A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled, and Open-label Comparator Study of Cotadutide in Participants Who Have Chronic Kidney Disease With Type 2 Diabetes Mellitus
Phase: PHASE2
Conditions: Type 2 Diabetes Mellitus, Chronic Kidney Diseases
Sponsor: AstraZeneca

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Clinical Study Protocol
Study Intervention
Cotadutide
Study Code
D5676C00001
Version
Amendment 2
Date
04Jan2021
A Phase 2b, Multicentre, Randomised, Double-blind, 
Placebo-controlled, and Open-label Comparator Study of 
Cotadutide in Participants Who Have Chronic Kidney Disease 
with Type 2 Diabetes Mellitus 
Global Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden
Local Sponsor: AstraZeneca KK, 3-1, Ofuka-cho, Kita-ku, Osaka 530-0011
Manufacturers:
AstraZeneca and a third party (cotadutide)
Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark (semaglutide [OZEMPIC®])
Regulatory Agency Identifier Number(s): 
EudraCT Number: 2020-000255-12
This clinical study protocol has been subject to a peer review according to AstraZeneca 
Standard procedures. The clinical study protocol is publicly registered, and the results are 
disclosed and/or published according to the AstraZeneca Global Policy on Bioethics and in 
compliance with prevailing laws and regulations.

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Protocol Amendment Number: Amendment 2
Study Intervention: Cotadutide
Study Phase: 2b
Short Title: Phase 2b Study of Cotadutide in Participants Who Have Chronic Kidney Disease 
with Type 2 Diabetes Mellitus
Study physician name and contact information will be provided separately.

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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document
Date
Amendment 2
04Jan2021
Amendment 1
29Jun2020
Original Protocol
01Apr2020
Amendment 2 (04Jan2021)
Overall Rationale for the Amendment:
This global amendment contains revisions to Amendment 1 of the global protocol dated 
(29Jun2020) to add time windows for specific visits to make the study more accessible to 
participants during the current coronavirus disease (COVID-19) pandemic. Other minor 
revisions such as clarifications and correction of typos were made. This amendment is 
considered to be non-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 because it 
neither significantly impacts the safety or physical/mental integrity of participants nor the 
scientific value of the study. Changes in global Amendment 2 are presented in the table below.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Figure 1
Updated to reflect 
measures to increase 
protocol flexibility
detailed in SoA
For enhanced site 
flexibility, in 
particular due to 
circumstances 
presented by the 
COVID-19 
pandemic
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 (Schedule of Activities)
! Time window added to 
Follow-up visit +/- 3 
days
! Increased time window 
for screening period by 
8 days
! Remote contact to 
advise on insulin dose 
adjustment prior to first 
dose (if required) and 
optional visit permitted
on Day -2 or -1 
!
 
 
 
 
 
 
 
 
 
 
 
! Flexibility added to 
time of vital sign 
collection (footnote f)
! Increased time window 
added to time of 4 hour 
PK sample (footnote l)
! Flexibility added to 
time of randomisation 
(footnote s)
For enhanced site 
flexibility, in 
particular due to 
circumstances 
presented by the 
COVID-19 
pandemic
Non-substantial
1.3 (Schedule of Activities)
Optional status of visit 
on Day -2 made clearer in 
table
For clarification
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.3 (Schedule of Activities)
Day -2 eligibility 
verification updated for 
consistency with other 
aspects of protocol; 
screening labs (UACR, 
HbA1c, eGFR and 
calcitonin) form part of 
eligibility check at Day -2
For clarification
Non-substantial
1.3 (Schedule of Activities)
 
 
For clarification
Non-substantial
1.3 (Schedule of Activities)
Notes: removal of 
wording “every 4 weeks” 
Correction of typo
Non-substantial
4.1.3 Dose reduction
More detailed 
clarification of 
circumstances under 
which dose reduction may 
occur
For clarification
Non-substantial
5.4 (Screen Failures)
Clarification around 
repeat screening
For clarification
Non-substantial
6.5 (Concomitant Therapy; 
Tables 8 and 13)
Clarified all alpha-
glucosidase inhibitors are 
permitted concomitant 
and rescue therapies
For clarification
Non-substantial
6.5.1.2 (Insulin Dose 
Adjustments)
Adjustment of text to 
provide consistency with 
updates in SoA
For consistency
Non-substantial
8.2.4 (Retinal Assessments)
Changes made to image 
storage conditions and 
removal of historical 
assessments as baseline
For clarification
Non-substantial
9.4.4 (Other Analyses; 
Immunogenicity Analysis) 
Clarification on handling
of ADA cross-reactivity
results post study 
completion
For clarification
Non-substantial
Appendix A 6 (Data Quality 
Assurance)
Correction to confirm that
records and documents 
will be retained for 25 
years at sites
Correction of typo
Non-substantial
Appendix G (Summary of 
Changes)
Created to cover SOC to 
Amendment 1 
(29Jun2020)
Administrative 
change
Non-substantial

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
 ADA = anti-drug antibody; eGFR = estimated glomerular 
filtration rate; COVID-19 = coronavirus disease; HbA1C = Glycated haemoglobin; PK = pharmacokinetic; SoA 
= schedule of assessments; SOC = System organ class; UACR = urine albumin to creatinine ratio

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TABLE OF CONTENTS
TITLE PAGE........................................................................................................................ 1
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ..................................... 3
TABLE OF CONTENTS ...................................................................................................... 7
1
PROTOCOL SUMMARY ................................................................................ 11
1.1
Synopsis ........................................................................................................... 11
1.2
Schema............................................................................................................. 15
1.3
Schedule of Activities ....................................................................................... 16
2
INTRODUCTION............................................................................................ 30
2.1
Study Rationale ................................................................................................ 30
2.2
Background ...................................................................................................... 30
2.3
Benefit/Risk Assessment................................................................................... 32
3
OBJECTIVES AND ENDPOINTS................................................................... 33
4
STUDY DESIGN ............................................................................................. 37
4.1
Overall Design.................................................................................................. 37
4.1.1
Treatment Groups and Titration Regimens ........................................................ 38
4.1.2
Dose Escalation ................................................................................................ 39
4.1.3
Dose Reduction ................................................................................................ 39
4.2
Scientific Rationale for Study Design ............................................................... 39
4.2.1
Rationale for Insulin Dose Adjustments ............................................................ 40
4.3
Justification for Dose........................................................................................ 41
4.4
End of Study Definition.................................................................................... 43
5
STUDY POPULATION.................................................................................... 44
5.1
Inclusion Criteria .............................................................................................. 44
5.2
Exclusion Criteria ............................................................................................. 46
5.3
Lifestyle Considerations ................................................................................... 48
5.3.1
Meals and Dietary Restrictions ......................................................................... 48
5.3.2
Tobacco ............................................................................................................ 48
5.4
Screen Failures ................................................................................................. 48
6
STUDY INTERVENTION ............................................................................... 49
6.1
Study Intervention(s) Administered................................................................... 49
6.1.1
Investigational Products.................................................................................... 49
6.1.2
Medical Devices ............................................................................................... 50
6.2
Preparation/Handling/Storage/Accountability of Interventions.......................... 51
6.3
Measures to Minimise Bias: Randomisation and Blinding................................. 51
6.4
Study Intervention Compliance......................................................................... 53
6.5
Concomitant Therapy........................................................................................ 53

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6.5.1
Management of Toxicities................................................................................. 54
6.5.1.1
Management of Nausea and/or Vomiting........................................................... 54
6.5.1.2
Insulin Dose Adjustments Prior to Initiation of Investigational Product............. 54
6.5.1.3
Insulin Dose Adjustments During the Dosing and Follow-up Period ................. 56
6.5.1.4
Management of Hyperglycaemia....................................................................... 57
6.5.1.5
Management of Hypoglycaemia........................................................................ 57
6.5.1.6
Management of Decline in Renal Function ....................................................... 58
6.5.2
Rescue Medicine............................................................................................... 58
6.6
Dose Modification ............................................................................................ 60
6.7
Intervention after the End of the Study.............................................................. 60
7
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL........................................................... 60
7.1
Discontinuation of Study Intervention............................................................... 60
7.2
Participant Withdrawal from the Study.............................................................. 61
7.3
Lost to Follow up.............................................................................................. 62
8
STUDY ASSESSMENTS AND PROCEDURES.............................................. 63
8.1
Efficacy Assessments........................................................................................ 63
8.1.1
Primary Outcome (UACR)................................................................................ 64
8.1.2
Secondary Outcomes ........................................................................................ 64
8.1.3
Body Weight..................................................................................................... 65
8.1.4
Glucose Measurements ..................................................................................... 65
8.1.5
Echocardiography............................................................................................. 66
8.1.6
Patient-reported Outcome Measures.................................................................. 67
8.2
Safety Assessments........................................................................................... 67
8.2.1
Physical Examinations...................................................................................... 67
8.2.2
Vital Signs ........................................................................................................ 67
8.2.3
Electrocardiograms........................................................................................... 67
8.2.4
Retinal Assessments.......................................................................................... 67
8.2.5
Clinical Safety Laboratory Assessments............................................................ 68
8.2.6
Other Safety Assessments ................................................................................. 69
8.3
Adverse Events and Serious Adverse Events..................................................... 69
8.3.1
Time Period and Frequency for Collecting AE and SAE Information................ 70
8.3.2
Follow-up of AEs and SAEs ............................................................................. 70
8.3.3
Causality Collection.......................................................................................... 71
8.3.4
Adverse Events Based on Signs and Symptoms ................................................ 71
8.3.5
Adverse Events Based on Examinations and Tests ............................................ 71
8.3.6
Hy’s Law.......................................................................................................... 72
8.3.7
Reporting of Serious Adverse Events................................................................ 72
8.3.8
Clinical Event Adjudication .............................................................................. 73
8.3.9
Pregnancy......................................................................................................... 74
8.3.9.1
Maternal Exposure............................................................................................ 74
8.3.10
Medication Error............................................................................................... 74
8.3.11
Medical Device Deficiencies............................................................................. 75
8.3.11.1
Time Period for Detecting Medical Device Deficiencies ................................... 75

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8.3.11.2
Follow-up of Medical Device Deficiencies ....................................................... 75
8.3.11.3
Prompt Reporting of Device Deficiencies to Sponsor........................................ 75
8.3.11.4
Regulatory Reporting Requirements for Device Deficiencies............................ 76
8.4
Overdose .......................................................................................................... 76
8.5
Human Biological Samples............................................................................... 76
8.5.1
Pharmacokinetics.............................................................................................. 77
8.5.1.1
Determination of Drug Concentration ............................................................... 77
8.5.2
Immunogenicity Assessments ........................................................................... 78
8.5.3
Pharmacodynamics........................................................................................... 78
8.5.3.1
Collection of Samples....................................................................................... 78
8.6
Human Biological Sample Biomarkers ............................................................. 78
8.6.1
Collection of Mandatory Samples for Biomarker Analysis ................................ 78
8.6.2
Collection of Optional Biomarker Samples ....................................................... 78
8.7
Optional Genomics Initiative Sample................................................................ 78
8.8
Health Economics or Medical Resource Utilisation and Health Economics....... 79
9
STATISTICAL CONSIDERATIONS................................................................ 79
9.1
Statistical Hypotheses....................................................................................... 79
9.2
Sample Size Determination............................................................................... 79
9.3
Populations for Analyses................................................................................... 80
9.4
Statistical Analyses ........................................................................................... 80
9.4.1
General Considerations..................................................................................... 81
9.4.2
Efficacy ............................................................................................................ 81
9.4.2.1
Primary Endpoint.............................................................................................. 81
9.4.2.2
Secondary Endpoints ........................................................................................ 82
9.4.2.3
Tertiary/Exploratory Endpoints......................................................................... 82
9.4.3
Safety ............................................................................................................... 82
9.4.4
Other Analyses.................................................................................................. 82
9.5
Interim Safety Review ...................................................................................... 83
9.6
Data Monitoring Committee ............................................................................. 83
10
SUPPORTING 
DOCUMENTATION 
AND 
OPERATIONAL
CONSIDERATIONS ........................................................................................ 84
11
REFERENCES............................................................................................... 114
LIST OF FIGURES
Figure 1
Study Design ........................................................................................... 15
Figure 2
Change in Total Daily Insulin Dose from Day -2 (Baseline) to Day 40 in 
Participants with Insulin Dose ≥20 U/day in Study D5670C00013.......... 40

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LIST OF TABLES
Table 1
Primary and Secondary Objectives and Endpoints.................................... 12
Table 2
Schedule of Activities.............................................................................. 16
Table 3
Objectives and Endpoints......................................................................... 33
Table 4
Titration Regimen.................................................................................... 38
Table 5
Change in Total Daily Insulin Dose from Baseline (Day -2) to End of 
Dosing (Day 32) in Participants on Insulin Dose ≥ 20 U/day (ITT 
Population, Study D5670C00013)............................................................ 41
Table 6
Proposed Study Doses and Predicted Safety Margins Based on Safety 
Data from the Cynomolgus Monkey ........................................................ 43
Table 7
Investigational Products........................................................................... 49
Table 8
Permitted Medications ............................................................................. 53
Table 9
Prohibited Medications............................................................................ 54
Table 10
Initial Insulin Dose Adjustment, Participants with Screening HbA1c 
< 8.0% and eGFR < 50 mL/min/1.73 m2.................................................. 55
Table 11
Initial Insulin Dose Adjustment, Participants with Screening HbA1c 
≥8.0% and eGFR ≥50 mL/min/1.73 m2 .................................................. 55
Table 12
A Guide for Insulin Dose Adjustments According to CGM Readings ...... 56
Table 13
Allowed Rescue Therapies....................................................................... 59
Table 14
Prohibited Rescue Therapies.................................................................... 60
Table 15
Laboratory Efficacy Variables ................................................................. 64
Table 16
Laboratory Safety Variables..................................................................... 68
Table 17
Populations for Analyses ......................................................................... 80
LIST OF APPENDICES
Appendix A
Regulatory, Ethical, and Study Oversight Considerations......................... 85
Appendix B
Adverse Events: Definitions and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ........................................................................ 90
Appendix C
Handling of Human Biological Samples .................................................. 95
Appendix D
Optional Genomics Initiative Sample....................................................... 97
Appendix E
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law......................................................................... 100
Appendix F
Abbreviations ........................................................................................ 106
Appendix G
Summary of Changes............................................................................. 108

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1
PROTOCOL SUMMARY
1.1
Synopsis
Protocol Title: A Phase 2b, Multicentre, Randomised, Double-blind, Placebo-controlled, and 
Open-label Comparator Study of Cotadutide in Participants Who Have Chronic Kidney 
Disease with Type 2 Diabetes Mellitus
Short Title: Phase 2b Study of Cotadutide in Participants Who Have Chronic Kidney Disease 
with Type 2 Diabetes Mellitus
Rationale:
Chronic kidney disease (CKD) leads to progressive decline of renal function and arises due to 
a combination of age-related decline in renal function exacerbated by conditions such as
diabetes mellitus, hypertension, obesity, and primary renal disorders (Hill et al, 2016). The 
global prevalence of CKD is approximately 11-13% and is increasing in parallel with aging 
populations and escalating prevalence of type 2 diabetes mellitus (T2DM) and obesity. Per 
2016 estimates, kidney disease is the ninth most common cause of death in high income 
countries globally (World Health Organization, 2018). The main causes of CKD are diabetes 
and high blood pressure (National Institute of Diabetes and Digestive and Kidney Diseases, 
2016), and diabetes accounts for 44% of new cases of kidney failure (National Kidney 
Foundation, 2016). Because dedicated treatments for CKD with T2DM are limited, a large 
unmet need exists for this patient group. This Phase 2b study is designed to evaluate the 
efficacy, safety, tolerability, and pharmacokinetic (PK) profile of cotadutide at different dose 
levels in participants who have CKD with T2DM.

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Objectives and Endpoints
Table 1
Primary and Secondary Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effects of cotadutide at different dose 
levels compared to placebo on UACR after 14 weeks 
Change and percentage change in UACR versus placebo 
from baseline to the end of 14 weeks of dosing 
Secondary
To assess the effects of cotadutide at different dose 
levels compared to placebo on UACR after 26 weeks 
Change and percentage change in UACR versus placebo 
from baseline to the end of 26 weeks of dosing
To assess the effects of cotadutide at different dose 
levels compared to placebo on HbA1c and fasting 
glucose 
•
Change in HbA1c versus placebo from baseline to 
the end of 14 and 26 weeks of dosing 
•
Change in fasting glucose from baseline versus 
placebo after 14 and 26 weeks of dosing
To assess the effects of cotadutide at different dose 
levels compared to placebo on glucose levels as 
measured by CGM 
•
Change in 10-day average glucose levels as 
measured by CGM versus placebo from baseline to 
the end of 14 and 26 weeks of dosing
•
Change in percentage time spent in hyperglycaemia 
(> 10 mmol/L), target range (3.9 –10 mmol/L), 
hypoglycaemia (< 3.9 mmol/L), and clinically 
significant hypoglycaemia (< 3.0 mmol/l) over 10 
days as measured by CGM versus placebo from 
baseline to the end of 14 and 26 weeks of dosing
To assess the effects of cotadutide at different dose 
levels compared to placebo on body weight 
•
Change and percentage change in body weight 
versus placebo from baseline to the end of 14 and 
26 weeks of dosing
•
Proportion of participants achieving ≥ 5% and 
≥10% body weight loss versus placebo from 
baseline to the end of 14 and 26 weeks of dosing
To evaluate the immunogenicity profile of cotadutide 
compared to placebo
ADAs during the titration treatment period and follow-
up period
Safety
To evaluate the safety and tolerability of cotadutide 
compared to placebo 
•
TEAEs and TESAEs 
•
Vital signs 
•
ECG
•
Clinical laboratory assessments
ADA = anti-drug antibody; BP = blood pressure; CGM = continuous glucose monitoring;
ECG = electrocardiogram; HbA1c = haemoglobin A1c; TEAE = treatment-emergent adverse event; 
TESAE = treatment-emergent serious adverse event; UACR = urine albumin to creatinine ratio
For tertiary/exploratory objectives and endpoints, see Section 3 of the protocol.
Overall Design
This is a randomised, double-blind, placebo-controlled, and open-label comparator study to 
evaluate the efficacy, safety, tolerability, and PK profile of cotadutide uptitrated from 

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50 to 100, 300, or 600 μg administered subcutaneously (SC) once daily over 26 weeks in 
participants who have CKD with T2DM (estimated glomerular filtration rate [eGFR] ≥ 20 and 
< 90 mL/min/1.73 m2 and micro- or macroalbuminuria). Placebo will be matched to 
cotadutide. The open-label comparator, semaglutide, will be administered SC from 
0.25 to 1.0 mg once weekly over 26 weeks. Cotadutide, placebo, and semaglutide will be 
administered using an injection pen device.
Approximately 225 participants will be randomised at multiple sites in approximately 
8 countries. Participants will be randomised in a 1:1:1:1:1 ratio to 1 of 3 blinded cotadutide 
arms (100, 300, or 600 μg), a blinded placebo arm, or an open-label semaglutide arm
(1.0 mg). The cotadutide and placebo arms will be double-blinded. Participants randomised to 
the placebo arm will be further randomised in a 1:1:1 ratio to follow 1 of 3 titration regimens 
matched to the cotadutide arms. Participants at sites in Japan will not be randomised to the 
semaglutide arm.
Disclosure Statement: This is a parallel treatment, double-blind study with 5 arms.
Number of Participants:
Approximately 563 participants will be screened/enrolled to achieve 225 participants 
randomly assigned to study intervention and 180 participants who complete study treatments.
Note: "Enrolled" means a participant'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 to study 
intervention, are considered “screen failures,” unless otherwise specified by the protocol. 
Intervention Groups and Duration:
Participants will be randomised to cotadutide 100, 300, or 600 μg, placebo, or semaglutide 
1.0 mg following differing periods of titration. Each cotadutide treatment arm will be placebo-
matched with respect to titration schedule and dose levels. Cotadutide and placebo will be 
administered SC once daily and semaglutide SC once weekly for a total of 26 weeks.
Cotadutide, placebo, and semaglutide will be administered via injection pen devices.
 
 
 
 
 
 
physician before implementing.

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Data Monitoring Committee: No
Statistical Methods
The total study sample size is 225 participants.
Participants will be randomised in a 1:1:1:1:1 ratio to 1 of 3 cotadutide arms, a placebo arm,
or open-label semaglutide arm. 
The sample size  was determined to provide 
 
 
 
 
 
Two analyses are planned for this study:
!
A primary analysis after the completion of 14 weeks of dosing for all participants 
!
A final analysis after the completion of 26 weeks of dosing and safety follow-up for all 
participants
Formal statistical modelling analysis for certain prespecified efficacy endpoints will be 
conducted but will not be performed for all endpoints. A subpopulation analysis for only 
participants at sites in Japan after the completion of 26 weeks of dosing and safety follow-up
will also be conducted, and the scope of the analysis will be defined in the statistical analysis 
plan (SAP).

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1.3
Schedule of Activities
Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Outpatient visit to 
clinic t
X
X
X
X
(Op
tion
al)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Visit on 
Day -2 is 
optional 
for 
specific 
device 
training 
Informed consent
X
Section 
5.1
Optional informed 
 
 
 
 

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Verify inclusion 
and exclusion 
criteriac
X
X
Assess 
and 
verify 
prior to 
random-
isation
Section 
5.1 and 
5.2
Fasting by 
participant 8 hours 
prior to outpatient 
visit
X
X
X
Section 
5.3.1
Diet and exercise 
advice
X
Demographics
X
Medical history 
and comorbid 
conditions (until 
first dose)
X
X
X
Height and BMI 
calculation
X
Concomitant 
medications  
Collected continuously throughout the study
Section 
6.5

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Consider 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Remote contact 3 
days prior to visit 
for participant 
reminderse
X
X

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Remote contact to 
participants to 
obtain AE 
information, 
provide any 
reminders, and 
discuss insulin use, 
if applicable
Weekly throughout study
Safety Assessments
AEs
Monitored continuously throughout the study
Section 
8.3.1
SAEs
Monitored continuously throughout the study
Section 
8.3.1
Pregnancy test 
(serum or urine) if 
applicable
X
(serum 
only)
X
X
X
X
X
X
X
Testing 
for 
women 
of child-
bearing 
potential
Section 
5.1
Full physical 
examination
X
X
Section 
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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Abbreviated 
physical 
examination
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.1
Vital signsf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.2
ECGg
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.3
Urinalysis
X
X
X
X
X
X
X
Section 
8.2.5
Safety Blood Tests
Haematology and 
clinical chemistry
(including eGFR 
calculation)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.2.5
Calcitonin
X
X
X
X
X
Xh
Section 
8.2.6
Lactate, lipase, and 
amylase
X
X
X
X
Section 
8.2.6
C peptidei
X
X
X
X
Section 
8.2.6
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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Body weightj
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.3
     Efficacy Blood Tests
HbA1c
X
X
X
X
X
X
X
X
Section 
8.1.2
 
 
     Efficacy Urine Tests
UACRk
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Section 
8.1.1
 
Biomarker Assessments
 
 
 
 

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
 
 
 
 
Biomarker Urine Tests
 
 
 
 
 
Pharmacokinetics and Immunogenicity
Cotadutide 
 
 
 
 

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ADA (predose)
X
X
X
X
X
X
X
X
X
Xm
Not
collected 
from 
partici-
pants 
random-
ised to 
sema-
glutide
Section 
8.5.2
Devices and Images
 
 
 
 
 
 
 
 
 
 
 
 

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
for 300 
and 600 
μg arms 
only
CGM device 
training and 
explanation
X
X
Pro™or
Flash™
device as 
appropri-
ate
Section 
8.1.4
 
 
 
 
 
 
Training for and 
provision of 
glucose/ketone 
meter and diary
X
Section 
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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Injection pen 
device 
demonstration and 
training (as 
required)
X
X
At 
investiga-
tor’s 
discretion 
and per 
site 
resources, 
a saline 
injection 
technique 
for 
training 
may be 
used
Study Intervention Administration and Randomisation
Randomisations
X
Section 
6.3
Dispense 
cotadutide/placebo 
X
X
X
X
X
X
X
X
X
X
X
Dispense 
semaglutide
X
X
X
X
X
X
X
Cotadutide/placebo 
administration in 
clinic
X
X
X
X
X
X
X
X
Xq

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Table 2
Schedule of Activities
Study Period
Screening
Run-in 
(Days -14 to -1)a
Treatment
E/D
± 7b
Follow-
up 
(28 days 
after last 
dose)
± 3
Notes
Details in 
CSP 
section or 
Appendix
Study Day ± Days
-50 to -15
-14
-5
-2
1
15 ± 1
29 ± 1
43 ± 1
57 ± 1
71 ± 1
85 ± 1
99 ± 1
113 ± 3
141 ± 3
169 ± 1
182
Week
1
3
5
7
9
11
13
15
17
21
25
26
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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2
INTRODUCTION
Cotadutide (MEDI0382) is a glucagon-like peptide 1 (GLP-1) and glucagon receptor co-
agonist that is being developed for the treatment of type 2 diabetes mellitus (T2DM), obesity,
and nonalcoholic steatohepatitis (NASH).
2.1
Study Rationale
Chronic kidney disease (CKD) leads to progressive decline of renal function and arises due to 
a combination of age-related decline in renal function exacerbated by conditions such as 
diabetes mellitus, hypertension, obesity, and primary renal disorders (Hill et al, 2016). The 
global prevalence of CKD is approximately 11-13% and is increasing in parallel with aging 
populations and escalating prevalence of T2DM and obesity. 
Per 2016 estimates, kidney disease is the ninth most common cause of death in high income 
countries globally (World Health Organization, 2018). The Global Burden of Disease Study 
2015 estimated that 1.2 million people died from kidney failure, which was an increase of 
32% since 2005 (GBD 2015 Mortality Causes of Death Collaborators, 2016). The main causes 
of CKD are diabetes and high blood pressure (National Institute of Diabetes and Digestive and 
Kidney Diseases, 2016), and diabetes accounts for 44% of new cases of kidney failure 
(National Kidney Foundation, 2016). Because dedicated treatments for CKD with T2DM are 
limited, a large unmet need exists for this patient group.
In a Phase 2a study of cotadutide in participants with T2DM and renal impairment (Study 
D5670C00013), once daily administration of cotadutide titrated from 50 to 300 μg over 
32 days demonstrated an acceptable safety and tolerability profile; the overall tolerability of 
cotadutide in this population with renal impairment was comparable to what had been 
observed in prior studies of cotadutide in populations without renal impairment. Clinically 
significant glycaemic control and significant body weight loss were also observed in 
participants who received cotadutide compared to those who received placebo. An exploratory 
analysis revealed a numerical reduction in urine albumin to creatinine ratio 
(UACR; -3.05 mg/mmol versus 2.02 mg/mmol, p = 0.077) along with an unchanged estimated 
glomerular filtration rate (eGFR) and body water volume.
This Phase 2b study is designed to evaluate the efficacy, safety, tolerability, and 
pharmacokinetic (PK) profile of cotadutide 
 
 participants who have CKD with T2DM. Participants will have an 
eGFR ≥20 mL/min/m2 and < 90 mL/min/1.73 m2 and micro- or macroalbuminuria.
2.2
Background
Glucagon-like peptide 1 receptors are expressed in a wide variety of tissues including the 
pancreas, kidney, heart, gastrointestinal tract, and brain. While GLP-1 receptor agonists are 

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primarily considered in context of their glucose-dependent stimulation of insulin secretion, 
they also have important effects on the kidney (Skov, 2014). Glucagon-like peptide 1 has been 
reported to increase glomerular filtration rate (GFR), renal blood flow, and the fractional 
excretion both of sodium and potassium, with renal GLP-1 receptors present in afferent 
arteriolar vascular smooth muscle cells, and some research studies have also reported GLP-1
receptor expression in glomerular endothelial cells and macrophages, juxtaglomerular cells, 
and the proximal tubule (Bloomgarden, 2018). Glucagon-like peptide 1 receptor agonists have 
been clinically shown to reduce decline in eGFR in patients with T2DM and moderate to 
severe CKD (Tuttle et al, 2018). Treatment with liraglutide has been associated with a 
significant reduction in albuminuria, with nearly a 25% lower likelihood of development of 
macroalbuminuria, and a 20% reduction in the albumin to creatinine ratio, regardless of grade 
of chronic kidney disease (CKD) (Marso et al, 2016b). Similarly, semaglutide has shown 
fewer participants progress to macroalbuminuria over long term follow up (Marso et al, 
2016a).
Glucagon receptors are also expressed in the kidney especially in the distal tubule and 
collecting duct (Bailly et al, 1985). Glucagon has been shown to promote transient increases 
in GFR and promote natriuresis, and to enhance secretion of urea and uric acid. Additional 
effects on potassium, calcium, and magnesium homeostasis are also thought to be regulated by 
glucagon. 
Cotadutide is a synthetic peptide with both GLP-1 and glucagon dual receptor agonist 
activity that promotes glucose lowering and weight loss and is targeted at patients with 
NASH, obesity, and T2DM. In a prior phase 2b study (Study D5670C00013), 32 days 
of cotadutide treatment in participants with T2DM and renal impairment (eGFR ≥ 30 and 
< 60 mL/min/1.73 m2) led to numerical reductions in UACRs and were of a magnitude (51% 
reduction versus placebo) in the subgroup with baseline micro or macroalbuminuria, which is
associated with longer term renoprotection (Heerspink et al, 2019). In addition, safety and 
tolerability was confirmed to be acceptable in this population, and a single dose PK/PD study 
(Study D5670C00008) conducted in participants with eGFR from ≥20-60 ml/min/1.73m2
demonstrated that cotadutide has an equivalent PK profile in participants with renal 
impairment to that of participants with no renal impairment, and single doses were confirmed 
to have acceptable tolerability in participants in this eGFR range.
In a phase 2a study of cotadutide in participants with T2DM who were overweight/obese 
(Study D5670C00030), cotadutide administered once daily demonstrated an acceptable 
tolerability and safety profile at higher doses (titrated from 20 μg to higher doses of 600 μg) 
and over a longer treatment duration (77 days). In this study, PK was linear with a terminal 
half-life of approximately 15 hours and minimal accumulation after multiple subcutaneous 
(SC) daily doses.

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In a Phase 2b study of cotadutide with an open-label active comparator (liraglutide) arm 
(Study D5670C00004), treatment with cotadutide for 54 weeks was associated with 
significant and clinically meaningful reductions in HbA1c and body weight at Week 14, Week 
26, and Week 54 at all dose levels compared to placebo. A dose-dependent reduction in liver 
enzymes was observed in cotadutide-treated participants. The safety profile of cotadutide was 
generally similar to that observed with GLP-1 receptor agonists.
A detailed description of the chemistry, pharmacology, efficacy, and safety of cotadutide is 
provided in the Investigator’s Brochure.
2.3
Benefit/Risk Assessment
This is the first clinical study in which cotadutide at doses greater than 300 μg will be 
administered to participants who have CKD with T2DM. Cotadutide has the potential to 
deliver improvements in proteinuria, glycaemic control, body weight, and lipid homeostasis,
and is predicted to be a useful therapy for participants who have CKD with T2DM.
Identified and potential risks for cotadutide are based on available published data for GLP-1 
receptor mono-agonists and glucagon receptor mono-agonists, as well as clinical and non-
clinical data for cotadutide. Identified risks/adverse drug reactions for cotadutide are nausea, 
vomiting, injection site reactions and increased heart rate. Potential risks for cotadutide 
include alterations in blood pressure, QT interval prolongation, anaphylactic-type reactions, 
skin rash, pancreatitis, pancreatic carcinoma, thyroid cancer, hypoglycaemia (with 
sulfonylurea/insulin), and diabetic ketoacidosis (following insulin reduction). The potential 
risk of hypoglycaemia will be updated to include “with glitinides” in an Investigator’s 
Brochure update (Edition 9.0). Due to the CKD with T2DM indication, acute renal failure 
secondary to dehydration will be included as an additional potential risk in an Investigator’s 
Brochure update (Edition 9.0).
The study design aims to minimise the impact of identified and potential risks to participants 
in this study based on the proposed inclusion/exclusion criteria, safety monitoring, and up-
titration dosing schedule. All participants will be monitored throughout the study to ensure 
adequate glycaemic control. Participants will be given appropriate training in use of the 
injection pen device for SC self-administration. Dose uptitrations will only be performed in 
the clinic. Training will also be provided to all study participants for use of other devices,
including continuous glucose monitoring (CGM) devices, heart rate monitors, and 
glucose/ketone meters.
Taking into account the measures taken to minimise risk to participants in this study, the 
potential risks identified in association with cotadutide are justified by the anticipated benefits 
that may be afforded to participants who have CKD with T2DM.

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More detailed information about the known and expected benefits and potential risks of 
cotadutide may be found in the Investigator’s Brochure.
3
OBJECTIVES AND ENDPOINTS
Table 3
Objectives and Endpoints
Objectives
Endpoints
Primary
To assess the effects of cotadutide at different dose 
levels compared to placebo on UACR after 14 weeks 
Change and percentage change in UACR versus placebo 
from baseline to the end of 14 weeks of dosing
Secondary
To assess the effects of cotadutide at different dose 
levels compared to placebo on UACR after 26 weeks 
Change and percentage change in UACR versus placebo 
from baseline to the end of 26 weeks of dosing 
To assess the effects of cotadutide at different dose 
levels compared to placebo on HbA1c and fasting 
glucose 
•
Change in HbA1c versus placebo from baseline to 
the end of 14 and 26 weeks of dosing 
•
Change in fasting glucose from baseline versus 
placebo after 14 and 26 weeks of dosing
To assess the effects of cotadutide at different dose 
levels compared to placebo on glucose levels as 
measured by CGM 
•
Change in 10-day average glucose levels as 
measured by CGM versus placebo from baseline to 
the end of 14 and 26 weeks of dosing
•
Change in percentage time spent in hyperglycaemia 
(> 10 mmol/L), target range (3.9 –10 mmol/L), 
hypoglycaemia (< 3.9 mmol/L), and clinically 
significant hypoglycaemia (< 3.0 mmol/l) over 10 
days as measured by CGM versus placebo from 
baseline to the end of 14 and 26 weeks of dosing
To assess the effects of cotadutide at different dose 
levels compared to placebo on body weight 
•
Change and percentage change in body weight 
versus placebo from baseline to the end of 14 and 
26 weeks of dosing
•
Proportion of participants achieving ≥ 5% and 
≥10% body weight loss versus placebo from 
baseline to the end of 14 and 26 weeks of dosing
To evaluate the immunogenicity profile of cotadutide 
compared to placebo 
ADAs during the titration treatment period and follow-
up period
Safety
To evaluate the safety and tolerability of cotadutide 
compared to placebo
•
TEAEs and TESAEs 
•
Vital signs
•
ECG
•
Clinical laboratory assessments
 

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4
STUDY DESIGN
4.1
Overall Design
This is a randomised, double-blind, placebo-controlled, and open-label comparator study to 
evaluate the efficacy, safety, tolerability and PK profile of cotadutide 
 
 by SC injection over 26 weeks in participants 
with T2DM and CKD (eGFR ≥ 20 and < 90 mL/min/1.73 m2 and micro- or 
macroalbuminuria). 
Approximately 225 participants will be randomised at multiple sites in approximately 8 
countries. Participants will be randomised in a 1:1:1:1:1 ratio to 1 of 3 blinded cotadutide 
arms (100, 300, or 600 μg), a blinded placebo arm, or an open-label semaglutide arm (1.0 
mg). The cotadutide and placebo arms will be double-blinded. Participants randomised to the 
placebo arm will be further randomised in a 1:1:1 ratio to follow 1 of 3 titration regimens 
matched to the cotadutide arms. Participants at sites in Japan will not be randomised to the 
semaglutide arm.
The randomisation will be stratified according to whether a participant is from a site in Japan 
or not and on the use of sodium-glucose cotransporter 2 (SGLT2) inhibitor therapy at 
screening. At least 40% of participants should be on an SGLT2 inhibitor that was initiated at 
least 4 weeks prior to screening. Up to approximately 20% of participants will be recruited in 
Japan.
The study will have a 14-day run-in period during which participants will be given advice on
diet and exercise and asked to wear a CGM sensor, followed by a 26-week treatment period 
and 28-day follow-up period. Diet and exercise guidance will be according to local practices. 
This study plans to randomise a total of approximately 225 participants across multiple study 
sites in approximately 8 countries. Participants will be consented, screened for eligibility, and 
if eligible, randomised within 48-50 days of screening. Participants may enter the run-in 
period but must not be randomised until confirmation of the calcitonin laboratory test result.
A 4-week washout prior to dosing on Day 1 is required for participants taking a sulfonylurea 
or glitinide at screening. Treatment with a dipeptidyl peptidase-4 inhibitor may continue at the 
investigator’s discretion as it is not specifically contraindicated; however, it is not a permitted 
rescue medication.
Once daily dosing with cotadutide or placebo will begin on Day 1 at 50 μg, and participants 
will follow the titration regimen to which they have been randomised. Participants randomised 
to the semaglutide arm will receive once weekly doses also beginning on Day 1 at a start dose 
of 0.25 mg once weekly and follow the titration regimen detailed in the label, reaching 1.0 mg 
once weekly after 8 weeks. 

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Urine albumin to creatinine ratio will be measured following three first morning void 
collections at home prior to the clinic visit during the run in and on Days 99 and 182. All other 
UACR calculations will be determined from single urine samples taken in the clinic. 
Participants will attend the visits detailed in the schedule of events and undergo the 
assessments therein.
The primary analysis will be conducted after all participants have completed 14 weeks of 
dosing, and a final analyses will be conducted once all participants have completed dosing and 
follow-up visits. A subpopulation analysis including only participants at sites in Japan will 
also be conducted once all participants have completed dosing and follow-up visits.
At the primary analysis, an analysis on UACR will be conducted on the subpopulation of 
participants on an SGLT-2 inhibitor therapy at screening
 
 
 
After 68 or 30% of participants  have completed Week 11, an interim safety review will be 
conducted. Data will be reviewed by the sponsor’s unblinded review committee (URC).
Details can be found in the Interim Analysis Charter.
4.1.1
Treatment Groups and Titration Regimens
Participants will be randomised to cotadutide 100, 300, or 600 μg, placebo, or semaglutide for 
a total of 26 weeks following differing periods of titration. Each cotadutide treatment arm will 
be placebo-matched with respect to titration schedule and dose levels. Cotadutide and placebo 
will be administered once daily and semaglutide once weekly, all via SC injection. Study 
treatments will be titrated in discrete steps as shown in Table 4.
Table 4
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 

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Table 4
Titration Regimen 
Treatment 
Arm (N)
Weeks –
Dose 
Weeks –
Dose 
Weeks –
Dose 
Weeks –
Dose
Weeks –
Dose 
Weeks –
Dose 
Semaglutide 
1.0 mg (45)a
1 to 4 –
0.25 mg
5 to 8 –
0.5 mg
9 to 26 –
1.0 mg
N = number of participants
a
Participants at sites in Japan will not be randomised to the semaglutide arm. 
b
Participants randomised to placebo will follow 1 of 3 titration regimens matched to the cotadutide arms 
and will be distributed evenly across the placebo arms.
4.1.2
Dose Escalation
Cotadutide/Placebo Arms
For participants assigned to cotadutide or 
Semaglutide Arm
For participants assigned to semaglutide, doses will commence at 0.25 mg and will be 
uptitrated every 4 weeks to a final dose of 1.0 mg (see Section 4.1.1).
4.1.3
Dose Reduction
 
 
 
 
 
The semaglutide Summary of Product Characteristics (SmPC) does not provide advice on 
dose adjustment in the event of nausea, vomiting, or other gastrointestinal symptoms. In 
exceptional circumstances and if intolerable gastrointestinal AEs occur in a participant treated 
with semaglutide, it may be possible to switch the participant to a lower dose level, but this 
decision must be discussed with the study physician beforehand.
4.2
Scientific Rationale for Study Design
Urine albumin to creatinine ratio is an established biomarker of renal disease and prior studies 
have demonstrated that improvements in UACR predict improvement in longer term renal 
outcomes (Heerspink et al, 2019). The primary endpoint of UACR will be measured by taking 
the average of three first morning void urine samples at baseline and at the end of treatment to 
evaluate the efficacy of each dose of cotadutide in this population of CKD with T2DM.

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for the last participant in the study globally.
5
STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrolment criteria, also known 
as protocol waivers or exemptions, is not permitted.
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1
Participants must be ≥18 and ≤79 years of age at the time of signing the informed 
consent.
Type of Participants and Disease Characteristics
2
Estimated glomerular filtration rate ≥ 20 to < 90 mL/min/1.73 m2 determined at the 
screening visit or a documented occurrence in their medical history at least 3 months prior 
to randomisation. Estimated glomerular filtration rate will be determined using the CKD
epidemiology collaboration equation. Retesting for eGFR may be repeated twice.
3
Receiving background standard of care treatment for renal disease and/or T2DM and 
being treated according to locally recognised guidelines, as appropriate. Guideline-
recommended medications should be used at recommended doses. 
4
Receiving optimised and stable treatment with an angiotensin-converting enzyme (ACE)
inhibitor or an angiotensin II receptor antagonist for ≥ 3 months at screening at the 
maximum tolerated dose (MTD) unless contraindicated, not tolerated, or in the opinion of 
the investigator, not practically available or suitable. Participants who cannot tolerate an 
ACE inhibitor or an angiotensin II receptor antagonist may still be eligible to enter the 
study at the investigator’s discretion.
5
Micro- or macroalbuminuria as defined by UACR > 50 mg/g or 5.7 mg/mmol. Retesting
on UACR may be repeated twice.
6
Diagnosed with T2DM with glucose control managed with any insulin and/or any oral 
therapy combination including metformin, SGLT2 inhibitor, thiazolidinedione, or 
acarbose where no major dose changes (eg, > 50% increase in dose) have occurred within 
the 4 weeks prior to the start of the run-in period. Participants taking sulfonylureas or 
glitinides may be randomised following a 4-week washout period of the 
sulfonylurea/glitinide. 
7
Haemoglobin A1c range of 6.5 % to 12.5% (inclusive) at screening

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Weight
8
Body mass index > 25 kg/m2 at screening or > 23 kg/m2 for participants enrolled in Japan
Sex
9
Males and females
Reproduction
10 Negative pregnancy test at screening (serum only) and randomisation (serum or urine) for 
female participants of childbearing potential and must not be breastfeeding. Women of 
childbearing potential are defined as those who are not surgically sterile (ie, surgical 
sterilisation includes bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) or 
those who are 1 year postmenopausal (defined as 12 months with no menses without an 
alternative medical cause).
11 Female participants of childbearing potential must use 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. They should 
have been stable on their chosen method of birth control for a minimum of 3 months 
before entering the study to 5 weeks after the last dose.
(a) Highly effective birth control methods include: total sexual abstinence (true 
abstinence in line with the preferred and usual lifestyle choice of the participant), 
vasectomised partner, tubal occlusion, intrauterine device (provided coils are copper-
banded), levonorgestrel intrauterine system, medroxyprogesterone injections, 
etonogestrel implants, normal and low dose combined oral pills, 
norelgestromin/ethinylestradiol transdermal system (eg, Evra Patch), intravaginal 
device (eg, ethinylestradiol and etonogestrel-NuvaRing), and Cerazette (desogestrel).
Periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.
Informed Consent
12 Capable of giving signed informed consent as described in Appendix A, which includes 
compliance with the requirements and restrictions listed in the informed consent form 
(ICF) and in this protocol
13 Provision of signed and dated informed consent prior to any mandatory study-specific 
procedures, sampling, and analyses
14 Provision of signed and dated optional informed consent prior to collection of samples for 
genetic research that supports the Genomic Initiative

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15 Provision of signed and dated optional informed consent prior to collection of samples for 
future nongenetic biomarker research
5.2
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1
History or presence of significant medical or psychological conditions, including 
significant abnormalities in laboratory parameters or vital signs including ECG, which in 
the opinion of the investigator, would compromise the participant’s safety or successful 
participation in the study. As an example, severe anaemia (haemoglobin < 7.0 g/dL) could 
be exclusionary due to blood sampling required by the protocol, at the discretion of 
investigator
2
Receiving renal replacement therapy or expected to require it within 6 months of being 
randomised
3
Renal transplant or on the waiting list for renal transplantation
Prior/Concomitant Therapy
4
Received a GLP-1 analogue-containing preparation within the last 30 days or 5 half-lives 
of the drug, if known (whichever is longer), at the time of Visit 2
5
Received any of the following medications within the specified time frame prior to the 
start of the study (Visit 2):
(a)
Aspirin (acetylsalicylic acid) at a dose greater than 150 mg once daily and within the 
last 3 days prior to the start of the run-in period (Visit 2)
(b) Paracetamol (acetaminophen) or paracetamol-containing preparations at a total daily 
dose of greater than 3000 mg and within the last 3 days prior to the start of the run-in 
period (Visit 2)
(c) Ascorbic acid (vitamin C) supplements at a total daily dose of greater than 1000 mg 
and within the last 3 days prior to the start of the run-in period (Visit 2)
Prior/Concurrent Clinical Study Experience
6
Participation in another clinical study with an investigational product administered in the 
last 30 days or 5 half-lives of the drug, if known (whichever is longer)
7
Participants with a known severe allergy/hypersensitivity to any of the proposed study
interventions or excipients of the product

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Diagnostic Assessments
8
Symptoms of acutely decompensated blood glucose control (eg, thirst, polyuria, weight 
loss) or recent episodes of severe hypoglycaemia
9
Type 1 diabetes mellitus (T1DM), history of diabetic ketoacidosis, or clinical suspicion of 
T1DM (eg, undetectable levels of C peptide and positive tests for antibodies indicative of 
T1DM)
10 Participants with recent acute or subacute renal function deterioration (eg, participants 
with large fluctuations of creatinine values documented within the 3 months prior to 
screening)
11 Significant inflammatory bowel disease, gastroparesis, or other severe disease or surgery 
affecting the upper gastrointestinal tract (including weight-reducing surgery and 
procedures) that may affect gastric emptying or could affect the interpretation of safety 
and tolerability data
12 History of acute or chronic pancreatitis
13 Significant hepatic disease (except for non-alcoholic steatohepatitis or nonalcoholic fatty 
liver disease without portal hypertension or cirrhosis) and/or participants with any of the 
following results:
(a) Aspartate transaminase (AST) ≥ 3 × upper limit of normal (ULN)
(b) Alanine transaminase (ALT) ≥ 3 × ULN
(c) Total bilirubin ≥ 2 × ULN
14 Poorly controlled hypertension defined as:
(a) Systolic blood pressure (SBP) > 180 mm Hg
(b) Diastolic blood pressure (DBP) ≥ 90 mm Hg 
#
After 10 minutes of seated or semi-supine rest and confirmed by repeated 
measurement at screening
#
Participants who fail blood pressure screening criteria may be considered for 24-hour 
ambulatory blood pressure monitoring at the discretion of the investigator. 
Participants who maintain a mean 24-hour SBP ≤ 180 or DBP < 90 mm Hg with a 
preserved nocturnal dip of > 15% will be considered eligible.
15 Unstable angina pectoris, myocardial infarction, transient ischemic attack or stroke within 
3 months prior to screening, or participants who have undergone percutaneous coronary 
intervention or a coronary artery bypass graft within the past 6 months or who are due to 
undergo these procedures at the time of screening
16 Decompensated heart failure or hospitalisation for heart failure in the 3 months prior to 
screening or symptoms consistent with New York Heart Association heart failure Class 
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17 Basal calcitonin level > 50 ng/L at screening or history/family history of medullary 
thyroid carcinoma or multiple endocrine neoplasia
18 History of neoplastic disease within 5 years prior to screening, except for adequately 
treated basal cell skin cancer, squamous cell skin cancer, or in situ cervical cancer
Other Exclusions
19 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site)
20 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
5.3
Lifestyle Considerations
Participants will be given general advice on diet and exercise during the run-in period and 
periodically reminded of such throughout the study. The guidance will be in accordance with 
the sites’ local processes.
Participants should be made aware that the site may contact them regularly by telephone or 
other means to provide reminders and provide or gather information on topics such as but not 
limited to dosing, AEs, and concomitant medication
Participants should be made aware they will be required to store investigational product in 
their home refrigerator.
5.3.1
Meals and Dietary Restrictions
Participants are required to fast for a minimum of 8 hours prior to attending the clinical unit 
on Days 1, 99, and 182; however, water is allowed ad libitum. It is recommended these visits 
are conducted in the morning to minimise participant discomfort, and participants may receive 
breakfast after fasted blood samples are collected.
5.3.2
Tobacco
Participants who use tobacco products will be instructed that use of such products may be 
restricted while they are in the clinical unit.
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 

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details, eligibility criteria, and any SAE.
Participants who fail screening should have the reason for study withdrawal recorded in the 
electronic case report form (eCRF).
Individuals who do not meet the eGFR and UACR inclusion criteria for participation in this 
study may have their eGFR and UACR retested twice as part of the screening procedure (see 
Section 5.1). Retesting is only allowed in the study for the eGFR and UACR inclusion criteria.
Participants may be rescreened once if, in the opinion of the investigator, there is a reason to 
believe they may be eligible. Repeat screenings may be considered at any time prior to 
randomisation and in particular, although not limited to, for reasons related to the COVID-19 
pandemic i.e. lack of available kits, local lockdowns and imposed quarantines.
6
STUDY INTERVENTION
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to 
the study protocol.
6.1
Study Intervention(s) Administered
6.1.1
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 7
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMP = investigational medicinal product; NA = not applicable; NIMP = noninvestigational medicinal product; 
SC = subcutaneous
a
Both the liquid drug product and prefilled pen constitute the investigational product. Adverse events and 
SAEs that occur with the investigational product should be reported per the processes outlined in Section 
8.3.
6.1.2
Medical Devices
1
Medical devices not manufactured by AstraZeneca but provided for use in this study are:

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(i)
Needles to be used with the cotadutide prefilled pens
(ii) NovoFine® Plus needles to be used with the semaglutide (OZEMPIC®) prefilled 
pens
(iii) FreeStyle Libre Pro™and Flash™CGM devices
(v) A glucose/ketone meter device
2
Medical devices will be used per manufacturer’s instructions.
3
All device deficiencies (including malfunction, use error, and inadequate labelling) shall 
be documented and reported by the investigator throughout the clinical investigation (see 
Section 8.3.11) and appropriately managed by the sponsor.
6.2
Preparation/Handling/Storage/Accountability of Interventions
1
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention.
2
Only participants enrolled in the study may receive study intervention and only authorised 
site staff may supply or administer study intervention. All study intervention must be 
stored in a secure, environmentally controlled, and monitored (manual or automated) area 
in accordance with the labelled storage conditions with access limited to the investigator 
and authorised site staff.
3
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(ie, receipt, reconciliation, and final disposition records).
4
Further guidance and information for the final disposition of unused study interventions 
are provided in the Investigational Medicinal Product Manual.
6.3
Measures to Minimise Bias: Randomisation and Blinding
Study randomisation 
using IVRS/IWRS
All participants will be centrally assigned to randomised study intervention using an 
Interactive Voice/Web Response System (IVRS/IWRS). Before the study is 
initiated, the telephone number and call-in directions for the IVRS and/or the log in 
information and directions for the IWRS will be provided to each site.
Study intervention will be dispensed at the study visits summarised in the SoA. 
Returned study intervention should not be redispensed to the participants.
IVRS = interactive voice response system; IWRS = interactive web response system; SOA = schedule of 
activities

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Cotadutide and Placebo Arms
Blinded studies using 
IVRS/IWRS
The IVRS/IWRS 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 IVRS/IWRS user manual that will be 
provided to each centre.
The randomisation code should not be broken except in medical emergencies 
when the appropriate management of the participant requires knowledge of the 
treatment randomisation.  The investigator documents and reports the action to 
AstraZeneca, without revealing the treatment given to participant to the 
AstraZeneca staff.
AstraZeneca retains the right to break the code for SAEs that are unexpected and 
are suspected to be causally related to an investigational product and that 
potentially require expedited reporting to regulatory authorities. Randomisation 
codes will not be broken for the planned analyses of data until all decisions on the 
evaluability of the data from each individual participant have been made and 
documented.
The exception to the above is for those personnel analysing the PK samples. The
randomisation code will be provided to ensure that only samples from participants 
who were on active study treatment are analysed. Samples from participants not 
dosed with the relevant active study treatment will only be analysed on a ‘for 
cause’ basis (eg, if there is suspicion that a participant has been dosed incorrectly). 
The treatment allocation information will be kept in a secure location until the end 
of the study.
Blind Break 
(IVRS/IWRS)
The IVRS/IWRS will be programmed with blind-breaking instructions. In case of 
an emergency, in which the knowledge of the specific blinded study treatment will 
affect the immediate management of the participant’s condition (eg, antidote 
available), the investigator has the sole responsibility for determining if unblinding 
of a participants’ intervention assignment is warranted. Participant safety must 
always be the first consideration in making such a determination. If a participant’s 
intervention assignment is unblinded, the sponsor must be notified within 24 hours 
after breaking the blind. The investigator documents and reports the action to 
AstraZeneca, without revealing the treatment given to participant to the 
AstraZeneca staff.
IVRS = interactive voice response system; IWRS = interactive web response system; PK = pharmacokinetic; 
SAE = serious adverse event
The sponsor, site, and participants will be blinded through the 14-week primary analysis. 
Thereafter, the sponsor will be unblinded, but the site and participants will remain blinded to 
minimise bias.

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Semaglutide Arm
Open-label using central 
randomisation via 
(IVRS/IWRS)
This is an open-label arm; however, the specific intervention to be taken by a 
participant will be assigned using an IVRS/IWRS. The site will contact the 
IVRS/IWRS prior to the start of study intervention administration for each 
participant. The site will record the intervention assignment on the applicable case 
report form, if required. Potential bias will be reduced by central randomisation.
IVRS = interactive voice response system; IWRS = interactive web response system
6.4
Study Intervention Compliance
Dosing at Site
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 if applicable, of 
dose administered in the clinic will be recorded in the source documents and eCRF.
Dosing at Home
When participants self-administer study interventions at home, the percent compliance is 
defined as the total dose consumed divided by the total dose that should have been taken 
between the site visits and multiplied by 100%. 
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 enrolment or 
receives during the study must be recorded along with:
!
Reason for use
!
Dates of administration including start and end dates
!
Dosage information including dose and frequency
The medications listed in Table 8 are permitted. See Section 5.1 for additional details.
Table 8
Permitted Medications
•
Standard of care treatment for renal disease and/or T2DM
•
ACE inhibitor or an angiotensin II receptor antagonist
•
Insulin and/or any oral therapy combination including metformin, SGLT2 inhibitor, thiazolidinedione, or 
acarbose/alpha-glucosidase inhibitors
•
Pharmacological treatments administered for hypoglycaemia (eg, dextrose/glucose tablets, glucagon)
ACE = angiotensin-converting enzyme; SGLT2 = sodium-glucose cotransporter 2 inhibitor; T2DM = type 2 
diabetes mellitus
The medications listed in Table 9 are prohibited. See Section 5.2 for additional details.

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Table 9
Prohibited Medications
•
GLP-1 analogue-containing preparation 
•
Aspirin (acetylsalicylic acid) > 150 mg once daily
•
Paracetamol (acetaminophen) or paracetamol-containing preparations, total daily dose > 3000 mg
•
Ascorbic acid (vitamin C) supplements, total daily dose > 1000 mg
GLP-1 = glucagon-like peptide 1
The study physician should be contacted if there are any questions regarding concomitant or 
prior therapy.
6.5.1
Management of Toxicities
Advice and guidance apply to participants treated in the cotadutide, placebo, or semaglutide 
arms unless otherwise stated.
6.5.1.1
Management of Nausea and/or Vomiting
If a participant experiences nausea and/or vomiting in relation to cotadutide or semaglutide, 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 cyclizine is preferable rather than antiemetics, which may affect gastric 
emptying, and dopamine receptor antagonists (eg, metoclopramide or domperidone). In
addition, for participants taking diuretics (eg, thiazides, loop diuretics), the investigator should 
consider temporarily stopping these agents to avoid further dehydration and acute kidney 
injury (AKI) risk. Investigators should monitor participants with vomiting for signs of 
hypovolemia. Participants with impaired renal function could be extra 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.
Dose reductions of cotadutide or semaglutide may be considered following discussion with 
the study physician. Please see Section 4.1.3 for further details.
6.5.1.2
Insulin Dose Adjustments Prior to Initiation of Investigational Product
For participants in the cotadutide or placebo arms:
Investigators should consider insulin dose reduction for any participant whom they consider 
may be at risk of hypoglycaemia upon initiation of investigational product. Investigators 
should be mindful to advise on both quick-acting and long-acting and premixed insulin 
preparations. Dose reductions of long-acting insulin preparations may occur the night before 
dosing (Day -1) if an evening dose is to be taken; dose reductions of quick-acting and 
premixed insulin preparations may occur the morning before dosing (Day 1). Regular contact 
should be maintained with participants, particularly during the first 2 weeks of treatment with 
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For participants in the semaglutide arm:
The semaglutide SmPc states that patients treated with semaglutide in combination with a 
sulfonylurea or insulin may have an increased risk of hypoglycaemia. The risk of 
hypoglycaemia can be lowered by reducing the dose of sulfonylurea or insulin when initiating 
treatment with semaglutide.
Investigators should use their discretion as to whether an insulin dose reduction is required 
and what magnitude of reduction is required for participants who are initiated on semaglutide.
6.5.1.3
Insulin Dose Adjustments During the Dosing and Follow-up Period
Once a dose reduction of insulin has occurred, it should be continued for the remainder of the 
study or until insulin dose titration is deemed necessary by the investigator. At the end of the 
study during the follow-up visit, investigators/the study team should aim to establish the 
participant back on their original regimen (or close to this) as guided by CGM and/or capillary 
plasma glucose readings and HbA1c measurements. 
Insulin dose adjustment may also be considered at visits where fasting is required; 
investigators/the study team should use their discretion as to whether a change is required, and 
what dose change is appropriate (see Table 12) in accordance with ongoing glucose readings 
(CGM, venous plasma, or capillary plasma readings) and the timetable of procedures at these 
visits.
Further dose adjustments of insulin (up or down) should be made at the discretion of the 
investigator and study team who may use results of capillary plasma glucose readings, HbA1c 
measurements, venous plasma glucose levels, or CGM readings obtained at each study visit. 
Table 12 may be used as a guide for adjustment of insulin doses during the study if required. 
All changes in insulin (including recording of the change in units) should be documented in 
the eCRF at each visit.
 
 
 
 
 
 

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Table 12
A Guide for Insulin Dose Adjustments According to CGM Readings
CGM = continuous glucose monitoring
a
Applies to all insulin doses administered over a 24-hour period, ie, a 10% reduction in a regime of 
10 units of quick-acting insulin 3 times daily and 20 units of long-acting insulin once daily would reduce 
to 9 units of quick-acting insulin 3 times daily and 18 units of long-acting once daily, unless an 
alternative dose adjustment is deemed preferable by the investigator.
6.5.1.4
Management of Hyperglycaemia
For participants where hyperglycaemia is suspected, additional venous fasting plasma glucose 
measurements may be performed, if necessary, to investigate further. In addition, and where 
applicable, study teams may provide ketone meters to participants if hyperglycaemia is 
suspected for additional monitoring.
See Section 6.5.2 for details on rescue therapy for participants who have sustained 
hyperglycaemia.
6.5.1.5
Management of Hypoglycaemia
A hypoglycaemic event is considered severe if associated with severe cognitive impairment 
requiring external assistance for recovery, as defined by the American Diabetes Association; 
clinically significant hypoglycaemia is defined as a capillary or venous plasma glucose 
reading of < 3.0 mmol/L (54 mg/dL).  Few events of clinically significant hypoglycaemia (< 3 
mmol/L) have been reported in participants treated with cotadutide up to 300 μg. In Study 
D5670C000013 conducted in participants with T2DM and an eGFR of 30-60 ml/min/1.73m2
3/21 (14.3%), participants who were treated with ≥ 20 units of insulin reported an AE of 
hypoglycaemia in comparison to 1/20 (5%) participants treated with placebo. No episodes of 
severe hypoglycaemia warranting third party assistance were observed. In addition, 
participants treated with cotadutide spent up to 2.9% of time in a clinically significant 
hypoglycaemic range (glucose < 3.0 mmol/l) on CGM. 
Per the semaglutide SmPC, clinically significant hypoglycaemia is reported to be very 
common with semaglutide in conjunction with insulin or sulfonylureas and common in 
association with other oral antidiabetic agents.
All participants will be provided with a diary and a glucose meter and will be advised to check 
their capillary plasma glucose level if they have symptoms of hypoglycaemia (hunger, 
dizziness, shaking, sweating, or irritability) or feel unwell and will be expected to record the 
level in their diary. Local protocols for treatment and follow-up of any hypoglycaemic episode 
should be followed. Any clinically significant hypoglycaemia (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 hypoglycaemia (eg, 
dextrose/glucose tablets, glucagon, etc) should be recorded in the eCRF as concomitant 
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For participants who experience a severe hypoglycaemic episode or a clinically significant 
episode of hypoglycaemia (defined as a capillary or venous plasma glucose reading of 
3.0 mmol/L (< 54 mg/dL) or an interstitial glucose reading 3.0 mmol/L (< 54 mg/dL) recorded 
on CGM on 2 occasions across 15 minutes, a reduction in total daily dose of insulin of 20% 
should be considered from the time of awareness of the event. If the participant is not using 
insulin during the study, a 50% dose reduction in oral medication should be considered in the 
following order of preference: sulfonylureas, glitinide, pioglitazone, metformin, dipeptidyl 
peptidase-4 (DPP-4) inhibitors. Dose reduction should also be considered at the discretion of 
the investigator and/or following discussion with the study physician if > 2% of interstitial 
glucose readings on CGM are 3.9 mmol/L (< 70 mg/dL).
6.5.1.6
Management of Decline in Renal Function
For participants who have a eGFR of 30-60 mL/min/1.73 m2 (inclusive) at screening and are 
taking an existing dose of metformin that is higher than the recommended dose for that degree 
of renal impairment, the dose of metformin should be reduced or discontinued at Visit 2 in 
accordance with local guidelines on metformin prescription in renal impairment, or to 500 mg 
once daily if no guidance is in place. Similarly, any participant experiencing a decline in 
eGFR during the study to 30-60 mL/min/1.73 m2 (inclusive) should have their dose of 
metformin reduced or discontinued as described above. 
Participants who have an eGFR < 30 mL/min/1.73 m2 at baseline or who experience a decline 
in renal function to eGFR < 30 mL/min/1.73 m2 during the study should be advised to stop 
metformin therapy. Any other medications that are contraindicated for this degree of renal 
impairment should be reviewed and discontinued where deemed appropriate by the 
investigator.
For participants who are eligible to take part in the study and are taking other medications for 
diabetes that are prescribed at a higher dose than recommended for their degree of renal 
insufficiency, dose reduction should be performed at Visit 2 in accordance with local treatment 
guidelines or the drug labelling.
For participants who are found to have a decline in renal function to eGFR < 15 mL/min/1.73 
m2 during the study, the participant should undergo a repeat eGFR level one week later, and if 
the eGFR remains < 15 mL/min/1.73 m2 on a second consecutive test, the investigational 
product or semaglutide should be discontinued, and the participant should also be advised to 
stop metformin therapy (if they have not already done so) and any other medications that are 
contraindicated for this degree of renal impairment. However, the participant should remain in 
the study for all other study procedures until their scheduled end of study.
6.5.2 Rescue Medicine
In participants who have sustained hyperglycaemia despite adjustment of insulin as described 

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in Section 6.5.1 (Insulin Dose Adjustments During the Dosing and Follow-up Period), 
additional open-label rescue therapy should be considered by the investigator and should be 
documented in the relevant section of the eCRF. 
Rescue therapy should be considered by the investigator following discussion with the study 
physician if any of the following apply:
!
Fasting plasma glucose 11.1 mmol/L (> 200 mg/dL) on 2 occasions less than 8 days apart
!
3 capillary plasma glucose levels 13.9 mmol/L (> 250 mg/dL) in 1 week
!
> 30% of readings in hyperglycaemic range on CGM defined as 13.9 mmol/L (> 250 
mg/dL) in 1 week
!
2 capillary plasma ketone levels > 1.6 mmol/L in 1 day
Rescue therapy with an increase in insulin and/or re-initiation of sulfonylurea/glitinide dose (if 
these agents were washed out at the beginning of the study) is the preferred option, but 
additional drug classes may also be used at the discretion of the investigator (see Table 13). 
Rescue therapy with a sodium glucose cotransporter-2 (SGLT2) inhibitor, any GLP-1
analogue, or DPP-4 inhibitor-based intervention is prohibited (Table 14); the latter is not 
contraindicated, but would not be expected to provide additional glucose-lowering in 
conjunction with a GLP-1 and glucagon receptor co-agonist.
If rescue medication is required, participants should continue to participate in the study and 
receive their study medication. An interim prescription of the rescue medication will be 
provided by the study site if necessary, but continued prescription of rescue therapy will 
remain the responsibility of the primary care physician or usual diabetes physician. Rescue 
medication will not be provided by the sponsor for this study.
Investigators should consider discontinuing the study intervention in participants with 
persistent fasting venous plasma glucose level of 14.4 mmol/L (> 260 mg/dL), despite an
MTD of rescue therapy, to enable optimisation of the participant’s glycaemic control. 
However, the participant should remain in the study for all other study procedures and 
continued follow-up until their scheduled end of study date.
Table 13
Allowed Rescue Therapies
•
Any type of insulin 
•
Sulfonylurea
•
Glitinide 
•
Pioglitazone
•
Acarbose/alpha-glucosidase inhibitors

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Table 14
Prohibited Rescue Therapies
•
GLP-1 analogue
•
DPP-4 inhibitor
•
GLP-1 analogue/insulin combination (eg, IDegLira)
•
Pramlintide
•
SGLT2 inhibitor
DPP-4 = dipeptidyl peptidase-4; GLP-1 = glucagon-like peptide 1; SGLT2 = sodium-glucose cotransporter 2
6.6
Dose Modification
For management of nausea and/or vomiting, dose reductions of cotadutide or semaglutide may 
be considered following discussion with the study physician. See Section 4.1.3 for additional 
details.
6.7
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 study intervention (ie, 
definitive discontinuation). If study intervention is permanently discontinued, the participant 
will be encouraged to remain in the study for all remaining study procedures as outlined in the 
SoA. See the SoA for data to be collected at the time of discontinuation of study intervention 
and follow-up and for any further evaluations that need to be completed.
Note that discontinuation from study intervention is NOT the same thing as withdrawal from 
the study (see Section 7.2).
An individual participant will not receive any further investigational product if any of the 
following occur:
1
Withdrawal of consent/assent from further treatment with investigational product
2
Lost to follow-up
3
An AE that, in the opinion of the investigator or the sponsor, contraindicates further 
dosing; specific examples include:
#
Dose-limiting symptoms with respect to gastrointestinal tolerability, and in particular,
if a participant requires intravenous fluids to treat volume depletion secondary to 
nausea and vomiting, even after measures are taken to reduce the risk of vomiting 
(eg, 2 dose reductions) and after discussion with the study physician

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#
Any signs or symptoms of severe hepatic impairment including abnormal laboratory 
values as follows: 
o
ALT and/or AST > 3 × ULN and total bilirubin > 2 × ULN
o
ALT and/or AST > 5 × ULN for ≥14 consecutive days at any time after initial 
confirmatory results
o
ALT and/or AST > 8 × ULN
#
eGFR < 15 mL/min/1.73 m2 on 2 consecutive blood tests across 1 week
#
AKI as defined by:
o
An increase in serum creatinine by ≥0.3 mg/dL (26.5 μmol/L) in at least 2 
readings within 48 hours 
o
An increase in serum creatinine to ≥1.5 times baseline in at least 2 readings
within 48 hours
Participants with serum creatinine above these levels will have their study medication 
held and a repeated serum creatinine test should be performed within 7 days. If serum 
creatinine is still elevated as specified above (increase ≥0.3 mg/dL (26.5 μmol/L) or 
≥1.5 times baseline), the participant should permanently discontinue the clinical 
study medication. If after interruption of study medication serum creatinine values 
are below these values, study medication can be re-started if appropriate in the 
judgement of the investigator and following consultation with the study physician.
#
A clinically significant tachyarrhythmia, including but not limited to a life-
threatening arrhythmia (eg, sustained ventricular tachycardia or ventricular 
fibrillation)
#
Persistent fasting glucose level of 14.4 mmol/L (> 260 mg/dL) despite an MTD of 
rescue therapy to enable optimisation of the participant’s glycaemic control
4
Noncompliance that, in the opinion of the investigator or sponsor, warrants withdrawal 
(eg, refusal to adhere to scheduled visits)
5
Pregnancy in a female participant
7.2
Participant Withdrawal from the Study
!
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioural,
compliance, or administrative reasons. This is expected to be uncommon.
!
A participant who considers withdrawing from the study must be informed by the 
investigator about modified follow-up options (eg, telephone contact, a contact with a 
relative or treating physician, or information from medical records).

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!
At the time of withdrawal from the study, if possible, an early discontinuation visit should 
be conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
withdrawal and follow-up and for any further evaluations that need to be completed.
#
The participant will discontinue the study intervention and be withdrawn from the 
study at that time.
!
If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent.
!
If a participant withdraws from the study, it should be confirmed if he/she still agrees for 
existing samples to be used in line with the original consent. If he/she requests withdrawal 
of consent for use of samples, destruction of any samples taken and not tested should be 
carried 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 or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
!
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study.
!
Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and,
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record.
!
Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
!
Site personnel, or an independent third party, will attempt to collect the vital status of the 
participant within legal and ethical boundaries for all participants randomised, including 
those who did not get investigational product. Public sources may be searched for vital 
status information. If vital status is determined as deceased, this will be documented and 
the participant will not be considered lost to follow-up. Sponsor personnel will not be 
involved in any attempts to collect vital status information.

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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 summarised in the SoA. 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.
!
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.
!
Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilised for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the time frame defined in the SoA.
8.1
Efficacy Assessments
Planned time points for all efficacy assessments are provided in the SoA.
Laboratory efficacy assessments are shown in Table 15.

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Secondary outcome measures of T2DM-related metabolic effects include:
!
HbA1c 
!
Fasting glucose 
!
Secondary outcome
8.1.3
Body Weight
Body weight will be measured at the time points specified in the SoA. Body weight should be 
measured in the morning while the participant is fasted and prior to breakfast. Body weight 
will be measured after the participant has toileted and removed bulky clothing including 
shoes. Whenever possible, after screening, the same properly calibrated scale should be used 
for each measurement for any given participant. The participant’s body weight will be 
recorded in kg to 1 decimal place at a minimum.
8.1.4
Glucose Measurements
A device for CGM should be worn continuously throughout the study. The device will be 
either a Freestyle Libre Pro™or Freestyle Libre Flash™CGM device in accordance with the 
SoA. The sensor should be applied to the arm with consideration of participant preference. 
The sensor applied to the skin is single-use and may not be reattached once removed. 
Participant training for CGM use should be conducted prior to use and prior to changing the 
type of sensor worn. The CGM sensor must be changed according to the schedule listed in the
SOA. CGM sensor application should occur at approximately the same time each scheduled 
sensor change day. If the sensor fails or needs to be replaced, it should be reapplied as soon as 
possible. Participants should report to the clinical site to have the sensor replaced at the 
earliest convenient opportunity. Approximately 1 hour after a new CGM sensor is applied, the 
site staff or participant should place the monitor in close proximity with the sensor to transfer 
data and ensure that the sensor and monitor are functioning adequately.
 
 
 
 

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8.2
Safety Assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical Examinations
!
A full physical examination will be performed and include assessments of the following:
general appearance, respiratory, cardiovascular, abdomen, and neurological systems.
!
An abbreviated physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).
A physical examination will be performed at the time points specified in the SoA.
8.2.2
Vital Signs
Vital signs, including temperature, pulse rate, blood pressure (seated or semi-supine), and 
respiratory rate, will be performed at the time points specified in the SoA.
8.2.3
Electrocardiograms
Electrocardiograms will be performed at the time points specified in the SoA.
8.2.4
 
 
 
 
 

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8.2.5
Clinical Safety Laboratory Assessments
A laboratory manual that specifies the procedures for collection, processing, storage, and 
shipment of samples, as well as laboratory contact information specific to this clinical 
research study, will be provided to sites. 
Clinical laboratory safety assessments will be performed in a licensed central clinical 
laboratory. Urine pregnancy tests may be performed at the site using a licensed test (eg, a 
urine dipstick human chorionic gonadotropin test). Abnormal laboratory results should be 
repeated as soon as possible (preferably within 24 to 48 hours).
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be collected at the time points specified in the SoA.
The following laboratory safety variables will be measured:
Table 16
Laboratory Safety Variables
Haematology (Whole Blood)
Clinical Chemistry 
(Serum or Plasma)
Urinalysis (dipstick)
B-Haemoglobin
S/P-Bilirubin, total
U-Hb/Erythrocytes/Blood
B-Leukocyte count
S/P-Alkaline phosphatase 
U-Glucose
B-Leukocyte differential count 
(absolute count)
S/P-Aspartate transaminase
U-pH
B-Platelet count
S/P-Alanine transaminase
U-Bilirubin
B-Haematocrit
S/P-Albumin
U-Ketones
B-RBC
S/P-Potassium
U-Urobilinogen
B-Mean corpuscular volume
S/P-Calcium, total
U-Nitrite
B-Mean corpuscular haemoglobin 
concentration
S/P-Sodium
U-Leukocyte esterase
S/P Glucose 
U-Protein
S/P-Bicarbonate 
U-Specific gravity
S/P-BUN 
U-Color
S/P-Phosphate 
U-Appearance
S/P-Creatinine 
U- Microscopy
S/P-Magnesium 
S/P-Beta-hydroxybutyrate 
ALP = alkaline phosphatase; ALT = alanine transaminase; AST = aspartate transaminase; BUN = blood urea 
nitrogen; Hb = haemoglobin; RBC = red blood cell; U = urinalysis; WBC = white blood cell
In case a participant shows an AST or ALT ≥3x ULN together with total bilirubin ≥2x ULN,

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please refer to Appendix E for further instructions.
8.2.6
Other Safety Assessments
Calcitonin, lactate, lipase, amylase, and C peptide levels will also be assessed as indicated in 
the SoA. All participants will be provided with a glucose/ketone meter and a diary during the 
run-in period, and site staff will explain how the glucose/ketone meter works and allow 
participants to demonstrate proper use under supervision before being discharged from the 
clinic. Participants will be advised to use the glucose meter to check their capillary blood 
glucose level as per their usual schedule, and if they have symptoms of hypoglycaemia 
(hunger, dizziness, shaking, sweating, or irritability) or feel unwell, participants will be 
expected to record their glucose levels and symptoms in their diaries. Participants must also 
use their ketometer to check their blood ketones if they have the following symptoms:
!
Polyuria, polydipsia
!
Malaise, generalised weakness, or fatigability
!
Nausea and vomiting that may be associated with diffuse abdominal pain, decreased 
appetite, and anorexia
!
Altered consciousness (eg, mild disorientation, confusion)
If a measured blood ketone value is > 3.0 mmol/L upon repeat testing, participants must 
contact the study site immediately. At the unit, the investigator should assess and determine 
whether the participant is at risk to develop ketoacidosis or is progressing towards 
ketoacidosis based on the participant’s medical history, physical examination, and supportive 
laboratory results.
Participants treated with either cotadutide or placebo (300 and 600 μg arms only) will also be 
provided with an ABPM device to wear for approximately 24 hours at the time points
specified in the SoA.
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 authorised representative). 
The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE.

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8.3.1
Time Period and Frequency for Collecting AE and SAE Information
Adverse events and SAEs will be collected from time of signature of the informed consent 
form throughout the treatment period and including the follow-up period (28 days post last 
dose).
If the investigator becomes aware of an SAE with a suspected causal relationship to the 
investigational medicinal product that occurs after the end of the clinical study in a participant
treated by him or her, the investigator shall, without undue delay, report the SAE to the 
sponsor.
8.3.2
Follow-up of AEs and SAEs
Any AEs that are unresolved at the participant’s last visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the eCRF. 
AstraZeneca retains the right to request additional information for any participant with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary.
Adverse event variables
The following variables will be collected for each AE:
!
AE (verbatim)
!
The date when the AE started and stopped
!
Intensity
!
Whether the AE is serious or not
!
Investigator causality rating against the investigational product(s) (yes or no)
!
Action taken with regard to investigational product(s)
!
AE caused participant’s withdrawal from study (yes or no)
!
Outcome
In addition, the following variables will be collected for SAEs:
!
Date AE met criteria for serious AE
!
Date investigator became aware of serious AE
!
AE is serious due to
!
Date of hospitalisation
!
Date of discharge
!
Probable cause of death
!
Date of death

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!
Autopsy performed
!
Causality assessment in relation to study procedure(s)
!
Causality assessment to other medication
8.3.3 Causality Collection
The investigator should assess causal relationship between investigational product and each 
AE, and answer ‘yes’ or ‘no’ to the question ‘Do you consider that there is a reasonable 
possibility that the event may have been caused by the investigational product?’
For SAEs, causal relationship should also be assessed for other medication and study 
procedures. Note that for SAEs that could be associated with any study procedure the causal 
relationship is implied as ‘yes’.
A guide to the interpretation of the causality question is found in Appendix B.
8.3.4 Adverse Events Based on Signs and Symptoms
All AEs spontaneously reported by the participant or reported in response to the open question 
from the study site staff: 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
Results from the mandated laboratory tests and vital signs will be summarised in the clinical 
study report (CSR). 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should therefore only be reported as AEs if they fulfil any of the SAE criteria, are the reason 
for discontinuation of treatment with the investigational product or are considered to be 
clinically relevant as judged by the investigator (which may include but not limited to 
consideration as to whether treatment or non-planned visits were required or other action was 
taken with the study treatment, eg, dose adjustment or drug interruption).
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator
uses the clinical, rather than the laboratory term (eg, anaemia versus low haemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).

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Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE unless unequivocally 
related to the disease under study.
8.3.6 Hy’s Law
Cases where a participant shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥ 3x ULN together with total bilirubin ≥ 2x ULN 
may need to be reported as SAEs. Please refer to Appendix E for further instruction on cases 
of increases in liver biochemistry and evaluation of Hy’s Law.
8.3.7
Reporting of Serious Adverse Events
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF.
If any SAE occurs in the course of the study, then investigators or other site personnel 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 works with the investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 1
calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. investigators or other site personnel inform 
AstraZeneca representatives of any follow-up information on a previously reported SAE 
within one calendar day ie, immediately but no later than 24 hours of when he or she 
becomes aware of it.
Once the investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative.
If the EDC system is not available, then the investigator or other study site staff reports an
SAE to the appropriate AstraZeneca representative by telephone and via paper back-up SAE 
form.
The AstraZeneca representative will advise the investigator/study site staff how to proceed.
The reference document for definition of expectedness/listedness is the IB for the AstraZeneca 

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drug (cotadutide) and the SmPC for the comparator product (semaglutide). 
8.3.8
Clinical Event Adjudication
A Clinical Event Adjudication (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
All deaths
2
Cardiac ischaemic events: myocardial infarction or unstable angina 
3
Cerebrovascular events: stroke or transient ischaemic attack 
4
Renal events: AKI and end-stage renal disease
5
Hospitalisation for heart failure 
6
Pancreatitis
7
Pancreatic carcinoma
8
Thyroid neoplasm
9
Diabetic ketoacidosis
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 CEA with appropriate and adequate information for adjudication of the listed 
events, please consult the CEA Charter and Event Handling Manual for Sites and site 
monitors.

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8.3.9
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:
!
If the pregnancy is discovered before the study participant has received any study drug
!
Pregnancies in the partner of male participants
8.3.9.1
Maternal Exposure
If a participant becomes pregnant during the course of the study despite contraceptive 
measures outlined in Section 5.1, the investigational product should be discontinued 
immediately, and the pregnancy reported to AstraZeneca.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational 
product under study may have interfered with the effectiveness of a contraceptive medication. 
Congenital abnormalities/birth defects and spontaneous miscarriages should be reported and 
handled as SAEs. Elective abortions without complications should not be handled as AEs. The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth or congenital abnormality) should be followed up and documented even if the 
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 and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
When the eCRF module is used include the following: The PREGREP module in the eCRF is 
used to report the pregnancy and the PREGOUT is used to report the outcome of the 
pregnancy.
8.3.10
Medication Error
If a medication error occurs in the course of the study, then the investigator or other site 
personnel informs the appropriate AstraZeneca representatives within 1 day (ie, immediately 
but no later than 24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the investigator to ensure that all 
relevant information is completed within 1 (Initial Fatal/Life-Threatening or follow up 

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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 and within 30 days for all other medication errors.
The definition of a medication error can be found in Appendix B.
8.3.11
Medical Device Deficiencies
Medical devices are being provided for use in this study (see Section 6.1.2). In order to fulfil
regulatory reporting obligations worldwide, the investigator is responsible for the detection 
and documentation of events meeting the definitions of device deficiency that occur during the 
study with such devices.
The definition of a medical device deficiency is as follows:
Device Deficiency Definition
A device deficiency is any malfunction or deterioration in the characteristics and/or 
performance of a device as well as any inadequacy in the labelling or the instructions for use.
NOTE: Incidents that fulfil the definition of an AE/SAE will follow the processes outlined in
Section 8.3.3.
8.3.11.1
Time Period for Detecting Medical Device Deficiencies
!
Medical device incidents or malfunctions of the device will be detected, documented, and
reported during all periods of the study in which the medical device is used.
!
If the investigator learns of any device deficiency at any time after a participant has been 
discharged from the study, and the incident is considered reasonably related to a medical 
device provided for the study, the investigator will promptly notify the sponsor.
8.3.11.2
Follow-up of Medical Device Deficiencies
!
Follow-up applies to all participants, including those who discontinue study intervention.
!
The investigator is responsible for ensuring that follow-up includes any supplemental 
investigations as indicated to elucidate the nature and/or causality of the deficiency.
!
New or updated information will be recorded on the originally completed form with all 
changes signed and dated by the investigator.
8.3.11.3
Prompt Reporting of Device Deficiencies to Sponsor
!
Device deficiencies will be reported to the sponsor within 1 calendar day after the 
investigator determines that the event meets the protocol definition of a medical device 
deficiency.
!
Device deficiencies can be reported through site monitors to the sponsor.

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8.3.11.4
Regulatory Reporting Requirements for Device Deficiencies
!
The investigator will promptly report all device deficiencies occurring with any medical 
device provided for use in the study in order for the sponsor to fulfil the legal 
responsibility to notify appropriate regulatory authorities and other entities about certain 
safety information relating to medical devices being used in clinical studies.
!
The investigator, or responsible person according to local requirements (eg, the head of 
the medical institution), will comply with the applicable local regulatory requirements 
relating to the reporting of device deficiencies to the IRB/IEC.
8.4
Overdose
For this study, any dose of cotadutide
 a 24-hour time period and 
any dose of semaglutide greater than 1.0 mg within a 7-day time period will be considered an 
overdose.
!
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the 
relevant AE modules in the eCRF and on the Overdose eCRF module.
!
An overdose without associated symptoms is only reported on the Overdose eCRF 
module
If an overdose on an AstraZeneca study drug occurs in the course of the study, 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 (see Section 8.3.7) and within 30 days 
for all other overdoses.
8.5
Human Biological Samples
Instructions for the collection and handling of biological samples will be provided in the study 
specific laboratory manual. Samples should be stored in a secure storage space with adequate 
measures to protect confidentiality. For further details on Handling of Human Biological 
Sample, see Appendix C.
Samples will be stored for a maximum of 15 years from the date of the issue of the CSR in 
line with consent and local requirements, after which they will be destroyed/repatriated. 

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!
Pharmacokinetic samples will be disposed of after CSR finalisation, unless consented for 
future analyses. 
#
Pharmacokinetic samples may be disposed of or anonymised by pooling. Additional 
analyses may be conducted on the anonymised, pooled PK samples to further 
evaluate and validate the analytical method. Any results from such analyses may be 
reported separately from the CSR.
!
Remaining anti-drug antibody (ADA) sample aliquots will be retained at AstraZeneca or 
its designee for a maximum of 15 years following issue of the CSR. Additional use 
includes but is not limited to further characterisation of any ADAs, confirmation and/or 
requalification of the assay as well as additional assay development work. The results 
from future analysis will not be reported in the CSR.
8.5.1
Pharmacokinetics
!
Plasma samples will be collected for measurement of cotadutide concentrations as 
specified in the SoA.
!
Samples may be collected at additional time points during the study if warranted and 
agreed upon between the investigator and the sponsor (eg, for safety reasons). The timing 
of sampling may be altered during the course of the study based on newly available data 
(eg, to obtain data closer to the time of peak or trough matrix concentrations) to ensure 
appropriate monitoring. 
!
Plasma samples will be used to analyse the PK of cotadutide. Samples collected for 
analyses of cotadutide concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study.
!
Samples will be collected, labelled, stored, and shipped as detailed in the laboratory 
manual.
!
Pharmacokinetic samples will not be collected from participants randomised to the 
semaglutide arm.
8.5.1.1
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.

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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.
8.5.2
Immunogenicity Assessments
Blood samples for determination of ADA in serum will be assayed by bioanalytical test sites 
operated by or on behalf of AstraZeneca using an appropriately validated bioanalytical 
method. Full details of the methods used will be described in a separate report.
Anti-drug antibody samples may also be further tested for characterisation of the ADA 
response.
Samples will be collected, labelled, stored, and shipped as detailed in the laboratory manual.
Anti-drug antibody samples will not be collected from participants randomised to the 
semaglutide arm.
8.5.3
Pharmacodynamics
There will be no pharmacodynamic assessments for this study.
8.5.3.1
Collection of Samples
Blood samples will be collected for measurement as specified in the SoA.
Urine samples will be collected for measurement as specified in the SoA.
For storage, reuse, and destruction of pharmacodynamic samples see Section 8.5 and 
Appendix C.
8.6
 
 
 
 
 

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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 see Appendix D.
8.8
Health Economics or Medical Resource Utilisation and Health 
Economics
Neither health economics nor medical resource utilisation and health economics parameters
will be evaluated in this study.
9
STATISTICAL CONSIDERATIONS
9.1
Statistical Hypotheses
Primary Hypothesis
Administration of cotadutide once daily titrated up to a dose level of either 100, 300, or 
600 μg will result in a superior reduction in UACR versus placebo after 14 weeks of treatment 
in participants who have CKD with T2DM.
Secondary Hypotheses
Administration of cotadutide once daily titrated up to a dose level of 600 μg will result in a 
superior reduction in UACR versus placebo after 26 weeks of treatment in participants who 
have CKD with T2DM.
Administration of cotadutide once daily titrated up to a maximum of 600 μg across 26 weeks 
will be well tolerated in participants who have CKD with T2DM.
Administration of cotadutide once daily titrated up to a maximum of 600 μg will result in 
superior weight loss versus placebo after 26 weeks of treatment in participants who have CKD 
with T2DM.
9.2
Sample Size Determination
 
 
 
 
 
 

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At the primary analysis, an analysis on UACR will be conducted on the subpopulation of 
participants on an SGLT-2 inhibitor therapy at screening. Based on the analysis results of this 
subpopulation for placebo and 2 optimal cotadutide arms, more participants may be enrolled 
to achieve 80% power for comparison of cotadutide versus placebo. In the event this is 
required, up to 22 more participants will be recruited into the placebo arm and to each of the 2 
selected cotadutide arms for a total of 66 additional participants. If the calculated sample size 
of each arm for this subpopulation exceeds 40 (including the participants for primary 
analysis), further enrolment may not be done. Additional details will be described in the 
statistical analysis plan (SAP). 
9.3
Populations for Analyses
Table 17
Populations for Analyses
Population/Analysis Set
Description
All-enrolled
All enrolled participants who have signed the informed consent form will be 
included in the all-enrolled population and will be analysed according to the 
randomised treatment group.
As-treated
Randomised participants who receive any study intervention will be 
included in the as-treated population and will be analysed according to the 
intervention they actually received.
ITT Population
Randomised participants included in the ITT population will be analysed 
according to the intervention they were randomised to.
Per Protocol Population
The Per Protocol population will include all enrolled participants who are 
randomised and who have received at least one dose of study intervention 
except for those who have discontinued study intervention and those with 
relevant IPDs. Relevant IPDs are those that have the potential to affect the 
result of the primary efficacy results. The PP population will be analysed 
according to the randomised treatment group.
PK Population
Randomised participants who have at least one measurable concentration 
time point of cotadutide will be included in the PK population.
Immunogenicity Population
Randomised participants who have at least one serum sample for 
immunogenicity testing will be included in the Immunogenicity population.
IPD = important protocol deviation; ITT = intent-to-treat; PK = pharmacokinetic
9.4
Statistical Analyses
The SAP will be finalised prior to first participant dosed and will include a more technical and 
detailed description of the statistical analyses described in this section. This section is a 
summary of the planned statistical analyses of the most important endpoints, including 
primary and key secondary endpoints.

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9.4.1
General Considerations
Participants will be randomised in a 1:1:1:1:1 ratio to 1 of 3 blinded cotadutide arms, a 
blinded placebo arm, or an open-label semaglutide arm. Participants randomised to the 
placebo arm will be further randomised in a 1:1:1 ratio to follow 1 of 3 titration regimens 
matched to the cotadutide arms. Participants at sites in Japan will not be randomised to the 
semaglutide arm.
The randomisation will be stratified according to whether a participant is from Japan or not
and on the use of SGLT2 inhibitor therapy at screening. Up to approximately 20% of 
participants will be recruited in Japan.
Two analyses are planned for this study:
!
A primary analysis after the completion of 14 weeks of dosing for all participants
!
A final analysis after the completion of 26 weeks of dosing and safety follow-up for all 
participants
Formal statistical modelling analysis for certain prespecified efficacy endpoints will be 
conducted but will not be performed for all endpoints. A subpopulation analysis for only 
participants at sites in Japan after the completion of 26 weeks of dosing and safety follow-up
will also be conducted, and the scope of the analysis will be defined in the SAP. 
9.4.2
Efficacy 
9.4.2.1
Primary Endpoint
The primary efficacy analysis will be performed using the intent-to-treat population. The 
primary efficacy endpoint, percentage change in UACR from baseline to the end of 14 weeks 
of treatment, will be analysed using an analysis of covariance (ANCOVA) model with a two-
sided significance level of 0.05. Fold change of UACR in original scale will firstly be log-
transformed, and then the ANCOVA analysis results will be transformed back to original scale 
for interpretation purposes. The model will include fixed effect of treatment and the baseline 
value as well as the stratification factors (whether a participant is from Japan and whether a 
participant is using SGLT2 inhibitor therapy at screening or not) as covariates. Absolute 
change in UACR will only be summarised.
A sensitivity analysis including only data when participants are on treatment will be 
performed using a similar method. Another sensitivity analysis including data from all 
available visits using a mixed model with repeated measurements will be performed with 
similar covariates.

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9.4.2.2
Secondary Endpoints
An ANCOVA model with fixed effect of treatment and the baseline value as well as the 
stratification factors (whether a participant is from Japan and whether a participant is using
SGLT2 inhibitor therapy at screening or not) as covariates will be used for continuous 
endpoints. Urine albumin to creatinine ratio-related analyses will follow a similar method as 
that for the primary endpoint. For proportion-related endpoints, a logistic regression model 
will be used with fixed effect of treatment and baseline measurement as a covariate.
9.4.2.3
Tertiary/Exploratory Endpoints
For analyses of the exploratory endpoints, an ANCOVA model similar to the secondary 
pharmacodynamic analysis will be used for continuous endpoints. For proportion-related 
endpoints, a logistic regression model will be used with fixed effects of treatment and baseline 
measurement. For eGFR slope analysis, a mixed model will be used.
For the following endpoints, if both percentage and absolute changes are needed, visualisation 
normality test will be performed first, then if log-transformation is needed, the similar analysis 
approach as that for the primary endpoint will be conducted. The relevant endpoints are: urine 
albumin, urinary creatinine, renal function, and exploratory renal and cardiac biomarkers
(eGFR not to be tested – assumed to be normally distributed), markers of liver health, lipid 
profile and echocardiography-determined parameters. 
9.4.3
Safety
Safety is a secondary endpoint. AEs and SAEs will be coded by the most updated version of 
Medical Dictionary for Regulatory Activities (MedDRA), and the type, incidence, severity, 
and relationship to study investigational product will be summarised by MedDRA System 
Organ Class and Preferred Term and by treatment. Adverse events leading to discontinuation, 
AEs leading to death, and deaths will also be summarised and will be marked in the listings or 
will be in a separate listing. Specific AEs will be counted once for each participant for 
calculating percentages. In addition, if the same AE occurs multiple times within a particular 
participant, the highest severity and level of relationship observed will be reported. 
Participant-level data listings of all AEs will be presented.
9.4.4
Other Analyses 
Immunogenicity Analysis
As a secondary endpoint, samples confirmed positive for ADA will be tested and analyzed for 
antibody titre and reported. The incidence and impact of ADA to cotadutide will be tabulated 
for each treatment. The number and percentage of participants with confirmed positive serum 
antibodies to cotadutide will be reported by dose level. Data on titres and cross-reactivity to 
GLP-1 and glucagon (where applicable) will be provided in the CSR as an appendix or part of 
the main results if available prior to publishing of the final CSR. If warranted by the data, the 
association of ADA positives with observed PK data may be explored.

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Pharmacokinetics Analysis
As an exploratory endpoint, cotadutide plasma concentrations prior to injection and 4 hours 
post injection at steady state at different dose levels and different visits will be summarised 
descriptively by arms. Population PK analysis will be performed but will not be reported in 
the CSR.
The PK of semaglutide will not be measured. 
Patient Reported Outcomes 
Descriptive analyses will be performed.
9.5
Interim Safety Review 
An interim safety review is planned after 68 or 30% of participants have completed Week 11. 
Data will be reviewed by the sponsor’s URC. No study team members involved in the conduct 
of the study should be unblinded for the purpose of the interim analysis; however, in case any 
study team members need to serve in the unblinded analysis group, they will stop day-to-day 
work on the study and other pre-selected personnel will take over these roles for the remainder 
of the study. The details and scope of the analysis can be found in the Interim Analysis 
Charter.
9.6
Data Monitoring Committee
No Data Monitoring Committee will be appointed for this study.

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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 International Ethical Guidelines
#
Applicable International Council for Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines
#
Applicable laws and regulations
!
The protocol, protocol amendments, informed consent form (ICF), Investigator’s
Brochure, and other relevant documents (eg, advertisements) must be submitted to an 
Institutional Review Boards (IRB)/Independent Ethics Committees (IEC) by the 
investigator and reviewed and approved by the IRB/IEC before the study is initiated.
!
Any amendments to the protocol will require IRB/IEC and applicable Regulatory 
Authority approval before implementation of changes made to the study design, except 
for changes necessary to eliminate an immediate hazard to study participants.
!
AstraZeneca will be responsible for obtaining the required authorisations to conduct the 
study from the concerned Regulatory Authority. This responsibility may be delegated to a 
contract research organisation, but the accountability remains with AstraZeneca.
Regulatory Reporting Requirements for SAEs
!
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.
!
The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, Institutional Review Boards 
(IRB)/Independent Ethics Committees (IEC), and investigators.
!
For all studies except those utilizing medical devices investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary.
!
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 and will notify the IRB/IEC, if 
appropriate according to local requirements.

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A 2
Financial Disclosure
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators 
are responsible for providing information on financial interests during the course of the study 
and for 1 year after completion of the study.
A 3
Informed Consent Process
!
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorised representative and answer all questions regarding 
the study.
!
Participants must be informed that their participation is voluntary, and they are free to 
refuse to participate and may withdraw their consent at any time and for any reason 
during the study. Participants 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 requirements, where applicable, and the IRB/IEC or 
study centre.
!
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorised person obtaining the informed consent must also sign the ICF.
!
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.
!
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorised representative.
A 4
Data Protection
!
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred.
!
The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local data protection law. The level of disclosure and use 
of their data must also be explained to the participant in the informed consent 
!
The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorised personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory authorities.

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A 5
Dissemination of Clinical Study Data
A description of this clinical study will be available on http://astrazenecaclinicaltrials.com and 
http://www.clinicaltrials.gov as will the summary of the study results when they are available. 
The clinical study and/or summary of study results may also be available on other websites 
according to the regulations of the countries in which the study is conducted.
A 6
Data Quality Assurance
!
All participant data relating to the study will be recorded on eCRF unless transmitted to 
the sponsor or designee electronically (eg, laboratory data). The investigator is 
responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the eCRF.
!
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
!
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
!
Monitoring details describing strategy (eg, risk-based initiatives in operations and quality 
such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the monitoring and other study plans.
!
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
!
The sponsor assumes accountability for actions delegated to other individuals (eg,
contract research organisations).
!
Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorised site personnel are accurate, complete, and verifiable from 
source documents; that the safety and rights of participants are being protected; and that 
the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
!
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the investigator for 25 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to the 
sponsor.

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A 7
Source Documents
!
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
!
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
!
Definition of what constitutes source data can be found in the source data verification 
plan.
A 8
Study and Site Start and Closure
The study start date is the date on which the clinical study will be open for recruitment of 
participants.
The first act of recruitment will be 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 
organisation(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.

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

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Appendix B
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
B 1
Definition of adverse events
An adverse event is the development of any untoward medical occurrence in a participant or 
clinical study participant administered a medicinal product and which does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (eg, an abnormal laboratory finding), symptom (for example nausea, chest 
pain), or disease temporally associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no Study treatment has been administered.
B 2
Definitions of serious adverse event
A serious adverse event is an AE occurring during any study phase (ie, run-in, treatment, 
washout, follow-up), that fulfils one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-participant hospitalisation or prolongation of existing hospitalisation 
!
Results in persistent or significant disability or incapacity. 
!
Is a congenital abnormality or birth defect
!
Is an important medical event that may jeopardise the participant or may require medical 
treatment to prevent one of the outcomes listed above.
Adverse Events (AEs) for malignant tumours reported during a study should generally be 
assessed as Serious AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ 
criterion should be used. In certain situations, however, medical judgement on an individual 
event basis should be applied to clarify that the malignant tumour event should be assessed 
and reported as a Non-Serious AE. For example, if the tumour is included as medical history 
and progression occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfil the attributes for being assessed as 
Serious, although reporting of the progression of the malignant tumour as an AE is valid and 
should occur. Also, some types of malignant tumours, which do not spread remotely after a 
routine treatment that does not require hospitalisation, may be assessed as Non-Serious; 
examples in adults include Stage 1 basal cell carcinoma and Stage 1A1 cervical cancer 
removed via cone biopsy.

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

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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 aetiology such 
as the underlying disease, other drugs, other host or environmental factors.
!
Re-challenge experience. Did the AE reoccur if the suspected drug was reintroduced after 
having been stopped? AstraZeneca would not normally recommend or support a re-
challenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship.
In difficult cases, other factors could be considered such as:
!
Is this a recognised feature of overdose of the drug?
!
Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case. The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.
The causality assessment is performed based on the available data including enough 

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

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

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Appendix C
Handling of Human Biological Samples
C 1
Chain of custody
A full chain of custody is maintained for all samples throughout their lifecycle.
The investigator at each centre keeps full traceability of collected biological samples from the 
participants while in storage at the centre until shipment or disposal (where appropriate) and 
records relevant processing information related to the samples 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.
C 2
Withdrawal of Informed Consent for donated biological samples 
If a participant withdraws consent to the use of donated biological samples, the samples will 
be disposed of/destroyed/repatriated, and the action documented. If samples are already 
analysed, AstraZeneca is not obliged to destroy the results of this research.
Following withdrawal of consent for biological samples, further study participation should be 
considered in relation to the withdrawal processes outlined in the informed consent.
The investigator:
!
Ensures participant’s withdrawal of informed consent to the use of donated samples is 
highlighted immediately to AstraZeneca or delegate.
!
Ensures that relevant human biological samples from that participant, if stored at the 
study site, are immediately identified, disposed of as appropriate, and the action 
documented
!
Ensures that the participant and AstraZeneca are informed about the sample disposal.
AstraZeneca ensures the organisation(s) holding the samples is/are informed about the 
withdrawn consent immediately and that samples are disposed of or repatriated as appropriate, 
and the action documented and study site notified.

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C 3
International Airline Transportation Association (IATA) 6.2 
Guidance Document
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES
International Airline Transportation Association (IATA) 
(https://www.iata.org/whatwedo/cargo/dgr/Pages/download.aspx) classifies infectious 
substances into 3 categories: Category A, Category B or Exempt
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals. 
Category A pathogens are (eg, Ebola, Lassa fever virus). Infectious substances meeting these 
criteria which cause disease in humans or both in humans and animals must be assigned to UN 
2814. Infectious substances which cause disease only in animals must be assigned to UN 
2900:
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A. Category B pathogens are (eg, hepatitis A, C, D, and E viruses). They 
are assigned the following UN number and proper shipping name
!
UN 3373 – Biological Substance, Category B
!
are to be packed in accordance with UN3373 and IATA 650
Exempt - Substances which do not contain infectious substances or substances which are 
unlikely to cause disease in humans or animals are not subject to these regulations unless they 
meet the criteria for inclusion in another class.
!
Clinical study samples will fall into Category B or exempt under IATA regulations.
!
Clinical study samples will routinely be packed and transported at ambient temperature in 
IATA 650 compliant packaging 
(https://www.iata.org/whatwedo/cargo/dgr/Documents/DGR-60-EN-PI650.pdf).
!
Biological samples transported in dry ice require additional dangerous goods specification 
for the dry-ice content.

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Appendix D
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
collection

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g this 
genetics research component, are outlined in Appendix A.

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Appendix E
Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law
E 1
Introduction
This Appendix describes the process to be followed in order to identify and appropriately 
report Potential Hy’s Law (PHL) cases and Hy’s Law (HL) cases. It is not intended to be a 
comprehensive guide to the management of elevated liver biochemistries. 
During the course of the study, the investigator will remain vigilant for increases in liver 
biochemistry. The investigator is responsible for determining whether a 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 total 
bilirubin (TBL) from a local laboratory. 
The investigator will also review Adverse Event data (for example, for AEs that may indicate 
elevations in liver biochemistry) for possible PHL events.
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether Hy’s Law (HL) criteria 
are met. HL criteria are met if there is no alternative explanation for the elevations in liver 
biochemistry other than drug induced liver injury (DILI) caused by the investigational 
medicinal product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting serious adverse events (SAEs) and adverse events (AEs) according to the outcome 
of the review and assessment in line with standard safety reporting processes.
E 2
Definitions
Potential Hy’s Law (PHL)
Aspartate transaminase (AST) or alanine transaminase (ALT) ≥ 3x upper Limit of Normal 
(ULN) together with TBL ≥ 2x ULN at any point during the study following the start of study 
medication irrespective of an increase in alkaline phosphatase (ALP).
Hy’s Law (HL)
AST or ALT ≥ 3x ULN together with TBL ≥ 2x ULN, where no other reason, other than the 
investigational medicinal product, can be found to explain the combination of increases, eg,
elevated ALP indicating cholestasis, viral hepatitis, another drug. 

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For PHL and HL the elevation in transaminases must precede or be coincident with (ie, on the 
same day) the elevation in TBL, but there is no specified time frame 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 ≥ 3x ULN
!
AST ≥ 3x ULN
!
TBL ≥ 2x ULN
Central laboratories being used:
When a participant meets any of the PHL identification criteria, in isolation or in combination, 
the central laboratory will immediately send an alert to the investigator (also sent to 
AstraZeneca representative). 
The investigator will also remain vigilant for any local laboratory reports where the PHL 
identification criteria are met, where this is the case the investigator will:
!
Notify the AstraZeneca representative
!
Request a repeat of the test (new blood draw) by the central laboratory without delay
!
Complete the appropriate unscheduled laboratory eCRF module(s) with the original local 
laboratory test result
When the identification criteria are met from central or local laboratory results the investigator
will without delay:
!
Determine whether the participant meets PHL criteria (see Section E 2 for definition) by 
reviewing laboratory reports from all previous visits (including both central and local 
laboratory results)
Local laboratories being used:
The investigator will without delay review each new laboratory report and if the identification 
criteria are met will:
!
Notify the AstraZeneca representative

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!
Determine whether the participant meets PHL criteria (see Section E 2 Definitions within 
this Appendix for definition) by reviewing laboratory reports from all previous visits
!
Promptly enter the laboratory data into the laboratory eCRF
E 4
Follow-up
E 4.1
Potential Hy’s Law Criteria not met
If the participant does not meet PHL criteria the investigator will:
!
Inform the AstraZeneca representative that the participant has not met PHL criteria
!
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the clinical study protocol.
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 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to the clinical study protocol process for SAE reporting.
!
For participants that met PHL criteria prior to starting investigational medicinal product, 
the investigator is not required to submit a PHL SAE unless there is a significant change#
in the participant’s condition
!
The study physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study participants’ follow-up (including any further laboratory testing) 
and the continuous review of data
!
Subsequent to this contact the investigator will:
#
Monitor the participant until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required.
#
Investigate the aetiology of the event and perform diagnostic investigations as 
discussed with the study physician. This includes deciding which tests available in 
the Hy’s law lab kit should be used.
#
Complete the three Liver eCRF Modules as information becomes available 

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#A ‘significant’ change in the participant’s condition refers to a clinically relevant change in 
any of the individual liver biochemistry parameters (ALT, AST, or total bilirubin) in isolation 
or in combination, or a clinically relevant change in associated symptoms. The determination 
of whether there has been a significant change will be at the discretion of the investigator, this 
may be in consultation with the study physician if there is any uncertainty.
E 5
Review and Assessment of Potential Hy’s Law Cases
The instructions in this Section should be followed for all cases where PHL criteria are met.
As soon as possible after the biochemistry abnormality was initially detected, the study 
physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than drug-induced liver 
injury (DILI) caused by the investigational medicinal product, to ensure timely analysis and 
reporting to health authorities within 15 calendar days from date PHL criteria was met. The 
AstraZeneca Global Clinical Lead or equivalent and Global Safety Physician will also be 
involved in this review together with other subject matter experts as appropriate. 
According to the outcome of the review and assessment, the investigator will follow the 
instructions below.
Where there is an agreed alternative explanation for the ALT or AST and TBL elevations, a 
determination of whether the alternative explanation is an AE will be made and subsequently 
whether the AE meets the criteria for a SAE:
!
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate eCRF
!
If the alternative explanation is an AE/SAE: update the previously submitted PHL SAE 
and AE eCRFs accordingly with the new information (reassessing event term; causality 
and seriousness criteria) following the AstraZeneca standard processes.
If it is agreed that there is no explanation that would explain the ALT or AST and TBL 
elevations other than the investigational medicinal product:
!
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.

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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 investigational medicinal 
product and seriousness criteria is medically important, according to the clinical study 
protocol 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 the clinical study protocol process for SAE reporting, according to the outcome 
of the review and amending the reported term if an alternative explanation for the liver 
biochemistry elevations is determined.
E 6
Laboratory tests
Hy’s Law lab kit for central laboratories 
Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Viral hepatitis
IgM anti-HAV 
IgM and IgG anti-HBc
HBsAg
HBV DNAa
IgG anti-HCV
HCV RNAa
IgM anti-HEV
HEV RNA
Other viral infections
IgM & IgG anti-CMV
IgM & IgG anti-HSV
IgM & IgG anti-EBV
Alcoholic hepatitis
Carbohydrate deficient transferrinb
Autoimmune hepatitis
Antinuclear antibody 
Anti-Liver/Kidney Microsomal Ab 
Anti-Smooth Muscle Ab
Metabolic diseases
Alpha-1-antitrypsin
Ceruloplasmin
Iron
Ferritin
Transferrinb

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Additional standard chemistry and coagulation 
tests
GGT
LDH
Prothrombin time
INR
Transferrin saturation
Ab = antibody; ANA = antinuclear antibody; anti-LKM = anti-liver/kidney microsomal; ASMA = anti-smooth 
muscle antibody; CD = carbohydrate deficient; CMV = cytomegalovirus; EBV = Epstein-Barr virus; 
GGT = gamma-glutamyl transferase; HAV = hepatitis A virus; HBc = hepatitis B core; HBsAg = hepatitis B 
surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HEV = hepatitis E virus; HSV = herpes 
simplex virus; Ig = immunoglobulin; INR = international normalised ratio; LDH = lactate dehydrogenase
a
HCV RNA; HCV DNA are only tested when IgG anti-HCV is positive or inconclusive.
b
CD-transferrin and Transferrin are not available in China. Study teams should amend this list accordingly.
E 7
References
Aithal et al, 2011
Aithal et al 2011, Clinical Pharmacology and Therapeutics 89(6):806-815.
FDA Guidance for Industry, July 2009
FDA Guidance for Industry (issued July 2009) ‘Drug-induced liver injury: Premarketing 
clinical evaluation’. Available from; https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/drug-induced-liver-injury-premarketing-clinical-evaluation

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Appendix F
Abbreviations
Abbreviation or special 
term
Explanation
ACE
angiotensin-converting enzyme
ADA
anti-drug antibody
AE
adverse event
AKI
acute kidney injury
ALP
alkaline phosphatase
ALT
alanine transaminase
ANCOVA
analysis of covariance
AST
aspartate transaminase
AUC
area under the concentration-time curve
CEA
clinical event adjudication
CGM
continuous glucose monitoring
CKD
chronic kidney disease
CKD-EPI
chronic kidney disease-epidemiology collaboration
Cmax
maximum observed concentration
COVID-19
coronavirus disease
CrCl
creatinine clearance
CSR
clinical study report
CV
cardiovascular
DBP
diastolic blood pressure
DILI 
drug-induced liver injury
DPP-4
dipeptidyl peptidase-4
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
eGFR
estimated glomerular filtration rate
GCP
Good Clinical Practice
GLP-1
glucagon-like peptide 1
GFR
glomerular filtration rate
HbA1c
haemoglobin A1c
HL
Hy’s law
IATA
International Airline Transportation Association
ICH
International Council for Harmonisation

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Abbreviation or special 
term
Explanation
ICF
informed consent form
IRB/IEC
Institutional Review Board/Independent Ethics Committee
IVRS
interactive voice response system
IWRS
interactive web response system
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
NASH
nonalcoholic steatohepatitis
NOAEL
no observed adverse effect level
PHL
potential Hy’s law
PK
pharmacokinetic(s)
SAE
serious adverse event 
SAP
statistical analysis plan
SBP
systolic blood pressure
SC
subcutaneous(ly)
SD
standard deviation
SGLT2
sodium-glucose cotransporter 2 
SmPC
Summary of Product Characteristics
SoA
schedule of activities
T1DM
type 1 diabetes mellitus
T2DM
type 2 diabetes mellitus
TBL
total bilirubin
UACR
urine albumin to creatinine ratio
ULN
upper limit of normal
URC
Unblinded Review Committee

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Appendix G
Summary of Changes
G 1
Amendment 01 (29Jun2020)
Overall Rationale for the Amendment:
This global amendment contains revisions to the original global protocol dated (01Apr2020) 
to remove Cohort 2, which is no longer needed due to completion of Study D5671C00003 
earlier than originally planned. Other minor revisions such as clarifications and correction of 
typos were made. This amendment is considered to be non-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 because it neither significantly impacts the safety or physical/mental 
integrity of participants nor the scientific value of the study. Changes in global amendment 1 
are presented in the table below.
Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
Title page, 1.1 (Synopsis: 
Intervention 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 (Synopsis: Overall Design), 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
1.1 (Synopsis: Statistical 
Methods), 4.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 questionnaires 
 
 

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Section # and Name
Description of Change
Brief Rationale
Substantial/
Non-substantial
3 (Objectives and 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11
REFERENCES
Bailly C, Roinel N, Amiel C. Stimulation by glucagon and PTH of Ca and Mg reabsorption in 
the superficial distal tubule of the rat kidney. Pflugers Arch. 1985;403(1):28-34.
Bloomgarden Z. The kidney and cardiovascular outcome trials. J Diabetes. 2018;10(2):88-9.
Center for Drug Evaluation and Research. Byetta Pharmacology Review. 2005a.
Center for Drug Evaluation and Research. Byetta (Exenatide) Injection Pharmacology Review 
2005b [updated 20 April 2005]. Available from: 
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2005/021773_Byetta_pharmr.PDF. 
Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic 
steatohepatitis: Current knowledge and implications for management. World J Hepatol. 
2017;9(11):533-43.
GBD 2015 Mortality Causes of Death Collaborators. Global, regional, and national life 
expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-
2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet. 
2016;388(10053):1459-544.
Heerspink HJL, Greene T, Tighiouart H, Gansevoort RT, Coresh J, Simon AL, et al. Change 
in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of 
treatment effects in randomised clinical trials. Lancet Diabetes Endocrinol. 2019;7(2):128-39.
Hill NR, Fatoba ST, Oke JL, Hirst JA, O'Callaghan CA, Lasserson DS, et al. Global 
Prevalence of Chronic Kidney Disease - A Systematic Review and Meta-Analysis. PLoS One. 
2016;11(7):e0158765.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, et al. Semaglutide and 
Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 
2016a;375(19):1834-44.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, et al. 
Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 
2016b;375(4):311-22.
National Institute of Diabetes and Digestive and Kidney Diseases. Causes of Chronic Kidney 
Disease 2016. Available from: https://www.niddk.nih.gov/health-information/kidney-
disease/chronic-kidney-disease-ckd/causes. 
National Kidney Foundation. Diabetes and Chronic Kidney Disease 2016. Available from: 
https://www.kidney.org/news/newsroom/factsheets/Diabetes-And-CKD. 
Skov J. Effects of GLP-1 in the kidney. Rev Endocr Metab Disord. 2014;15(3):197-207.

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Tuttle KR, Lakshmanan MC, Rayner B, Busch RS, Zimmermann AG, Woodward DB, et al. 
Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe 
chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet 
Diabetes Endocrinol. 2018;6(8):605-17.
World Health Organization. The Top 10 Causes of Death 2018 [updated 24 May 2018]. 
Available from: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-
death. 

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Document Name: d5676c00001-csp-v3
Document Title:
D5676C00001 Clinical Study Protocol version 3
Document ID:
Doc ID-004183309
Version Label:
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Server Date
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Victoria Parker
Author Approval
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