only, 
together with a flag indicating subjects excluded from the PD analysis set. Only subjects or 
samples in the PD analysis set will be included in the descriptive summary tables.
The PD analysis set will be used to analyse the lipid parameters (PCSK9, LDL-C and other 
lipids). 
3.3
General Considerations
There is no formal statistical hypothesis testing in this study. Safety and tolerability after 
multiple dosing of AZD8233 
 (or placebo) will be descriptively evaluated. The 
following principles will be followed throughout the study:


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
Continuous variables will be summarized by the number of non-missing observations, 
mean, standard deviation (SD), median, first and third quartiles, and the minimum 
and maximum as appropriate.

Log-transformed continuous variables will be summarized in a similar manner where 
applicable. In addition, the relative change from baseline will be calculated by back-
transforming the change from baseline of the logarithmic variable. 

Categorical variables will be summarized as counts (n) and percentages (%). Unless 
otherwise stated, percentages will be calculated using the relevant analysis set 
population total as the denominator. Percentages will not be presented for zero counts.

Mean and medians will be rounded to one additional decimal place relative to the 
original data, the SD will be rounded to two additional decimal places, and the 
maximum, minimum and quartiles will be displayed with the same accuracy as the
original data. 95% confidence intervals (CIs) will be presented to one more decimal 
place than the raw data. Percentages (proportion) will be rounded to one decimal 
place. 

Summaries will be provided by study visit where appropriate. Where summaries are 
over time, study day will be calculated in relation to the date of first dose of study 
treatment.

Corresponding listings will be provided for all tabulated results unless stated 
otherwise. Any additional listings that are required will be described in the 
appropriate sections of the SAP.

SAS® version 9.3 or higher will be used for all data analyses.
3.3.1
General Study Level Definitions
3.3.1.1
Definition of Baseline
Unless otherwise specified, ‘baseline’ refers to the last measurement obtained before the first 
dose of study intervention. For all lipid parameters (PCSK9, LDL-C and other lipid 
parameters listed in Section 4.2.8.1) the geometric mean of the two measures taken pre-dose 
at Visit 2 (Day -1 and pre-dose Day 1) will be considered as baseline. 
3.3.1.2
Handling of Missing Data
In general, missing data will not be imputed and will be treated as missing unless specifically 
described in an analysis section. The following considerations are made for missing safety 
data, adverse event (AE) dates, and concomitant medication/diseases dates:


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
Safety assessment values of the form ‘<x’ or ‘>x’ (i.e., above or below the limits of 
quantifications) will be imputed as ‘x’ in the calculation of summary statistics but 
displayed as ‘<x’ or ‘>x’ in the listings.

Adverse events that have missing causality after data querying will be assumed to be 
related to study drug. 

For missing AE/concomitant medication/disease start dates, the following will be 
applied:
o
Missing day: Impute 1st of the month unless the month is the same as that of 
the first dose of study drug in which case impute first dose date.
o
Missing day and month: Impute 1st January unless the year is the same as that 
of the first dose date in which case impute first dose date.  
o
Missing year: Impute the year of dosing.
o
Completely missing: Impute first dose date unless the end date suggests it 
could have started prior to this in which case impute 1st January of the same 
year as the end date.

For missing AE/concomitant medication/disease end dates, the following will be 
applied:
o
Missing day: Impute the last day of the month unless the month is the same 
as that of the last dose of the study drug in which case impute the date of last 
dose.
o
Missing day and month: Impute 31st December unless the year is the same as 
that of the last dose of study drug in which case impute date of last dose.
o
Missing year: Impute the year of dosing.
o
Completely missing: Do not impute a date i.e., assume that AE/concomitant 
medication/disease is ongoing.
For all missing start/end dates, flags will be retained in the analysis datasets indicating where 
any programmatic imputation has been applied, and in such cases, any durations would not 
be calculated. When imputing missing/partial dates, programmatic checks will be done to 
ensure a future date has not been imputed. 


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If a subject is known to have died where only a partial death date is available, then the date 
of death will be imputed as the latest of the last known date to be alive + 1 from the database 
and the death date using the available information provided:

Missing day only: Use the 1st of the month.

Missing day and month: Use 1st January.

Missing year: Impute the year of dosing.
3.3.1.3
Study Periods
For listings of adverse events, lipid levels, laboratory values, vital signs and 
electrocardiogram (ECG), values will be allocated to a study period. The allocation to the 
study periods will be performed after any imputation of missing dates (for AEs only) as 
described in Section 3.3.1.2. The study periods are defined as follows:

Pre-treatment: Up to 28 days prior to administration of study drug (Day <1).

Treatment Period: From Day 1 to date of last dose + 2 days (from visit 2 up to visit 
9).

Follow-up Period: From day of last dose + 3 days onwards (visit 10 to visit 17).
3.3.2
Visit Window
Study visits windows are defined in the table below.
Screening
Treatment Period
Follow-up Period
Visit 
Number 
1
2
3
3,6
4, 5, 7, 
8
9
10 to 16
17
(Final
Follow-up
Visit/ ED
Visit)
Study 
Day/Week
Days -28 
to -4
Day 
-1
Days 1 
to 3
Day 8
Day 29
Days 
15, 22, 
36, 44
Day 
56
Days 
57 to 
59
Weeks 2, 
4, 6,
8, 10, 12, 
14 (after 
last dose)
Week 16
(after last
dose)
Visit 
Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days










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For summaries showing the maximum or minimum values, the maximum/minimum value 
recorded on treatment will be used, regardless of where it falls in an interval. For summaries 
at a subject level (i.e., the maximum) all values will be included regardless of whether they 
appear in a corresponding visit-based summary.
3.3.3
Handling of Unscheduled Visits 
Visits that fall outside the visit windows defined in the CSP will be classified as Unscheduled 
Visits. Unscheduled visits will be numbered sequentially with an increment of 0.1. For 
example, if two measurements are done in an unscheduled visit that occurs between Day 3 
and Day 8, then these visits will be numbered UNS 2.1 and 2.2 in the order they occurred. 
The values measured at unscheduled visits will not be included in the by-visit summary 
tables, they will be included in the overall summary tables (for abnormalities, 
minimum/maximums etc.) and will be presented in the listings. 
3.3.4
Multiplicity/Multiple Comparisons
Not applicable.
3.3.5
Handling of Protocol Deviations in Study Analysis
Important protocol deviations are defined as those deviations from the protocol likely to have 
an impact on the perceived efficacy and/or safety of study treatments. The impact of 
important protocol deviations on the safety results will be investigated by assessing the 
robustness of the study results and conclusions to the choice of analysis set, both including 
and excluding data potentially affected by important protocol deviations.
This estimation will be performed on a Data Review Meeting (DRM) shortly before database 
lock. Results and population assignments will be summarized in a DRM report which will be 
agreed up on by all relevant scientific experts.
During the study, a list of important protocol deviations (IPD) will be developed, which will 
include inclusion/exclusion/discontinuation criteria deviations, investigational product 
deviations and excluded medication taken. These will be taken into consideration when 
interpreting the data. Subjects with an IPD may be excluded from the analysis of the PK 
and/or PD data. 
4
STATISTICAL ANALYSIS
This section provides information on definitions, derivations and analysis/data presentation 
per domain.


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4.1
Study Population
The domain study population covers subject disposition, analysis sets, protocol deviations, 
demographics, baseline characteristics medical and surgical history, prior and concomitant 
medication and study drug compliance. 
4.1.1
Subject Disposition and Completion Status
4.1.1.1
Definitions and Derivations
Not applicable. 
4.1.1.2
Presentation
Subject disposition will be summarized based on the Enrolled Set and will include the 
following information: the number of subjects enrolled, randomized and who received at least 
one dose of study drug, the number and percentage of subjects who completed 
treatment/discontinued treatment (including reasons for investigational medicinal product 
(IMP) discontinuation), and the number and percentage of subjects who completed or 
discontinued study (including reason for early withdrawal). Summaries will be by treatment 
group and overall. 
A randomization listing will be presented and will include the following information: 
randomization number, full enrolment number, date of randomization and randomized 
treatment group.
Subjects affected by the COVID-19 pandemic and subjects with reported issues in the 
Clinical Trial Management System due to COVID-19 pandemic will be listed.
4.1.2
Analysis Sets
4.1.2.1
Definitions and Derivations
Analysis sets are defined in Section 3.2.
4.1.2.2
Presentation
Analysis sets will be summarized based on the Randomized Set. The number of subjects 
included and excluded (including reason for exclusion) in each analysis population will be 
presented by treatment group.
4.1.3
Protocol Deviations
4.1.3.1
Definitions and Derivations
Important protocol deviations will be defined in the Non-compliance Handling Plan and are 
considered as those deviations from the protocol likely to have an impact on the perceived 
efficacy or safety of study treatment. The final list of IPDs will be determined before DBL.


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4.1.3.2
Presentation
IPDs will be summarized based on the Randomized Set. The number and percentage of 
subjects meeting each IPD criterion will be summarized by treatment group. Subjects who 
deviate from a given criterion more than once will be counted once for that criterion. Any 
subjects with more than one IPD will be counted once in the overall summary.
4.1.4
Demographics
4.1.4.1
Definitions and Derivations
Demographics include age, sex, race and ethnicity. Age is measured in years and calculated 
as:
Age (years) = (Date of randomization – date of birth + 1) / 365.25
4.1.4.2
Presentation
Demographics will be summarized based on the Safety Analysis Set. Summaries will be 
presented by treatment group and overall according to the principles outlined in Section 3.3.  
4.1.5
Baseline Characteristics
4.1.5.1
Definitions and Derivations
Baseline characteristics include height (m), weight (kg), body mass index (BMI) (kg/m2), 
nicotine use and alcohol use. Body mass index (BMI) is calculated as:
BMI (kg/m2) = weight (kg) / height2 (m)
4.1.5.2
Presentation
Baseline characteristics will be summarized based on the Safety Analysis Set. Summaries 
will be presented by treatment group and overall according to the principles outlined in 
Section 3.3.  
4.1.6
Disease Characteristics
4.1.6.1
Definition and Derivations
Disease characteristics are defined as the following lipid related parameters measured at 
baseline:

Direct LDL-C.

LDL-C with reflex to PUC/beta-Quantification equals to: 
o
LDL-C derived by Friedewald formula if LDL-C (Friedewald) ≥40mg/dL 
and Triglycerides (TG) < 400mg/dL.
o
LDL-C (PUC/beta-Quantification) if LDL-C (Friedewald) < 40mg/dL or TG 
≥400mg/dL.

LDL-C derived by the Friedewald formula.


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
LDL-C derived by the Martin/Hopkins formula.

Total cholesterol

HDL-C and Non-HDL-C.

VLDL-C.

ApoA1 and ApoB.

Lp(a).

Triglycerides.
4.1.6.2
Presentation
Disease characteristics will be summarized based on the Safety Analysis set. Summaries will 
be presented by treatment group and overall according to the principles outlined in Section 
3.3.  
4.1.7
Medical History and Concomitant Disease
4.1.7.1
Definitions and Derivations
Medical/surgical history, and concomitant (called “current”) diseases are coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) [using the latest MedDRA version]. 
The imputation method described in Section 3.3.1.2 will be used in the instance that partial 
or missing dates are recorded. 
A current disease is defined as any disease with an end date on or after the first dose date. A 
disease with a completely missing end date will be considered as current. 
4.1.7.2
Presentation
Medical/surgical history and current diseases will be summarized based on the Safety 
Analysis Set. The number and percentage of subjects with relevant medical/surgical history 
and current diseases will be presented by treatment group and overall, and summarized by 
System Organ Class (SOC) and Preferred Term (PT). Subjects with histories in more than 
one SOC/PT will be counted only once in that SOC/PT. Tables will be sorted alphabetically 
by SOC and PT.
4.1.8
Prior and Concomitant Medications
4.1.8.1
Definitions and Derivations
Prior and concomitant medications are coded using the WHO-DD. The imputation method 
described in Section 3.3.1.2 will be used in the instance that partial or missing dates are 
recorded.
Prior medications are defined as those that stopped and started prior to the first dose date. All 
medications on or after the first dose date are considered as concomitant, this includes those 
medications that started prior to date of first dose but continued after.






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The term AE is used to include both serious (SAE) and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study intervention has been administered.
A treatment-emergent adverse event (TEAE) is defined as an AE with an onset date on or 
after the first dose date. 
4.2.1.2
Derivations
Adverse events will be coded using the latest MedDRA version.
4.2.1.3
Handling of Dropouts and Missing Data
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2.
4.2.1.4
Primary Analysis of Primary Endpoint
All summaries of adverse event data will be based on the Safety Analysis Set and will be 
presented by treatment group. Summary tables will include TEAEs only whereas listings will 
include all reported AEs.
A subject-level overview of AEs (the number and percent of subjects and the number of 
events) will be tabulated for:

All AEs.

AEs possibly related to study treatment.

AEs with an outcome of death.

AEs with outcome of death possibly related to study treatment.

All serious adverse events.

SAEs possibly related to study treatment.

AEs leading to discontinuation of study treatment.

AEs leading to discontinuation of study treatment, possibly related to study treatment.

AEs leading to dose interruption and reduction (separately).

AEs leading to withdrawal from the study.


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Separate AE summary tables of the number and percentage of subjects with AEs and the 
number of events in each of the categories above will be produced by SOC and PT, sorted by 
international order for SOC and alphabetically by PT.
Additionally, the following tables will be presented by SOC and PT:

AEs by the maximum reported intensity.

AEs by causality assessment.

Bleeding AEs (both laboratory and non-laboratory terms).
Subjects with multiple events in the same category are counted once in that category. Subjects 
with events in more than one category are counted once in each of those categories. 
4.2.2
Primary Endpoint – Injection Site Reactions
4.2.2.1
Definition
Injection site reactions (ISRs) are reported using standard AE collection criteria.
4.2.2.2
Derivations
Injection site criteria will be coded using the latest version of MedDRA.
4.2.2.3
Handling of Dropouts and Missing Data
Imputation of partial dates and handling of missing data will be conducted as defined in 
Section 3.3.1.2.
4.2.2.4
Primary Analysis of Primary Endpoint
All summaries of injection site reactions will be based on the Safety Analysis Set and will be 
summarized by treatment group. The number and percentage of subjects with an injection 
site reaction and the number of events will be summarized by High Level Term (HLT) and 
preferred term, sorted by HLT and alphabetically by PT. 
Subjects with multiple events in the same category are counted once in that category. Subjects 
with events in more than one category are counted once in each of those categories. 
4.2.3
Primary Endpoint – Clinical Laboratory Assessments
4.2.3.1
Definition
Clinical laboratory assessments consist of hematology parameters, clinical chemistry, 
coagulation, urine renal safety biomarkers (called PFC Index) and composite measure (CM), 
and other laboratory assessments. The parameters to be summarized are listed in Appendix 
7.2. 


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The composite measure is a geometric mean of the fold changes from baseline of the uCr-
normalised 6 urine biomarkers (the PFC index): clusterin, cystatin C, KIM 1,NAG, NGAL, 
and osteopontin.
4.2.3.2
Derivations
Clinical laboratory results will be assigned to analysis visits as described in Section 3.3.2.
Except for lipids (section 4.2.6.2, 4.2.7.2 and 4.2.8.2), safety clinical laboratory results below 
the lower limit of quantification (LLOQ) for which the exact value cannot be determined will 
be replaced with the LLOQ. 
After replacements of LLOQ, the change from baseline will be calculated for all post-baseline 
timepoints as the respective timepoint value minus the baseline value. The percent change 
from baseline will be calculated for hematology parameters, for all post-baseline timepoints,
as the change from baseline at the respective timepoint divided by the baseline value and 
multiplied by 100.
Based on the respective reference range indicators, the following flags will be applied to all 
laboratory assessments; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 
(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range). 
eGFR
Subject’s eGFR will be calculated from serum creatinine (SCr) concentration, according to 
the Japanese equation as follows:
eGFR = 194 × SCr(mg/dL)*+.-./ × Age*-.123 × α
where α is 1 for males and 0.739 for females.
Composite measure
The CM and the ratio between treatment and placebo will be calculated as follows.
1. For each subject, calculate the (uCr)-normalised fold-change from baseline for each 
biomarker in the PFC index. The (uCr)-normalised concentration at a given timepoint 
is calculated as the concentration of the biomarker at that timepoint, divided by the 
concentration of urinary creatinine (uCr) at the same timepoint. The fold change from 
baseline is then calculated as the uCr-normalised concentration at a given timepoint, 
divided by the uCr-normalised concentration at baseline. Define the fold-change as 
FCij for subject i and biomarker j, where j = 1, 2,…,6.
2. For each subject i, calculate CM:


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3. Calculate the geometric mean of CM for cohort k (k = Treatment, Placebo):
4. Calculate the ratio of the geometric means (GMratio) for the two cohorts:
Liver enzyme abnormalities
Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and total bilirubin (TBL) 
will be categorised as follows:
AST and ALT:

<3 × upper limit of normal (ULN) (or below the LLOQ).

≥3 to <5 × ULN.

≥5 to < 8 × ULN.

≥8 × ULN.
TBL:

<1 × ULN (or below the LLOQ).

≥1 to <2 × ULN.

≥2 × ULN.
Occurrences of AST or ALT ≥3 × ULN together with TBL ≥ 2 × ULN are reported as SAE 
(Potential Hy’s Law).
Platelet count
Platelet count will be classified as follows:

< LLN

>ULN

< 50 (10^9/L)


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
< 75 (10^9/L) 

< 100 (10^9/L)

<150 (10^9/L) 

>30% decrease from baseline 

<150 (10^9/L) and >30% decrease from baseline.
Shift to minimum value on-treatment value for platelet count will be classified as follows:

<50 (10^9/L)

≥50 and < 75 (10^9/L)

≥75 and < 100 (10^9/L)

≥100 and < 150 (10^9/L)

≥150 (10^9/L)
4.2.3.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.
4.2.3.4
Primary Analysis of Primary Endpoint
Laboratory data will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. An additional table will be presented for 
hematology results, displaying the percent change from baseline (i.e. the relative change), 
presented by treatment group and visit. The number and proportion of patients with liver 
enzyme abnormalities will summarized by treatment group and visit including a summary of 
the maximum recorded post-baseline value. Treatment-emergent platelet count abnormalities 
will be summarised by treatment group and visit, including the shift to minimum value and 
key subject information will be presented.
The composite measure of the PFC index and corresponding ratio of AZD8233 to placebo 
will be presented by treatment group and visit. Box plots over time will be produced by 
treatment group for the composite measure and for the fold-change of the six individual 
biomarkers. A spaghetti plot over time of the fold-change of the six individual biomarkers 
will also be produced for each subject.
Shift tables will be presented for select laboratory parameters (clinical chemistry and 
hematology). Spaghetti plots over time will be produced for ALT, AST, TBL and gamma 
GPT, with the corresponding reference range overlaid on top. The following plots will be 
presented for platelet count only:

Empirical cumulative distribution function curves for the absolute change from 
baseline to minimum value. 


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
A spaghetti plot of the relative change from baseline in subjects with platelet count 
<150 (10^9/L) or > 30% decrease from baseline. 

A spaghetti plot of the absolute change from baseline in subjects with platelet count 
<150 (10^9/L) or > 30% decrease from baseline. 
Clinical laboratory data will be reported in standard international units.
4.2.4
Primary Endpoint – Vital Signs, ECG and Cardiac Telemetry
4.2.4.1
Definition
Vital Signs
The vital sign measurements to be summarized are: 

Systolic blood pressure (mmHg)

Diastolic blood pressure (mmHg)

Pulse rate (bpm)

Body temperature (oral) (ºC).
ECG
The following parameters or time intervals will be recorded for each ECG: RR, PR interval, 
QRS duration, QT interval, QTcF interval, and ECG mean heart rate (HR). The Investigator 
will judge whether the overall interpretation is ‘normal’ or ‘abnormal’. 
Cardiac Telemetry
Cardiac telemetry results will be reviewed by the Investigator and clinically important results 
are stored.
4.2.4.2
Derivations
Vital sign measurements (including weight, height and BMI), ECG and cardiac telemetry 
results will be assigned to analysis visits as described in Section 3.3.2.
Change from baseline for vital sign measurements and ECG parameters (where applicable) 
will be calculated for all post-baseline visits as the respective visit value minus the baseline 
value.
Height is measured once at baseline and this measure is used to calculate BMI at all 
proceeding visits.
Vital Signs
Based on the respective reference range indicators, the following flags will be applied to all 
vital sign measurements; ‘Normal’ (if the value is within the normal reference range), ‘Low’ 


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(if the value is below the normal reference range) or ‘High’ (if the values is above the normal 
reference range). 
Parameter 
Normal Reference Ranges
Systolic blood pressure 
80 - 140 mmHg
Diastolic blood pressure 
50 -90 mmHg
Heart rate 
50 - 100 bpm
Temperature 
<=37ºC
ECG
Outlier categories with respect to QTcF will be defined as follows:

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  
4.2.4.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.
4.2.4.4
Primary Analysis of Primary Endpoint
Vital Signs
Vital signs will be summarized based on the Safety Analysis Set. Summaries of the individual 
values and change from baseline will be presented by treatment group and visit according to 
the principles outlined in section 3.3.1. 
Weight, height and BMI will be listed only. 
ECG
ECG parameters will be summarized based on the Safety Analysis Set. Summaries of the 
individual values and change from baseline will be presented by treatment group and visit 
according to the principles outlined in section 3.3.1. Outliers with respect to QTcF will be 
tabulated using the categories defined in Section 4.2.4.2.
Cardiac Telemetry
Results for 12-lead ECG real-time cardiac telemetry will be listed based on the Safety 
Analysis Set including the overall assessment, specifics of abnormalities and the start and 
stop date/time.


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4.2.5
Secondary Endpoint - Pharmacokinetics
4.2.5.1
Definition
Where possible, the following PK parameters will be determined.
AUCinf
Area under the plasma concentration-time curve from time zero 
extrapolated to infinity. AUC is estimated by AUC(0-last) + 
Clast/λz where Clast is the last observed quantifiable concentration.
AUC(0-last)
Area under the plasma concentration-curve from time zero to the 
time of last quantifiable analyte concentration.
AUC(0-24)
Area under the concentration-time curve from time zero to 24 hours 
post-dose.
AUC(0-48)
Area under the concentration-time curve from time zero to 48 hours 
post-dose.
AUCτ
Area under the plasma concentration-time curve during the dosing 
interval
CL/F 
Apparent total body clearance of drug from plasma after 
extravascular administration.
Cmax
Maximum observed plasma concentration.
Ctrough
Observed trough plasma concentration
λz 
Terminal rate constant, estimated by log-linear least-squares 
regression of the terminal part of the concentration-time curve.
MRT
Mean residence time of the unchanged drug in the systemic 
circulation.
RAC (AUC)
Accumulation ratio based on AUC
RAC (AUC) (0-48)
Accumulation ratio based on AUC from time zero to 24 hours post 
dose
RAC (AUC) (0-168)
Accumulation ratio based on AUC from time zero to 168 hours post 
dose
RAC (Cmax)
Accumulation ratio based on Cmax
t1/2z 
Half-life associated with the terminal slope (λz) of a semi-
logarithmic concentration-time curve
tlag
Time delay between drug administration and the first observed 
concentration in plasma
tlast
Time of last quantifiable concentration.
tmax 
Time to reach peak or maximum observed concentration following 
drug
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration.
The following PK parameters will be determined, where possible, from urine concentrations.
Ae(t1-t2)
Amount of analyte excreted unchanged in urine from time t1 to t2
fe(t1-t2)
Percentage of analyte excreted unchanged in urine from t1 to t2


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Ae(0-last)
Cumulative amount of analyte excreted at the last sampling 
interval
fe(0-last)
Cumulative percentage of dose excreted unchanged into the urine 
from time zero to the last measured time point for an analyte, 
estimated by dividing Ae(0-last) by dose
CLR 
Renal clearance of drug from plasma, estimated by dividing Ae(0-
24) by AUC(0-24)
Additional PK parameters may be determined where appropriate.
4.2.5.2
Derivations
The geometric mean is calculated as the exponential of the arithmetic mean calculated from 
the data on the natural log scale.
The percent coefficient of variation is calculated as: CV (%) = 5(exp(81) −1 where s is 
the standard deviation of the data on a log scale.
Handling of values below the lower limit of quantification (BLQ)
Plasma concentrations below the limit of quantification (BLQ) from the time of pre dose 
sampling (t = 0) up to the time of the first quantifiable concentration will be set to a value of 
0. After the first quantifiable concentration, BLQ plasma concentrations will be set to missing 
for the calculation of PK parameters unless it is considered to be a true characteristic of the 
profile of the drug. 
If two or more consecutive BLQ concentrations are followed by quantifiable concentrations 
in the terminal portion of the concentration curve, the profile will be deemed to have 
terminated and therefore these quantifiable values will be set to missing for the calculation 
of the PK parameters unless there is a scientific rationale not to do so, which will be 
documented in the CSR. 
Any embedded BLQ value (between two quantifiable concentrations) will be set to missing 
for the PK analysis.
If an entire concentration-time profile is BLQ, the profile is excluded from the PK analysis.
For descriptive statistics plasma concentrations that are below the LLOQ will be handled as 
follows:

At a time point where less than or equal to 50% of the values are BLQ, all BLQ values 
will be set to LLOQ, and all descriptive statistics will be calculated.


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
At a time point where more than half of the values are BLQ, the mean, SD, geometric 
mean and CV% will be set to Not Determined (ND). The max value will be reported 
from the individual data, and the min and median will be set to BLQ.

If all values are BLQ at a time point, no descriptive statistics will be calculated for 
that time point. Not applicable (NA) will be written in the field for SD and CV% and 
BLQ will be written in fields for mean, geometric mean, min, median, and max.

The number of BLQ values (n below LLOQ) will be reported for each time point.

Where there is no result, these will be set to missing. 
Urine concentrations that are below the LLOQ will be handled as follows:

BLQ values should be set to zero for the calculation of individual Ae.

Any resulting Ae values equal to zero should be set to missing for the calculation of 
the summary statistics.
4.2.5.3
Handling of Dropouts and Missing Data
Not applicable 
4.2.5.4
Primary Analysis of Secondary Endpoint
A listing of PK blood sample collection times as well as derived sampling time deviations 
will be provided. A listing of urine sample collection start and stop times will be provided. 
Urine amount and fraction of dose excreted (by interval and cumulative) will be listed.
Pharmacokinetic Concentrations
Plasma concentrations, amount excreted in urine (Ae), and fraction of dose excreted (per 
collection interval and cumulative) and PK parameters will be summarized by analytes and 
timepoints using descriptive statistic, number of non-missing observations, n below LLOQ, 
arithmetic mean, SD, geometric mean, geometric coefficient of variation (CV%), min, 
median, max and based upon the PK analysis set.
Where the actual time that a sample was taken deviates by more than the specified time 
allowances from the nominal time then concentration will be excluded from the summary 
statistics and statistical analysis. 
Nominal Time
Time allowance
Pre-dose
Up to 30 minutes prior to dosing
0.5 h post dose
± 2 minutes
1 h post dose
± 5 minutes


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1.5 h post dose
± 5 minutes
2 h post dose
± 5 minutes
2.5 h post dose
± 5 minutes
3 h post dose
± 10 minutes
4 h post dose
± 10 minutes
5 h post dose
± 10 minutes
6 h post dose
± 10 minutes
8 h post dose
± 10 minutes
10 h post dose
± 30 minutes
12 h post dose
± 30 minutes
24 h post dose
± 1 hour
36 h post dose
± 1 hour
48 h post dose
± 1 hour
Data from subjects excluded from the PK population will be included in the data listings, but 
not in the summaries or in the inferential statistics.
For tmax and time of last quantifiable plasma concentration (tlast) only n, median, minimum 
and maximum will be used. 
Pharmacokinetic parameters will be rounded for reporting purposes in the summary tables 
and subject listings, as per the PK order form provided by AZ.
Individual plasma concentrations versus actual time will be plotted by analyte in linear and 
semi-logarithmic scale, with separate plots for each subject and study day. Plots will be based 
on the PK analysis set and displayed up to 48 hours post-dose.
Combined individual plasma concentration versus actual times will be plotted by analyte and 
study day in linear and semilogarithmic scale. Plots will be grouped by dose level, based on 
the PK analysis set and displayed up to 48 hours post-dose. 
Figures for the arithmetic mean concentration-time data will be presented for all groups (pool 
data from all treatment groups) overlaid on the same plot, in both a linear and semi-
logarithmic scale (SD on the linear scale and gSD on the semi-logarithmic scale) with 
separate plots for each study day.
Additional graphical presentations of PK data may be added at the discretion of the PK 
scientist.
Pharmacokinetic data will be presented by analytes and timepoints. A listing of all 
concentration-time data will be presented by dose level. 


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The following rules will be followed with regards to the number of decimal places and 
presentation of data in the tables and listings of concentration data: 
1. Source data shall be used in all derived PK concentrations without prior rounding.
2. The mean, standard deviation, geometric mean and median will be tabulated to one 
more significant digit compared to the source data, but with a maximum of four 
significant digits.
3. Minimum and maximum values will be tabulated to the same precision as the source 
data, but with a maximum of four significant digits.
4. Geometric coefficient of variation and coefficient of variation will be presented to 
one decimal place.
Graphical Presentation 
For individual figures, concentrations that are BLQ will be regarded as missing, with the 
exception of pre-dose BLQ values which will be set to zero for linear scale plots. 
For mean plots, BLQ values will be handled as described for the summary tabulations so that 
the same plasma concentration values are used in the mean data graphs as those given in the 
descriptive statistics summary table for each time point. All mean plots will be based on the 
PK analysis set.
Pharmacokinetic Parameters
Pharmacokinetic parameters will be derived using noncompartmental methods with 
WinNonlin® Professional Version 8.3, or higher, (Certara) and/or SAS® Version 9.3, or 
higher (SAS Institute, Inc., Cary, North Carolina). All descriptive and inferential statistical 
computations will be performed using SAS® Version 9.3, or higher.
The actual sampling times, recorded in the raw data, will be used in the final plasma PK 
parameter calculations. If actual times are missing, nominal times may be used.
Nominal sampling times will be used for interim plasma PK parameter calculations.
Nominal times will be used for the calculation of urine PK parameters.
Concentration data will be used as supplied by the analytical laboratory for PK analysis. The 
units of concentration and resulting PK parameters, with amount and concentration units, 
will be presented as they are received from the analytical laboratory.


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Dose normalized parameters for AUClast, AUC and Cmax will be calculated by dividing the 
original parameter by dose. 
The Cmax and time to reach peak or maximum observed concentration or response following 
drug administration (tmax) will be derived directly from the plasma concentration-time 
profiles. For multiple peaks the highest post dose concentration will be reported as Cmax. In 
the case that the multiple peaks are of equal magnitude, the earliest tmax will be reported.
Terminal elimination half-life, estimated as (ln2)/λz, where λz refers to the terminal 
elimination rate constant, will be estimated by log linear least squares regression of the 
terminal part of the concentration-time curve.
The choice of data points used to estimate λz should follow the general guidelines:

If there is more than 1 phase, use only observations from the terminal phase.

In general, the minimum data requirements are 3 measured concentrations spanning 
three half-lives. Where t1/2 is estimated over less than three half-lives, the values will 
be flagged in the data listings.

Should include the last measurable concentration.

Include only observations after Cmax.

The adjusted correlation coefficient (regression coefficient adjusted for λz, N, 
goodness of fit statistic for calculation of λz; Rsq adj) should be ≥ 0.8. 
Area under the plasma concentration-curve will be calculated using trapezoidal methods 
when concentration is increasing and logarithmic trapezoidal method when concentrations 
are decreasing (linear up log down).
Three concentrations higher than the LLOQ are required as a minimum for the AUC 
parameter to be calculated. 
If the pre-dose concentration prior to the first dose is missing it will be set to zero by default. 
If the pre-dose sample on Day 57 is missing it may be set equal to the concentration at the 
end of the dosing interval for the calculation of area under the plasma concentration-time 
curve in the dosing interval (AUCassuming linear PK and steady state conditions apply.
If the sample at the end of the profile is missing on Day 57 the concentration may be set equal 
to the pre-dose value for the calculation of AUCassuming linear PK and steady state 
conditions apply. 


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If a plasma or urine concentration value is considered anomalous due to being inconsistent 
with the expected pharmaceutical profile it may be appropriate to exclude this data point from 
the PK analysis. However, the exclusion of any data must have strong justification and will 
be documented in the study report. Embedded BLQs may be considered anomalous 
depending on the characteristics of the drug. 
Urine PK parameters will be calculated based on measurements with the ECL assay. In case 
of an incomplete urine collection in any of the specified collection intervals (eg, spilled 
sample), the calculation of the fraction of dose excreted into urine as well as renal clearance 
will be subject to discretion of the AZ study pharmacokineticist.
The amount excreted in urine (Ae) will be calculated using a urine density of 1.0 g/mL. Urine
concentrations below LLOQ will be treated as numerical zero. 
The amount of analyte excreted into the urine from time t1 to t2 [Ae(t1-t2)] and percentage
excreted unchanged in urine from t1 to t2 [fe(t1-t2)] will be calculated by collection interval 
and cumulatively for all collection intervals.
4.2.6
Secondary Endpoint – Change from baseline in log-transformed 
PCSK9 in plasma
4.2.6.1
Definition
Not applicable.
4.2.6.2
Derivations
PCSK9 measurement will be assigned to analysis visits as described in Section 3.3.2. 
Measurements below the LLOQ for which the exact value cannot be determined will be 
replaced by the LLOQ divided by the square root of 2. After replacement of LLOQ, PCSK9 
the absolute change and percent change from baseline are calculated for each study visit. 
Change from baseline of the log-transformed variable is calculated as the visit value in natural 
logarithm minus the baseline value in natural logarithm. Percent change from baseline is 
calculated using the raw values as the visit value minus the baseline value divided by the 
baseline value *100.
4.2.6.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.2.6.4
Primary Analysis of Secondary Endpoint
PCSK9 endpoints will be summarized as continuous log-normal variables and based on the 
PD Analysis Set. The absolute change and percent change from baseline will presented. 


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Summaries of the raw and log-transformed variables will be presented by visit and treatment 
group using the principles defined in Section 3.3. 
Plots will be presented by treatment group for the following summaries:

Arithmetic mean (± SD) of observed PCSK9 by visit.

Arithmetic mean (± SD) of change from baseline by visit.

Arithmetic mean (± SD) of percent change from baseline by visit.

Geometric mean (± gSD) of PCSK9 by visit.
4.2.7
Secondary Endpoint – Percent change from baseline in LDL-C
4.2.7.1
Definition
Three measures of LDL-C will be assessed; LDL-C derived by Friedewald formula, LDL-C 
derived by the Martin/Hopkins formula and direct LDL-C.
4.2.7.2
Derivations
LDL-C values will be assigned to analysis visits as defined in Section 3.3.2. Measurements 
below the LLOQ for which the exact value cannot be determined will be replaced by the 
LLOQ divided by the square root of 2. 
LDL-C derived by Friedewald or Martin/Hopkins formula are indirectly calculated and hence 
may take 0 or negative values (reported as ‘Unable to Calculate’ by Central lab) (Sampson 
et al, 2020). LLOQs will not be defined for these indirectly calculated measurements 
according to Central lab. These data will be replaced by 1/square root of 2 for the analysis
and displayed as reported from Central lab in the listings.
After replacements are made, the percent change from baseline is calculated as the visit value 
minus the baseline value divided by the baseline value * 100. Change from baseline of the 
log-transformed variable is calculated as the visit value in natural logarithm minus the 
baseline value in natural logarithm.
4.2.7.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2. 
4.2.7.4
Primary Analysis of Secondary Endpoint
LDL-C values will be summarized based on the PD Analysis Set. Summaries of the change 
and percent change from baseline, as well as the observed values and the log-transformed 
variables will be presented by visit and treatment group using the principles defined in 
Section 3.3.
Plots will be presented by treatment group for the following summaries:


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
Arithmetic mean (± SD) of observed LDL-C by visit.

Arithmetic mean (± SD) of change from baseline by visit.

Arithmetic mean (± SD) of percent change from baseline by visit.

Geometric mean (± gSD) of LDL-C by visit.
4.2.8
Secondary Endpoint – Other Lipid Parameters
4.2.8.1
Definition
The following lipid parameters will be summarized:

Total cholesterol (TC).

High-density lipoprotein cholesterol (HDL-C).

Non-HDL-C.

Very low density lipoprotein cholesterol (VLDL-C).

Apolipoproteins (Apo) A1.

ApoB.

Lp(a)

Triglycerides.
4.2.8.2
Derivations
Lipid parameters will be assigned to analysis visits as defined in Section 3.3.2. Measurements 
below the LLOQ for which the exact value cannot be determined will be replaced by the 
LLOQ divided by the square root of 2. After replacement of LLOQ, lipid values will be log-
transformed and the change from baseline, and the percent change from baseline will be 
calculated for each study visit. 
Change from baseline of the log-transformed variable is calculated as the visit value in natural 
logarithm minus the baseline value in natural logarithm. Percent change from baseline is 
calculated on the raw scale as the visit value minus the baseline value divided by the baseline 
value * 100.
4.2.8.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.
4.2.8.4
Primary Analysis of Secondary Endpoint
All lipid endpoints listed in Section 4.2.8.1 will be summarized as continuous log-normal 
variables and based on the PD Analysis Set. The absolute change and the percent change 
from baseline will presented. Summaries of the log-transformed variables will be presented 
by visit and treatment group using the principles defined in Section 3.3. 


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Plots will be presented by treatment group for the following summaries:

Arithmetic mean (± SD) of observed lipid parameters by visit.

Arithmetic mean (± SD) of change from baseline by visit.

Arithmetic mean (± SD) of percent change from baseline by visit.
4.2.9
Exploratory Endpoint - Immunogenicity
4.2.9.1
Definition
Development of anti-drug antibodies and ADA titre will be used to evaluate the 
immunogenicity of AZD8233. Titre evaluations are conducted only on those samples that are 
confirmed positive for ADA. 
4.2.9.2
Derivations
ADA parameters will be assigned to an analysis visit as defined in Section 3.3.2. 
4.2.9.3
Handling of Dropouts and Missing Data
Missing data will not be imputed and only observed values will be reported in the summary 
tables and listings. Treatment discontinuation visit will be mapped according to Section 3.3.2.
4.2.9.4
Primary Analysis of Other Endpoint
ADA endpoints will be analyzed based on the Safety Analysis Set. The number and 
percentage of subjects with a positive result will be tabulated for: any time in study, baseline, 
any time post-baseline, and by visit and treatment group along with a summary of ADA titre 
using the principles defined in Section 3.3.
4.3
Pharmacodynamic Endpoint(s) 
Refer to Sections 4.2.6, 4.2.7 and 4.2.8.
4.4
Pharmacokinetics 
Refer to Section 4.2.5.
4.5
Immunogenicity 
Refer to Section 4.2.9.
4.6
Safety Analyses 
The domain safety covers exposure, overdoses and physical examinations. Adverse events, 
clinical laboratory, vital signs, and ECG have been summarized in previous sections.


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4.6.1
Exposure
4.6.1.1
Definitions and Derivations
Treatment exposure will be calculated in days as the treatment duration from date of first 
dose to date of last dose, inclusive.
Duration of exposure (days) = last dose date – first dose date + 1
4.6.1.2
Presentation
Duration of exposure will be summarized based on the Safety Analysis Set. Summaries will 
be presented by treatment group using the principles outlined in Section 3.3 for continuous 
variables.
4.6.2
Overdose and Medication Error
4.6.2.1
Definitions and Derivations
An overdose is considered as any dose of AZD8233 greater than the planned dose. 
4.6.2.2
Presentation
All overdose data and medication errors data will be listed.
4.6.3
Physical Examinations
4.6.3.1
Definitions and Derivations
The full physical examination includes an assessment of general appearance and a review 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.
Abbreviated physical examinations will include, at a minimum, assessments of the skin,
lungs, cardiovascular system, and abdomen (liver and spleen).
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.    
4.6.3.2
Presentation
Physical examination data will not be presented in CSR.
5
INTERIM ANALYSIS
No planned interim analyses.


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6
REFERENCES
[1] Sampson, Maureen, Clarence Ling, Qian Sun, Roa Harb, Mohmed Ashmaig, Russell 
Warnick, Amar Sethi et al. "A new equation for calculation of low-density lipoprotein 
cholesterol in patients with normolipidemia and/or hypertriglyceridemia." JAMA 
cardiology 5, no. 5 (2020): 540-548.


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7
APPENDIX
7.1
Schedule of Activities
Screening
Treatment Period
Follow-up Period
Visit Number 
1
2
3
3,6
4, 5, 7, 8
9
10 to 16
17
(Final Follow-up 
Visit/ ED Visit)
Study Day/Week
Days -28 to 
-4
Day -1
Days 1 to 
3
Day 8 a
Day 29
Days 15, 
22, 36, 44
Day 56
Days 57 to 
59
Weeks 2, 4, 6,
8, 10, 12, 14 
(after last 
dose)
Week 16
(after last
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
Informed consent
X
Inclusion/ exclusion 
criteria b
X
X
Demographic
data
X
Weight and
height (BMI) c
X
X
X 
(Day 57)
X
Medical history
X
Concomitant
medication
X
X
X
X
X
X
X
X
X
X
Drug abuse and
alcohol screen d
X
X
Smoking history
X
Viral serology e
X
Pregnancy test (females 
only)
X n
X o
Pregnancy and 
reproductive status 
(females only p) 
X




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Screening
Treatment Period
Follow-up Period
Visit Number 
1
2
3
3,6
4, 5, 7, 8
9
10 to 16
17
(Final Follow-up 
Visit/ ED Visit)
Study Day/Week
Days -28 to 
-4
Day -1
Days 1 to 
3
Day 8 a
Day 29
Days 15, 
22, 36, 44
Day 56
Days 57 to 
59
Weeks 2, 4, 6,
8, 10, 12, 14 
(after last 
dose)
Week 16
(after last
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
2.5, 3, 4, 6, 
8, 12, 24, 
36 and 48h
post-dose)
24, 36 and 
48h post-
dose)
Body temperature
X
X
(pre-dose)
X
X
(pre-dose)
X
(pre-dose)
X
X
12-lead safety ECG
X
X
(pre-dose 
and then 
0.5, 1, 2,
3, 4, 6, 8, 
12, 24, 36 
and 48h 
post-dose)
X
X
(pre-dose)
X
(pre-dose 
and then 
0.5, 1, 2,
3, 4, 6, 8, 
12, 24, 36 
and 48h 
post-dose)
X
X
Cardiac telemetry
X
(for at 
least 
4h)
X
(pre-dose 
to 24h 
post-dose)
X
(pre-dose to 
24h post-
dose)
Hematology, chemistry 
and coagulation 
including hs-CRP
X
X
X
(24h post-
dose)
X
X
(pre-dose)
X
(pre-dose)
X
(Week 2, 4, 8, 
and 12 after 
last dose)
X
Sampling for renal 
safety biomarkers
X
X
(pre-dose 
and then 
X
X
(pre-dose)
X
(pre-dose)






STATISTICAL ANALYSIS PLAN
AstraZeneca
D7790C00006–ed. 2.0 (Part C)
03-Nov-2022
CONFIDENTIAL AND PROPRIETARY
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Screening
Treatment Period
Follow-up Period
Visit Number 
1
2
3
3,6
4, 5, 7, 8
9
10 to 16
17
(Final Follow-up 
Visit/ ED Visit)
Study Day/Week
Days -28 to 
-4
Day -1
Days 1 to 
3
Day 8 a
Day 29
Days 15, 
22, 36, 44
Day 56
Days 57 to 
59
Weeks 2, 4, 6,
8, 10, 12, 14 
(after last 
dose)
Week 16
(after last
dose)
Visit Window
-
-
-
-
± 1 day
± 1 day
± 1 day
± 2 days
± 2 days
0-6, 6-12, 
12-24 h 
post-dose)
0-6, 6-12, 
12-24 h 
post-dose)
ASO: Antisense oligonucleotides; BMI = body mass index; ET = early termination; FSH = follicle-stimulating hormone; hs-CRP = high 
sensitive C-reactive protein; IMP: Investigational medicinal product; LDL-C = low-density lipoprotein cholesterol; LH = luteinizing 
hormone; PCSK9 = proprotein convertase subtilisin/kexin type-9; SAE: Serious adverse event.
Participants are required to be fasted for at least 10 hours overnight prior to all study visits except for Visit 1 (only for the purpose of 
signing his/her informed consent); subjects are permitted to drink water during this period of fasting until 1 hour before blood sampling. 
On days when subjects attend the clinic in a fasting state, blood and urine samples should be obtained prior to administration of IMP.
a Day 8: no allowances.
b The eligibility check should be based on all clinical measurements and blood tests taken during the screening visit (Visit1).
c At Visit 1 and on Day −1, BMI be calculated. For Day −1, the height measured on Visit 1 will be utilised. At all other time points, only 
weight will bemeasured.
d Drugs of abuse and alcohol screen: Investigator will interview participants regarding their use of drugs and alcohol.
e Samples for HIV should be tested at a local laboratory.
f Allowances: pre-dose and then 0.25 h (± 2 minutes), 0.5 h (± 10 minutes), 1 h (± 10 minutes), 1.5 h (± 10 minutes), 2 h (± 15 minutes), 
2.5 h ( ±15 minutes), 3 h (±15 minutes), 4 h (± 15 minutes), 6 h (± 15 minutes), 8 h (± 15 minutes), 12 h (± 30 minutes), 24 h (± 1 hour), 
36 h (± 1 hour) and 48 h (±1 hour) post-dose. Screening and Day-1: Sitting position, Day1 to Follow-up Period (Final Follow-up Visit 
/ EDV ); Supine position.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D7790C00006–ed. 2.0 (Part C)
03-Nov-2022
CONFIDENTIAL AND PROPRIETARY
48 of 50
g Allowances: pre-dose and then 0.5 h (±10 minutes), 1 h (± 10 minutes), 2 h (±15 minutes), 3 h (±15 minutes), 4 h (±15 minutes), 6h 
(±15 minutes), 8 h (±15 minutes), 12 h (±30 minutes), 24 h (± 1 hour), 36 h (±1 hour) and 48 h (±1 hour) post-dose. 
h Blood samples for complement activation panel will be collected pre-dose and 1(±5 minutes), 2(±5 minutes) and 4 h (±10 minutes) 
post-dose so that the samples can be taken around Cmax.
i Plasma and urine samples for biobanking must be collected at the same hour every morning after an overnight (10-hour) fast.
j allowance; pre-dose and then 0.5 h (±2 minutes), 1 h (±5 minutes), 1.5 h (±5 minutes), 2 h (±5 minutes), 2.5 h (±5 minutes), 3 h (±10 
minutes), 4 h (±10 minutes), 5 h (±10 minutes), 6 h (± 10 minutes), 8 h (±10 minutes), 10 h (± 30 minutes), 12 h (± 30 minutes), 24 h 
(± 1 hour), 36 h (± 1hour) and 48 h (± 1 hour) post dose.
k Participants will be discharged after the results from the 48 h post-dose assessments have been reviewed by the Investigator.
l The sample should be taken in a fasting state in the morning (after a 10 hour fasting) at approximately the same time point as the pre-
dose sample on Day 1.
m Sampling to be done at approximately the same time points on the days of dosing (pre-dose) as on the non-dosing days (in the morning).
n Pregnancy test: Serum β-human chorionic gonadotropin (β-hCG) will be performed on all the women participants , irrespective of 
childbearing potential.
o Pregnancy test (Day1): Urine pregnancy test using dipstick will be performed before randomization on all the women participants, 
irrespective of childbearing potential at a local laboratory.
p All the women participants should have FSH and LH levels determined, irrespective of childbearing potential.


STATISTICAL ANALYSIS PLAN
AstraZeneca
D7790C00006–ed. 2.0 (Part C)
03-Nov-2022
CONFIDENTIAL AND PROPRIETARY
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7.2
Clinical Laboratory Assessments
Hematology
WBC count 
Neutrophils absolute count
Red blood cell (RBC) count 
Lymphocytes absolute count
Hemoglobin (Hb) 
Monocytes absolute count
Hematocrit (HCT) 
Eosinophils absolute count
Mean corpuscular volume (MCV) 
Basophils absolute count
Mean corpuscular haemoglobin (MCH) 
Platelets absolute count
Mean corpuscular haemoglobin concentration 
(MCHC) 
Reticulocytes absolute count
Clinical Chemistry
Sodium 
Alkaline phosphatase (ALP)
Potassium 
ALT
Blood urea nitrogen (BUN) 
AST
Creatinine 
Gamma glutamyl transpeptidase (GGT)
Calcium 
Total bilirubin
Phosphate 
Direct bilirubin
Glucose (fasting) 
Indirect bilirubin
Creatine kinase (CK) 
Glutamate dehydrogenase (GLDH)
Bicarbonate 
Lactate dehydrogenase (LDH)
HbA1c 
Uric acid
Serum β-human chorionic gonadotropin (β-
hCG)(women only)
FSH (women only)
eGFR
Luteinizing hormone (LH) (women only)
Coagulation
aPTT 
Prothrombin time
International normalized ratio (INR)
Urine renal safety biomarkers
Albumin 
N-acetyl-beta-D-glucosaminidase (NAG)


STATISTICAL ANALYSIS PLAN
AstraZeneca
D7790C00006–ed. 2.0 (Part C)
03-Nov-2022
CONFIDENTIAL AND PROPRIETARY
50 of 50
Total protein 
Kidney Injury Molecule-1 (KIM-1)
Creatinine 
Neutrophil gelatinase-associated lipocalin (NGAL)
Clusterin
Osteopontin
Cystatin-C 
UACR
Composite Measure
Other laboratory assessments
Complement activation panel ( Bb, C5a) 
High-sensitive C-reactive protein (hs-CRP)
Dipstick urinalysis for hematuria 
Dipstick urinalysis for human chorionic
gonadotropin (hCG)(women only)
Viral serology (screening only)
HIV I
Hepatitis B surface antigen (HBsAg)
HIV II
Hepatitis C virus antibody


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Statistical Analysis Plan Part C Edition 2
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