Clinical trial NCT04170543
Conditions: Diabetic Kidney Disease
Sponsor: AstraZeneca
Start date: 2019-11-18; Completion date: 2023-05-16
Enrollment: 609 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2b Randomized, Double-blind, Placebo-controlled, Study to Evaluate the Efficacy and Safety of MEDI3506 in Subjects with Diabetic Kidney Disease

Detailed description:
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 on top of standard of care, including angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and dapagliflozin in adult subjects with diabetic kidney disease, defined as subjects with type 2 diabetes mellitus (T2DM) and an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2 with a UACR in the range of 100-3000 mg/g, who meet all eligibility criteria. Approximately 565 subjects, among multiple countries will be randomized to MEDI3506 dose 1, 2, 3 or dose 4, or placebo during a treatment period of 24 weeks. All subjects will receive Dapagliflozin daily, as administered orally from Day 85 to Day 168. The primary objective is to evaluate the effect of MEDI3506 on albuminuria in subjects with DKD. Secondary objectives include evaluating safety, PK and the incidence of ADA during the treatment period.

Arms: arm 1: MEDI3506 Dose 1 plus Dapagliflozin (Day 85 to Day 168). arm 2: MEDI3506 Dose 2 plus Dapagliflozin (Day 85 to Day 168). arm 3: MEDI3506 Dose 3 plus Dapagliflozin (Day 85 to Day 168). arm 4: MEDI3506 Dose 4 plus Dapagliflozin (Day 85 to Day 168). arm 5: Placebo (volume matched) plus Dapagliflozin (Day 85 to Day 168).
Interventions: intervention 1: MEDI3506 intervention 2: Placebo intervention 3: Dapagliflozin
Intervention descriptions: intervention 1: Dose 1, Dose 2, Dose 3, Dose 4 intervention 2: Placebo intervention 3: Dapagliflozin 10 mg

Protocol documents:
Prot_000.pdf: 
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A Phase 2b Randomized, Double-blind, Placebo-controlled, Study 
to Evaluate the Efficacy and Safety of MEDI3506 in Subjects with 
Diabetic Kidney Disease
Sponsor Protocol Number: D9183C00001 
Application Number:
IND 145520 
NCT 04170543 
Investigational Product:
MEDI3506 
Sponsor:
AstraZeneca AB, SE-151 85, Södertälje, Sweden 
(Japan) AstraZeneca K.K., 3-1, Ofuka-cho, Kita-ku Osaka 
530-0011, Japan
Contract Research Organization: Covance 
Protocol History, Date: 
Original Protocol, 13Sep2019 
Amendment 1, 18Feb2020 
Amendment 2, 30Jul2020 
Amendment 3, 29Mar2021 
Amendment 4, 13Oct2021 
Amendment 5, 14Feb2022 
This document contains trade secrets and commercial information that is privileged or 
confidential and may not be disclosed without prior authorization from AstraZeneca. 
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Redacted for Public Disclosure
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TARGET SUBJECT POPULATION 
$GXOWPHQRUZRPHQ\HDUVRIDJHZLWK7'0DQGDQH*)5YDOXHRI-75 mL/min/1.73 m2 with a 
UACR of 100 - 3000 mg/g. 
 
 
• 
Group 1: MEDI3506 30 mg (0.2 mL), n = 95 
• 
Group 2: MEDI3506 60 mg (0.4 mL), n = 95 
• 
Group 3: MEDI3506 120 mg (0.8 mL), n = 95 
• 
Group 4: MEDI3506 300 mg (2 mL), n = 140 
• 
Group 5: Placebo (0.2 mL), n = 32 
• 
Group 6: Placebo (0.4 mL), n = 32 
• 
Group 7: Placebo (0.8 mL), n = 32 
• 
Group 8: Placebo (2 mL), n = 44 
All subjects will also receive 10 mg dapagliflozin by mouth daily starting on Day 85 until Day 168. Subjects 
already taking a sodium-glucose cotransporter-2 inhibitor (SGLT2i) will be rolled over to 10 mg 
dapagliflozin. Subjects who have completed 12 weeks of treatment prior to approval of Amendment 2 will 
continue on treatment with MEDI3506/placebo without dapagliflozin. 
STATISTICAL METHODS 
Sample size: A sample size of 565 subjects randomized using a 95:95:95:140:140 ratio to receive either 30, 
60 mg, 120 mg, or 300 mg MEDI3506 or matching placebo will give approximately 85:85:85:125:125 
evaluable subjects per group. This will provide at least 85% power for the 300 mg arm and 80% power for the 
30, 60, and 120 mg arms to detect a 30% reduction in change from baseline to Day 169 (Week 24) in UACR 
between each MEDI3506 treatment group and placebo group (or placebo/MEDI3506 ratio of 1.429) with a 
one-sided alpha of 0.05 without multiplicity adjustment, assuming a coefficient of variation of 1.31 or 
standard deviation of 1.0 in log scale. 
Statistical analyses: The primary efficacy analysis of change from baseline to Day 169 (Week 24) in UACR 
compared to placebo (on treatment with dapagliflozin as standard of care) will be based on the Per Protocol 
Population. UACR will be log-transformed and analyzed using mixed model repeated measures (MMRM) 
method adjusting for fixed categorical effects of treatment, visit, and treatment-by-visit interaction, 
randomization stratification factors, and the continuous covariates of baseline log UACR and baseline log 
UACR-by-visit interaction. An unstructured covariance structure may be used to model the within-subject 
errors. The primary efficacy endpoint will also be analyzed using an analysis of covariance adjusting for 
treatment, randomization stratification factors, and baseline log UACR with last-observation-carried-forward 
(LOCF) imputation for missing post-baseline measurements. 
The secondary efficacy analysis of change from baseline to Day 85 (Week 12) in UACR and change from 
Day 85 (Week 12) to Day 169 (Week 24) in UACR will be analyzed similarly to that of the primary efficacy 
analysis and be based on the Full Analysis Population and Per Protocol Population, respectively. For the 
proportions of subjects with > 30%, > 40%, and > 50% reduction in UACR, logistic regression models will be 
used, adjusting for treatment, randomization stratification factors, and baseline albuminuria status based on 
the Full Analysis Population and the Per Protocol Population. 
Safety analysis will be based on the Safety Analysis Population. AE collection will begin after the subject 
signs the informed consent form and lasts until the end of the study. AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) by system organ class (SOC) and preferred term (PT). 
Specific AEs will be counted once for each subject for calculating rates, but will be presented in total in 
subject listings. In addition, if the same AE occurs multiple times within a particular subject, the highest 
severity and level of causality will be reported. All TEAEs will be summarized overall and by MedDRA SOC 
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and PT, by severity and relationship to investigational product. All TEAEs related to dapagliflozin will also 
be summarized. In addition, summaries of deaths, SAEs, and treatment discontinuations due to TEAEs will be 
provided. Injection-site reactions will be presented. 
Clinical laboratory safety tests including serum chemistry and hematology parameters will be summarized 
using descriptive statistics at each time point by treatment group. Change from baseline to each post baseline 
time point in these data will also be summarized, where appropriate. A shift table will be provided for these 
clinical laboratory parameters as well, where possible. 
Vital signs, echocardiogram, ECGs, and BNP will be summarized using descriptive statistics at each time 
point by treatment group. 
The incidence rate of positive antibodies to MEDI3506 and ADA titer will be reported by treatment group. 
Samples confirmed positive for ADA will be tested and analyzed for neutralizing antibodies (nAbs) and 
summarized similarly. 
MEDI3506 serum concentration time profiles will be summarized for MEDI3506-treated subjects by dose 
cohort. Dapagliflozin concentration time profiles will also be summarized for dapagliflozin-treated subjects. 
Exploratory endpoints will be summarized by treatment group. 
 
 
 
Safety monitoring: An independent Data and Safety Monitoring Board has been formed to evaluate safety 
data. 
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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS .......................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................. 11 
1 
INTRODUCTION ................................................................................................ 14 
1.1 
Disease Background ............................................................................................. 14 
1.2 
MEDI3506 Background ....................................................................................... 14 
1.3 
Dapagliflozin Background .................................................................................... 15 
1.4 
Summary of Nonclinical Experience .................................................................... 15 
1.4.1 
MEDI3506 ............................................................................................................ 15 
1.4.2 
Dapagliflozin ........................................................................................................ 16 
1.5 
Summary of Clinical Experience .......................................................................... 16 
1.5.1 
MEDI3506 ............................................................................................................ 16 
1.5.2 
Dapagliflozin ........................................................................................................ 17 
1.6 
Rationale for Conducting the Study ..................................................................... 17 
1.7 
Benefit-risk and Ethical Assessment .................................................................... 18 
1.7.1 
MEDI3506 ............................................................................................................ 18 
1.7.2 
Dapagliflozin ........................................................................................................ 19 
1.7.3 
Other Risks ........................................................................................................... 20 
1.7.4 
Overall Benefit/Risk Conclusion .......................................................................... 21 
1.8 
Research Hypotheses ............................................................................................ 21 
1.8.1 
Primary Hypothesis .............................................................................................. 21 
1.8.2 
Secondary Hypotheses .......................................................................................... 21 
2 
OBJECTIVES AND ENDPOINTS ...................................................................... 21 
2.1 
Primary Objective and Associated Endpoint ........................................................ 21 
2.2 
Secondary Objectives and Associated Endpoints ................................................. 21 
 
 
3 
STUDY DESIGN ................................................................................................. 24 
3.1 
Description of the Study ....................................................................................... 24 
3.1.1 
Overview .............................................................................................................. 24 
3.1.2 
Treatment Regimen .............................................................................................. 26 
3.1.3 
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................. 26 
3.2 
Rationale for Dose, Population, and Endpoints .................................................... 27 
3.2.1 
Dose Rationale ...................................................................................................... 27 
3.2.2 
Rationale for Study Population ............................................................................. 27 
3.2.3 
Rationale for Endpoints ........................................................................................ 27 
4 
MATERIALS AND METHODS ......................................................................... 28 
4.1 
Subjects ................................................................................................................. 28 
4.1.1 
Number of Subjects .............................................................................................. 28 
4.1.2 
Inclusion Criteria .................................................................................................. 28 
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4.6.3.1 
Unblinding in the Event of a Medical Emergency ............................................... 56 
4.6.3.2 
Unblinding for DSMB Purposes ........................................................................... 56 
4.6.3.3 
Unblinding for Interim Analysis Purposes ........................................................... 56 
4.7 
Restrictions During the Study and Concomitant Treatment(s) ............................ 57 
4.7.1 
Permitted Concomitant Medications .................................................................... 57 
4.7.2 
Prohibited Concomitant Medications ................................................................... 57 
4.7.3 
Considerations for SGLT2i and RAASi ............................................................... 58 
4.7.4 
Vaccination Against COVID-19 .......................................................................... 60 
4.8 
Statistical Evaluation ............................................................................................ 60 
4.8.1 
General Considerations ......................................................................................... 60 
4.8.2 
Sample Size .......................................................................................................... 61 
4.8.3 
Efficacy ................................................................................................................. 61 
4.8.3.1 
Primary Efficacy Analysis .................................................................................... 61 
4.8.3.2 
Secondary Efficacy Analysis ................................................................................ 62 
4.8.3.3 
Exploratory Analyses ........................................................................................... 62 
4.8.3.4 
Subgroup Analyses ............................................................................................... 62 
4.8.3.5 
Sensitivity Analysis .............................................................................................. 63 
4.8.4 
Safety .................................................................................................................... 63 
4.8.4.1 
Analysis of Adverse Events .................................................................................. 63 
4.8.4.2 
Analysis of Clinical Laboratory Parameters ......................................................... 63 
4.8.4.3 
Analysis of Vital Signs and ECGs ........................................................................ 63 
4.8.4.4 
Other Safety Endpoints ......................................................................................... 63 
4.8.5 
Analysis of Immunogenicity/Pharmacokinetics ................................................... 63 
4.8.6 
Data and Safety Monitoring Board ....................................................................... 64 
 
 
5 
ASSESSMENT OF SAFETY .............................................................................. 65 
5.1 
Definition of Adverse Events ............................................................................... 65 
5.2 
Definition of Serious Adverse Events .................................................................. 65 
5.3 
Definition of Adverse Events of Special Interest ................................................. 65 
5.4 
Recording of Adverse Events ............................................................................... 66 
5.4.1 
Time Period for Collection of Adverse Events..................................................... 66 
5.4.2 
Follow-up of Unresolved Adverse Events ............................................................ 66 
5.4.3 
Deaths ................................................................................................................... 67 
5.4.4 
Adverse Events Based on Signs and Symptoms .................................................. 67 
5.4.5 
Adverse Events Based on Examination and Tests ................................................ 67 
5.4.6 
Hy’s Law .............................................................................................................. 68 
5.4.7 
Disease Progression .............................................................................................. 68 
5.4.8 
Disease under Study ............................................................................................. 68 
5.5 
Reporting of Serious Adverse Events ................................................................... 68 
5.6 
Other Events Requiring Immediate Reporting ..................................................... 69 
5.6.1 
Overdose ............................................................................................................... 69 
5.6.2 
Pregnancy ............................................................................................................. 70 
5.6.2.1 
Maternal Exposure ................................................................................................ 70 
5.6.2.2 
Paternal Exposure ................................................................................................. 71 
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5.6.3 
Medication Error ................................................................................................... 71 
6 
STUDY AND DATA MANAGEMENT ............................................................. 72 
6.1 
Training of Study Site Personnel .......................................................................... 72 
6.2 
Monitoring of the Study ....................................................................................... 72 
6.2.1 
Source Data ........................................................................................................... 73 
6.2.2 
Study Agreements ................................................................................................. 73 
6.2.3 
Archiving of Study Documents ............................................................................ 73 
6.3 
Study Timetable and End of Study ....................................................................... 73 
6.4 
Data Management ................................................................................................. 74 
6.5 
Medical Monitor Coverage ................................................................................... 74 
7 
ETHICAL AND REGULATORY REQUIREMENTS ....................................... 74 
7.1 
Subject Data Protection ........................................................................................ 74 
7.2 
Ethics and Regulatory Review ............................................................................. 75 
7.3 
Informed Consent ................................................................................................. 75 
7.4 
Changes to the Protocol and Informed Consent Form ......................................... 76 
7.5 
Audits and Inspections .......................................................................................... 76 
8 
REFERENCES ..................................................................................................... 77 
9 
CHANGES TO THE PROTOCOL ...................................................................... 80 
9.1 
Protocol Amendment 5 ......................................................................................... 80 
9.2 
Protocol Amendment 4 ......................................................................................... 81 
9.3 
Protocol Amendment 3 ......................................................................................... 85 
9.4 
Protocol Amendment 2 ......................................................................................... 87 
9.5 
Protocol Amendment 1 ......................................................................................... 93 
 
LIST OF TABLES 
Table 1 
Primary Objective and Associated Endpoint .............................................. 21 
Table 2 
Secondary Objectives and Associated Endpoints ....................................... 21 
 
 
Table 4 
Guidelines for Handling Missed Doses of MEDI3506 ............................... 35 
Table 5 
Schedule of Screening Procedures .............................................................. 37 
Table 6 
Schedule of Treatment Period Study Procedures ........................................ 39 
Table 7 
Schedule of Follow-up Procedures ............................................................. 42 
Table 8 
Estimate of Blood Volumes ........................................................................ 48 
 
 
 
 
Table 11 
Study Populations ........................................................................................ 61 
Table C1 
Hy’s Law Laboratory Kit for Central Laboratories .................................. 107 
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LIST OF FIGURES 
Figure 1 
Study Flow Diagram ................................................................................... 25 
 
LIST OF APPENDICES 
Appendix A 
Additional Safety Guidance ........................................................................ 98 
Appendix B 
National Institute of Allergy and Infectious Diseases and Food Allergy 
and Anaphylaxis Network Guidance for Anaphylaxis Diagnosis ............. 102 
Appendix C 
Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ............................................................................ 103 
Appendix D 
Genetic Research ....................................................................................... 108 
Appendix E 
Patient Treatment Guidelines .................................................................... 111 
Appendix F 
COVID-19 Specifics ................................................................................. 112 
Appendix G 
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis .............................. 115 
 


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LIST OF ABBREVIATIONS 
Abbreviation or 
Specialized Term 
Definition 
ACEi 
angiotensin converting enzyme inhibitors 
ADA 
anti-drug antibodies 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
anti-HBc 
antibody to hepatitis B core antigen 
ARB 
angiotensin receptor blockers 
AST 
aspartate aminotransferase 
AUC 
area under the concentration-time curve 
BMI 
body mass index 
 
 
BP 
blood pressure 
CKD 
chronic kidney disease 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
Cmax 
maximum observed concentration 
COPD 
chronic obstructive pulmonary disease 
CSP 
clinical study protocol 
CSR 
clinical study report 
CYP450 
cytochrome P450 
DILI 
drug-induced liver injury 
DKA 
diabetic ketoacidosis 
DKD 
diabetic kidney disease 
DM 
diabetes mellitus 
DSMB 
Data and Safety Monitoring Board 
DUS 
disease under study 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EMA 
European Medicines Agency 
EOS 
end of study 
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Abbreviation or 
Specialized Term 
Definition 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
Good Manufacturing Practice 
GOLD 
Global Initiative for Chronic Obstructive Lung Disease 
Hb 
hemoglobin 
HBsAg 
hepatitis B surface antigen 
HCP 
Healthcare Professional 
HIV 
human immunodeficiency virus 
HL 
Hy’s Law 
 
 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
Ig 
immunoglobulin 
IL 
interleukin 
IRB 
Institutional Review Board 
IV 
intravenous 
IXRS 
interactive voice/web response system 
LSLV 
last subject last visit 
LV 
left ventricular 
 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
mixed model repeated measures 
mAb 
monoclonal antibody 
nAb 
neutralizing antibody 
NOAEL 
no observed adverse effect level 
PD 
pharmacodynamic 
PEF 
peak expiratory flow 
PHL 
Potential Hy’s Law 
PK 
pharmacokinetic(s) 
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Abbreviation or 
Specialized Term 
Definition 
PT 
preferred term 
QW 
once every week 
Q2W 
every 2 weeks 
Q28D 
every 28 days 
RAASi 
renin-angiotensin aldosterone system inhibitors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SGLT2 
sodium-glucose cotransporter-2 
SGLT2i 
sodium-glucose cotransporter-2 inhibitor(s) 
SID 
subject identification 
SOC 
system organ class 
SOP 
standard operating procedure 
 
 
T1DM 
type 1 diabetes mellitus 
T2DM 
type 2 diabetes mellitus 
TB 
tuberculosis 
TBL 
total bilirubin 
TEAE(s) 
treatment-emergent adverse event(s) 
TESAE(s) 
treatment-emergent serious adverse event(s) 
 
 
 
 
TPV 
third-party vendor 
UACR 
urine albumin:creatinine ratio 
ULN 
upper limit of normal 
URC 
unblinded review committee 
USA 
United States of America 
WOCBP 
women of childbearing potential 
 
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1 
INTRODUCTION 
1.1 
Disease Background 
Chronic kidney disease (CKD) secondary to diabetes mellitus (DM) is known as diabetic 
kidney disease (DKD), and is a worldwide public health problem associated with high levels 
of morbidity and mortality; DM is the leading cause of end-stage renal disease (Koye et al, 
2018; Mills et al, 2015). In 2017, 425 million people had DM, of whom 20% to 40% have or 
will develop DKD (International Diabetes Federation, 2017). Between 1990 and 2010, the 
number of deaths due to DKD increased by 94% (Lozano-Maneiro and Puente-Garcia, 2015). 
Current guidelines recommend the use of renin-angiotensin aldosterone system inhibitors 
(RAASi), such as angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor 
blockers (ARB), and sodium–glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) for risk 
management in patients with DKD (ADA, 2020). While RAASi have been the standard of 
care in DKD for decades, the full risk/benefit profile of SGLT2i is still emerging (Neuen et al, 
2019). 
However, the pathophysiology of DKD is multifactorial, with both hemodynamic effects and 
inflammation, which is not addressed by current standard of care, contributing to disease 
progression (Hickey and Martin, 2018). Inflammatory pathways in DKD are mediated through 
infiltrating immune cells and proinflammatory cytokines, chemokines, and adhesion 
molecules (Hickey and Martin, 2018). Accumulating evidence supports the hypothesis that the 
activation of inflammatory molecules and pathways mediates the instigation and progression 
of DKD (Alicic et al, 2017; Alicic et al, 2018). 
Interleukin (IL)-33 is an “alarmin” cytokine that is constitutively expressed in endothelial and 
epithelial barrier surfaces. When released in response to stimuli such as infection, mechanical 
stress, or cell death, IL-33 serves to augment the innate and adaptive immune response. 
Released IL-33 binds to its receptor, ST2, inducing activation of downstream inflammatory 
pathways (Chen et al, 2017). Inappropriate persistence and skewing of the immune response 
has been hypothesized to induce glomerular and tubulointerstitial inflammation and fibrosis 
leading to progressive loss of kidney function (Alicic et al, 2018; Chen et al, 2017; Navarro-
Gonzalez and Mora-Fernandez, 2008). 
 
 
 
1.2 
MEDI3506 Background 
MEDI3506 is a human immunoglobulin (Ig) G1 monoclonal antibody (mAb) that binds to 
human IL-33, prevents binding of IL-33 to its receptor ST2, and inhibits conversion to 
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disulfide-bonded IL-33. Through this dual mechanism of action, MEDI3506 has the potential 
to slow progression of DKD, a widespread and potentially fatal condition. 
Refer to the current MEDI3506 Investigator’s Brochure (IB) (Edition 5.2) for details.  
1.3 
Dapagliflozin Background 
Dapagliflozin (FORXIGA) is a highly potent, selective, and reversible inhibitor of SGLT2 
that improves glycemic control in patients with DM and provides cardio-renal benefits in 
patients with T2DM and without diabetes. As of October 2021, dapagliflozin is approved in 
more than 100 countries to treat T2DM, 100 countries for heart failure indications, and 51 
countries for chronic kidney disease indications. Dapagliflozin is commercially available as 
5 mg and 10 mg tablet formulations to be taken once daily. Dapagliflozin has a 
well-established safety profile across indications. 
Refer to the current dapagliflozin IB (Edition 17) for details.  
1.4 
Summary of Nonclinical Experience 
1.4.1 
MEDI3506 
Nonclinical pharmacology studies demonstrated that MEDI3506 binds human IL-33 
specifically and with high affinity. In addition, in vitro and in vivo studies have demonstrated 
the mechanism of action of MEDI3506. Nonclinical pharmacokinetic (PK) characteristics 
were established in cynomolgus monkeys following single, subcutaneous (SC) administration 
in a non-Good Laboratory Practice (GLP) study, and following repeat SC or intravenous (IV) 
administration in 4- and 26-week GLP studies. In the single-dose study, MEDI3506 exhibited 
linear PK at the tested doses. In the repeat-dose toxicology studies, MEDI3506 mean 
maximum observed concentration (Cmax) and area under the concentration-time curve (AUC) 
values after SC dosing generally increased in a dose proportional manner from 
 to 
 mg/kg. Slight accumulation (mean accumulation ratios were 
 to 
) of MEDI3506 
was observed after multiple SC or IV doses after  or 
 weeks of dosing. 
The potential toxicity of MEDI3506 was evaluated in 2 repeat-dose studies. In a repeat-dose 
GLP toxicity study in cynomolgus monkeys following SC or IV administration every week 
(QW) for  weeks (5 doses in total), there were no adverse MEDI3506-related findings noted. 
The no observed adverse effect level (NOAEL) at the highest doses tested was 
 mg/kg via 
SC injection and 
 mg/kg via IV injection. At the NOAEL for the SC and IV routes, mean 
MEDI3506 Cmax values were 
 and 
 μg/mL, respectively, and mean area under the 
concentration-time curve from 0 to 
 days (AUC0-31d) values were 
 and 
ȝJ × day/mL, respectively. In a GLP 
-week, repeat-dose toxicity study in sexually 
mature cynomolgus monkeys, MEDI3506 was administered QW via SC injection at 
 or 
 mg/kg for 
 weeks and compared with vehicle control. No MEDI3506-related adverse 
effects were observed. One mid-dose female was pre-terminally euthanized on Day 
 due to 
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poor and deteriorating condition, and was noted as having necrotizing, ulcerative colitis with 
peritonitis and bacteremia at necropsy. In the absence of similar findings in other animals 
treated with equal or higher doses of MEDI3506, this was considered an incidental finding. 
Based on the results of this study, the NOAEL was considered to be the highest dose of 
mg/kg/week, corresponding to mean Cmax and AUC from 0 to 7 days (AUC0-7d) values of 
 ȝJP/DQG
 ȝJ × day/mL, respectively, on Day
. 
Refer to the current MEDI3506 IB (Edition 5.2) for further details.  
1.4.2 
Dapagliflozin 
Refer to the dapagliflozin IB (Edition 17) for a summary of nonclinical experience with 
dapagliflozin. 
1.5 
Summary of Clinical Experience 
1.5.1 
MEDI3506 
One Phase 1 clinical study of MEDI3506 (Study D9180C00001) has closed and Phase 2 
studies in atopic dermatitis (Study D9182C00001), asthma (Study D9181C00001), and 
chronic obstructive pulmonary disease (COPD) (Study D9180C00002) are ongoing. Two 
Phase 3 studies in COPD have started (Studies D9180C00003 and D9180C00004). 
Study D9180C00001 was a Phase 1, first-time-in-human, randomized, blinded (investigator 
and subject blinded; sponsor unblinded), placebo-controlled clinical study to evaluate the 
safety, tolerability, PK, and immunogenicity of single and repeated doses of MEDI3506. The 
study entailed 3 parts. Part I involved single ascending dose administration of MEDI3506, 
either SC or IV to healthy adult subjects with a history of mild atopy; Part II involved multiple 
ascending dose administration of MEDI3506 SC to adult subjects with Global Initiative for 
Chronic Obstructive Lung Disease (GOLD) I to II COPD; Part III involved single dose 
administration of MEDI3506 IV to healthy adult Japanese subjects.  
In healthy subjects with a history of mild atopy in Part I of the study, a similar proportion of 
subjects experienced at least 1 treatment-emergent adverse event (TEAE; ie, adverse events 
[AEs] occurring after the first dose of investigational product [MEDI3506 or placebo]) in the 
MEDI3506 and placebo groups. All reported TEAEs were Grade 1 or 2 (mild or moderate) in 
severity. There were no TEAEs leading to discontinuation of investigational product, 
treatment-emergent serious adverse events (TESAEs), or deaths. 
In subjects with GOLD I to II COPD in Part II of the study, a similar proportion of subjects 
experienced at least 1 TEAE in the MEDI3506 SC and placebo groups. A majority of reported 
TEAEs were Grade 1 (mild) or Grade 2 (moderate) in severity. One subject experienced a 
TEAE leading to discontinuation of investigational product (MEDI3506 
 
), and 3 subjects experienced TESAEs. There was 1 death due to non-
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small cell lung cancer (MEDI3506 
) and 1 death due to coronary artery 
thrombosis (MEDI3506 
), and 1 Grade 3 TESAE of ankle fracture. 
The TEAE leading to discontinuation of investigational product, TESAEs, and deaths were 
considered not related to investigational product by the investigator. 
In healthy Japanese subjects in Part III of the study, a similar proportion of subjects 
experienced at least 1 TEAE in the 
 MEDI3506 and placebo groups. All reported 
TEAEs were Grade 1 (mild) in severity. There were no TEAEs leading to discontinuation of 
investigational product, TESAEs, or deaths. 
The MEDI3506 serum concentration versus time profiles from healthy subjects with a history 
of mild atopy showed linear and time-invariance first order absorption and first order 
elimination for single doses of 
. For multiple Q2W SC doses in subjects with 
GOLD I to II COPD, slight accumulation was observed, based on the trough concentration, 
following the first and third dose. The multiple and single dose half-lives were consistent. No 
relevant differences were found in Cmax in healthy western subjects with mild atopy and 
healthy Japanese subjects at 
, but a trend towards lower AUC was observed in the 
Japanese subjects. These differences may be related to the small number of subjects included 
in the comparison (6 healthy non-Japanese subjects and 6 healthy Japanese subjects dosed 
with 
 
Treatment-emergent anti-drug antibodies (ADA) were detected in 4 out of 66 subjects in the 
MEDI3506 groups. No subjects in the placebo groups (n = 22) had treatment-emergent ADA. 
TEAEs were similar in frequency and severity for ADA-positive and ADA-negative subjects. 
No impact of ADA on MEDI3506 PK was observed, except in 1 subject where the onset of 
treatment-emergent ADA coincided with a decrease in MEDI3506 serum concentration. 
Refer to the current MEDI3506 IB (Edition 5.2) for further details.  
1.5.2 
Dapagliflozin 
Refer to the current dapagliflozin IB (Edition 17) for a summary of clinical experience with 
dapagliflozin. 
1.6 
Rationale for Conducting the Study 
This Phase 2b study is being conducted to assess functional improvement, as defined by 
change in urine albumin excretion, in subjects with DKD dosed with MEDI3506. 
Additionally, the safety, PK, and immunogenicity profile of MEDI3506 will be evaluated 
across the dose range to enable future studies. The interaction of MEDI3506 with standard of 
care on albuminuria will be assessed by treatment of subjects with, first MEDI3506/placebo 
and ACEi or ARB and, second MEDI3506/placebo and ACEi or ARB together with 
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dapagliflozin. Several exploratory endpoints will also be determined to document target 
engagement, proof of mechanism, and potential treatment responders. 
1.7 
Benefit-risk and Ethical Assessment 
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation of 
Technical Requirements for Pharmaceuticals for Human Use (ICH)/Good Clinical Practice 
(GCP), and applicable regulatory requirements. 
1.7.1 
MEDI3506 
Safety data from the Phase 1 clinical study for MEDI3506 (Study D9180C00001) has not 
identified medically important risks associated with single SC doses of
, and a 
single IV dose of 
 MEDI3506 in healthy subjects with a history of mild atopy 
(N = 42). In addition, no medically important risks are associated with multiple SC doses of 
 MEDI3506 in subjects with GOLD I to II COPD (N = 18), or a single IV dose 
of 
 MEDI3506 in healthy Japanese subjects (N = 6). Phase 1 data do not suggest any 
increase in frequency of TEAEs with increased dose, with the exception of injection-site 
reactions. Except for the TESAEs described (Section 1.5), all TEAEs were Grade 1 or 2 in 
severity. No new safety findings related to MEDI3506 have been identified. 
The purpose of this Phase 2b clinical study is to evaluate the efficacy and safety of MEDI3506 
in subjects with DKD. For subjects randomized to MEDI3506, there is a potential benefit in 
terms of functional improvement of their DKD disease status. However, as the efficacy of 
MEDI3506 in subjects with DKD is yet to be determined, subjects might not receive any 
individual benefit from participating in this study. Subjects will be expected to continue all 
their diabetes maintenance treatment throughout the study to minimize the risk of disease 
status worsening. 
To date, there are no identified risks associated with MEDI3506. Potential risks for 
MEDI3506 include: 
x 
Gastrointestinal adverse reactions. This is based on the observation of what was 
considered an incidental finding of ulcerative colitis in the 26-week toxicity study in 
cynomolgus monkeys (Section 1.4.1). The gastrointestinal effects of IL-33 blockade in 
humans is currently unclear. IL-33 is expressed in the gastrointestinal tract, where it has 
multiple downstream effects (Hodzic et al, 2017). Expression of IL-33 is elevated in 
patients with active ulcerative colitis. 
x 
Serious infections (including opportunistic infections). This is based on the putative 
mechanism of action of MEDI3506, in particular, the role of IL-33 as an “epithelial 
alarmin” (Martin and Martin, 2016). Some evidence suggests that IL-33 may enhance the 
ability of neutrophils and macrophages to respond to bacterial invasion (Alves-Filho et al, 
2010; Li et al, 2014). Therefore, blocking this pathway could potentially ameliorate 
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certain anti-infection response in the human immune system. In regard to SARS-CoV-2, 
AstraZeneca is not aware of any current evidence of a direct link between IL-33, or IL-33 
suppression, and contracting SARS-CoV-2 and early stages of COVID-19 illness post 
infection. Moreover, it is hypothesized that IL-33 suppression might be beneficial in the 
later, hyperinflammatory phase of severe COVID-19 illness; MEDI3506 will be tested in 
patients with severe COVID-19 infections as part of the Accelerating COVID-19 
Research and Development (ACCORD) study 2 (ACCORD-2; EudraCT number 2020-
001736-95). To date, no opportunistic infections have been reported in the MEDI3506 
program. 
x 
Progression of heart failure. IL-33 is widely expressed in cardiovascular tissues 
(Moussion et al, 2008) and can be released locally upon tissue injury (Martin and Martin, 
2016). The precise cardiac function of IL-33 signaling has remained unclear. Non-clinical 
toxicology studies conducted with MEDI3506 (Section 1.4.1) have not indicated any 
adverse cardiovascular outcomes in non-human primates. Likewise, there have been no 
cases of heart failure in the completed study of MEDI3506 conducted in healthy 
volunteers and patients with mild COPD (Section 1.5.1). 
x 
Injection-site reactions. This is based on the SC route of administration and the nature of 
MEDI3506 as an exogenous protein substance. In the nonclinical 26-week repeat dose 
toxicity studies in cynomolgus monkeys (Section 1.4.1), non-adverse microscopic 
changes related to MEDI3506 were seen at the injection site. Overall, injection of 
MEDI3506 was well tolerated in Phase 1. 
x 
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions). As mAbs are 
foreign proteins, they have the potential to provoke hypersensitivity reactions. 
x 
Reproductive toxicity. Consistent with ICH guidance on the timing of nonclinical studies, 
MEDI3506 has not been evaluated in embryo-fetal development toxicity studies. 
 
The study design aims to minimize potential risks to subjects through the inclusion/exclusion 
criteria, screening procedures and safety monitoring with the establishment of an independent 
Data and Safety Monitoring Board (DSMB). This includes exclusion of subjects who are more 
likely to experience the potential risks, stipulating contraceptive requirements for subjects, 
routine clinical monitoring of subjects including monitoring for injection-site reactions, and 
routine blinded review of the safety data including potential anaphylactic symptoms by the 
medical monitor and the sponsor study team. In addition, sites should be equipped to manage 
anaphylaxis and serious allergic reactions until the subject can be transferred to a suitable 
facility. These risk mitigation strategies mean that the potential benefits should outweigh the 
risks supporting study conduct. 
A more detailed description of each potential risk and mitigation strategy can be found in the 
current MEDI3506 IB (Edition 5.2). 
1.7.2 
Dapagliflozin 
The safety profile of dapagliflozin has been evaluated in clinical development programs for 
T2DM, T1DM, heart failure and CKD. This includes more than 15,000 subjects treated with 


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dapagliflozin for T2DM, more than 1,000 subjects treated with dapagliflozin for T1DM, more 
than 1,400 subjects treated with dapagliflozin for DKD, and more than 2,000 subjects treated 
with dapagliflozin for heart failure. Overall, treatment with dapagliflozin 5 mg was similar to 
treatment with dapagliflozin 10 mg in both T1DM and T2DM. The safety profile of 
dapagliflozin was overall consistent across the studied indications.  
The most commonly reported AEs associated with the use of dapagliflozin include genital 
infections, urinary tract infections, back pain, and polyuria. In addition, rash has been 
identified as an AE of unknown frequency in marketed use of dapagliflozin. 
In the cardiovascular outcomes study, dapagliflozin on the Incidence of Cardiovascular Events 
(DECLARE), 8,574 patients received dapagliflozin 10 mg and 8,569 patients received placebo 
for a median exposure time of 48 months. Events of diabetic ketoacidosis (DKA) were 
reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. 
The events occurred evenly distributed over the study period. Of the 27 patients with DKA 
events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the 
event. 
The DAPA-CKD renal outcome study has shown 10 mg dapagliflozin to be efficacious and 
well tolerated in a wide range of patients with CKD (2152 patients treated with dapagliflozin; 
median follow-up = 2.4 years) (Heerspink et al, 2020a). In patients with an estimated 
glomerular filtration rate (eGFR) 25 to 75 mL/min/1.73m2 dapagliflozin was shown to 
significantly reduce the combined risk of: 1) sustained decline in eGFR of at least 50%; 2) 
end-stage kidney disease; 3) or death from renal or cardiovascular causes (Heerspink et al, 
2020a). 
Taken together, SGLT2i have been shown to consistently reduce the risk of clinically 
important, patient-level cardiovascular outcomes and emerging data suggest that the 
combination of ACEi or ARB and SGLT2i should be routinely offered to patients with T2DM 
who have, or are at high risk of, progressive kidney disease (de Boer et al, 2020). 
More detailed information about the known and expected benefits and potential risks of 
dapagliflozin may be found in the respective current IB (Edition 17). 
1.7.3 
Other Risks 
Given the distinct molecular mechanisms of action of MEDI3506 and dapagliflozin, no 
adverse drug-drug interaction is expected when both drugs are taken together. 
For details on background information, risks and mitigations plans, and impact of COVID-19 
on the current study, see Appendix F. 


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1.7.4 
Overall Benefit/Risk Conclusion 
Taking into account the measures taken to minimize risk to the subjects of this study, the 
potential risks identified in association with MEDI3506 and MEDI3506/dapagliflozin are 
justified by the anticipated benefits that may be afforded to subjects with DKD. 
1.8 
Research Hypotheses 
1.8.1 
Primary Hypothesis 
MEDI3506 will reduce albuminuria compared with placebo on top of standard of care, 
including ACEi or ARB, and dapagliflozin. 
1.8.2 
Secondary Hypotheses 
MEDI3506 will reduce albuminuria compared with placebo on top of standard of care, 
including ACEi or ARB, and will exhibit an acceptable safety, immunogenicity, and PK 
profile in subjects with DKD. Dapagliflozin on top of MEDI3506 will further reduce 
albuminuria. 
2 
OBJECTIVES AND ENDPOINTS 
2.1 
Primary Objective and Associated Endpoint 
Table 1 
Primary Objective and Associated Endpoint 
Type 
Objective 
Endpoint 
Efficacy 
To evaluate the effect of MEDI3506 on 
albuminuria in subjects with DKD 
Change from baseline to Day 169 
(Week 24) in UACR compared to placebo. 
Central laboratory UACR results will be 
blinded to Investigators and Sponsor team 
starting from Visit 3 (Day 1) up to and 
including the EOS Visit. 
DKD = Diabetic Kidney Disease; UACR = Urine albumin:creatinine ratio 
 
2.2 
Secondary Objectives and Associated Endpoints 
Table 2 
Secondary Objectives and Associated Endpoints 
Type 
Objective 
Endpoint 
Safety 
To evaluate safety and tolerability of 
MEDI3506 with and without dapagliflozin 
in subjects with DKD 
Measures of safety and tolerability 
including but not limited to: 
• 
Incidence of TEAEs and TESAEs 
• 
Assessment of vital signs (SBP, DBP, 
heart rate, respiratory rate and body 
temperature) 
• 
ECG 
• 
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Table 2 
Secondary Objectives and Associated Endpoints 
Type 
Objective 
Endpoint 
• 
BNP 
• 
Laboratory assessments (hematology, 
clinical chemistry, and urinalysis) 
• 
For subjects testing positive for 
COVID-19 during the intervention and 
follow-up periods, the number and 
proportion of subjects with AEs/SAEs, 
as well as the number and proportion 
of subjects with COVID-19 
AEs/SAEs, and the proportion of 
asymptomatic subjects. 
PK, 
Immunogenicity 
To describe the PK and immunogenicity of 
MEDI3506 in subjects with DKD 
MEDI3506 serum concentrations and ADA 
incidence occurring throughout the study 
Efficacy 
To evaluate the effect of MEDI3506 in 
combination with ACEi or ARB with and 
without dapagliflozin on albuminuria in 
subjects with DKD 
• 
Proportion of subjects with > 30% 
reduction in UACR at Day 169 
(Week 24) 
• 
Proportion of subjects with > 40% 
reduction in UACR at Day 169 
(Week 24) 
• 
Proportion of subjects with > 50% 
reduction in UACR at Day 169 
(Week 24) 
• 
Change from baseline to Day 85 
(Week 12) in UACR 
• 
Change from Day 85 (Week 12) to 
Day 169 (Week 24) in UACR 
ACEi = angiotensin converting enzyme inhibitors; ADA = anti-drug antibody; AE(s) = adverse event(s); 
ARB = angiotensin receptor blockers; BNP = B-type natriuretic peptide; ECG = electrocardiogram; 
EOS = end of study; DBP = diastolic blood pressure; DKD = Diabetic Kidney Disease; LVEF = left 
ventricular ejection fraction; PK = pharmacokinetic; SAE(s) = serious adverse event(s); SBP = systolic blood 
pressure; TEAE(s) = treatment emergent adverse event(s); TESAE(s) = treatment emergent serious adverse 
event(s); UACR = urine albumin to creatinine ratio 
 


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3 
STUDY DESIGN 
3.1 
Description of the Study 
3.1.1 
Overview 
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to 
evaluate the efficacy, safety, PK, and immunogenicity of MEDI3506 in adult subjects with 
DKD; defined as subjects with T2DM and an eGFR of 25-75 mL/min/1.73 m2 with a urine 
albumin:creatinine ratio (UACR) in the range of 100-3000 mg/g, who meet all eligibility 
criteria. Furthermore, the additive effect of the SGLT2i dapagliflozin taken together with 
MEDI3506 on albuminuria will be assessed for 12 weeks when subjects will be treated with 
MEDI3506/placebo and dapagliflozin. Subjects who have started on the Phase 2a study prior 
to Amendment 2 will be transitioned to the Phase 2b and given dapagliflozin starting on 
Day 85 (Week 12). Subjects who have completed 12 weeks of treatment prior to 
implementation of Amendment 2 will continue on treatment with MEDI3506/placebo without 
dapagliflozin. 
Approximately 565 subjects, from around 130 study sites among multiple countries will be 
randomized (95:95:95:140:140) to MEDI3506 30, 60, 120, or 300 mg, or volume-matched 
placebo. Note that the 19 subjects who were enrolled and discontinued prior to the study hold 
on 24 March 2020 due to COVID-19 are not included in the total count of 565 subjects. 
Subjects will be dosed subcutaneously
 
 
 
 
Following the signing of informed consent, subjects will be assessed for study eligibility 
during a screening period of up to 35 days (Day -37 to Day -3) followed by a 168-day 
(24-week) treatment period and a 70-day (10-week) follow-up period (Figure 1). 
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Figure 1 
Study Flow Diagram 
ACEi = angiotensin converting enzyme inhibitor; ARB = angiotensin receptor blocker; eGFR = estimated glomerular filtration rate in mL/min/1.73m2; 
Q4W = every 4 weeks; QD = once daily; T2DM = type 2 diabetes mellitus; UACR = urine albumin to creatinine ratio in mg/g. 


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3.1.2 
Treatment Regimen 
 
 
x 
Group 1: MEDI3506 30 mg (0.2 mL), n = 95 
x 
Group 2: MEDI3506 60 mg (0.4 mL), n = 95 
x 
Group 3: MEDI3506 120 mg (0.8 mL), n = 95 
x 
Group 4: MEDI3506 300 mg (2 mL), n = 140 
x 
Group 5: Placebo (0.2 mL), n = 32 
x 
Group 6: Placebo (0.4 mL), n = 32 
x 
Group 7: Placebo (0.8 mL), n = 32 
x 
Group 8: Placebo (2 mL), n = 44 
 
All subjects will also receive daily oral tablets of 10 mg dapagliflozin starting on Day 85 until 
Day 168. Subjects already taking an SGLT2i will be rolled over to 10 mg dapagliflozin.  
Dapagliflozin should be taken in the morning with or without food. 
3.1.3 
Study Conduct Mitigation During Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis  
The guidance given below supersedes instructions provided elsewhere in this protocol and 
should be implemented only during cases of civil crisis, natural disaster, or public health crisis 
(eg, during quarantines and resulting site closures, regional travel restrictions, and 
considerations if site personnel or study subjects become infected with SARS-CoV-2 or 
similar pandemic infection) which would prevent the conduct of study-related activities at 
study sites, thereby compromising the study site staff or the subject’s ability to conduct the 
study. The investigator or designee should contact the study sponsor to discuss whether the 
mitigation plans below should be implemented. 
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study subjects, maintain 
compliance with Good Clinical Practice, and minimize risks to study integrity. 
Where allowable by local health authorities, ethics committees, healthcare provider guidelines 
(eg, hospital policies) or local government, these changes may include the following options: 
x 
Obtaining consent for the mitigation procedures (note, in the case of verbal consent, 
informed consent form (ICF) should be signed at the subject’s next contact with the study 
site). 
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The evaluation of MEDI3506/placebo taken with ACEi or ARB, or with ACEi or ARB plus 
dapagliflozin will clarify the interaction with standard care. The treatment duration allows a 
suitable assessment of safety and immunogenicity following multiple dose administration and 
is of sufficient length to evaluate effects on urine albumin excretion (Heerspink et al, 2019).  
Standard measures of PK analysis will be used to inform understanding of MEDI3506 and 
dapagliflozin PK in subjects with DKD as well as help to inform the exposure-response 
relationship. Standard safety and immunogenicity measures will be assessed. 
 
 
4 
MATERIALS AND METHODS 
4.1 
Subjects 
4.1.1 
Number of Subjects 
Approximately 565 subjects are planned to be randomized in this study into 8 treatment 
groups (Section 3.1.2). 
4.1.2 
Inclusion Criteria 
Subjects must meet all of the following criteria: 
1 
$GXOWPHQRUZRPHQ\HDUVRIDJHDW9LVLW 
2 
Written informed consent and any locally required authorization (eg, data privacy) 
obtained from the subject prior to performing any protocol-related procedures, including 
screening evaluations. 
3 
DKD defined as 
(a) diagnosis of T2DM and 
(b) eGFR 25-75 mL/min/1.73 m2 based on Chronic Kidney Disease Epidemiology 
Collaboration (CKD-EPI) equation a and 
(c) UACR defined as 100-3000 mg albumin/g creatinine based on the mean of 
3 sequential first morning void midstream urine samples at Visit 2. 
4 
%3PP+JDW9LVLWDQG9LVLW 
5 
Stable dose of ACEi or ARB for at least 6 weeks prior to Visit 1 and throughout the 
screening period with ACEi and ARB dosing according to local guidelines. Subjects who 
have been deemed unable to tolerate ACEi or ARB therapy due to allergy or 
complications may be enrolled. Minor dose adjustment within 2 weeks before Visit 1 is 
acceptable (see Section 4.7.2). 
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6 
For subjects on any additional antihypertensive medication (including diuretic therapy), 
doses must be stable for at least 6 weeks prior to Visit 1 and throughout the screening 
period. 
7 
For subjects on SGLT2i treatment prior to enrollment, doses must be stable for at least 
4 weeks prior to Visit 3. Existing SGLT2i treatment will be stopped and switched to 
10 mg dapagliflozin on Day 85. 
8 
Up-to-date influenza and pneumococcal pneumonia vaccinations (subject-reported) 
according to local recommendations, at least 28 days prior to Visit 3 OR confirmation of 
off-season intent to get vaccinated. Patients screened outside of the influenza season 
(including those who were not vaccinated in the previous season) are eligible for 
randomization provided that the vaccination is planned once the influenza vaccine for the 
next season becomes available. For such patients, investigators are asked to confirm the 
patient’s intent to get vaccinated for the next season. Patients who do not plan to get 
vaccinated against influenza should not be randomized. 
9 
Contraceptive use by men or women should be consistent with local regulations regarding 
the methods of contraception for those participating in clinical studies. 
(a) Male subjects: 
x 
For genotoxic investigational products, the male subject should use condom 
during treatment and until the end of relevant systemic exposure in the male 
subject, plus a further 90-day period (until 24 weeks after the last dose of study 
intervention (MEDI3506). For a non-pregnant women of childbearing potential 
(WOCBP) partner, contraception recommendations should also be considered. 
(b) Female subjects: 
x 
Women not of childbearing potential are defined as women who are either 
permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy), or who are postmenopausal. Women will be considered 
postmenopausal if they have been amenorrhoeic for 12 months prior to the 
planned date of Visit 3 without an alternative medical cause. The following 
age-specific requirements apply: 
 
Women < 50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of exogenous 
hormonal treatment and follicle-stimulating hormone levels in the 
postmenopausal range. 
 
:RPHQ 50 years old would be considered postmenopausal if they have 
been amenorrhoeic for 12 months or more following cessation of all 
exogenous hormonal treatment. 
x 
Female subjects 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. Women of childbearing potential who are sexually active with a 
non-sterilized male partner must agree to use one highly effective method of 
birth control, as defined below, from enrollment throughout the study and until at 
least 12 weeks after last dose of study intervention (MEDI3506). Cessation of 
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Periodic abstinence (calendar, symptothermal, post-ovulation methods), 
withdrawal (coitus interruptus), spermicides only, and lactational amenorrhea 
method are not acceptable methods of contraception. Female condom and male 
condom should not be used together. All WOCBP must have a negative serum 
pregnancy test result at Visit 1. 
x 
Highly effective birth control methods include: sexual abstinence (periodic 
abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of exposure to investigational product 
[MEDI3506], and withdrawal are not acceptable methods of contraception], a 
vasectomized partner, Implanon®, bilateral tubal occlusion, intrauterine 
device/levonorgestrel intrauterine system, Depo-Provera™ injections, oral 
contraceptive, and Evra Patch™, Xulane™, or NuvaRing®. Women of 
childbearing potential must agree to use one highly effective methods of birth 
control, as defined above, from enrollment throughout the study up to the end of 
the follow-up period at Visit 10. 
10 Able and willing to comply with the requirements of the protocol and complete the study. 
 
a 
CKD-(3,HTXDWLRQH*)5 îPLQ6FUțĮ îPD[6FUț-1.209 × 0.993Age × 1.018 [if female] × 
1.159 [if black] (Levey et al, 2009). For subjects with amputation, eGFR will be adjusted based on 
estimated body weight loss. 
 
4.1.3 
Exclusion Criteria 
Any of the following would exclude the subject from participation in the study: 
1 
Concurrent enrollment in another clinical study involving an investigational treatment or 
drug, or received administration of an investigational drug or participation in a device 
trial within 3 months prior to Visit 1. 
2 
Previous participation in a MEDI3506 clinical trial. 
3 
Diagnosis of CKD other than diabetic renal disease (hypertensive nephrosclerosis 
superimposed on DKD is acceptable). 
4 
Serum potassium > 5.5 PPRO/DW9LVLWWKDWFDQQRWEHDGMXVWHGWRYDOXHV 5.5 mmol/L 
by appropriate management (Appendix E). 
5 
Significant hepatic disease, including, but not limited to, acute hepatitis, chronic active 
hepatitis, or severe hepatic insufficiency, including subjects with ALT and/or 
AST > 3 × 8/1DQGRU7%/!PJG/!ȝPRO/6XEMHFWVZLWK7%/!PJG/
(> 34.2 ȝPRO/DQGGRFXPHQWHG*LOEHUW¶VV\QGURPHZLOOEHDOORZHGWRSDUWLFLSDWH 
6 
Hemoglobin (Hb) A1c > 10.5% measured at Visit 1. 
7 
B-type natriuretic peptide (BNP) level > 200 pg/mL at Visit 1. 
8 
History of clinically significant heart disease including but not limited to any of the 
following: 
(a) Clinically significant congenital or acquired valvular disease, cardiomyopathy or 
severe pulmonary hypertension, unstable ischemic heart disease, or recent myocardial 
infarction < 6 months of Visit 1; 


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(b) Left ventricular (LV) ejection fraction < 40%, based on transthoracic echocardiogram 
performed during Visit 2; 
(c) New York Heart Association Class 3 or 4 or history of hospitalization for heart 
failure within the past 12 months prior to Visit 1; 
(d) History of unstable arrhythmias. 
9 
Any of the following concomitant conditions or diseases at Visit 1: 
(a) History of treated ulcerative colitis, Crohn’s disease, or microscopic colitis within the 
last 3 years; 
(b) Anticipated dialysis or renal transplantation within 1 year; 
(c) A history of alcohol and/or substance abuse (including positive drugs of abuse screen 
at Visit 1) that could interfere with the conduct of the trial; 
(d) Prior malignancy other than: 
(i) non-melanoma skin cancer (squamous or basal cell carcinoma) treated for 
complete cure 
(ii) cervical cancer in situ treated for complete cure 
(iii) any other history of malignancy treated with apparent success with curative 
therapy (response duration of > 5 years); 
(e) History of underlying condition that predisposes the subject to infections (eg, history 
of splenectomy, known primary or secondary immune deficiency syndromes, 
cirrhosis); 
(f) Infections: 
(i) Significant infection (viral, bacterial, or fungal) including unexplained diarrhea 
within 4 weeks prior to Visit 3 
(ii) History of Herpes zoster with last flare occurring within 3 months of Visit 1 
(iii) Positive test for or history of treatment for hepatitis B, hepatitis C, or human 
immunodeficiency virus (HIV). Subjects positive for hepatitis B surface antigen 
(HBsAg) or antibody to hepatitis B core antigen (anti-HBc) are excluded. Those 
with a history of hepatitis B vaccination without a history of hepatitis B are 
permitted to enroll 
(g) History or evidence of active tuberculosis (TB) infection at Visit 1 or one of the risk 
factors for tuberculosis such as but not limited or exclusive to: 
(i) History of residence in a congregate setting (eg, jail or prison, homeless shelter, 
or chronic care facility) or healthcare workers with unprotected exposure to 
subjects who are at high risk of TB 
(ii) Close contact (ie, share the same air space in a household or other enclosed 
environment for a prolonged period [days or weeks, not minutes or hours]) with 
a person with active pulmonary tuberculosis (TB) disease within the last 
12 months; 
(h) Amputation due to peripheral artery disease; 
(i) Any other medical condition or clinically relevant abnormal findings in physical 
examination, laboratory results, or electrocardiogram (ECG) during screening that, in 
the opinion of the investigator, may compromise the safety of the subject in the 


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study, reduce the subject’s ability to participate in the study, or interfere with 
evaluation of MEDI3506. 
10 Vaccinations 
(a) Live or attenuated virus vaccination within 28 days of Visit 3 until the end of the 
follow-up period is not allowed. 
(b) Vaccination against COVID-19 (either first or subsequent dose) within 28 days 
before Visit 3; for details, see Section 4.7.4. 
11 Allergic reactions 
(a) History of severe allergic reaction requiring hospitalization; 
(b) History of severe reaction to any medication including biologic agents or human 
gamma globulin therapy; 
(c) History of allergy or reaction to any component of MEDI3506 or dapagliflozin 
formulation. 
12 Subjects with a known positive diagnostic nucleic acid or antigen test for 
SARS-CoV-2 within 6 weeks prior to randomization visit. a 
13 Subjects with a significant COVID-19 illness within 6 months of randomization:  
(a) Subjects with a diagnosis of COVID-19 pneumonia based on radiological 
assessment;  
(b) Subjects with diagnosis of COVID-19 with significant findings from pulmonary 
imaging tests; 
(c) Subjects with a diagnosis of COVID-19 requiring hospitalization and/or oxygen 
supplementation therapy.  
14 Receiving any of the prohibited concomitant medications (see Section 4.7.2) including: 
(a) Renin inhibitor or an aldosterone antagonist when used in combination with an ACEi 
or an ARB within 2 months of Visit 1; 
(b) Ongoing use of any biologic drug and/or small molecule targeting the immune 
system (eg, TNF blockers, anakinra, rituximab, abatacept, tocilizumab, 
cyclophosphamide, cyclosporine, tacrolimus, mycophenolate mofetil, or 
corticosteroids other than topical or inhaled); 
(c) Subjects on serum creatinine-altering drugs should be on long-term treatment at a 
stable dose prior to study entry. Drugs considered serum-altering include but are not 
limited to amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, 
probenecid, ranolazine, trimethoprim, aminoglycosides, or cephalosporins. 
*HQHUDOO\DQ\GUXJWKDWKDVDSXWDWLYHHIIHFWRQVHUXPFUHDWLQLQHLVFRQVLGHUHG
serum creatinine-altering. The following exclusion criteria apply: 
(i) New treatment or change of dose within 6 weeks prior to Visit 1 
(ii) Expected change of dosing regimen during the study 
(iii) Minor ACEi or ARB dose adjustment within 2 weeks of Visit 1 is acceptable, 
but any dose adjustments during the course of the study (ie, for control of 
hyperkalemia) should be discussed with the sponsor/ medical monitor 
(iv) Clinically indicated short-term use of serum creatinine-altering drugs to treat 
acute conditions during the study may be allowed. 


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15 Donation of blood or significant blood loss 
(a) All sites except Japan: Donation of blood or significant blood loss in excess of 
500 mL within 3 months prior to Visit 3 (or > 1200 mL in the year prior to Visit 3).  
(b) For Japan only:  
(i) For male subjects, donation of whole blood or significant blood loss in excess of 
400 mL within 3 months prior to Visit 3 or > 1200 mL in the year prior to 
Visit 3.  
(ii) For female subjects, donation of whole blood or significant blood loss in excess 
of 400 mL within 4 months prior to Visit 3 or > 800 mL in the year prior to 
Visit 3.  
16 Plasma donation within 60 days prior to Visit 3. 
17 Subjects who are institutionalized. 
18 An employee, or close relative of an employee, of AstraZeneca, the contract research 
organization, or the study site, regardless of the employee’s role. 
19 Pregnancy or intention to become pregnant during the course of the study, breastfeeding, 
or unwillingness to use a highly effective method of contraception throughout the study in 
female subjects of childbearing potential. 
 
a 
Investigators should use their best clinical judgement to decide on measures needed to minimize the risk of 
randomizing patients with an active SARS-CoV-2 infection. To do so, they should consider the local status 
of the COVID-19 pandemic, the subject’s medical and vaccination history, local recommendations 
regarding outpatient COVID-19 screening, and testing policies. 
 
4.1.4 
Subject Enrollment and Randomization 
Study participation begins (ie, a subject is “enrolled”) once written informed consent is 
obtained. Once informed consent is obtained, a subject identification (SID) number will be 
assigned by a central system (eg, an interactive voice/web response system [IXRS]), and the 
screening evaluations may begin to assess study eligibility (inclusion/exclusion) criteria. The 
SID number will be used to identify the subject during the screening process and throughout 
study participation, if applicable. 
A master log of all consented subjects will be maintained at the site and will document all 
screening failures (ie, subjects who are consented but do not meet study eligibility criteria 
and/or are not randomized), including the reason(s) for screening failure. 
Subjects who fail to meet the inclusion/exclusion criteria may be rescreened any time during 
the recruitment period and receive a new SID number. Subjects can be rescreened up to 
2 times. Prior to rescreening, subjects must be reconsented and receive a new SID number. 
Subjects who have been discontinued from treatment will not be rescreened. 
Where subjects who do not meet the inclusion and/or exclusion criteria are randomized in 
error, or incorrectly started on treatment, or where subjects subsequently fail to meet the study 


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criteria post initiation, the investigator should inform the medical monitor immediately. The 
investigator and/or medical monitor may determine that the incorrectly randomized subject 
will not receive any further investigational product if the inclusion/exclusion criteria violation 
would put the subject at undue risk. 
4.1.5 
Withdrawal from the Study 
Subjects are free to withdraw their consent to participate in the study (investigational product 
and assessments) at any time, without prejudice to further treatment. A subject 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). Subjects who withdraw consent will be asked about the reason(s) and 
the presence of any AEs. If the subject is willing, the subject will be seen and assessed by the 
investigator.  
AEs will be followed up; all study materials should be returned by the subject. If a subject 
withdraws from further participation in the study, then no further study visits or data 
collection should take place. 
4.1.6 
Discontinuation of Investigational Product 
Subjects are free to discontinue study drugs at any time, without prejudice to further 
treatment. 
x 
Subjects who choose to discontinue MEDI3506 prior to the dapagliflozin period (Day 85 
to Day 168) will not proceed on dapagliflozin and are expected to attend their next 
scheduled study visit for an Early Discontinuation Visit (see Table 6) and then to 
complete the assessments per the follow-up visit described in Table 7. Visit 10/EOS will 
be conducted 60 days (± 5 days) after the last visit performed. 
x 
Subjects who choose to discontinue MEDI3506 during the dapagliflozin period (Day 85  
to Day 168) prior to the end of the treatment period are expected to attend their next 
scheduled study visit for an Early Discontinuation Visit (see Table 6) and then to 
complete the assessments per the follow-up visit described in Table 7. Visit 10/EOS will 
be conducted 60 days (± 5 days) after the last visit performed. 
x 
Subjects who choose to discontinue dapagliflozin during the dapagliflozin period (Day 85 
to Day 168) prior to the end of the treatment period are expected to continue in the study 
on remaining study therapy according to the schedule of study procedures for the 
remainder of the study. 
 
An individual subject will not receive any further investigational product if any of the 
following occur in the subject in question: 
1 
Withdrawal of consent from further treatment with investigational product 
2 
Lost to follow-up 


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3 
An AE that, in the opinion of the investigator or the sponsor, warrants discontinuation of 
further dosing or meets criteria for discontinuation from investigational product 
(including, but not limited to, anaphylactic reaction to investigational product, new onset 
or progression of heart failure). 
4 
After initial dosing, there exists a clinically significant safety issue based on information 
not known or not disclosed prior to randomization 
5 
Subject noncompliance that, in the opinion of the investigator or sponsor, warrants 
treatment discontinuation for safety reasons (eg, refusal or inability to adhere to scheduled 
visits) 
6 
Pregnancy 
 
Appendix C describes actions required in cases of increases in liver biochemistry. 
Consider temporary interruption of dapagliflozin if DKA is suspected. The subject should be 
promptly evaluated. If DKA is confirmed, dapagliflozin should be discontinued permanently. 
Subjects who have a positive SARS-CoV-2 nucleic acid test should be immediately evaluated 
by the investigator and sponsor. Based on investigator and sponsor judgement, subjects may 
be temporarily or permanently discontinued from treatment. 
Subjects who are permanently discontinued from receiving investigational product will be 
followed for protocol-specified assessments including follow-up of any AEs unless consent is 
withdrawn from further study participation (Section 4.1.5), the subject is lost to follow-up, or 
the subject is enrolled in another clinical study. 
4.1.6.1 
Missed Doses of MEDI3506 or Dapagliflozin 
A subject who misses a scheduled dosing visit of MEDI3506 (due to COVID-19 or other 
reasons) can continue study intervention if dosing is performed within 14 days of the missed 
visit (Table 4). If subjects cannot be rescheduled within 14 days, the dose is considered missed 
and study intervention should continue at the next scheduled visit per Table 6. Up to 1 dose of 
MEDI3506 may be missed. If the subject misses more than one dose, he/she will be 
considered dropped out/discontinued.  
Missed/delayed doses should be captured in the eCRF. Refer to Appendix F for information 
on dealing with missed doses as a result of the COVID-19 pandemic. 
Table 4 
Guidelines for Handling Missed Doses of MEDI3506 
Missed visit 
Subject to be rescheduled for dosing within 14 days of missed visit. If subject is 
unable to be rescheduled within 14 days, skip dose (see below for missed dose). 
1 missed dose 
Administer next dose according to schedule 
2 missed doses  
Subject to be considered dropped out/discontinued  
 


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Missed doses of dapagliflozin should be handled as detailed in Section 4.7.3. 
4.1.7 
Replacement of Subjects 
Subjects who are randomized but do not receive investigational product (MEDI3506 or 
placebo) may be replaced (with identical investigational product assignment, if applicable) to 
maintain the stipulated cohort sizes. This would include subjects who are randomized and then 
withdraw consent before receipt of the investigational product. 
Subjects who are discontinued from further dosing or follow-up procedures or withdraw their 
informed consent to all follow-up prior to the end of study (EOS) visit may be replaced, if 
deemed necessary by the medical monitor to ensure that data are collected from a sufficient 
number of subjects. The medical monitor should be notified within 48 hours if a subject 
permanently discontinues study drug or withdraws consent to all follow-up. A determination 
whether to replace the subject will be made by the medical monitor. 
Subject retention for dosing and for study procedures, even if dosing has been discontinued, is 
key to the success of this study. Sites must have a subject retention plan in place. The 
following approaches should be included to minimize loss of data: asking a subject for the 
name and contact number of a family member or friend who can be contacted to reach the 
subject (signed consent should be obtained); use of email contact (with care to avoid revealing 
confidential medical information over nonsecure email); and coverage of the cost of 
transportation to clinic, if needed. 
For any missing visit/contact or missing data, the reason for the missing visit/contact and/or 
data must be recorded in the electronic data capture (EDC) system. 
4.1.8 
Withdrawal of Informed Consent for Data and Biological Samples 
AstraZeneca ensures that biological samples are returned to the source or destroyed at the end 
of a specified period as described in the informed consent. 
If a subject withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented. If samples are already analyzed, 
AstraZeneca is not obliged to destroy the results of this research. 
As collection of the biological samples is an integral part of the study, then the subject is 
withdrawn from further study participation. 
The Principal Investigator: 
x 
Ensures subjects’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AstraZeneca. AstraZeneca will ensure the organization(s) holding 
the samples is/are informed about the withdrawn consent immediately and that samples 


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are disposed of/destroyed, the action documented and the signed document returned to the 
study site. 
x 
Ensures that biological samples from that subject, if stored at the study site, are 
immediately identified, disposed of/destroyed, and the action documented and 
AstraZeneca are informed about the sample disposal. 
 
4.2 
Schedule of Study Procedures 
Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the same nominal 
time, the blood draws should occur last. The timing of the first 2 assessments should be such 
that it allows the blood draw (eg, PK blood sample) to occur at the proper nominal time. 
Randomization should only proceed if all required assessments have been performed and all 
inclusion/exclusion criteria as well as other protocol restrictions have been evaluated; see 
Section 4.1.2, Section 4.1.3, and Section 4.7. 
Dosing of subjects should only be carried out if all required assessments have been performed 
and evaluated. Dosing is not allowed to proceed until the investigator has determined that the 
results are within acceptable range according to the defined stopping criteria; see Section 
4.1.6. Laboratory assessment results should also be reviewed at every visit to ensure that 
stopping criteria have not been met. 
4.2.1 
Enrollment/Screening Period 
Table 5 shows all procedures to be conducted at the screening visit. 
Table 5 
Schedule of Screening Procedures 
Study Period 
Screening 
Visit Number 
Visit 1 
Phone Call 1 a 
Visit 2 
Procedure / Study Day 
Day -37 to Day -3 
Informed consent (main study) 
X 
 
 
Informed consent (future use blood and urine b) 
X 
 
 
Informed consent (genetic b) 
X 
 
 
Verify eligibility criteria 
X 
X 
 
Safety assessments: 
Full medical history review 
X 
 
 
Assessment of AEs/SAEs 
 
X 
X 
Physical examination (full) 
X 
 
 
Weight, height, and BMI calculation 
X 
 
 
Vital signs 
X 
 
 
ECG 
X 
 
 


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Table 5 
Schedule of Screening Procedures 
Study Period 
Screening 
Visit Number 
Visit 1 
Phone Call 1 a 
Visit 2 
Procedure / Study Day 
Day -37 to Day -3 
Transthoracic echocardiogram 
 
 
X c 
Concomitant medications 
X 
X 
X 
Blood collection for: 
Serum chemistry 
X 
 
 
 
X 
 
 
 
X 
 
 
Serum beta-hCG, FSH (for women) d 
X 
 
 
Complete blood count with differential 
X 
 
 
eGFR calculation e 
X 
 
 
Hepatitis B, C; HIV-1, HIV-2 
X 
 
 
Urine collection for: 
Urinalysis 
X 
 
 
Drug and alcohol screen f 
X 
 
 
Spot urine for UACR 
X 
 
 
Procedure: 
Dispense supply of containers for urine samples 
X 
 
 
Reminder to collect first morning void midstream urine 
samples 3 days before the next visit 
 
X 
 
Subjects return first morning void midstream urine 
collection samples for UACR analysis g 
 
 
X 
AE(s) = adverse event(s); ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body 
mass index; 
; ECG = 12-lead electrocardiogram; eGFR = estimated 
glomerular filtration rate; FSH = follicle-stimulating hormone; 
 hCG = human 
chorionic gonadotropin; HIV = human immunodeficiency virus; PTT = partial thromboplastin time; 
SAE(s) = serious adverse event(s); UACR = urine albumin:creatinine ratio. 
NOTE: Where the values for clinical laboratory tests (Section 4.3.3) are outside the usual range for a subject 
during screening, based on their medical history, retesting may be undertaken on one occasion without 
requiring a re-screen. 
NOTE: Investigator should ensure that all subjects are contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and are asked to follow up suspected reports according to local 
guidelines. 
a 
Phone Call 1 will occur after results from the initial screening visit are available and the subject is 
confirmed otherwise eligible in order to remind subjects to collect the first morning void and schedule 
Visit 2.  
b 
Optional informed consent is required for agreement to the future use of blood and urine samples and 
genetic testing, if appropriate. 
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Table 5 
Schedule of Screening Procedures 
Study Period 
Screening 
Visit Number 
Visit 1 
Phone Call 1 a 
Visit 2 
Procedure / Study Day 
Day -37 to Day -3 
c 
If otherwise eligible at Screening Visit 1, a Screening Visit 2 will be scheduled to conduct the 
transthoracic echocardiogram, which may be performed independently of other Visit 2 procedures during 
the screening period. 
d 
Testing for menopause will only be performed if menopausal status cannot be established from full 
medical history review.  
e 
For subjects  with amputation, eGFR will be adjusted based on estimated body weight loss. 
f 
Alcohol screen breathalyzer to be performed in line with local practices. Drug screen to be performed in 
line with local practices and investigator discretion. 
g 
Subjects collect 3 consecutive first morning void midstream urine samples (ideally day of visit and 
preceding 2 days [refrigerated overnight]) which are returned on the day of visit. This collection may be 
repeated once during the course of screening. Eligibility will be determined based on the results. 
 
4.2.2 
Randomized Treatment Period 
Table 6 shows all procedures to be conducted during the treatment period.  
Table 6 
Schedule of Treatment Period Study Procedures 
Study Period 
Treatment Period 
Visit Number 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Early 
D/c 
Visit 
Procedure / Study Day 
Day 1 
Day 
29  
(± 5 
days) 
Day 
57  
(± 5 
days) 
Day 
85  
(± 5 
days) 
Day 
113  
(± 5 
days) 
Day 
141  
(± 5 
days) 
Day 
169  
(± 5 
days) 
Verify eligibility criteria 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Safety assessments: 
Physical examination 
(abbreviated) with weight a 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs b 
X 
X 
X 
X 
X 
X 
X 
X 
Transthoracic 
echocardiogram 
 
 
 
 
 
 
X c 
X 
Assessment of AEs/SAEs 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Blood collection for: 
Serum chemistry 
X 
X 
 
X 
 
X 
X 
X 
 
X 
X 
 
X 
 
 
X 
X 
 
 
 
 
 
 
 
X 
X 
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Table 6 
Schedule of Treatment Period Study Procedures 
Study Period 
Treatment Period 
Visit Number 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Early 
D/c 
Visit 
Procedure / Study Day 
Day 1 
Day 
29  
(± 5 
days) 
Day 
57  
(± 5 
days) 
Day 
85  
(± 5 
days) 
Day 
113  
(± 5 
days) 
Day 
141  
(± 5 
days) 
Day 
169  
(± 5 
days) 
a 
Including focused cardiac exam (Section 4.3.2.2). 
b 
)RUWKHILUVWGRVHVRI0(',RUSODFHERSDWLHQWVDUHWRUHPDLQDWWKHVLWHIRU 2 hours or until 
stable, whichever is later. In addition, vital signs will be taken before and immediately after 
administration of MEDI3506 or placebo, and at 30 minutes (± 5 minutes) as well as 120 minutes 
(± 10 minutes) thereafter or until stable, whichever is later. Following the observation period, subject 
discharge will be at the discretion of the investigator. For all other dosing visits, vital signs will be 
collected 30 minutes (± 5 minutes) after administration of MEDI3506 or placebo or when stable. 
c 
May be performed independently of other Visit 9 procedures within the visit window. 
d 
PK samples on MEDI3506/placebo dosing days will be collected pre-dose of MEDI3506/placebo 
administration. 
e 
Dapagliflozin PK samples will be collected at the following time points relative to dapagliflozin 
administration: Day 141 (predose and 2 h postdose) and Day 169 on study visit. Patients will be 
reminded to take dapagliflozin on site visits during dapagliflozin administration time (Day 85 to 
Day 168/Visit 6 to Visit 8). 
g 
If consent obtained. 
h 
After randomization. If, for any reason, the sample is not drawn pre-dose on Visit 3 (Day 1), it may be 
taken at any visit until the final follow-up visit/Early Discontinuation Visit. 
i 
Subjects collect 3 consecutive first morning void midstream urine samples (ideally day of visit and 
preceding 2 days [refrigerated overnight]) which are returned on the day of visit. 
j 
In the event that a dose cannot be administered within the window of the scheduled dosing date, the dose 
may be administered outside of the dosing window as long as it is at least 14 days prior to the next dose 
and recorded as a protocol deviation. 
k 
Subjects enrolled that have reached the Day 85 visit prior to Amendment 2 approval should continue in 
the study without the addition of dapagliflozin to their dosing regimen. 
 
4.2.3 
Follow-up Period 
Table 7 shows all procedures to be conducted during the follow-up period.  
Follow-up of subjects who discontinue MEDI3506 or dapagliflozin is detailed in 
Section 4.1.6. 
Subjects who wish to withdraw from the study should be asked if they are willing to have an 
EOS visit prior to withdrawal. 
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4.3 
Description of Study Procedures 
4.3.1 
Efficacy 
The primary efficacy endpoint of change from baseline to Day 169 (Week 24) in UACR 
compared to placebo will be analyzed based on the Per Protocol Population. Urine will be 
collected for UACR analysis based on the schedule of study procedures in Table 5, Table 6, 
and Table 7. Containers for urine sample collection will be dispensed at Visit 1. Subjects will 
be reminded by phone call to bring in 3 first morning void midstream urine samples: day of 
visit and preceding 2 days (refrigerated overnight, which are return on the day of visit). 
Ideally, first morning void midstream urine samples should be collected after at least 6 hours 
of supine rest, even if the subject returns to sleep; if not possible/convenient, then first 
morning void midstream urine samples should be collected when the subject gets up for the 
day. 
4.3.2 
Medical History and Physical Examination, Electrocardiogram, 
Weight, Height, BMI Calculation, and Vital Signs 
In addition to the medical history, physical examinations, weight, height, body mass index 
(BMI) calculation, vital signs, and ECG assessments described below, additional assessments 
may be performed at the investigator’s discretion. 
4.3.2.1 
Medical History 
Complete medical history will include history of and current medical conditions, past or 
present cardiovascular disorders, respiratory, gastrointestinal, renal, hepatic, neurological, 
endocrine, lymphatic, hematologic, immunologic, psychiatric, genitourinary, menopausal 
status, drug and surgical history, or any other diseases or disorders. In relation to the study 
objectives, diagnosis date for T2DM and CKD will also be recorded. 
4.3.2.2 
Physical Examination, Height, Weight, and BMI calculation 
Full and abbreviated physical examinations will be performed by a licensed healthcare 
provider (eg, physician, physician’s assistant, or licensed nurse practitioner). Full physical 
examinations will include, but are not limited to, assessment of general appearance, head, 
ears, eyes, nose, throat, neck, skin, as well as cardiovascular, respiratory, abdominal, and 
nervous systems. Abbreviated physical examinations will include assessment of 
cardiovascular, respiratory, and nervous systems. Each clinically significant abnormal finding 
will be recorded in the medical history, and each treatment-emergent abnormality including 
injection-site reactions identified by assessing SC injection sites will be recorded as a TEAE. 
Physical examinations, weight, height, and BMI calculation will be performed according to 
the schedule of study procedures where indicated (Table 5, Table 6, and Table 7). 
The focused cardiac exam conducted as part of the abbreviated physical examination will 
include: 


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x 
precordial palpation for LV displacement and parasternal lift, and 
x 
auscultation for S3 gallop and increased intensity of P2. 
 
Additional findings to document any volume overload/volume expansion will include: 
x 
auscultation of lung fields for crackles, and 
x 
assessment for jugular venous distension and lower extremity edema (if present at 
baseline, any changes to be noted at study visit). 
 
Urogenital exam may be omitted at the discretion of the Principal Investigator. 
Weight should be measured in light street clothes, without shoes, after a prior visit to the 
bathroom.  
4.3.2.3 
Vital Signs 
BP will be measured at each study visit along with other vital signs of temperature, pulse, and 
respirations. The nominal timing of vital signs, ECGs, and blood draws is described 
(Section 4.2). Whenever vital signs, 12-lead ECGs, and blood draws are scheduled for the 
same nominal time, the blood draws should occur last. 
For the first 2 doses of MEDI3506 or placebo, vital signs will be taken before and 
immediately after administration of investigational product, and at 30 minutes (± 5 minutes) 
as well as 120 minutes (± 10 minutes) thereafter or until stable, whichever is later. Following 
the observation period, subject discharge will be at the discretion of the investigator. For all 
other dosing visits, vital signs will be collected 30 minutes (± 5 minutes) after administration 
of MEDI3506 or placebo or when stable. 
The subject should be in a seated or supine position for at least 10 minutes prior to the 
collection of vital signs, as follows: 
x 
Oral, axillary, or tympanic temperature 
x 
Diastolic BP 
x 
Systolic BP 
x 
Heart (pulse) rate 
x 
Respiratory rate 
 
For each BP measurement, the same arm and the same appropriately sized BP cuff should be 
used. 
Vital signs are to be recorded in the EDC system. Vital signs may be repeated once after an 
additional 5 minutes of rest. Clinically significant abnormalities in vital signs will be recorded 
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4.3.2.4 
Assessment for Injection-site Reactions 
Site staff will check the injection site for local reactions and assess for any systemic reactions 
for 30 minutes post injection of MEDI3506 or placebo on designated visit days as described in 
Table 6. Local and systemic reactions will be recorded as AEs according to the criteria 
described in Section 5.1. 
4.3.2.5 
Echocardiogram 
A transthoracic echocardiogram will be performed during screening to document baseline 
characteristics and screen for clinically significant congenital or valve disease or a reduction 
in LV ejection fraction of < 40% as described in Section 4.1.3. A subsequent transthoracic 
echocardiogram will be obtained at Visit 9 to reassess LV function and other cardiac 
parameters after treatment. Echocardiograms will be performed as described in a separate 
manual. 
4.3.2.6 
Electrocardiogram 
At the visits specified in Table 5 and Table 7, 12-lead ECGs will be obtained after 10 minutes 
supine rest. Triplicate ECGs will be performed (all 3 ECGs within a 10-minute time period, at 
least 1 minute apart). 
The investigator should date and sign the ECG tracing and record the clinical significance of 
any abnormal result on the tracing. The ECGs will be interpreted by a qualified physician (the 
investigator or qualified designee) at the clinical study site. The ECGs will be stored at the 
study site. ECG evaluation will be recorded in the electronic case report form (eCRF). 
The same recorder should be used for each subject at each time point, if possible. Date and 
time settings should be checked at the start of each study day and aligned with an official 
timekeeper for all machines used in the study. 
The investigator may add extra 12-lead ECG safety assessments if there are any abnormal 
findings or if the investigator considers it is required for any other safety reason. 
4.3.3 
Clinical Laboratory Tests 
A Laboratory Manual will be provided to the sites that specifies the procedures for collection, 
processing, storage, and shipment of samples, as well as laboratory contact information, 
specific to this clinical research study. 
Clinical laboratory safety tests including serum pregnancy tests will be performed in a 
licensed central clinical laboratory. Urine pregnancy tests may be performed at the site using a 
licensed test (dipstick). Abnormal clinically significant laboratory results should be repeated 
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In the event of an urgent or unexpected situation, or emergency, licensed local laboratory 
assessments may be used at the discretion of the investigator. Licensed local laboratories 
should also be used to ensure continuous subject monitoring, if the central laboratory kit were 
to become unavailable. Local laboratory results should be documented in the eCRF.  
The following clinical laboratory tests will be performed (see Table 5, Table 6, and Table 7 
for the schedule of tests): 
Serum Chemistry 
Potassium 
Creatinine 
Sodium 
Blood urea nitrogen 
AST 
Albumin 
ALT 
Total protein 
ALP 
Uric acid 
TBL (if result is > 1.5 × ULN, indirect and direct 
bilirubin will be measured) 
 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; TBL = total 
bilirubin; ULN = upper limit of normal. 
Note for serum chemistry: Tests for AST, ALT, ALP, and TBL must be conducted concurrently and assessed 
concurrently. 
 
Hematology 
Complete blood count with differential 
Platelet count 
RBC count 
Hemoglobin (including 
) 
Hematocrit 
Prothrombin time and PTT 
HbA1c = hemoglobin A1c; PTT = partial thromboplastin time; RBC = red blood cell. 
 
Urinalysis 
Color 
Glucose 
Appearance 
Ketones 
Specific gravity 
Blood 
pH 
Bilirubin 
Protein 
Leukocytes 
Microscopy including WBCs, RBCs, and casts 
 
RBC = red blood cell; WBC = white blood cell. 
 
Pregnancy Tests (female subjects only) 
Serum beta-hCG (at screening only) 
Urine hCG 
hCG = human chorionic gonadotropin. 
 
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Additional Tests 
FSH (female subjects only; screening) 
Cystatin 
Hepatitis B (HBsAg, anti-HBs, and anti-HBc) and C 
antibodies (screening) 
BNP blood samples 
HIV-1 and HIV-2 antibodies (screening) 
eGFR a 
Spot urine for UACR 
Serial draws urine for UACR 
Urine alcohol screen  
Urine drug screen 
a 
CKD-EPI equation based on serum creatinine will be used for eligibility. 
anti-HBc = antibody to hepatitis B core antigen; anti-HBs = antibody to hepatitis B surface antigen; 
BNP = B-type natriuretic peptide; CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; 
eGFR = estimated glomerular filtration rate; EOS = end of study; FSH = Follicle-stimulating hormone; 
; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus, 
UACR = urine albumin:creatinine ratio. 
 
4.3.4 
Pharmacokinetic Evaluation and Methods 
Blood will be collected to evaluate PK of MEDI3506 and dapagliflozin in serum and plasma, 
respectively (see Section 4.2 for collection time points). Samples for determination of 
MEDI3506 and dapagliflozin concentration in serum/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 Method Validation Report. 
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. 
Samples collected for analyses of MEDI3506 and/or dapagliflozin serum/plasma 
concentration may also be used to evaluate safety or efficacy aspects related to concerns 
arising during or after the study. 
Samples from subjects who received placebo may be analyzed at selected time points to 
confirm no dosing with MEDI3506 took place. 
MEDI3506 and dapagliflozin serum/plasma PK concentrations and descriptive statistics will 
be tabulated. Additional PK analyses may be conducted as appropriate. If the data allow, 
population PK analysis will be performed but will not be reported in the clinical study report 
(CSR). 
Instructions for sample collection, processing, storage, and shipment can be found in a 
separate Laboratory Manual provided to sites. 
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4.3.5 
Immunogenicity Evaluation and Methods 
Blood samples will be collected to evaluate ADA responses to MEDI3506 (see Section 4.2 for 
collection time points). Evaluations will be performed using a validated immunoassay. Tiered 
analyses will be performed to include screening, confirmatory, and titer assay components, 
and the positive-negative cut points will be statistically determined from drug-naïve validation 
samples. Samples should be stored for 2 years after marketing approval and may be utilized 
for further characterization of the ADA response, including possible assessment of 
neutralizing antibody (nAb). 
4.3.6 
Genetic Evaluations and Methods 
Genetic evaluation is optional for this study, for details see Appendix D. 
4.3.7 
Biomarker Evaluation and Methods 
The subject’s consent to the use of donated biological samples is mandatory. 
Biological samples will be collected and may be analyzed for exploratory biomarkers to assess 
correlations with disease activity, effects of study drug, clinical outcomes and toxicity. More 
specifically, exploratory serum/plasma and urine biomarkers will be evaluated for the 
potential effects of MEDI3506 on renal inflammation. The relevant biomarkers may include, 
but are not limited to,
. 
4.3.7.1 
Storage, Re-use and Destruction of Biological Samples 
Samples will be stored for a maximum of 15 years from the date of the last subject last visit 
(LSLV), after which they will be destroyed. The results of exploratory biomarker research will 
be included in a scientific report or publication but may or may not be reported in the CSR. 
The results of this biomarker research may be pooled with biomarker data from other studies 
with the study drug to generate hypotheses to be tested in future research. 
4.3.8 
Estimate of Volume of Blood to Be Collected 
The estimated total volume of blood to be collected from each subject at each visit from 
screening through to the EOS is 196.3 mL (Table 8). If repeats of any blood tests are required, 
the volume of blood collection will increase accordingly. Additional blood may be collected at 
the discretion of the investigator in the event of abnormal laboratory findings or an AE. 
Table 8 
Estimate of Blood Volumes 
Visit Day  
Estimated Blood Volume (mL) 
Screening (Day -37 to Day -3) 
approximately 22.2 
Randomization to follow-up (Day 1 to Day 230) 
approximately 174.1 
Total  
approximately 196.3 
 
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4.4 
Study or Study Component Suspension or Termination 
AstraZeneca reserves the right to temporarily suspend or permanently terminate this study or 
component of the study at any time. The reasons for temporarily suspending or permanently 
terminating the study may include but are not limited to the following: 
1 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to subjects 
2 
Subject enrollment is unsatisfactory 
3 
Non-compliance that might significantly jeopardize the validity or integrity of the study 
4 
Sponsor decision to terminate development of MEDI3506 for this indication 
5 
Sponsor decision to terminate the study based on a planned futility analysis 
 
If AstraZeneca determines that temporary suspension or permanent termination of the study or 
component of the study is required, AstraZeneca will discuss the reasons for taking such 
action with all participating investigators (or head of the medical institution, where 
applicable). When feasible, AstraZeneca will provide advance notice to all participating 
investigators (or head of the medical institution, where applicable) of the impending action. 
If the study or component of the study is suspended or terminated for safety reasons, 
AstraZeneca will promptly inform all investigators, heads of the medical institutions (where 
applicable), and/or institutions conducting the study. AstraZeneca will also promptly inform 
the relevant regulatory authorities of the suspension/termination along with the reasons for 
such action. Where required by applicable regulations, the investigator or head of the medical 
institution must inform the Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) promptly and provide the reason(s) for the suspension/termination. If the study or 
component of the study is suspended for safety reasons and it is deemed appropriate by 
AstraZeneca to resume the study or component of the study, approval from the relevant 
regulatory authorities (and IRBs/IECs when applicable) will be obtained prior to resuming the 
study. 
4.5 
Investigational Products 
4.5.1 
Identity of Investigational Products 
AstraZeneca will provide the investigators with investigational products (Table 9) using 
designated distribution centers. 


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As with any biologic product, allergic reactions to dose administration are possible. Therefore, 
appropriate drugs and medical equipment to treat acute anaphylactic reactions must be 
immediately available, and study personnel must be trained to recognize and treat 
anaphylaxis. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.5.4 
Treatment Compliance 
MEDI3506/placebo is administered by study site personnel, who will monitor compliance. For 
dapagliflozin, when administered at the study site, the date, and time if applicable, of dose 
administered in the clinic will be recorded in the source documents and eCRF. The dose of the 
study drugs and study subject identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study drug. 
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When the subjects self-administer dapagliflozin study drug at home, compliance with 
dapagliflozin will be assessed at each visit. Compliance will be assessed by direct questioning, 
counting returned tablets etc, during the study site visits and documented in the source 
documents and eCRF. Deviation(s) from the prescribed dosage regimen should be recorded in 
the eCRF.  
A record of the number of dapagliflozin tablets dispensed to and taken by each subject must 
be maintained and reconciled with study drugs and compliance records. Study drug start and 
stop dates, including dates for intervention delays and/or dose reductions will also be recorded 
in the eCRF. 
Site personnel should support patient urine collection, and dapagliflozin compliance by: 
1 
Clear instructions on the exact activities (orally and written) 
2 
Emphasize that dapagliflozin treatment in patients with chronic kidney disease has 
demonstrated cardiovascular and renal benefits (ADA, 2020; DeSantis, 2020; McMurray 
et al, 2019; Wiviott et al, 2019) 
3 
Stress importance of compliance at each visit 
4 
Recognize patient’s efforts to comply at each visit 
5 
Refer to the patient’s spouse or other partner for support 
 
4.5.5 
Accountability 
The site’s designated investigational product manager is required to maintain accurate 
investigational product accountability records. Upon completion of the study, copies of 
investigational product accountability records will be returned to AstraZeneca. 
Upon authorization by AstraZeneca, all unused investigational product should be destroyed at 
site, in accordance with local standard operating procedures (SOPs). Destruction can be 
outsourced to a third party. Certificates of destructions must be collected. Only if the site is 
unable to destroy unused investigational product, will it be returned to an 
AstraZeneca-authorized depot. 
4.6 
Treatment Assignment and Blinding 
4.6.1 
Methods for Assigning Treatment Groups 
An IXRS will be used for randomization to a treatment group and assignment of blinded 
investigational product kit numbers. A subject is considered randomized into the study when 
the investigator notifies the IXRS that the subject meets eligibility criteria and the IXRS 
provides the assignment of blinded investigational product kit numbers to the subject. 
Subjects will be stratified at the time of randomization in order to ensure approximate balance 
between treatment groups within each sub-population. 


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x 
Stratum 1: Subjects without SGLT2i background outside Japan 
x 
Stratum 2: Subjects with SGLT2i background outside Japan 
x 
Stratum 3: Subjects without SGLT2i background in Japan 
x 
Stratum 4: Subjects with SGLT2i background in Japan 
 
Subjects will be randomized to receive 30, 60, 120, or 300 mg MEDI3506 (95, 95, 95, and 
140 subjects, respectively)
 placebo (32, 32, 32, and 
44 subjects, respectively) by an IXRS system. 
IXRS will also allocate 2 bottles of dapagliflozin (35 tablets each) at Visit 6 and 1 bottle of 
dapagliflozin (35 tablets) at Visit 7 to eligible subjects that will be used to cover the need of 
daily administration between two visits of MEDI3506/placebo administration. This will 
ensure that the patient has sufficient stock of dapagliflozin if a visit is delayed. If there is any 
issue with one of the bottles (eg, lost or damaged), the patient can receive a replacement at any 
visit (Visit 7 or Visit 8); kit replacement option is available in IXRS. 
The procedure for using IXRS is as follows: 
x 
The investigator or designee contacts the IXRS and provides the SID number and 
subject’s baseline characteristic(s) used to verify that it is the same subject 
x 
The correct amount of kits of MEDI3506 and/or placebo will be assigned to the subject 
x 
Confirmation of kit assignment is sent to the unblinded investigational product manager 
who prepares the investigational product to be dispensed to the subject per the response 
system and records the appropriate information in the investigational product 
accountability log 
x 
Blinded study personnel will receive a notification containing a dose tracking number, 
that will not disclose how many kits are assigned to the subject. 
 
Investigational product (MEDI3506 or placebo) must be administered the same day the 
investigational product is assigned. If there is a delay in the administration of investigational 
product such that it will not be administered within the specified timeframe, the study monitor 
must be notified immediately. 
4.6.2 
Methods to Ensure Blinding 
This is a double-blinded study in which MEDI3506 and placebo are not identical in 
appearance or viscosity. Neither the subject nor any of the investigator or sponsor staff who 
are involved in the treatment or clinical evaluation of the subjects will be aware of the 
treatment received (ICH E9) (see Section 4.6.3 for unblinding related to planned analysis). 
An investigational product monitor will be designated to perform product accountability. 
Since MEDI3506 and placebo are not identical, investigational product will be administered 
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by a study team member who will not be directly involved in the management of study 
subjects. In the event that the treatment allocation for a subject becomes known to the 
investigator or other study staff involved in the management of study subjects, AstraZeneca 
must be notified immediately. If the treatment allocation for a subject needs to be known to 
treat an individual subject for an AE, the investigator must notify AstraZeneca immediately. 
The site will maintain a written plan detailing which staff members are blinded/unblinded and 
the process of investigational product preparation and administration used to maintain the 
blind. 
To facilitate the in-stream analysis of PK and ADA samples, the randomization schedule may 
be provided to limited personnel who have responsibility for analyzing the samples. These 
unblinded sample analysts will not have any other involvement with the conduct of the study. 
4.6.3 
Methods for Unblinding 
4.6.3.1 
Unblinding in the Event of a Medical Emergency 
In the event of a medical emergency, the investigator may unblind an individual subject’s 
investigational product (MEDI3506 or placebo) allocation. Instructions for unblinding an 
individual subject’s investigational product allocation are contained in the IXRS manual. In 
general, unblinding should only occur if management of the medical emergency would be 
different based on the subject having received investigational product. In the majority of 
cases, the management of a medical emergency would be the same whether or not 
investigational product was received by the subject. If this was the case, the investigational 
product allocation should not be unblinded. In the event there is unblinding, the investigator 
should promptly document and explain to AstraZeneca the reason for any premature 
unblinding. 
AstraZeneca retains the right to unblind the treatment allocation 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. 
4.6.3.2 
Unblinding for DSMB Purposes 
If unblinding is required by the DSMB (Section 4.8.6), details of the methods for unblinding 
(sponsor will remain blinded) will be provided in a separate DSMB charter. 
4.6.3.3 
Unblinding for Interim Analysis Purposes 
An interim analysis is planned for this study as described in Section 4.8.7. This will require 
unblinding of sponsor staff including those with clinical, medical, statistical, and 
programming expertise, who will form a firewalled unblinded review committee (URC) for 
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Sponsor staff who are unblinded at the interim analysis will not be involved in any study 
activities after they are unblinded. The unblinded sponsor staff will not reveal interim analysis 
results or treatment codes to any sponsor staff who will continue to be involved in the conduct 
of the study before the final database lock. In addition, the interim analysis results will not be 
shared with investigators or subjects. 
4.7 
Restrictions During the Study and Concomitant Treatment(s) 
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until the final study visit. Any concomitant medication(s), including herbal 
preparations, taken during the study will be recorded in the eCRF. 
4.7.1 
Permitted Concomitant Medications 
In general, subjects are expected to be on stable medication regimens during the study. 
Investigators may prescribe concomitant medications or treatments deemed necessary to 
provide adequate supportive care except for those medications identified as “excluded” as 
listed in Section 4.7.2. Specifically, subjects should receive full supportive care during the 
study, and treatment with antibiotics, anti-emetics, anti-diarrheals, and analgesics, and other 
care as deemed appropriate, and in accordance with their institutional guidelines. Subjects 
may require adjustment of other glucose-lowering treatments on commencing dapagliflozin to 
avoid hypoglycemia. As long as it is safe, and according to the investigator’s best clinical 
judgement, RAASi and other antihypertensive therapy, including diuretics, should be kept 
stable throughout the duration of the study. 
4.7.2 
Prohibited Concomitant Medications 
Other than the medications described above, use of concomitant medications including 
over-the-counter medications, herbal supplements, vitamins, etc, from screening through to 
the Early Discontinuation Visit/EOS is discouraged. Subjects must be instructed not to take 
any medications, including over-the-counter products, without first consulting with the 
investigator. While SGLT2 inhibitors are allowed if subjects have been on a stable dose for at 
least 4 weeks prior to Visit 3, these agents should not be initiated after enrollment in the study 
(see Section 4.7.3 for detailed information regarding SGLT2i use). 
Subjects are not permitted to receive any of the following during the study: 
x 
Systemic (oral or injectable) corticosteroids within 28 days of Visit 1 until the end of the 
follow-up period. 
x 
Any other immunosuppressive therapy within 3 months of randomization until the end of 
the follow-up period. 
x 
Any immunotherapy within 3 months of randomization, except for stable maintenance 
dose allergen-specific immunotherapy started 28 days prior to Visit 1 until the end of 
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x 
Interferon gamma within 3 months of randomization until the end of the follow-up period. 
x 
Investigational products other than the investigational products (MEDI3506, placebo, or 
dapagliflozin) administered in this study within 4 months or 5 half-lives of randomization 
until the end of the follow-up period. 
x 
Ig or blood products within 28 days of Visit 1 until the end of the follow-up period. 
x 
Live or attenuated vaccines within 28 days of Visit 3 until the end of the follow-up 
period. 
x 
Renin inhibitor or an aldosterone antagonist in combination with an ACEi or an ARB 
within 2 months of Visit 1 until the end of the follow-up period. 
x 
Ongoing use of any biologic drug targeting the immune system (for example, TNF 
blockers, anakinra, rituximab, abatacept, tocilizumab, cyclophosphamide, cyclosporine, 
tacrolimus, mycophenolate mofetil, or corticosteroids other than topical or inhaled). 
x 
Patients on serum creatinine-altering drugs should be on long-term treatment at a stable 
dose prior to study entry. Drugs considered serum-altering include but are not limited to 
amphotericin, cimetidine, clofibrate, dronedarone, ketoconazole, probenecid, ranolazine, 
trimethoprim, aminoglycosides, or cephalosporins. Generally, any drug that has a putative 
HIIHFWRQVHUXPFUHDWLQLQHLVFRQVLGHUHGVHUXPFUHDWLQLQH-altering. The following 
exclusion criteria apply: 
 
New treatment or change of dose within 6 weeks prior to Visit 1 
 
Expected change of dosing regimen during the study. 
 
Minor ACEi or ARB dose adjustment within 2 weeks of Visit 1 is acceptable, but any 
dose adjustments during the course of the study (ie, for control of hyperkalemia) 
should be discussed with the sponsor/ medical monitor.  
 
Clinically indicated short-term use of serum creatinine-altering drugs to treat acute 
conditions during the study may be allowed. 
 
The activity of cytochrome P450 (CYP450) enzymes can be altered by increased levels of 
certain cytokines (eg, IL-1, IL-6, IL-10, tumor necrosis factor alpha, interferon) during 
chronic inflammation (Huang et al, 2010). Thus, MEDI3506, through its downstream 
mechanism of action, has the potential to normalize the formation of CYP450 enzymes 
indirectly, through the alteration of local and systemic cytokine levels. However, a role for 
IL-33 in the regulation of CYP450 enzymes has not been reported. As a precaution, upon 
initiation or discontinuation of MEDI3506, in patients who are receiving concomitant drugs 
that have a narrow therapeutic index and are CYP450 substrates (eg, warfarin), the 
investigator should consider whether (increased) monitoring is indicated. 
4.7.3 
Considerations for SGLT2i and RAASi 
If a subject is on SGLT2i treatment prior to enrollment into this study, they must have been on 
a stable dose for at least 4 weeks prior to the randomization visit. Starting additional SGLT2i 
therapy during the study, before Day 169/Early Discontinuation Visit, is not permitted. Any 
existing SGLT2i treatment will be discontinued on Day 85. All subjects will receive 10 mg 


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dapagliflozin by mouth daily starting on Day 85 until Day 168. Starting additional SGLT2i 
therapy at or after Day 169/Early Discontinuation Visit is permitted. 
In general, any dose changes of SGLT2i treatment should be avoided during the study unless 
due to medical necessity. If the subject needs to interrupt SGLT2i treatment for any reason, 
they should be allowed to re-start it again once the respective medical condition gets resolved. 
Subjects who have started on the Phase 2a study prior to Amendment 2 will be transitioned to 
the Phase 2b and given 10 mg dapagliflozin starting on Day 85 (Week 12). Any existing 
SGLT2i treatment will be discontinued. Subjects who have completed 12 weeks of treatment 
prior to approval of Amendment 2 will continue on treatment with MEDI3506/placebo 
without dapagliflozin. 
For patients with T2DM and albuminuria, clinical guidelines recommend treatment with ACEi 
or ARB and SGLT2i (dapagliflozin in this study) (de Boer et al, 2020). The recommendation 
of treating patients with T2DM, CKD, and an eGFR > 30 ml/min per 1.73 m2 with an SGLT2i 
and RAASi is based on the highest level of evidence (1A) that these therapies are safe and 
efficient in reducing adverse kidney events. 
Once daily 10 mg dapagliflozin has been studied in large cardiovascular and renal outcomes 
studies on top of standard of care, including ACEi or ARB (DAPA-HF and DAPA-CKD 
studies) (Heerspink et al, 2020b; McMurray et al, 2019). Among patients with CKD and 
T2DM, the risk of a composite of a sustained decline in eGFR of at least 50%, end-stage 
kidney disease, or death from renal or cardiovascular causes was significantly lower with 
dapagliflozin than with placebo. Hence, discontinuation of ACEi or ARB or dapagliflozin 
should be avoided. Permanent discontinuation should be regarded as a last resort. 
In the event of treatment interruption of any duration, resuming administration of ACEi or 
ARB and dapagliflozin should be considered as early as possible. Careful consideration 
should be given to the individual risk/benefit profile and the subject’s needs. 
Dapagliflozin may decrease blood pressure. Adjust other antihypertensive therapies after the 
start of the study if needed.  
Dapagliflozin is a mild diuretic. Adjust other diuretic therapies after the start of the study if 
needed. 
Starting dapagliflozin may require a gradual dose reduction of insulin and/or insulin 
secretagogues (sulfonylureas, meglitinides) to avoid hypoglycemia (Garber et al, 2020).  
Treatment with dapagliflozin should be stopped immediately if diabetic ketoacidosis is 
suspected or confirmed, and treatment should not be re-started unless another clear 
precipitating factor for the condition is identified and resolved (AstraZeneca, 2020). 


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For more details, refer to the dapagliflozin drug label. 
Modest hyperkalemia should generally be managed, if possible, without reducing or 
discontinuing ACEi or ARB, unless there is another reason to do so (Kidney Disease: 
Improving Global Outcomes Diabetes Work, 2020). 
4.7.4 
Vaccination Against COVID-19 
There are no clinical data available to assess the interaction (if any) of MEDI3506 with any 
COVID-19 vaccine. 
The sponsor accepts that vaccination against COVID-19, when and where it is available, and 
when subjects are eligible according to the applicable guidelines, is in the subject’s best 
interest. Consequently, vaccination during the study is, in general, permitted and any delays in 
receiving the vaccination due to study participation should be minimized.  
To help ensure the interpretability of the safety data, receipt of the COVID-19 vaccine (either 
the first or subsequent dose) is prohibited within 28 days before randomization or within 
7 days before or after any dose of MEDI3506/placebo. Receipt of, at least, the first dose of a 
COVID-19 vaccine more than 28 days before randomization, without significantly delaying 
enrollment, is preferred but may not be possible, eg, not locally available at the time, subject 
not eligible at the time, express subject decision not to be vaccinated. Otherwise, vaccination 
may be performed at any time outside the prohibited 7-day window before or after any dose of 
MEDI3506/placebo. If the (approximate) date of a subsequent dose of COVID-19 vaccination 
is known, then enrollment of the subject should be timed so that the dose is not within 28 days 
before the scheduled randomization. If this date is not known, then enrollment into the study 
should not be delayed. If an enrolled subject does (unexpectedly) receive the COVID-19 
vaccine within 28 days before the scheduled randomization, the site should contact the 
AstraZeneca Study Physician for advice on how the situation should be managed. 
If and when a subject receives a COVID-19 vaccination, the following information will be 
recorded in the eCRF as a concomitant medication: the date, dose, brand name, site of 
administration, and lot number (if known) of each vaccine dose (eg, 10 Feb 2021; first dose; 
Pfizer-BioNTech COVID-19 Vaccine; left Deltoid; Lot xxx).  
 
Any AEs suspected to be due to the vaccination should be captured in the AE form including 
the causality assessment related to COVID-19 vaccine. 
4.8 
Statistical Evaluation 
4.8.1 
General Considerations 
Tabular summaries will be presented by treatment group, with the 4 volume-matched placebo 
groups combined. Categorical data will be summarized by the number and percentage of 


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subjects in each category. Continuous variables will be summarized by descriptive statistics. 
Study populations are described in Table 11. Additional details of statistical analyses will be 
described in the statistical analysis plan (SAP). 
Table 11 
Study Populations 
Population 
Description 
Enrolled 
All subjects who sign the informed consent form. 
Full Analysis 
Population 
All subjects who are randomized and receive any study drug. Subjects are evaluated 
according to the treatment assigned at randomization. 
The Full Analysis Population will be used for all analyses of demographic baseline 
characteristics and efficacy data. 
Per Protocol 
Population 
A subset of the Full Analysis Population consisting of all subjects who receive the 
additional treatment with dapagliflozin post Week 12 and do not violate the terms of the 
protocol in a way that may affect the primary efficacy endpoint significantly. All decisions 
to exclude subjects from the per protocol analysis set will be made and documented prior 
to the unblinding of the study. 
Safety Analysis 
Population 
All subjects who are randomized and receive any study drug. Subjects are evaluated 
according to the actual treatment they received. 
The Safety Analysis set will be used for all safety analyses. 
PK Population 
All subjects in the Full Analysis Population who have at least one detectable MEDI3506 
serum concentration measurement posttreatment. The PK Analysis set will be used for all 
PK analyses. 
PK = pharmacokinetic(s). 
 
4.8.2 
Sample Size 
A sample size of 565 subjects randomized using a 95:95:95:140:140 ratio to receive either 30, 
60 mg, 120 mg, or 300 mg MEDI3506 or placebo will give approximately 85:85:85:125:125 
evaluable subjects per group. This will provide at least 85% power for the 300 mg arm and 
80% power for the 30, 60, and 120 mg arms to detect a 30% reduction in change from 
baseline to Day 169 (Week 24) in UACR between each MEDI3506 treatment group and 
placebo group (or placebo/ MEDI3506 ratio of 1.429) with a one-sided alpha of 0.05 without 
multiplicity adjustment, assuming a coefficient of variation of 1.31 or standard deviation of 
1.0 in log scale. 
4.8.3 
Efficacy 
4.8.3.1 
Primary Efficacy Analysis 
The primary efficacy endpoint for this study is change from baseline to Day 169 (Week 24) in 
UACR compared to placebo and will be analyzed based on the Per Protocol Population. For 
the intercurrent events, if a subject is lost to follow-up, discontinues treatment due to AE or 
lack of efficacy, or uses prohibited medication, the UACR data are treated as missing after the 
event and no imputation is performed. As UACR is assumed to follow a log-normal 


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distribution, it will be log-transformed for statistical analysis purposes. The primary analysis 
will use a mixed model repeated measures (MMRM) analysis of change from baseline in 
UACR without multiplicity adjustment. The model will adjust for fixed categorical effects of 
treatment, visit, and treatment-by-visit interaction, randomization stratification factors, and the 
continuous covariates of baseline log UACR and baseline log UACR-by-visit interaction. 
UACR will be log-transformed before entering the data in the MMRM analysis to alleviate the 
skewness of the data. Randomization stratification factors are with SGLT2i background or 
not, in Japan or rest of world. 
To allow generality for the covariance structure for the repeated measures, the 
variance-covariance matrix will be assumed to be unstructured ie, purely data dependent. If 
the unstructured variance-covariance matrix will not fit, then suitable alternatives will be 
considered with details provided in the SAP. In this MMRM model, all subjects and all data 
points will be included. No subjects will be excluded because of missing data, and no 
imputation will be done for missing data. Additionally, there will be no adjustment for 
multiplicity. 
Additionally, the primary efficacy endpoint will also be analyzed using an analysis of 
covariance adjusting for treatment, randomization stratification factors, and baseline log 
UACR with last-observation-carried-forward (LOCF) imputation for missing postbaseline 
measurements. 
4.8.3.2 
Secondary Efficacy Analysis 
The change from baseline to Day 85 (Week 12) in UACR will be analyzed similarly to that of 
the primary efficacy endpoint based on the Full Analysis Population. Change from Day 85 
(Week 12) to Day 169 (Week 24) in UACR will be analyzed similarly to that of the primary 
efficacy endpoint based on the Per Protocol Population. For the proportions of patients with 
> 30%, > 40%, and > 50% reduction in UACR, logistic regression models will be used 
adjusting for treatment, randomization stratification factors, and baseline albuminuria status 
based on the Full Analysis Population and the Per Protocol Population. 
4.8.3.3 
Exploratory Analyses 
Exploratory endpoints will be summarized by treatment group based on the Full Analysis 
Population and/or the Per Protocol Population. 
Additional details of the exploratory endpoint analyses will be described in the SAP. 
4.8.3.4 
Subgroup Analyses 
Subgroup analyses may be performed and will be described in the SAP as required. 


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4.8.3.5 
Sensitivity Analysis 
Sensitivity analyses will be performed to assess the potential impact on study endpoints due to 
COVID-19. Other sensitivity analyses may also be performed. Details will be described in the 
SAP. 
4.8.4 
Safety 
4.8.4.1 
Analysis of Adverse Events 
Safety analysis will be based on the Safety Analysis Population. AE collection will begin after 
the subject signs the ICF and lasts until the end of the study. AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA) by system organ class (SOC) and 
preferred term (PT). Specific AEs will be counted once for each subject for calculating rates, 
but will be presented in total in subject listings. In addition, if the same AE occurs multiple 
times within a particular subject, the highest severity and level of causality will be reported. 
All TEAEs will be summarized overall and by MedDRA SOC and PT, by severity and 
relationship to investigational product. All TEAEs related to dapagliflozin will also be 
summarized. In addition, summaries of deaths, SAEs and treatment discontinuations due to 
AEs will be provided. Injection-site reactions will be presented. For subjects testing positive 
for COVID-19, the number and proportion of subjects with COVID-19 AEs and SAEs and the 
proportion asymptomatic subjects will be summarized. Number of subjects seropositive for 
SARS-CoV-2 at end of study who were seronegative at randomization visit will also be 
summarized. 
4.8.4.2 
Analysis of Clinical Laboratory Parameters 
Clinical laboratory safety tests including serum chemistry and hematology parameters will be 
summarized using descriptive statistics at each time point by treatment group. Change from 
baseline to each post baseline time point in these data will also be summarized, where 
appropriate. A shift table will be provided for these clinical laboratory parameters as well, 
where possible. 
4.8.4.3 
Analysis of Vital Signs and ECGs 
Vital sign results and ECGs will be summarized using descriptive statistics at each time point 
by treatment group. 
4.8.4.4 
Other Safety Endpoints 
Other safety endpoints, such as left ventricular ejection fraction (LVEF) as measured by 
echocardiogram and BNP, will be summarized using descriptive statistics at each time point 
by treatment group. 
4.8.5 
Analysis of Immunogenicity/Pharmacokinetics 
The incidence rate of positive antibodies to MEDI3506 and ADA titer will be reported by 
treatment group. Samples may be utilized for further characterization of the ADA response, 


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including possible assessment of nAbs. If there is a high incidence of ADAs, the association 
of ADA with MEDI3506 concentration will be assessed. In addition, the relationship between 
ADA and PD, efficacy, and safety parameters may be evaluated. 
MEDI3506 serum PK concentrations and descriptive statistics will be tabulated per dose 
group. Additional PK analyses may be conducted as appropriate. If the data allow, population 
PK analysis will be performed but will not be reported in the CSR.  
As an exploratory analysis, dapagliflozin plasma concentrations will be summarized by 
descriptive statistics for each visit and each sample point for dapagliflozin-treated subjects by 
dose cohort. Further details of this will be provided in the SAP. Additional PK analyses may 
be conducted as appropriate. If the data allow, population PK analysis will be performed, but 
will not be reported in the CSR. 
4.8.6 
Data and Safety Monitoring Board 
An independent DSMB will be formed to evaluate safety data from concurrently conducted 
MEDI3506 Phase 2 clinical studies in other indications. Unblinded review of safety data will 
be required for indications where the potential risks of MEDI3506 are high due to the disease 
under study (DUS) and the common comorbidities of particular subject populations. Safety 
data from this study will be provided to the DSMB in order to perform the oversight of all 
safety data. 
The DSMB will be responsible for safeguarding the interests of the subjects in the study by 
assessing the safety of the intervention during the trial and for reviewing the overall conduct 
of the study. The DSMB will be composed of independent experts and will conduct safety 
reviews on a scheduled and, if needed, ad hoc basis. The DSMB will have access to data 
aggregated by treatment group and will be able to review collected study data by treatment 
while the study is ongoing. The DSMB will review prespecified data periodically to ensure 
subject safety and make recommendations to the sponsor regarding further conduct of the 
study. A separate charter will detail the rules, meeting frequency and scope of the 
responsibilities of the DSMB. 
 
 
 
 
 
 
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5 
ASSESSMENT OF SAFETY 
5.1 
Definition of Adverse Events 
An AE is the development of any untoward medical occurrence in a subject or clinical study 
subject administered a medicinal product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(eg, an abnormal laboratory finding), symptom (eg, nausea, chest pain), or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
The term AE is used to include both serious and non-serious AEs and can include a 
deterioration of a pre-existing medical occurrence. An AE may occur at any time, including 
run-in or washout periods, even if no study treatment has been administered.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to 
the subject being enrolled into the study) for a documented pre-existing condition that did not 
worsen from baseline is not considered an AE (serious or nonserious). An untoward medical 
event occurring during the prescheduled elective procedure or routinely scheduled treatment 
should be recorded as an AE or SAE. 
5.2 
Definition of Serious Adverse Events 
An SAE is any AE that: 
x 
Results in death 
x 
Is immediately life-threatening 
x 
Requires inpatient hospitalization or prolongation of existing hospitalization  
x 
Results in persistent or significant disability/incapacity  
x 
Is a congenital anomaly/birth defect in offspring of the subject 
x 
Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
Medical or scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in this situation. Examples of medically important events are intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of drug dependency or drug abuse. 
5.3 
Definition of Adverse Events of Special Interest 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of MEDI3506 and may require close monitoring and rapid communication by 
the investigator to AstraZeneca. An AESI may be serious or non-serious. The rapid reporting 


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of AESIs allows ongoing surveillance of these events in order to characterize and understand 
them in association with the use of this investigational product. 
The following AESIs will be particularly monitored in this study (see the Safety Handling 
Plan for instructions and timing on completing any additional information required for 
specific types of events related to the categories noted below): 
x 
Serious hypersensitivity (including Type 1 to 4 hypersensitivity reactions), for example 
anaphylaxis (see also Appendix B) and severe allergic reactions, and immune complex 
disease. 
x 
Injection-site reactions. 
x 
Heart failure. 
x 
Serious infections (including opportunistic infections and viral reactivations), for example 
varicella zoster/herpes simplex virus, Epstein Barr virus/cytomegalovirus, and TB. 
x 
Gastrointestinal adverse events. 
 
5.4 
Recording of Adverse Events 
AEs will be recorded on the eCRF using a recognized medical term or diagnosis that 
accurately reflects the event. AEs will be assessed by the investigator for severity, relationship 
to the investigational product, possible etiologies, and whether the event meets criteria of an 
SAE and therefore requires immediate notification to AstraZeneca (see Section 5.5). See 
Section 5.2 for the definition of SAEs and Appendix A for guidelines for assessment of 
severity and relationship. 
If an AE evolves into a condition that meets the regulatory definition of “serious”, it will be 
reported on the SAE Report Form. 
5.4.1 
Time Period for Collection of Adverse Events 
AEs will be collected from time of signature of informed consent throughout the treatment 
period and including the follow-up period at Visit 10 or to date of last contact. 
All SAEs will be recorded from the time of informed consent. 
5.4.2 
Follow-up of Unresolved Adverse Events 
Any AEs that are unresolved at the subject’s last AE assessment or other assessment/visit as 
appropriate 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 subject with ongoing AE(s)/SAE(s) at the end of the study, if judged 
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5.4.3 
Deaths 
All deaths that occur during the study, including the protocol-defined follow-up period must 
be reported as follows: 
• Death clearly the result of disease progression should be reported and documented in the 
eCRF but should not be reported as an SAE. 
• Where death is not due (or not clearly due) to disease progression, the AE causing the 
death must be reported as an SAE within 24 hours. The report should contain a comment 
regarding the co-involvement of disease progression, if appropriate, and should assign 
main and contributory causes of death. 
Deaths with an unknown cause should always be reported as an SAE. A post-mortem 
(autopsy) may be helpful in the assessment of the cause of death, and if performed a copy of 
the post-mortem results should be forwarded to AstraZeneca representative(s) within the usual 
timeframes (refer to Section 5.5 for additional information). 
 
5.4.4 
Adverse Events Based on Signs and Symptoms 
All AEs spontaneously reported by the subject or reported in response to the open question 
from the study site staff: ‘Have you had any health problems since the previous visit/you were 
last asked?’, or revealed by observation will be collected and recorded in the eCRF. When 
collecting AEs, the recording of diagnoses is preferred (when possible) to recording a list of 
signs and symptoms. However, if a diagnosis is known and there are other signs or symptoms 
that are not generally part of the diagnosis, the diagnosis and each sign or symptom will be 
recorded separately. 
5.4.5 
Adverse Events Based on Examination and Tests 
The results from the protocol-mandated laboratory tests and vital signs will be summarized in 
the CSR. An abnormal laboratory finding (including ECG finding) that requires medical 
intervention by the investigator, or a finding judged by the investigator as medically 
significant should be reported as an AE. If clinical sequelae are associated with a laboratory 
abnormality, the diagnosis or medical condition should be reported (eg, renal failure, 
hematuria) not the laboratory abnormality (eg, elevated creatinine, urine red blood cell 
increased). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign 
will be considered as additional information. Wherever possible the reporting investigator 
uses the clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value). In 
the absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s). 


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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. 
5.4.6 
Hy’s Law 
Cases where a subject shows elevations in liver biochemistry may require further evaluation 
DQGRFFXUUHQFHVRI$67RU$/7î 8/1WRJHWKHUZLWK7%/ × ULN may need to be 
reported as SAEs. Please refer to Appendix C for further instruction on cases of increases in 
liver biochemistry and evaluation of HL. 
5.4.7 
Disease Progression 
Disease progression can be considered as a worsening of a subject’s condition attributable to 
the disease for which the investigational product is being studied. It may be an increase in the 
severity of the DUS and/or increases in the symptoms of the disease. Death clearly resulting 
from disease progression should not be reported as an SAE (see reporting guidelines in 
Section 5.4.3). 
The term disease progression should not be reported as an AE or SAE, however, medically 
significant individual events and/or laboratory abnormalities associated with disease 
progression (see definition of disease progression below) that fulfill the AE or SAE definition 
should be reported. 
5.4.8 
Disease under Study 
Symptoms of DUS are those which might be expected to occur as a direct result of DKD. 
Events which are unequivocally due to DUS should not be reported as an AE during the study 
unless they meet SAE criteria or lead to discontinuation of the investigational product. 
5.5 
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 must 
inform the appropriate sponsor representative(s) within 1 day, ie, immediately but no later 
than 24 hours after becoming aware of the event. 
The designated study representative works with the investigator to ensure that all the 
necessary information is provided to the sponsor’s patient safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar days 
of initial receipt for all other SAEs. 
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately. Investigators or other site personnel inform sponsor 


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representatives of any follow-up information on a previously reported SAE within 1 calendar 
day, ie, immediately but no later than 24 hours after becoming aware of the event. 
Once the investigators or other site personnel indicate an AE is serious in the EDC system, an 
automated email alert is sent to inform the designated sponsor representative(s). 
If the EDC system is not available, then the investigator or other study site personnel reports 
an SAE to the appropriate sponsor representative by telephone. The sponsor representative 
will advise the investigator/study site personnel how to proceed.  
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 subjects and the safety of a study 
intervention under clinical investigation are met. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study intervention under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting 
to the regulatory authority, IRB/IEC, and investigators. 
For all studies except those using medical devices, investigator safety reports must be 
prepared for suspected unexpected serious adverse reactions (SUSAR) according to local 
regulatory requirements and sponsor policy and forwarded to investigators as necessary. 
An investigator who receives an investigator safety report describing 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 IB or and will notify the IRB/IEC, if appropriate according to local 
requirements. 
5.6 
Other Events Requiring Immediate Reporting 
5.6.1 
Overdose 
For MEDI3506, an overdose is defined as a subject receiving a dose of investigational product 
in excess of that specified in the IB (Edition 5.2), unless otherwise specified in this protocol. 
Dapagliflozin has been well tolerated at doses up to 500 mg/day in single dose testing in 
healthy volunteers and up to 100 mg/day in repeat dose testing for 14 days in healthy 
volunteers and in patients with T2DM. Only suspected single intake of more than 500 mg 
dapagliflozin or repeated intake of more than 100 mg dapagliflozin should be reported on the 
eCRF overdose module. If an overdose is suspected, monitoring of vital functions as well as 
treatment should be performed as appropriate. 


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x 
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. 
x 
An overdose without associated symptoms is only reported on the Overdose eCRF 
module. 
 
If an overdose on an AstraZeneca investigational product occurs during the course of the 
study, then the investigator or other site personnel should inform appropriate sponsor 
representatives immediately, but no later than 24 hours after becoming aware of the event. 
The designated sponsor representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply; see Section 5.5. 
For other overdoses (ie, those not associated with an AE or SAE), reporting must occur within 
30 days. 
5.6.2 
Pregnancy 
All pregnancies and outcomes of pregnancy should be reported to the sponsor except for if the 
pregnancy is discovered before the study subject has received any study drug. 
5.6.2.1 
Maternal Exposure 
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 
subject was discontinued from the study. 
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel will inform the appropriate sponsor representatives within 1 day, ie, immediately 
but no later than 24 hours after becoming aware of the event. 
The designated study representative works with the investigator to ensure that all relevant 
information is provided to the sponsor’s patient safety data entry site within 1 or 5 calendar 
days for SAEs (see Section 5.5) and within 30 days for all other pregnancies. 
The same timelines apply when outcome information is available. 
The pregnancy reporting module in the eCRF is used to report the pregnancy and the 
pregnancy outcome module is used to report the outcome of the pregnancy. 


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5.6.2.2 
Paternal Exposure 
Pregnancy of the subject’s partners is not considered to be an AE. However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth or congenital abnormality), occurring from the date of the first dose until the end of the 
follow-up period (Visit 10) or date of last contact should, if possible, be followed up and 
documented. 
5.6.3 
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 subject or 
has the potential to cause harm to the subject. 
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 subject. 
Medication error includes situations where an error: 
x 
Occurred 
x 
Was identified and intercepted before the subject received the drug 
x 
Did not occur, but circumstances were recognized that could have led to an error 
 
Examples of events to be reported in clinical studies as medication errors: 
x 
Drug name confusion (ie, instead of receiving the investigational product, the subject 
received a drug that has a similar-sounding name) 
x 
Dispensing error, eg, medication prepared incorrectly, even if it was not actually given to 
the subject 
x 
Drug not administered as indicated, for example, wrong route or wrong site of 
administration 
x 
Drug not taken as indicated, eg, tablet dissolved in water when it should be taken as a 
solid tablet  
x 
Drug not stored as instructed, eg, kept in the refrigerator when it should be at room 
temperature  
x 
Wrong subject received the medication (excluding IXRS errors) 
x 
Wrong drug administered to subject (excluding IXRS errors) 
 
Examples of events that do not require reporting as medication errors in clinical studies: 
x 
Errors related to or resulting from IXRS - including those which lead to one of the above 
listed events that would otherwise have been a medication error  
x 
Subject accidentally missed drug dose(s), eg, forgot to take medication 


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x 
Accidental overdose (will be captured as an overdose) 
x 
Subject failed to return unused medication or empty packaging 
x 
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. 
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 or 5 calendar days if there is an SAE associated 
with the medication error (see Section 5.5) and within 30 days for all other medication errors. 
Medication errors should be reported using a Medication Error Report Form. 
6 
STUDY AND DATA MANAGEMENT 
6.1 
Training of Study Site Personnel 
Before the first subject is entered into the study, an AstraZeneca representative will review 
and discuss the requirements of the protocol and related documents with the investigational 
staff and also train them in any study-specific procedures and system(s) utilized. 
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
the study team staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved. 
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing, and other staff). 
6.2 
Monitoring of the Study 
During the study, an AstraZeneca representative will have regular contacts with the study site, 
including visits to: 
x 
Provide information and support to the investigator(s) 
x 
Confirm that facilities remain acceptable 
x 
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately and timely recorded in the eCRFs, that biological samples are handled in 
accordance with the Laboratory Manual and that study drug accountability checks are 
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x 
Perform source data verification (a comparison of the data in the eCRFs with the subject’s 
medical records at the hospital or practice, and other records relevant to the study) 
including verification of informed consent of participating subjects. This will require 
direct access to all original records for each subject (eg, clinic charts) 
x 
Ensure withdrawal of informed consent to the use of the subject’s biological samples is 
reported and biological samples are identified and disposed of/destroyed accordingly, and 
the action is documented, and reported to the subject. 
 
The AstraZeneca representative will be available between visits if the investigator(s) or other 
staff at the center needs information and advice about the study conduct. 
6.2.1 
Source Data 
Refer to the Clinical Study Agreement for location of source data. 
6.2.2 
Study Agreements 
The Principal Investigator at each/the center should comply with all the terms, conditions, and 
obligations of the Clinical Study Agreement, or equivalent, for this study. In the event of any 
inconsistency between this protocol and the Clinical Study Agreement, the terms of protocol 
shall prevail with respect to the conduct of the study and the treatment of subjects and in all 
other respects, not relating to study conduct or treatment of subjects, the terms of the Clinical 
Study Agreement shall prevail. 
Agreements between AstraZeneca and the Principal Investigator must be in place before any 
study-related procedures can take place, or subjects are enrolled. 
6.2.3 
Archiving of Study Documents 
The investigator follows the principles outlined in the Clinical Study Agreement. 
6.3 
Study Timetable and End of Study 
An individual subject will be considered to have completed the study if the subject was 
followed through their last protocol-specified visit/assessment (including telephone contact) 
regardless of the number of doses of investigational product that was received. 
Subjects will be considered not to have completed the study if consent was withdrawn or the 
subject was lost to follow-up (see Sections 4.1.5 and 4.1.6). 
The end of the study (“study completion”) is defined as the date of the last protocol-specified 
visit/assessment (including telephone contact) for the last subject in the study. 


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6.4 
Data Management  
Data management will be performed by AstraZeneca Data Management staff or other party 
according to the Data Management Plan. 
An electronic data capture system will be used for data collection and query handling. The 
investigator will ensure that data are recorded in the eCRFs as specified in the study protocol 
and in accordance with the eCRF instructions provided. 
The investigator ensures the accuracy, completeness, and timeliness of the data recorded and 
of the provision of answers to data queries according to the Clinical Study Agreement. The 
investigator will sign the completed eCRFs. A copy of the completed eCRFs will be archived 
at the study site. 
6.5 
Medical Monitor Coverage 
Each subject will be provided with contact information for the Principal Investigator. In 
addition, each subject will receive a toll-free number intended to provide the subject’s 
physician access to a medical monitor 24 hours a day, 7 days a week in the event of an 
emergent situation where the subject’s health is deemed to be at risk. In this situation, when a 
subject presents to a medical facility where the treating physician or healthcare provider 
requires access to a physician who has knowledge of the investigational product and the 
clinical study protocol and the Principal Investigator is not available, the treating physician or 
healthcare provider can contact a medical monitor through this system, which is managed by a 
third-party vendor. 
7 
ETHICAL AND REGULATORY REQUIREMENTS 
7.1 
Subject Data Protection 
Each subject will be assigned a SID to ensure that personally identifiable information is kept 
separate from the study data. Subject data that are relevant to the trial, eg, demographic 
information, physical or mental health condition, diagnosis, comorbidities, laboratory test 
results, etc. will only be collected with the subject’s informed consent. The ICF will 
incorporate (or, in some cases, be accompanied by a separate document incorporating) 
wording that describes how subject data will be collected, used, and distributed in compliance 
with relevant data protection and privacy legislation. 
Extra precautions will be taken to preserve confidentiality and prevent genetic data being 
linked to the identity of the subject. AstraZeneca will not provide individual genotype results 
to subjects, any insurance company, any employer, their family members, general physician or 
any other third party, unless required to do so by law. 


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7.2 
Ethics and Regulatory Review 
The IRB/IEC responsible for each site must review and approve the final study protocol, 
including the final version of the ICF and any other written information and/or materials to be 
provided to the subjects. The IRB/IEC must also approve all advertising used to recruit 
subjects for the study. The investigator is responsible for submitting these documents to the 
applicable IRB/IEC, and distributing them to the study site staff. 
The opinion of the IRB/IEC must be given in writing. The investigator must provide a copy of 
the written approval to AstraZeneca before enrollment of any subject into the study.  
AstraZeneca should approve any substantive modifications to the ICF that are needed to meet 
local requirements. 
If required by local regulations, the protocol must be re-approved by the IRB/IEC annually. 
Before the study is initiated, AstraZeneca will ensure that the national regulatory authority in 
each country has been notified and their approval has been obtained, as required. AstraZeneca 
will provide safety updates/reports according to local requirements, including suspected 
unexpected serious adverse reactions where relevant, to regulatory authorities, IRB/IEC, and 
Principal Investigators. 
Each Principal Investigator is responsible for providing reports of any serious and unexpected 
adverse drug reactions from any other study conducted with the investigational product to the 
IRB/IEC. AstraZeneca will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements. 
7.3 
Informed Consent 
Informed consent of each subject will be obtained through a written and verbal explanation 
process that addresses all elements required by ICH/GCP. AstraZeneca will develop a core 
informed consent form for use by all investigators in the clinical study. AstraZeneca must 
approve any modifications to the informed consent form that are needed to meet local 
requirements. Subjects should be adequately educated during the informed consent process 
about the continued scientific relevance of their data even if they discontinue treatment, as 
well as the effect that missing data has on trial integrity and credibility. 
The Principal Investigator(s) at each center will: 
x 
Ensure each subject is given full and adequate oral and written information about the 
nature, purpose, possible risk and benefit of the study 
x 
Ensure each subject is notified that they are free to discontinue from the study at any time 
x 
Ensure that each subject is given the opportunity to ask questions and allowed time to 
consider the information provided 


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x 
Ensure each subject provides signed and dated informed consent before conducting any 
procedure specifically for the study 
x 
Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study File 
x 
Ensure a copy of the signed ICF is given to the subject 
x 
Ensure that any incentives for subjects who participate in the study as well as any 
provisions for subjects harmed as a consequence of study participation are described in 
the ICF that is approved by an IRB/IEC 
 
7.4 
Changes to the Protocol and Informed Consent Form 
Study procedures will not be changed without the mutual agreement of the Principal 
Investigator and AstraZeneca. Any changes must be documented in a study protocol 
amendment. 
For a substantial change to the protocol, AstraZeneca will distribute amended versions of the 
protocol to the Principal Investigator(s). Before implementation, amended protocols must be 
approved by relevant IRB/IEC (see Section 7.2) and reviewed as per local regulatory authority 
requirements. The IRB/IEC must also approve revisions to the ICF, advertising, and any other 
written information and/or materials resulting from the change to the protocol. 
Any non-substantial changes will be communicated to or approved by each IRB/IEC. 
7.5 
Audits and Inspections 
Authorized representatives of AstraZeneca, a regulatory authority, or an IRB/IEC may 
perform audits or inspections at the center, including source data verification. The purpose of 
an audit or inspection is to systematically and independently examine all study-related 
activities and documents, to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported according to the protocol, GCP, guidelines of the 
ICH, and any applicable regulatory requirements. The investigator will contact AstraZeneca 
immediately if contacted by a regulatory agency about an inspection at the site. 


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8 
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Alicic RZ, Rooney MT, Tuttle KR. Diabetic Kidney Disease: Challenges, Progress, and 
Possibilities. Clin J Am Soc Nephrol. 2017;12(12):2032-45. 
Alicic RZ, Johnson EJ, Tuttle KR. Inflammatory Mechanisms as New Biomarkers and 
Therapeutic Targets for Diabetic Kidney Disease. Adv Chronic Kidney Dis. 2018;25(2):181-
91. 
Alves-Filho JC, Sônego F, Souto FO, Freitas A, Verri WA, Jr., Auxiliadora-Martins M, et al. 
Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nature 
medicine. 2010;16(6):708-12. 
AstraZeneca. Forxiga (dapagliflozin) Summary of Product Characteristics.  2020. 
Chen WY, Li LC, Yang JL. Emerging Roles of IL-33/ST2 Axis in Renal Diseases. Int J Mol 
Sci. 2017;18(4):783. 
de Boer IH, Caramori ML, Chan JCN, Heerspink HJL, Hurst C, Khunti K, et al. Executive 
summary of the 2020 KDIGO Diabetes Management in CKD Guideline: evidence-based 
advances in monitoring and treatment. Kidney international. 2020;98(4):839-48. 
DeSantis A. Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in 
type 2 diabetes mellitus. UpToDate. 2020. 
Garber AJ, Handelsman Y, Grunberger G, Einhorn D, Abrahamson MJ, Barzilay JI, et al. 
Consensus Statement by the American Association of Clinical Endocrinologists and American 
College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm - 
2020 Executive Summary. Endocr Pract. 2020;26(1):107-39. 
Go AS, Yang J, Tan TC, Cabrera CS, Stefansson BV, Greasley PJ, et al. Contemporary rates 
and predictors of fast progression of chronic kidney disease in adults with and without 
diabetes mellitus. BMC nephrology. 2018;19(1):146. 
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. 
Heerspink HJL, Stefansson BV, Chertow GM, Correa-Rotter R, Greene T, Hou FF, et al. 
Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic 
Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrology, dialysis, 
transplantation : official publication of the European Dialysis and Transplant Association - 
European Renal Association. 2020a;35(2):274-82. 


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Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. 
Dapagliflozin in Patients with Chronic Kidney Disease. The New England journal of 
medicine. 2020b;383(15):1436-46. 
Hickey FB, Martin F. Role of the Immune System in Diabetic Kidney Disease. Curr Diab 
Rep. 2018;18(4):20. 
Hodzic Z, Schill EM, Bolock AM, Good M. IL-33 and the intestine: The good, the bad, and 
the inflammatory. Cytokine. 2017;100:1-10. 
Huang SM, Zhao H, Lee JI, Reynolds K, Zhang L, Temple R, et al. Therapeutic protein-drug 
interactions and implications for drug development. Clin Pharmacol Ther. 2010;87(4):497-
503. 
International Diabetes Federation. IDF Diabetes Atlas Eighth Edition 2017 
https://www.idf.org/component/attachments/attachments.html?id=1405&task=download2017.  
Accessed on: 
Kidney Disease: Improving Global Outcomes Diabetes Work G. KDIGO 2020 Clinical 
Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney 
international. 2020;98(4S):S1-S115. 
Koye DN, Magliano DJ, Reid CM, Jepson C, Feldman HI, Herman WH, et al. Risk of 
Progression of Nonalbuminuric CKD to End-Stage Kidney Disease in People With Diabetes: 
The CRIC (Chronic Renal Insufficiency Cohort) Study. American journal of kidney diseases : 
the official journal of the National Kidney Foundation. 2018;72(5):653-61. 
Levey AS, Stevens LA, Schmid CH, Zhang Y, Castro AF, Feldman HI, et al. A New Equation 
to Estimate Glomerular Filtration Rate. Annals of Internal Medicine. 2009;150(9):604-12. 
Li D, Guabiraba R, Besnard AG, Komai-Koma M, Jabir MS, Zhang L, et al. IL-33 promotes 
ST2-dependent lung fibrosis by the induction of alternatively activated macrophages and 
innate lymphoid cells in mice. The Journal of allergy and clinical immunology. 
2014;134(6):1422-32.e11. 
Lozano-Maneiro L, Puente-Garcia A. Renin-Angiotensin-Aldosterone System Blockade in 
Diabetic Nephropathy. Present Evidences. J Clin Med. 2015;4(11):1908-37. 
Martin NT, Martin MU. Interleukin 33 is a guardian of barriers and a local alarmin. Nature 
immunology. 2016;17(2):122-31. 
McMurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. 
Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. The New England 
journal of medicine. 2019;381(21):1995-2008. 
Mills KT, Xu Y, Zhang W, Bundy JD, Chen CS, Kelly TN, et al. A systematic analysis of 
worldwide population-based data on the global burden of chronic kidney disease in 2010. 
Kidney international. 2015;88(5):950-7. 


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Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in 
the nucleus of endothelial cells and epithelial cells in vivo: a novel 'alarmin'? PLoS One. 
2008;3(10):e3331. 
Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic 
nephropathy. Journal of the American Society of Nephrology : JASN. 2008;19(3):433-42. 
Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, et al. SGLT2 inhibitors 
for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and 
meta-analysis. Lancet Diabetes Endocrinol. 2019;7(11):845-54. 
Perlman AS, Chevalier JM, Wilkinson P, Liu H, Parker T, Levine DM, et al. Serum 
Inflammatory and Immune Mediators Are Elevated in Early Stage Diabetic Nephropathy. 
Annals of clinical and laboratory science. 2015;45(3):256-63. 
Tuttle KR, Brosius FC, Adler SG, Kretzler M, Mehta RL, Tumlin JA, et al. JAK1/JAK2 
inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized 
controlled clinical trial. Nephrology, dialysis, transplantation : official publication of the 
European Dialysis and Transplant Association - European Renal Association. 
2018;33(11):1950-9. 
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and 
Cardiovascular Outcomes in Type 2 Diabetes. The New England journal of medicine. 
2019;380(4):347-57. 
 




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9.2 
Protocol Amendment 4 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 4. The rationale for this amendment is to take measures to reduce the burden on 
the participant, hence most of the changes applied are removals of procedures. 
With the exception of spelling mistakes, specific changes are listed below. 
1 
Throughout the document: To reflect changes in the schedule of procedures (see Tables 6 
and 7), replaced all instances of Visit 12 with Visit 10 as the new EOS, previous mentions 
of Visit 10 with Visit 9, Visit 9 with Visit 8, Visit 8 with Visit 7, and Visit 7 with Visit 6. 
Deleted all mentions of Interim Analysis (Statistical Methods in the Synopsis, Figure 1, 
Sections 4.6.3.3, and 4.8.7). 
2 
Synopsis (Exploratory objectives): Removed “for 12 weeks” from assessment of PK of 
dapagliflozin: “To assess the PK of dapagliflozin after repeated oral dosing when given 
with MEDI3506 for 12 weeks in subjects with DKD”. 
3 
Synopsis (Secondary endpoints): Deleted Endpoint “Number of subjects seropositive for 
SARS-CoV-2 at end of study who were seronegative at randomization visit”. 
4 
Synopsis (Secondary endpoints): Changed Endpoint about subjects testing positive for 
COVID-19 to “For subjects testing positive for COVID-19 SARS CoV 2 (by nucleic acid 
or serology test), during the intervention and follow-up periods, the number and 
proportion of subjects with COVID-19 AEs/SAEs, as well as the number and proportion 
of subjects with COVID-19 AEs/SAEs, and the proportion of asymptomatic subjects.” 
5 
Synopsis (Exploratory endpoints): Replaced “Dapagliflozin plasma concentrations from 
baseline to Day 141 (Week 20)” with “Dapagliflozin plasma concentrations after repeated 
oral dosing, when given with MEDI3506, on Day 141 (Week 20) and Day 169 (Week 
24)”. 
6 
Synopsis (Study design): Reduced number of study sites from 150 to 130. 
7 
Synopsis (Statistical Methods): Removed mention of summarizing COVID-19 related 
tests, AEs, and SAEs. 
8 
Section 1.1 (Disease Background): Deleted “In its reduced form, IL-33 signals through 
ST2 and co-receptor IL-1 receptor accessory protein” from last paragraph. 
9 
Section 1.3 (Dapagliflozin Background): Inserted mention of dapagliflozin providing 
benefits in patients without diabetes and being approved in 100 countries to treat T2DM, 
100 countries for heart failures indications, and 51 countries for chronic kidney disease 
indications. 
10 Section 1.5.1 (MEDI3506): Added mention to a trend towards lower AUC in Japanese 
subjects compared with healthy western subjects. 
11 Section 1.7.1 (MEDI3506): Updated the content of “Serious infections (including 
opportunistic infections)”, “Progression of heart failure”, and Injection-site reactions” to 
match with the current MEDI3506 IB.  
12 Section 1.7.1: Added reference Moussion et al, 2008 and added to reference list in 
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13 Section 1.7.2 (Dapagliflozin): Added CKD to the list of conditions for which the safety 
profile of dapagliflozin has been evaluated in clinical development programs; replaced 
reference Neuen et al, 2019 with de Boer et al, 2020. 
14 Section 2.1 (Primary Objective and Associated Endpoint, Table 1): Added mention to 
blinding central laboratory UACR results from Visit 3 (Day 1) up to and including the 
EOS Visit. 
15 Section 2.2 (Secondary Objectives and Associated Endpoints, Table 2): Deleted Endpoint 
“Number of subjects seropositive for SARS-CoV-2 at end of study who were 
seronegative at randomization visit”. 
16 Section 2.2 (Secondary Objectives and Associated Endpoints, Table 2): Changed 
Endpoint about subjects testing positive for COVID-19 to “For subjects testing positive 
for COVID-19 SARS CoV 2 (by nucleic acid or serology test), during the intervention 
and follow-up periods, the number and proportion of subjects with COVID 19 AEs/SAEs, 
as well as the number and proportion of subjects with COVID-19 AEs/SAEs, and the 
proportion of asymptomatic subjects.” 
17 Section 2.3(Exploratory Objectives and Associated Endpoints, Table 3, PK Objective): 
Removed “for 12 weeks”: “To assess the PK of dapagliflozin after repeated oral dosing 
when given with MEDI3506 for 12 weeks in subjects with DKD”.  
18 Section 2.3(Exploratory Objectives and Associated Endpoints, Table 3, PK Endpoint): 
Replaced “Dapagliflozin plasma concentrations from baseline to Day 141 (Week 20)” 
with “Dapagliflozin plasma concentrations after repeated oral dosing, when given with 
MEDI3506, on Day 141 (Week 20) and Day 169 (Week 24)”. 
19 Section 3.1.1 (Overview): Reduced number of study sites from 150 to 130. 
20 Section 3.1.1. (Overview, Figure 1): Removed “Interim Analysis”, added “Primary 
Endpoint: Day 169”, and moved Primary Analysis to the end of follow up period. 
21 Section 3.2.3 (Rationale for Endpoints): Removed mention to monitoring the number of 
SARS-COV-2-positive patients. 
22 Section 4.1.2 (Inclusion Criteria, criterion 5): Included that subjects must have a stable 
dose of ACEi or ARB for at least 6 weeks prior to Visit 1 and throughout the screening 
period, and that minor dose adjustments are acceptable if performed within 2 weeks 
before Visit 1. 
23 Section 4.1.2 (Inclusion Criteria, criterion 6): Included that subjects must have a stable 
dose of antihypertensive medication for at least 6 weeks prior to Visit 1 and throughout 
the screening period. 
24 Section 4.1.2 (Inclusion Criteria, criterion 8): Added mention of confirmation of off-
season intent to get vaccinated against influenza. 
25 Section 4.1.2 (Inclusion Criteria, criterion 8): Reduced number of days prior to Visit 3 
from 
 to have updated influenza and pneumococcal pneumonia vaccinations. 
26 Section 4.1.3 (Exclusion Criteria, criterion 9e): Added “cirrhosis” to the list of underlying 
condition that predisposes the subject to infections. 
27 Section 4.1.3 (Exclusion Criteria, criterion 12): Updated to exclude patients with a known 
positive diagnostic nucleic acid test for SARS-CoV-2, within 6 weeks prior to 
randomization visit. 
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28 Section 4.1.3 (Exclusion Criteria, criterion 12): Added “antigen” and footnote a: 
“Investigators should use their best clinical judgement to decide on measures needed to 
minimize the risk of randomizing patients with an active SARS-CoV-2 infection. To do 
so, they should consider the local status of the COVID-19 pandemic, the subject’s 
medical and vaccination history, local recommendations regarding outpatient COVID-19 
screening, and testing policies”. 
29 Section 4.1.3 (Exclusion Criteria, criterion 13): Replaced “enrollment” with 
“randomization”. 
30 Section 4.1.3 (Exclusion Criteria, criterion 14b): Added “cyclosporine, 
tacrolimus” to the list of molecules targeting the immune system. 
31 Section 4.1.3 (Exclusion Criteria, criteria 15 and 16): Replaced mentions to 
“Day 1” with “Visit 3”, for consistency. 
32 Section 4.1.6 (Discontinuation of Investigational Product): Visit 10/EOS will now happen 
60 days, instead of 30, after the last visit performed. 
33 Section 4.1.6 (Replacement of Subjects): Removed mention to a jointly determination 
between the Principal Investigator and the medical monitor whether to replace a subject 
who permanently discontinued the study drug or withdrew consent to all follow-up . Such 
decision will be made only by the medical monitor. 
34 Section 4.2.1 (Enrollment/Screening Period, Table 5): Removed phone call 2. 
35 Section 4.2.1 (Enrollment/Screening Period, Table 5): Removed performance of 
nasopharyngeal swabs. 
36 Section 4.2.1 (Enrollment/Screening Period, Table 5): Removed measurement of Weight, 
height, and BMI calculation on Visit 2. Removed footnote “Height measured at Visit 1 
only”, which was linked to this visit. 
37 Section 4.2.1 (Enrollment/Screening Period, Table 5): Added footnote (d) to “serum beta-
hCG, FSH (for all women)” to clarify that testing for menopause will only be performed 
if menopausal status cannot be established from reviewing the full medical history. 
38 Section 4.2.1 (Enrollment/Screening Period, Table 5): Removed measurement of 
antibodies to SARS-CoV-2 virus. 
39 Section 4.2.1 (Enrollment/Screening Period, Table 5): Edited first NOTE to mention that 
retesting will be performed for clinical laboratory tests that are outside the usual range 
and not only for blood pressure, eGFR, ALT, AST, bilirubin, and serum potassium. 
40 Section 4.2.1 (Enrollment/Screening Period, Table 5): Deleted mention of retesting serum 
creatinine for eGFR calculation from footnote f. 
41 Section 4.2.2 (Randomized Treatment Period, Table 6): Removed Visit 4 (Day 15) from 
the schedule. The treatment period ends now with Visit 9 (instead of Visit 10). 
42 Section 4.2.2 (Randomized Treatment Period, Table 6): Included a measurement of 
Cystatin BNP on Early D/c Visit. 
43 Section 4.2.2 (Randomized Treatment Period, Table 6): Reduced the frequency of 
measurements for
, complete blood count with differential, prothrombin time, and 
PTT, PK (MEDi3506), and PK (dapagliflozin). 
44 Section 4.2.2 (Randomized Treatment Period, Table 6): Removed at home weight 
measurements and eGFR calculation. 
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45 Section 4.2.2 (Randomized Treatment Period, Table 6): Included “placebo” in “IP 
administration (MEDI3506)”. 
46 Section 4.2.2 (Randomized Treatment Period, Table 6): Footnote e: Removed Days 85 (2 
h postdose) and 113. Added Day 169 and the mention that patients will be reminded to 
take dapagliflozin on site visits during dapagliflozin administration time (Day 85 to Day 
168). 
47 Section 4.2.3 (Follow-up Period, Table 7): Removed follow-up Visit 11. After removing 
Visit 4 from Table 6, the EOS visit corresponds now to Visit 10 (instead of Visit 12). 
48 Section 4.2.3 (Follow-up Period, Table 7): Removed nasopharyngeal swabs for SARS-
CoV-2 nucleic acid test, eGFR calculation, measurement of antibodies to SARS-CoV-2 
virus, BMI from Physical examination (full) with weight, and Physical examination 
(abbreviated) with weight. 
49 Section 4.3.2.1 (Medical History): Included menopausal status. 
50 Section 4.3.2.2 (Physical Examination, Height, Weight, and BMI Calculation): Removed 
mention of additional weight assessments. 
51 Section 4.3.2.3 (Vital Signs): Added “axillary” to methods of measuring the body 
temperature. 
52 Section 4.3.3 (Clinical Laboratory Tests, Additional Tests): Removed mention of SARS-
CoV-2 nucleic acid and antibodies tests. 
53 Section 4.3.3 (Clinical Laboratory Tests, Additional Tests): Added distinction between 
Spot urine for UACR and Serial draws urine for UACR. 
54 Section 4.3.7.1 (Storage, Re-use and Destruction of Biological Samples): Specified that 
the results of exploratory biomarker research will not be reported in the CSR, but in a 
scientific report or publication. 
55 Section 4.5.1.4 (Treatment Administration): Added mention that during study visits, 
patients will be reminded to take dapagliflozin at the clinical site until Day 168. 
56 Section 4.5.4 (Treatment Compliance): Removed “weight measurement” from the 
procedures with which the site personnel will support patients. 
57 
. 
58 Section 4.7.1 (Permitted Concomitant Medications): Added mention that in general, 
subjects are expected to be on stable medication regimens during the study and that 
RAASi and other antihypertensive therapy as concomitant medications should be kept 
stable throughout the study duration. 
59 Section 4.7.2 (Prohibited Concomitant Medications): Added “cyclophosphamide, 
cyclosporine, tacrolimus, mycophenolate mofetil” to the list of drugs targeting the 
immune system. 
60 Section 4.7.3 (Considerations for SGLT2i and RAASi): Clarified that starting SGLT2i 
therapy during the study, ie, before Day 169/Early Discontinuation Visit, is not permitted. 
61  Section 4.7.3 (Considerations for SGLT2i and RAASi): Clarified that starting SGLT2i 
therapy at, or after, Day 169 or Early Discontinuation Visit, is permitted. 
 
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9.3 
Protocol Amendment 3 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 3. The principal rationale for this amendment is to clarify the use of vaccines 
against COVID-19 during the study. In addition, the exclusion criterion for prior malignancy 
was clarified, and an exclusion criterion for the COVID-19 vaccination was added, including 
recommendations regarding vaccination against COVID-19 during the study. It was clarified 
that a local laboratory can be used for COVID-19 testing when necessary and also that local 
laboratory assessments may be used at the discretion of the investigator in the event of urgent 
unexpected medical situations, or an emergency. Guidelines for treatment with RAASi and 
dapagliflozin administration, including safety precautions, were added. The requirement for 
subjects to be fasted before blood or urine collection was removed. The visits schedule, 
including an Early Discontinuation Visit, to be followed after discontinuation of 
MEDI3506/placebo was clarified. The definition of investigational product was clarified 
throughout as MEDI3506, placebo, or dapagliflozin, as appropriate. 
With the exception of typographical changes, specific changes are listed below. 
1 
Throughout protocol: when referring to “investigational product” clarified if this referred 
to MEDI3506, placebo, or dapagliflozin, as appropriate. 
2 
Synopsis (statistical methods): Clarified that all TEAEs related to dapagliflozin will also 
be summarized. 
3 
Section 1.5.1 (MEDI3506): Updated details of ongoing studies. 
4 
Section 1.7.2 (Dapagliflozin): Updated with details of the number of subjects treated with 
dapagliflozin for DKD, and added details of the DAPA-CKD study. 
5 
Section 4.1.2 (Inclusion Criteria, criterion 9): Clarified that male subjects should use a 
condom until 24 weeks after the last dose of MEDI3506, and updated the duration for 
which female subjects of childbearing potential must agree to use a highly effective 
method of birth control from “at least 16 weeks” to “at least 12 weeks” after the last dose 
of MEDI3506. 
6 
Section 4.1.3 (Exclusion Criteria, criterion 9): Clarified that exclusion of prior 
malignancy other than (i) ‘non-melanoma skin cancer (squamous or basal cell 
carcinoma)’ and (ii) ‘cervical cancer in situ’, relates to prior malignancies of this nature 
that have been treated for complete cure.  
7 
Section 4.1.3 (Exclusion Criteria, criterion 10): Added 2 exclusion criteria related to 
vaccination against COVID-19 (either first or subsequent dose). 
8 
Section 4.1.3 (Exclusion Criteria, criterion 14): Added cross-reference to Section 4.7.2. 
9 
Section 4.1.6 (Discontinuation of Investigational Product): Clarified which visits subjects 
are expected to attend after discontinuation of MEDI3506 or dapagliflozin. 
10 Section 4.1.6.1 (Missed Doses of MEDI3506): Clarified that the missed doses refer to 
missed doses of MEDI3506. Added cross-reference to Section 4.7.3 for the handling of 
missed doses of dapagliflozin. 


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11 Section 4.2.1 (Enrollment/Screening Period, Table 5) and Section 4.2.3 (Follow-up 
Period): Clarified that subjects will return first morning void midstream urine collection 
samples for UACR analysis. 
12 Section 4.2.1 (Enrollment/Screening Period, Table 5) and Section 4.2.3 (Follow-up 
Period): Footnote e corrected to state that the samples that may be collected for a 
blood-based SARS-CoV-2 nucleic acid test if nasopharyngeal swabs are not available 
should be serum samples, not plasma samples. 
13 Section 4.2.1 (Enrollment/Screening Period, Table 5) and Section 4.2.3 (Follow-up 
Period): Clarified that the alcohol screen breathalyzer is to be performed in line with local 
practices. 
14 Section 4.2.1 (Enrollment/Screening Period, Table 5): Clarified that height is measured at 
Visit 1 only by adding a new footnote d. 
15 Section 4.2.2 (Randomized Treatment Period, Table 6): Added a new column for an Early 
Discontinuation Visit.  
16 Section 4.2.2 (Randomized Treatment Period, Table 6): Removed the criterion for 
subjects to be fasted before blood or urine collection, and clarified that ADA assessments 
will be performed in the sponsor’s laboratory in footnote g.  
17 Section 4.2.2 (Randomized Treatment Period, Table 6): New footnote i added. 
18 Section 4.2.3 (Follow-up Period): Text regarding the EOS visit replaced with a 
cross-reference to Section 4.1.6 where more details are presented. 
19 Section 4.2.3 (Follow-up Period, Table 7): Changed plasma to serum for sample 
collection for blood-based SARS-CoV-2 nucleic acid tests. 
20 Section 4.2.3 (Follow-up Period, Table 7): Removed height from physical examination 
assessment as height should be measured at Visit 1 only. 
21 Section 4.3.2.3 (Vital Signs): Text regarding order of assessments clarified to confirm that 
blood draws should occur last. 
22 Section 4.3.3 (Clinical Laboratory Tests): Added details of the SARS-CoV-2 nucleic acid 
tests. 
23 Section 4.3.4 (Pharmacokinetic Evaluation and Methods): Text added to indicate that PK 
analysis will be performed at selected time points for subjects who received placebo to 
confirm that no dosing with MEDI3506 took place. 
24 Section 4.6.1 (Methods for Assigning Treatment Groups): Requirement for approximately 
113 Japanese subjects removed. 
25 Section 4.6.2 (Methods to Ensure Blinding): Text to allow unblinding for PK and ADA 
analysis added. 
26 Section 4.7.2 (Prohibited Concomitant Medications): Clarified that subjects are not 
permitted to receive investigational products other than the investigational products 
administered in this study within 4 months or 5 half-lives of randomization until the end 
of the follow-up period. Also corrected that subjects are not permitted to receive live or 
attenuated vaccines within 28 days of Visit 3 (rather than Visit 1) until the end of the 
follow-up period. Clarified that renin inhibitor or an aldosterone antagonist in 
combination with an ACEi or an ARB is not permitted within 2 months of Visit 1 until 
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27 Section 4.7.3 (Considerations for SGLT2i and RAASi): Section updated to include 
treatment guidelines for ACEi or ARB and SGLT2i (dapagliflozin). 
28 Section 4.7.4 (Vaccination Against COVID-19) was added. 
29 Section 4.8.4.1 (Analysis of Adverse Events): Clarified that all TEAEs related to 
dapagliflozin will also be summarized. 
30 Section 4.8.5 (Analysis of Immunogenicity/Pharmacokinetics): Text amended to indicate 
that samples may be utilized for further characterization of ADA response, including 
possible assessment of nAbs. 
31 Section 8 (References): New references in Section 4.7.3 added. 
32 Appendix D: Corrected the timing of the collection of the blood sample for genetic 
research from Visit 1 to Visit 3. 
33 Appendix F4: Clarified that safety clinical laboratory tests can be performed in a local 
licensed laboratory. 
 
9.4 
Protocol Amendment 2 
The primary rationale for this amendment is to explore the efficacy of different doses of 
MEDI3506 on DKD on top of current standard of care in DKD (ACEi or ARB) as well as 
expected future standard of care (ACEi or ARB and SGLT2i). SGLT2i have been shown to 
consistently reduce the risk of clinically important, patient-level cardiovascular outcomes, and 
emerging data suggest that the combination of ACEi or ARB and SGLT2i should be routinely 
offered to patients with T2DM who have, or are at high risk of, progressive kidney disease. 
The study was therefore expanded from a Phase 2a (N = 168) to Phase 2b (N = 565). The 
expanded sample size is expected to facilitate decisive subgroup analysis and prevent biased 
patient recruitment. An additional rationale for this amendment was to add study mitigation 
language and language flexibility due to COVID-19 which will provide sites with measures 
that may be implemented if a subject is not able to visit a study site. With the exception of 
typographical changes, specific changes are listed below. All changes listed below were also 
made to the Protocol Synopsis where required. 
1 
Section 1.1 (Disease Background): Background text was updated to reflect the current 
recommendations for risk management in patients with DKD. 
2 
Section 1.3 (Dapagliflozin Background), Section 1.4.2 (Dapagliflozin), Section 1.5.2 
(Dapagliflozin), Section 1.7.2 (Dapagliflozin), and Section 1.7.3 (Other Risks): 
Introductory sections added to reflect the addition of dapagliflozin to the study and to 
provide background information, references to nonclinical and clinical experience, and 
benefit-risk assessment. 
3 
Section 1.4.1 (MEDI3506): Added the underlined text: “Slight accumulation (mean 
accumulation ratios were 1.1 to 1.8) of MEDI3506 was observed after multiple SC or IV 
doses after 
 weeks of dosing” for additional clarity. 
4 
Section 1.5.1 (MEDI3506): Summary of clinical experience was updated to reflect the 
completion of Study D9180C00001 and summarize safety and PK observations. 
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37 Section 4.1.6 (Discontinuation of Investigational Product): Dapagliflozin administration 
criteria were added for suspected/confirmed cases of DKA. 
38 Section 4.1.6.1 (Missed Doses): Guidelines were added in case of missed dosing in light 
of the COVID-19 pandemic. 
39 Section 4.2.1 (Enrollment/Screening Period): To minimize burden on patients it was 
clarified that ‘where the values for the following investigations are outside the usual range 
for a subject during screening, based on their medical history, retesting may be 
undertaken on one occasion without requiring a re-screen: Blood pressure, eGFR, ALT, 
AST, bilirubin, and serum potassium’. 
40 Section 4.2.1 (Enrollment/Screening Period): HIV-2 screening was added to Table 5 as it 
was previously omitted in error. 
41 Section 4.2.1 (Enrollment/Screening Period): Hepatitis A screening was removed from 
Table 5 as it was previously included in error. 
42 Section 4.2.1 (Enrollment/Screening Period): Spot urine in footnote e was removed as 
spot urine for UACR calculation for eligibility was removed in a previous amendment. 
43 Section 4.2.1 (Enrollment/Screening Period), Section 4.2.3 (Follow-up Period): Added 
blood collection for antibodies to SARS-CoV-2 virus and nasopharyngeal swabs for 
SARS-CoV-2 nucleic acid test as well as a footnote stating that nasopharyngeal swabs 
may be replaced by plasma collection if the swabs are unavailable. 
44 Section 4.2.1 (Enrollment/Screening Period), Section 4.2.2 (Randomized Treatment 
Period), Section 4.2.3 (Follow-up Period): Added a note instructing investigators to 
contact patients by phone prior to scheduled visit to assess COVID-19 signs and 
symptoms. 
45 Section 4.2.1 (Enrollment/Screening Period), Section 4.2.3 (Follow-up Period), Section 
4.3.3 (Clinical Laboratory Tests): SARS-CoV-2 nucleic acid test and antibody test were 
added. 
46 Section 4.2.2 (Randomized Treatment Period): Language in Table 6, footnote e regarding 
MEDI3506 PK sample collection was simplified. 
47 Section 4.2.2 (Randomized Treatment Period): Note was added to specify that subject 
with symptoms consistent with COVID-19 should be tested on an ad hoc basis. 
48 Section 4.2.2 (Randomized Treatment Period), Section 4.3.2.2 (Physical Examination, 
Height, Weight, and BMI calculation): Capture of at-home weight measurements was 
extended to the end of the treatment period to obtain data during non-visit weeks. 
49 Section 4.2.2 (Randomized Treatment Period):  Day 15 blood and urine sample collection 
time point added for exploratory biomarkers.  
50 Section 4.2.2 (Randomized Treatment Period): In Table 6, footnote g, regarding samples 
for ADA, exploratory biomarkers, urinalysis, pregnancy test, future use, and genetic 
research, added: ‘Subjects should be requested to be in a fasting state (except water) for at 
least 8 hours prior to sample collection and samples should be collected in the morning. 
All the assessments to be performed in central laboratories.’ 
51 Section 4.2.2 (Randomized Treatment Period), Section 4.2.3 (Follow-up Period): Deleted 
‘Japan only’ following 
 and deleted the corresponding footnote to indicate that 
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samples should be collected from all subjects and that testing will be performed in a 
central laboratory.  
52 Section 4.2.3 (Follow-up Period): Table 7, footnote d was modified for additional clarity 
as follows: Bring inSubjects collect 3 consecutive first morning void midstream urine 
samples (ideally day of visit and preceding 2 days [refrigerated overnight] which are 
returned on the day of visit. 
53 Section 4.3.1 (Efficacy), Section 4.8.3.1 (Primary Efficacy Analysis): ITT population was 
changed to Per Protocol Population as the basis of the primary efficacy endpoint analysis 
based on the updated study design. 
54 Section 4.3.2.5 (Echocardiogram): Added statement that echocardiogram procedures are 
described in a separate manual. 
55 Section 4.3.3 (Clinical Laboratory Tests): Local lab testing option for clinical laboratory 
safety tests including serum pregnancy tests was removed as these tests are to only be 
done centrally. 
56 Section 4.3.3 (Clinical Laboratory Tests): 
was removed from ‘Additional Tests’ 
table as it is already included in the Hematology panel. 
57 Section 4.3.4 (Pharmacokinetic Evaluation and Methods): Added language stating that 
PK samples may be used to evaluate safety or efficacy aspects and that samples may be 
collected at additional time points if needed for safety reasons. 
58 Section 4.3.8 (Estimate of Volume of Blood to Be Collected): Blood volume estimates 
were updated based on additional collections for dapagliflozin PK and COVID-19 testing. 
59 Section 4.5.1 (Identity of Investigational Products): Dapagliflozin supplied concentration 
and formulation, and packaging information was added. 
60 Section 4.5.1.3 (Dose Preparation Steps): Preparation information for MEDI3506 
30 mg/120 mg and placebo 0.2 mL/0.8 mL doses were added. 
61 Section 4.5.1.4 (Treatment Administration): Dapagliflozin treatment administration 
information was added. 
62 Section 4.5.1.6 (Reporting Product Complaints). Email address for reporting product 
complaints was updated. 
63 Section 4.5.3 (Storage): Dapagliflozin storage information added.  
64 Section 4.5.4 (Treatment Compliance): Information regarding the monitoring of 
dapagliflozin treatment compliance was added. Added additional guidelines for site 
personnel to support compliance. 
65 Section 4.6.1 (Methods for Assigning Treatment Groups): Details on stratification of 
randomized subjects was added in order to ensure approximate balance between treatment 
groups within each sub-population. 
66 Section 4.7.1 (Permitted Concomitant Medications): Added language stating that 
adjustment of other glucose-lowering treatments on commencing dapagliflozin may be 
required to avoid hypoglycemia. 
67 Section 4.7.2 (Prohibited Concomitant Medications): Precaution wording for CYPs was 
added based on previous discussions with MHRA regarding a MEDI3506 clinical study 
in a different indication. 
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68 Section 4.7.3 (SGLT2 Inhibitors): Added section containing detailed information on 
SGLT2i use during the study. 
69 Section 4.8.1 (General Considerations): Study population categories were updated 
appropriately based on the updated study design. 
70 Section 4.8.2 (Sample Size): Calculations of statistical power were updated based on the 
updated study design. 
71 Section 4.8.3.1 (Primary Efficacy Analysis): Added text to clarify UACR data treatment 
in case of intercurrent events, and updated to reflect that analysis will be based on the Per 
Protocol Population 
72 Section 4.8.3.1 (Primary Efficacy Analysis): Text was added to indicate that UACR will 
be log-transformed for statistical analysis purposes as UACR is assumed to follow a log-
normal distribution.  
73 Section 4.8.3.1 (Primary Efficacy Analysis): Covariates were updated to simplify models. 
74 Section 4.8.3.5 (Sensitivity Analysis): Section was added to describe sensitivity analysis 
to assess COVID-19 impact on study endpoints. 
75 Section 4.8.4.1 (Analysis of Adverse Events): Text was updated to reflect that safety 
analysis will be based on the Safety Analysis Population. Description of safety analysis 
related to COVID-19 prevalence among study patients was also added. 
76 Section 4.8.7 (Interim Analysis): Change from baseline to Day 85 (Week 12) in UACR 
was defined as part of the interim analysis. Other changes in this section were made for 
clarity and descriptiveness. 
77 Section 5.3 (Definition of Adverse Events of Special Interest): Replaced “Gastrointestinal 
adverse reactions assessed as related to study treatment” with “Gastrointestinal adverse 
events” as all GI events should be recorded as an AESI. 
78 Section 5.6.1 (Overdose): Instructions in the event of a dapagliflozin overdose were 
added. 
79 Appendix F (COVID-19 Specifics): Appendix F was added to describe the background 
information, risks and mitigations plans, and impact of COVID-19 on the current study. 
 
9.5 
Protocol Amendment 1 
Text revisions resulting from this amendment are incorporated in the body of Protocol 
Amendment 1. The principal reason for this amendment is to provide administrative 
clarification.  
All changes to the protocol were considered to be non-substantial and are summarized below: 
1 
Title Page: Replaced Marvin Sinsakul with Alexis Hofherr as Medical Monitor 
2 
Protocol Synopsis: Updated to be consistent with the changes made to the body of the 
protocol. 
3 
Section 3.1.1 (Overview): Approximate number of study sites and potential number of 
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4 
Section 3.1.1 (Overview) and Figure 1 (Study Flow Diagram): Treatment period was 
updated to 168 days as it was incorrectly listed as 169 days previously. 
5 
Section 4.1.2 (Inclusion Criteria [Inclusion criterion 3b]) and Table 4 (Schedule of 
Screening Procedures [footnote e]): Clarified that for subjects with amputation, eGFR 
will be adjusted based on estimated body weight loss. 
6 
Section 4.1.2 (Inclusion Criteria): Inclusion criterion 3c, Spot urine was removed from the 
inclusion criteria as it was intended to pre-select patients for first morning void UACR 
analysis; however, first morning void is more reliable for UACR analysis than spot urine.  
7 
Section 4.1.2 (Inclusion Criteria): Inclusion criterion 4b was revised from “Stable dose of 
ACEi or ARB for at least 6 weeks prior to Visit 1 at the maximum labelled or maximum 
tolerated dose” to “Stable dose of ACEi or ARB for at least 6 weeks prior to Visit 1 with 
ACEi and ARB dosing according to local guidelines” to allow investigator discretion 
based on local guidelines as to appropriate dose of ACEi or ARB therapy. Additionally, 
edits were made to the following (as indicated) for clarification: “Minor Ddose 
adjustment of the next/previous titration dose within 2 weeks of Visit 1 is acceptable.” 
8 
Section 4.1.2 (Inclusion Criteria): Inclusion criterion 4c was changed to criterion 5, to 
clarify that subjects are not required to be on both ACEi/ARB and other hypertensive 
medications, but if subjects are on other hypertensive medication, they should be on 
stable doses for at least 6 weeks prior to Visit 1. 
9 
Section 4.1.2 (Inclusion Criteria): For inclusion criterion 6, up-to-date influenza and 
pneumococcal pneumonia vaccinations (patient reported) was clarified to be ‘according to 
local recommendations’. 
10 Section 4.1.3 (Exclusion Criteria): Exclusion criterion 3a, Replaced “Evidence of chronic 
liver disease at Visit 1” with exclusion criteria 4 for “History or presence of hepatic 
disease” to avoid ambiguity in the former sentence. 
11 Section 4.1.3 (Exclusion Criteria): Exclusion criterion 8d(i-iii), Clarified that non-
melanoma skin cancer, including squamous or basal cell carcinoma, or cervical cancer in 
situ, as well as any other history of malignancy treated with apparent success with 
curative therapy are not excluded. 
12 Section 4.1.3 (Exclusion Criteria): Exclusion criterion 8f(ii), For history of herpes zoster, 
added “with last flare occurring” for clarity, and changed to “within 3 months of Visit 1” 
rather than Visit 3, as it should be part of screening before requesting the transthoracic 
echocardiogram and first morning void urine.  
13 Section 4.1.3 (Exclusion Criteria): Exclusion criterion 9, “Live or attenuated virus 
vaccination within 28 days of Visit 1 until the end of the follow-up period is not allowed” 
was changed to “Live or attenuated virus vaccination within 28 days of Visit 3 until the 
end of the follow-up period is not allowed” to align risk mitigation strategy for potential 
risk of infection while on study. 
14 Section 4.1.3 (Exclusion Criteria [Exclusion criterion 11c]) and Section 4.7.2 (Prohibited 
Concomitant Medications): Clarified that only chronic use of any serum creatinine-
altering drugs within 1 month prior to Visit 1 is prohibited. 
15 Section 4.1.3 (Exclusion Criteria): Exclusion criterion 12, Japan-specific exclusion 
criteria for blood donation and blood loss were added. 


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16 Section 4.2.1 (Enrollment/Screening Period), Section 4.2.2 (Randomized Treatment 
Period) and Section 4.2.3 (Follow-up Period): “Assessments should be performed in the 
order shown in the table” was deleted to allow investigator judgement and the orders of 
certain procedures are already listed in appropriate sections of the protocol. 
17 Table 4 (Schedule of Screening Procedures): Weight, height, and BMI calculation was 
added for Visit 2 for an additional assessment time point. 
18 Table 4 (Schedule of Screening Procedures): “protime” was corrected to “prothrombin 
time”. 
19 Table 4 (Schedule of Screening Procedures), Section 4.3.2 (Medical History and Physical 
Examination, Electrocardiogram, Weight, Height and Vital Signs), and Section 4.3.2.2 
(Physical Examination, Height, Weight, and BMI calculation): Added BMI as an 
additional safety assessment. 
20 Table 4 (Schedule of Screening Procedures) and Table 7 (Estimate of Blood Volumes): 
Screening period was updated from Day -35-Day -1 to Day -37-Day -3 to allow clinical 
study sites sufficient time to remind participants to collect first morning void urine 
samples 3 days prior to the next visit. 
21 Table 4 (Schedule of Screening Procedures), Table 5 (Schedule of Treatment Period 
Study Procedures), and Table 6 (Schedule of Follow-up Procedures): Reminder to 
participants “to collect first morning void urine samples from the 3 mornings before visit” 
was changed to “to collect first morning void urine samples 3 days before the next visit” 
for clarity. A phone call reminder 3 days prior to Visit 3 was also added in Table 4. 
22 Table 4 (Schedule of Screening Procedures): Footnote d, Clarified that, if otherwise 
eligible based on screening Visit 1, transthoracic echocardiogram may be performed 
independently of other Visit 2 procedures within the screening period for additional 
flexibility. 
23 Table 4 (Schedule of Screening Procedures): Footnote e, Added clarification that serum 
creatinine for eGFR calculation and spot urine for UACR may be retested once during the 
course of screening. 
24 Table 4 (Schedule of Screening Procedures): Footnote f, Clarified that drug screen is to be 
performed in line with local practices and investigator discretion to allow for patients who 
may be using tetrahydrocannabinol for medical reasons. 
25 Table 5 (Schedule of Treatment Period Study Procedures): Visit windows that were 
previously ± 2 days were increased to ± 5 days for patient centricity to allow greater 
flexibility for clinical visit. 
26 Table 5 (Schedule of Treatment Period Study Procedures): Rows for Physical 
examination and Weight were combined for brevity and consistency. 
27 Table 5 (Schedule of Treatment Period Study Procedures): Added the underlined text to 
the ‘At home weight measurements’ row for clarity and consistency with footnote b: “To 
be completed at least weekly for the first 12 weeks to capture…”. 
28 Table 5 (Schedule of Treatment Period Study Procedures) and Table 6 (Schedule of 
Follow-up Procedures): Added monthly testing for 
 for sites in Japan.  
29 Table 5 (Schedule of Treatment Period Study Procedures), Table 6 (Schedule of 
Follow-up Procedures), and Section 4.3.2.5 (Echocardiogram): Transthoracic 
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echocardiogram was moved from Visit 11 to Visit 10 in order to assess cardiac benefits 
during the treatment period. 
30 Table 5 (Schedule of Treatment Period Study Procedures): Revised language in footnote 
b for the at-home weight scale and app to allow a designee of the investigator to train 
subjects on their usage and to state that the scale will be distributed to subjects at Visit 3 
(rather than Visit 1) since the first at-home measurements will be done at Visit 3. 
31 Table 5 (Schedule of Treatment Period Study Procedures) and Table 6 (Schedule of 
Follow-up Procedures): eGFR calculation was added to complement serum chemistry. 
32 Table 5 (Schedule of Treatment Period Study Procedures): Pregnancy test was added to 
Visit 10 for additional monitoring. 
33 Table 5 (Schedule of Treatment Period Study Procedures): Footnote c, removed vital 
signs measurements at 60 minutes and increased window to ± 10 minutes for the 
120 minute vital sign measurement after administration of investigational product to 
reduce burden of unnecessary procedures and flexibility of measurement. 
34 Table 5 (Schedule of Treatment Period Study Procedures): Footnote d, Clarified that 
transthoracic echocardiogram may be performed independently of other Visit 10 
procedures within the visit window for additional flexibility. 
35 Table 5 (Schedule of Treatment Period Study Procedures): Footnote f, removed Day 169 
PK sample collection as there will be no investigational product administered at this time 
point. 
36 Table 6 (Schedule of Follow-up Procedures): Height and BMI calculation were added for 
Visit 12 for an end of study visit assessment. 
37 Section 4.3.1 (Efficacy): Added clarification as to what constitutes a ‘first morning void’ 
sample.  
38 Section 4.3.2.2 (Physical Examination, Height, and Weight): Deleted “Weight assessment 
will be conducted at every study visit” to avoid redundancy with text in the same 
paragraph: “Physical examinations, weight, height, and BMI calculation will be 
performed according to the schedule of study procedures where indicated” 
39 Section 4.3.2.2 (Physical Examination, Height, and Weight): Specified that weight should 
be measured in light street clothes, without shoes, after a prior visit to the bathroom to 
ensure that measurements are under similar conditions. 
40 Section 4.3.2.2 (Physical Examination, Height, Weight, and BMI calculation): Added text 
for clarity and for consistency with Table 5 (Schedule of Treatment Period Study 
Procedures): 1) additional remote weight assessments will be obtained at least weekly at 
home using a remote digital scale for the first 12 weeks after initial dose of investigational 
product; 2) subjects will be trained on how to use the app and weight scale by 
investigators or designee and take the scale home at Visit 3; and 3) if needed, subjects 
may be provided with a smartphone in order to use the app, and that data will be available 
to site and sponsor in real time for review. 
41 Section 4.3.2.3 (Vital Signs): Revised the order of procedures for vital signs to occur prior 
to 12-lead ECG for consistency with the Schedule of Study Procedures. 
42 Section 4.3.2.6 (Electrocardiogram): Revised text to state that only ECG evaluation will 
be recorded in the eCRF and removed the specific ECG variables (RR, PR, QRS, QT 
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43 Section 4.3.3 (Clinical Laboratory Tests): Clarified that clinical laboratory safety tests 
including serum pregnancy tests will be performed in a licensed local or licensed central 
clinical laboratory to avoid ambiguity. 
44 Section 4.3.3 (Clinical Laboratory Tests): Added a footnote to specify that the CKD-EPI 
equation based on serum creatinine for eGFR calculation will be used to determine 
eligibility. 
45 Section 4.3.3 (Clinical Laboratory Tests): Added alcohol and drug screening tests for 
consistency with Table 4 (Schedule of Screening Procedures). 
46 Section 4.5.1.4 (Treatment Administration) and Table 5 (Schedule of Treatment Period 
Study Procedures [footnote j]): Added instructions for cases where dosing is not 
performed within the dosing window: “In the event that a dose cannot be administered 
within the window of the scheduled dosing date, the dose may be administered outside of 
the dosing window as long as it is at least 14 days prior to the next dose and recorded as a 
protocol deviation”. 
47 Section 4.7.2 (Prohibited Concomitant Medications): Removed “cyclophosphamide” from 
the bullet for chronic use of any serum creatinine-altering drugs for consistency with 
Section 4.1.3 (Exclusion Criteria). 
48 Section 4.8.3.2 (Additional Analyses of the Primary Endpoint): Replaced “each” with 
“Day 169” in the following, “The primary endpoint at the Day 169 post baseline time 
point will also be analyzed using…” for specificity. 
49 Section 4.8.7 (Interim Analysis): Added UACR as a potential parameter for interim 
analysis. 
50 Section 5.3 (Definition of Adverse Events of Special Interest): Clarified that only 
gastrointestinal adverse reactions that are assessed as study treatment related will be 
classified as an AESI. 
 


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Appendix A Additional Safety Guidance 
Further Guidance on the Definition of a Serious Adverse Event (SAE) 
Life-threatening 
‘Life-threatening’ means that the subject was at immediate risk of death from AE as it 
occurred or it is suspected that use or continued use of the product would result in the 
subject’s death. ‘Life-threatening’ does not mean that had an AE occurred in a more severe 
form it might have caused death (eg, hepatitis that resolved without hepatic failure). 
Hospitalization 
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema). Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the subject was enrolled in the study, provided that it did not deteriorate in an 
unexpected way during the study. 
Important Medical Event or Medical Intervention 
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life-threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the subject or may require 
medical intervention to prevent one or more outcomes listed in the definition of serious. These 
should usually be considered as serious. 
Simply stopping the suspect drug does not mean that it is an important medical event; medical 
judgment must be used. 
Examples of such events are: 
x 
Angioedema not severe enough to require intubation but requiring intravenous 
hydrocortisone treatment 
x 
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring treatment with 
N-acetylcysteine 
x 
Intensive treatment in an emergency room or at home for allergic bronchospasm 
x 
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion) or convulsions 
that do not result in hospitalization 
x 
Development of drug dependency or drug abuse 
 
AEs for malignant tumors reported during a study should generally be assessed as Serious 
AEs. If no other seriousness criteria apply, the ‘Important Medical Event’ criterion should be 
used. However, in certain situations medical judgement on an individual event basis should be 
applied to clarify that the malignant tumor event should be assessed and reported as a 
Non-Serious AE. For example, if the tumor is included as medical history and progression 


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occurs during the study, but the progression does not change treatment and/or prognosis of the 
malignant tumor, the AE may not fulfill the attributes for being assessed as Serious, although 
reporting of the progression of the malignant tumor as an AE is valid and should occur. Also, 
some types of malignant tumors, which do not spread remotely after a routine treatment that 
does not require hospitalization, may be assessed as Non-Serious; examples include Stage 1 
basal cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
Assessment of Severity 
Assessment of severity is one of the responsibilities of the investigator in the evaluation of 
AEs and SAEs. The determination of severity should be made by the investigator based upon 
medical judgment and the severity categories of Grade 1 to 5 as defined below. 
Grade 1 
An event of mild intensity that is usually transient and may 
require only minimal treatment or therapeutic intervention. The 
event does not generally interfere with usual activities of daily 
living. 
Grade 2 
An event of moderate intensity that is usually alleviated with 
additional specific therapeutic intervention. The event interferes 
with usual activities of daily living, causing discomfort but 
poses no significant or permanent risk of harm to the subject. 
Grade 3 
A severe event that requires intensive therapeutic intervention. 
The event interrupts usual activities of daily living, or 
significantly affects the clinical status of the subject. 
Grade 4 
An event, and/or its immediate sequelae, that is associated with 
an imminent risk of death. 
Grade 5 
 
 
Death as a result of an event. 
It is important to distinguish between serious criteria and severity of an AE. Severity is a 
measure of intensity whereas seriousness is defined by the criteria in Section 5.2. A Grade 3 
AE need not necessarily be considered an SAE. For example, a Grade 3 headache that persists 
for several hours may not meet the regulatory definition of an SAE and would be considered a 
nonserious event, whereas a Grade 2 seizure resulting in a hospital admission would be 
considered an SAE. 


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Assessment of Relationship 
A guide to Interpreting the Causality Question 
The investigator is required to provide an assessment of relationship of AEs and SAEs to the 
investigational product. The following factors should be considered when deciding if there is a 
“reasonable possibility” that an AE may have been caused by the investigational product. 
x 
Time Course. Exposure to suspect investigational product. Has the subject actually 
received the suspect investigational product? Did the AE occur in a reasonable temporal 
relationship to the administration of the suspect investigational product? 
x 
Consistency with known investigational product profile. Was the AE consistent with the 
previous knowledge of the suspect investigational product (pharmacology and toxicology) 
or products of the same pharmacological class? OR could the AE be anticipated from its 
pharmacological properties?  
x 
De-challenge experience. Did the AE resolve or improve on stopping or reducing the dose 
of the suspect investigational product? 
x 
No alternative cause. The AE cannot be reasonably explained by another etiology such as 
the underlying disease, other drugs, or other host or environmental factors. 
x 
Re-challenge experience. Did the AE reoccur if the suspected investigational product was 
reintroduced after having been stopped? AstraZeneca would not normally recommend or 
support a re-challenge. 
x 
Laboratory tests. A specific laboratory investigation (if performed) has confirmed the 
relationship? 
 
In difficult cases, other factors could be considered such as: 
x 
Is this a recognized feature of overdose of the investigational product? 
x 
Is there a known mechanism? 
 
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship. 
The causality assessment is performed based on the available data including enough 
information to make an informed judgment.  With limited or insufficient information in the 
case, it is likely that the event(s) will be assessed as ‘not related’. 
Causal relationship in cases where the disease under study has deteriorated due to lack of 
effect should be classified as no reasonable possibility. 


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Relationship to Protocol Procedures 
The investigator is also required to provide an assessment of relationship of SAEs to protocol 
procedures on the SAE Report Form. This includes nontreatment-emergent SAEs (ie, SAEs 
that occur prior to the administration of investigational product) as well as treatment-emergent 
SAEs. A protocol-related SAE may occur as a result of a procedure or intervention required 
during the study (eg, blood collection, washout of an existing medication). The following 
guidelines should be used by investigators to assess the relationship of SAEs to the protocol: 
Protocol related: 
The event occurred due to a procedure/intervention that was described 
in the protocol for which there is no alternative etiology present in the 
subject’s medical record. 
Not protocol related: The event is related to an etiology other than the procedure/ 
intervention that was described in the protocol (the alternative etiology 
must be documented in the study subject’s medical record). 
 


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Appendix B National Institute of Allergy and Infectious Diseases and 
Food Allergy and Anaphylaxis Network Guidance for 
Anaphylaxis Diagnosis 
Sampson HA, Muñoz-Furlong A, Campbell RL, Adkinson FN Jr, Bock SA, Branum A, et al. 
Second symposium on the definition and management of anaphylaxis: Summary report -- 
Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006;117:391-7. 
National Institute of Allergy and Infectious Diseases (NIAID) and Food Allergy and 
Anaphylaxis Network (FAAN) define anaphylaxis as a serious allergic reaction that is rapid in 
onset and may cause death. They recognize 3 categories of anaphylaxis, with criteria 
designated to capture from 80% of cases (category 1) to > 95% of all cases of anaphylaxis (for 
all 3 categories).  
1 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) 
AND AT LEAST ONE OF THE FOLLOWING 
(a) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow (PEF), hypoxemia) 
(b) Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction (eg, 
hypotonia [collapse], syncope, incontinence) 
2 
Two or more of the following that occur rapidly after exposure to a likely allergen for that 
patient (minutes to several hours): 
(a) Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
(b) Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced PEF, 
hypoxemia) 
(c) Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
(d) Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
3 
Reduced BP after exposure to known allergen for that patient (minutes to several hours): 
(a) Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP 
(b) Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
 


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Appendix C Actions Required in Cases of Increases in Liver Biochemistry 
and Evaluation of Hy’s Law 
C 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 subject meets 
potential PHL criteria at any point during the study. 
All sources of laboratory data are appropriate for the determination of PHL and HL events; 
this includes samples taken at scheduled study visits and other visits including central and all 
local laboratory evaluations even if collected outside of the study visits; for example, PHL 
criteria could be met by an elevated ALT from a central laboratory and/or elevated TBL from 
a local laboratory. 
The investigator will also review AE data (for example, for AEs that may indicate elevations 
in liver biochemistry) for possible PHL events. 
The investigator participates, together with AstraZeneca clinical project representatives, in 
review and assessment of cases meeting PHL criteria to agree whether HL criteria are met. HL 
criteria are met if there is no alternative explanation for the elevations in liver biochemistry 
other than drug-induced liver injury (DILI) caused by the investigational product. 
The investigator is responsible for recording data pertaining to PHL/HL cases and for 
reporting SAEs and AEs according to the outcome of the review and assessment in line with 
standard safety reporting processes. 
C 2 
Definitions 
Potential Hy's Law 
$67RU$/7 î8/1WRJHWKHUZLWK7%/ 2 × ULN at any point during the study 
following the start of study medication irrespective of an increase in alkaline phosphatase 
(ALP).  
Hy's Law 
$67RU$/7 î8/1WRJHWKHUZLWK7%/ 2 × ULN, where no other reason, other than the 
investigational product, can be found to explain the combination of increases, eg, elevated 
ALP indicating cholestasis, viral hepatitis, or 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 timeframe within which the 
elevations in transaminases and TBL must occur. 
C 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 subject who meets any of the following identification criteria in 
isolation or in combination: 
x 
$/7 3 × ULN 
x 
$67 3 × ULN 
x 
7%/ 2 × ULN 
 
Central laboratories being used: 
When a subject 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: 
x 
Request a repeat of the test (new blood draw) by the central laboratory without delay 
x 
Complete the appropriate unscheduled laboratory CRF 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: 
x 
Determine whether the subject meets PHL criteria (see Section C 2 within this Appendix 
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: 
x 
Determine whether the subject meets PHL criteria (see Section C 2 within this Appendix 
for definition) by reviewing laboratory reports from all previous visits 
x 
Promptly enter the laboratory data into the laboratory CRF 
 


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C 4 
Follow-up 
C 4.1 
Potential Hy’s Law Criteria Not Met 
If the subject does not meet PHL criteria, the investigator will: 
x 
Perform follow-up on subsequent laboratory results according to the guidance provided in 
the Clinical Study Protocol. 
 
C 4.2 
Potential Hy’s Law Criteria Met 
If the subject does meet PHL criteria, the investigator will: 
x 
Notify the AstraZeneca representative who will then inform the central Study Team 
x 
Within 1 day of PHL criteria being met, the investigator will report the case as an SAE of 
Potential Hy’s Law; serious criteria ‘Important medical event’ and causality assessment 
‘yes/related’ according to clinical study protocol (CSP) process for SAE reporting. 
x 
For subjects that met PHL criteria prior to starting investigational product, the 
investigator is not required to submit a PHL SAE unless there is a significant change# in 
the subject’s condition 
x 
The Study Physician contacts the investigator, to provide guidance, discuss and agree an 
approach for the study subjects’ follow-up (including any further laboratory testing) and 
the continuous review of data 
x 
Subsequent to this contact the investigator will: 
 
Monitor the subject until liver biochemistry parameters and appropriate clinical 
symptoms and signs return to normal or baseline levels, or as long as medically 
indicated. Completes follow-up SAE Form as required. 
 
Investigate the etiology of the event and perform diagnostic investigations as 
discussed with the Study Physician. This includes deciding which the tests available 
in the HL lab kit should be used  
 
Complete the three Liver CRF Modules as information becomes available  
 
# A ‘significant’ change in the subject’s condition refers to a clinically relevant change in any of the individual 
liver biochemistry parameters (ALT, AST or TBL) in isolation or in combination, or a clinically relevant change 
in associated symptoms.  The determination of whether there has been a significant change will be at the 
discretion of the investigator, this may be in consultation with the Study Physician if there is any uncertainty. 
 
C 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. 


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As soon as possible after the biochemistry abnormality was initially detected, the Study 
Physician contacts the investigator in order to review available data and agree on whether 
there is an alternative explanation for meeting PHL criteria other than DILI caused by the 
investigational 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: 
x 
If the alternative explanation is not an AE, record the alternative explanation on the 
appropriate CRF 
x 
If the alternative explanation is an AE/SAE: update the previously submitted Potential 
Hy’s Law SAE and AE CRFs 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 product: 
x 
Send updated SAE (report term ‘Hy’s Law’) according to AstraZeneca standard 
processes.  
x 
The ‘Medically Important’ serious criterion should be used if no other serious criteria 
apply 
x 
As there is no alternative explanation for the HL case, a causality assessment of ‘related’ 
should be assigned. 
 
If there is an unavoidable delay of over 15 calendar days in obtaining the information 
necessary to assess whether or not the case meets the criteria for HL, then it is assumed that 
there is no alternative explanation until such time as an informed decision can be made: 
x 
Provides any further update to the previously submitted SAE of Potential Hy’s Law, 
(report term now ‘Hy’s Law case’) ensuring causality assessment is related to 
investigational product and seriousness criteria is medically important, according to CSP 
process for SAE reporting. 
x 
Continue follow-up and review according to agreed plan. Once the necessary 
supplementary information is obtained, repeat the review and assessment to determine 
whether HL criteria are still met. Update the previously submitted PHL SAE report 
following CSP process for SAE reporting, according to the outcome of the review and 


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amending the reported term if an alternative explanation for the liver biochemistry 
elevations is determined. 
 
C 6 
Laboratory Tests 
Table C1 
Hy’s Law Laboratory Kit for Central Laboratories 
Additional standard chemistry and coagulation tests 
GGT 
LDH 
Prothrombin time 
INR 
Viral hepatitis 
IgM anti-HAV  
IgM and IgG anti-HBc 
HBsAg 
HBV DNA 
IgG anti-HCV 
HCV RNA a  
IgM anti-HEV 
HEV RNA 
Other viral infections 
IgM and IgG anti-CMV 
IgM and IgG anti-HSV 
IgM and IgG anti-EBV 
Alcoholic hepatitis 
Carbohydrate deficient transferrin (CD-transferrin) b 
Autoimmune hepatitis 
Antinuclear antibody (ANA) 
Anti-Liver/Kidney Microsomal Ab (Anti-LKM) 
Anti-Smooth Muscle Ab (ASMA) 
Metabolic diseases 
alpha-1-antitrypsin 
Ceruloplasmin 
Iron 
Ferritin 
Transferrin 
Transferrin saturation 
a 
HCV RNA is only tested when IgG anti-HCV is positive or inconclusive 
b 
Carbohydrate deficient transferrin (CD-transferrin) is not available in China. Study teams should amend this 
list accordingly 
 


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Appendix D Genetic Research 
Rationale and Objectives 
AstraZeneca intends to collect and store DNA for genetic research to explore how genetic 
variations may affect clinical parameters, risk and prognosis of diseases, and the response to 
medications. Genetic research may lead to better understanding of diseases, better diagnosis of 
diseases or other improvements in health care and to the discovery of new diagnostics, 
treatments or medications. 
In addition, collection of DNA samples from populations with well described clinical 
characteristics may lead to improvements in the design and interpretation of clinical trials and, 
possibly, to genetically guided treatment strategies. 
Genetic Research Plan and Procedures 
Selection of genetic research population 
Study selection record 
All subjects will be asked to participate in this genetic research. Participation is voluntary and 
if a subject declines to participate there will be no penalty or loss of benefit. The subject will 
not be excluded from any aspect of the main study. 
Inclusion criteria 
For inclusion in this genetic research, subjects must fulfil all of the inclusion criteria described 
in the main body of the Clinical Study Protocol and: 
x 
Provide informed consent for the genetic sampling and analyses. 
 
Exclusion criteria 
Exclusion from this genetic research may be for any of the exclusion criteria specified in the 
main study or any of the following: 
x 
Previous allogeneic bone marrow transplant 
x 
Non-leukocyte depleted whole blood transfusion in 120 days of genetic sample collection 
 
Discontinuation of subjects from this genetic research 
Specific reasons for discontinuing a subject from this genetic research are: 
Withdrawal of consent for genetic research: Subjects may withdraw from this genetic research 
at any time, independent of any decision concerning participation in other aspects of the main 
study. Voluntary discontinuation will not prejudice further treatment. Procedures for 
discontinuation are outlined in Section 4.1.8 of the protocol. 


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Collection of samples for genetic research 
The blood sample for genetic research will be obtained from the subjects at Visit 3 at or after 
randomization. Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding subjects who may withdraw due to an AE, such subjects 
would be important to include in any genetic analysis. If for any reason the sample is not 
drawn at Visit 3, it may be taken at any visit until the last study visit. Only one sample should 
be collected per subject for genetics during the study. Samples will be collected, labelled, 
stored and shipped as detailed in the Laboratory Manual. 
Coding and storage of DNA samples 
The processes adopted for the coding and storage of samples for genetic analysis are 
important to maintain subject confidentiality. Samples will be stored for a maximum of 15 
years, from the date of LSLV, after which they will be destroyed. DNA is a finite resource 
that is used up during analyses. Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached. 
An additional second code will be assigned to the blood either before or at the time of DNA 
extraction replacing the information on the sample tube. Thereafter, the sample will be 
identifiable by the second, unique number only. This number is used to identify the sample 
and corresponding data at the AstraZeneca genetics laboratories, or at the designated 
organization. No personal details identifying the individual will be available to any person 
(AstraZeneca employee or designated organizations working with the DNA). 
The link between the subject enrollment/randomization code and the second number will be 
maintained and stored in a secure environment, with restricted access at AstraZeneca or 
designated organizations. The link will be used to identify the relevant DNA samples for 
analysis, facilitate correlation of genotypic results with clinical data, allow regulatory audit 
and to trace samples for destruction in the case of withdrawal of consent. 
Ethical and Regulatory Requirements 
The principles for ethical and regulatory requirements for the study, including this genetics 
research component, are outlined in Section 7 of the protocol. 
Informed consent 
The genetic component of this study is optional and the subject may participate in other 
components of the main study without participating in the genetic component. To participate 
in the genetic component of the study the subject must sign and date both the consent form for 
the main study and the genetic component of the study. Copies of both signed and dated 
consent forms must be given to the subject and the original filed at the study site. The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 


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subject understands that they may freely discontinue from the genetic aspect of the study at 
any time. 
Subject data protection 
AstraZeneca will not provide individual genotype results to subjects, any insurance company, 
any employer, their family members, general physician unless required to do so by law. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the subject. In exceptional circumstances, however, certain individuals might 
see both the genetic data and the personal identifiers of a subject. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a subject’s 
identity and also have access to his or her genetic data. Also, Regulatory authorities may 
require access to the relevant files, though the subject’s medical information and the genetic 
files would remain physically separate. 
Data management 
Any genotype data generated in this study will be stored at a secure system at AstraZeneca 
and/or designated organizations to analyze the samples. 
The results from this genetic research may be reported in a separate report from the CSR or 
published in scientific journals. 
AstraZeneca and its designated organizations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic Organization or Health Insurance Companies. This 
can be done by placing the results in scientific databases, where they can be combined with 
the results of similar studies to learn even more about health and disease. The researchers can 
only use this information for health related research purposes. Researchers may see summary 
results but they will not be able to see individual subject data or any personal identifiers. 
Some or all of the clinical datasets from the main study may be merged with the genetic data 
in a suitable secure environment separate from the clinical database. 
Statistical Methods and Determination of Sample Size 
The number of subjects that will agree to participate in the genetic research is unknown. It is 
therefore not possible to establish whether sufficient data will be collected to allow a formal 
statistical evaluation or whether only descriptive statistics will be generated. A Statistical 
Analysis Plan will be prepared where appropriate. 


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Appendix E Patient Treatment Guidelines 
Hyperkalemia 
Subjects will have their serum potassium measured by a Central Laboratory. If the serum 
potassium is between 5.6 and 5.9 mEq/L, inclusive (5.6 to 5.9 mmol/L), application of 
standard clinical assessment and care for the medical circumstance at hand should be 
implemented. Assuming that the result represents a true case of hyperkalemia, corrective 
measures should be initiated to prevent further increases in serum potassium, including review 
of the patient’s dietary intake, any use of nonsteroidal anti-inflammatory drugs (NSAIDs), use 
of potassium-sparing medications, and use of potassium supplements. The need for diuretics, 
sodium polystyrene sulphonate and/or acute therapies may need to be considered. The ACEi 
or ARB dose may also need to be reduced, but this should be done only after review with the 
medical monitor.  
,IWKHVHUXPSRWDVVLXPPHDVXUHGE\WKH&HQWUDO/DERUDWRU\LV 6.0 mEq/L (6.0 mmol/L), 
immediate measures must be carried out to determine the cause and corrective actions 
instituted. Decisions to adjust or discontinue the ACEi and ARB will be at the discretion of 
the Principal Investigator and the medical monitor. 
If after corrective measures are taken, including temporary discontinuation of ACEi or ARB, 
LQDSDWLHQWZKRKDVDVHUXPSRWDVVLXPRI 6.0 mEq/L (6.0 mmol/L), and the potassium fails 
WRGHFUHDVHWR 5.5 mEq/L (5.5 mmol/L), the ACEi or ARB must be discontinued 
permanently and the medical monitor should be notified. 
Subjects who discontinue ACEi or ARB may remain on investigational drug following 
consultation with the medical monitor and should be followed for the full duration of the 
study. 


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Appendix F COVID-19 Specifics 
F 1 
Background to COVID-19 
There is currently an outbreak of respiratory disease (COVID-19) caused by a novel 
SARS-CoV-2 that was first detected in Wuhan City, Hubei Province, China in 2019. This new 
virus has rapidly spread across the globe causing the World Health Organisation to declare a 
pandemic situation on 12 March 2020. The countermeasures initiated by national and local 
governments worldwide and the recommendations issued by the health authorities have 
impacted current and new clinical studies. As the threat of pandemic burden including new 
outbreaks, locally or globally, will impact the further conduct of clinical studies, appropriate 
risk assessments and mitigation measures will need to be taken into consideration in all 
clinical studies to protect subjects, site staff, and society as a whole. 
Both European Medicines Agency (EMA) and Food and Drug Administration (FDA) as well 
as national health authorities in Europe have issued new guidelines that aim to provide 
recommendations for actions for conduct of clinical studies of medical products during 
COVID-19 pandemic. Since the pandemic situation is evolving, guidelines, recommendations, 
national laws, and local restrictions may change at high pace. Given the circumstances of 
potentially relapsing pandemic or epidemic situation with regard to the spread of COVID-19 
in future, special attention will be paid to protect subjects participating in the study and site 
staff involved in the investigations against infection with SARS-CoV-2 as requested by the 
newly issued EMA guideline. 
F 2 
Risk Assessment for COVID-19 Pandemic 
There are 2 investigational products with different mechanisms of action that are unlikely to 
impact on the course of infection with SARS-CoV-2. MEDI3506 does have an 
anti-inflammatory mode of action with inhibition of IL-33 and prevention of binding to its 
receptor ST2. While this poses a theoretical risk of adversely influencing the antiviral 
response, this is judged to be unlikely. Dapagliflozin is an anti-glycemic agent and is believed 
not to cause immune suppression. Therefore, risk of the subjects exposed to SARS-CoV-2 or 
to suffer from COVID-19 is expected to be similar to the background population with the 
same co-morbidities as those in the study, in particular CKD and T2DM. The risk of exposure 
to infected people cannot be completely excluded as the subjects may need to expose 
themselves to public areas (eg, commute to the site) and have additional human contact (eg, 
with site staff and other subjects of the clinical study). 
Measures to mitigate the additional risks caused by COVID-19 are: 
x 
This study will resume enrolling only when the sponsor and contract research 
organization in collaboration deem it is safe to start the study. In addition, the study will 
not resume until the local confinement measures or other safety restrictions linked to the 


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COVID-19 pandemic imposed by the local authorities are compatible with safe conduct 
of the study. 
x 
Current national laws and local recommendations for prevention of pandemic will be 
strictly adhered to. 
x 
Subjects will be closely monitored for any signs and symptoms of COVID-19, including 
fever, dry cough, dyspnea, sore throat and fatigue throughout the study during the 
pandemic. Once clinical signs of infection are reported by subjects, the investigator needs 
to determine whether samples can be collected, and safety data can be recorded on site. If 
not, AEs and concomitant medications will be obtained via phone calls. The decision to 
continue with dosing the subject with the study drugs in the event of him/her showing 
symptoms of COVID-19 infection will be per investigator’s discretion. 
x 
If, for reasons related to the COVID-19 pandemic, a subject is not able to attend their 
scheduled visit within the visit window, they can have their visit rescheduled within 
14 days of the original scheduled visit; however, visits that cannot be rescheduled within 
a 14-day window must be skipped and subjects should continue at the next scheduled 
visit. 
x 
During the COVID-19 pandemic, on-site visits may be replaced by a telemedicine visit if 
allowed by local/regional guidelines. Having a telemedicine contact with the subjects will 
allow collection of data for AEs, concomitant medications, adherence to the eDiary and 
patient-reported outcome measures to be reported and documented. The term 
telemedicine visit refers to remote contact with the subjects using telecommunications 
technology including phone calls, virtual or video visits, and mobile health devices. 
x 
The probability of virus transmission will be controlled as much as possible by: 
 
Advising subjects to adhere to local requirements for reduction of the public 
exposure while ambulatory. 
 
Assessment of potential COVID-19 infection by optional laboratory assessment 
based on availability (test capacity and turnaround time) of approved tests and on 
investigator’s discretion. 
 
Requesting all subjects to be contacted by phone 1 day prior to every visit for 
assessing COVID-19 symptoms and signs and asking subjects to not attend the site in 
case of suspected reports. In addition, sites will ask subjects regarding any contact 
with a person who has tested positive for SARS-CoV-2. If applicable, subjects will 
be referred to the local healthcare system for further follow-up and treatment. 
 
Applying physical distancing and person-to-person contact restrictions during site 
visits and in-house confinement. 
 
Use of personal protective equipment by study subjects (surgical face mask, gloves) 
and staff (for example but not limited to masks, gloves, protectors, medical suits) 


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CONFIDENTIAL AND PROPRIETARY 
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where physical distancing is not possible if deemed appropriate by the investigators 
and site staff and guided by local requirements. 
 
Implementation of logistical improvements of the site and structural measures of the 
study site building to further improve physical distancing. 
 
F 3 
Restrictions Related to COVID-19 
During the COVID-19 pandemic, subjects are advised to adhere to local requirements for 
reduction of the public SARS-CoV-2 exposure while ambulatory. If applicable, prior to 
Screening Visit 1, potential subjects should be called to confirm they are not experiencing any 
COVID-19 symptoms and signs and are asked not to attend the site in case of suspected 
infection. If appropriate, subjects will be referred to the local healthcare system. Physical 
distancing and person-to-person contact restrictions will be applied and explained to subjects 
while staying at the study site. Where physical distancing is not possible, study subjects will 
be asked to use surgical face masks and/or gloves if deemed appropriate by the investigator 
and site staff and guided by local requirements. 
F 4 
Data Quality Assurance Related to COVID-19 
Monitoring visits at site will be limited to a minimum required as deemed appropriate during 
COVID-19 pandemic, per local regulations. 
In addition, where possible, other measures for carrying out protocol-related activities, such as 
but not limited to home nursing and safety clinical laboratory tests performed in a local 
licensed laboratory, may be employed as required. 
F 5 
References 
1. Guidance on the Management of Clinical Trials during the COVID 19 (Coronavirus) 
pandemic, EMA, Version 3 (28/04/2020). 
https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
10/guidanceclinicaltrials_covid19_en.pdf 
2. FDA Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency, March 2020, Updated on April 16, 2020 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/fda-
guidance-conduct-clinical-trials-medical-products-during-covid-19-public-health-
emergency 
 
 


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14Feb2022; Final 
CONFIDENTIAL AND PROPRIETARY 
115 of 117 
Appendix G Changes Related to Mitigation of Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health 
Crisis 
Note: Changes below should be implemented only during study disruptions due to any of or a 
combination of civil crisis, natural disaster, or public health crisis (eg, during quarantines and 
resulting site closures, regional travel restrictions and considerations if site personnel or study 
patients become infected with SARS-CoV-2 or similar pandemic infection) during which 
patients may not wish to or may be unable to visit the study site for study visits. These 
changes should only be implemented if allowable by local/regional guidelines and following 
notification from the sponsor and instructions on how to perform these procedures will be 
provided at the time of implementation.   
G 1 
Reconsent of Study Patients During Study Interruptions 
During study interruptions, it may not be possible for the patients to complete study visits and 
assessments on site and alternative means for carrying out the visits and assessments may be 
necessary, eg, remote visits. Reconsent should be obtained for the alternative means of 
carrying out visits and assessments and should be obtained prior to performing the procedures 
described in Sections G 2 to G 6. Local and regional regulations and/or guidelines regarding 
reconsent of study patients should be checked and followed. Reconsent may be verbal if 
allowed by local and regional guidelines (note, in the case of verbal reconsent the ICF should 
be signed at the patient’s next contact with the study site). Visiting the study sites for the sole 
purpose of obtaining reconsent should be avoided.  
G 2 
Rescreening of Patients To Reconfirm Study Eligibility 
Additional rescreening for screen failure due to study disruption can be performed in 
previously screened subjects. The investigator should confirm this with the designated Study 
Physician. 
In addition, during study disruption there may be a delay between confirming eligibility of a 
patient and either enrollment into the study or commencing of dosing with IP. If this delay is 
outside the screening window specified in Section 4.2.1, the patient will need to be rescreened 
to reconfirm eligibility before commencing study procedures. This will provide another 
opportunity to re-screen a patient in addition to that detailed in Section 4.2.1. The procedures 
detailed in Section 4.2.1 must be undertaken to confirm eligibility using the same 
randomization number as for the patient. 


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14Feb2022; Final 
CONFIDENTIAL AND PROPRIETARY 
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G 3 
Home or Remote Visit to Replace On-site Visit (where applicable) 
A qualified HCP from the study site or TPV service will visit the patient’s home / or other 
remote location as per local SOPs, as applicable. Supplies will be provided for a safe and 
efficient visit. The qualified HCP will be expected to collect information per the CSP.  
G 4 
Telemedicine Visit to Replace On-site Visit (where applicable) 
In this appendix, the term telemedicine visit refers to remote contact with the patients using 
telecommunications technology including phone calls, virtual or video visits, and mobile 
health devices. 
During a civil crisis, natural disaster, or public health crisis, on-site visits may be replaced by 
a telemedicine visit if allowed by local/regional guidelines. Having a telemedicine contact 
with the patients will allow adverse events and concomitant medication to be reported and 
documented. If applicable, safety procedures and blood sample collection will be performed 
according to the revised SoA in the Study Instructions for Mitigation Due to Civil Crisis, 
Natural Disaster, or Public Health Crisis. 
G 5 
At-home or Remote Location Investigational Product 
Administration Instructions 
If a site visit is not possible, at-home or remote location administration of investigational 
product may be performed by a qualified HCP, provided this is acceptable within local 
regulation/guidance, or by the patient or his/her caregiver. The option of at-home or remote 
location investigational product administration ensures patients safety in cases of a pandemic 
where patients may be at increased risk by traveling to the site/clinic. This will also minimize 
interruption of investigational product administration during other study disruptions, eg, site 
closures due to natural disaster.  
G 5.1 
At-home or Remote Location Investigational Product Administration 
by a Qualified HCP or TPV Service 
A qualified HCP from the study site or TPV service should administer the investigational 
product at the patient’s home or other remote location according to the CSP. All necessary 
supplies and instructions for administration and documentation of investigational product 
administration will be provided. Additional information related to the visit can be obtained via 
a telemedicine or home visit. 
G 5.2 
At-home or Remote Location Investigational Product Administration 
by the Patient or His/Her Caregiver 
Prior to at-home or remote location investigational product administration the investigator 
must assess the patient or his/her caregiver to determine whether they are appropriate for at-


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Protocol Amendment 5, D9183C00001 
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14Feb2022; Final 
CONFIDENTIAL AND PROPRIETARY 
117 of 117 
home or remote location administration of investigational product. Once the patient or his/her 
caregiver is deemed appropriate for at-home or remote location administration, he/she must 
receive appropriate training. All necessary supplies and instructions for administration and 
documentation of investigational product administration will be provided. More information 
related to the visit can be obtained via a telemedicine or home / remote visit. 
G 6 
Data Capture During Telemedicine or Home / Remote Visits 
Data collected during telemedicine or home / remote visits will be captured by the qualified 
HCP from the study site or TPV service 
 

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SIGNATURE PAGE
This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic signature
Document Name: d9183c00001-sap-ed-6
Document Title:
Statistical Analysis Plan Edition 6
Document ID:
Doc ID-004810933
Version Label:
6.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
05-Jul-2023 20:20 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.
PPD