A Phase II Randomized, Double-blind, Placebo-controlled, Proof-of-Concept Study to Evaluate the Safety and Efficacy of Cotadutide in Participants With Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Phase: PHASE2
Conditions: Non-cirrhotic Non-alcoholic Steatohepatitis With Fibrosis
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
Cotadutide
Study Code
D5671C00006
Version
3.0
Date
15 May 2023
A Phase II Randomized, Double-blind, Placebo-controlled, Proof-
of-Concept Study to Evaluate the Safety and Efficacy of 
Cotadutide in Participants with Non-cirrhotic Non-alcoholic 
Steatohepatitis with Fibrosis
Sponsor Name: AstraZeneca AB
Legal Registered Address: AstraZeneca AB, 151 85 Södertälje, Sweden
Local Sponsor: AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011, Japan
Regulatory Agency Identifier Number(s)
EudraCT: 2021-005484-53
IND: 139975
Clinicaltrials.gov: NCT05364931
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The Clinical Study Protocol is publicly registered and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.
Protocol Number: D5671C00006
Amendment Number: 2
Study Intervention: Cotadutide, placebo

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Study Phase: Phase II
Short Title: A study to evaluate the safety and efficacy of cotadutide given by subcutaneous 
injection in adult participants with non-cirrhotic non-alcoholic steatohepatitis with fibrosis 
Acronym: PROXYMO-ADVANCE 
Study Physician Name and Contact Information will be provided separately
International co-ordinating investigator: 
Virginia Commonwealth University
Richmond, VA 23298
PPD
PPD
PPD

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
CSP version 2
07-Nov-2022
CSP version 1
28-Jan-2022
CSP version 3: 15 May 2023
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union
and in the EU Clinical Trial Regulation Article 2, 2 (13).
Overall Rationale for the Amendment:
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. This study was designed to evaluate the safety and efficacy of cotadutide given 
by SC injection in adult participants with biopsy-proven NASH with fibrosis stage F2 or F3. 
After careful consideration, the sponsor has decided to discontinue the development of 
cotadutide (a daily injectable GLP-1/glucagon co-agonist) to focus efforts on other, more 
convenient treatments for patients with NASH. Randomized participants and participants in 
active screening (having signed the ICF) will be allowed to continue participation in the study 
as per protocol unless they decide to withdraw from the study. The Phase III (Part B) portion 
of the study will no longer be conducted. As a consequence of these changes, the number of 
participants in the study will be significantly reduced. Therefore, the primary objective for this 
study will be safety, and efficacy objectives will be considered exploratory. The protocol has 
been revised accordingly to reflect these key changes. 
Substantial changes to the protocol are summarized below.

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Section # and Name
Description of Change and Brief Rationale
Study title
Updated title to reflect the key changes in the study design.
Section 1 (Protocol Summary)
Section 3.2 (Objectives and 
Endpoints: Part B)
Section 3.3 (Estimands)
Section 4 (Study Design)
Section 5.4 (Screen Failures)
Section 6.3.1 (Method for 
Assigning Treatment Groups)
Section 6.3.3 (Methods for 
Unblinding)
Section 7.1 (Discontinuation of 
Study Intervention)
Section 8 (Study Assessments and 
Procedures)
Section 9 (Statistical 
Considerations)
Appendix F (Patient-Reported 
Outcomes)
Removal of content related to Part B (Phase III) due to the decision to 
not conduct that part of the study, including, but not limited to, 
removal of: 
•
General description of Part B throughout
•
Endpoints that were only planned for Part B
•
Part B study schema, SoA, sample size, and statistical analysis
•
Description of dose adaptation decision process and 
implementation.
Section 1.1 (Synopsis)
Section 3.1 (Objectives and 
Endpoints: Part A)
Section 4.1 (Overall Design)
Section 4.2.3 (Rationale for 
Endpoints)
Section 8.1.5 (Exploratory 
Biomarker Assessments)
Section 9 (Statistical 
Considerations)
Revised the study objectives and endpoints due to the decision to 
discontinue enrollment. The primary objective and endpoints for this 
study were updated to safety. Efficacy endpoints are all exploratory.
•
Reduced the number of histology-based endpoints for Part A.
•
Eliminated the objectives/endpoints for absolute change from 
baseline in body weight, eGFR, and uACR.
•
Combined objectives related to glycemic control and lipid profile.
•
Assessment of change from baseline in HbA1c will no longer be 
restricted to participants with T2DM.
The rationale for endpoints and statistical considerations were also 
updated, and “proof of concept” was added to the study description.
Section 1.1 (Synopsis)
Section 3.3 (Estimands)
Section 9 (Statistical 
Considerations)
Revised statistical analysis description to reflect the updated study 
design and objectives and endpoints. 
•
Updated the statistical hypotheses and sample size description. 
•
Removed analysis and adaptations descriptions for Part B.
•
Removed the multiplicity plan.
•
Revised the analysis of efficacy endpoints to use nominal p value.
•
Simplified the primary estimand to use a treatment policy 
approach for intercurrent events.
•
Added the Per Protocol population definition.
Section 1.1 (Synopsis)
Section 2.1 (Study Rationale)
Section 4.1 (Overall Design)
Provided explanation for the change in study design.

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Section # and Name
Description of Change and Brief Rationale
Section 1.1 (Synopsis)
Section 1.2 (Schema)
Section 4.1 (Overall Design)
Section 9.2 (Sample Size 
Determination)
Updated the number of countries, screened participants, and 
randomized participants.
Section 1.3.2.1 (Part A Schedule of 
Activities: Treatment Period and 
Follow-up)
Removed the requirement for ADA monitoring for participants who 
test positive at the follow-up visit. No safety concerns related to the 
development of ADAs have been identified in the cotadutide clinical 
development program to date. Because the cotadutide NASH clinical 
program has been terminated, further ADA monitoring after the 
follow-up visit is not needed.
Section 2.3.1 (Risk Assessment)
Added gallbladder-related disorders to the potential risks to align with 
the IB. 
Section 1.3.2.1 (Part A Schedule of 
Activities: Treatment Period and 
Follow-up)
Section 3.1 (Objectives and 
Endpoints: Part A)
Section 4.2.3.2 (Rationale for 
Exploratory Endpoints)
Section 8.1.3 (FibroScan and 
FibroScan-derived Biomarkers)
Section 8.1.5 (Exploratory 
Biomarker Assessments)
Clarified the FibroScan-derived biomarkers by adding the Agile 3+ 
endpoint (and components) and the components of FAST score. 
Section 6.5.2 (Prohibited 
Concomitant Medications)
Added instructions to address use of any drugs with new regulatory 
approvals for the treatment of NASH with fibrosis. Use of the newly 
approved treatment can be considered after discussion with study 
physician, if the investigator deems it not to be safe for the participant 
to postpone the start of such treatment until study end.
Section 7.1 (Discontinuation of 
Study Intervention)
Changed the liver-related potential reason for discontinuation to 
“suspected or confirmed diagnosis of DILI” for consistency with 
Figure 2 and Figure 3 and added cross reference to the figures. 
Section 8.4.2 (Immunogenicity 
Assessments)
Section 9.4.4 (Analysis of 
Pharmacokinetics and 
Immunogenicity)
Due to change in scope of the study:
•
Revised text on assessment of cross-reactivity to GLP-1 and 
glucagon from “will be performed” to “may be performed.”
•
Removed the analysis of presence of neutralizing ADAs and the 
effect of immunogenicity on biomarkers and efficacy.

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Nonsubstantial changes to the protocol are summarized below.
Section # and Name
Description of Change and Brief Rationale
Section 1.3.2.1 (Part A Schedule of 
Activities: Treatment Period and 
Follow-up)
Clarified text on requirement for follow-up visits after early 
discontinuation or end of treatment visits. 
Section 2.2.1 (Disease Background)
Minor update to language on approved pharmacological therapies to 
align with Section 2.3.2 (Benefit Assessment).
Section 2.2.2 (Cotadutide 
Background)
Updated the IB edition to 10.0 to reflect the most recently approved IB. 
Section 3.1 (Objectives and 
Endpoints: Part A)
Moved the definitions of NASH endpoints to the footnote of the 
objectives and endpoints table for clarity. 
Section 5.2 (Exclusion Criteria)
Changed the units for platelets to match units used by the central 
laboratory. 
Section 5.4 (Screen Failures)
Removed GGT from the list of central laboratory criteria for retesting 
to correct an administrative error. 
Section 6.5.2 (Prohibited 
Concomitant Medications)
Added paracetamol to the description for clarity. 
Section 6.7 (Missed Dose)
Clarified that 7-day interruptions of IP that constitute an important 
protocol deviation must be consecutive. 
Section 7.3 (Lost to Follow Up)
Correction of text on participants who become unreachable.
Section 8.2.5 (Clinical Safety 
Laboratory Assessments)
Added eGFR to the list of safety assessments because it was removed 
from the efficacy assessments. 
All sections
Minor typographical and administrative edits.

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 7
LIST OF FIGURES ............................................................................................................ 10
LIST OF TABLES .............................................................................................................. 10
LIST OF APPENDICES ..................................................................................................... 11
1
PROTOCOL SUMMARY ................................................................................ 12
1.1
Synopsis ........................................................................................................... 12
1.2
Schema............................................................................................................. 19
1.3
Schedule of Activities ....................................................................................... 20
1.3.1
Schedule of Activities: Screening...................................................................... 20
1.3.2
Schedule of Activities: Treatment Period and Follow-up................................... 24
1.3.2.1
Part A Schedule of Activities: Treatment Period and Follow-up......................... 24
1.3.2.2
Part B Schedule of Activities: Treatment Period and Follow-up ........................ 28
1.3.3
Unscheduled Visits for Dose Modification........................................................ 28
1.3.4
Unscheduled Visit for Safety or Any Other Reason ........................................... 29
2
INTRODUCTION............................................................................................ 29
2.1
Study Rationale ................................................................................................ 29
2.2
Background ...................................................................................................... 30
2.2.1
Disease Background ......................................................................................... 30
2.2.2
Cotadutide Background..................................................................................... 31
2.3
Benefit/Risk Assessment................................................................................... 32
2.3.1
Risk Assessment ............................................................................................... 32
2.3.2
Benefit Assessment........................................................................................... 34
2.3.3
Overall Benefit: Risk Conclusion...................................................................... 35
3
OBJECTIVES, ENDPOINTS, AND ESTIMANDS .......................................... 35
3.1
Objectives and Endpoints: Part A...................................................................... 35
3.2
Objectives and Endpoints: Part B...................................................................... 38
3.3
Estimands ......................................................................................................... 39
4
STUDY DESIGN ............................................................................................. 40
4.1
Overall Design.................................................................................................. 40
4.1.1
Part A Overall Design ....................................................................................... 41
4.1.2
Part B Overall Design....................................................................................... 41
4.2
Scientific Rationale for Study Design ............................................................... 41
4.2.1
Rationale for Study Population ......................................................................... 41
4.2.2
Rationale for Treatment Duration...................................................................... 41
4.2.3
Rationale for Endpoints .................................................................................... 42
4.2.3.1
Rationale for Primary/Safety Endpoints ............................................................ 42

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4.2.3.2
Rationale for Exploratory Endpoints................................................................. 42
4.2.4
Participant Input into Design............................................................................. 43
4.3
Justification for Dose........................................................................................ 44
4.4
End of Study Definition.................................................................................... 44
5
STUDY POPULATION.................................................................................... 45
5.1
Inclusion Criteria .............................................................................................. 45
5.2
Exclusion Criteria ............................................................................................. 47
5.3
Lifestyle Considerations ................................................................................... 50
5.3.1
Diet and Lifestyle Education............................................................................. 50
5.3.2
Meals and Dietary Restrictions ......................................................................... 50
5.3.3
Alcohol............................................................................................................. 50
5.3.4
Activity............................................................................................................. 50
5.4
Screen Failures ................................................................................................. 51
6
STUDY INTERVENTION ............................................................................... 52
6.1
Study Interventions Administered ..................................................................... 52
6.1.1
Investigational Products.................................................................................... 52
6.1.2
Medical Devices ............................................................................................... 53
6.2
Preparation/Handling/Storage/Accountability ................................................... 53
6.3
Measures to Minimize Bias: Randomization and Blinding ................................ 54
6.3.1
Method for Assigning Treatment Groups........................................................... 54
6.3.2
Methods to Ensure Blinding.............................................................................. 55
6.3.3
Methods for Unblinding.................................................................................... 55
6.3.3.1
Unblinding for Analysis.................................................................................... 55
6.4
Study Intervention Compliance......................................................................... 55
6.5
Concomitant Therapy........................................................................................ 56
6.5.1
Permitted Concomitant Medications ................................................................. 56
6.5.2
Prohibited Concomitant Medications ................................................................ 57
6.5.3
Management of Nausea and Vomiting............................................................... 58
6.5.4
Management of Type 2 Diabetes Mellitus ......................................................... 58
6.5.4.1
Use of Medications Known to Cause Hypoglycemia in Type 2 Diabetes Mellitus
......................................................................................................................... 58
6.5.4.2
Therapies for Management of Type 2 Diabetes Mellitus.................................... 58
6.5.4.3
Management of Hypoglycemia ......................................................................... 59
6.5.4.4
Management of Hyperglycemia ........................................................................ 59
6.6
Dose Modification ............................................................................................ 60
6.7
Missed Dose ..................................................................................................... 60
6.8
Treatment of Overdose...................................................................................... 61
6.9
Intervention After the End of the Study............................................................. 61
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 61
7.1
Discontinuation of Study Intervention............................................................... 61

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7.2
Participant Withdrawal from the Study.............................................................. 62
7.3
Lost to Follow Up............................................................................................. 63
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 63
8.1
Efficacy Assessments........................................................................................ 64
8.1.1
Liver Biopsy-based Histopathology .................................................................. 64
8.1.2
Artificial Intelligence-based Histopathology ..................................................... 64
8.1.3
FibroScan and FibroScan-derived Biomarkers .................................................. 64
8.1.4
Height and Weight ............................................................................................ 65
8.1.5
Exploratory Biomarker Assessments................................................................. 65
8.2
Safety Assessments........................................................................................... 65
8.2.1
Medical History................................................................................................ 66
8.2.2
Physical Examinations...................................................................................... 66
8.2.3
Vital Signs ........................................................................................................ 66
8.2.4
Electrocardiograms........................................................................................... 67
8.2.5
Clinical Safety Laboratory Assessments............................................................ 68
8.2.6
Other Safety Assessments ................................................................................. 70
8.2.6.1
Assessment of Injection Sites............................................................................ 70
8.3
Adverse Events and Serious Adverse Events..................................................... 70
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 70
8.3.2
Follow-up of AEs and SAEs ............................................................................. 71
8.3.3
Causality Collection.......................................................................................... 72
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 72
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 72
8.3.6
Adverse Events of Special Interest.................................................................... 73
8.3.7
Adverse Events Related to Liver Biopsy........................................................... 74
8.3.8
Hy’s Law.......................................................................................................... 74
8.3.9
Reporting of Serious Adverse Events ................................................................ 74
8.3.10
Clinical Events for Adjudication ....................................................................... 75
8.3.11
Pregnancy......................................................................................................... 79
8.3.11.1
Maternal Exposure............................................................................................ 79
8.3.12
Medication Error, Drug Abuse, and Drug Misuse.............................................. 79
8.3.12.1
Timelines.......................................................................................................... 79
8.3.12.2
Medication Error............................................................................................... 80
8.3.12.3
Drug Abuse....................................................................................................... 80
8.3.12.4
Drug Misuse ..................................................................................................... 80
8.3.12.5
Reporting of Overdose...................................................................................... 80
8.3.13
Medical Device Deficiencies............................................................................. 81
8.4
Human Biological Samples............................................................................... 81
8.4.1
Pharmacokinetics.............................................................................................. 81
8.4.2
Immunogenicity Assessments ........................................................................... 82
8.4.3
Pharmacodynamics........................................................................................... 82
8.5
Human Biological Sample Biomarkers ............................................................. 82
8.5.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 82
8.5.2
Collection of Optional Biomarker Samples ....................................................... 83
8.6
Optional Genomics Initiative Sample................................................................ 83

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9
STATISTICAL CONSIDERATIONS................................................................ 83
9.1
Statistical Hypotheses....................................................................................... 83
9.2
Sample Size Determination............................................................................... 83
9.3
Populations for Analyses................................................................................... 84
9.4
Statistical Analyses ........................................................................................... 85
9.4.1
General Considerations..................................................................................... 85
9.4.2
Efficacy ............................................................................................................ 85
9.4.3
Safety ............................................................................................................... 86
9.4.4
Analysis of Pharmacokinetics and Immunogenicity .......................................... 87
9.5
Interim Analyses............................................................................................... 88
9.6
Data Monitoring Committee ............................................................................. 88
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 88
11
REFERENCES............................................................................................... 127
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 19
Figure 2
Stopping Criteria and Dose Adaptations for Possible Hepatocellular 
DILI in Participants with Normal/Near Normal ALT at Baseline ............. 77
Figure 3
Stopping Criteria and Dose Adaptations for Possible Hepatocellular 
DILI in Participants with Elevated ALT at Baseline................................. 78
LIST OF TABLES
Table 1
Objectives and Endpoints: Part A............................................................. 13
Table 2
Schedule of Activities in the Screening Period for Participants with a 
Historical Biopsy (Part A)........................................................................ 20
Table 3
Schedule of Activities in the Screening Period for Participants 
Undergoing On-study Biopsy (Part A)..................................................... 22
Table 4
Schedule of Activities for Part A: Treatment Period and Follow-up ......... 24
Table 5
Schedule of Activities for Unscheduled Dose Modification Site Visit ...... 28
Table 6
Schedule of Activities for Unscheduled Visit for Safety or Any Other 
Reason..................................................................................................... 29
Table 7
Risk Assessment...................................................................................... 33
Table 8
Objectives and Endpoints: Part A............................................................. 35
Table 9
Restricted Medications............................................................................. 57

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Table 10
Prohibited Medications............................................................................ 57
Table 11
Permitted and Prohibited Therapies for the Management of Type 2 
Diabetes Mellitus..................................................................................... 59
Table 12
Exploratory Biomarker Assessments........................................................ 65
Table 13
Laboratory Safety Variables..................................................................... 68
Table 14
Populations for Analysis .......................................................................... 84
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 89
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 96
Appendix C
Handling of Human Biological Samples ................................................ 102
Appendix D
Optional Genomics Initiative Sample..................................................... 104
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 107
Appendix F
Alcohol Use Disorder Identification Test (AUDIT)................................ 113
Appendix G
West Haven Criteria for Hepatic Encephalopathy .................................. 115
Appendix H
Abbreviations ........................................................................................ 116
Appendix I
Protocol Version History ....................................................................... 119

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1
PROTOCOL SUMMARY
1.1
Synopsis 
Protocol Title: A Phase II, randomized, double-blind, placebo-controlled, proof-of-concept
study to evaluate the safety and efficacy of cotadutide in participants with non-cirrhotic non-
alcoholic steatohepatitis with fibrosis
Short Title: A study to evaluate the safety and efficacy of cotadutide given by subcutaneous 
injection in adult participants with non-cirrhotic non-alcoholic steatohepatitis with fibrosis
Rationale: This study was originally a 2-part Phase IIb/III study to evaluate the safety and 
efficacy of cotadutide in adults with biopsy-proven non-cirrhotic NASH with fibrosis stage F2 
or F3. GLP-1 receptor mono-agonists reduce liver fat and improve histological features of 
NASH (Armstrong et al 2016, Petit et al 2017, Newsome et al 2021). Cotadutide, an 
oxyntomodulin-like peptide with targeted balanced GLP-1 and glucagon receptor activity, has 
been associated with robust improvements in body weight, glucose and insulin homeostasis, 
markers of hepatic health, lipid lowering, collagen turnover, liver fibrosis profile, and 
renoprotection in a number of animal models of NASH, CKD, obesity, and T2DM. 
Importantly, cotadutide has demonstrated robust and significant histologic benefits, including 
reduction in NASH disease activity and improvement in fibrosis in animal models (Boland et 
al 2020). In obese patients with T2DM, cotadutide had a robust and significant treatment 
effect on HFF (Ambery et al 2018) and other non-invasive measures of NAFLD (Nahra et al 
2021). In patients with biopsy-proven non-cirrhotic NASH with fibrosis (F1, F2, F3), 
cotadutide has demonstrated robust and significant improvements in HFF, liver enzymes, and 
non-invasive markers of NASH and fibrosis.
After careful consideration, foremost being the identification of other, more convenient 
treatments in development for patients with NASH, the sponsor decided to discontinue 
development of cotadutide and recruitment into this study. Randomized participants and 
participants in active screening in the Phase II (Part A) portion of the study will be allowed to 
continue participation. The Phase III portion of the study (Part B) will not be conducted. 
Given the reduced sample size, the primary goal of this study is to evaluate the safety of 
cotadutide in participants with non-cirrhotic NASH with fibrosis. All efficacy evaluations will 
be exploratory objectives.  

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Objectives and Endpoints: Part A
Table 1
Objectives and Endpoints: Part A
Objectives
Endpoints
Primary/Safety
To evaluate the safety and tolerability of 
cotadutide as compared with placebo in 
participants with non-cirrhotic NASH with 
fibrosis
Safety and tolerability will be evaluated in terms of AEs, 
vital signs, clinical and laboratory assessments, and ECG.
Assessments related to AEs cover:
•
Occurrence/Frequency
•
Relationship to IP as assessed by the investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
AEs leading to dose reduction of IP
•
AEs of special interest 
•
Adjudicated CV events including MACE, selected 
liver events, diabetic ketoacidosis, pancreatitis, 
pancreatic carcinoma, and thyroid carcinoma
Vital signs parameters include SBP, DBP, and pulse. 
Assessments cover:
•
Observed value
•
Absolute change from baseline values over time
•
Abnormality at least once on treatment
Laboratory parameters include Clinical Chemistry 
(including MELD score) and Hematology parameters as 
well as urinalysis. A complete list of parameters is 
presented in Section 8.2.5. 
Assessments cover: 
•
Observed value 
•
Absolute change from baseline values over time
•
Abnormality/Clinically significant abnormality in 
laboratory parameters at least once on treatment  
•
Treatment-emergent increase in hematuria, 
proteinuria, and glucose in urinalysis defined as 
change from negative/trace at baseline to ++, +++, or 
++++ at any visit after baseline or an increase of at 
least ++ 
Electrocardiogram measurements include heart rate, RR, 
PR, QRS, and QT intervals. Derived variables cover 
QTcF. 
Assessments cover:
•
Observed value
•
Absolute change from baseline values over time 

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•
ECG parameters fulfilling potentially clinically
significant criteria at any time during treatment,
including QRS duration > 118 ms, PR interval > 210
ms, RR < 600 ms (resting heart rate > 100 bpm), and
RR > 1330 ms (resting heart rate < 45 bpm)
•
QTcF exceeding 450, 480, and 500 ms at any time
during treatment
•
Change in QTcF at any time during treatment as
compared to baseline exceeding 30 ms and 60 ms
•
To assess the immunogenicity of
cotadutide
•
Incidence of ADAs to cotadutide and titer during
treatment and follow-up
Exploratory
•
To determine whether cotadutide is
superior to placebo on resolution of NASH
without worsening of liver fibrosis in
participants with non-cirrhotic NASH with
fibrosis
•
Proportion of participants with resolution of NASH
without worsening of liver fibrosis based on biopsy at
Week 48
•
To assess the effect of cotadutide versus
placebo on improvement in fibrosis by at
least one stage without worsening of
NASH
•
Proportion of participants with improvement of liver
fibrosis by at least one stage without worsening of
NASH based on biopsy at Week 48
•
To assess the effect of cotadutide versus
placebo on resolution of NASH and
improvement in fibrosis
•
Proportion of participants with both resolution of
NASH and improvement in fibrosis by at least one
stage based on biopsy at Week 48
•
To assess the effect of cotadutide versus
placebo on improvement in fibrosis by at
least one stage
•
Proportion of participants with improvement in
fibrosis by at least one stage based on biopsy at
Week 48
•
To assess the effect of cotadutide versus
placebo on improvement in NAS
•
Proportion of participants with improvement in NAS
based on biopsy at Week 48
•
Change from baseline in NAS based on biopsy at
Week 48
•
To assess the effect of cotadutide versus
placebo on change in fibrosis
•
Change from baseline in fibrosis stage based on
biopsy at Week 48
•
Proportion of participants with progression, no
change, or regression in fibrosis stage based on
biopsy at Week 48
•
To assess the effect of cotadutide versus
placebo on improvement in each key
histological feature of NASH
•
Proportion of participants with improvement in key
histological features of NASH based on biopsy at
Week 48, including:

Inflammation

Steatosis

Ballooning
•
To characterize using AI-based histology
assessment the effect of cotadutide versus
placebo on NASH histology, including:

Resolution of NASH without
worsening of liver fibrosis
•
AI-based histology assessment of:

Proportion of participants with resolution of
NASH without worsening of liver fibrosis based
on biopsy at Week 48

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
Improvement of liver fibrosis by at 
least one stage without worsening of 
NASH

Resolution of NASH and 
improvement in fibrosis

Improvement in fibrosis by at least 
one stage

Improvement in NAS

Change in fibrosis 

Improvement in each key histological 
feature of NASH

Proportion of participants with improvement of 
liver fibrosis by at least one stage without 
worsening of NASH based on biopsy at 
Week 48

Proportion of participants with both resolution 
of NASH and improvement in fibrosis by at 
least one stage based on biopsy at Week 48

Proportion of participants with improvement in 
fibrosis by at least one stage based on biopsy at 
Week 48

Proportion of participants with improvement in 
NAS based on biopsy at Week 48

Change from baseline in NAS based on biopsy 
at Week 48 

Change from baseline in fibrosis stage based on 
biopsy at Week 48

Proportion of participants with progression, no 
change, or regression in fibrosis stage based on 
biopsy at Week 48

Proportion of participants with improvement in 
histological features of NASH based on biopsy 
at Week 48, including:
Inflammation
Steatosis
Ballooning
•
To assess the effect of cotadutide versus 
placebo on circulating markers of hepatic 
inflammation
•
Change from baseline in liver enzymes including 
ALT and AST through Week 48
•
To assess the effect of cotadutide versus 
placebo on lipid profile and glycemic 
control
•
Change from baseline in triglycerides, LDL 
cholesterol, HDL cholesterol, non-HDL cholesterol, 
total cholesterol, and HbA1c through Week 48
•
To summarize the PK profile of cotadutide 
•
Cotadutide PK exposure will be summarized and 
compared with prior data for consistency
•
To assess the effect of cotadutide versus 
placebo on liver stiffness 
•
Change from baseline at Week 48 in:

LSM as assessed by FibroScan

Percentage CAP as assessed by FibroScan
•
To assess the effect of cotadutide versus 
placebo on disease-specific biomarkers
•
Changes from baseline at Week 48 in non-invasive 
disease-specific biomarkers, including but not limited 
to:

Collagen turnover (Pro-C3)

ELF score

FIB-4

APRI

NFS

BARD score

FAST score 

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ADA, anti-drug antibody; AE, adverse event; AI, artificial intelligence; ALT, alanine aminotransferase; APRI, 
AST-to-platelet ratio index; AST, aspartate aminotransferase; BARD, body mass index, AST/ALT ratio, 
diabetes; BP, blood pressure; CAP, controlled attenuation parameter; CV, cardiovascular; DBP, diastolic blood 
pressure; ECG, electrocardiogram; ELF, enhanced liver fibrosis; FAST, FibroScan-AST; FIB-4, fibrosis-4; 
HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; IP, investigational product; LDL, low-density 
lipoprotein; LSM, liver stiffness measurement; MACE, major adverse cardiovascular event(s); MELD, model for 
end-stage liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic 
steatohepatitis; NFS, non-alcoholic fatty liver disease fibrosis score; PK, pharmacokinetic(s); QTcF, Fridericia-
corrected QT interval; SBP, systolic blood pressure
Overall Design
This study was originally designed as a 2-part (Phase IIb/III) study. However, given the 
decision to terminate recruitment, only Part A (Phase II) will be conducted. 
This is a Phase II, global, randomized, parallel-group, double-blind, placebo-controlled, 
multicenter, proof-of-concept study to assess the safety and efficacy of 300 μg and 600 μg 
cotadutide compared with placebo, given once daily as an SC injection administered via a 
multidose pen, in adults with non-cirrhotic NASH with fibrosis stage F2 or F3. 
The study will assess safety of cotadutide treatment. All efficacy endpoints are exploratory
and include whether treatment with cotadutide results in a significant improvement compared 
to placebo in the proportion of participants with resolution of NASH without worsening of 
liver fibrosis at Week 48. Participants who are eligible according to the inclusion/exclusion 
criteria will be randomized in a 2:1:2:1 ratio to receive cotadutide 300 µg, placebo matching 
cotadutide 300 µg, cotadutide 600 µg, or placebo matching cotadutide 600 µg. 
Participants will be ≥18 to ≤75 years of age (inclusive) with biopsy-proven NASH (historical 
biopsy performed ≤180 days from randomization or on-study biopsy) demonstrating a 
NAS ≥4 (with a score of at least 1 for each component: steatosis, lobular inflammation, and 
ballooning) and liver fibrosis stage F2 or F3. At randomization, participants will be stratified 
by the presence/absence of T2DM and by fibrosis stage. Each cotadutide treatment group will 
be placebo-matched with respect to titration schedule and dose levels. Participants will be 
screened in approximately 20 countries.
All liver biopsies will be read by a central pathology review committee.
An independent DMC will be established to monitor data on an ongoing basis to ensure safety 
•
To determine whether cotadutide is 
superior to placebo for weight reduction
•
Percent change from baseline in body weight at 
Week 48
•
To assess the effect of cotadutide versus 
placebo on glucose, adiponectin, and 
C-peptide
•
Change from baseline in fasting plasma glucose, 
adiponectin, and C-peptide at Week 48
•
To determine whether treatment with 
cotadutide compared with placebo will 
result in a reduction of BP
•
Change from baseline in SBP through Week 48

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of participants enrolled in this study and to ensure the integrity of the study.
Disclosure Statement: This is a parallel group treatment study that is blinded to the 
participants and investigators. The study will include 4 treatment arms.  
Number of Participants:
Approximately 600 participants will be screened/enrolled and approximately 55 are planned to 
be randomized to study intervention.
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.” 
Intervention Groups and Duration:
Participants will be in the study for at least approximately 1.2 years (60 weeks), including a 
screening period of up to 8 weeks, a 48-week treatment period, and a 4-week safety follow-up 
period.
Participants will undergo dose titration steps every 4 weeks to reach the target dose of 300 μg 
or 600 μg qd. Dose titration will start from 50 μg cotadutide (or matching placebo) qd and 
increase to 100 μg qd after 4 weeks, and then increase by 100 μg increments every 4 weeks, 
until reaching the final intended dose at Week 12 for the 300 μg treatment groups and Week 24 
for the 600 μg treatment groups.
The study will be blinded. After all participants have completed the study and database lock 
has occurred, the study will be unblinded and analyzed. 
Data Monitoring Committee: Yes
Statistical Methods
The primary analyses will be of safety, and analyses will be performed using the safety 
analysis set. Safety data will be presented using descriptive statistics unless otherwise 
specified and will not be formally tested. Safety events and findings will be summarized by 
treatment group. No formal hypothesis testing will be performed. 
Exploratory efficacy analyses will use nominal 2-sided 5% significance levels (equivalent to 
nominal 1-sided 2.5% significance levels) unless otherwise stated.
The primary estimand of interest for the histological endpoints will use the treatment policy 
strategy. The treatment policy approach will apply to intercurrent events of treatment 
discontinuation, deviations from the protocol titration schedule, changes in background 
medication, liver events, or use of prohibited medication or other protocol deviations. The 

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treatment policy strategy will also be used to handle the intercurrent events for continuous 
endpoints.
Participants will be analyzed according to their randomized IP assignment and dose, 
irrespective of the treatment they actually received. Analyses will be performed using the FAS 
and/or per protocol analysis sets, as appropriate. The FAS will include all randomized and 
treated participants who received at least one dose of IP irrespective of their protocol 
adherence, addition or modification of background medications, discontinuation of study 
intervention or switches to alternative medications, and continued participation in the study.
For the exploratory analysis of binary histological endpoint(s) using FAS, participants with 
missing histology data due to any reason will be imputed as non-responders. The binary 
endpoint(s) will be analyzed using a Cochran-Mantel-Haenszel test with stratification by 
T2DM presence and F2/F3 fibrosis stages. The treatment effects will be summarized by the 
difference in proportions, 95% CI, and p-value. 
In Part A, 300 participants were originally planned to be randomized to provide > 90% power 
for the test of each dose versus pooled placebo to detect a difference of 20% in NASH 
resolution assuming a placebo response rate of 15%. As a result of the decision to terminate 
recruitment, approximately 55 participants are planned to be randomized in the study.

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1.2
Schema
Figure 1
Study Design 
Pbo, placebo; R, randomization

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1.3
Schedule of Activities
1.3.1
Schedule of Activities: Screening
The SoA for participants with a qualifying historical biopsy is presented in Table 2, and the 
SoA for participants undergoing an on-study biopsy for screening is presented in Table 3.
Table 2
Schedule of Activities in the Screening Period for Participants with a 
Historical Biopsy (Part A)
Screening 
(procedures may occur 
over more than one day)
Visit
V1
Procedure/Study Day
Day-56 to -1
Informed consent (Appendix A 3) 
X
Optional informed consent for Genomics Initiative research (Appendix D 2)
X
Confirmation of fasting (Section 5.3.2)
X
Inclusion and exclusion criteria (Sections 5.1 and 5.2)
X
Demography
X
Full physical examination including height and weight (Section 8.2.2)
X
Medical history (includes AUDIT questionnaire and substance usage) 
(Section 8.2.1)
X
Historical liver biopsy (Section 8.1.1) a
X
Serum pregnancy test (WOCBP only) (Section 8.2.5)
X
Hepatitis B and C and HIV screening (Section 8.2.5) b
X
Urinalysis for drugs of abuse (Section 8.2.5)
X
Clinical safety laboratory assessments, including eGFR and MELD score 
calculation (Section 8.2.5)
X
Amylase and lipase (Section 8.2.5)
X
Coagulation parameters (Section 8.2.5)
X
12-lead ECG (Section 8.2.4) c
X
Vital signs (Section 8.2.3) d
X
Assessment of AEs (Section 8.3) e
X
Concomitant medication (Section 6.5)
X
Blood sampling for ELF (Section 8.1.5)
X
FIB-4 computed score (Section 8.1.5)
X
HbA1c (Section 8.1.5)
X
Fasting serum lipid panel (Section 8.1.5)
X
Calcitonin (Section 8.2.5)
X

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Table 2
Schedule of Activities in the Screening Period for Participants with a 
Historical Biopsy (Part A)
Screening 
(procedures may occur 
over more than one day)
Visit
V1
Procedure/Study Day
Day-56 to -1
Check participant’s ability to self-administer SC injection f
X
Demonstration of and training on self-administration of SC injection 
(Section 6.2) g
X
Review diet and lifestyle advice (Section 5.3.1)
X
Enrollment in IRT/RTSM
X
Participants should withhold alcohol and refrain from intense exercise for 24 hours prior to each study site visit.
a
Review of participant’s medical history, including historical biopsy procedure report and histopathological 
findings report that meet the inclusion and exclusion criteria in Section 5.1 and 5.2. In the event the 
historical biopsy is deemed not evaluable and a participant screen fails, an on-study liver biopsy may be 
scheduled. Such an on-study biopsy, if considered, should only be performed on a date that is ≥180 days 
after the date of the historical biopsy and after all other eligibility criteria are met. Biopsy tissue and/or 
biopsy tissue block and/or slides should be sent for the central histopathology review laboratory to 
determine eligibility at least 21 days prior to planned day of randomization. 
b
HbsAg, anti-HCV, HCV RNA, HIV-1 and HIV-2 antibodies. 
c
ECGs will be recorded in triplicate after a 10-minute supine rest period with no more than about 2 minutes 
between individual ECGs, completing all 3 ECGs within a maximum of about 5 minutes. ECGs should be 
collected prior to vital signs, PK sample collection, or other assessments as these may alter autonomic tone. 
d
Whenever vital signs and blood draws are scheduled for the same nominal time, the blood draws should 
occur last.
e
AE/SAEs will be collected from the time of signature of informed consent, throughout the treatment period 
and the follow-up period. 
f
At screening, the investigator will judge if the participant is able to self-administer SC injection.
g
Activities related to demonstration and training on SC administration can be conducted at Visit 1 and/or 
prior to randomization at Visit 2.
AE, adverse event; AUDIT, Alcohol Use Disorder Identification Test; ECG, electrocardiogram; eGFR, estimated 
glomerular filtration rate; ELF, enhanced liver fibrosis; FIB-4, Fibrosis-4; HbA1c, hemoglobin A1c; HbsAg, 
hepatitis B surface antigen; HCV, hepatitis C virus; HIV, human immunodeficiency virus; IRT, interactive 
response technology; MELD, model for end-stage liver disease; PK, pharmacokinetic(s); RTSM, randomization 
and trial supply management; SAE, serious adverse event; SC, subcutaneous; V, visit; WOCBP, women of 
childbearing potential

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Table 3
Schedule of Activities in the Screening Period for Participants
Undergoing On-study Biopsy (Part A)
Screening 
(procedures may occur over 
more than one day)
Visit
V1
Procedure/Study Day
Day -56 to -21 a
Informed consent (Appendix A 3) 
X
Optional informed consent for Genomics Initiative research (Appendix D 2)
X
Confirmation of fasting (Section 5.3.2)
X
Inclusion and exclusion criteria (Sections 5.1 and 5.2)
X
Demography
X
Full physical examination including height and weight (Section 8.2.2)
X
Medical history (includes AUDIT questionnaire and substance usage) 
(Section 8.2.1)
X
Serum pregnancy test (WOCBP only) (Section 8.2.5)
X
Hepatitis B and C and HIV screening (Section 8.2.5) b
X
Urinalysis for drugs of abuse (Section 8.2.5)
X
Clinical safety laboratory assessments, including eGFR and MELD score 
calculation (Section 8.2.5)
X
Amylase and lipase (Section 8.2.5)
X
Coagulation parameters (Section 8.2.5)
X
12-lead ECG (Section 8.2.4) c
X
Vital signs (Section 8.2.3) d
X
Assessment of AEs (Section 8.3) e
X
Concomitant medication (Section 6.5)
X
FibroScan (Section 8.1.3) f
X
Blood sampling for ELF (Section 8.1.5) g
X
Blood sampling for NIS4 g, h
X
FIB-4 computed score (Section 8.1.5) h
X
FAST score (Section 8.1.3) g, h
X
HbA1c (Section 8.1.5)
X
Fasting serum lipid panel (Section 8.1.5)
X
Calcitonin (Section 8.2.5)
X
Check participant’s ability to self-administer SC injection i
X
Demonstration of and training on self-administration of SC injection 
(Section 6.2) j
X

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Table 3
Schedule of Activities in the Screening Period for Participants
Undergoing On-study Biopsy (Part A)
Screening 
(procedures may occur over 
more than one day)
Visit
V1
Procedure/Study Day
Day -56 to -21 a
Review diet and lifestyle advice (Section 5.3.1)
X
Enrollment in IRT/RTSM
X
Liver biopsy for histology (Section 8.1.1) a
X
Participants should withhold alcohol and refrain from intense exercise for 24 hours prior to each study site visit.
a
For participants without a historical biopsy, the screening liver biopsy procedure is to be performed after all 
other screening procedures are complete and after confirmation that the participant meets all other 
inclusion/exclusion criteria. The biopsy procedure may be conducted on a different day but is part of 
Visit 1. Sites to ensure biopsy tissue block and/or slides are sent to the central histopathology review 
laboratory to determine eligibility at least 21 days prior to the planned day of randomization.
b
HbsAg, anti-HCV, HCV RNA, HIV-1 and HIV-2 antibodies.
c
ECGs will be recorded in triplicate after a 10-minute supine rest period, with no more than about 2 minutes 
between individual ECGs, completing all 3 ECGs within a maximum of about 5 minutes. ECGs should be 
collected prior to vital signs, PK sample collection, or other assessments as these may alter autonomic tone. 
d
Whenever vital signs and blood draws are scheduled for the same nominal time, the blood draws should 
occur last.
e
AE/SAEs will be collected from the time of signature of informed consent, throughout the treatment period 
and the follow-up period.  
f
If a site has access to appropriate FibroScan equipment, as well as compatible software and probes, they 
must complete the assessments per the schedule for any participant who does not have a previous FibroScan 
assessment conducted within 90 days of initiating screening activities. If not and the assessment cannot be 
conducted, this will not constitute a deviation from the protocol. Fibroscan study must be performed in a 
fasting state.
g
A pre-biopsy screening strategy prior to conduct of on-study liver biopsy, using a sequential combination of 
the following, namely, BMI, FIB-4, NIS4 (if available), FAST score or FibroScan, ELF, is strongly 
recommended. Investigator may choose an alternative pre-biopsy screening strategy that may not include 
one or more of the above parameters. It is recommended that investigators discuss the alternative pre-biopsy 
screening strategy with the sponsor prior to conduct of on-study biopsy.
h
FAST score will be calculated only at sites that have the required software.
i
At screening, the investigator will judge if the participant is able to self-administer SC injection. 
j
Activities related to demonstration and training on SC administration can be conducted at Visit 1 and/or 
prior to randomization at Visit 2.
AE, adverse event; AUDIT, Alcohol Use Disorder Identification Test; BMI, body mass index; ECG, 
electrocardiogram; eGFR, estimated glomerular filtration rate; ELF, enhanced liver fibrosis; FAST, FibroScan-
AST; FIB-4, Fibrosis-4; HbA1c, hemoglobin A1c; HbsAg, hepatitis B surface antigen; HCV, hepatitis C virus; 
HIV, human immunodeficiency virus; IRT, interactive response technology; MELD, model for end-stage liver 
disease; NIS4, non-invasive diagnostic score 4; PK, pharmacokinetic(s); RTSM, randomization and trial supply 
management; SAE, serious adverse event; SC, subcutaneous; V, visit; WOCBP, women of childbearing potential

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1.3.2
Schedule of Activities: Treatment Period and Follow-up
1.3.2.1
Part A Schedule of Activities: Treatment Period and Follow-up
Table 4
Schedule of Activities for Part A: Treatment Period and Follow-up
Treatment Period
E/D
Visit b
Follow-up
4 weeks after EOT 
or E/D (± 5d) a
Week
0
4
8
12
16
20
24
32
40
48
Visit
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(EOT)
Day
(visit window ± x days) a
1
29
± 5d
57
± 5d
85
± 5d
113
± 5d
141
± 5d
169
± 5d
225
± 5d
281
± 5d
337
± 5d
Confirmation of fasting (Section 5.3.2)
X
X
X
Demonstration of and training on self-
administration of SC injection (Section 6.2) c
X
Review of adherence to diet and lifestyle advice 
(Section 5.3.1)
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medication (Section 6.5)
X
X
X
X
X
X
X
X
X
X
X
X
12-lead dECG (Section 8.2.4) d
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (Section 8.2.3) e
X f
X
X
X
X
X
X
X
X
X
X
X
Abbreviated (symptom-directed) physical 
examination including weight (Section 8.2.2, 
Section 8.1.4)
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of AEs and injection site reactions
(Section 8.3; Section 8.2.6.1) g, h
X
X
X
X
X
X
X
X
X
X
X
X
Clinical safety laboratory assessments, including 
eGFR and MELD score calculation 
(Section 8.2.5)
X
X
X
X
X
X
X
X
X
X
X
Amylase and lipase (Section 8.2.5)
X
X
X
X
X
X
Coagulation parameters (Section 8.2.5)
X
X
X
X
X
X
Calcitonin (Section 8.2.5)
X
X
X

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Table 4
Schedule of Activities for Part A: Treatment Period and Follow-up
Treatment Period
E/D
Visit b
Follow-up
4 weeks after EOT 
or E/D (± 5d) a
Week
0
4
8
12
16
20
24
32
40
48
Visit
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(EOT)
Day
(visit window ± x days) a
1
29
± 5d
57
± 5d
85
± 5d
113
± 5d
141
± 5d
169
± 5d
225
± 5d
281
± 5d
337
± 5d
Urine pregnancy test (WOCBP only) 
(Section 8.2.5)
X
X
X
X
X
X
Liver biopsy for histology (Section 8.1.1)
X i
X j
FibroScan, LSM, CAP, FAST Score, Agile 3+
(Section 8.1.3) k, l
X
X
X
Randomization in IRT/RTSM (Section 6.3)
X
Study intervention administration in clinic m
X
X
X
X
X
X
X
X
X
Study intervention dispensed for at home 
administration
X
X
X
X
X
X
X
X
X
Instructions for use dispensed
X
X
X
X
X
X
X
X
X
Uptitration step for 300 µg cotadutide/placebo
X
X
X
Uptitration step for 600 µg cotadutide/placebo
X
X
X
X
X
X
Study intervention compliance (Section 6.4)
X
X
X
X
X
X
X
X
X
X
Urine for albumin and creatinine
X
X
X
X
X
HbA1c (Section 8.1.5)
X
X
X
X
X
Fasting serum lipid panel (Section 8.1.5)
X
X
X
Pre-dose blood for PK analysis (Section 8.4) 
X
X
X
X
X
X
X
Serum for immunogenicity (ADA) (Section 8.4.2) 
n
X
X
X
X
X
X
X
Blood sampling for ELF (Section 8.1.5)
X
X
X

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Table 4
Schedule of Activities for Part A: Treatment Period and Follow-up
Treatment Period
E/D
Visit b
Follow-up
4 weeks after EOT 
or E/D (± 5d) a
Week
0
4
8
12
16
20
24
32
40
48
Visit
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
(EOT)
Day
(visit window ± x days) a
1
29
± 5d
57
± 5d
85
± 5d
113
± 5d
141
± 5d
169
± 5d
225
± 5d
281
± 5d
337
± 5d
Blood sampling for Pro-C3 (Section 8.1.5)
X
X
X
FIB-4 computed score (Section 8.1.5)
X
X
X
Blood for fasting plasma glucose (Section 8.1.5)
X
X
X
Blood for C-peptide (Section 8.1.5)
X
X
X
Blood for adiponectin (Section 8.1.5)
X
X
X
Genomics Initiative optional, exploratory genetic 
sample (Section 8.6, Appendix D) o
X
Optional biomarker serum sample (for biomarker 
research) (Section 8.5.2)
X
X
X
Participants should withhold alcohol and refrain from intense exercise for 24 hours prior to each study site visit.
a
Visit windows should be calculated from Day 1. Visit 2 (randomization) may be scheduled any day following confirmation that participant meets all 
eligibility criteria including eligibility reading from the central pathology review of the biopsy (historical or on-study) sample and laboratory report 
assessments from the central laboratory (eg, the screening period does not need to be a full 8 weeks). Follow-up visit conducted 4 weeks (± 5 d) after EOT 
visit or E/D visit. For participants who discontinue study intervention permanently and do not continue with study visits, follow-up visit should be 
performed 4 weeks (± 5 d) after the E/D visit. For participants who discontinue study intervention early but continue with study visits, follow-up visit 
should be performed 4 weeks (± 5 d) after the EOT.
b
Performed in event of early discontinuation of study intervention or withdrawal from study. 
c
Activities related to demonstration and training on SC administration can be conducted at Visit 1 and/or prior to randomization at Visit 2.
d
ECGs will be recorded in triplicate after a 10-minute supine rest period, with no more than about 2 minutes between individual ECGs, completing all 3 
ECGs within a maximum of about 5 minutes. ECGs should be collected prior to vital signs, PK sample collection, or other assessments as these may alter 
autonomic tone. 
e
Whenever vital signs and blood draws are scheduled for the same nominal time, the blood draws should occur last.
f
At Visit 2, vital signs should be assessed prior to first dose of study intervention. 
g
AE/SAEs will be collected from the time of signature of informed consent, throughout the treatment period and follow-up period. 
h
Assessment of injection site reactions to be conducted after injection of study intervention. 

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i
The post-baseline biopsy to occur within a window from -2 weeks prior to Visit 11 (Week 48) until 4 weeks after Visit 11.
j
Biopsy should only be conducted as part of the E/D visit activities in participants who have received study intervention for at least 36 weeks and who are 
unwilling or unable to wait until Week 48. For participants who continue the study after an E/D visit and have a biopsy at the E/D visit, an additional biopsy 
should not be collected at Week 48. Biopsy should be scheduled within -2 weeks prior to +4 weeks after the E/D visit. 
k
If a site has access to appropriate FibroScan equipment, as well as compatible software and probes, they must complete the assessments per the schedule 
with extended visit windows. For V2, FibroScan must be performed pre-dose within extended visit window of -14 days but only for participants who meet 
all inclusion/exclusion criteria (including histology central read) and are determined to be eligible for randomization. For all other visits, Fibroscan must be 
performed within extended visit window of ±14 days. If a site does not have access to appropriate FibroScan equipment, as well as compatible software and 
probes, and the assessment cannot be conducted, this will not constitute a deviation from the protocol. FibroScan should be conducted in a fasting state.
l
FAST score will be calculated only at sites that have the required software.
m
Study intervention should be administered after all assessments have been conducted and samples have been collected.
n
ADA samples will be collected prior to administration of IP.
o
Genomics sample: If for any reason, the sample is not drawn at Visit 2, it may be taken at any visit until the last study visit. Only one sample should be 
collected per participant for genetics during the study. The optional informed consent for Genomics Initiative research must be signed prior to sample 
collection. Refer to Appendix D for inclusion/exclusion criteria specific to the Genomics Initiative and further details on the optional Genomics Initiative 
sample.
ADA, anti-drug antibody; AE, adverse event; CAP, controlled attenuation parameter; dECG, digital electrocardiogram; E/D, early study intervention 
discontinuation; ECG, electrocardiogram; eGFR, estimated glomerular filtration rate; ELF, enhanced liver fibrosis; EOT, end of treatment; FAST, 
FibroScan-AST; FIB-4, fibrosis-4; HbA1c, hemoglobin A1c; IP, investigational product; IRT, interactive response technology; LSM, liver stiffness 
measurement; MELD, model for end-stage liver disease; PK, pharmacokinetic(s); Pro-C3, released N-terminal propeptide of type III collagen; RTSM, 
randomization and trial supply management; SAE, serious adverse event; V, visit; WOCBP, women of childbearing potential

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1.3.2.2
Part B Schedule of Activities: Treatment Period and Follow-up
Due to the decision to end recruitment into the study, Part B of the study will not be 
conducted. 
1.3.3
Unscheduled Visits for Dose Modification
If an investigator feels a site visit is required for a participant to discuss dose modification 
(Section 6.6), activities that should be conducted are presented in Table 5. Further activities 
may be conducted as judged by the investigator.
Table 5
Schedule of Activities for Unscheduled Dose Modification Site Visit
Unscheduled Titration Visit
Review of adherence to diet and lifestyle advice(Section 5.3.1)
X
Concomitant medication (Section 6.5)
X
Vital signs (Section 8.2.3) a
X
Abbreviated (symptom-directed) physical examination including weight 
(Section 8.2.2; Section 8.1.4)
X
Assessment of AEs and injection site reactions (Section 8.3; Section 8.2.6.1) b, c
X
Study intervention administration in clinic d
X
Study intervention dispensed for at home administration
X
Instructions for use dispensed
X
Dose titration step for cotadutide/placebo
X
Study intervention compliance (Section 6.4)
X
Participants should withhold alcohol and refrain from intense exercise for 24 hours prior to each study site visit.
a
Whenever vital signs and blood draws are scheduled for the same nominal time, the blood draws should 
occur last.
b
AE/SAEs will be collected from the time of signature of informed consent, throughout the treatment period 
and follow-up period.
c
Assessment of injection site reactions to be conducted after injection of study intervention. 
d
Study intervention should be administered after all assessments have been conducted and samples have 
been collected.
AE, adverse event; SAE, serious adverse event

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1.3.4
Unscheduled Visit for Safety or Any Other Reason
Unscheduled visits for safety or any other reason may be initiated as needed, at the discretion 
of the investigator. A list of activities for unscheduled safety visits is presented in Table 6.
Table 6
Schedule of Activities for Unscheduled Visit for Safety or Any Other 
Reason
Unscheduled Safety Visit
Review of adherence to diet and lifestyle advice(Section 5.3.1)
X
Concomitant medication (Section 6.5)
X
Clinical safety laboratory assessments based on clinical judgment 
(Section 8.2.5)
X
Vital signs (Section 8.2.3) a
X
Abbreviated (symptom-directed) physical examination including weight 
(Section 8.2.2; Section 8.1.4)
X
Assessment of AEs and injection site reactions (Section 8.3; Section 8.2.6.1) b, c
X
Study intervention administration in clinic d
X
Participants should withhold alcohol and refrain from intense exercise for 24 hours prior to each study site visit.
a
Whenever vital signs and blood draws are scheduled for the same nominal time, the blood draws should 
occur last.
b
AE/SAEs will be collected from the time of signature of informed consent, throughout the treatment period 
and follow-up period.
c
Assessment of injection site reactions to be conducted after injection of study intervention. 
d
Study intervention should be administered after all assessments have been conducted and samples have 
been collected.
AE, adverse event; SAE, serious adverse event
2
INTRODUCTION
Cotadutide (MEDI0382) is a synthetic analog of the human hormone glucagon that has been 
modified, using only natural amino acids, to have a balanced activity at both GLP-1 and 
glucagon receptors. The combination of GLP-1 and glucagon receptor agonist activity is 
expected to delay disease progression and potentially reverse disease in NASH with fibrosis, 
and CKD with T2DM, through direct disease-modifying effects alongside improved lipid 
homeostasis, enhanced glycemic control, and body weight loss.
2.1
Study Rationale
Non-alcoholic steatohepatitis has a prevalence of approximately 2% to 3% in the general 
population and can lead to cirrhosis, hepatocellular carcinoma, and end-stage liver disease. It 
has been previously demonstrated that GLP-1 receptor mono-agonists reduce liver fat and 
improve histological features of NASH (Armstrong et al 2016, Petit et al 2017, Newsome et al 
2021). Cotadutide, an oxyntomodulin-like peptide with targeted balanced GLP-1 and 

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glucagon receptor activity, has been associated with improvements in body weight, glucose 
and insulin homeostasis, markers of hepatic health, lipid lowering, collagen turnover, liver 
fibrosis profile, and renoprotection in a number of animal models of NASH, CKD, obesity, 
and T2DM. Importantly, cotadutide has demonstrated robust and significant histologic benefit 
to reduce NASH disease activity leading to NASH resolution and on improvement in fibrosis 
in animal models of NASH with fibrosis (Boland et al 2020). In 2 separate studies in obese 
patients with T2DM, cotadutide had a significant treatment effect on HFF, and treatment with 
cotadutide for 54 weeks in obese T2DM led to significant treatment effects on non-invasive 
measures of NAFLD as well as effects on body weight, glucose lowering, and lipid profile 
parameters (Ambery et al 2018, Nahra et al 2021). 
In a Phase II randomized, double-blind, placebo-controlled study (D5671C00002; 
PROXYMO) in overweight/obese participants (n = 74) with biopsy-proven non-cirrhotic 
NASH with fibrosis, treatment with cotadutide at 300 µg and 600 µg doses for 19 weeks was 
generally safe and well-tolerated. The AE profile was consistent with the incretin class, and 
the majority of events were mild-to-moderate in severity. Cotadutide demonstrated dose- and 
time-dependent improvements in HFF and other measures of NASH. Dose-dependent 
reductions in liver enzymes were observed, with robust and significant treatment effects on 
AST and ALT in the 600 μg group. Additionally, improvements in biomarkers of NASH and 
fibrosis were observed. 
This study was originally a 2-part Phase IIb/III study to evaluate the safety and efficacy of 
cotadutide in adults with biopsy-proven non-cirrhotic NASH with fibrosis stage F2 or F3. 
After careful consideration, the sponsor decided to discontinue development of cotadutide and 
recruitment into this study to focus efforts on other, more convenient treatments for patients 
with NASH. Randomized participants and participants in active screening (having signed the 
ICF) will be allowed to continue participation in the study as per protocol unless they decide 
to withdraw from the study. The Phase III (Part B) portion of the study will no longer be
conducted. As a consequence of these changes, the number of participants in the study will be 
significantly reduced. Therefore, the primary objective for this study will be safety, and 
efficacy objectives will be considered exploratory.
2.2
Background
2.2.1
Disease Background
Non-alcoholic steatohepatitis is part of the spectrum of liver diseases known as NAFLD, 
ranging from simple steatosis or non-alcoholic fatty liver to NASH. Non-alcoholic 
steatohepatitis, the progressive form of the disease with a prevalence of approximately 2% to 
3% in the general population, can lead to cirrhosis and its complications, hepatocellular 
carcinoma, and end-stage liver disease (Bellentani et al 2010). Non-alcoholic steatohepatitis is 
expected to become the leading cause for liver transplantation over the next decade (Wong et 

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al 2014, Pais et al 2016, Cholankeril et al 2017). 
Non-alcoholic steatohepatitis is closely associated with metabolic risk factors including 
obesity, T2DM, and dyslipidemia. Epidemiological studies have demonstrated the prevalence 
of comorbid obesity and T2DM in approximately 80% of patients with NASH and at least 
45% of patients with NASH, respectively (Younossi et al 2016). Pathophysiologically, NASH 
is frequently associated with a hyperinsulinemic or insulin-resistant state, leading to adipose 
tissue dysfunction and increased hepatic de novo lipogenesis. Therefore, it is believed that 
both increased adipose tissue lipolysis and hepatic de novo lipogenesis contribute to increased 
liver fat and formation of lipid metabolites causing lipotoxicity. Lipotoxicity, oxidative stress, 
and mitochondrial dysfunction are believed to contribute to the hallmarks of NASH including 
signs of cell death or hepatocyte ballooning, lobular or portal inflammation, and ultimately in 
some patients, liver fibrosis (Marra et al 2013, Neuschwander-Tetri 2017).
Non-alcoholic steatohepatitis is defined histologically as a multicomponent condition 
composed of hepatic steatosis, inflammation, and hepatocyte ballooning in varying 
proportions. Approximately 25% to 35% of patients with NASH develop liver fibrosis (Mishra 
and Younossi 2012). Fibrosis stage (F1 to F4) has been shown to have significant prognostic 
value in NASH correlating with liver-related outcomes and mortality (Angulo et al 2015, 
Dulai et al 2017). Several factors have been shown to increase the risk of liver fibrosis 
progression to cirrhosis including presence of comorbid T2DM, increasing age, hypertension, 
and high BMI (Angulo 2007, Angulo et al 2015).
There are currently no approved pharmacological therapies for NASH, and lifestyle 
modifications are the mainstay of treatment. Many patients do not achieve or maintain dietary 
goals and weight loss. Consequently, the development of new therapies for NASH is an area 
of high unmet medical need, particularly given the expected increasing burden of this disease 
in parallel with the rising global epidemics of obesity and T2DM (Estes et al 2018).
2.2.2
Cotadutide Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of cotadutide is 
provided in the IB.
Cotadutide has shown potent agonism of both the GLP-1 receptor and glucagon receptor in 
human and animal in vitro assays. In vivo, this has translated into the anticipated 
pharmacological effects on body weight reduction, improved glucose and insulin homeostasis, 
improvements in markers of hepatic health, lipid lowering, reduced collagen turnover, an 
improved liver fibrosis profile, and renoprotective effects in a number of animal models of 
NASH, CKD, obesity, and T2DM. For a summary of nonclinical pharmacology and 
toxicology studies, see the IB edition 10.0 Section 4. 

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Safety
For an overall summary of safety in humans, see the IB edition 10.0 Section 5.2.1.
In completed clinical studies, the safety profile of cotadutide was generally similar to that 
observed with GLP-1 receptor agonists. In the cotadutide groups, treatment-emergent AEs in 
the SOCs of Gastrointestinal Disorders, Metabolism and Nutrition Disorders, and Nervous 
System Disorders were generally more common compared with placebo. In general, including 
in the PROXYMO study of overweight and obese participants with biopsy-proven non-
cirrhotic NASH with fibrosis, treatment-emergent AEs of nausea and vomiting were reported 
at higher incidences in the cotadutide groups compared with placebo. Most 
treatment emergent AEs were Grade 1 or 2 in severity and not serious. 
Efficacy
For an overall summary of efficacy in humans, see the IB edition 10.0 Section 5.2.2.
In obese patients with T2DM, treatment with cotadutide was associated with improvements in 
glycemic control and hepatic parameters and reductions in body weight in clinical studies 
(Nahra et al 2021).
In overweight/obese participants with biopsy-proven non-cirrhotic NASH with fibrosis 
(PROXYMO study D5671C00002), statistically significant reductions in HFF, ALT, AST, 
Pro-C3, and APRI from baseline to Week 19 (end of treatment) were observed for the 600 μg 
cotadutide group compared with placebo, and nominal reductions were observed for the 
300 μg group. Nominal reductions in body weight from baseline to Week 19 were observed 
for the 300 μg cotadutide group and the 600 μg cotadutide compared with placebo. Nominal 
reductions in HbA1c and total cholesterol from baseline to Week 19 in participants with 
NASH with or without comorbid T2DM were observed for the 300 and 600 μg cotadutide 
groups compared with placebo. In general, greater changes in efficacy parameters were 
observed for 600 versus 300 μg cotadutide compared with placebo.
2.3
Benefit/Risk Assessment
More detailed information about the known and expected benefits and potential risks of 
cotadutide may be found in the IB.
2.3.1
Risk Assessment
The current IB has further information on the potential benefits of cotadutide and an 
assessment of the potential and known risks. Risks associated with cotadutide and with study-
related procedures are presented in Table 7 along with mitigation strategies. Additionally, 
participants will be monitored throughout the study for signs, symptoms, and/or laboratory 
analyses suggestive of hepatic decompensation. Participants with hepatic decompensation will 

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be excluded from further participation in this study (Section 5.2) and will be treated 
immediately according to standard of care. Specified clinical events, including all potential 
cases of DILI and CV events, will be adjudicated by an external, independent, and blinded 
events adjudication committee (Section 8.3.10).
Table 7
Risk Assessment
Identified and potential risks of 
clinical significance
Summary of data/rationale for 
risk
Mitigation strategy
Cotadutide
Identified risks associated with 
cotadutide:
•
Nausea
•
Vomiting
•
Injection site reactions
•
Increased heart rate
Potential risks include: 
•
Alterations in blood pressure 
•
QT interval prolongation
•
Anaphylactic-type reactions
•
Skin rash
•
Hypoglycemia (with 
sulfonylurea, glitinides, and 
insulin)
•
Diabetic ketoacidosis 
(following insulin reduction)
•
Acute renal failure secondary 
to dehydration
•
Pancreatitis
•
Pancreatic carcinoma
•
Thyroid cancer
•
Gallbladder-related disorders
Potential risks for cotadutide are 
based on available published data 
for GLP-1 receptor agonists and 
glucagon, as well as clinical and 
nonclinical data.
Some potential risks 
(pancreatitis, pancreatic 
carcinoma, thyroid cancer, 
gallbladder-related disorders) are 
based solely on GLP-1 agonists 
as a class finding 
•
Inclusion/exclusion criteria 
(Section 5.1 and Section 5.2)
•
Safety monitoring (Section 
8.2) 
•
Uptitration dosing schedule 
(Section 4.3)
•
Pen device and instruction on 
proper injection technique 
(Section 6.2)

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Table 7
Risk Assessment
Identified and potential risks of 
clinical significance
Summary of data/rationale for 
risk
Mitigation strategy
Study Procedures
Liver biopsy 
•
The most common risks 
associated with liver biopsy 
are mild pain and minimal 
bleeding at the procedure 
site. 
•
Rare complications of liver 
biopsy include major 
bleeding (0.1%) and death 
(0.01%) (Nalbantoglu and 
Brunt 2014). 
Risks associated with liver biopsy 
will be minimized by:
•
Requiring that each 
investigator or designee that 
obtains a liver biopsy is 
experienced and qualified to 
perform the procedure
•
Excluding patients with 
cirrhosis, hepatic 
decompensation, and/or 
coagulopathy (Section 5.2)
•
Checking relevant laboratory 
parameters prior to the 
procedure (eg, INR and 
platelet count) (Section 1.3)
Blood draws
Routine blood draws have a 
well-established risk profile.
The risk is addressed by following 
institutional standards. 
Injection administration
•
Pain at the injection site
•
Pen device
•
Training in proper SC 
injection technique
•
Rotation of injection sites
GLP-1, glucagon-like peptide; INR, international normalized ratio; SC, subcutaneous
2.3.2 Benefit Assessment
There are currently no approved pharmacological therapies for NASH, with lifestyle 
modifications being the mainstay of treatment. Several factors have been shown to increase 
the risk of liver fibrosis progression to cirrhosis and eventual decompensation including 
presence of comorbid T2DM, increasing age, hypertension, and high BMI. The successful 
development of new therapies for NASH would address a high unmet medical need, 
particularly given the expected increasing burden of this disease in parallel with the rising 
global prevalence of obesity and especially T2DM. A significant unmet need exists among 
patients with NASH, especially those with comorbid obesity and T2DM, for treatments that 
simultaneously improve liver health, reduce CV and renal disease, provide glycemic control, 
and promote weight loss. In a Phase IIb study in participants with overweight or obesity and 
T2DM with prevalent NAFLD, treatment with cotadutide for 54 weeks resulted in significant 
decrease in HbA1c and body weight as well as improvements in triglycerides, AST and ALT 
levels, and indices of liver fibrosis such as propeptide of type III collagen level (Pro-C3), FIB-
4 index, and NFS. In a Phase II study in overweight and obese participants with biopsy-proven 
non-cirrhotic NASH with fibrosis, statistically significant reductions in HFF, ALT, AST, Pro-

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C3, and APRI from baseline to Week 19 (end of treatment) were observed for the 600 μg 
cotadutide group compared with placebo, and nominal reductions were observed for the 
300 μg group. Changes in body weight and glycemia were generally consistent with prior 
observations within the program.
Participants randomized to the placebo control arm in the study may benefit from frequent 
medical monitoring, lifestyle coaching, and close assessment of their disease and associated 
pathologies that may not otherwise be performed, especially the identification of progression 
to cirrhosis.
2.3.3 Overall Benefit: Risk Conclusion
The study design aims to minimize potential risks to participants based on the protocol 
inclusion and exclusion criteria, safety monitoring, titrated dosing scheme, and other measures 
(Table 7). Taking into account the measures to minimize risk to participants in this study, the 
potential and identified risks associated with cotadutide are justified by the anticipated 
benefits that may be afforded to participants with non-cirrhotic NASH with stage F2 or F3 
fibrosis.
3
OBJECTIVES, ENDPOINTS, AND ESTIMANDS
3.1
Objectives and Endpoints: Part A
Table 8
Objectives and Endpoints: Part A
Objectives
Endpoints
Primary/Safety
To evaluate the safety and tolerability of 
cotadutide as compared with placebo in 
participants with non-cirrhotic NASH with 
fibrosis
Safety and tolerability will be evaluated in terms of AEs, 
vital signs, clinical and laboratory assessments, and ECG.
Assessments related to AEs cover:
•
Occurrence/Frequency
•
Relationship to IP as assessed by the investigator
•
Intensity
•
Seriousness
•
Death
•
AEs leading to discontinuation of IP
•
AEs leading to dose reduction of IP
•
AEs of special interest 
•
Adjudicated CV events including MACE, selected 
liver events, diabetic ketoacidosis, pancreatitis, 
pancreatic carcinoma, and thyroid carcinoma
Vital signs parameters include SBP, DBP, and pulse. 
Assessments cover:
•
Observed value

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•
Absolute change from baseline values over time
•
Abnormality at least once on treatment
Laboratory parameters include Clinical Chemistry 
(including MELD score) and Hematology parameters as 
well as urinalysis. A complete list of parameters is 
presented in Section 8.2.5. 
Assessments cover: 
•
Observed value 
•
Absolute change from baseline values over time
•
Abnormality/Clinically significant abnormality in 
laboratory parameters at least once on treatment  
•
Treatment-emergent increase in hematuria, 
proteinuria, and glucose in urinalysis defined as 
change from negative/trace at baseline to ++, +++, or 
++++ at any visit after baseline or an increase of at 
least ++ 
Electrocardiogram measurements include heart rate, RR, 
PR, QRS, and QT intervals. Derived variables cover 
QTcF. 
Assessments cover:
•
Observed value
•
Absolute change from baseline values over time 
•
ECG parameters fulfilling potentially clinically 
significant criteria (PCS) at any time during 
treatment, including QRS duration > 118 ms, PR 
interval > 210 ms, RR < 600 ms (resting heart rate 
> 100 bpm), and RR > 1330 ms (resting heart rate 
< 45 bpm)
•
QTcF exceeding 450, 480, and 500 ms at any time 
during treatment 
•
Change in QTcF at any time during treatment as 
compared to baseline exceeding 30 ms and 60 ms
•
To assess the immunogenicity of 
cotadutide 
•
Incidence of ADAs to cotadutide and titer during 
treatment and follow-up
Exploratory
•
To determine whether cotadutide is 
superior to placebo on resolution of NASH 
without worsening of liver fibrosis in 
participants with non-cirrhotic NASH with 
fibrosis
•
Proportion of participants with resolution of NASH 
without worsening of liver fibrosis based on biopsy at 
Week 48
•
To assess the effect of cotadutide versus 
placebo on improvement in fibrosis by at 
least one stage without worsening of 
NASH
•
Proportion of participants with improvement of liver 
fibrosis by at least one stage without worsening of 
NASH based on biopsy at Week 48
•
To assess the effect of cotadutide versus 
placebo on resolution of NASH and 
improvement in fibrosis
•
Proportion of participants with both resolution of 
NASH and improvement in fibrosis by at least one 
stage based on biopsy at Week 48

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•
To assess the effect of cotadutide versus 
placebo on improvement in fibrosis by at 
least one stage
•
Proportion of participants with improvement in 
fibrosis by at least one stage based on biopsy at 
Week 48
•
To assess the effect of cotadutide versus 
placebo on improvement in NAS
•
Proportion of participants with improvement in NAS 
based on biopsy at Week 48
•
Change from baseline in NAS based on biopsy at 
Week 48
•
To assess the effect of cotadutide versus 
placebo on change in fibrosis
•
Change from baseline in fibrosis stage based on 
biopsy at Week 48
•
Proportion of participants with progression, no 
change, or regression in fibrosis stage based on 
biopsy at Week 48
•
To assess the effect of cotadutide versus 
placebo on improvement in each key 
histological feature of NASH
•
Proportion of participants with improvement in key 
histological features of NASH based on biopsy at 
Week 48, including:

Inflammation

Steatosis

Ballooning
•
•
To characterize using AI-based histology 
assessment the effect of cotadutide versus 
placebo on NASH histology, including:

Resolution of NASH without 
worsening of liver fibrosis

Improvement of liver fibrosis by at 
least one stage without worsening of 
NASH

Resolution of NASH and 
improvement in fibrosis

Improvement in fibrosis by at least 
one stage

Improvement in NAS

Change in fibrosis 

Improvement in each key histological 
feature of NASH
•
AI-based histology assessment of: 

Proportion of participants with resolution of 
NASH without worsening of liver fibrosis based 
on biopsy at Week 48

Proportion of participants with improvement of 
liver fibrosis by at least one stage without 
worsening of NASH based on biopsy at 
Week 48

Proportion of participants with both resolution 
of NASH and improvement in fibrosis by at 
least one stage based on biopsy at Week 48

Proportion of participants with improvement in 
fibrosis by at least one stage based on biopsy at
Week 48

Proportion of participants with improvement in 
NAS based on biopsy at Week 48

Change from baseline in NAS based on biopsy 
at Week 48

Change from baseline in fibrosis stage based on 
biopsy at Week 48

Proportion of participants with progression, no
change, or regression in fibrosis stage based on 
biopsy at Week 48

Proportion of participants with improvement in 
histological features of NASH based on biopsy 
at Week 48, including:
Inflammation
Steatosis
Ballooning

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Resolution of NASH is defined as the absence of fatty liver disease or isolated simple steatosis without 
steatohepatitis and a NAS ballooning score of 0, inflammation score of 0 to 1, and steatosis score of any degree 
(from 0 to 3), as assessed by NASH Clinical Research Network/NAS score.
Improvement in fibrosis is defined as a one or more category improvement in the fibrosis category (NASH 
Clinical Research Network fibrosis stage) without worsening of NASH.
Worsening of NASH is defined as any increase in the ballooning, inflammation, or steatosis scores even if total 
NAS does not increase.
ADA, anti-drug antibody; AE, adverse event; AI, artificial intelligence; ALT, alanine aminotransferase; APRI, 
AST-to-platelet ratio index; AST, aspartate aminotransferase; BARD, body mass index, AST/ALT ratio, 
diabetes; BP, blood pressure; CAP, controlled attenuation parameter; CV, cardiovascular; DBP, diastolic blood 
pressure; ECG, electrocardiogram; ELF, enhanced liver fibrosis; FAST, FibroScan-AST; FIB-4, fibrosis-4; 
HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; IP, investigational product; LDL, low-density 
lipoprotein; LSM, liver stiffness measurement; MACE, major adverse cardiovascular event(s); MELD, model for 
end-stage liver disease; NAS, non-alcoholic fatty liver disease activity score; NASH, non-alcoholic 
steatohepatitis; NFS, non-alcoholic fatty liver disease fibrosis score; PK, pharmacokinetic(s); QTcF, Fridericia-
corrected QT interval; SBP, systolic blood pressure
3.2
Objectives and Endpoints: Part B
Due to the decision to end recruitment into the study, Part B of the study will not be 
•
To assess the effect of cotadutide versus 
placebo on circulating markers of hepatic 
inflammation
•
Change from baseline in liver enzymes including 
ALT and AST through Week 48
•
To assess the effect of cotadutide versus 
placebo on lipid profile and glycemic 
control
•
Change from baseline in triglycerides, LDL
cholesterol, HDL cholesterol, non-HDL cholesterol, 
total cholesterol, and HbA1c through Week 48
•
To summarize the PK profile of cotadutide 
•
Cotadutide PK exposure will be summarized and 
compared with prior data for consistency
•
To assess the effect of cotadutide versus 
placebo on liver stiffness 
•
Change from baseline at Week 48 in:

LSM as assessed by FibroScan

Percentage CAP as assessed by FibroScan
•
To assess the effect of cotadutide versus 
placebo on disease-specific biomarkers
•
Changes from baseline at Week 48 in non-invasive 
disease-specific biomarkers, including but not limited 
to:

Collagen turnover (Pro-C3)

ELF score

FIB-4

APRI

NFS

BARD score

FAST score 

Agile 3+ 
•
To determine whether cotadutide is 
superior to placebo for weight reduction
•
Percent change from baseline in body weight at 
Week 48
•
To assess the effect of cotadutide versus 
placebo on glucose, adiponectin, and C-
peptide
•
Change from baseline in fasting plasma glucose, 
adiponectin, and C-peptide at Week 48
•
To determine whether treatment with 
cotadutide compared with placebo will 
result in a reduction of BP
•
Change from baseline in SBP through Week 48

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conducted.
3.3
Estimands
The primary clinical questions of interest are:
Part A
In patients with non-cirrhotic NASH with liver fibrosis with a treatment strategy to titrate to a 
maximum dose of 300 or 600 µg cotadutide versus placebo, what is the difference in 
proportion achieving resolution of NASH without worsening of liver fibrosis at Week 48 in 
patients regardless of treatment discontinuation, deviations from the protocol titration 
schedule, changes in background medication, liver events, or use of prohibited medication or 
other protocol deviations.  
The primary estimands are described by the following attributes:
Population: Patients with non-cirrhotic NASH with liver fibrosis (F2 or F3), with or without 
T2DM.
Endpoints: Resolution of NASH without worsening of liver fibrosis at Week 48
Treatment condition: Treatment strategy to titrate to a maximum dose of 300 µg or 600 µg 
cotadutide or matching placebo. The planned titration schedule is described in Section 4.1, 
and possible modifications to the titration schedule are described in Section 6.6. Permitted 
concomitant medications are described in Section 6.5.1, and restricted or prohibited 
concomitant medications are described in Section 6.5.2. 

Treatment Policy Strategy: If a biopsy is obtained within the analysis window, the 
endpoint will be defined based on the observed biopsy result regardless of the occurrence 
of intercurrent events of treatment discontinuation, deviations from the protocol titration 
schedule, changes in background medication, liver event, or use of prohibited medications 
or other protocol deviations.
Population-level summary: Difference in proportion of responders
Rationale for estimand: The endpoints and intercurrent event strategies for the primary 
estimands are aligned to current regulatory guidance for investigation of non-cirrhotic NASH 
therapies.

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4
STUDY DESIGN
4.1
Overall Design
This study was originally designed as a 2-part, Phase IIb/III, global, randomized, parallel-
group, double-blind, placebo-controlled, multicenter, proof of concept study to assess the 
safety and efficacy of 300 and 600 µg cotadutide compared with placebo, given once daily as 
an SC injection administered via a multidose pen, in adults with non-cirrhotic NASH with 
fibrosis stage F2 or F3. After carefully considering several factors, foremost being the 
identification of other, more convenient treatments for patients with NASH, the sponsor made 
a strategic decision to discontinue development of cotadutide and recruitment into this study. 
Randomized participants and participants in active screening will be allowed to continue 
participation. Given the reduced sample size, the primary goal of this study is to evaluate the 
safety and tolerability of cotadutide in participants with non-cirrhotic NASH with fibrosis.
The Phase III portion of the study (Part B) will not be conducted. 
Part A (Phase II) will assess the safety and efficacy of 300 µg and 600 µg cotadutide 
treatment. 
Participants will be ≥18 to ≤75 years of age (inclusive) with biopsy-proven NASH (historical 
biopsy performed ≤ 180 days from randomization or on-study biopsy) demonstrating a 
NAS ≥4 (with a score of at least 1 for each component: steatosis, lobular inflammation, and 
ballooning) and liver fibrosis stage F2 or F3. Approximately 600 participants will be
screened/enrolled in the study (in approximately 20 countries) to achieve approximately 55
randomly assigned to study intervention.
At randomization, participants will be stratified by the presence/absence of T2DM and by 
fibrosis stage (Section 6.3.1). Participants will undergo dose titration steps every 4 weeks to 
reach the target dose of 300 μg or 600 μg qd. Dose titration will start from 50 μg cotadutide 
(or matching placebo) qd and increase to 100 μg qd after 4 weeks, and then increase by 
100-μg increments every 4 weeks, until reaching the final intended dose at Week 12 for the 
300 μg treatment groups and Week 24 for the 600 μg treatment groups. To mitigate the risk of 
gastrointestinal AEs, it is important to follow the 4-week dose escalation intervals (refer to
Section 6.6 for dose modifications). Each cotadutide treatment group will be placebo-matched 
with respect to titration schedule and dose levels.
An independent DMC will be established to monitor data on an ongoing basis to ensure safety 
of participants enrolled in this study (Section 9.6).
Figure 1 (Section 1.1) is an overview of the study design. Details on treatments given during 
the study are presented in Section 6. Details on what is included in the efficacy and safety 
endpoints are presented in Section 3.  

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4.1.1
Part A Overall Design
Part A will evaluate whether treatment with cotadutide results in a significant improvement 
compared to placebo in the proportion of participants with resolution of NASH without 
worsening of liver fibrosis at Week 48. In Part A, 300 adult participants who are eligible
according to the inclusion/exclusion criteria were planned to be randomized in a 2:1:2:1 ratio 
to receive cotadutide 300 µg, placebo matching cotadutide 300 µg, cotadutide 600 µg, or 
placebo matching cotadutide 600 µg. The representation by each fibrosis stage (F2 or F3) was 
to be capped at approximately 70%. Due to termination of recruitment, approximately 55
participants are planned to be randomized. Participants will be in the study for up to 1.2 years 
(60 weeks), including a screening period of up to 8 weeks, a 48-week treatment period, and a 
4-week safety follow-up period. Participants will return unused study intervention at the end 
of treatment (or early discontinuation) visit, and assessments will be conducted as described in 
the SoA (Section 1.3). The follow-up visit should be scheduled to occur 4 weeks (± 5 days) 
later.
4.1.2
Part B Overall Design
Due to the decision to end recruitment into the study, Part B of the study will not be 
conducted.
4.2
Scientific Rationale for Study Design
4.2.1 Rationale for Study Population
In order to focus on the patient population with the greatest need and potential effect on health 
(currently identified as the target population within NASH with fibrosis who warrant 
pharmacologic intervention), this study will be conducted in patients with non-cirrhotic 
NASH with liver fibrosis. Participants with biopsy-proven non-cirrhotic NASH with NAS ≥4 
with a component score of ≥1 for steatosis, lobular inflammation, and ballooning, as well as 
liver fibrosis stage F2 or F3 on histology with or without T2DM will be recruited. Participants 
will be stratified based on fibrosis stage and the presence or absence of T2DM at 
randomization. Participants with stage F4 fibrosis (cirrhosis, compensated and 
decompensated) will not be included. 
4.2.2 Rationale for Treatment Duration
Histological evidence of NASH resolution may be observed as early as 36 weeks after 
initiation of treatment (Harrison et al 2019). Therefore, a 48-week treatment period as 
proposed in Part A should be sufficient to detect a potential signal on NASH resolution, while 
also providing sufficient treatment exposure for safety monitoring. 

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4.2.3 Rationale for Endpoints
4.2.3.1
Rationale for Primary/Safety Endpoints
Standard safety endpoints will be assessed, including vital signs, ECG, safety laboratory 
analysis, AEs, and SAEs. Increases in heart rate have been observed in clinical studies 
conducted to date with cotadutide (studies D5670C00001, D5670C00002, and 
D5670C00004), accompanied by a trend toward a reduction in BP with repeat dosing. A 
particular focus on CV safety will involve monitoring of CV events, which will be adjudicated 
by an external, independent, and blinded events adjudication committee (Section 8.3.10).
The ADA and titer (if participants are ADA positive) will be used to assess potential 
immunogenicity in NASH.
4.2.3.2
Rationale for Exploratory Endpoints
The goal for therapies for NASH with fibrosis is to slow or reverse disease progression. 
However, rate of disease progression in NASH with fibrosis and event rates for liver outcomes 
require prolonged trial durations to evaluate and demonstrate improvements in liver outcome 
events. Histological features of NASH, including fibrosis, appear to have predictive value for 
liver outcomes and have been designated as surrogate endpoints of efficacy for novel NASH 
therapeutics. Therefore, improvements in histology-based endpoints in response to cotadutide 
treatment will be explored in this trial.
Currently applied manual methods of disease staging for NASH with fibrosis, particularly for 
staging of fibrosis, have limited sensitivity and reproducibility. AI-based methods are expected 
to provide improved sensitivity and reproducibility of histopathology reporting. AI-based 
histopathology assessments will be collected for all histology endpoints.
The endpoint on body weight will provide assessment of the beneficial effect of cotadutide on 
body weight in non-cirrhotic NASH with fibrosis and allow for correlation with improvement 
in NASH liver histology and other parameters related to metabolic control. Glycemic control 
as measured by HbA1c will be assessed in participants with T2DM as a high proportion of 
patients with NASH have comorbid T2DM. Evaluation of triglycerides will provide 
assessment of the beneficial effects of cotadutide on lipid profile in participants with NASH 
and attendant comorbidities.
Cotadutide is expected to lead to improvements in glucose and lipid homeostasis. Therefore, 
measures of metabolic homeostasis in circulation will be measured including but not limited 
to HbA1c, lipid profile, adiponectin, and C-peptide. 
Although histology remains the preferred tool for diagnosis and assessment of treatment 
effects for NASH with fibrosis, given the invasive nature of a liver biopsy, there is a major 
unmet need to identify non-invasive tools that can reduce or replace the number of biopsies in 

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clinical trials. In order to validate and qualify one or more non-invasive tools for such 
purposes, these tools need to be calibrated against histology in both observational and 
interventional settings. It is also possible that the temporal profile for changes in these non-
invasive markers may be faster than that for histology. Therefore, a number of non-invasive 
assessments of steatosis, steatohepatitis, and fibrosis will be performed throughout the course 
of this study. Data from these assessments are expected to inform on the value of each of these 
non-invasive tools as potential candidates to replace biopsy-based histology. Such data also 
carry the potential of being able to be deployed in clinical treatment settings to predict and 
monitor responsiveness to cotadutide therapy. 
Hepatocellular injury will be assessed by liver enzymes (ie, ALT and AST). In addition, liver 
fibrosis will be assessed non-invasively by the ELF™ test, which is a composite measure of 
hyaluronic acid, TIMP-1, and the amino-terminal propeptide of type III procollagen (PIIINP). 
Non-invasive imaging-based tools are emerging as potential candidates to inform on disease 
progression and treatment effects in NASH. FibroScan-based transient elastography and 
FibroScan-based markers (FAST score, Agile 3+ score) will be used to assess liver stiffness 
and related biology, indicators of reduced tissue elasticity associated with inflammation and 
fibrosis (LSM [kPa]), and independently of steatosis (CAP [dB/m]) as well. 
A marker of collagen extracellular matrix turnover (specifically, released N-terminal 
propeptide of type III collagen [Pro-C3]) will be measured. 
Various non-invasive indices such as FIB-4, APRI, BARD, NFS, FLI have been reported to 
have value for monitoring of disease and treatment response. These indices leverage routinely 
measured parameters and will be assessed in the current trial. 
4.2.4 Participant Input into Design
During protocol development, the study team met with patients living with NASH to provide 
their feedback on the study. Five participants were interviewed from 3 countries (Italy, United 
States, United Kingdom). The visit schedule, visit procedures, and study burden were 
discussed to gain a better understanding of whether participants will be able to manage the 
visit schedule for the duration of the trial and whether the procedures would cause them to 
withdraw from the study. These interviews provided an opportunity for the patients to provide 
their input as a person living with NASH. 
The following support will be added to the study based on patient input: 

The sites being considered for the study should have the capabilities to complete all the 
assessments at one location where possible as recommended by the patients. 

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
A digital platform will be included as part of study support to house study 
communication, information, and resources. Some sites will have their own platform and 
may prefer that method of communication to support their patients. 

The study team will work with local countries supporting the study at AstraZeneca to 
encourage an option for transportation support for patients and caregivers participating in 
the study (where acceptable for local ethics boards). 

The study team will work with sites to encourage reminders and stress the need for 
diabetic patients to have morning appointments while fasting. In addition, where allowed 
by local ethics boards, meals or snacks after fasting visits may be provided. 
4.3
Justification for Dose
Observed and modeled data within the program have shown that while both the 300 µg and 
600 µg doses lead to weight loss and glycemic control in obese and T2DM participants, 
respectively, the 600 µg dose appears to have more robust effects. Cotadutide led to beneficial 
effects on HFF, ALT, AST and body weight in non-cirrhotic NASH with fibrosis in 
PROXYMO, with robust effects at the 600 µg dose and more modest effects at the 300 µg 
dose (Section 2.2.2). Cotadutide 600 µg also led to improvements over baseline in high 
molecular weight adiponectin, non-invasive diagnostic score 4, APRI, and Pro-C3. Known 
translatability of decreases in non-invasive measures such as HFF, ALT, AST, Pro-C3, and 
APRI to improvements in histology and the totality of the efficacy data available together 
provide confidence that the 600 µg dose has the potential to deliver meaningful histologic and 
clinical benefits in NASH with fibrosis. While the 300 µg dose may have a less robust effect 
than the 600 µg dose, the 300 µg dose demonstrated benefit on liver-related biology in obese 
patients with T2DM when treated for up to 54 weeks. Therefore, the current trial will evaluate 
the treatment effects of the 300 µg and 600 µg doses in a population of non-cirrhotic NASH 
with fibrosis for up to 48 weeks. Importantly, the 300 µg and 600 µg dose levels were found 
to have an acceptable safety (including hepatic safety) profile in non-cirrhotic NASH with 
fibrosis and in previous trials in obesity and T2DM. Taken together it is reasonable to carry 
forward the 300 µg and 600 µg dose levels for further assessment in non-cirrhotic NASH with 
fibrosis. 
To mitigate the risk of gastrointestinal AEs it is important to follow the 4-week dose escalation 
intervals. Dose titration will start from 50 μg, increase to 100 μg daily after 4 weeks, and then 
increase by 100 μg increments every 4 weeks, until reaching the final intended dose at Week 
12 for the 300 μg treatment groups and Week 24 for the 600 μg treatment groups. 
4.4
End of Study Definition
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under FDA and EU regulatory requirements:
European Union requirements define study completion as the last visit of the last participant 
for any protocol related activity.
Food and Drug Administration requirements defines 2 completion dates:
Primary Completion Date – the date that the final participant is examined or receives an 
intervention for the purposes of final collection of data for the primary outcome measure, 
whether the clinical study concluded according to the pre-specified protocol or was 
terminated. In the case of clinical studies with more than one primary outcome measure with 
different completion dates, this term refers to the date on which data collection is completed 
for all of the primary outcomes.
Study Completion Date – the date the final participant is examined or receives an intervention 
for purposes of final collection of data for the primary and secondary outcome measures and 
AEs (for example, last participant’s last visit), whether the clinical study concludes according 
to the pre-specified protocol or is terminated.
A participant is considered to have completed the study if he/she has completed all phases of 
the study including the 4-week follow-up 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 enrollment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participant must be ≥18 to ≤75 years of age (inclusive) at the time of signing the 
informed consent. 
Type of Participant and Disease Characteristics
2
Histologically confirmed NASH per NASH Clinical Research Network criteria as 
diagnosed by histology from a liver biopsy performed ≤180 days from randomization and 
fulfilling all of the following histological criteria, read by a central pathology review 
committee:
(a) NAS ≥4 with a score of ≥1 for each component: steatosis, lobular inflammation, and 
ballooning

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(b) Presence of fibrosis stage F2 or F3 
OR
(c) Willingness to undergo a liver biopsy at screening, result of which should fulfill the 
above histological criteria
Investigators should determine eligibility for liver biopsy on participants who are found to 
be eligible with respect to all other criteria, based on local procedures and clinical 
judgment, including the use of non-invasive techniques (such as FibroScan, FIB-4, and 
other clinical and laboratory-based measures).
3
HbA1c ≤10.5% in patients with T2DM managed on a stable dose of antidiabetic 
medication and/or diet for at least 90 days prior to screening. HbA1c testing may be 
repeated once.
Sex
4
Male or female (non-pregnant and non-breastfeeding)
Reproduction and Contraception
There is no requirement for male participants to alter their usual contraceptive practices. 
Contraceptive use by women should be consistent with local regulations regarding the 
methods of contraception for those participating in clinical studies.
5
Female participants of childbearing potential must use at least one highly effective form 
of birth control. A highly effective method of contraception is defined as one that can 
achieve a failure rate of less than 1% per year when used consistently and correctly. 
Women of childbearing potential who are sexually active with a non-sterilized male 
partner must agree to use at least one highly effective method of birth control, as defined 
below, from enrollment throughout the study and until at least 4 weeks after last dose of 
study intervention. Cessation of contraception after this point should be discussed with a 
responsible physician. All WOCPB must have a negative serum pregnancy test result at 
Visit 1. 
(a) Women not of childbearing potential are defined as women who are either 
permanently sterilized (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 randomization without an alternative medical cause. The following age-
specific requirements apply:

Women < 50 years old would be considered postmenopausal if they have been 
amenorrhoeic for 12 months or more following cessation of exogenous hormonal 
treatment and are found to have follicle-stimulating hormone levels in the 
postmenopausal range.

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
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.
(b) Highly effective birth control methods include sexual abstinence (when this is the 
preferred and usual lifestyle of the participant), a vasectomized partner, Implanon®, 
bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, 
Depo-Provera™ injections, oral contraceptive, and Evra Patch™, Xulane™, or 
NuvaRing®. Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea method 
are not acceptable methods of contraception. Female condom and male condom 
should not be used together, and neither is considered to be a highly effective birth 
control method.
6
Female participants must refrain from egg cell donation and breastfeeding while on study 
and for 4 weeks after the final dose of study intervention.
Informed Consent
7
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
8
Provision of signed and dated written Optional Genetic Research Information informed 
consent prior to collection of samples for optional genetic research that supports Genomic 
Initiative
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History of, or any existing condition that, in the opinion of the investigator, would 
interfere with evaluation of the study intervention, put the participant at risk, influence the 
participant’s ability to participate, or affect the interpretation of the results of the study
2
Liver disease of other etiologies (eg, alcoholic steatohepatitis; drug-induced, viral, or 
autoimmune hepatitis; primary biliary cirrhosis; primary sclerosing cholangitis;
hemochromatosis; alpha 1 antitrypsin deficiency; Wilson's disease). Participants cured of 
HCV infection less than 2 years prior to the Screening visit are not eligible
3
History of cirrhosis and/or hepatic decompensation, including evidence of portal 
hypertension (eg, low platelet count, splenomegaly, ascites, history of hepatic 
encephalopathy, esophageal varices, or variceal bleeding)
4
Prior or planned liver transplantation
5
Prior or planned bariatric surgery 

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6
Alcohol consumption > 21 units (units calculated per local regulations) per week (21 
standard drinks per week) for men and > 14 units per week (14 standard drinks per week) 
for women on average within 2 years prior to baseline liver biopsy (historical or at 
screening). Evidence of alcohol dependence as assessed by the AUDIT questionnaire at 
screening
7
Type 1 diabetes mellitus, a history of diabetic ketoacidosis, or symptoms of acutely 
decompensated blood glucose control (eg, thirst, polyuria, weight loss)
8
History of acute pancreatitis (unless previously resolved gallstone pancreatitis and post 
cholecystectomy), or current chronic pancreatitis
9
Clinically significant inflammatory bowel disease, gastroparesis, or other severe disease 
or surgery affecting the upper gastrointestinal tract (including bariatric surgery) that may 
affect gastric emptying or could affect the interpretation of the safety and tolerability data
10 History of any of the following that in the opinion of the investigator is not stable within 
90 days prior to the screening visit: 
(a) > 5% weight loss (self-reported or documented)
(b) Treatment with glucose-lowering agent(s) 
(c) Treatment with lipid-lowering agent(s)
(d) Participation in weight loss programs
11 Clinically significant CV or cerebrovascular disease within 90 days prior to screening, 
including but not limited to, myocardial infarction, acute coronary syndrome, unstable 
angina pectoris, transient ischemic attack, or stroke, or participants who have undergone 
percutaneous coronary intervention or a coronary artery bypass graft within the past 
90 days or who are due to undergo these procedures at the time of screening
12 Cardiac arrhythmia
(a) Second or third degree atrial ventricular block or sinus node dysfunction with 
clinically significant pause, not treated with pacemaker
(b) Ventricular arrhythmia requiring treatment
(c) Participants with atrial fibrillation/flutter with ventricular rate (> 100 bpm at rest) 
13 Severe congestive heart failure (New York Heart Association Class IV)
14 History of malignant neoplasms within 5 years prior to screening, except for adequately 
treated basal cell, squamous cell skin cancer, or any in situ carcinoma 
15 History of substance dependence or positive screen for drugs of abuse at screening or 
psychiatric disorder likely to impact participant safety or compliance with study 
procedures, at the discretion of the investigator
Prior/Concomitant Therapy
16 Recent (within 90 days of screening biopsy or historical biopsy through screening) use of 
therapies associated with development of NAFLD (eg, methotrexate, tamoxifen, 

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amiodarone, or long-term use of tetracyclines or systemic corticosteroids [inhaled, nasal, 
topical are allowed])
17 Recent (within 180 days of screening biopsy or historical biopsy through screening) use 
of obeticholic acid or other therapy under investigation for NASH
18 Pioglitazone or high dose vitamin E (> 400 IU) unless on a stable dose for at least 
180 days prior to the baseline biopsy (either screening or historical) and not initiated after 
the biopsy was taken 
19 Recent (within 90 days of screening biopsy or historical biopsy through screening) use of 
GLP-1 receptor agonist or GLP-1 receptor agonist containing therapies and weight loss 
medication(s) (approved and/or off-label use)
Prior/Concurrent Clinical Study Experience
20 Participation in another clinical study with an IP administered within the last 30 days or 
5 half-lives of the therapy (whichever is longer) at the time of screening or the time of the 
historical biopsy, not covered under exclusion criteria 16 or 17
21 Concurrent participation in another interventional study of any kind or prior 
randomization in this study
22 Severe allergy/hypersensitivity to any of the proposed study treatments or excipients
Diagnostic Assessments
23 Contraindication to liver biopsy (eg, bleeding diathesis, such as hemophilia, suspected 
hemangioma, or suspected echinococcal infection) or inability to safely obtain a liver 
biopsy as determined by the investigator (Section 8.1.1) 
24 Participants with serum triglyceride concentrations above 1000 mg/dL (11.3 mmol/L) at 
screening
25 Abnormal laboratory values at screening, including any of the following: 
(a) AST or ALT ≥5 × ULN
(b) Alkaline phosphatase > 2 × ULN 
(c) Impaired renal function defined as eGFR ≤30 mL/minute/1.73 m2 at screening 
(estimated according to the CKD Epidemiology collaboration) (Inker et al 2021)
(d) Albumin < 3.5 g/dL (35 g/L)
(e)
INR ≥1.3
(f) TBL ≥1.3 mg/dL in the absence of known Gilbert’s syndrome or in individuals with 
Gilbert’s syndrome, TBL ≥3 mg/dL
(g) Platelet count < 150 × 103 /μL
(h) Any other clinically significant abnormalities in serum chemistry, hematology, or 
urinalysis results as judged by the investigator

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26 Severely uncontrolled hypertension defined as SBP ≥180 mmHg or DBP ≥110 mmHg 
on the average of 2 seated BP measurements after being at rest for at least 10 minutes at 
screening or randomization 
27 Basal calcitonin level ≥50 ng/L (ie, ≥50 pg/mL) at screening, or history/family history of 
medullary thyroid carcinoma or multiple endocrine neoplasia type 1 or multiple endocrine 
neoplasia type 2
28 Any positive results for HIV infection, positive results for hepatitis B surface antigen or 
hepatitis C antibody test along with a positive HCV RNA test
Other Exclusions
29 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
30 Judgment by the investigator that the participant should not participate in the study if the 
participant is unlikely to comply with study procedures, restrictions, and requirements
31 Fibrosis stage F2 if the cap has been reached on F2 participants or fibrosis stage F3 if the 
cap has been reached on F3 participants
5.3
Lifestyle Considerations
5.3.1
Diet and Lifestyle Education
Diet and lifestyle education advice should begin at the screening visit for all participants.
Participants will be advised to adhere to specific dietary and lifestyle recommendations from 
screening until the end of the safety follow-up period and will be reminded at each study visit. 
The guidance will be in accordance with the sites’ local processes. 
In addition to the scheduled clinic visits, investigators may contact participants during the 
titration phase by telephone. During the telephone contacts, participants should be asked about 
their general wellbeing and reminded to adhere to diet and lifestyle advice. Participants should 
also be counseled about mitigation of gastrointestinal side-effects. 
5.3.2
Meals and Dietary Restrictions
Participants should fast overnight for at least 8 hours, ie, no food or beverage except water, 
prior to study site visits according to the SoA (Section 1.3). 
5.3.3
Alcohol
Participants should withhold alcohol for 24 hours prior to each study site visit.
5.3.4
Activity
Participants should refrain from intense exercise for 24 hours prior to each study site visit.

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5.4
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study but 
are not subsequently randomly assigned 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 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 during the 56-day 
screening period (screen failure) may be rescreened if the reason for screen failure was 
transient (including but not limited to laboratory tests or unforeseen personal events that 
mandate missed screening visits as determined by and at the discretion of the investigator 
documenting a rationale for rescreening). Rescreening may be considered at any time prior to 
randomization and in particular, although not limited to, for reasons related to the COVID-19 
pandemic (ie, lack of available kits, local lockdowns and imposed quarantines). Up to 2 
rescreenings are allowed in the study. Rescreened participants should re-sign informed 
consent on the rescreening visit. If a participant is rescreened, he/she must continue to meet all 
inclusion/exclusion criteria. Procedures performed within 56 days from randomization that 
meet the eligibility criteria should not be repeated. 
Participants who do not meet one or more of the central laboratory criteria for complete blood 
count with platelets, INR, ALT, AST, alkaline phosphatase, and TBL may have their 
applicable laboratory test(s) retested once as part of the screening procedure if the reason for 
failing the laboratory criteria was transient (as determined by and at the discretion of the 
investigator documenting a rationale for retest). If they fail twice to meet the applicable 
laboratory criteria during the screening period, they may still be rescreened.
Participants who do not meet the central HbA1c inclusion criteria for participation in the study 
may have their HbA1c retested once as part of the screening procedure. If they fail twice to 
meet the HbA1c inclusion criterion during the screening period, they may still be rescreened 
but no sooner than 12 weeks following the date of the second failed test. 
For participants for whom rescreening or retest is considered and for whom a historical biopsy 
was already submitted for central eligibility read, it is recommended that sites wait for the 
central histopathology eligibility read report prior to scheduling a rescreening or retest visit.
In the event the historical biopsy is deemed not evaluable and the site has determined that no 
additional historical samples are available for an additional central pathology review and a 
participant screen fails, participant may be rescreened and an on-study liver biopsy may be 
scheduled only if the on-study liver biopsy is scheduled for a date that is ≥180 days after the 
date of the historical biopsy and after all other screening procedures are completed and once it 

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has been confirmed that the participant meets all other inclusion/exclusion criteria.
Rescreened participants should be assigned the same participant number as for the initial 
screening. However, rescreening should be documented so that its effect on study results, if 
any, can be assessed.
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) utilized by a study participant 
according to the study protocol. Study intervention in this study refers to cotadutide or 
placebo.
6.1
Study Interventions Administered
6.1.1
Investigational Products
Intervention name
Cotadutide
Placebo
Type
Drug and Device Combination
Drug and Device Combination 
Dose formulation
Solution for injectiona
Solution for injectiona
Unit dose strength(s)
Multidose prefilled pen device 
containing 2.7 mL at a 
concentration of 1 mg/mL for 
doses 50-100 μg.
Multidose prefilled pen device 
containing 2.7 mL at a 
concentration of 5 mg/mL for 
doses 200-600 μg.
Multidose prefilled pen device 
containing 2.7 mL at a 
concentration of 1 mg/mL for 
doses 50-100 μg.
Multidose prefilled pen device 
containing 2.7 mL at a 
concentration of 5 mg/mL for 
doses 200-600 μg.
Dosage level(s)
50 to 600 μg once daily 
Matched to 50 to 600 μg 
cotadutide once daily
Route of 
administration
Single SC injection 
Single SC injection
Administration 
instructions 
One single injection per calendar 
day, preferably at the same time of 
the day following guidance in the 
IFU
One single injection per calendar 
day, preferably at the same time of 
the day following guidance in the 
IFU
Use
Experimental
Placebo
IMP and NIMP
IMP
IMP
Sourcing
Provided centrally by the sponsor
Provided centrally by the sponsor
Packaging and 
labeling
Study intervention will be 
provided in a carton a. Each carton 
Study intervention will be 
provided in a carton a. Each carton 

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Intervention name
Cotadutide
Placebo
and prefilled pen will be labeled as 
required per country requirement.
and prefilled pen will be labeled as 
required per country requirement.
Current/former 
name(s) or alias(es)
MEDI0382
NA
a
Both the liquid drug product and prefilled pen constitute the investigational product. AEs and SAEs that 
occur with the investigational product should be reported per the processes outlined in Section 8.3.
AE, adverse events; IFU, instructions for use; IMP, investigational medicinal product; NA, not applicable; 
NIMP, non-investigational medicinal product; SAE, serious adverse event; SC, subcutaneous
6.1.2
Medical Devices
Medical devices (stand-alone medical device products) not manufactured by or for 
AstraZeneca but provided for use in this study are:
1
Professional, multichannel electrocardiograph devices for cardiac safety monitoring 
(MAC2000). Electrocardiographs will be delivered only to sites participating in Part A of 
the study. 
2
Laboratory kits that include tubes, butterflies, urine containers, glass slides, and other 
items required to collect blood and urine samples that will be evaluated by central 
laboratory. 
3
Single-use disposable pen needles to be used with pen injection devices (applicable only 
for countries where it is not possible to locally reimburse the cost of needle purchase).
Medical devices will be used per manufacturer’s instructions, which will be provided to the 
sites prior to site initiation visit. All device deficiencies (including malfunction, use error, and 
inadequate labeling) shall be documented and reported by the investigator throughout the 
clinical investigation (Section 8.3.13) and appropriately managed by the sponsor.
6.2
Preparation/Handling/Storage/Accountability
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants randomized in the study may receive study intervention and only 
authorized 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 labeled storage conditions with access limited to 
the investigator and authorized site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).

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4
Further guidance and information for the final disposition of unused study interventions 
are provided in the pharmacy manual.
5
Participants will be supplied with cooling bags, needles, alcohol wipes, and biohazard 
bags to properly administer the study intervention and return used pens to the sites. 
Sharps containers will be provided to patients for safe needle disposal. Sponsor will 
reimburse the cost of needles and alcohol wipes. Biohazard bags, cooling bags and sharps 
containers will be supplied by the sponsor. 
At screening, the investigator will assess whether the participant is able to self-administer SC 
injection. Participants will be trained on proper SC injection technique at Visit 1 (screening) or 
at Visit 2 prior to randomization (Section 1.3). For handling of study intervention and 
instructions on administration, see the Instructions for Use. Study intervention should be 
stored at the recommended storage conditions according to the label. Storage conditions are 
also to be found in the Instructions for Use.  
6.3
Measures to Minimize Bias: Randomization and Blinding
6.3.1
Method for Assigning Treatment Groups
All participants will be centrally assigned to randomized study intervention using an 
IRT/RTSM. Before the study is initiated, the log-in information and directions for the 
IRT/RTSM will be provided to each site. 
A participant is considered randomized into the study when the investigator notifies the 
IRT/RTSM that the participant meets eligibility criteria and the IRT/RTSM provides the 
assignment of blinded IP kit numbers to the participant.
In Part A, participants will be randomized 2:1:2:1 to receive cotadutide 300 µg, placebo 
matching cotadutide 300 µg, cotadutide 600 µg, or placebo matching cotadutide 600 µg. The 
randomization will be stratified by the presence/absence of T2DM and by fibrosis stage.
T2DM at the time of randomization is based on:

Established diagnosis of T2DM
OR

HbA1c ≥6.5% (48 mmol/mol) by central laboratory assessment at Visit 1
Study intervention will be dispensed at the study visits summarized in Section 1.3. 
Returned study intervention should not be re-dispensed to the participants.

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6.3.2
Methods to Ensure Blinding
The IRT/RTSM will provide to the investigator(s) or pharmacists the kit identification number 
to be allocated to the participant at the dispensing visit. Routines for this will be described in 
the IRT/RTSM user manual that will be provided to each site. 
The randomization code should not be broken except in medical emergencies when the 
appropriate management of the participant requires knowledge of the treatment 
randomization. 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 IP and that potentially require expedited reporting to 
regulatory authorities. Randomization codes will not be broken for the planned analyses of 
data until all decisions on the evaluability of the data from each individual participant have 
been made and documented. 
6.3.3
Methods for Unblinding
The IRT/RTSM will be programmed with blind-breaking instructions. In case of an 
emergency, in which the knowledge of the specific blinded study intervention will affect the 
immediate management of the participant’s condition, the investigator has the sole 
responsibility for determining if unblinding of a participants’ intervention assignment is 
warranted. Participant safety must always be the first consideration in making such a 
determination. If a participant’s intervention assignment is unblinded, the sponsor must be 
notified within 24 hours after breaking the blind. The investigator documents and reports the 
action to AstraZeneca, without revealing the treatment given to participant to the AstraZeneca 
staff.
6.3.3.1
Unblinding for Analysis
After all participants of the study have completed the study, a database lock will be performed 
and the data will be unblinded and analyzed. 
6.4
Study Intervention Compliance
When participants are dosed at the site, they will self-administer the study intervention under 
medical supervision from the investigator or designee. The date and time of dose administered 
in the clinic will be recorded in the source documents and in the eCRF. 
When participants self-administer study intervention(s) at home, compliance with study 
intervention will be assessed at each visit. Compliance will be assessed by the investigator or 
designee by counting the returned unused pens during the site visits and documented in the 
source documents and eCRF. Deviation(s) from the prescribed dosage regimen based on 
patient recall should be recorded in the eCRF.

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It is not recommended to inspect by opening used/returned pens, so it is particularly important 
to discuss with the patient at each visit whether he/she has used the medicine on a daily basis, 
in the prescribed dose, and whether the medicine has been stored under appropriate 
conditions. If there is a suspicion that a patient is not using the correct dose or is not 
administering the drug regularly, retraining and discussion with the patient should take place. 
If, despite additional training, the patient still does not comply with the investigator's 
instructions, discontinuation of study intervention should be considered (Section 7.1).
A record of the number of pens dispensed to each participant must be maintained and 
reconciled with study intervention and compliance records. Intervention start and stop dates, 
including dates for intervention delays and/or dose reductions will also be recorded in the 
eCRF. 
6.5
Concomitant Therapy
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or 
receives during the study must be recorded along with:

Reason for use

Dates of administration including start and end dates

Dosage information including dose and frequency
The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Permitted Concomitant Medications
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 6.5.2. Specifically, participants with T2DM should continue to take their 
antidiabetic medication at the regular dose prescribed and any other medication prescribed for 
the treatment of comorbidities associated with T2DM. When intensifying T2DM treatment 
during the trial, investigators should follow guidelines such the American Diabetes 
Association and European Association for the Study of Diabetes treatment guidelines or other 
similar regionally accepted treatment guidelines. 
Participants should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines. Participants should receive care for hypertension and CV risk factors according to 
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Participants on a stable dose (for at least 180 days) of pioglitazone or high-dose vitamin E 
(> 400 IU) at the time of the baseline biopsy will be permitted to remain on this medication 
during the course of the study, provided no changes are made to the dose.
6.5.2
Prohibited Concomitant Medications
Participants must be instructed not to take any medications, including NASH-related over-the-
counter products, without first consulting with the investigator
Use of the following medications will be restricted (Table 9) or prohibited (Table 10) as 
specified:
Table 9
Restricted Medications
Medication/class of drug:
Usage (including limits for duration permitted and 
special situations in which it is allowed ):
Systemic corticosteroids by oral, intravenous, or 
intramuscular route
Not to be used within 90 days prior to baseline biopsy 
(historical or screening) and during the study unless 
prescribed for a very brief period of less than 14 days
Prokinetic agents such as domperidone and 
metoclopramide
Only to be used during the study for the treatment of 
nausea and vomiting if a centrally acting antiemetic is 
deemed ineffective or not tolerated by the participant
Analgesics and antipyretics
Careful use of paracetamol (acetaminophen) is allowed, 
not to exceed 3 g/d
Table 10
Prohibited Medications
Prohibited medication/class of drug:
Usage
Therapies associated with development of 
NAFLD such as methotrexate, tamoxifen, 
amiodarone, or long-term use of tetracyclines or 
systemic corticosteroids
Within 90 days prior to baseline biopsy (historical or 
screening) until the end of the study. Systemic 
corticosteroid and tetracycline use are restricted during 
the study unless prescribed for a very brief period of 
≤14 days.
Therapies in classes under investigation for the 
treatment of NASH (except for SGLT-2 
inhibitors), such as obeticholic acid, pioglitazone, 
and Vitamin E
Within 180 days of baseline biopsy until the end of the 
study. In the case of pioglitazone or high-dose vitamin E, 
these drugs are restricted during the study unless the 
participant has been on a stable dose for at least 180 days 
prior to baseline biopsy (historical or on-study). Potential 
drugs with new regulatory approvals for the treatment of 
NASH with fibrosis stage F2/F3 could be considered 
after discussion with study physician, if the investigator 
deems it not to be safe for the participant to postpone the 
start of such treatment until study end.
GLP-1 receptor agonists and GLP-1 receptor 
agonist containing therapies 
Within 90 days of baseline biopsy (historical or on-
study) until the end of the study

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Table 10
Prohibited Medications
Prohibited medication/class of drug:
Usage
Drugs approved for weight loss (eg, orlistat, 
bupropion/naltrexone, phentermine-topiramate, 
phentermine, lorcaserin), as well as those drugs 
used off-label
Concurrent or previous use within 90 days of baseline 
biopsy (historical or on-study) until the end of the study
Herbal preparations or dietary supplements 
marketed for control of body weight or appetite or 
with any suspected hepatotoxicity
Concurrent or prior use in the period starting within 
14 days prior to the start of screening and for the duration 
of the study. Furthermore, starting new herbal 
preparations or dietary supplements of any kind is not 
allowed once screening activities are initiated.
GLP-1, glucagon-like peptide-1; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; 
SGLT-2, sodium-glucose co transporter 2
If any unintentional use of a prohibited medication occurs, consult with the AstraZeneca study 
physician for a case-by-case resolution. 
6.5.3
Management of Nausea and Vomiting
If a participant experiences nausea or vomiting in relation to study intervention, in the first 
instance, conservative measures should be advised, including reducing meal size and 
maintaining adequate hydration. If there is persistent vomiting, a participant may be given an 
antiemetic to control his/her symptoms; a 5-hydroxytryptamine-3 receptor antagonist (eg, 
ondansetron) or anti-histamine (eg, cyclizine) is preferable rather than antiemetics, which may 
affect gastric emptying, and dopamine receptor antagonists (eg, metoclopramide or 
domperidone). Investigators should monitor participants with vomiting for signs of 
hypovolemia. Participants with impaired renal function could be especially sensitive to 
hypovolemia; such participants should be informed about the importance of adequate 
hydration in case of nausea and vomiting. These participants should also undergo additional 
laboratory testing for potential creatinine increases as appropriate. Additional laboratory 
testing will be recorded in the eCRF. 
6.5.4
Management of Type 2 Diabetes Mellitus
6.5.4.1
Use of Medications Known to Cause Hypoglycemia in Type 2 Diabetes 
Mellitus
Insulin and insulin secretagogues are known to cause hypoglycemia. Therefore, patients 
treated with insulin or sulfonylurea have a higher risk of experiencing hypoglycemic events 
compared with those treated with other antidiabetic agents. Investigators should consider 
insulin and sulfonylurea dose reduction for any participant whom they consider may be at risk 
of hypoglycemia upon initiation of study intervention. 
6.5.4.2
Therapies for Management of Type 2 Diabetes Mellitus
Participants with T2DM should be managed on a stable dose of antidiabetic (glucose-

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lowering) medication and/or diet for at least 90 days prior to screening (Section 5.1). Minimal 
change (≤20%) to the total daily insulin dose within the 90-day period prior to screening will 
not be considered exclusionary. For participants with T2DM, additional management of 
glycemic control should be according to local guidelines as required. Details concerning 
permitted and prohibited therapies for the management of T2DM are provided in Table 11.
Table 11
Permitted and Prohibited Therapies for the Management of Type 2 
Diabetes Mellitus
Permitted therapies
Prohibited therapies
•
Any type of insulin 
•
Biguanides
•
Sulfonylurea
•
Glitinide
•
Acarbose/alpha-glucosidase inhibitors
•
SGLT2 inhibitor
•
DPP-4 inhibitor
•
GLP-1 analog
•
GLP-1 analog/insulin combination (eg, 
IDegLira)
•
Pramlintide
DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide; SGLT2, sodium-glucose cotransporter 2
6.5.4.3
Management of Hypoglycemia
A hypoglycemic event is considered severe if associated with severe cognitive impairment 
requiring external assistance for recovery, as defined by the American Diabetes Association; 
clinically significant hypoglycemia is defined as a capillary or venous plasma glucose reading 
of < 3.0 mmol/L (54 mg/dL). Few events of clinically significant hypoglycemia (< 3 mmol/L) 
have been reported in participants treated with cotadutide up to 300 µg. All participants with 
T2DM will be advised to check their capillary plasma glucose level if they have symptoms of 
hypoglycemia (hunger, dizziness, shaking, sweating, or irritability) or feel unwell. Local 
protocols for treatment and follow-up of any hypoglycemic episode should be followed. Any 
clinically significant hypoglycemia (glucose < 3.0 mmol/l) should be reported by investigators 
as an AE regardless of whether the participant is experiencing symptoms or not. 
Pharmacological treatments administered for hypoglycemia (eg, dextrose/glucose tablets, 
glucagon, etc) should be recorded in the eCRF as concomitant medications. When possible, 
participants with T2DM should be prioritized for early/morning visits on days when the 
participant is fasting (Section 1.3).
6.5.4.4
Management of Hyperglycemia
When hyperglycemia is suspected, if deemed appropriate by the investigator and in 
accordance with local T2DM guidelines, additional venous fasting plasma glucose 
measurements may be performed. In addition, home glucose and urine ketone monitoring to 
be performed by participants as directed by the investigator based on local clinical practice. 
In participants who have sustained hyperglycemia, the following options are preferred:

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
An increase in insulin (if used)

Open-label changes to antidiabetic therapy such as uptitration of sulfonylurea/glitinide 
dose (if these agents were dose adjusted at the beginning of the study)
Additional drugs listed under the permitted therapies in Table 11 may also be used at the 
discretion of the investigator or the participant’s general practitioner. Any changes should be 
documented in the relevant section of the eCRF.
6.6
Dose Modification
It is strongly recommended that the investigator make every effort to work with the participant 
to uptitrate to the target dose.
If a participant is unable to successfully uptitrate to 200 µg or needs to reduce the dose below 
200 μg, they should discontinue treatment with study intervention. The lowest target dose of 
IP allowed for a participant to continue in the study is 200 µg.
Once the participant uptitrates to the 200 µg dose, in the event the participant experiences 
significant tolerability issues during the uptitration or maintenance phase, the investigator may 
allow the participant to remain at the current dose level for up to 14 days if a dose uptitration 
step is imminent, before resuming the uptitration regimen, without it constituting a deviation 
from the protocol. 
Once the participant uptitrates to the 300 µg dose, in the event the participant experiences 
significant tolerability issues during the uptitration or maintenance phase, the investigator may 
reduce the dose level to the previous titration step for 14 days or remain at the current dose 
level for up to 14 days if a dose uptitration step is imminent, before resuming the uptitration 
regimen, without it constituting a deviation from the protocol. 
The investigator may contact the sponsor for assistance with questions related to titration and 
tolerability. For management of conditions other than nausea and vomiting, dose reductions of 
cotadutide may be considered following discussion with the sponsor. Any sponsor agreed dose 
modification will not constitute a protocol deviation.
6.7
Missed Dose
If a participant forgets to inject a study intervention dose, the dose can be administered as 
soon as the participant remembers. However, if it is more than 12 hours since the participant 
should have administered the dose, the participant should skip the missed dose and take the 
next dose as usual on the following day. Please note that when taking the next dose after a 
missed dose, participant should not take a double dose to make up for the missed dose.
If a participant has missed several consecutive doses of study intervention, there might be a 

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risk for increased nausea when the participant restarts treatment. Therefore, the investigator 
should consult with the sponsor for guidance on restarting treatment.
Any interruption of the IP for 7 consecutive days during the uptitration phase or for 14 days 
during the treatment period (after reaching the target dose of 300 or 600 μg) will constitute an 
important protocol deviation. 
6.8
Treatment of Overdose
For this study, any dose of cotadutide greater than 600 µg within a calendar day will be 
considered an overdose.
In the event of an overdose, the investigator should:

Evaluate the participant to determine, in consultation with the sponsor, if possible, 
whether study intervention should be interrupted or whether the dose should be reduced.

Closely monitor the participant for any AE/SAE and laboratory abnormalities as 
medically appropriate. Refer to Section 8.3.12.5 for details of AE/SAE reporting related 
to overdose.
6.9
Intervention After the End of the Study
There is no intervention following the end of the study. 
7
DISCONTINUATION OF STUDY INTERVENTION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1
Discontinuation of Study Intervention
It may be necessary for a participant to permanently discontinue (definitive discontinuation) 
study intervention. Participants who discontinue study intervention early will have an early 
discontinuation visit as described in the SoA (Section 1.3). After the early discontinuation 
visit, participants will be encouraged to remain in the study for all remaining visits and study 
procedures as outlined in the SoA, with the exception of the urine pregnancy test, dispensation 
of study intervention and Instructions for Use, and PK sampling. Participants will be 
encouraged to have the biopsy at Week 48 as planned in the SoA. Participants who are 
unwilling or unable to wait until Week 48 will have the biopsy procedure as part of the early 
discontinuation visit if they have received study intervention for at least 36 weeks. Samples 
for clinical safety laboratory assessments, amylase and lipase, coagulation parameters, and 
calcitonin do not need to be collected at visits occurring more than 30 days after 
discontinuation of study intervention except as needed for lab abnormalities/AEs that require 
follow-up to resolution. 

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Note that discontinuation from study intervention is NOT the same thing as a withdrawal from 
the study.
An individual participant will not receive any further IP if any of the following occur:

Withdrawal of consent/assent from further treatment with IP.

Lost to follow-up.

Noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal 
(eg, refusal to adhere to scheduled visits).

Pregnancy in a female participant.

An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing; specific examples include:

Clinically significant tachyarrhythmias, including but not limited to life-threatening 
arrhythmia, eg, sustained ventricular tachycardia or ventricular fibrillation.

Acute pancreatitis 
o
Participants will be instructed to contact the investigator or other healthcare 
provider if they experience persistent severe abdominal pain, with or without 
vomiting, because this is the hallmark symptom of acute pancreatitis warranting 
prompt evaluation of serum amylase and lipase and prompt abdominal 
ultrasound. If pancreatitis is suspected, study medication should be discontinued. 
If pancreatitis is confirmed, appropriate treatment should be initiated, and the 
participant should be carefully monitored until recovery. 

Suspected or confirmed diagnosis of DILI
o
In case a participant shows an AST or ALT ≥ 3 × ULN together with TBL 
≥2 × ULN, refer to Appendix E. Figure 2 and Figure 3 provide additional 
guidance in evaluating for DILI in this study population.
Refer to the SoA (Section 1.3) for data to be collected at the time of intervention 
discontinuation and 4-week follow-up.
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, behavioral, 
compliance, or administrative reasons (after discussion with the sponsor). 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).

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
Refer to SoA for data to be collected at the time of study withdrawal and 4-week follow-
up and for any further evaluations that need to be completed.

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 Global Study Team.
7.3
Lost to Follow Up
A participant will be considered lost to follow-up if he/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 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 be lost to 
follow up. 
Discontinuation of specific sites or of the study as a whole are handled as part of Appendix A.
8
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol waivers 
or exemptions are not allowed.
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence 
or awareness to determine if the participant should continue or discontinue study intervention.

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Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct.
The COVID-19 pandemic and associated guidelines, recommendations, national laws, and 
local restrictions are constantly evolving. Thus, where possible, other measures for carrying 
out protocol-related activities, such as but not limited to home nursing, may be required to 
ensure participant safety. 
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.
8.1
Efficacy Assessments
8.1.1
Liver Biopsy-based Histopathology
Liver biopsy samples taken at baseline (either historical [collected within 180 days of 
randomization] or taken during the screening period), at Week 48, or at Early Discontinuation 
will be assessed centrally by a Central Pathology Review Committee to determine the NAS 
and fibrosis staging. Details of liver biopsy procedure are described in the Histopathology 
Manual. 
8.1.2
Artificial Intelligence-based Histopathology
Artificial intelligence-based histopathology assessments will be conducted for all histology 
endpoints related to NAS and fibrosis staging (Bosch et al 2021, Taylor-Weiner et al 2021) at 
the time points specified in Section 1.3. 
8.1.3
FibroScan and FibroScan-derived Biomarkers
FibroScan® will be used to assess liver stiffness and CAP at sites where it is feasible to do so, 
at the time points specified in Section 1.3. If a site has access to appropriate FibroScan 
equipment, as well as compatible software and probes, they must complete the assessments 
per the schedule. If not and the assessment cannot be conducted, this will not constitute a 
deviation from the protocol. The LSM must be performed in a fasting state and according to 
site standard procedures. At sites with FibroScan equipment with CAP option available, 
measurements of liver steatosis must be performed at the specified visits. FibroScan-derived 
biomarkers will be assessed. FAST score (a combination of FibroScan-derived CAP, LSM, 
and AST level) and Agile 3+ score (a combination of FibroScan-derived LSM, AST, ALT, 
platelet, age, sex, and diabetes status) will be calculated for participants at sites that have the 
required software or access to the website.

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8.1.4
Height and Weight
Standing height and body weight will be measured at the time points specified in the SoA 
(Section 1.3). 
Height will be measured once at screening only and recorded in centimeters. 
The participant's weight should be measured after the participant has removed bulky clothing 
including shoes. The participant's body weight will be recorded in kilograms to 1 decimal 
place. Whenever possible, the same scale should be used throughout the study and calibrated 
on a regular basis as recommended by the manufacturer.
8.1.5
Exploratory Biomarker Assessments
Table 12 presents protocol-defined exploratory biomarker assessments. These assessments 
will be made in accordance with the Laboratory Manual and Section 1.3.
Table 12
Exploratory Biomarker Assessments
Assessment
Biomarker
Hepatic inflammation
ALT and AST (Section 8.2.5)
Disease-specific 
biomarkers
Collagen turnover: Pro-C3
ELF™ (components): PIIINP, hyaluronic acid, and TIMP-1
FIB-4 index (components): platelet count, ALT, AST
APRI (components): AST, platelet count
NFS (components): ALT, AST, platelet count, albumin
BARD score (components): ALT, AST
FAST score a (components): CAP, LSM, AST (Section 8.1.3)
Agile 3+ a (components): LSM, AST, ALT, platelet count, age, sex, diabetes status
(Section 8.1.3)
Glucose control
HbA1c, fasting plasma glucose, adiponectin, C-peptide
Blood pressure 
SBP (Section 8.2.3)
Lipids
Total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, non-HDL 
cholesterol
Optional biomarkers 
(serum based)
Biomarker research, including markers disease status and response to cotadutide 
(Section 8.5.2)
a
FAST score and Agile 3+ will be calculated only at sites that have the required software.
ALT, alanine aminotransferase; APRI, AST-to-platelet ratio index; AST, aspartate aminotransferase; BARD, body mass
index, AST/ALT ratio, diabetes; CAP, controlled attenuation parameter; ELF, enhanced liver fibrosis score; FAST, 
FibroScan-AST; FIB-4, fibrosis-4; HbA1c, hemoglobin A1c; HDL, high-density lipoprotein; LDL, low-density lipoprotein; 
LSM, liver stiffness measurement; NFS, non-alcoholic fatty liver disease fibrosis score; PIIINP, amino-terminal propeptide of 
type III-procollagen, Pro-C3, released N-terminal propeptide of type III collagen; SBP, systolic blood pressure; TIMP-1, 
tissue inhibitor of metalloproteinase type-1 
8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA (Section 1.3).

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8.2.1
Medical History
Complete medical history will include history and current medical conditions; past or present 
CV disorders; respiratory, gastrointestinal, renal, hepatic, neurological, endocrine, lymphatic, 
hematologic, immunologic, dermatological, psychiatric, genitourinary, or any other diseases 
or disorders; drug and surgical history; and history of alcohol and tobacco use. If the 
participant reports a history of gallbladder ultrasound performed < 12 months prior to 
screening, the ultrasound report should be obtained and should be noted on the eCRF. 
Presence or absence of gallbladder disease/cholelithiasis should be noted for all participants 
and recorded on the eCRF.
The AUDIT questionnaire (Appendix F) to assess alcohol use habits will be completed at 
screening only (Section 1.3). The results will be used for determining participant eligibility 
(Section 5.2). 
8.2.2
Physical Examinations
Physical examination will be performed at timepoints as specified in Section 1.3. 

A full physical examination will be performed and include assessments of the following: 
general appearance including skin inspection, lymph nodes, thyroid, 
musculoskeletal/extremities, CV system, lungs, abdomen, and reflexes. 

An abbreviated physical examination will include, at a minimum, assessments of the skin, 
extremities, CV system, lungs, and abdomen.
Clinically significant abnormalities in physical examination findings at study termination must 
be followed up by the investigator and evaluated with additional tests/procedures if necessary, 
until the underlying cause is diagnosed or resolution occurs. As appropriate, the diagnosis and 
resolution date of the physical examination abnormalities must be reported as AEs.
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
New or worsening abnormalities may qualify as AEs; additional details are provided in 
Section 1.3. 
8.2.3
Vital Signs
Vital sign measurements (SBP, DBP, pulse, body temperature, and respiratory rate) will be 
obtained in accordance with appropriate guidelines after the participant has rested in the 
seated position for at least 10 minutes in a quiet setting without distractions at the visits 
specified in Section 1.3. 
Vital sign measurements should be taken prior to IP administration (where applicable) and 
before blood drawing. BP and pulse measurements will be assessed with a completely 
automated device. Manual techniques will be used only if an automated device is not 

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available. BP readings should be taken while the participant is in a comfortable seated position 
with the arm supported at the level of the heart. At screening the seated BP will be recorded 2 
times in both the left and the right arms. The 2 measurements should be made in 1 arm before 
transferring the cuff to the other arm. Whenever possible, the arm with the highest mean 
seated systolic BP readings will be the one used for all subsequent readings throughout the 
study.
At each study visit, after the participant has rested in the seated position for at least 
10 minutes, 3 consecutive BP readings will be taken at intervals of at least 1 minute and 
recorded in the eCRF. 
If BP is uncontrolled at study entry, investigators should carefully monitor the BP levels 
according to applicable guidelines, with consideration for the individual patient and potential 
comorbidities. BP treatment should be optimized to reduce the overall CV risk.
Route of body temperature measurement will be according to local procedures but should be 
consistent throughout the study for an individual participant.
8.2.4
Electrocardiograms
ECGs will be recorded at the sites using 12-lead ECG recorders in the supine position after the 
participant has been resting for at least 10 minutes, according to the SoA (Section 1.3). The 
investigator may add extra 12-lead ECG safety assessments if there are any abnormal findings 
or if the investigator considers it is required for any other safety reason. 
Digital ECGs will be recorded in triplicate on standardized study ECG machines and assessed 
centrally. 
Standardized 12-lead digital ECG equipment and all requisite hook up supplies will be 
provided. ECGs will be uploaded via a secure portal for high-resolution measurement of the 
cardiac intervals and morphological assessment by a central cardiologist blinded to the study 
treatment. Where digital transmission is not possible, a process for receipt and analysis of 
scanned or paper ECGs is also established.
Confirmed ECGs will be available on a study portal within the contracted turnaround time.
On-screen measurements of the RR, PR, QRS, and QT interval durations will be performed, 
and variables for QTcF, QTcB, and heart rate will be calculated. Each fiducial point (onset of 
P wave, onset of Q wave, offset of S wave, and offset of T wave) will be electronically 
marked. The original ECG waveform and such annotations will be saved separately in XML 
format for independent review.
The investigator or authorized delegate will make an initial assessment of whether the ECG 

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findings are normal or abnormal and if abnormal, clinically significant or not. In the case of a 
discrepancy between the investigator’s initial assessment and the central ECG reading, the 
central reading will take precedence.  
If a site requires expedited reporting for ECGs due to suspected ECG abnormalities or for 
urgent decision making, the site should contact the ECG provider per instructions to request 
expedited ECG processing.
In case of an ECG device malfunction, the site should follow the steps recommended within 
the Cardiac Safety Study Manual in order to have the ECG analyzed in a timely manner. 
8.2.5
Clinical Safety Laboratory Assessments
The clinical chemistry, hematology and urinalysis assessments will be performed at a central 
laboratory. A Laboratory Manual will be provided to the sites that specifies the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information, specific to this clinical research study. Blood and urine samples for determination 
of clinical chemistry, hematology, coagulation, and urinalysis will be collected at the visits 
indicated in the SoA (Section 1.3).
The investigator should make an assessment of the available results with regard to clinically 
relevant abnormalities. The laboratory results should be signed and dated and retained at 
center as source data for laboratory variables. The investigator should follow all clinically 
significant laboratory abnormalities occurring during the study that were not present at 
baseline. These abnormalities should be evaluated with additional tests, if necessary, until the 
underlying cause is diagnosed, or resolution occurs. The diagnosis and resolution date must be 
reported to the sponsor.
Information about how AEs based on laboratory tests should be recorded and reported are 
provide in Section 8.3.5.
Additional safety samples may be collected if clinically indicated at the discretion of the 
investigator. The date of collection will be recorded on the appropriate eCRF.
Laboratory variables to be measured are listed in Table 13.
Table 13
Laboratory Safety Variables
Hematology/hemostasis (whole blood)
Clinical chemistry (plasma or serum)
  B-Hemoglobin
  S/P-Creatinine
  B-Leukocyte count
  S/P-Bilirubin, total
  B-Leukocyte differential count (absolute count)
  S/P-Alkaline phosphatase
  B-Platelet count
  S/P-AST

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Table 13
Laboratory Safety Variables
  B-Red blood cell count
  S/P-ALT
  B-Hematocrit
  S/P-Albumin
  B-Mean corpuscular hemoglobin concentration
  S/P-Potassium
  B-Mean corpuscular volume
  S/P-Calcium, total
  B-Red cell distribution width
  S/P-Sodium
  B-Red blood cell morphology
  S/P-Blood urea nitrogen
  S/P-Phosphorous
Urinalysis (dipstick)
  S/P-Bicarbonate
  U-Hemoglobin/erythrocytes/blood
  S/P-Glucose
  U-Protein
  S/P-Chloride
  U-Microscopic analysis (if positive for blood, nitrites, or protein)
  S/P-GGT
  U-Glucose
  U-Ketones
  U-pH
  U-Specific gravity
  U-Bilirubin
  U-Color
  U-Appearance
  U-Nitrites
  U-Leukocytes
  U-Urobilinogen
  U-Drugs of abuse, standard panel (Screening only)
ALT, alanine aminotransferase; AST, aspartate aminotransferase; B, blood; GGT, gamma glutamyl transferase;
P, plasma; S, serum; U, urine
NB. In case a participant shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN 
please refer to Appendix E. Actions required in cases of increases in liver biochemistry and 
evaluation of HL, for further instructions. Figure 2 and Figure 3 provide additional guidance 
in evaluating for DILI in this study population.Reproduction (Female Participants of 
Childbearing Potential Only)

Serum beta-hCG at screening only 

Urine hCG, by dipstick, thereafter 

Follicle-stimulating hormone at screening only (if not measured in the previous 
12 months) 

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Additional Laboratory Assessments
Safety

Serum calcitonin

Serum amylase and lipase

HBsAg, anti-HCV, HCV RNA (screening only)

HIV-1 and HIV-2 antibodies (screening only)

Coagulation parameters (prothrombin time, activated partial thromboplastin time, and 
INR)

MELD score (composite of INR, sodium, bilirubin, and creatinine) 

Direct bilirubin (in the presence of Gilbert's syndrome)

eGFR (CKD-EPI creatinine formula [Inker et al 2021])
8.2.6
Other Safety Assessments
8.2.6.1
Assessment of Injection Sites
Site staff will assess the injection site for injection site reactions at the times specified in the 
SoA (Section 1.3). Injection site reactions will be recorded as AEs. The site of injection should 
be rotated to avoid previously injected sites. In the case of an injection site reaction, these 
should be initially managed with a cold compress. Symptomatic treatment with antihistamines 
may be required in the presence of itching, and/or topical corticosteroids to reduce erythema 
and tenderness, particularly if the reaction progresses over several days. Oral nonsteroidal 
anti-inflammatory therapy may also be considered.
8.3
Adverse Events and Serious Adverse Events
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section.
The definitions of an AE or SAE can be found in Appendix B.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE. Information about how to follow up AEs is provided 
in Section 8.3.2.
8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected from the time of signing of the ICF throughout the 
treatment period and the 4-week follow-up period. 

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If the investigator becomes aware of an SAE with a suspected causal relationship to the IMP
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/SAEs that are unresolved at the participant’s final visit of 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 when the AE started and stopped

Maximum intensity

Whether the AE is serious or not

Investigator causality rating against the IP(s) (yes or no)

Investigator causality rating against the study procedure(s) (yes or no) 

Action taken with regard to IP(s)

AE caused participant’s withdrawal from study (yes or no) 

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for SAE

Date investigator became aware of SAE

AE is serious due to

Date of hospitalization

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment to other medication

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8.3.3 Causality Collection
The investigator should assess causal relationship between Investigational Product, study 
procedure, medical device 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, study procedures, 
or medical devices. 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?” or 
revealed by observation will be collected and recorded in the eCRF. When collecting AEs, the 
recording of diagnoses is preferred (when possible) to recording a list of signs and symptoms. 
However, if a diagnosis is known and there are other signs or symptoms that are not generally 
part of the diagnosis, the diagnosis and each sign or symptom will be recorded separately.
8.3.5 Adverse Events Based on Examinations and Tests
The results from the CSP mandated laboratory tests and vital signs will be summarized in the 
CSR. 
Deterioration as compared to baseline in protocol-mandated laboratory values or vital signs 
should therefore only be reported as AEs if they fulfill any of the SAE criteria, are the reason 
for discontinuation of treatment with the IP 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 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 

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related to the disease under study.
8.3.6 Adverse Events of Special Interest
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring and collection of additional information by the investigator. An AESI 
may be serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of 
these events in order to characterize and understand them in association with the use of this IP. 
Adverse events of special interest for this study include: 

Nausea

Vomiting

Increased heart rate

Injection site reaction

Blood pressure alteration (hypotension/hypertension)

Hypoglycemia

Diabetic ketoacidosis

Anti-drug antibody

Pancreatitis

Pancreatic carcinoma

Thyroid carcinoma

Acute renal failure secondary to dehydration

Drug-induced liver injury

Cardiovascular events

Gallbladder-related disease
These AESIs are to be reported as described in Section 8.3.1 and Section 8.3.2. Information on 
AESIs of hypoglycemia, diabetic ketoacidosis, injection site reaction, pancreatitis, pancreatic 
carcinoma, thyroid carcinoma, drug-induced liver injury, and CV events should be reported in 
the appropriate eCRF. Participants with significant vomiting should be monitored for 
electrolytes. Refer to Section 6.5.3 for a discussion of gastrointestinal tolerability and 
mitigating strategies. Hepatic enzyme abnormality meeting the definition of PHL is also 
considered an AESI. Refer to Section 8.3.8 for the definition and reporting of AESIs of 
hepatic enzyme abnormality.
Refer to the IB for a discussion of potential risks. 

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8.3.7 Adverse Events Related to Liver Biopsy
Signs or symptoms suggestive of liver biopsy complication (eg, pain, bleeding [intraperitoneal 
hemorrhage, hematoma, hemobilia], etc) should be reported as AEs or SAEs, as applicable. 
8.3.8 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with TBL ≥2 × ULN may 
need to be reported as SAEs. Please refer to Figure 2, Figure 3, and Appendix E for further 
instruction on cases of increases in liver biochemistry and evaluation for HL.
8.3.9
Reporting of Serious Adverse Events
All SAEs have to be reported, whether considered causally related to the IP, 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 1 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 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up will be undertaken immediately. Investigators or other site personnel will inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within 1 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 system, an automated email alert is sent to the designated AstraZeneca representative.
If the electronic data capture system is not available, then the investigator or other study site 
staff reports the SAE via secure method to the appropriate AstraZeneca representative.
When the electronic data capture system is temporarily not accessible, the AstraZeneca Study 
Representative should confirm that the investigator/site staff enters the SAE in the 
AstraZeneca electronic data capture system when access resumes.
For further guidance on the definition of an SAE, refer to Appendix B. The reference 
document for definition of expectedness/listedness is the IB. 

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8.3.10
Clinical Events for Adjudication
A CEA committee, blinded to the treatment of the participant, will independently adjudicate 
certain clinical AEs. The CEA committee will operate in accordance with the CEA Charter 
and Event Handling Manual for sites and site monitors. 
The CEA committee will adjudicate events possibly related to the following:
1
Events of hepatic decompensation include:
(a) Clinically apparent ascites requiring treatment
(b) Complication of ascites (eg, spontaneous bacterial peritonitis, diuretic-resistant 
ascites [refractory ascites], hepato-pleural effusion)
(c) Hepatic encephalopathy of Grade 2 or above (according to the West Haven criteria as 
defined in Appendix G) requiring treatment
(d) Portal hypertension-related upper gastrointestinal bleeding identified by endoscopy 
and requiring hospitalization, including events of bleeding from esophageal varices, 
gastric varices, and portal hypertensive gastropathy
(e) Liver transplantation or qualification for liver transplantation, defined as a MELD 
score ≥ 15 on at least 2 consecutive occasions at least 4 weeks apart
2
Clinical cirrhosis
3
Events of suspected DILI
4
Hepatocellular carcinoma
5
All deaths (and CV deaths)
6
Cardiac ischemic events:
(a) Myocardial infarction
(b) Hospitalization for unstable angina
7
Cerebrovascular events:
(a) Stroke
8
Hospitalization for heart failure 
9
Diabetic ketoacidosis
10 Events of thyroid carcinoma, pancreatitis, and pancreatic carcinoma 
For all Clinical Events identified for adjudication, the investigator will complete the 
appropriate modules of the eCRF and provide source documentation. In order to provide the 
independent adjudication committee with appropriate and adequate information for 
adjudication of the listed events, consult the CEA Charter and Event Handling Manual for 
Sites and Monitors.
Possible cases of DILI will be monitored and managed using the algorithm described in 

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Figure 2 and Figure 3, which is based on the IQ DILI Initiative consensus guideline (Regev et 
al 2019) as well as Appendix E, which will be used for the reporting of PHL cases.

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Figure 2
Stopping Criteria and Dose Adaptations for Possible Hepatocellular DILI in Participants with Normal/Near 
Normal ALT at Baseline
a
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain.
Baseline pretreatment ALT is derived from the average of the last ALT measurement prior to randomization and the randomization visit (V2) based on central 
laboratory assessments. Elevated baseline is defined as ALT > 1.5 × ULN. 
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; INR, international normalized 
ratio; TBL, total bilirubin; ULN, upper limit of normal

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Figure 3
Stopping Criteria and Dose Adaptations for Possible Hepatocellular DILI in Participants with Elevated ALT 
at Baseline
a
Liver-related symptoms include: severe fatigue, nausea, vomiting, right upper quadrant pain.
Baseline pretreatment ALT is derived from the average of the last ALT measurement prior to randomization and the randomization visit (V2) based on central 
laboratory assessments. Elevated baseline is defined as ALT > 1.5 × ULN. If on treatment a participant has 2 or more consecutive ALT values at scheduled visits
based on central laboratory assessments, each less than 50% of the baseline ALT and they are within 40% of each other (with percentage calculated based on the 
larger value as the denominator), then a new baseline should be set to be the minimum of the latest consecutive pair of values that are “stable” (ie, within 40% of 
each other).
ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; DILI, drug-induced liver injury; INR, international normalized 
ratio; TBL, total bilirubin; ULN, upper limit of normal

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8.3.11
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

Pregnancies in the partner of male participants
8.3.11.1
Maternal Exposure
If a participant becomes pregnant during the course of the study, IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP 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 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 provided to the AstraZeneca Patient Safety data entry site within 1 or 
5 calendar days for SAEs (Section 8.3.9) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the eCRF is used to report the pregnancy and the paper-based 
PREGOUT module is used to report the outcome of the pregnancy.
8.3.12
Medication Error, Drug Abuse, and Drug Misuse
8.3.12.1
Timelines
If an event of medication error, drug abuse, or drug misuse occurs during the study, then the 
investigator or other site personnel informs the appropriate AstraZeneca representatives within 
1 calendar day, ie, immediately but no later than 24 hours of when they become aware of it.
The designated AstraZeneca representative works with the investigator to ensure that all 
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Fatal/Life-Threatening) or 5 (other serious initial and follow up) calendar days if there is an 
SAE associated with the medication error, drug abuse, or misuse (Section 8.3.9) and within 
30 days for all other medication errors.
8.3.12.2
Medication Error
For the purposes of this clinical study, a medication error is an unintended failure or mistake 
in the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the 
participant or has the potential to cause harm to the participant.
The full definition of medication error can be found in Appendix B 4. 
8.3.12.3
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition of drug abuse can be found in Appendix B 4. 
8.3.12.4
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
The full definition of drug misuse can be found in Appendix B 4. 
8.3.12.5
Reporting of Overdose
Refer to Section 6.8 for definition and treatment of overdose. 

An overdose with associated AEs is recorded as the AE diagnoses/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 IMP or AstraZeneca NIMP 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 1 or 
5 calendar days for overdoses associated with an SAE (Section 8.3.9) and within 30 days for 
all other overdoses.

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8.3.13
Medical Device Deficiencies
As described in Section 6.1.2, third-party medical devices will be supplied under the study 
protocol.
In this study any deficiency observed with a third-party medical device will be collected and 
reported to the manufacturer. 
A medical device deficiency is an inadequacy of a medical device with respect to its identity, 
quality, durability, reliability, safety, or performance. Medical device deficiencies include 
malfunctions, use errors, and information supplied by the manufacturer.
The AstraZeneca medical device complaint report will be used to collect the deficiency. 
8.4
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 refer to 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. 

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. 

PK samples may be disposed of or anonymized by pooling. Additional analyses may 
be conducted on the anonymized, pooled PK samples to further evaluate and validate 
the analytical method. Any results from such analyses may be reported separately 
from the CSR.

Remaining ADA sample aliquots will be retained at AstraZeneca or its designee for a 
maximum of 15 years following issue of the CSR. Additional use includes but is not 
limited to further characterization of any ADAs, confirmation and/or requalification of 
the assay as well as additional assay development work. The results from future analysis 
will not be reported in the CSR.
8.4.1
Pharmacokinetics

Plasma samples will be collected for measurement of concentrations of cotadutide as 
specified in Section 1.3.

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 

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of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 

Plasma samples will be used to analyze the PK of cotadutide. Samples collected for 
analyses of cotadutide plasma concentration may also be used to evaluate safety or 
efficacy aspects related to concerns arising during or after the study.

Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory 
Manual.
Determination of Drug Concentration
Samples for determination of drug concentration in plasma will be assayed by bioanalytical 
test sites operated by or on behalf of AstraZeneca, using an appropriately validated 
bioanalytical method. Full details of the analytical method used will be described in a separate 
Bioanalytical Report.
Drug concentration information that may unblind the study will not be reported to 
investigative sites or blinded personnel.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis 
of the test samples. The results from the evaluation, if performed, will be reported in a 
separate Bioanalytical Report.
8.4.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be collected at time points listed in 
Section 1.3 and assayed by bioanalytical test sites operated by or on behalf of AstraZeneca, 
using appropriately validated bioanalytical methods. Tiered analyses will be performed to 
include screening, confirmatory, and titer assay components. Assessment of cross-reactivity to 
GLP-1 and glucagon may be performed on samples that are confirmed positive for ADA.
ADA samples may also be further tested for characterization of the ADA response. Additional 
analyses may be conducted on anonymized, individual or pooled immunogenicity samples to 
further evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.
8.4.3
Pharmacodynamics 
8.5
Human Biological Sample Biomarkers
8.5.1
Collection of Mandatory Samples for Biomarker Analysis
Required samples for biomarker research (Section 8.1.5) will be collected from all participants 

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in this study as specified in the SoA (Section 1.3).
Analysis of biosamples may be performed for safety analytes or for biomarkers or analytes 
that may play a role in NASH and related conditions including but not limited to their 
association with disease progression and observed clinical responses to cotadutide. The results 
of this biomarker research may be reported either in the CSR or as an addendum, or separately 
in a scientific report or publication. The results of this biomarker research may be pooled with 
biomarker data from other studies to generate hypotheses to be tested in future research.
8.5.2
Collection of Optional Biomarker Samples
Collection of optional samples for biomarker research is also part of this study as specified in 
the SoA (Section 1.3) and is subject to agreement to optional consent. Optional blood samples 
will be collected, and analysis may be performed for safety analytes or for biomarkers thought 
to play a role in NASH and related conditions including, but not limited to, their association 
with disease progression and observed clinical responses to cotadutide. Optional biomarker 
samples will be collected according to local regulatory approval. 
8.6
Optional Genomics Initiative Sample
Collection of optional samples for Genomics Initiative research is also part of this study as 
specified in the SoA and is subject to agreement in the ICF addendum. A 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. Refer 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 either in the 
appendices or in the Laboratory Manual. For storage and destruction of genetic samples refer 
to Appendix D. 
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
For the primary safety objective, analyses will compare cotadutide treatment to placebo. The 
exploratory efficacy analyses will test the null hypotheses of no treatment effect for cotadutide 
versus placebo in the FAS. 
9.2
Sample Size Determination
Approximately 7440 participants were originally planned to be screened/enrolled to achieve 
1860 randomly assigned to study intervention, including 300 in Part A. However, this study 
has prematurely stopped randomization as the cotadutide program has been discontinued. The 
sample size for this study includes approximately 55 randomized participants. The original 

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sample size calculations for Part A are detailed below.
In Part A, 300 participants were originally to be randomized in a 2:1:2:1 ratio. Approximately 
100 participants were planned for each for each dose of cotadutide and 50 participants for 
each matching placebo group. This sample size was derived with respect to the comparison of 
each cotadutide group to the pooled placebo group for the proportion of participants with 
resolution of NASH without worsening of liver fibrosis at Week 48. The sample size would 
provide > 90% power for the test of each dose versus placebo to detect a difference of 20% in 
NASH resolution assuming a placebo response rate of 15%. The calculations assumed a 
2-sided alpha level of 0.05.
The effects were assumed after any impacts from treatment discontinuation, early withdrawal, 
missing data imputation, etc. The assumed effect sizes for the histology-based endpoints took 
into account the PROXYMO interim analysis results as well as the published effects for a 
GLP-1 receptor agonist (Newsome et al 2021).
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.” 
9.3
Populations for Analyses
The following populations are defined:
Table 14
Populations for Analysis
Population/Analysis 
set
Description
Enrolled 
All participants who sign the ICF.
Randomized 
All participants randomized into the study.
FAS
All participants who have been randomized to and received at least one dose of IP.
PP
Subset of FAS population with evaluable post-baseline biopsy after at least 36 weeks 
of treatment.
Safety
The Safety analysis set consists of all participants who have received at least one dose 
of IP. Erroneously treated participants (eg, those randomized to treatment A but 
actually given treatment B) are accounted for in the treatment group with the majority
of estimated usage. In all cases, the dose level for analysis will correspond to the 
randomized dose. 
PK
The PK population includes all participants who receive at least 1 dose of study 
intervention and have at least 1 complete intended PK sample containing detectable 
cotadutide concentrations.
FAS, full analysis set; ICF, informed consent form; IP, investigational product; PK, pharmacokinetic(s); PP, per 
protocol

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9.4
Statistical Analyses
This section is a summary of the planned statistical analyses of the endpoints. A more 
technical and detailed description of the statistical analyses will be provided in the SAP.
9.4.1
General Considerations
The primary analyses will be of safety. No formal hypothesis testing will be performed. 
Treatments will be compared in tables using descriptive statistics.
Exploratory efficacy analyses will use nominal 2-sided 5% significance levels (equivalent to 
nominal 1-sided 2.5% significance levels) unless otherwise stated.  
The primary estimand of interest for the histological endpoints will use the treatment policy 
strategy. The treatment policy approach applies to intercurrent events of treatment 
discontinuation, deviations from the protocol titration schedule, changes in background 
medication, liver events, or use of prohibited medication or other protocol deviations. The 
treatment policy strategy will also be used to handle the intercurrent events for continuous 
endpoints.
Participants will be analyzed according to their randomized IP assignment and dose, 
irrespective of the treatment they actually received. Analyses will be performed using the FAS 
and/or per protocol analysis sets, as appropriate (Table 14). The FAS will include all 
randomized and treated participants who received at least one dose of IP irrespective of their 
protocol adherence, addition or modification of background medications, discontinuation of 
study intervention or switches to alternative medications, and continued participation in the 
study.
9.4.2
Efficacy 
The following exploratory endpoints will be analyzed descriptively versus placebo with 
95% CIs at the nominal 2-sided alpha 5% level:  

Resolution of NASH at Week 48 without worsening of fibrosis

Improvement in fibrosis at Week 48 without worsening of NASH

Resolution of NASH and improvement in fibrosis at Week 48

Improvement in fibrosis by at least one stage at Week 48

Change from baseline in triglycerides, LDL cholesterol, HDL cholesterol, non-HDL 
cholesterol, total cholesterol, and HbA1c through Week 48
Additional exploratory endpoints and their analyses will be detailed in the SAP.  

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The binary endpoint(s) will be analyzed using a Cochran-Mantel-Haenszel test with 
stratification by T2DM presence and F2/F3 fibrosis stages. The treatment effects will be 
summarized by the difference in proportions, 95% CI, and p-value. For the exploratory 
analysis of binary histological endpoints using FAS, participants with no liver outcome and 
missing histology data due to any reason may be imputed as non-responders. 
Continuous endpoints (absolute change in body weight, change in HbA1c, percent change in 
triglycerides) will be analyzed using Analysis of Covariance models, adjusting for baseline 
value, presence of T2DM, and fibrosis stage (F2/F3). For the primary analyses of these 
endpoints, missing data will be imputed via multiple imputations.
9.4.3
Safety
Safety analyses will be performed using the safety analysis set. Safety data will be presented 
using descriptive statistics unless otherwise specified and will not be formally tested. 
Safety events and findings will be summarized by treatment group. Erroneously treated 
participants (eg, those randomized to treatment A but actually given treatment B) are 
accounted for in the treatment group with the majority estimated usage. The majority 
estimated usage will be determined based on which treatment had more kits dispensed (not 
including kits returned unused). In the case of a tie, the randomized treatment will be used for 
safety analyses. In all cases, the dose group will be the same as randomized dose level.
Adverse Events
Adverse events will be coded using the most recent version of the MedDRA that will have 
been released for execution at AstraZeneca. AEs will be presented for each treatment group by 
SOC and/or Preferred Term covering number and percentage of participants reporting at least 
one event and number of events where appropriate. Exposure-adjusted incidence rates may be 
provided as appropriate. Only treatment-emergent AEs will be summarized.
An overview of AEs will present the number and percentage of participants with any AE, AEs 
with outcome of death, serious AEs, AEs leading to discontinuation of IP, and AEs leading to 
dose reduction of IP for each treatment group.
Separate AE tables will be provided taking into consideration the relationship as assessed by 
the investigator, maximum intensity, seriousness, death and events leading to discontinuation 
of IP as well as AESIs. 
In accordance with the requirements of the FDA, a separate table will present non-serious AEs 
occurring in more than 5% of participants in any treatment group. 
Vital Signs
Vital sign parameters will be presented for each treatment group. Summary statistics for 

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continuous variables cover n, mean, SD, min, median, and max. 
For each scheduled post-baseline visit, descriptive statistics for all vital sign parameters will 
be presented for observed values and change from baseline.
A frequency table will be presented with the number of participants reporting at least one on-
treatment abnormality. 
Laboratory
Laboratory parameters will be presented for each treatment group. Summary statistics for 
continuous variables will cover n, mean, SD, min, median, and max. Frequency tables will 
cover number and percentage of participants in the respective category. 
For each scheduled post-baseline visit, descriptive statistics for all clinical chemistry and 
hematology parameters will be presented for observed values and change from baseline.
A frequency table will present number of participants reporting at least one treatment 
emergent change in laboratory parameters outside predefined criteria. 
Elevation in liver parameters for assessment of HL will be reported appropriately if potential 
cases have been identified during the course of the study. 
Electrocardiogram
ECG parameters will be presented for each treatment group. Summary statistics for 
continuous variables will cover n, mean, SD, min, median and max. Frequency tables will 
cover number and percentage of participants in the respective category. The (uncorrected) QT
interval will be corrected according to the Fridericia’s formula. Parameters to be tabulated are 
listed in Section 3.1.
For each scheduled post-baseline assessment, descriptive statistics for all ECG parameters will 
be presented for observed values and change from baseline. Additionally, summaries will be 
made of all ECG parameters fulfilling potentially clinically significant criteria during the 
treatment period.
9.4.4
Analysis of Pharmacokinetics and Immunogenicity
Immunogenicity results will be analyzed descriptively by summarizing the number and 
percentage of participants who develop detectable ADAs against cotadutide. The 
immunogenicity titer, and ADA cross-reactive to GLP-1 and glucagon will be reported for 
samples confirmed positive for the presence of ADAs. The effect of immunogenicity on PK 
and safety will be evaluated, if data allow. Sparsely collected plasma concentrations will be 
descriptively summarized. Any issues considered to impact the PK data (such as, but not 
limited to participants not receiving complete/full intended cotadutide dose) may result in the 

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exclusion of concentration data from the PK analysis or exclusion from the PK summaries or
descriptive statistics, the reason(s) for exclusion will be documented. The available 
concentration data for any participants excluded from the PK data summaries or descriptive 
statistics will be listed. If data are used in the population PK and the exposure-response 
analyses, the results will be reported in a separate report. 
9.5
Interim Analyses
Not applicable. 
9.6
Data Monitoring Committee
An independent DMC will be established to monitor data on an ongoing basis to ensure the 
safety of participants enrolled in this study and the integrity of the study. The DMC will meet 
periodically during the study to review the safety data and operate according to the procedures 
and processes described in full detail in the DMC charter. 
For details on the DMC, 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 GCP Guidelines.

Applicable laws and regulations.

The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.

AstraZeneca will be responsible for obtaining the required authorizations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
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 Serious Adverse Events

Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities toward the safety of participants and the safety of a 
study intervention under clinical investigation are met.

The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.

For all studies except those utilizing medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary.

European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), and all other applicable local regulations

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
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] and will 
notify the IRB/IEC, if appropriate according to local requirements.
Regulatory Reporting Requirements for Serious Breaches

Prompt notification by the investigator to AstraZeneca of any (potential) serious breach of 
the protocol or regulations is essential so that legal and ethical obligations are met.

A ‘serious breach’ means a breach likely to affect to a significant degree the safety 
and rights of a participant or the reliability and robustness of the data generated in the 
clinical study.

If any (potential) serious breach occurs in the course of the study, investigators or other 
site personnel will inform the appropriate AstraZeneca representatives immediately after 
he or she becomes aware of it.

In certain regions/countries, AstraZeneca has a legal responsibility to notify both the local 
regulatory authority and other regulatory agencies about such breaches.

AstraZeneca will comply with country-specific regulatory requirements relating to 
serious breach reporting to the regulatory authority, IRB/IEC, and investigators. If 
EU Clinical Trials Regulation 536/2014 applies, AstraZeneca is required to enter 
details of serious breaches into the European Medicines Agency CTIS. It is important 
to note that redacted versions of serious breach reports will be available to the public 
via CTIS.

The investigator should have a process in place to ensure that:

The site staff or service providers delegated by the investigator/institution are able to 
identify the occurrence of a (potential) serious breach.

A (potential) serious breach is promptly reported to AstraZeneca or delegated party, 
through the contacts (email address or telephone number) provided by AstraZeneca.
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.

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A 3
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study.

Participants must be informed that their participation is voluntary and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants or their legally authorized representative will be required to 
sign a statement of informed consent that meets the requirements of 21 CFR 50, local 
regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
(HIPAA) requirements, where applicable, and the IRB/IEC or study center.

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 

A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
Participants who are rescreened are required to sign a new ICF.
The ICF will contain a separate section that addresses and documents the collection and use of 
any mandatory and/or optional human biological samples. The investigator or authorized 
designee will explain to each participant the objectives of the analysis to be done on the 
samples and 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 authorized personnel appointed by the
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

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A 5
Committees Structure
Data Monitoring Committee 
An independent DMC will be appointed and will report to AstraZeneca. The DMC will be 
responsible for safeguarding the interests of the participants in the study by assessing the 
safety of the study intervention during the study. The DMC will have access to the individual 
treatment codes and be able to merge these with the collected study data while the study is 
ongoing. 
A DMC charter will be prepared to detail precise roles and responsibilities and procedures to 
ensure maintenance of the blinding and integrity of the study in the review of accumulating 
data and interactions with AZ. The DMC will ensure that the study meets high standards of 
ethics and patient safety.
Clinical Event Adjudication
The role of the CEA is to independently review, interpret and adjudicate the types of events 
experienced by the participants listed in Section 8.3.10. Events for adjudication will be 
identified preliminarily by the investigators, and also by AstraZeneca personnel, or in the CEA 
process as specified in the CEA charter. The CEA member(s) will not have access to 
individual treatment codes for any participant. The precise responsibilities and procedures 
applicable for CEA will be detailed in the CEA charter.
A 6
Dissemination of Clinical Study Data
For scientific reasons (as otherwise statistical analysis is not relevant), any results for this 
study (both technical and lay summaries) will be submitted to EU CTIS within a year from the 
global End of Study date in all participating countries.
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 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.

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
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management, 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 and Protocol Deviations 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, CROs).

Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.

Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for the required retention period 
(https://www.astrazenecapersonaldataretention.com/patients.html) unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.
A 8
Source Documents

Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.

Data 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 GCP, ie, all information in 
original records and certified copies of original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Source data are contained in source documents (original records or certified copies). 

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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 when the first participant is screened, which will be the study 
start date. 
The sponsor designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study site closure visit has been performed.
The investigator may initiate study site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to:

Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the investigator.

Discontinuation of further study intervention development.
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by 
the applicable regulatory requirements. The investigator shall promptly inform the participant 
and should assure appropriate participant therapy and/or follow-up.
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 

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publication of multicenter studies only in their entirety and not as individual site data. In 
this case, a coordinating investigator will be designated by mutual agreement.

Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.

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

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Life-threatening
‘Life-threatening’ means that the participant was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
participant’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the participant was enrolled in the study, provided that it did not deteriorate in 
an unexpected way during the study.
Important Medical Event or Medical Treatment
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability, or incapacity but may jeopardize the participant or may 
require medical treatment to prevent one or more outcomes listed in the definition of serious. 
These should usually be considered as serious.
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used.

Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic bronchospasm

Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc.) or 
convulsions that do not result in hospitalization

Development of drug dependency or drug abuse
Intensity Rating Scale:

Mild (awareness of sign or symptom, but easily tolerated)

Moderate (discomfort sufficient to cause interference with normal activities)

Severe (incapacitating, with inability to perform normal activities)
It is important to distinguish between serious and severe AEs. Severity is a measure of 

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

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information to make an informed judgment. With no available facts or arguments to suggest a 
causal relationship, the event(s) will be assessed as ‘not related’.
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility.
B 4
Medication Error, Drug Abuse, and Drug Misuse
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 recognized 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 IRT/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

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
Accidental overdose (will be captured as an overdose)

Participant failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AstraZeneca product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error.
Drug Abuse
For the purpose of this study, drug abuse is defined as the persistent or sporadic intentional, 
non-therapeutic excessive use of IMP or AstraZeneca NIMP for a perceived reward or desired 
non-therapeutic effect.
Any events of drug abuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Abuse Report Form. This form should be used both if the drug abuse 
happened in a study participant or if the drug abuse involves a person not enrolled in the study 
(such as a relative of the study participant).
Examples of drug abuse include but are not limited to:

The drug is used with the intent of getting a perceived reward (by the study participant 
or a person not enrolled in the study)

The drug in the form of a tablet is crushed and injected or snorted with the intent of 
getting high
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorized product information, or 
for unauthorized IMPs or AstraZeneca NIMPs, outside the intended use as specified in the 
protocol and includes deliberate administration of the product by the wrong route.
Events of drug misuse, with or without associated AEs, are to be captured and forwarded to 
the DES using the Drug Misuse Report Form. This form should be used both if the drug 
misuse happened in a study participant or if the drug misuse regards a person not enrolled in 
the study (such as a relative of the study participant).
Examples of drug misuse include but are not limited to:

The drug is used with the intention to cause an effect in another person

The drug is sold to other people for recreational purposes 

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
The drug is used to facilitate assault in another person

The drug is deliberately administered by the wrong route

The drug is split in half because it is easier to swallow, when it is stated in the protocol 
that it must be swallowed whole

Only half the dose is taken because the study participant feels that he/she is feeling 
better when not taking the whole dose

Someone who is not enrolled in the study intentionally takes the drug

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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 center keeps full traceability of collected biological samples from the
participants while in storage at the center until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples while at site.
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps record of receipt of arrival and onward 
shipment or disposal.
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 sooner.
C 2
Withdrawal of Informed Consent for Donated Biological Samples 
Where required, AstraZeneca ensures that biological samples are returned to the source or 
destroyed at the end of a specified period as described in the informed consent. 
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 
analyzed, 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.

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
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 
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
LABELING 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 healthcare and to the discovery of new 
diagnostics, treatments, or medications. Therefore, where local regulations and IRB/IEC 
allow, a blood sample will be collected for DNA analysis from consenting participants.

This optional genetic research may consist of the analysis of the structure of the 
participant´s DNA ie, the entire genome. 

The results of genetic analyses may be reported in a separate study summary.

The sponsor will store the DNA samples in a secure storage space with adequate 
measures to protect confidentiality.
D 2
Genetic Research Plan and Procedures
Selection of Genetic Research Population

All participants will be asked to participate in this genetic research. Participation is 
voluntary and if a participant declines to participate there will be no penalty or loss of 
benefit. The participant will not be excluded from any aspect of the main study.
Inclusion Criteria
For inclusion in this genetic research, participants must fulfill all of the inclusion criteria 
described in 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 within 120 days of genetic sample 
collection
Withdrawal of Consent for Genetic Research

Participants may withdraw from this genetic research at any time, independent of any 
decision concerning participation in other aspects of the main study. Voluntary 

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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 2. 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 Visit 2, it may be taken at any visit until the last study visit. 
Only one sample should be collected per participant for genetics during the study. 
Coding and Storage of DNA Samples

The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain participant confidentiality. Samples will be stored for a maximum 
of 15 years from the date of last participant last visit, after which they will be destroyed. 
DNA is a finite resource that is used up during analyses. Samples will be stored and used 
until no further analyses are possible or the maximum storage time has been reached.

An additional second code will be assigned to the sample either before or at the time of 
DNA extraction replacing the information on the sample tube. Thereafter, the sample will 
be identifiable only by the second, unique number. This number is used to identify the 
sample and corresponding data at the AstraZeneca genetics laboratories, or at the 
designated organization. No personal details identifying the individual will be available to 
any person (AstraZeneca employee or designated organizations working with the DNA).

The link between the participant enrollment/randomization code and the second number 
will be maintained and stored in a secure environment, with restricted access at 
AstraZeneca or designated organizations. The link will be used to identify the relevant 
DNA samples for analysis, facilitate correlation of genotypic results with clinical data, 
allow regulatory audit, and permit tracing of samples for destruction in the case of 
withdrawal of consent.
Ethical and Regulatory Requirements

The principles for ethical and regulatory requirements for the study, including this 
genetics research component, are outlined in Appendix A.
Informed Consent

The genetic component of this study is optional and the participant may participate in 
other components of the main study without participating in this genetic component. To 
participate in the genetic component of the study, the participant must sign and date both 
the consent form for the main study and the addendum for the Genomics Initiative 

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component of the study. Copies of both signed and dated consent forms must be given to 
the participant and the original filed at the study center. The Principal Investigator(s) is 
responsible for ensuring that consent is given freely and that the participant understands 
that they may freely 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, or general physician unless required to do 
so by law.

Extra precautions are taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the participant. In exceptional circumstances, however, certain 
individuals might see both the genetic data and the personal identifiers of a participant. 
For example, in the case of a medical emergency, 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 analyze the samples.

AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with 
other researchers, such as hospitals, academic organizations, or health insurance 
companies. This can be done by placing the results in scientific databases, where they can 
be combined with the results of similar studies to learn even more about health and 
disease. The researchers can only use this information for health-related research 
purposes. Researchers may see summary results but they will not be able to see individual 
participant data or any personal identifiers. 

Some or all of the clinical datasets from the main study may be merged with the genetic 
data in a suitable secure environment separate from the clinical database.

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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report PHL cases and HL cases. It is not intended to be a comprehensive guide to the 
management of elevated liver biochemistries. 
Specific guidance on managing liver anomalies can be found in Sections 7.1 and 8.3.10 of the 
Clinical Study Protocol. 
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 AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than DILI caused by the 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
Aspartate Aminotransferase or ALT ≥3 × ULN together with TBL ≥2× ULN at any point 
during the study following the start of study intervention 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 

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cholestasis, viral hepatitis, or 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 
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
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 (refer to Section E 2 for definition) 
by reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:

Inform the AstraZeneca representative that the participant has not met PHL criteria. 

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
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol.
E 4.2
Potential Hy’s Law Criteria met
If the participant does meet PHL criteria the investigator will:

Notify the AstraZeneca representative who will then inform the central Study Team 

Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
PHL; serious criteria ‘Important medical event’ and causality assessment ‘yes/related’ 
according to CSP process for SAE reporting.

For participants that met PHL criteria prior to starting IMP, the investigator is not 
required to submit a PHL SAE unless there is a significant change# in the participant’s
condition.

The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data.

Subsequent to this contact the investigator will:

Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.

Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which of the tests 
available in the HL lab kit should be used. 

Complete the 3 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 TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 
whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the Study Physician if there is any uncertainty.
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 

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date PHL criteria was met. The AstraZeneca Global Clinical Head or equivalent and Global 
Safety Physician will also be involved in this review together with other subject matter experts 
as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:

If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF.

If the alternative explanation is an AE/SAE, update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the 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 PHL, (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
Actions Required When Potential Hy’s Law Criteria are Met 
Before and After Starting Study Intervention 
This section is applicable to participants who meet PHL criteria on study intervention, having 
previously met PHL criteria at a study visit prior to starting study intervention.
At the first on-study intervention occurrence of PHL criteria being met, the investigator will 
determine if there has been a significant change in the participants’ condition# compared with 
the last visit where PHL criteria were met#

If there is no significant change, no action is required

If there is a significant change, notify the AstraZeneca representative, who will inform the 
central Study Team, then follow the subsequent process described in Section E 4.2  
E 7
Actions Required for Repeat Episodes of Potential Hy’s Law
This section is applicable when a participant meets PHL criteria on study intervention and has 
already met PHL criteria at a previous on-study intervention visit
The requirement to conduct follow-up, review, and assessment of a repeat occurrence(s) of 
PHL is based on the nature of the alternative cause identified for the previous occurrence. 
The investigator should determine the cause for the previous occurrence of PHL criteria being 
met and answer the following question:
Was the alternative cause for the previous occurrence of PHL criteria being met found 
to be the disease under study eg, chronic or progressing malignant disease, severe 
infection, or liver disease?
If No: follow the process described in Section E 4.2 for reporting PHL as an SAE.
If Yes: Determine if there has been a significant change in the participant’s condition#
compared with when PHL criteria were previously met.

If there is no significant change, no action is required.

If there is a significant change,# follow the process described in Section E 4.2 for 
reporting PHL as an SAE.
# A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or TBL) in isolation or in 
combination, or a clinically relevant change in associated symptoms. The determination of 

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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 8
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 and IgG anti-CMV
IgM and IgG anti-HSV
IgM and IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrin (CD-
transferrin) c
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 
c
CD-transferrin is not available in China. Study teams should amend this list accordingly

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Appendix F
Alcohol Use Disorder Identification Test (AUDIT)
Subject Number: 
Visit Number:
Assessment Date:
The Alcohol Use Disorders Identification Test: Interview Version
Read questions as written. Record answers carefully. Begin the AUDIT by saying “Now I am 
going to ask you some questions about your use of alcoholic beverages during this past year.” 
Explain what is meant by “alcoholic beverages” by using local examples of beer, wine, vodka, etc. 
Code answers in terms of “standard drinks.” Place the correct answer number in the box at the 
right.
1. How often do you have a drink containing alcohol?
(0) Never [Skip to Qs 9-10]
(1) Monthly or less
(2) 2 to 4 times a month
(3) 2 to 3 times a week
(4) 4 or more times a week
6. How often during the last year have you needed a first drink 
in the morning to get yourself going after a heavy drinking
session?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
2. How many drinks containing alcohol do you haveon a
typical day when you are drinking?
(0) 1 or 2
(1) 3 or 4
(2) 5 or 6
(3) 7, 8, or 9
(4) 10 or more
7. How often during the last year have you had a feeling of
guilt or remorse after drinking?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
3. How often do you have six or more drinks on one
occasion?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
Skip to Questions 9 and 10 if Total Score for 
Questions 2 and 3 = 0
8. How often during the last year have you been unable to
remember what happened the night before because you
had been drinking?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
4. How often during the last year have you found that you
were not able to stop drinking once you had started?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
9. Have you or someone else been injured as a result of your
drinking?
(0) No
(2) Yes, but not in the last year
(4) Yes, during the last year
5. How often during the last year have you failed to do 
what was normally expected from you because of
drinking?
(0) Never
(1) Less than monthly
(2) Monthly
(3) Weekly
(4) Daily or almost daily
10. Has a relative or friend or a doctor or another health worker
been concerned about your drinking or suggested you cut
down?
(0) No
(2) Yes, but not in the last year
(4) Yes, during the last year
Record total of specific items here  
If total is greater than recommended cut-off, consult User’s Manual.
AUDIT-Test_cv1_Orig_WS_Paper_English-US_02Dec2021_D5671C00006

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Scoring the AUDIT Questionnaire
Scores for each question range from 0 to 4, with the first response for each question (eg, 
never) scoring 0, the second (eg, less than monthly) scoring 1, the third scoring 2, the fourth 
scoring 3, and the last response (eg, 4 or more times a week) scoring 4. For questions 9 and 
10, which only have 3 responses, the scoring is 0, 2, and 4. A score of 8 or more is associated 
with harmful or hazardous drinking, a score of 13 or more in women, and 15 or more in men, 
is likely to indicate alcohol dependence.
Definition of a standard drink
In the AUDIT questions 2 and 3, it is assumed that a standard drink equivalent is 10 grams of 
alcohol. The alcohol content of a drink depends on the strength of the beverage and the 
volume of the container. The investigator should adjust the number of drinks in the response 
categories for these questions in order to fit the most common drink sizes and alcohol strength 
in their country.

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Appendix G
West Haven Criteria for Hepatic Encephalopathy
Grade
Description
I
Trivial lack of awareness
Euphoria or anxiety
Shortened attention span
Impairment of addition or subtraction
II
Lethargy or apathy
Disorientation for time
Obvious personality change
Inappropriate behavior
III
Somnolence to semi-stupor
Responsive to stimuli
Confused
Gross disorientation
Bizarre behavior
IV
Coma

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Appendix H
Abbreviations
Abbreviation or special 
term
Explanation
ADA
anti-drug antibody
AE
adverse event
AI
artificial intelligence
ALT
alanine aminotransferase/transaminase
ANA
antinuclear antibody
APRI
AST-to-platelet ratio index
AST
aspartate aminotransferase/transaminase
AUDIT
Alcohol Use Disorder Identification Test
BARD
BMI, AST/ALT ratio, diabetes
BMI
body mass index
BP
blood pressure
CAP
controlled attenuation parameter
CEA
clinical event(s) adjudication
CKD
chronic kidney disease
CRO
contract research organization
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTIS
Clinical Trial Information System
CV
cardiovascular
DBP
diastolic blood pressure
DES
data entry site
DILI
drug-induced liver injury
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic Case Report Form
eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis
FAS
full analysis set
FAST
FibroScan-AST
FDA
United States Food and Drug Administration
FIB-4
fibrosis-4
GCP
good clinical practice
GGT
gamma glutamyl transferase

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Abbreviation or special 
term
Explanation
GLP-1
glucagon-like peptide 1
HbA1c
hemoglobin A1c
HbsAg
hepatitis B surface antigen
HCV
hepatitis C virus
HDL
high-density lipoprotein
HFF
hepatic fat fraction
HIV
human immunodeficiency virus
HL
Hy’s Law
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
INR
international normalized ratio
IP
investigational product
IRB
institutional review board
IRT
interactive response technology
LDL
low-density lipoprotein
LSM
liver stiffness measurement
MACE
major adverse cardiovascular event
max
maximum
MedDRA
Medical Dictionary for Regulatory Activities
MELD
model for end-stage liver disease
min
minimum
NAFLD
non-alcoholic fatty liver disease
NAS
non-alcoholic fatty liver disease activity score
NASH
non-alcoholic steatohepatitis
NFS
non-alcoholic fatty liver disease fibrosis score
PHL
potential Hy’s Law
PK
pharmacokinetic(s)
QTcF
Fridericia-corrected QT interval
RTSM
randomization and trial supply management
SAE
serious adverse event 
SAP
statistical analysis plan

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Abbreviation or special 
term
Explanation
SBP
systolic blood pressure
SC
subcutaneous
SD
standard deviation
SoA
schedule of activities
SOC
System Organ Class
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
TIMP-1
tissue inhibitor of metalloproteinase type-1
ULN
upper limit of normal
WOCBP
women of childbearing potential

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Appendix I
Protocol Version History
The Summary of Changes Table for the current revision is located directly before the Table of 
Contents.
Clinical Study Protocol Version 2
Overall Rationale for the Amendment:
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 2. The principal reason for this amendment is to address feedback from the FDA 
on the study protocol in its entirety including revision of the study design of Part A to remove 
the 36-week extension period. The primary intent for the 36-week extension period of Part A 
was to collect additional comparative safety data, especially cardiovascular events; however, 
with only 300 participants, it is unlikely that a significant number of cardiovascular events 
would be observed during the extension period. The 36-week extension was also removed to 
enable full read out and closure of Part A prior to read out of Part B. This will further help 
delineate the Phase IIb portion from the Phase III portion of the trial. The amendment also 
includes other changes aimed at clearer articulation of inclusion/exclusion criteria and 
potential operational simplifications, both based on feedback from study investigators.
Substantial changes to the protocol are summarized below.
Section # and Name
Description of Change and Brief Rationale
Section 1.1 (Synopsis), Section 1.2 
(Schema), Table 5 (Part A Schedule 
of Activities), Section 4.1.1 (Part A 
Overall Design), Section 4.1.3 
(Adaptation Considerations and 
Dose Selection in Part B), Section 
6.3.3.1 (Unblinding for Part A 
Analysis), Section 6.3.3.2 
(Unblinding for Part B Analysis), 
Section 9.4.1 (General 
Considerations), Section 9.4.1.1 
(Possible Adaptations for Part B), 
Section 9.5 (Interim Analysis)
•
Removed the 36-week extension in Part A because it is unlikely 
that a significant number of cardiovascular events would be 
observed during the extension period. 
•
Removed the interim analysis from the study because the Week 
48 analysis of Part A will now be a complete analysis of the Part 
A data after database lock. Text on adaptive actions resulting 
from analysis of Part A has been moved from Section 9.5 (Interim 
Analysis) to Section 9.4.1.1 (Possible Adaptations for Part B).
•
Adjusted wording on blinding of Part A because of the 
elimination of the 36-week extension. After database lock, sites, 
participants, and sponsor will be unblinded.
Section 1.1 (Synopsis), Section 5.1 
(Inclusion Criteria), Section 8.1.1 
(Liver Biopsy-based 
Histopathology)
Updated the timeframe for historical biopsy in the inclusion criteria so 
that it is only defined from the time of randomization to provide 
clarity. 
Section 1.1 (Synopsis), Section 4.1 
(Overall Design), Section 9.2 
(Sample Size Determination)
The estimated number of participants to be screened was increased 
from 3500 to 7440 to reflect updated estimate of the screen failure rate. 

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Section # and Name
Description of Change and Brief Rationale
Section 1.1 (Synopsis), Section 
9.4.1 (General Considerations)
•
The strategy for the primary estimand of histology endpoints was 
clarified to be a hybrid of the treatment policy and composite 
strategies.
•
The strategy for intercurrent events for liver outcomes was 
clarified. 
Section 1.3.1 (Schedule of 
Activities: Screening), Table 6 (Part 
B Schedule of Activities), Section 
3.2 (Objectives and Endpoints Part 
B), Section 4.2.3.3 Rationale for 
Exploratory Endpoints, Section 5.1 
(Inclusion Criteria), Section 7.1 
(Discontinuation of Study 
Intervention), Section 8.1.3 
(MRE/MRI)
The substudy in Part B to assess endpoints using MRI, MRE, and 
abdominal ultrasound was removed to enhance operational feasibility 
of the study and focus on the primary objectives. The abdominal 
ultrasound is replaced by the collection of additional baseline data on 
gallbladder health in all study participants, which will provide a more 
thorough knowledge base than performing ultrasounds in a sub 
population.
Section 1.3.1 (Schedule of 
Activities: Screening), Section 8.2.5 
(Clinical Safety Laboratory 
Assessments)
Removed assessment of blood alcohol at screening. Alcohol 
dependence will be based on urine ethanol drug screen and AUDIT 
questionnaire, which determines participant eligibility over the past 2 
years, rather than a blood test, which only reflects recent alcohol 
consumption.
Section 1.3.1 (Schedule of 
Activities: Screening)
•
Description of the timing of the biopsy and collection of tissue 
from a historical biopsy were edited to clarify that tissue must be 
sent for central evaluation at least 21 days from planned 
randomization to allow enough time for histopathology 
assessment.
•
Clarified that on-study biopsy tissue must be submitted to the 
central histopathology review laboratory at least 21 days prior to 
planned randomization. 
Section 1.3.1 (Schedule of 
Activities: Screening), Table 5 (Part 
A Schedule of Activities), Table 6 
(Part B Schedule of Activities), 
Section 6.2 
(Preparation/Handling/Storage/Acc
ountability)
Edited to allow training activities related to subcutaneous 
administration to be completed on Visit 2 (randomization day) to allow 
more flexibility to sites and participants. 
Section 1.3.1 (Schedule of 
Activities: Screening), Table 5 (Part 
A Schedule of Activities), Table 6 
(Part B Schedule of Activities), 
Section 3.1 (Objectives and 
Endpoints: Part A), Section 3.2 
(Objectives and Endpoints: Part B), 
Section 4.2.3.3 (Rationale for 
Exploratory Endpoints); Section 
8.1.8 (Exploratory Biomarker 
Assessments)
Reduced the list of exploratory biomarkers to be assessed to reduce the 
blood volume required for study participants. The study will still retain 
optional serum samples for exploratory purposes, and therefore 
additional biomarker analysis can be conducted post hoc. 

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Section # and Name
Description of Change and Brief Rationale
Section 1.3.1 (Schedule of 
Activities: Screening), Table 5 (Part 
A Schedule of Activities), Table 6 
(Part B Schedule of Activities), 
Section 8.1.3 (Fibroscan)
•
Clarified that FibroScan and FAST score assessment are only 
required at sites with software and probes and for participants 
who do not have a historical FibroScan within 90 days. 
•
Added that FibroScan assessment must be conducted in a fasted 
state. 
•
Clarified FibroScan visit windows. 
Section 1.3.1 (Schedule of 
Activities: Screening)
Changed the requirement for discussion of alternative pre-biopsy 
screening strategy with sponsor to a recommendation to allow more 
flexibility. 
Table 5 (Part A Schedule of 
Activities) 
Clarified that participants who discontinue study intervention and have 
an early discontinuation visit in Part A should also have a follow-up 
visit 4 weeks later.
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities)
Added a review of adherence to diet and lifestyle advice to Visit 9 and 
Visit 11 for both Part A and Part B to ensure consistency with Section 
5.3.1 (Diet and Lifestyle Education).
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities), Section 
8.5.2 (Collection of Optional 
Biomarker Samples)
Removed optional biomarker plasma collection to reduce blood 
volume and burden on participants. 
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities)
Added text describing scheduling of Visit 2 (randomization) to clarify 
that the visit can occur after confirmation that the participant meets all 
eligibility criteria. 
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities), Section 7.1 
(Discontinuation of Study 
Intervention) 
Removed the requirement for conducting a biopsy at the early 
discontinuation visit for participants who discontinue study 
intervention; instead, participants will be encouraged to have the 
biopsy at Week 48 (Part A) or Week 84 (Part B) but can have the 
biopsy at early discontinuation if they are unwilling or unable to wait 
until Week 48 (Part A) or Week 84 (Part B). 
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities)
•
Edited the footnote on ADA follow-up to note that monitoring is 
required only for participants with titer ≥30 at the Follow-Up 
visit for consistency with FDA recommendations. 
•
Provided additional guidance for handling of ADA monitoring for 
participants who still meet the criteria 12 months after the last IP 
dose. 
Table 6 (Part B Schedule of 
Activities)
Added confirmation of fasting at EOT in Part B to ensure collection of 
the optional biomarker sample in fasted state.
Table 6 (Part B Schedule of 
Activities)
Added 2 additional ECG timepoints to Part B (Visit 9 and Visit 11) for 
alignment with Part A. 
Table 6 (Part B Schedule of 
Activities)
Removed the urine pregnancy test in Part B at Visit 12 and added 
assessment at V14. 
Table 6 (Part B Schedule of 
Activities)
•
Added assessment of calcitonin at EOT in Part B for consistency 
with Part A.
•
Removed assessment of calcitonin at visits between Week 84 and 
EOT to correct an administrative error. 

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Section # and Name
Description of Change and Brief Rationale
Table 6 (Part B Schedule of 
Activities)
Edited the schedule of activities to note that a follow-up visit should be 
conducted for all participants in Part B, regardless of whether their 
previous visit for EOT or E/D or whether they discontinued study 
intervention but remained in the study. 
Section 3.1 (Objectives and 
Endpoints: Part A)
Added an exploratory objective and endpoint to Part A and Part B to 
assess improvements in other histological features of NASH including 
portal inflammation.
Section 4.4 (End of Study 
Definition)
Added FDA and EU definitions of the end of study to align with 
sponsor template. 
Section 5.2 (Exclusion Criteria)
Added evidence of portal hypertension to the exclusion criterion on 
hepatic decompensation to provide further clarification on the 
definition. 
Section 5.2 (Exclusion Criteria); 
Appendix G
Definition of alcohol unit was updated to use local regulations because 
the definition of a standard drink varies across countries/regions. 
Section 5.2 (Exclusion Criteria)
To align with Table 13 (Prohibited Medications), edited the criterion 
on weight loss medications so that they are not allowed even with 
stable use.
Section 5.2 (Exclusion Criteria)
Added a total bilirubin cut-off for participants with Gilbert’s syndrome 
to the exclusion criteria.
Section 5.4 (Screen Failures)
•
Added more laboratory tests that can be retested without 
rescreening to reduce burden on investigators and participants.
•
Clarified that an on-study biopsy for participants being rescreened 
must occur at least 180 days from the date of the previous biopsy 
and only once the participant has met all other eligibility criteria 
and completed other screening requirements.
Section 6.5.2 (Prohibited 
Concomitant Medications)
•
Added herbal preparations with any suspected hepatotoxicity to 
the list of prohibited concomitant medications. 
•
Added that starting new herbal preparations or dietary 
supplements is not allowed once screening activities are initiated. 
Section 6.5.4.2 (Therapies for 
Management of Type 2 Diabetes 
Mellitus)
Provided additional guidance on insulin dose to clarify that minimal 
change (≤ 20%) to the total daily insulin dose within the 90-day period 
prior to screening will not be considered exclusionary
Section 6.6 (Dose Modification)
•
Clarified that participants should discontinue treatment either 
because they are unable to successfully uptitrate to 200 µg or 
because their dose needs to be reduced below 200 µg. 
•
Added a sentence stating that the lowest dose of IP allowed for a 
participant to continue in the study is 200 µg to provide further 
clarification. 
Section 6.7 (Missed Dose)
Clarified IP compliance and criteria for defining IP-related important 
protocol deviation. 

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Section # and Name
Description of Change and Brief Rationale
Section 6.8 (Treatment of 
Overdose) (previously Section 8.4), 
Section 8.3.9 (Reporting of Serious 
Adverse Events), Section 8.3.12 
(Medication Error, Drug Abuse, and 
Drug Misuse), Appendix B4
Updated sections on overdose, drug abuse, and drug misuse and on 
reporting of serious adverse events to align with sponsor template 
language. Text on actions to take in the event of an overdose was 
added.
Section 6.8 (Treatment of 
Overdose)
The time frame for the definition of an overdose was changed from 
24 hours to one calendar day to avoid reporting an overdose if the 
second dose is given slightly less than 24 hours after the first. 
Section 7.1 (Discontinuation of 
Study Intervention)
Corrected the guidance on early discontinuation visits due to the 
removal of the extension period from Part A and clarified that the early 
discontinuation visit is to be conducted for participants who 
discontinue study intervention early.
Section 8.2.1 (Medical History)
Added collection of gallbladder disease history to Medical History 
because gallbladder-related disease was added as an adverse event of 
special interest.
Section 8.2.5 (Clinical Safety 
Laboratory Assessments)
•
Added red cell distribution width and red blood cell morphology 
to reflect that these are part of the standard complete blood count 
panel. 
•
Follicle-stimulating hormone was added to Section 8.2.5 (Clinical 
Safety Laboratory Assessments) to support assessment of 
menopausal status for inclusion criterion 5. 
•
Added direct bilirubin to the list of additional laboratory 
assessments in participants with Gilbert’s syndrome.
Section 8.3.6 (Adverse Events of 
Special Interest)
Added gallbladder-related disease to the list of AESIs because 
gallbladder disease has been associated with the use of GLP-1 receptor 
agonists.
Section 8.3.10 (Clinical Events for 
Adjudication)
•
Added CV deaths parenthetically after all deaths for consistency 
with MACE endpoint.
•
Edited the wording on the clinical event for adjudication related 
to heart failure. This adjudication endpoint was streamlined to 
hospitalization for heart failure as this includes all types of heart 
failure. 
•
Edited a footnote in Figure 2 and Figure 3 to clarify the definition 
of baseline pretreatment ALT for management of possible drug-
induced liver injury. 
•
Added a cross reference to Appendix E (Actions Required in 
Cases of Increases in Liver Biochemistry and Evaluation of Hy’s 
Law) for clarification. 
Section 8.8 (Mobile Software 
Applications[s])
Removed the section on software applications because the study will 
no longer use a digital support system. 

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Section # and Name
Description of Change and Brief Rationale
Section 9.3 (Populations for 
Analyses), Section 9.4.3 (Safety)
Changed the definition of the Safety Population to majority of 
estimated usage to minimize potential bias in estimated rates of AEs 
based on exposure, while relying on objective and programmable 
criteria. Participants receiving the wrong treatment will be analyzed 
according to the actual treatment (majority treatment received) and 
randomized dose level (to avoid bias in assigning participants with 
tolerability issues prior to reaching a 400 μg dose to the 300 μg 
analysis arm).
Section 9.4.2.2 (Secondary 
Endpoint[s])
•
Primary analysis of progression to cirrhosis will use multiple 
imputation (placebo washout) to provide more realistic estimates 
of cirrhosis progression rates by making imputations in both arms 
based on rates observed in the placebo arm. Because progression 
to cirrhosis may not be very common (especially compared to the 
degree of missing data), results using non-responder imputation 
for missing data would be difficult to interpret for this endpoint, 
while multiple imputation will better estimate the progression 
rates.
•
Clarified that binary endpoints will utilize a composite strategy 
for intercurrent events of liver outcomes. 
Section 9.4.2.3 (Multiplicity Plan)
Multiplicity strategy for Part B was changed to allow for the possibility 
of reaching statistical significance in 600 μg secondary endpoint 
analyses without necessarily reaching significance for the 300 μg 
primary endpoint analyses, while still controlling the familywise Type 
I error. 
Appendix A1 (Regulatory and 
Ethical Considerations), Appendix 
A6 (Dissemination of Clinical
Study Data)
Updated sections on regulatory reporting requirements for serious 
breaches and dissemination of clinical study data to align with sponsor 
template language. 
Nonsubstantial changes to the protocol are summarized below.
Section # and Name
Description of Change and Brief Rationale
Section 1.1 (Synopsis)
The number of evaluable participants was removed for clarity because 
it is the same as the number of randomized participants. 
Section 1.1 (Synopsis), Section 4.1 
(Overall Design)
Corrected the description of the study population to include the upper 
limit of the age range. 
Section 1.1 (Synopsis), Section 3.1 
(Objectives and Endpoints: Part A), 
Section 3.2 (Objectives and 
Endpoints: Part B)
Minor clarifications to the safety endpoints to align with planned 
analyses. 

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Section # and Name
Description of Change and Brief Rationale
Section 1.3 (Schedule of Activities: 
Screening), Table 5 (Part A 
Schedule of Activities), Table 6 
(Part B Schedule of Activities), 
Section 8.2.4 (Electrocardiograms)
•
ECG-related footnote was added to the schedule of activities for 
the treatment period of Part B for consistency with the schedule 
of activities for the treatment period of Part A. 
•
The rest period was updated to 10 minutes in the footnotes and in 
Section 8.2.4 (Electrocardiograms) to correct an administrative 
error.
•
Greater detail regarding triplicate ECG procedures in Part A was 
added. 
•
Guidance for ECG device malfunction was added. 
Table 5 (Part A Schedule of 
Activities)
Clarification to note that V11 is also the EOT visit for Part A.
Section 2.1 (Study Rationale)
•
Changed the length of the PROXYMO study treatment period 
from 52 to 19 weeks to correct an administrative error. 
•
Changed ALT to AST to correct a typographical error.
Table 5 (Part A Schedule of 
Activities), Table 6 (Part B 
Schedule of Activities), Section 
4.2.3.3 (Rationale for Exploratory 
Endpoints), Section 8.1 (Efficacy 
Assessments)
Added controlled attenuation parameter to the schedule of activities 
and the description of efficacy assessments to align with the endpoint 
related to FibroScan for Part A and Part B.
Section 3.1 (Objectives and 
Endpoints: Part A), Section 3.2 
(Objectives and Endpoints: Part B), 
Section 4.2.3.3 (Rationale for 
Exploratory Endpoints)
Added C-Peptide to the exploratory biomarker endpoints to correct an 
administrative error.  
Section 3.3 (Estimands)
Added a description of the estimands to Section 3 (Objectives and 
Endpoints) to align with sponsor template. 
Section 4.1.2 (Part B Overall 
Design)
Clarified that participants will remain on study intervention until the 
end of treatment visit, not the common study end date. 
Section 5.1 (Inclusion Criteria)
•
Clarified that there are no contraceptive requirements for male 
participants. 
•
Original protocol stated that women must use one highly effective 
form of birth control. Clarified that women must use at least one 
highly effective method of birth control.
Section 5.2 (Exclusion Criteria)
Added the albumin cut-off value in units (g/L) used by the central 
laboratory. 
Section 6.1.1 (Investigational 
Products)
Additions were made to the description of the investigational products 
to improve clarity on number of doses and instructions for use.
Section 6.1.2 (Medical Devices)
Updated the ECG device model.
Section 6.2 
(Preparation/Handling/Storage/ 
Accountability)
•
Updated the location of the guidance for final disposition of 
unused study intervention to correct an administrative error.
•
Removed sharps containers from list of supplies provided to 
participants that need to be returned. Clarified that sharps 
containers are provided to participants for safe needle disposal.
•
Added cooling bags to the list of items supplied by the sponsor.

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Section # and Name
Description of Change and Brief Rationale
Section 6.5.3 (Management of 
Nausea and Vomiting)
Added the class of medication (anti-histamine) for cyclizine for 
consistency with other medications listed. 
Section 7.2 (Participant Withdrawal 
from the Study)
•
For clarity, removed text on early discontinuation that was 
inconsistent with other sections of the protocol. 
Section 8.1.1 (Liver Biopsy-based 
Histopathology)
•
Added the early discontinuation visit as a timepoint for biopsy for 
consistency with the Schedule of Activities. 
Section 8.1.2 (Artificial 
Intelligence-based Histopathology)
•
Added literature references for AI histopathology read. 
•
Removed reference to the Histopathology Manual in Section 
8.1.2 (Artificial Intelligence-based Histopathology) because the 
manual does not have information on artificial intelligence-based 
read.
Section 8.2.3 (Vital Signs)
Corrected the timing of the initial blood pressure from baseline to 
screening and clarified that the selection of the arm to use for readings 
through the study should be based on the systolic blood pressure. 
Appendix A6 (Dissemination of 
Clinical Study Data)
Edited for clarity and consistency with terminology used elsewhere in 
the protocol. 

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