A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients With Chronic Kidney Disease
Phase: PHASE3
Conditions: Chronic Kidney Disease
Sponsor: AstraZeneca

Clinical Study Protocol (CSP), ANGEL
Version 17.  0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
This submission document contains confidential commercial information, disclosure of which is prohibited 
without providing advance notice to AZ and opportunity to object.  
This Clinical Study Protocol has been subject to a peer review according to AZ Standard procedures.  The 
clinical study protocol is publicly registered and the results are disclosed and/or published according to the AZ 
Global Policy on Bioethics and in compliance with prevailing laws and regulations.  
Clinical Study Protocol 
Drug Substance
Dapagliflozin
Study Code
D169AC00001
Version
4.0
Date
17 March 2020 
A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and 
Cardiovascular Mortality in Patients with Chronic Kidney Disease
Sponsor: AZ AB, 151 85 Södertälje, Sweden

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
3 (98)
5.1.1 Endpoint reporting overview
5.1.3 Potential renal endpoints
Removing the requirement of adjudicating potential endpoints 
related to estimated glomerular filtration rate (eGFR) decline.  
The rational for this change is that the endpoint criteria are not 
justifying adjudication of these events. 
6.3 Recording of adverse events
6.3.2.2 Renal events
Clarification added based on feedback that the criteria was too 
vague, regarding what is considered an adverse event (AE) of 
interest in terms renal events. 
6.3 Recording of adverse events
6.3.7 Adverse events based on 
examination and tests
Limiting the recording of AEs to not include potential renal 
endpoints that are based on examination and tests, i.e., 
laboratory results only, unless fulfilling the serious adverse 
event (SAE) criteria or Discontinuation of investigational 
product due to adverse event (DAE) criteria. The reason not to 
record these endpoints related to laboratory findings is that 
protocol mandated laboratory values will be systematically 
analysed.  
6.4.1 Reporting of SAEs 
considered to be potential 
endpoints
Limiting the event types that are being withheld from reporting 
to health authorities to include only heart failure endpoints and 
fatal AE. i.e., AEs related to renal endpoints will not be 
withheld. The rationale for this limitation is to simplify the SAE 
reporting and to minimise the risk for withholding renal AEs of 
interest, which should be reported, and which could be confused 
for being a primary or secondary renal endpoint. 
6.9 Medication Error
Adding information about Medication Error definition and 
reporting.
7.7.2 Prohibited medication
Clarifying that open label treatment with Sodium glucose co-
transporter 2 (SGLT2) in combination with IP is not allowed and 
that open label treatment with SGLT2 inhibitors should be 
avoided during the course of the study, i.e., clarifying that usage 
of open label treatment with SGLT2 inhibitors are not prohibited 
if the patient is not taking study medication but should be 
avoided. The rational for this update is to clarify that it is 
administration of an open label SGLT2 inhibition in 
combination with IP that is a protocol deviation and not if the 
patient is off IP. 
7.7.3 Recording of concomitant 
medication
Including cardiovascular (CV) medications to be recorded in 
detail in the electronic case report form (eCRF) during the 
course of the study.

Clinical Study Protocol (CSP), ANGEL
Version 17.  0
Template Form Doc ID: LDMS_001_00026737
Parent Doc ID: SOP AZDoc0018580
PROTOCOL SYNOPSIS
A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and 
Cardiovascular Mortality in Patients with Chronic Kidney Disease
International Coordinating Investigator
Prof. 
, MB ChB, MD, FRCP
Centre for Nephrology Royal Free Campus 
University College London
London, United Kingdom
Scientific Coordinator
Prof.
, PharmD, PhD, 
Dept. Clinical Pharmacy & Pharmacology
University Medical Center Groningen, 
Groningen, Netherlands
Study site(s) and number of patients planned
Study period
Phase of development
Estimated date of first patient enrolled
Q1 2017
Phase III
Estimated date of last patient completed
Q4 2020
Study design
This is an international, multicentre, event-driven, randomised, double-blind, parallel group, 
placebo-controlled study, evaluating the effect of dapagliflozin 10 mg versus placebo, given 
once daily in addition to standard of care, to prevent the progression of chronic kidney disease 
(CKD) or cardiovascular (CV)/renal death.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
7 (98)
Objectives
Primary Objective:
Outcome Measure:
To determine if dapagliflozin is superior to 
placebo in reducing the incidence of the primary 
composite endpoint of ≥50% sustained decline in 
estimated glomerular filtration rate (eGFR), 
reaching end stage renal disease (ESRD), CV or 
renal death when added to current background 
therapy in patients with eGFR ≥25 and 
≤75 mL/min/1.73m2 and albuminuria (urine 
albumin creatinine ratio [UACR] ≥200 and 
≤5000 mg/g).
Time to the first occurrence of any of the 
components of this composite: 
1.
≥50% sustained* decline in eGFR 
2.
Reaching ESRD 

Sustained* eGFR 
<15 mL/min/1.73m2 or, 

Chronic* dialysis treatment or,

Receiving a renal transplant
3.
CV death 
4.
Renal death
*As defined in the Clinical Event Adjudication (CEA) charter
Secondary Objective:
Outcome Measure:
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of the composite endpoints of 
worsening of renal function.  
Time to the first occurrence of any of the 
components of this composite: 
1.
≥50% sustained decline in eGFR
2.
Reaching ESRD
3.
Renal death
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of the composite endpoint of CV death 
or hospitalisation for heart failure.  
Time to the first occurrence of either of the 
components of this composite: 
1.
CV death 
2.
Hospitalisation for heart failure 
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of all-cause mortality.  
Time to death from any cause

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
dapagliflozin in this patient population.  
1.
Serious adverse event (SAE)
2.
Discontinuation of investigational 
product (IP) due to adverse event 
(DAE)s
3.
Changes in clinical 
chemistry/haematology parameters
4.
Adverse events (AEs) of interest 
(volume depletion, renal events, major 
hypoglycaemic events, fractures, 
diabetic ketoacidosis (DKA), Adverse 
events (AEs) leading to amputation 
and AEs leading to a risk for lower 
limb amputations [“preceding 
events”])
Target patient population
The target population will have CKD (eGFR ≥25 and ≤75 mL/min/1.73m2) with albuminuria 
(urine albumin creatinine ratio [UACR] ≥200 and ≤5000 mg/g) with or without type 2 
diabetes (T2D).  However, patients with known polycystic kidney disease, glomerulonephritis 
with flares (lupus or anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis) or 
ongoing active renal inflammation will be excluded.
Duration of treatment
This study is event-driven.  The anticipated duration of the study is approximately 45 months 
with an estimated mean treatment period for a patient of 33 months.  The study closure 
procedures will be initiated when the predetermined number of primary endpoints are 
predicted to have occurred (n=681), i.e., the study end date (SED).  The study duration may be 
changed if the event rate or randomisation rate is different than anticipated.  The study may be 
terminated early if either a clear beneficial or harmful effect of the study treatment is detected 
during the Data Monitoring Committee (DMC) review.  
Investigational product (IP), dosage and mode of administration
Patients will be randomised 1:1 to either dapagliflozin 10 mg or placebo.  Every attempt 
should be made to maintain patients on dapagliflozin 10 mg or matching placebo during the 
course of the study.  In addition to the preferred 10 mg dose, the 5 mg dose of dapagliflozin 

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
9 (98)
can be used in the study when clinically indicated.  If the dose has been decreased to 5 mg, the 
dose should be increased back to dapagliflozin 10 mg or matching placebo as soon as, in the 
opinion of the investigator, the patient’s condition is stable.
Statistical methods
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint.  Assuming a true hazard 
ratio of 0.78 between dapagliflozin and placebo, using a one-sided alpha of 2.5%, 681 primary 
endpoint events will provide a statistical power of 90% for the test of the primary composite 
endpoint.  This is based on an overall 1:1 allocation between dapagliflozin and placebo.  The 
study is event-driven.
With an annual event rate of 7.5% in the placebo treatment group, 4000 patients are estimated 
to provide the required number of primary events, based on an anticipated recruitment period 
of 24 months and an average follow-up period of approximately 33 months.
All patients who have been randomised to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study.  
The primary variable is the time to first event included in the primary composite endpoint.  
The primary analysis will be based on the intention to treat (ITT) principle using the FAS.  In 
the analysis of the primary composite endpoint, dapagliflozin versus placebo will be compared 
using a Cox proportional hazards model with a factor for treatment group, stratified by 
randomisation stratification factors (T2D, UACR), and adjusting for eGFR.  
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilized.  No multiplicity control is placed on the exploratory 
endpoints.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
10 (98)
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................1
VERSION HISTORY..........................................................................................2
PROTOCOL SYNOPSIS.....................................................................................6
TABLE OF CONTENTS................................................................................... 10
1.
INTRODUCTION ............................................................................................. 19
1.1
Background and rationale for conducting this study ........................................... 19
1.2
Rationale for study design, doses and control groups.......................................... 20
1.2.1
Rationale for study design and study population................................................. 20
1.2.2
Rationale for primary outcome measure ............................................................. 21
1.2.3
Rationale for secondary outcome measure.......................................................... 21
1.2.4
Rationale for dose selection................................................................................ 21
1.3
Benefit/risk and ethical assessment .................................................................... 22
1.3.1
Potential risks .................................................................................................... 22
1.3.1.1
Protection against risks ...................................................................................... 23
1.3.2
Potential benefits to patients............................................................................... 23
1.3.3
Conclusion......................................................................................................... 23
1.4
Study design ...................................................................................................... 23
2.
STUDY OBJECTIVES...................................................................................... 26
2.1
Primary objective............................................................................................... 26
2.2
Secondary objectives.......................................................................................... 26
2.3
Safety objectives................................................................................................ 27
2.4
Exploratory objectives ....................................................................................... 27
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL..................... 29
3.1
Inclusion criteria ................................................................................................ 30
3.2
Exclusion criteria ............................................................................................... 30
3.3
Patient enrolment and randomisation.................................................................. 31
3.4
Procedures for handling incorrectly enrolled or randomised patients .................. 32
3.5
Methods for assigning treatment groups............................................................. 32
3.5.1
Stratification and capping................................................................................... 33
3.5.1.1
Stratification ...................................................................................................... 33
3.5.1.2
Capping ............................................................................................................. 33

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Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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3.6
Methods for ensuring blinding ........................................................................... 33
3.7
Methods for unblinding...................................................................................... 34
3.7.1
Unblinding for bioanalytical laboratory personnel.............................................. 34
3.8
Restrictions........................................................................................................ 34
3.9
Discontinuation of investigational product ......................................................... 34
3.9.1
Evaluation of volume status and investigational product (IP) dose 
reduction/interruption......................................................................................... 35
3.9.2
Investigational product (IP) restart or dose increase from dapagliflozin 5 mg 
to 10 mg or matching placebo ............................................................................ 36
3.9.3
Procedures for discontinuation of a patient from investigational product (IP) ..... 36
3.9.3.1
Patient undergoes the premature treatment discontinuation visit (PTDV) and 
continues according to plan................................................................................ 37
3.9.3.2
Patient agrees to undergo modified follow-up .................................................... 37
3.10
Criteria for withdrawal....................................................................................... 37
3.10.1
Screen failures ................................................................................................... 37
3.10.2
Withdrawal of informed consent ........................................................................ 37
3.11
Discontinuation of the study............................................................................... 38
4.
STUDY PLAN AND TIMING OF PROCEDURES........................................... 39
4.1
Enrolment period ............................................................................................... 43
4.1.1
Visit 1, enrolment (day -14 ±7) .......................................................................... 43
4.2
Treatment period................................................................................................ 44
4.2.1
Visit 2, randomisation (day 0) ............................................................................ 44
4.2.2
Visit 3 (day 14 ±3) ............................................................................................. 45
4.2.3
Visit 4 (day 60 ±7) ............................................................................................. 45
4.2.4
Visit 5 (day 120 ±7) ........................................................................................... 46
4.2.5
Visit 6, (day 240 ±14) ........................................................................................ 46
4.2.6
Visit 7, 8, 9 etc., on-site visits; (day 360 ±14 and; every 4th month).................... 47
4.2.7
Premature treatment discontinuation visit (PTDV) ............................................. 47
4.2.8
Study closure visit (SCV)................................................................................... 48
4.2.9
Unscheduled visits ............................................................................................. 49
4.3
Follow-up period (Not applicable)...................................................................... 49
5.
STUDY ASSESSMENTS.................................................................................. 49
5.1
Efficacy assessments.......................................................................................... 49
5.1.1
Endpoint reporting overview.............................................................................. 49
5.1.2
Classification of death........................................................................................ 50
5.1.3
Potential renal endpoints .................................................................................... 50
5.1.3.1
Endpoints related to eGFR decline ..................................................................... 50
5.1.3.2
Dialysis and renal transplantation....................................................................... 51
5.1.3.3
Doubling of serum creatinine ............................................................................. 51
5.1.4
Hospitalisation for heart failure.......................................................................... 51

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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5.1.5
New diagnosis of type 2 diabetes (T2D)............................................................. 51
5.1.6
Cardiac ischaemic events ................................................................................... 51
5.1.7
Cerebrovascular events ...................................................................................... 51
5.1.8
Patient reported outcomes (PROs)...................................................................... 52
5.1.8.1
The Kidney Disease Quality of Life-36 (KDQOL™-36) .................................... 52
5.1.8.2
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L)......................... 52
5.1.8.3
Administration of patient reported outcomes (PROs).......................................... 52
5.2
Safety assessments............................................................................................. 53
5.2.1
Laboratory assessments...................................................................................... 53
5.2.1.1
Unscheduled laboratory assessments.................................................................. 54
5.2.2
Physical examination ......................................................................................... 54
5.2.3
Electrocardiogram (ECG)................................................................................... 54
5.2.4
Vital signs.......................................................................................................... 55
5.2.4.1
Pulse and blood pressure (BP)............................................................................ 55
5.2.4.2
Body weight and height...................................................................................... 55
5.3
Other assessments (not applicable)..................................................................... 55
5.4
Pharmacokinetics (PK)....................................................................................... 55
5.4.1
Collection of samples......................................................................................... 55
5.4.2
Determination of drug concentration.................................................................. 55
5.4.3
Storage and destruction of pharmacokinetics (PK) samples ................................ 55
5.5
Pharmacodynamics (not applicable) ................................................................... 56
5.6
Genetics............................................................................................................. 56
5.7
Biomarker analysis............................................................................................. 56
5.7.1
Storage, re-use and destruction of biological samples......................................... 56
5.7.2
Labelling and shipment of biological samples .................................................... 56
5.7.3
Chain of custody of biological samples .............................................................. 57
5.7.4
Withdrawal of informed consent for donated biological samples........................ 57
6.
SAFETY REPORTING AND MEDICAL MANAGEMENT............................. 58
6.1
Definition of adverse events............................................................................... 58
6.2
Definitions of serious adverse event (SAE) ........................................................ 58
6.3
Recording of adverse events............................................................................... 58
6.3.1
Time period for collection of adverse events ...................................................... 58
6.3.2
Adverse events of interest .................................................................................. 59
6.3.2.1
Volume depletion............................................................................................... 59
6.3.2.2
Renal events....................................................................................................... 59
6.3.2.3
Major hypoglycaemic events.............................................................................. 60
6.3.2.4
Fractures............................................................................................................ 60
6.3.2.5
Diabetic ketoacidosis (DKA).............................................................................. 60
6.3.2.6
Adverse events (AEs) leading to amputation and AEs leading to a risk for 
lower limb amputations (“preceding events”)..................................................... 60
6.3.3
Follow-up of unresolved adverse events............................................................. 60

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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6.3.4
Variables............................................................................................................ 60
6.3.5
Causality collection............................................................................................ 61
6.3.6
Adverse events based on signs and symptoms.................................................... 62
6.3.7
Adverse events based on examinations and tests ................................................ 62
6.4
Reporting of serious adverse events (SAEs) ....................................................... 62
6.4.1
Reporting of serious adverse events (SAEs) considered to be potential 
endpoints ........................................................................................................... 63
6.5
Overdose............................................................................................................ 63
6.6
Pregnancy .......................................................................................................... 64
6.6.1
Maternal exposure.............................................................................................. 64
6.7
Management of IP related toxicities (not applicable).......................................... 64
6.8
Study governance and oversight......................................................................... 64
6.8.1
Executive Committee......................................................................................... 64
6.8.2
National Lead Investigator (NLI) Committee ..................................................... 65
6.8.3
Data Monitoring Committee (DMC) .................................................................. 65
6.8.4
Clinical Event Adjudication (CEA) Committee.................................................. 65
6.8.5
Diabetic Ketoacidosis Adjudication Committee T2D ......................................... 65
6.9
Medication Error................................................................................................ 66
7.
INVESTIGATIONAL PRODUCT (IP) AND OTHER TREATMENTS ............ 67
7.1
Identity of investigational product (IP)............................................................... 67
7.2
Dose and treatment regimens ............................................................................. 67
7.3
Labelling............................................................................................................ 68
7.4
Storage............................................................................................................... 68
7.5
Compliance........................................................................................................ 68
7.6
Accountability.................................................................................................... 68
7.7
Concomitant and other treatments ...................................................................... 68
7.7.1
Restricted medication......................................................................................... 69
7.7.2
Prohibited medication ........................................................................................ 69
7.7.3
Recording of concomitant treatment................................................................... 69
7.7.4
Chronic kidney disease (CKD) medications ....................................................... 69
7.7.5
Anti-diabetes treatment of patients with established diagnosis of type 2 
diabetes (T2D) ................................................................................................... 70
7.7.5.1
Use of medications known to cause hypoglycaemia in type 2 diabetes (T2D) 
patients .............................................................................................................. 70
7.7.6
Other concomitant treatment .............................................................................. 70
7.8
Post Study Access to Study Treatment ............................................................... 70
8.
STATISTICAL ANALYSES BY ASTRAZENECA (AZ) ................................. 70
8.1
Statistical considerations .................................................................................... 70

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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8.2
Sample size estimate .......................................................................................... 71
8.3
Definitions of analysis sets................................................................................. 71
8.3.1
Full analysis set (FAS)....................................................................................... 71
8.3.2
Safety analysis set.............................................................................................. 71
8.4
Outcome measures for analyses.......................................................................... 71
8.4.1
Primary outcome measure.................................................................................. 71
8.4.2
Secondary outcome measure .............................................................................. 71
8.4.3
Safety outcome measure..................................................................................... 71
8.4.4
Exploratory outcome measure............................................................................ 71
8.5
Methods for statistical analyses.......................................................................... 72
8.5.1
Hypotheses ........................................................................................................ 72
8.5.2
Closed testing procedure.................................................................................... 72
8.5.3
Analysis of the primary variable (s).................................................................... 72
8.5.4
Analysis of the secondary variables.................................................................... 73
8.5.5
Subgroup analysis.............................................................................................. 73
8.5.6
Interim analysis.................................................................................................. 73
8.5.7
Sensitivity analysis............................................................................................. 73
8.5.8
Analysis of safety variables................................................................................ 73
8.5.9
Exploratory analysis........................................................................................... 73
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA (AZ) ................ 73
9.1
Training of study site personnel ......................................................................... 73
9.2
Monitoring of the study...................................................................................... 74
9.2.1
Risk based quality management ......................................................................... 74
9.2.2
Source data ........................................................................................................ 75
9.2.3
Study agreements............................................................................................... 75
9.2.4
Archiving of study documents............................................................................ 75
9.3
Study timetable and end of study........................................................................ 75
9.4
Data management by AstraZeneca (AZ)............................................................. 75
10.
ETHICAL AND REGULATORY REQUIREMENTS....................................... 76
10.1
Ethical conduct of the study ............................................................................... 76
10.2
Subject data protection....................................................................................... 76
10.3
Ethics and regulatory review .............................................................................. 76
10.4
Informed consent ............................................................................................... 77
10.5
Changes to the protocol and informed consent form (ICF).................................. 77
10.6
Audits and inspections ....................................................................................... 78
11.
LIST OF REFERENCES ................................................................................... 79

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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LIST OF TABLES
Table 1
Study plan.............................................................................................39
Table 2
Laboratory variables..............................................................................54
LIST OF FIGURES
Figure 1
Study design .........................................................................................25
LIST OF APPENDICES
Appendix A
Additional Safety Information...............................................................82
Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document..............................................................................84
Appendix C
New York Heart Association (NYHA) Functional Classification...........85
Appendix D
Patient Reported Outcome (PRO) questionnaires ..................................86
Appendix E
Genetic Research ..................................................................................96

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Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
The following abbreviations and special terms are used in this study Clinical Study Protocol.  
Abbreviation or 
special term
Explanation
ACE-I
Angiotensin converting enzyme inhibitor
ALP
Alkaline phosphatase
ALT
Alanine transaminase
ANCA
Anti-neutrophil cytoplasmic antibody
ARB
Angiotensin receptor blockers
AST
Aspartate transaminase
AZ
AstraZeneca, sponsor
BP
Blood pressure
BUN
Blood urea nitrogen
CABG
Coronary artery bypass grafting
CEA
Clinical Event Adjudication
CKD
Chronic kidney disease
CRO
Clinical research organization
CSA
Clinical study agreement
CSR
Clinical study report
CV
Cardiovascular
DAE
Discontinuation of investigational product due to adverse event
DGR
Dangerous Goods Regulations 
DKA
Diabetic ketoacidosis
DMC
Data Monitoring Committee
DMP
Data management plan
E-code
Enrolment number
EASD
European Association of the Study of Diabetes
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EMA
European Medicines Agency

Clinical Study Protocol
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Study Code D169AC00001
Version 4.0
Date 17 March 2020
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Abbreviation or 
special term
Explanation
EQ-5D-5L
EuroQol five-dimensional five-level questionnaire
ESRD
End stage renal disease
FAS
Full analysis set
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
Hb
Haemoglobin
HbA1c
Glycated haemoglobin
hCG
Human chorionic gonadotropin
HR
Hazard ratio
IATA
International Airline Transportation Association
IB
Investigator’s brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IRB/IEC
Institutional review board/independent ethics committee
International 
Ccoordinating
investigator
If a study is conducted in several countries the International Coordinating 
Investigator is the Investigator coordinating the investigators and/or 
activities internationally.  
IP
Investigational Product (dapagliflozin or matching placebo)
ITT
Intention to treat
IxRS
Interactive Voice/Web Response System
KDQOL™-36
Kidney Disease Quality of Life-36
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
NYHA
New York Heart Association
PCI
Percutaneous coronary intervention
PI
Principal Investigator
PK
Pharmacokinetics
PRO
Patient reported outcomes
PTH
Parathyroid hormone
PTDV
Premature treatment discontinuation visit
RAAS
Renin-angiotensin-aldosterone system
SAE
Serious adverse event

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
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Abbreviation or 
special term
Explanation
SAP
Statistical analysis plan
SCV
Study closure visit
SED
Study end date
SGLT2
Sodium glucose co-transporter 2
SU
Sulfonylurea
T1D
Type 1 diabetes
T2D
Type 2 diabetes
TIA
Transient ischemic attack
UACR
Urine albumin creatinine ratio
ULN
Upper limit of normal
WBDC
Web based data capture

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Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
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1.
INTRODUCTION
1.1
Background and rationale for conducting this study
Chronic kidney disease (CKD) affects approximately 10% of the adult population worldwide 
(Eckart et al 2013).  The most common causes of CKD are diabetes, hypertension and chronic 
glomerulonephritis.  Treatment for CKD encompasses angiotensin converting enzyme inhibitor 
(ACE-I) and angiotensin II receptor blockers (ARBs), lipid and blood pressure (BP) control as 
well as a tight glucose control in diabetic patients.  
Dapagliflozin (Forxiga™/Farxiga™) is a highly selective and reversible inhibitor of the sodium 
glucose co-transporter 2 (SGLT2), the major transporter responsible for glucose reabsorption in 
the kidney.  Dapagliflozin’s mechanism of action results in a direct and insulin independent 
elimination of glucose by the kidneys, which results in reduced blood glucose levels in 
type 2 diabetes (T2D) patients.  In addition, dapagliflozin has a mild diuretic and natriuretic 
effect.  The persistent loss of glucose with associated calories in the urine, results in a 
consistent and maintained reduction of the total body weight, predominantly a result of a 
reduction in fat mass including both visceral and subcutaneous adipose tissue.  Moreover, 
dapagliflozin has also been shown to reduce BP and albuminuria, two essential prognostic risk 
factors for progression of CKD.  
There is a growing body of evidence indicating that SGLT2 inhibition is nephroprotective.  
This effect is thought to be achieved partly by mechanisms independent of blood glucose 
reductions (Rajasekeran et al 2016, Heerspink at al 2016b), such as reduced intra-glomerular 
pressure through an enhanced tubuloglomerular feedback mechanism (De Nicola et al 2014, 
Thomas 2014), reduced glucose and sodium transport over the proximal tubule cells (Komala et 
al 2013, Pollock et al 1991), increased natriuresis (Heerspink et al 2013) and reduced systemic 
BP (Baker et al 2015, Sjöström et al 2015a).  Interestingly, there is a theoretical rationale for an 
improved oxygen availability in the impaired kidney during dapagliflozin treatment.  This 
could potentially be achieved via two mechanisms.  Firstly, an improved oxygen delivery due 
to a small but consistently observed haemo-concentration and secondly through a reduced renal 
oxygen consumption due to a reduced energy requirement from the potassium sodium pump 
situated on the basal-lateral membrane striving to retain the sodium gradient over the tubular 
cells (Gilbert RE 2016, Korner et al 1994).  Finally, there are emerging theories around 
metabolic benefits connected to a mild ketosis induced by SGLT2 inhibition (Mudaliar et al 
2016).
Notably, the total amount of glucose excreted in the urine following dapagliflozin 
administration, declines with decreasing kidney function and clinically important reduction in 
glycated haemoglobin (HbA1c) has not been demonstrated in T2D patients with estimated 
glomerular filtration rate (eGFR) <45 ml/min (Kohan et al 2014).  However, similar reductions 
of non-glycaemic variables such as BP, body weight and albuminuria have been observed with 

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dapagliflozin (Kohan et al 2014) and other SGLT2 inhibitors (Barnett et al 2014, Yale et al 
2013) in patients with impaired renal function as in patients with normal renal function.  
Furthermore, post-hoc analyses of data from the dapagliflozin phase II and phase III 
programme have shown in T2D patients with moderate renal impairment on renin-angiotensin-
aldosterone system (RAAS) blockade a reduction of around 40% in albuminuria and 
stabilization of eGFR decline for up to one year (Sjöström et al 2015b) and two years  (Fioretto 
et al 2016).  The EMPA-REG outcome trial, examining the cardiovascular (CV) effect of 
empagliflozin in T2D patients has further indicated beneficial renal effects of SGLT2 
inhibition.  After an initial drop in eGFR, kidney function was stable over time while a 
progressive decrease in eGFR was seen in the placebo group.  The trial also suggested 
substantial risk reductions for new onset of macroalbuminuria, doubling of serum creatinine 
and initiation of dialysis treatment (Wanner et al 2016).  
Nephroprotective effects not related to glucose excretion, rationale for use in non-T2D
As indicated above many of the effects from SGLT2 inhibition thought to contribute to a 
nephroprotective effect seem to be largely unrelated to glucose control per se.  Accordingly, 
regression analyses on data from the dapagliflozin phase III program indicate that the 
albuminuria lowering effect is not dependent on the glucose lowering actions seen during 
SGLT2 inhibition (Heerspink et al 2016, Fioretto et al 2016).  Furthermore, pooled data from 
the phase III program does not indicate a reduced effect on volume constriction (as measured 
by changes in haematocrit), systolic BP, pulse pressure, albuminuria and body weight in 
subjects with low glucose excretion due to renal impairment as compared with subjects 
excreting larger amounts of glucose in the urine (Sjöström et al 2016, EASD 2016).
Data on the effect of SGLT2 inhibition in patients without diabetes is limited.  However, 
dapagliflozin has safely been administered in healthy volunteers over a broad dose range (up to 
500 mg given as single dose) (Kasichayanula et al 2014).  Dapagliflozin effectively inhibited 
SGLT2 also in healthy volunteers without any observed events of hypoglycaemia.  
Furthermore, a clinical trial with canagliflozin, showed clinically relevant BP and weight 
reductions in obese non-diabetic patients without an increased incidence of hypoglycaemia 
(Bays et al 2013).  
Overall, the available data strongly indicate that non-diabetic CKD patients would also benefit 
from SGLT2 inhibition induced changes in variables important for nephroprotection.  As a 
consequence, this study will include CKD patients with and without T2D.
1.2
Rationale for study design, doses and control groups
1.2.1
Rationale for study design and study population
This is a randomised, double-blind, parallel-group study.  Randomisation and double blinding 
will minimize potential bias.  Parallel group design was chosen because a crossover study 
cannot assess major renal outcome events.  The study will be multicentre in numerous 
geographic regions to provide a wide applicability of results.  

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The study population chosen for this study is a broad population of patients with impaired 
kidney function.  Patients with CKD are at high risk of CV events, terminal renal failure and 
death (Go et al 2004).  Albuminuria adds to this risk, hence, the target population will have 
CKD (eGFR ≥25 and ≤75 mL/min/1.73m2) with albuminuria (urine albumin creatinine ratio 
[UACR] ≥200 and ≤5000 mg/g).  However, patients with known polycystic kidney disease, 
glomerulonephritis with flares (lupus or anti-neutrophil cytoplasmic antibodies [ANCA] 
associated vasculitis) or ongoing active renal inflammation will be excluded.
There is scientific rationale for beneficial effects of SGLT2 inhibition also in patients with 
CKD but without diabetes.  Patients with CKD have similar clinical picture with increased 
intra-glomerular pressure, hypertension, proteinuria and fluid/sodium overload regardless of 
underlying disease.  SGLT2 inhibition can improve on all these abnormalities through 
metabolic-independent mechanisms.  Moreover, the reduction on CV and renal events with 
empagliflozin cannot be explained by the glucose lowering effect alone (Rajasekeran et al 
2016, Mudaliar et al 2016, Gilbert RE 2016).
1.2.2
Rationale for primary outcome measure
The primary outcome measure is based on the requirements as outlined in the European 
Medicines Agency (EMA)’s draft guideline, which states that a composite endpoint of ≥50% 
sustained decline in eGFR, end stage renal disease (ESRD) and renal death (death due to ESRD 
when dialysis is not given) are acceptable outcome measures (EMA 2016).  This endpoint has 
also been used in a number of previous outcome studies.  
CV mortality is added as a component of the composite endpoint since CV mortality in the 
population being studied is high and the risk for CV death correlates with the risk of developing 
ESRD.  Thus, CV mortality is a competitive risk component and dapagliflozin is expected to 
have a beneficial effect on both CV death and renal outcome (Wanner et al 2016).
1.2.3
Rationale for secondary outcome measure 
It is of importance to separately look at the effect on composite renal endpoints and the 
composite heart failure endpoints (hospitalisation for heart failure and CV death).  Heart failure 
is particularly common in patients with CKD.  SGLT2 inhibition has previously shown to have 
beneficial effects on heart failure outcomes in patients with T2D and established CV disease 
(Zinman et al 2015).  All-cause mortality will be assessed as a secondary endpoint because it is 
important to evaluate the effect of dapagliflozin on non-CV, as well as CV, mortality and hence 
overall mortality.
1.2.4
Rationale for dose selection
The marketed dose, 10 mg, of dapagliflozin has been demonstrated to be well tolerated and 
effective for the treatment of T2D and post hoc analyses in patients with CKD and albuminuria 
have shown that this dose effectively reduces renal surrogate markers, i.e., BP and albuminuria, 
independent of the glucose lowering effect.  In a dedicated CKD 3 study (eGFR 30 to 60 
mL/min/1.73m2) this dose was found to be well tolerated (Kohan et al 2014).  From a 
pharmacokinetics (PK) and pharmacodynamics perspective, dapagliflozin 10 mg is appropriate 

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for use in patients with renal impairment.  The marketed 5 mg dose of dapagliflozin may be 
used in the study, but it is expected to provide less inhibition of SGLT2 and thus exert less 
pharmacodynamics effects (for details on when 5 mg or matching placebo can be used, see 
Section 3.9.1).
1.3
Benefit/risk and ethical assessment 
Dapagliflozin has global market approval and based on global cumulative sale figures up to
March 2016 it is estimated that dapagliflozin has been administered for >1 000 000 patient 
years.
1.3.1
Potential risks
The potential risks of treatment with dapagliflozin are described in the Investigator’s Brochure 
(IB).  Additional considerations relevant for the target population are described below.  
Dapagliflozin has not been shown to induce hypoglycaemia in non-diabetes patients.  In 
clinical pharmacology studies, healthy subjects have been treated with single oral doses up to 
500 mg and multiple oral doses of 100 mg up to 14 days without any hypoglycaemic event.
Events related to volume depletion (including reports of dehydration, hypovolemia, or 
hypotension) and events related to changes in renal function have been thoroughly evaluated in 
the dapagliflozin phase III program.  In a large pool consisting of 21 active- and placebo-
controlled studies, serious adverse events (SAEs) of volume depletion were infrequently 
reported and the proportion was even lower for subjects treated with dapagliflozin than control 
(0.1% versus 0.2%).  SAEs of renal impairment/failure were also rarely reported and balanced 
between treatment groups in the clinical trial program.  In total, 9 (0.2%) SAEs were reported 
in the dapagliflozin group and 5 (0.1%) SAEs in the control group.  
Although the phase III data in patients with CKD 3 show an increased frequency of overall 
renal events in patients treated with dapagliflozin as compared with placebo, most of these 
events have been related to laboratory detected transient increases in creatinine.  
In an analysis using pooled data on a subset of patients with CKD 3, micro or macro 
albuminuria and treatment with ACE-I or ARB there was no meaningful difference between 
dapagliflozin and placebo in terms of SAEs of renal impairment/failure or SAEs of volume 
depletion (Sjöström et al 2015b).  
Similarly, in a recent analysis of patients with pre-existing heart failure (HF) using pooled data 
from previous dapagliflozin studies (Kosiborod et al 2016), the rate of hypovolemic events was 
similar between patients treated with dapagliflozin and patients treated with placebo.  
Loop-diuretics are widely used in the target patient population and are also allowed in this 
study.  In the dapagliflozin phase III program, patients using loop diuretics were more likely to 
have an event related to volume depletion regardless of whether they were treated with 
dapagliflozin or placebo.  A pooled analysis of the short-term treatment periods showed 
6 (2.5%) subjects with events in patients on dapagliflozin 10 mg and 4 (1.5%) in patients on 

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placebo.  When including the long-term extension periods of the phase III trials in the analysis, 
the corresponding values were 7 (3.0%) versus 7 (2.7%) for dapagliflozin and placebo, 
respectively.  
Furthermore, other post hoc safety analyses of importance to the current target population have 
not identified any indication of an increased risk of marked abnormalities in potassium levels 
(≥6 mmol/L) in either patients with CKD 3 and ACE-I/ARB treatment (Sjöström et al 2015b)
or in patients on concomitant treatment with potassium sparing agents (Kosiborod et al 2016). 
1.3.1.1
Protection against risks
This study has been designed with appropriate measures in place to monitor and minimize any 
potential health risks to participating patients.  In order to ensure the safety of all patients 
participating in AstraZeneca (AZ) sponsored studies, reviews of all safety information from all 
ongoing clinical dapagliflozin studies are conducted as they become available.  In addition, an 
independent Data Monitoring Committee (DMC) will be responsible for safeguarding the 
interests of the patients by reviewing safety data throughout the study.
1.3.2
Potential benefits to patients
In this study, the dose of dapagliflozin 10 mg was chosen based on previous clinical 
experience.  Dapagliflozin is believed to be nephroprotective through non-glycaemic 
mechanisms and the hypothesis is that patients treated with dapagliflozin will have delayed 
progression of CKD and reduction in CV mortality.  Dapagliflozin has been shown to reduce 
UACR, HbA1c, BP and body weight in patients with T2D.  
Patients, irrespective of treatment, in clinical studies may receive greater medical care/attention 
than in ordinary clinical practice.
1.3.3
Conclusion
At the time of writing this clinical study protocol, no available SGLT2 inhibitors are indicated 
for treatment of CKD in patients with and without T2D.  Considering the non-clinical and 
clinical experience with dapagliflozin and the precautions included in the study protocol, 
participation in this study should present a minimal and thus acceptable risk to patients who 
meet the inclusion/exclusion criteria and consent to take part in the study.
1.4
Study design 
This is an international, multicentre, event-driven, randomised, double-blind, parallel-group, 
placebo-controlled study, evaluating the effect of dapagliflozin 10 mg versus placebo, given 
once daily in addition to standard of care, to prevent the progression of CKD or CV/renal death.  
It is estimated that approximately 10 000 patients at approximately 450 study sites in 
approximately 20 countries will be enrolled to reach the target of approximately 
4000 randomised patients.

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The anticipated duration of the study is approximately 45 months.  The study closure 
procedures will be initiated when the predetermined number of primary endpoints is predicted 
to have occurred (n=681), i.e., the study end date (SED) (see Figure 1).  The study duration 
may be changed if the event rate or randomisation rate is different than anticipated.  The study 
may be terminated early if either a clear beneficial or harmful effect of the study treatment is 
detected during the DMC review.

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Figure 1
Study design

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2.
STUDY OBJECTIVES
2.1
Primary objective
Primary Objective:
Outcome Measure:
To determine if dapagliflozin is superior to 
placebo in reducing the incidence of the primary 
composite endpoint of ≥50% sustained decline in 
eGFR, reaching ESRD, CV or renal death when 
added to current background therapy in patients 
with eGFR ≥25 and ≤75 mL/min/1.73m2 and 
albuminuria (UACR ≥200 and ≤5000 mg/g).
Time to the first occurrence of any of the 
components of this composite: 
1.
≥50% sustained* decline in eGFR 
2.
Reaching ESRD 

Sustained* eGFR 
<15 mL/min/1.73m2 or, 

Chronic* dialysis treatment or,

Receiving a renal transplant
3.
CV death 
4.
Renal death
*As defined in the Clinical Event Adjudication (CEA) charter
2.2
Secondary objectives
Secondary Objective:
Outcome Measure:
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of the composite endpoints of 
worsening of renal function.  
Time to the first occurrence of any of the 
components of this composite: 
1.
≥50% sustained decline in eGFR
2.
Reaching ESRD
3.
Renal death
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of the composite endpoint of CV death 
or hospitalisation for heart failure.  
Time to the first occurrence of either of the 
components of this composite: 
1.
CV death 
2.
Hospitalisation for heart failure 
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of all-cause mortality.  
Time to death from any cause

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2.3
Safety objectives 
Safety Objective:
Outcome Measure:
To evaluate the safety and tolerability of 
dapagliflozin in this patient population.  
1.
Serious adverse event (SAE)
2.
Discontinuation of investigational 
product (IP) due to adverse event 
(DAE)s
3.
Changes in clinical 
chemistry/haematology parameters
4.
AEs of interest (volume depletion, 
renal events, major hypoglycaemic 
events, fractures, diabetic ketoacidosis 
(DKA), AEs leading to amputation and 
AEs leading to a risk for lower limb 
amputations [“preceding events”])
2.4
Exploratory objectives  
Exploratory Objective:
Outcome Measure:
To determine whether dapagliflozin compared 
with placebo will result in a reduction in the 
incidence of the composite endpoint of chronic 
dialysis, renal death or receiving a renal 
transplant.
Time to the first occurrence of any of the 
components of this composite:
1.
Chronic dialysis
2.
Receiving renal transplant 
3.
Renal death
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of the individual components of the 
primary endpoint.
Time to the first occurrence of each of the 
individual components:
1.
≥50% sustained decline in eGFR
2.
Reaching ESRD 
3.
CV death
or
4.
Renal death

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Exploratory Objective:
Outcome Measure:
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of sustained reduction in kidney 
function.
Time to the first occurrence of two consecutives 
central laboratory values showing either of the 
following:
1.
≥30% decline in eGFR from baseline
2.
≥40% decline in eGFR from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on eGFR over 
time.  
The effect on eGFR over time will be measured:
1.
From baseline to end of treatment
2.
From first on treatment measurement 
to end of treatment
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of patients reaching CKD 4 (eGFR 
<30 mL/min/1.73m2).
Proportion of patients with eGFR >40 
mL/min/1.73m2 at baseline that enter CKD 4 
during the study.
To determine whether dapagliflozin compared 
with placebo will have effect on UACR.
Changes in UACR from baseline.
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of hyper- and hypokalaemia.  
Time to the first occurrence of each of any of the 
following central laboratory levels of serum 
potassium:

>6.0 mmol/L

>5.5 mmol/L

<3.5 mmol/L

<3.0 mmol/L
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of events of doubling of serum 
creatinine.
Time to the first occurrence of an event of 
doubling of serum creatinine (compared to the 
most recent central laboratory measurement)
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of new diagnosis of T2D in patients 
without diabetes at baseline.
Proportion of patients without diabetes at baseline 
with a new diagnosis of T2D during the study
To determine whether dapagliflozin compared 
with placebo will have effect on HbA1c in T2D 
patient subgroup.
Changes in HbA1c from baseline

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Exploratory Objective:
Outcome Measure:
To determine whether dapagliflozin compared 
with placebo will have an effect on systolic BP.
Change in systolic BP from baseline
To determine whether dapagliflozin compared 
with placebo will have an effect on body weight.
Change in body weight from baseline
To determine whether dapagliflozin compared 
with placebo will result in a reduction in the 
incidence of the composite endpoint of CV death, 
MI or stroke.
Time to the first occurrence of any of the 
components of this composite:
1.
CV death
2.
MI
3.
Stroke
To determine whether dapagliflozin compared 
with placebo will result in a reduction in the 
incidence of heart failure hospitalisation.
Time to first hospitalisation for heart failure
To determine whether dapagliflozin compared 
with placebo will result in a reduction in the 
incidence of myocardial infarction (MI).
Time to first fatal or non-fatal MI
To determine whether dapagliflozin compared 
with placebo will result in a reduction of the 
incidence of any stroke (ischemic, haemorrhagic, 
or undetermined).
Time to first fatal or non-fatal stroke of any cause
To compare the effect of dapagliflozin versus 
placebo on the Kidney Disease Quality of Life-36 
(KDQOL™-36) questionnaire.
Change from baseline in the overall summary 
score of the KDQOL™-36 
To compare the effect of dapagliflozin versus 
placebo on health status assessed by EuroQol five-
dimensional five-level questionnaire (EQ-5D-5L) 
to support health economic analysis and health 
technology assessment.
Changes in health status measured by the 
EQ-5D-5L
To collect and analyse PK samples for 
dapagliflozin concentration.
Not applicable. Results will be reported 
separately.
To collect and store blood/urine samples for future 
exploratory biomarker and genetic research.
Not applicable. Results will be reported 
separately.
3.
PATIENT SELECTION, ENROLMENT, RANDOMISATION, 
RESTRICTIONS, DISCONTINUATION AND WITHDRAWAL 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study.  Under no circumstances can there be exceptions to this rule.  

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3.1
Inclusion criteria
For inclusion in the study patients should fulfil the following criteria:
1.
Provision of signed informed consent prior to any study specific procedures
2.
Female or male aged ≥18 years at the time of consent
3.
eGFR ≥25 and ≤75 mL/min/1.73m2 (CKD-EPI Formula) at visit 1
4.
Evidence of increased albuminuria 3 months or more before visit 1 and UACR 
≥200 and ≤5000 mg/g at visit 1
5.
Stable, and for the patient maximum tolerated labelled daily dose, treatment with 
ACE-I or ARB for at least 4 weeks before visit 1, if not medically contraindicated
3.2
Exclusion criteria
Patients should not enter the study if any of the following exclusion criteria are fulfilled:
1.
Autosomal dominant or autosomal recessive polycystic kidney disease, lupus 
nephritis or ANCA-associated vasculitis
2.
Receiving cytotoxic therapy, immunosuppressive therapy or other immunotherapy 
for primary or secondary renal disease within 6 months prior to enrolment
3.
History of organ transplantation
4.
Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrolment or 
previous intolerance of an SGLT2 inhibitor
5.
Type 1 diabetes mellitus (T1D)
6.
New York Heart Association (NYHA) class IV Congestive Heart Failure at the time 
of enrolment (see Appendix C)
7.
MI, unstable angina, stroke or transient ischemic attack (TIA) within 12 weeks prior 
to enrolment
8.
Coronary revascularization (percutaneous coronary intervention [PCI] or coronary 
artery bypass grafting [CABG]) or valvular repair/replacement within 12 weeks 
prior to enrolment or is planned to undergo any of these procedures after 
randomisation
9.
Any condition outside the renal and CV disease area, such as but not limited to 
malignancy, with a life expectancy of less than 2 years based on investigator´s 
clinical judgement

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10.
Active malignancy requiring treatment at the time of visit 1 (with the exception of 
successfully treated basal cell or treated squamous cell carcinoma).  
11.
Hepatic impairment (aspartate transaminase [AST] or alanine transaminase [ALT] 
>3x the upper limit of normal [ULN]; or total bilirubin >2x ULN at time of 
enrolment).  An isolated increase in bilirubin in patients with known Gilbert’s 
syndrome is not a reason for exclusion.
12.
Known blood-borne diseases such as specified in Appendix B (category A and B).
13.
Women of child-bearing potential (i.e., those who are not chemically or surgically 
sterilised or who are not post-menopausal) who are not willing to use a medically 
accepted method of contraception that is considered reliable in the judgment of the 
investigator, from the time of signing the informed consent throughout the study 
and 4 weeks thereafter, OR women who have a positive pregnancy test at enrolment 
or randomisation OR women who are breast-feeding.
14.
Involvement in the planning and/or conduct of the study (applies to both AZ 
personnel and/or site personnel).
15.
Previous randomisation in the present study.
16.
Participation in another clinical study with an IP during the last month prior to 
enrolment.
17.
Inability of the patient, in the opinion of the investigator, to understand and/or 
comply with IP, procedures and/or follow-up OR any conditions that, in the opinion 
of the investigator, may render the patient unable to complete the study.  

Patients who cannot complete the patient reported outcome (PRO) 
assessments can still participate in the study (see Section 5.1.8.3 for 
details regarding the patient exclusion from the PRO assessments during 
certain circumstances).  
Procedures for withdrawal of incorrectly enrolled patients see Section 3.4.
3.3
Patient enrolment and randomisation
Investigator(s) should keep a record, the patient screening log, of patients who entered pre-
study screening.  
The Investigator(s) will:
1.
Obtain signed informed consent from the patient or their guardian/legal 
representative before any study specific procedures are performed.

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2.
Assign the patient a unique enrolment number (E-code), beginning with ‘E#’, which 
will be used to identify the patient throughout the study.  The E-code to be assigned 
in the Interactive Voice/Web Response System (IxRS). 
3.
Determine patient eligibility.  See Section 3.
4.
At visit 2, perform the randomisation transaction in the IxRS.
Re-enrolment is allowed one single time considering that the patient was not randomised.  The 
same E-code that the patient received at the first enrolment will be used.  All enrolment 
assessments and procedures (see Section 4.1.1), including re-signing the informed consent 
form (ICF), should be performed again.  
3.4
Procedures for handling incorrectly enrolled or randomised 
patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, be 
enrolled or receive IP.  There can be no exceptions to this rule.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be randomised or initiated 
on treatment, and must be withdrawn from the study. 
Where a patient does not meet all the eligibility criteria but is randomised in error, or 
incorrectly started on treatment, the Investigator should inform the AZ study physician 
immediately, and a discussion should occur between the AZ study physician and the 
investigator regarding whether to continue or discontinue the patient from treatment. Study 
treatment must be discontinued in all cases where continued treatment is deemed to pose a 
safety risk to the patient. In those cases where continuation of study therapy is judged not to 
present a concern related to safety and disease management, the rationale for continuing study 
therapy must be clearly documented. Regardless of what is decided about IP all randomised 
patients should remain in the study and the patients should continue to be followed up in 
accordance with defined study procedures. 
3.5
Methods for assigning treatment groups
Randomisation to IP will be performed via IxRS at visit 2 in balanced blocks to ensure 
approximate balance between the treatment groups (1:1).
The IxRS will allocate the IP through a randomisation scheme and provide the randomisation 
number and the appropriate Kit IDs from IP available at the study site.  The randomisation
codes will be computer generated and loaded into the IxRS database.  
At all visits where IP is dispensed, site personnel will do a kit verification in IxRS before
providing the IP bottle to the patient.  
Detailed instruction on use of the IxRS system will be provided to study sites.  

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3.5.1
Stratification and capping
The recruitment will be continuously monitored in order to achieve adequate proportions of 
patient sub-populations.
Randomisation of patients based on geographic region will be monitored to ensure a global 
representation.  Also, the proportion of patients not on ACE-I or ARB at randomisation, due 
to intolerance, will be monitored to ensure that the target population is reflected in regards to 
background therapy.
3.5.1.1
Stratification
Randomisation will be stratified in IxRS based on patients with and without T2D at the time 
of randomisation in order to ensure approximate balance between treatment groups within 
each sub-population.  T2D at the time of randomisation is based on:

Established diagnosis of T2D 
OR 

HbA1c more or equal to 6.5% (48 mmol/mol) shown at central laboratory 
test at enrolment (visit 1) 
Randomisation will also be stratified in IxRS for patients with UACR >1000 mg/g to ensure 
an equal proportion of patients in each treatment group.
3.5.1.2
Capping
The number of randomised patients with and without T2D will be monitored in order to 
ensure a minimum of 30% in each sub-population.  Randomisation may be capped in IxRS 
(i.e., no more patients in a specific sub-population can be randomised) if the pre-determined 
limit is reached.
The number of patients with eGFR 60 to 75 mL/min/1.73m2 at the time of randomisation, 
shown with a laboratory test at enrolment (visit 1), will be monitored and randomisation in 
IxRS may be capped to ensure that the number of patients in this sub-population does not 
exceed approximately 10%.  
3.6
Methods for ensuring blinding
The blinding of treatment is ensured by using a double-blind technique.  The dapagliflozin 
tablets and the respective placebo tablets will be identical in size, colour, smell, and taste.  The 
bottles with IP will be labelled with unique identification numbers.  
No member of the extended AZ study team, site personnel, or any clinical research 
organization (CRO) handling study data will have access to the randomisation scheme during 
the study.  The AZ personnel or delegate generating the randomisation scheme and the Supply 
Chain Study Management may be able to access the randomisation scheme as appropriate.  

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3.7
Methods for unblinding 
Individual treatment codes, indicating the randomised treatment for each patient, will be 
available to the Investigator(s) or pharmacists from the IxRS.  Instructions for code breaking/ 
unblinding will be described in the IxRS user manual that will be provided to each site.  
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment randomisation.  The 
Investigator documents and reports the action to AZ, without revealing the treatment given to 
patient to the AZ personnel.  It is always the investigator who decides when to unblind but it is 
recommended that the investigator first contacts the AZ study physician for consultation 
regarding the need for unblinding.  If unblinding is deemed necessary, the investigator will 
perform the unblinding in IxRS and must document all actions taken.  The number of 
individuals at the study site who become aware of treatment status should be kept to the 
absolute minimum (including keeping the patient blinded if possible).  Treatment with study 
medication should be continued if possible.  
AZ retains the right to break the code for SAEs that are unexpected and are suspected to be 
causally related to an IP and that potentially require expedited reporting to regulatory 
authorities.  Treatment codes will not be broken for the planned analyses of data until all 
decisions on the evaluability of the data from each individual patient have been made and 
documented.  
3.7.1
Unblinding for bioanalytical laboratory personnel 
PK samples will be analysed at the bioanalytical laboratory only for patients on active IP.  The 
bioanalytical laboratory will therefore have access to the treatment codes but will not share the 
codes with the sponsor or others involved in the study until the blinding is broken for the 
study after closure.
3.8
Restrictions
There are no specific dietary or activity restrictions.  For restricted concomitant medications 
see Section 7.7.  
3.9
Discontinuation of investigational product
If the patient temporarily or permanently discontinues from IP, it is important that the 
scheduled study visits, data collection and procedures continue according to the study protocol 
until study closure (see Section 3.9.3).  
Patients may be discontinued from IP in the following situations:
1.
Patient decision.  The patient is at any time free to discontinue treatment, without 
prejudice to further treatment.

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2.
AE or other safety reasons that, in the opinion of the investigator contraindicates 
further dosing with IP.
3.
Severe non-compliance with the study protocol.
4.
DKA, consider to temporary interrupt IP if DKA is suspected.  If DKA is 
confirmed, IP should be discontinued permanently.  
5.
Positive pregnancy test (discontinue IP and notify AZ representative).
3.9.1
Evaluation of volume status and investigational product (IP) dose 
reduction/interruption
Dapagliflozin is a SGLT2 inhibitor which by its mechanism of action reduces the reabsorption 
of glucose and sodium in the proximal tubules in the kidney.  SGLT2 inhibition has a mild 
diuretic effect and an initial haemodynamic change with an initial increase in creatinine may 
occur.
Unexpected acute declines in eGFR 
If an unexpected, acute decline in kidney function is observed, the patient should be evaluated.  
Volume depletion, hypotension, inter-current medical problems and concomitant drugs may 
cause increases in blood creatinine.  Urinary tract infection and urinary obstruction should be 
considered (the latter especially in men).  Several drugs may cause a decline in kidney 
function, especially non-steroidal anti-inflammatory drugs (NSAID) and certain antibiotics 
such as trimethoprim.  If any drug is suspected of causing or contributing to worsening kidney 
function, their use should be re-considered.  
Volume depletion/hypotension
Patients with clinically relevant symptoms/signs of suspected volume depletion and/or 
hypotension, should have their regular medication reviewed, and consideration given to 
reducing the dose of, or stopping concomitant non-essential medications, as assessed on an 
individual basis, including diuretics and drugs that lower BP (except essential treatments – see 
below).  The need for conventional diuretics (or the dose of diuretic used) should be re-
evaluated in light of the patient’s symptoms and signs.  In patients with heart failure, 
discontinuation of diuretic should only be undertaken cautiously.  Hypotension may also occur 
with other BP lowering drugs and once again the need for (and dose of) non-essential agents 
of this type (e.g., calcium channel blockers, alpha adrenoceptor antagonists and nitrates) 
should also be re-considered.
Essential treatments
Essential disease modifying/evidence based treatments such as ACE-I/ARBs, for patients with 
proteinuric CKD and ACE-I/ARBs, sacubitril/valsartan, mineralocorticoid receptor 
antagonists and beta-blockers for patients with heart failure, should NOT be reduced in dose 
or discontinued unless all other measures fail to improve the patient’s situation. In the setting 
of acute worsening of HF or other acute situations it may be acceptable to interrupt treatment 

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on a temporary basis in certain circumstances (e.g., an ACE-I/ARB if the patient has 
experienced a significant deterioration in renal function, a beta-blocker if the patient is unduly 
bradycardic or hypotensive, a mineralocorticoid receptor antagonist (MRA) if the patient has 
hyperkalaemia).
IP dose reduction 
If the above mentioned measures do not lead to a resolution of clinically relevant volume 
depletion, hypotension and/or unexpected worsening of kidney function, a dose reduction of 
IP to dapagliflozin 5 mg or matching placebo may be considered and the patient’s condition 
re-evaluated.
Patients at risk of volume depletion
Temporary interruption of IP may be considered in patients thought to be at risk of volume 
depletion/hypotension, such as patients with an acute medical illness potentially causing 
volume depletion because of inadequate fluid intake or fluid/blood loss (e.g., gastroenteritis, 
gastrointestinal haemorrhage), or those undergoing major surgery.  
3.9.2
Investigational product (IP) restart or dose increase from dapagliflozin 5 mg to
10 mg or matching placebo
Restart of randomised IP is always encouraged.  Even if a premature treatment discontinuation 
visit (PTDV) was completed due to the discontinuation of IP, this should not prevent the 
patient to return to randomised treatment if deemed appropriate.  
Every attempt should be made to maintain patients on dapagliflozin 10 mg or matching 
placebo during the course of the study.  If the dose has been decreased to 5 mg or interrupted, 
the dose should be increased back to dapagliflozin 10 mg or matching placebo or 
re-introduced as soon as, in the opinion of the investigator, the patient’s condition is stable.  
3.9.3
Procedures for discontinuation of a patient from investigational product (IP)
At any time, patients are free to discontinue IP.  A patient that decides to discontinue will 
always be asked about the reason(s) and the presence of any AEs.  If possible, the patient will 
be seen and assessed by an investigator.  Adverse events will be followed up, see Section 6, 
and all IP should be returned by the patient.
Generally, AEs, SAEs and potential endpoint events should not lead to IP discontinuation, 
unless there is a clear clinical rationale to do so.
Discontinuation from IP is not the same as complete withdrawal from the study.  If a patient is 
completely withdrawn from study, see Section 3.10.2.
It is essential to collect data for all patients throughout the study.  Optimally, a patient who 
discontinue from IP should for that reason attend all study visits according to plan until study 
closure.  Alternatively, if the patient does not agree to this approach, modified follow-up 
should be arranged.  Patients who agree to some kind of modified follow up are still 

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participating in the study.  The modified visits and procedures that are done will be recorded 
in the electronic Case Report Form (eCRF).
If a patient for some reason cannot be reached during the study, every attempt should be made 
to retrieve as much information regarding this patient as possible.  The site should 
continuously try to reach the patient, the patient’s family or pre-identified appropriate contact 
person(s) and, search for information regarding the patient’s status in applicable sources to 
protect the validity of data.  The attempts should be registered in the medical records.
3.9.3.1
Patient undergoes the premature treatment discontinuation visit (PTDV) and 
continues according to plan
The preferred follow-up approach for all patients who prematurely and permanently 
discontinue IP is that the patient undergoes the PTDV and then continues study visits 
according to plan (Table 1).  The PTDV should be done as soon as possible after last IP dose.
3.9.3.2
Patient agrees to undergo modified follow-up
If the patient does not agree to continue study visits according to plan, but agrees to undergo 
modified follow up, a PTDV should be done (Table 1).  The subsequent visits until the study 
closure will be done as modified follow-up (e.g., less frequent visits, regular telephone 
contacts, a contact at study closure, or other means) in order to ascertain whether any 
endpoints or safety events have occurred.
3.10
Criteria for withdrawal 
3.10.1
Screen failures 
Screen failures are enrolled patients who do not fulfil the eligibility criteria for the study, and 
therefore must not be randomised.  These patients should have the reason for study withdrawal 
recorded as ‘Screen failure’ (i.e., patient does not meet the required inclusion/exclusion 
criteria) in the eCRF.  This reason for study withdrawal is only valid for screen failures (not 
randomised patients).  
3.10.2
Withdrawal of informed consent
Patients are free to withdraw from the study at any time (IP and assessments), without 
prejudice to further treatment.  Withdrawal of consent should only occur if the patient does 
not agree to any kind of further assessments or contact whatsoever.  If agreed by the patient, a 
PTDV should be performed.  Discontinuation of IP in itself is not considered withdrawal of 
consent.  
Withdrawal of consent must be ascertained and documented in writing by the investigator who 
must inform the AZ representative and document the withdrawal of consent in the eCRF and 
medical records. 
A patient who withdraws consent will always be asked about the reason(s) and the presence of 
any AE.  The investigator will follow up AEs reported outside of the clinical study.

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If a patient withdraws from participation in the study, then his/her enrolment and 
randomisation codes cannot be reused.  Withdrawn patients will not be replaced.  Data 
generated to the time of complete withdrawal from the study will not be destroyed.
To ensure validity of study data, it is very important to collect as much data as possible 
throughout the study and especially vital status (dead or alive) at study closure (also for 
patients who have withdrawn their informed consent).  The investigator will therefore attempt 
to collect information on all patients’ vital status from publicly available sources at study 
closure, even if informed consent has been withdrawn completely, in compliance with local 
privacy laws/practices.  
3.11
Discontinuation of the study
The study may be stopped if, in the judgment of AZ, patients are placed at undue risk because 
of clinically relevant findings. The judgment may be based on recommendations from the 
DMC, see DMC Charter for details.  
In terminating the study, the Sponsor will ensure that adequate consideration is given to the 
protection of the patients’ interests.  

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4.
STUDY PLAN AND TIMING OF PROCEDURES 
The schedule of study visits and assessments is shown in Table 1 and explained further in Sections 4.1 and 4.2.  
Table 1
Study plan
Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontinua-
tion visit
Study 
closure visit
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
360
(±14 and 
every 4th
month)
≤6 weeks 
from SED
Sign Informed Consent 
Form (ICF)
X
Inclusion/exclusion criteria
X
X
3.1/3.2
Enrolment in IxRS
X
3.3
Randomisation in IxRS
X
3.3
Demography
X
Medical/surgical history
X

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Table 1
Study plan
Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontinua-
tion visit
Study 
closure visit
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
360
(±14 and 
every 4th
month)
≤6 weeks 
from SED
Vital signs
(BP, pulse and body weight)
X
X
X
X
X
X
X
X
X
5.2.4
Height
X
5.2.4
Local laboratory 
assessment a
X a
5.2.1
Central laboratory 
assessment b
X
X
X
X
X
X
X
X
X
5.2.1
Spot UACR, central 
laboratory sampling
X
X
X
X
X
X
X
X
X
5.2.1
Pregnancy testing
X
X
5.2.1
Sample for biomarker 
research, if applicable c
X
X c
5.7
Sample for genetic research, 
if applicable c
X
Appendix E

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Study Code D169AC00001
Version 4.0
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Table 1
Study plan
Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontinua-
tion visit
Study 
closure visit
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
360
(±14 and 
every 4th
month)
≤6 weeks 
from SED
PK sampling (pre-dose)
X d
5.4
Potential endpoints, SAEs 
DAEs etc, AEs of interest e
X e
X
X
X
X
X
X
X
X
6
KDQOL™-36 questionnaire
X
X f
X
X
5.1.8.1
EQ-5D-5L questionnaire
X
X
X
X f
X
X
5.1.8.2
General physical 
examination
X
X
X
5.2.2
Targeted physical 
examination
X
X
X
X
X
5.2.2
Electrocardiogram (ECG)
X
5.2.3
Concomitant medication
X
X
X
X
X
X
X
X
7.7

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Table 1
Study plan
Activity
Enrolment
Randomi-
sation
Site visits
Premature 
treatment 
discontinua-
tion visit
Study 
closure visit
Reference 
in CSP
Visit number
1
2
3
4
5
6
7, 8, 9 etc.
PTDV
SCV
Day
-14
(±7)
0
14
(±3)
60
(±7)
120
(±7)
240
(±14)
360
(±14 and 
every 4th
month)
≤6 weeks 
from SED
Dispense (including kit 
verification in IxRS)/Collect 
IP
X
X
X
X
X
X
3.5
IP compliance reminder
X
X
X
X
X
X
a
Local laboratory assessment is optional and may be used to assess eligibility (according to local routine) of eGFR and/or albuminuria. If used, the ICF needs to be signed 
before the optional assessment starts. 
b
Central laboratory assessments include alkaline phosphatase (ALP), ALT, AST, bilirubin, blood urea nitrogen (BUN), creatinine (including eGFR assessment), 
haematocrit, haemoglobin (Hb), HbA1c, phosphate, potassium, and sodium will be analysed as specified in Table 2.
c
Blood and urine samples for future biomarker and/or genetic research is optional.  The biomarker and/or genetic sampling is subject to separate consent by the patient.  
Biomarker samples will be collected at visit 2 and 7, and genetic samples will be collected at visit 2.
d
PK samples will be collected at visit 7.
e
SAEs will be collected from the time of informed consent throughout the study until and including the patient’s last visit.  Potential endpoints, DAEs, AEs leading to dose 
reduction and temporary interruptions and AEs of interest will be collected from randomisation throughout the study until and including the patient’s last visit.
f
The PRO questionnaires will be completed as specified until visit 7 and thereafter every 12 months, and at PTDV and study closure visit (SCV).

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4.1
Enrolment period
4.1.1
Visit 1, enrolment (day -14 ±7)
During enrolment period the following assessments and procedures will be completed:

Patient signs the ICF before any study procedures.

Patients who agree to the optional sampling of blood and urine for 
potential future biomarker and/or genetic research will provide their 
consent.  

Patient will be enrolled and assigned an E-code in IxRS.

Optional local laboratory assessment 
Failure to meet the criteria for eGFR and/or albuminuria is expected to be 
the main reason for screen failure in this study.  Therefore, sites will be 
allowed to perform an optional assessment, which will include local 
laboratory assessments of eGFR and/or albuminuria.  Investigators will 
only assess patients who are potentially eligible for the study based on 
their medical conditions and existing therapies, and only those who are 
expected to meet all other entry criteria.  
Local laboratory assessments of eGFR and/or albuminuria will be done 
according to local routine.
When the local results of eGFR are available and indicate that the patient 
may be eligible based on the clinical judgement of the investigator, the 
patient may proceed to further enrolment procedures.

The investigator reviews the inclusion and exclusion criteria.  Patients 
who do not meet these criteria must not be randomised in the study.  

Demography (date of birth, sex, race, ethnic group) and relevant medical 
and surgical history, including smoking history, will be recorded.  

Vital signs (BP, pulse and body weight) and height will be assessed and 
recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

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
Due to high day to day variability of creatinine (eGFR) and UACR, one 
central laboratory retest is allowed, if in the opinion of the investigator 
values are close to the inclusion criteria.

Pregnancy test for women of child-bearing potential will be done locally 
with a dipstick provided by central laboratory.
4.2
Treatment period
4.2.1
Visit 2, randomisation (day 0)
Prior to visit 2, the investigator assesses eligibility based on the laboratory results received from 
central laboratory from visit 1.  Patients not eligible will be considered screen failures and 
should not continue to visit 2.  
At randomisation, the following assessments and procedures will be done:

KDQOL™-36 and EQ-5D-5L will be completed by the patient prior to 
any other site activities and before the patient meets the investigator.

The investigator will re-assess the inclusion and exclusion criteria.

The investigator will perform a general physical examination.  

Vital signs will be assessed and recorded. 

Electrocardiogram (ECG) will be done.

Randomisation to IP will be done in IxRS.

For stratification/capping purposes (see Section 3.5.1), information 
about eGFR and UACR (based on results received from central
laboratory), and whether patient has T2D or not will be recorded in 
IxRS.  

Concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

Patients who have consented to sampling for potential future 
biomarker analysis and/or genetic research, will provide blood and 
urine samples.  

Pregnancy test for women of child-bearing potential will be done locally 
with a dipstick provided by central laboratory.

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
If the patient has experienced any SAEs since last visit, this will be 
recorded in the eCRF.

The IP will be dispensed via IxRS to the patient.  The patient will be 
instructed to take the IP in accordance with protocol without interruptions.  
4.2.2
Visit 3 (day 14 ±3)
At visit 3, the following assessments and procedure will be done:

The investigator will perform a targeted physical examination.  

Vital signs will be assessed and recorded.

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

The patient will be reminded to take the IP in accordance with the protocol 
and without interruptions.
4.2.3
Visit 4 (day 60 ±7)
At visit 4, the following assessments and procedure will be done:

The investigator will perform a targeted physical examination.  

Vital signs will be assessed and recorded.

Any relevant changes in concomitant medication will be recorded.  

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

The patient will be reminded to take the IP in accordance with the protocol 
and without interruptions.  

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4.2.4
Visit 5 (day 120 ±7)
At visit 5, the following assessments and procedures will be done:

EQ-5D-5L will be completed by the patient prior to any other site 
activities and before the patient meets the investigator.  

The investigator will perform a targeted physical examination.  

Vital signs will be assessed and recorded.

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

IP will be dispensed via IxRS to the patient and drug accountability of the 
returned medication will be checked.  The patient will be instructed to take 
the IP in accordance with the protocol and without interruptions.  
4.2.5
Visit 6, (day 240 ±14)
At visit 6, the following assessments and procedures will be done:

EQ-5D-5L will be completed by the patient prior to any other site 
activities and before the patient meets the investigator.  

The investigator will perform a targeted physical examination.  

Vital signs will be assessed and recorded.

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

IP will be dispensed via IxRS to the patient and drug accountability of the 
returned medication will be checked.  The patient will be instructed to take 
the IP in accordance with the protocol and without interruptions.  

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
At visit 6, patient will be reminded to not take IP until after the visit at 
visit 7 to enable pre-dose PK sampling.  
4.2.6
Visit 7, 8, 9 etc., on-site visits; (day 360 ±14 and; every 4th month)
At visit 7 and all subsequent visits until SCV, the following assessments and procedures will be 
done:

KDQOL™-36 and EQ-5D-5L will be completed by the patient prior to 
any other site activities and before the patient meets the investigator.  

The PRO questionnaires will be done at visit 7 and thereafter every 12 
months.  

The investigator will perform a targeted physical examination.  

Vital signs will be assessed and recorded.

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

At visit 7, pre-dose, a PK sample will be collected.  The patient should 
not take IP before the visit this day.  The date and time of last dose 
before sampling will be recorded in eCRF.  

At visit 7, patients who have consented to sampling for potential future 
biomarker analysis, will provide blood and urine samples.  

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in eCRF.

IP will be dispensed via IxRS to the patient and drug accountability of the 
returned medication will be checked.  The patient will be instructed to take 
the IP in accordance with protocol without interruptions.  
4.2.7
Premature treatment discontinuation visit (PTDV) 
Patients who prematurely and permanently discontinue treatment with IP should return for a 
PTDV, which will be done as soon as possible after last IP dose.  

KDQOL™-36 and EQ-5D-5L will be completed by the patient prior to 
any other site activities and before the patient meets the investigator.  

The investigator will perform a general physical examination.  

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
Vital signs will be assessed and recorded.  

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

Drug accountability of the returned medication will be checked.  
Patients who discontinue treatment prematurely should attend all following study visits 
according to plan, including the SCV.
For further details regarding discontinuations from IP, refer to Section 3.9.
4.2.8
Study closure visit (SCV)
All patients will be asked to return for an SCV visit when the predetermined number of primary 
endpoints is predicted to have occurred, i.e., the SED.  All randomised patients (including any 
patients who have discontinued treatment with IP) should return for their SCV visit as soon as 
possible but no later than 6 weeks after the SED.

KDQOL™-36 and EQ-5D-5L will be completed by the patient prior to 
any other site activities and before the patient meets the investigator.

The investigator will perform a general physical examination.  

Vital signs will be assessed and recorded

Any relevant changes in concomitant medication will be recorded.

Laboratory samples will be collected and sent to the central laboratory as 
specified in Table 2.  

If the patient has experienced any potential endpoints, SAEs, DAEs, 
and/or AEs of interest since the last visit, this will be recorded in the 
eCRF.

The patient will return remaining IP and drug accountability will be 
checked.  
After stopping IP the investigator should ensure that the patient is treated according to standard 
clinical practice and ascertain there is a proper medical follow-up plan in place.

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4.2.9
Unscheduled visits
An unscheduled visit may occur in-between scheduled visits e.g., to follow up on potential 
endpoints such as re-sampling for eGFR (see Section 5.1.3.1).
4.3
Follow-up period (Not applicable)
5.
STUDY ASSESSMENTS
The Rave web based data capture (WBDC) system will be used for data collection and query 
handling.  The investigator will ensure that data are recorded in the eCRFs in Rave 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 (CSA).
The investigator will sign the completed eCRFs.  A copy of the completed eCRF will be 
archived at the study site.  
5.1
Efficacy assessments
5.1.1
Endpoint reporting overview
Potential endpoints will be identified through laboratory data (refer to Table 2 for laboratory 
assessments and timings); when questioning the patient about his/her overall health; or through 
information received through standard medical practice.  Investigators will be encouraged to 
have a low threshold to submit any potential/possible event that might represent an endpoint.  
The following potential endpoints will be recorded in the eCRF and submitted for central 
adjudication:

All deaths

Renal endpoints:

Dialysis

Kidney transplantations

Doubling of serum creatinine (compared to the most recent central 
laboratory measurement)

Hospitalisation for heart failure 

Cardiac ischaemic events (MI and unstable angina)

Cerebrovascular events (stroke and TIA)

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
DKA (not considered an efficacy variable but will be adjudicated as a 
safety variable)
In addition, eGFR declines ≥50% from baseline, eGFR values <15 mL/min/1.73m2 and new 
diagnosis of T2D will be recorded in the eCRF but will not be adjudicated.  
For each potential endpoint, the investigator or delegate will record the endpoint specific 
information the eCRF.  If the event is subject to adjudication, relevant source documents will 
be assembled.  The source documents and relevant eCRF data will be sent for central 
adjudication.  
Detailed instructions regarding endpoint reporting will be provided to the study sites.  
Additional details about the evaluations of potential endpoints will be described in the Clinical 
Event Adjudication (CEA) charter.  
5.1.2
Classification of death
The CEA committee members will adjudicate and classify all deaths based on definitions 
described in the CEA charter.  For the purpose of the efficacy analysis, deaths will be sub-
classified into CV and non- CV as well as renal primary cause (death due to ESRD when 
dialysis is not given).  The investigator will record the classification of death as CV or non-CV 
death in the eCRF.  
5.1.3
Potential renal endpoints
5.1.3.1
Endpoints related to eGFR decline
eGFR baseline is defined as the mean central laboratory value from visit 1 and visit 2. 
Laboratory values related to eGFR decline will trigger an action by site in the following 
situations: 

Local laboratory values indicate that eGFR value has declined ≥50% 
compared with baseline, or is below 15 mL/min/1.73m2.

As soon as possible, patient should come to the study site for 
confirmation by a central laboratory testing. 
OR

Central laboratory values, collected during a study visit, indicating that 
eGFR value has declined ≥50% compared with baseline, or is below 
15 mL/min/1.73m2.  
The central laboratory will notify site if eGFR is <15 mL/min/1.73m2 or if there is ≥50% 
decline in eGFR compared to baseline. A re-sampling should be done at an unscheduled visit 
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central laboratory value is <15 mL/min/1.73m2 or if there is ≥50% decline in eGFR compared 
to baseline it should be recorded as a potential endpoint in the eCRF. 
The central laboratory will calculate eGFR using CKD-EPI equation (Levey at al 2009).
5.1.3.2
Dialysis and renal transplantation  
If a patient starts dialysis and or go through a renal transplantation this will be recorded in the 
eCRF and submitted for adjudication.  
5.1.3.3
Doubling of serum creatinine
Doubling of serum creatinine (compared to the most recent central laboratory measurement) 
will be recorded in the eCRF and submitted for adjudication.  
Recording of doubling of serum creatinine compared to the most recent central laboratory result 
can be triggered by a local laboratory result OR a central laboratory result.
5.1.4
Hospitalisation for heart failure 
All potential hospitalizations for heart failure should be recorded in the eCRF and submitted to 
adjudication.  The CEA committee members will adjudicate the events as specified in the CEA 
Charter.
5.1.5
New diagnosis of type 2 diabetes (T2D)
New onset of T2D, post randomisation, is defined according to the following criteria:

Reporting of new onset of T2D necessitating initiation of anti-diabetic 
medication 
OR

HbA1c >6.5% (48 mmol/mol) measured by central lab at two consecutive 
study visits
New onset of T2D will be recorded as an AE and on a separate eCRF page.  
5.1.6
Cardiac ischaemic events 
Sites should record potential acute coronary syndromes such as MIs and unstable angina in the 
eCRF and submit for adjudication.  The CEA committee members will adjudicate all potential 
cardiac ischaemic events to decide if they qualify as MIs according to the criteria defined in the 
CEA charter.
5.1.7
Cerebrovascular events
Sites should record potential strokes and TIAs in the eCRF and submit for adjudication.  The 
CEA committee members will adjudicate all potential cerebrovascular events to decide if they 
qualify as stroke according to the criteria defined in the CEA charter.

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5.1.8
Patient reported outcomes (PROs)
PROs is an umbrella term referring to all outcomes and symptoms that are directly reported by 
the patient.  PROs have become important endpoints for regulatory and reimbursement 
authorities when evaluating effectiveness of treatments in clinical trials.  The following PROs 
will be administered in the study: KDQOL™-36 and EQ-5D-5L (see Appendix D).  Patients 
will be asked to complete the EQ-5D-5L and the KDQOL™-36 at the visits as specified in 
Table 1.
5.1.8.1
The Kidney Disease Quality of Life-36 (KDQOL™-36)
The KDQOL™-36 is an abbreviated form of the KDQOL, which is a self-reported 
questionnaire that combines generic and disease-specific components for assessing the health-
related quality of life of patients with CKD, see Appendix D.  
5.1.8.2
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L)
The EQ-5D-5L is a self-reported questionnaire that is used to derive a standardized measure of 
health status, also referred to as a utility score, see Appendix D.  EQ-5D-5L utility scores are 
widely accepted by reimbursement authorities and will be used to support health economic 
evaluations.  
5.1.8.3
Administration of patient reported outcomes (PROs)
All PROs will be administered electronically.  Randomised patients will complete the PRO 
assessments at site using the same handheld electronic device (ePRO).  Each site must allocate 
the responsibility for the administration of the ePROs to a specific individual and, if possible, 
assign a backup person to cover if that individual is absent.  
All assessments should be completed as follows:

Patient must not receive help from relatives, friends, or site personnel to 
answer or clarify the PRO questionnaires, in order to avoid bias.  If a 
patient uses visual aids (e.g., spectacles or contact lenses) for reading and 
does not have them at hand, the patient will be exempted from completing 
the PROs questionnaires on that visit.

Before any other study procedures are conducted at a given visit.

Before being seen by the investigator.

PRO questionnaires must be completed by the patient in private.

The appointed site personnel should explain to patient the value and 
relevance of ePRO assessments and inform that these questions are being 
asked to find out, directly from patients, how he/she feels.  The appointed 
site personnel should also stress that the information is confidential.

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
The appointed site personnel must show patients how to use the ePRO 
device, in accordance with the instructions provided.

The appointed site personnel should remind patients that there are no right 
or wrong answers, and the patient should be given sufficient time to 
complete the PRO questionnaires.

If the patient is unable to read the questionnaire (e.g., is blind or illiterate), 
the patient will be exempted from completing the PRO questionnaires and 
may still participate in the study.
5.2
Safety assessments
5.2.1
Laboratory assessments
Blood and urine samples for determination of clinical chemistry, haematology, and urinalysis 
will be taken at the times indicated in Table 1.  The date of central laboratory sample collection 
will be recorded in the eCRF, excluding local laboratory samples if taken at enrolment.  All 
laboratory samples will be analysed at the central laboratory, with the exception of urine human 
chorionic gonadotropin (hCG) (pregnancy test, using a dipstick provided by the central 
laboratory), and laboratory samples taken at enrolment, which will be analysed locally.
All samples should be taken by adequately trained site personnel and handled in accordance 
with instructions in the Laboratory Manual.  Up to date reference ranges will be provided 
during the study and laboratory results will be compared with the laboratory standard normal 
ranges and reported back to site.
Samples sent to the central laboratory will be collected, labelled, stored and shipped as detailed 
in the Laboratory Manual.

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The following laboratory variables will be measured:
Table 2
Laboratory variables
Haematology
Clinical chemistry 
Haemoglobin (Hb) b
Alanine transaminase (ALT) b
Haematocrit a
Alkaline phosphatase (ALP) b
Aspartate transaminase (AST) b
Urinalysis (dipstick)
Bilirubin b
hCG (pregnancy test)
Blood urea nitrogen (BUN) a
Creatinine (including eGFR assessment) a
Spot urinalysis
HbA1c a
U-Albumin (including UACR assessment) a
Phosphate c
U-Creatininea
Potassium a
Sodium a
a
Central laboratory analysis at all visits
b
Central laboratory analysis at visit 1, PTDV and SCV
c
Central laboratory analysis at visit 2, 5, PTDV and SCV
The Investigator should make an assessment of the laboratory results with regards to clinically 
relevant abnormalities.  The laboratory results should be signed and dated and retained at the 
study site as source data for laboratory variables.  
5.2.1.1
Unscheduled laboratory assessments
Unscheduled laboratory samples will be requested by the central laboratory for follow-up on 
e.g., eGFR values.  Follow-up samples related to eGFR should be collected during an 
unscheduled visit and sent to central laboratory for analysis.  
5.2.2
Physical examination
A general physical examination, including volume status, will be performed at the time of 
randomisation and when the patient stops IP.  
A targeted physical examination with focus on volume status will be performed as specified in 
the study plan (see Table 1).
The assessment dates will be recorded in the eCRF.
5.2.3
Electrocardiogram (ECG)
A 12-lead ECG (standard ECG with a paper speed of 25 to 50 mm/second covering at least 
6 sequential beats) will be recorded at randomisation (visit 2) after the patient has been lying 
down to rest for at least 5 minutes.  The baseline ECG should be made available for CEA upon 

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request, to facilitate adjudication of potential cardiac ischaemic events.  The ECG date will be 
recorded in the eCRF.  
5.2.4
Vital signs
Vital signs will be assessed according to the study plan, Table 1.
5.2.4.1
Pulse and blood pressure (BP)
Pulse and BP will be measured three times at all visits, and all measurements will be recorded 
in the eCRF.  The measurements should be done before any blood sampling using a 
standardized cuff adapted to the size of the patient’s arm after the patient has been sitting and 
resting for least 5 minutes.  Preferably, the same arm should be used at all visits.
5.2.4.2
Body weight and height
The patient’s body weight will be measured with light clothing and no shoes at all visits.  If the 
patient has a prosthetic limb, this should be consistently worn or not worn during all weight 
measurements.  The patient’s height will be measured at visit 1, with no shoes.  The weight and 
height will be recorded in the eCRF.  
5.3
Other assessments (not applicable) 
5.4
Pharmacokinetics (PK)
5.4.1
Collection of samples
One pre-dose blood sample for determination of the dapagliflozin concentration in plasma will 
be taken at visit 7.  Information about last intake of IP and sampling ID, date and time will be 
recorded in the eCRF.  
Samples will be collected, labelled stored and shipped as detailed in the Laboratory Manual.
5.4.2
Determination of drug concentration
Samples for determination of dapagliflozin concentration in plasma will be analysed by the 
bioanalytical laboratory on behalf of AZ, using an appropriate validated bioanalytical method.  
Full details of the analytical method used will be described in a separate bioanalytical report.  
5.4.3
Storage and destruction of pharmacokinetics (PK) samples
PK samples will be analysed during the course of the study and disposed of after the 
Bioanalytical Report finalization or six months after issuance of the draft Bioanalytical Report 
(whichever is earlier).  The results of the PK analyses will be kept at the laboratory until the 
end of the study to prevent unblinding.  
PK samples may be disposed of or destroyed and anonymised by pooling.  Additional analyses 
may be conducted on the anonymised, pooled PK samples to further evaluate and validate the 
analytical method.  Any results from such analyses may be reported separately from the clinical 
study report (CSR).

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Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples.  The results from the evaluation will not be reported in the CSR but separately 
in a Bioanalytical Report.  
5.5
Pharmacodynamics (not applicable)
5.6
Genetics
Refer to Appendix E for details regarding optional genetic sampling.  
For withdrawal of consent to the optional genetic sampling, refer to Section 5.7.4.  
5.7
Biomarker analysis 
Serum and plasma as well as urine will be collected and stored for potential future analysis for 
exploratory biomarkers to assess correlations with disease activity, effects of dapagliflozin, 
clinical outcomes and toxicity.  Biomarker samples will be collected, handled and shipped as 
detailed in the laboratory manual.  
It is mandatory to obtain the patient’s consent to the donation and use of biological samples.  
The consent date will be recorded in the eCRF.  Patient not consenting to donate biological 
samples for future biomarker analysis are still able to participate in the study, but without 
providing samples for biomarker analysis.  
The biomarkers to be studied will be selected on possible relevance on pathophysiology of the 
studied diseases.
5.7.1
Storage, re-use and destruction of biological samples
Samples will be stored in AZ biobank for a maximum of 15 years from the date of the last 
patient’s last visit, after which they will be destroyed.  The results of this biomarker research 
will be reported either in the CSR itself or as an addendum, or separately in a scientific report 
or publication.  The results of this biomarker research may be pooled with biomarker data from 
other studies with dapagliflozin to generate hypotheses to be tested in future research.  
5.7.2
Labelling and shipment of biological samples
The Principal Investigator (PI) ensures that samples are labelled and shipped in accordance 
with the Laboratory Manual and the Biological Substance, Category B Regulations (materials 
containing or suspected to contain infectious substances that do not meet Category A criteria), 
see Appendix B.  
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AZ and appropriate labelling, 
shipment and containment provisions are approved.  Samples can be shipped to specialist labs 
around the world and analysed by academic collaborators or commercial partners.  

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5.7.3
Chain of custody of biological samples 
A full chain of custody is maintained for all samples throughout their lifecycle.  
The PI at each site keeps full traceability of collected biological samples from the patients 
while in storage at the study site until shipment or disposal (where appropriate) and keeps 
documentation of receipt of arrival.  
The sample receiver keeps full traceability of the samples while in storage and during use until 
used or disposed of or until further shipment and keeps documentation of receipt of arrival.  
AZ keeps oversight of the entire life cycle through internal procedures, monitoring of study 
sites and auditing of external laboratory providers.  
Samples retained for further use are registered in the AZ biobank during the entire life cycle.  
5.7.4
Withdrawal of informed consent for donated biological samples 
If a patient withdraws consent to the use of donated biological samples, the samples will be 
disposed of/destroyed, and the action documented.  If samples are already analysed, AZ is not 
obliged to destroy the results of this research.  
As collection of donated biological samples is an optional part of the study, the patient may 
continue in the study.
The PI:

Ensures patients’ withdrawal of informed consent to the use of donated 
samples is notified as soon as possible to AZ.

Ensures that biological samples from that patient, if stored at the study site, 
are identified as soon as possible, disposed of /destroyed, and the action 
documented.

Ensures the laboratory(ies) holding the samples is/are informed about the 
withdrawn consent as soon as possible and that samples are disposed 
of/destroyed, the action documented and the signed document returned to 
the study site.

Ensures that the patient and AZ are informed about the sample disposal.
AZ ensures the laboratory(ies) or biobank holding the samples is/are informed about the 
withdrawn consent as soon as possible and that samples are disposed of/destroyed and the 
action documented and returned to the study site.  

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6.
SAFETY REPORTING AND MEDICAL MANAGEMENT
The PI is responsible for ensuring that all personnel involved in the study are familiar with the 
content of this section.  
6.1
Definition of adverse events
An AE is the development of an undesirable medical condition or the deterioration of a pre-
existing medical condition following or during exposure to a pharmaceutical product, whether 
or not considered causally related to the product.  An undesirable medical condition can be 
symptoms (e.g., nausea chest pain), signs (e.g., tachycardia, enlarged liver) or the abnormal 
results of an investigation (e.g., laboratory findings, ECG).  In clinical studies, an AE can 
include an undesirable medical condition occurring at any time, including run-in or washout 
periods, even if no study treatment has been administered.  
The term AE is used to include both serious and non-serious AEs.  The term AE in this 
document refers only to the categories of events described in Section 6.3.  
6.2
Definitions of serious adverse event (SAE)
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout and follow-
up), that fulfils one or more of the following criteria:

Results in death

Is immediately life-threatening

Requires in-patient hospitalisation or prolongation of existing
hospitalisation

Results in persistent or significant disability/incapacity or substantial 
disruption of the ability to conduct normal life functions

Is a congenital abnormality or birth defect

Is an important medical event that may jeopardize the patient or may 
require medical intervention to prevent one of the outcomes listed above
For further guidance on the definition of a SAE, see Appendix A to the Clinical Study Protocol.  
6.3
Recording of adverse events
6.3.1
Time period for collection of adverse events
AEs will be collected from randomisation (visit 2) throughout the treatment period until and 
including the patient’s last study visit.  

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SAEs will be recorded from the time of informed consent throughout the treatment period until 
and including the patient's last visit.  
AEs should be recorded in the eCRF only if:

It qualifies as an SAE (as defined in Section 6.2)

The AE is the reason for permanent discontinuation from IP (DAE)

The AE is the reason for IP interruption or dose reduction

It qualifies as an AE of interest

Volume depletion 

Renal events 

Major hypoglycaemic events

Fractures

Potential DKAs

AEs leading to amputation and AEs leading to a risk for lower limb 
amputations (“preceding events”)

A potential endpoint (see Section 5.1) fulfils the AE criteria. NB: not all 
potential endpoints are per definition an AE e.g., a potential endpoint 
solely related to laboratory findings (see Section 6.3.7) should not be 
recorded unless any of the above mentioned criteria is met. 
An AE/SAE could be associated with more than one potential endpoint. In such scenario, only 
one AE/SAE should be recorded but all potential endpoints should be recorded individually.
6.3.2
Adverse events of interest
6.3.2.1
Volume depletion
Events of volume depletion (e.g., dehydration, hypovolemia, or hypotension) will be recorded 
in the eCRF as AEs.  
6.3.2.2
Renal events
Renal events, such as an acute clinically relevant decline in kidney function as judged by the 
investigator, will be recorded in the eCRF as AEs. If the event also qualifies as a potential 
endpoint as defined in Section 5.1.3.2, a separate eCRF will be completed.

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6.3.2.3
Major hypoglycaemic events
A major hypoglycaemic event is defined as an event that requires assistance of another person 
to actively administer carbohydrates, glucagon, or take other corrective actions.
Plasma glucose concentrations may not be available during an event, but neurological recovery 
following the corrective actions is considered sufficient evidence that the event was induced by 
a low plasma glucose concentration.  Major hypoglycaemic episodes will be recorded in the 
eCRF as an AE and on an additional eCRF page.  
6.3.2.4
Fractures
All fractures will be recorded in the eCRF as AEs.
6.3.2.5
Diabetic ketoacidosis (DKA)
All potential events of DKA will be recorded in the eCRF and submitted to an independent 
DKA Adjudication Committee (see Section 6.8.5).
6.3.2.6
Adverse events (AEs) leading to amputation and AEs leading to a risk for lower 
limb amputations (“preceding events”)
To ensure that data on amputations is systematically collected, amputations and underlying 
conditions relevant to amputation will be recorded on a specific eCRF page. The adverse event 
leading to amputation should be recorded in the eCRF as AE/SAE.
In addition, non-serious and serious events potentially placing the patient at risk for a lower 
limb amputation (“preceding events”) should also be recorded in the eCRF as AE/SAE, 
whether or not an amputation has taken place. The lower limb “preceding events” of interest 
include diabetic foot related conditions, vascular, wounds/injury/trauma, infection and 
neuropathy. If any of these or other potentially relevant event have occurred, relevant 
information must be provided (this will be collected on a dedicated eCRF page - for details see 
eCRF instruction).
6.3.3
Follow-up of unresolved adverse events
Any AEs that are unresolved at the patient’s last study visit in the study are followed up by the 
investigator for as long as medically indicated, but without further recording in the CRF.  AZ 
retains the right to request additional information for any patient with ongoing AE(s)/SAE(s) at 
the end of the study, if judged necessary.  
6.3.4
Variables 
The following variables will be collect for each AE:

AE (verbatim)

The date when the AE started and stopped

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
Maximum intensity (mild/moderate/severe)

Whether the AE is serious or not

Investigator causality rating against the IP (yes or no)

Action taken with regard to IP

Outcome
In addition, the following variables will be collected for SAEs:

Date AE met criteria for serious AE

Date investigator became aware of serious AE

AE is serious due to

Date of hospitalisation

Date of discharge

Probable cause of death

Date of death

Autopsy performed

Causality assessment in relation to Study procedure(s) and/or other 
medication

Description of AE
It is important to distinguish between serious and severe AEs.  Severity is a measure of 
intensity whereas seriousness is defined by the criteria described in Section 6.2. An AE of 
severe intensity need not necessarily be considered serious. For example, nausea that persists 
for several hours may be considered severe nausea, but not a SAE unless it meets the criteria 
shown in Section 6.2. On the other hand, a stroke that results in only a limited degree of 
disability may be considered a mild stroke but would be a SAE when it satisfies the criteria 
shown in Section 6.2.  
6.3.5
Causality collection
The investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’

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For SAEs causal relationship will also be assessed for other medication and study procedures.  
Note that for SAEs that could be associated with any study procedure the causal relationship is 
implied as ‘yes’.  
A guide to the interpretation of the causality question is found in Appendix A.
6.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient, or reported in response to the open question 
from the site personnel: ‘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 (if 
fulfilling the criteria for recording as specified in Section 6.3.1). 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.  
6.3.7
Adverse events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarised in the 
CSR. Deterioration as compared with baseline in protocol-mandated laboratory values or vital 
signs should therefore only be reported as AEs if they fulfil any of the SAE criteria or are the 
reason for discontinuation of treatment with the investigational product. 
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 (e.g., anaemia versus low Hb value).  In the absence 
of clinical signs or symptoms, clinically relevant deteriorations in non-mandated parameters 
should be reported as AE(s).  
6.4
Reporting of serious adverse events (SAEs)
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the eCRF.  
If any SAE occurs in the course of the study, then Investigators or other site personnel inform 
the appropriate AZ representatives within one day i.e., immediately but no later than 24 hours 
of when he or she becomes aware of it.  
The designated AZ representative works with the investigator to ensure that all the necessary 
information is provided to the AZ 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 AZ 

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representatives of any follow-up information on a previously reported SAE within one calendar 
day i.e., immediately but no later than 24 hours of when he or she becomes aware of it.  
Once the Investigators or other site personnel indicate an AE is serious in the WBDC system, 
an automated email alert is sent to the designated AZ representative.  
If the WBDC system is not available, then the investigator or other site personnel reports a SAE 
to the appropriate AZ representative by telephone in accordance with SAE reporting timelines.  
The AZ representative will advise the investigator/site personnel how to proceed. 
6.4.1
Reporting of serious adverse events (SAEs) considered to be potential endpoints
In order to avoid unnecessary unblinding of efficacy endpoint events, certain SAEs which are 
also potential endpoints (i.e., fatal events and heart failure events) will not be reported to health 
authorities.  Clinical data for the above mentioned events will be recorded as AEs/SAEs as well 
as on separate event forms in the eCRF.  Recording of a suspected endpoint should be done 
within the same timeframes as defined for SAEs (see Section 6.4).  
In addition, fatal AEs and potential heart failure endpoints will be centrally adjudicated by an 
independent CEA committee (see Section 5.1.1 and 6.8.4). If adjudication confirms the 
endpoint, the SAE will not be reported to health authorities. However, if it is determined by the 
CEA committee that a potential endpoint in the above mentioned categories does not meet the 
endpoint criteria, the event will be reported (according to the timelines specified in Section
6.3.1) to AZ patient safety data entry site and if applicable to the health authorities (note that 
the clock starts when the adjudication results are available).
6.5
Overdose
Dapagliflozin has been well tolerated at doses of 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 patients with T2D.  Suspected single intake of more than 50 tablets of 10 mg 
dapagliflozin tablets or repeated intake of more than 10 tablets of 10 mg dapagliflozin tablets 
should be recorded in the eCRF.  If an overdose is suspected, monitoring of vital functions as 
well as treatment should be performed as appropriate.  
For further information regarding overdose, refer to the IB.

An overdose with associated AEs is recorded as the AE 
diagnosis/symptoms on the relevant AE modules in the eCRF and on the 
Overdose eCRF module.  

An overdose without associated symptoms is only recorded in the 
Overdose eCRF module.  

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If an overdose on an AZ study drug occurs in the course of the study, then the investigator or 
other site personnel inform appropriate AZ representatives immediately, or no later than 
24 hours of when he or she becomes aware of it.  
The designated AZ representative works with the investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site.  
For overdoses associated with a SAE, the standard reporting timelines apply (see Section 6.4).  
For other overdoses, reporting must occur within 30 days.  
6.6
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AZ.  
6.6.1
Maternal exposure
If a patient becomes pregnant during the course of the study IP should be discontinued 
immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication. Congenital 
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 patient was 
discontinued from the study.  
If any pregnancy occurs during the course of the study, then the investigator or other site 
personnel informs the appropriate AZ representatives within 1 day i.e., immediately but no 
later than 24 hours of when he or she becomes aware of it.  
The designated AZ representative works with the investigator to ensure that all relevant 
information is provided to the AZ Patient Safety data entry site within 1 or 5 calendar days for 
SAEs (see Section 6.4) and within 30 days for all other pregnancies.  
The same timelines apply when outcome information is available.  
The PREGREP module in the eCRF is used to report the pregnancy and the PREGOUT paper 
CRF form is used to report the outcome of the pregnancy.  
6.7
Management of IP related toxicities (not applicable)
6.8
Study governance and oversight
6.8.1
Executive Committee
Together with AZ the Executive Committee will be responsible for the final overall study 
design, including the development of the study protocol and eCRF, and any protocol 

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amendments, supervision of the study conduct and progress, development of any protocol 
amendments needed during the study, liaison with the CEA Committee and DMC, as needed, 
development of the statistical analysis plan (SAP), interpretation of the final data and reporting 
(presentations at international congresses and publications in peer reviewed journals) of the 
study.  
The Executive Committee will make recommendations to AZ with regard to early stopping or 
modifications of the study based on the information received from the DMC.  The Executive 
Committee will be comprised of designated international academic leaders and non-voting 
members of the Sponsor, and will operate under an Executive Committee charter.  
6.8.2
National Lead Investigator (NLI) Committee
The National Lead Investigator (NLI) Committee will be comprised of NLIs from each country 
where the study is conducted and supervised by the Executive Committee.  Members of the 
committee will be responsible for providing clinical guidance on study implementation, 
recruitment and study conduct in their respective country.  
6.8.3
Data Monitoring Committee (DMC)
An independent DMC will be appointed and will report to the Executive Committee.  The 
DMC will be responsible for safeguarding the interests of the patients in the study by assessing 
the safety of the IP during the study, and for reviewing the overall conduct of the study.  The 
DMC will have access to the individual treatment codes and be able to merge these with the 
collected study data while the study is ongoing.  A DMC charter will be prepared to detail 
precise roles and responsibilities and procedures to ensure maintenance of the blinding and 
integrity of the study in the review of accumulating data and interactions with the Executive 
Committee.  
6.8.4
Clinical Event Adjudication (CEA) Committee
The role of the CEA committee is to independently review, interpret and adjudicate potential 
endpoints that are experienced by the patients.  Endpoints will be identified preliminary by the 
Investigators, and also by AZ personnel or in the CEA process as specified in the CEA charter.  
The CEA committee members will not have access to individual treatment codes for any 
patient or clinical efficacy endpoint and safety event.  The precise responsibilities and 
procedures applicable for CEA will be detailed in the CEA charter.  
6.8.5
Diabetic Ketoacidosis Adjudication Committee T2D
All potential events of DKA will be submitted to an independent DKA Adjudication 
Committee.  The committee will be kept blinded to the treatment codes.  A separate DKA 
Adjudication Manual will define and describe the procedures for the collection of DKA 
information, handling, adjudication criteria and reporting of these events.

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6.9
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 

occurred

was identified and intercepted before the subject received the drug

did not occur, but circumstances were recognized that could have led to an error
Examples of events to be reported in clinical studies as medication errors:

Drug name confusion

Dispensing error e.g. medication prepared incorrectly, even if it was not actually given 
to the subject

Drug not administered as indicated, for example, wrong route or wrong site of 
administration

Drug not taken as indicated e.g. tablet dissolved in water when it should be taken as a 
solid tablet 

Drug not stored as instructed e.g. kept in the fridge when it should be at room 
temperature 

Wrong subject received the medication (excluding IVRS/IWRS errors)

Wrong drug administered to subject (excluding IVRS/IWRS errors)
Examples of events that do not require reporting as medication errors in clinical studies:

Errors related to or resulting from IVRS/IWRS - including those which lead to one of 
the above listed events that would otherwise have been a medication error 

Subject accidentally missed drug dose(s) e.g. forgot to take medication

Accidental overdose (will be captured as an overdose)

Subject failed to return unused medication or empty packaging

Errors related to background and rescue medication, or standard of care medication in 
open label studies, even if an AZ product 
Medication errors are not regarded as AEs but AEs may occur as a consequence of the 
medication error. 

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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 i.e., 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 6.4) and within 30 days for all other medication errors.
7.
INVESTIGATIONAL PRODUCT (IP) AND OTHER 
TREATMENTS
7.1
Identity of investigational product (IP)
Investigational product (IP)
Dosage form and strength
Manufacturer
Dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated tablets 10 mg
AZ
Matching placebo for 
Dapagliflozin 10 mg
Green, plain, diamond shaped, 
film coated tablets placebo
AZ
Dapagliflozin 5 mg
Green, plain, diamond shaped, 
film coated tablets 5 mg
AZ
Matching placebo for 
Dapagliflozin 5 mg
Green, plain, diamond shaped, 
film coated tablets placebo
AZ
Dapagliflozin and its matching placebo tablets will be packed in bottles.  The tablets may 
contain lactose, which may cause discomfort in lactose-intolerant individuals.
7.2
Dose and treatment regimens
At randomisation, visit 2 (day 0), eligible patients will be randomly assigned to 1 of 2 
treatments:

Dapagliflozin 10 mg, given once daily per oral use

Placebo – one placebo tablet to match dapagliflozin 10 mg, given once 
daily per oral use
Randomisation and treatment pack assignment will be managed via an IxRS at visit 2.  The IP 
should be taken per oral once daily in the morning and at approximately the same time every 
day, during the study period.  If the patient, for any reason prefers not to administer the IP in 
the morning, any other time point during the day may be applied, provided the patient routinely 
administer the IP in approximate 24 hours intervals.  The IP should not be altered (e.g., 
crushed, put in another vehicle) and should not be given by nasogastric tube or other routes.

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If the dose is adjusted (i.e., lowered to 5 mg or increased back to 10 mg) during the study (see 
Section 3.9.1 and 3.9.2), this will be handled in IxRS and the dose change will be recorded in 
the eCRF.
Missed doses of dapagliflozin or placebo blinded study medication should not be compensated 
for (i.e., if a dose is missed, the next regularly scheduled dose should be taken and should not 
be doubled).
7.3
Labelling
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines.  The labels will fulfil GMP Annex 13 requirements for labelling.  Label 
text will be translated into local language.  
7.4
Storage
All IPs should be kept in a secure place under appropriate storage conditions.  The IP label on 
the bottle specifies the appropriate storage.  
7.5
Compliance
The administration of all IPs should be recorded in the appropriate sections of the eCRF.
7.6
Accountability
The study drug provided for this study will be used only as directed.  
The study personnel will account for all study drugs dispensed to and returned from the patient.  
Patients will be asked to bring all unused IP and empty packages to the study site at all visits.  
The investigator or delegate will record the amount of returned tablets in the eCRF.  Any 
patient found to be noncompliant would be counselled on the importance of taking their IP as 
prescribed.
Any IP deliberately or accidentally destroyed must be recorded.  Any discrepancy between 
dispensed and returned IP should be explained.
The investigator will retain the returned medication until the AZ representative or delegate 
collects it, along with any medication not dispensed.  The AZ representative or delegate is 
responsible for confirming that the investigator or delegate has recorded the quantities of 
returned and unused tablets at a patient level before medication is destroyed.  The AZ 
representative or delegate will advise on the appropriate method for destruction of unused IP.
7.7
Concomitant and other treatments 
All patients should be treated according to regional standards of care for CV risk factors (e.g., 
BP, lipids, and antithrombotic treatment), diabetes and CKD complications (e.g., 
hyperphosphatemia, hyperparathyroidism, hyperkalaemia, acidosis and renal anaemia).

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Background medication will not be provided by the Sponsor.
7.7.1
Restricted medication
Treatment with non-steroidal anti-inflammatory drugs (NSAID) should, if possible, be avoided 
during the study.
7.7.2
Prohibited medication
Concomitant treatment (i.e., treatment in combination with IP) with open label SGLT2 
inhibitors e.g., dapagliflozin, empagliflozin, canagliflozin, ertugliflozin, tofogliflozin and 
luseogliflozin and fix dose combinations containing these drugs is prohibited.  Also in 
situations when the patient is not on IP, treatment with open label SGLT2 inhibitors during the 
study, could interfere with the interpretation of study results and should therefore not be given 
unless all other possibilities to treat the patient properly has been considered.  
7.7.3
Recording of concomitant treatment
Detailed recording of medications related to CKD (see Section 7.7.4), diabetes (see Section 
7.7.5) as well as other relevant cardiovascular medications (e.g., statins, antihypertensive and 
antithrombotic agents) will be made throughout the study. In addition, concomitant medications 
will be recorded at the time of any SAEs, potential endpoints and AEs of interest (as defined in
Section 6.3). Recording of other concomitant medications will be made at randomisation 
(visit 2) and at SCV.
7.7.4
Chronic kidney disease (CKD) medications
To be eligible, the patient needs to be on stable and for the patient maximum tolerated labelled 
daily dose of ACE-I or ARB for at least 4 weeks before visit 1, if not medically 
contraindicated.  If the patient is not on an ACE-I or ARB at the time of enrolment the reason 
will be recorded in the eCRF.
Details regarding the following CKD related treatments will be recorded in the eCRF 
throughout the study:

RAAS inhibition: ACE-I/ARBs, renin inhibitors, mineralocorticoid 
antagonists

Diuretics: Loop diuretics, thiazide diuretics and other diuretics

Treatment of underlying kidney disease: cytotoxic agents, 
immunosuppressive agents, other immunotherapy

Phosphate binders

Potassium binders 

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7.7.5
Anti-diabetes treatment of patients with established diagnosis of type 2 diabetes 
(T2D)
Patients with T2D at randomisation in this study will continue their T2D treatment.  Treatment 
should be based on established guidelines and according to local laboratory values.  Patients are 
eligible for adjustments in their anti-diabetes treatment at the discretion of their diabetes health 
care provider.  Diabetes medications at baseline and any changes throughout the study, will be 
recorded in the eCRF.  
7.7.5.1
Use of medications known to cause hypoglycaemia in type 2 diabetes (T2D) 
patients 
Insulin and insulin secretagogues are known to cause hypoglycaemia.  Therefore, patients 
treated with insulin or sulfonylurea (SU) have a higher risk of experiencing hypoglycaemic
events compared with those treated with other antidiabetic agents.  Therefore a lower dose of 
insulin or insulin secretagogues may be required to minimize the risk of hypoglycaemia when 
used in combination with study medication.
Reduction of insulin by 10 to 20% (total daily dose) and SU by 25 to 50% and increased 
frequency of blood glucose monitoring may be considered in patients receiving insulin and/or 
SU and with baseline HbA1c ≤7% at randomisation.
7.7.6
Other concomitant treatment
Medications other than described above, which is considered necessary for the patient’s safety 
and wellbeing, may be given at the discretion of the investigator and recorded in the 
appropriate sections of the eCRF, as applicable.  
7.8
Post Study Access to Study Treatment
Post-study treatment will not be provided by the Sponsor.  
8.
STATISTICAL ANALYSES BY ASTRAZENECA (AZ)
8.1
Statistical considerations
All personnel involved with the analysis of the study will remain blinded until database lock 
and protocol violations have been identified and documented.  
A comprehensive SAP will be developed prior to first randomised patient and any subsequent 
amendments will be documented, with final amendments completed prior to unblinding of the 
data.
The results of the key study outcome will be independently validated by an external statistical 
team.  

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8.2
Sample size estimate
The primary objective of the study is to determine the superiority of dapagliflozin versus 
placebo in reducing the incidence of the primary composite endpoint.  Assuming a true hazard 
ratio of 0.78 between dapagliflozin and placebo, using a one-sided alpha of 2.5%, 681 primary 
endpoints will provide a statistical power of 90% for the test of the primary composite 
endpoint.  This is based on an overall 1:1 allocation between dapagliflozin and placebo.  The 
study is event-driven.  The assumed hazard ratio of 0.78 is considered as clinically relevant and 
has taken into account the renal outcomes in the EMPA-REG trial.  
With an annual event rate of 7.5% in the placebo treatment group, 4000 patients are estimated 
to provide the required number of primary events, based on an anticipated recruitment period of 
24 months and an average follow-up period of approximately 33 months.  The assumed placebo 
event rate of 7.5% is based on a review of published data in the CKD population. In addition, 
the expected number of patients who will be lost to follow-up is expected to be small; hence, 
they are not considered in the determination of the sample size.  
8.3
Definitions of analysis sets
8.3.1
Full analysis set (FAS)
All patients who have been randomised to study treatment will be included in the full analysis 
set (FAS) irrespective of their protocol adherence and continued participation in the study.  
Patients will be analysed according to their randomised IP assignment, irrespective of the 
treatment actually received.  The FAS will be considered the primary analysis set for the 
primary and secondary variables and for the exploratory efficacy variables.  
8.3.2
Safety analysis set
All patients who receive at least one dose of randomised treatment will be included in the 
safety population.  Patients will be analysed according to the treatment actually received.  The 
Safety analysis set will be considered the primary analysis set for all safety variables.
8.4
Outcome measures for analyses
8.4.1
Primary outcome measure 
The primary outcome measures are detailed in Section 2.1.  
8.4.2
Secondary outcome measure
The secondary outcome measures are detailed in Section 2.2.
8.4.3
Safety outcome measure
The safety outcome measures are detailed in Section 2.3.  
8.4.4
Exploratory outcome measure
The exploratory outcome measures are detailed in Section 2.4.  

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8.5
Methods for statistical analyses
8.5.1
Hypotheses
For the primary endpoint the following hypothesis will be tested at the 2.5% 1-sided level:
H0: HR [dapagliflozin:placebo] ≥1
Versus
H1: HR [dapagliflozin:placebo] <1
8.5.2
Closed testing procedure
A closed testing procedure including a pre-specified hierarchical ordering of the primary and 
secondary endpoints will be utilized.  The Type I error will be controlled at a one-sided 
0.025 level for multiplicity across primary and secondary endpoints.  Statistical significance 
will be assessed in the pre-specified order of the endpoints as specified in Section 2.1 and 2.2.  
The testing procedure will continue down the hierarchy if the preceding endpoint is rejected at 
a one-sided 0.025 level and will stop if the preceding endpoint is not rejected at a one-sided 
0.025 level.  Exploratory endpoints will be tested at a one-sided 0.025 level without adjustment 
for multiplicity.
8.5.3
Analysis of the primary variable (s)
The primary variable is the time to first event included in the primary composite endpoint.  The 
primary analysis will be based on the intention to treat (ITT) principle using the FAS.  
In the analysis of the primary composite endpoint, treatments (dapagliflozin versus placebo) 
will be compared using a Cox proportional hazards model with a factor for treatment group, 
stratified by randomisation stratification factors (T2D, UACR), and adjusting for eGFR. In 
general, the analysis will use each patient's last contact as the censoring date for patients 
without any primary events.  The p-value, hazard ratio (HR) and 95% confidence interval will 
be reported.
The contribution of each component of the primary composite endpoint to the overall treatment 
effect will be examined.  Methods similar to those described for the primary analysis will be 
used to separately analyse the time from randomisation to the first occurrence of each 
component of the primary composite endpoint.  Last contact will be treated as the censoring 
date for patients without the endpoint of interest.  Hazard ratios (HR) and 95% confidence 
intervals will be reported.
Kaplan-Meier estimates of the cumulative incidence to the first occurrence of any event in the 
primary endpoint will be calculated and plotted, for overall analysis and for the individual 
components.  

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8.5.4
Analysis of the secondary variables
The secondary variables will be analysed in the similar manner as the primary variable.  
8.5.5
Subgroup analysis
Subgroup variables for the primary efficacy endpoint and secondary efficacy endpoints include 
demography, baseline disease characteristics, baseline concomitant medications and others.
Cox proportional hazards models will be performed to examine treatment effects within 
relevant subgroups separately.  The p-values for the subgroup analyses will not be adjusted for 
multiple comparisons as the tests are exploratory and will be interpreted descriptively.  Event 
rates by treatment and HRs with 95% confidence intervals will be reported for each subgroup.  
HRs and CIs for overall analysis and subgroups will be presented with forest plots.  Further 
details of the subgroup analysis, including the list of subgroup variables, will be provided in the 
SAP.
8.5.6
Interim analysis
Not applicable.
8.5.7
Sensitivity analysis
Details of the sensitivity analysis will be provided in the SAP.  
8.5.8
Analysis of safety variables
The number and percent of patients with SAEs, DAEs, AEs leading to dose reductions and 
temporary interruptions, AEs of interest, will be summarized by treatment group.  Changes in 
clinical chemistry/haematology parameters will be summarized over time by treatment group.  
In addition, the number and percent of patients with a marked abnormality in clinical laboratory 
tests will be summarized over time by treatment group.  For safety analyses, summaries will be 
provided using both on treatment observations and using all observations regardless of whether 
patients are on or off study treatment.  
8.5.9
Exploratory analysis
The exploratory variables (excluding PK and biomarkers for future exploratory research) will 
be analysed as specified in the SAP.  
9.
STUDY AND DATA MANAGEMENT BY ASTRAZENECA (AZ)
9.1
Training of study site personnel
Before the first patient is entered into the study, an AZ representative will review and discuss 
the requirements of the Clinical Study Protocol and related documents with the site personnel 
and also train them in any study specific procedures and the WBDC, ePROs system and other 
relevant systems utilised.  

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The PI will ensure that appropriate training relevant to the study is given to all site personnel, 
and that any new information relevant to the performance of this study is forwarded to the 
personnel involved.  
The PI will maintain a record of all individuals involved in the study (medical, nursing and 
other personnel).  
9.2
Monitoring of the study
During the study, an AZ representative will have regular contacts with the study site, including 
visits to:

Provide information and support to the investigator(s) and site personnel.

Confirm that facilities remain acceptable.

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 being performed.

Perform source data verification (a comparison of the data in the eCRFs 
with the patient’s medical records at the hospital or practice, and other 
records relevant to the study) including verification of informed consent of 
participating patients.  This will require direct access to all original records 
for each patient (e.g., medical records).

Perform source data review, i.e., review of source documentation to check 
quality of source, review protocol compliance, ensure critical processes 
and source documentation are adequate.

Ensure withdrawal of informed consent to the use of the patient’s 
biological samples is reported and biological samples are identified and 
disposed of/destroyed accordingly, and the action is documented, and 
reported to the patient.
The AZ representative will be available between visits if the investigator(s) or other personnel 
at the study site needs information and advice about the study conduct.
9.2.1
Risk based quality management
Quality by design will be implemented, including a focus on identifying key risks to patient 
safety, data quality, and Good Clinical Practice (GCP)/regulatory compliance, to build quality 
into the design, conduct, analysis and reporting of the study.  
A risk based monitoring approach will be applied for this study.  This includes a mix of 
monitoring strategies: on-site monitoring, remote monitoring (site level monitoring activities 

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performed at a location other than the study site) and centralized monitoring.  Monitoring 
strategies will be tailored to consider risks, permit timely oversight (through central/remote 
monitoring and use of technology), and will be focused on critical processes and critical data.  
Central monitoring will be used to check that data is consistent and complete, identify unusual 
distribution of data, identify higher risk sites to target additional monitoring, and to ensure 
routine review of data is completed in real time.
9.2.2
Source data
Refer to the CSA for location of source data.  The investigator must provide direct access to 
source data/documents for monitoring, audits, (institutional review board/independent ethics 
committee) IRB/IEC review, and regulatory inspections.
9.2.3
Study agreements
The PI at each/the study site should comply with all the terms, conditions, and obligations of 
the CSA, or equivalent, for this study.  In the event of any inconsistency between this Clinical 
Study Protocol and the CSA, the terms of Clinical Study Protocol shall prevail with respect to 
the conduct of the study and the treatment of patients and in all other respects, not relating to 
study conduct or treatment of patients, the terms of the CSA shall prevail.  
Agreements between AZ and the PI should be in place before any study related procedures can 
take place, or patients are enrolled.  
9.2.4
Archiving of study documents
The investigator follows the principles outlined in the CSA.  
9.3
Study timetable and end of study
The end of the study is defined as ‘the last visit of the last patient undergoing the study’.  
The study is expected to start in Q1 2017 and to end by Q4 2020.
The study may be terminated at individual study sites if the study procedures are not being 
performed according to GCP, or if recruitment is slow.  AZ may also terminate the entire study 
prematurely if concerns for safety arise within this study or in any other study with 
dapagliflozin.
9.4
Data management by AstraZeneca (AZ)
Data management will be performed by IQVIA Ltd, according to the Data Management Plan 
(DMP).
Data entered into the eCRF will be immediately saved to a central database and changes 
tracked to provide an audit trail.  The data will then be reviewed, queried and updated as 
needed.

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AEs and medical/surgical history will be classified according to the terminology of the latest 
version the Medical Dictionary for Regulatory Activities (MedDRA).  Medications will be 
classified according to the WHO Drug Dictionary. Classification coding will be performed by
the Medical Coding Team at the IQVIA Ltd.  
The data will be validated as defined in the DMP.  Quality control procedures will be applied to 
each stage of data handling to ensure that all data are reliable and have been processed 
correctly.  The DMP will also clarify the roles and responsibilities of the various functions and 
personnel involved in the data management process.
When all data have been coded, validated, signed and locked, clean file will be declared.  Any 
treatment revealing data may thereafter be added and the final database will be locked.  
Serious adverse event (SAE) Reconciliation
SAE reconciliation will be done between the study database and safety database.  
10.
ETHICAL AND REGULATORY REQUIREMENTS
10.1
Ethical conduct of the study
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH)/GCP, applicable regulatory requirements and the AZ policy on Bioethics and Human 
Biological Samples.  
10.2
Subject data protection
The ICF will incorporate (or, in some cases, be accompanied by a separate document 
incorporating) wording that complies with relevant data protection and privacy legislation.  
10.3
Ethics and regulatory review
An IRB/IEC should 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 patients.  The investigator 
will ensure the distribution of these documents to the applicable IRB/IEC, and to the site 
personnel.  
The opinion of the IRB/IEC should be given in writing.  The investigator should submit the 
written approval to AZ before enrolment of any patient into the study.
The IRB/IEC should approve all advertising used to recruit patients for the study.  
AZ should approve any modifications to the ICF that are needed to meet local requirements.  
If required by local regulations, the protocol should be re-approved by the IRB/IEC annually.  

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Before enrolment of any patient into the study, the final study protocol, including the final 
version of the ICF, is approved by the national regulatory authority or a notification to the 
national regulatory authority is done, according to local regulations.  
AZ will handle the distribution of any of these documents to the national regulatory authorities.  
AZ will provide Regulatory Authorities, IRB/IECs and PIs with safety updates/reports 
according to local requirements.  
10.4
Informed consent
The PI at each site will:

Ensure each patient is given full and adequate oral and written information 
about the nature, purpose, possible risk and benefit of the study.

Ensure each patient is notified that they are free to discontinue from the 
study at any time.

Ensure that each patient is given the opportunity to ask questions and 
allowed time to consider the information provided.

Ensure each patient provides signed and dated informed consent before 
conducting any procedure specifically for the study.

Ensure the original, signed ICF(s) is/are stored in the Investigator’s Study 
File.

Ensure a copy of the signed ICF is given to the patient.

Ensure that any incentives for patients who participate in the study as well 
as any provisions for patients harmed as a consequence of study 
participation are described in the ICF that is approved by an IRB/IEC.  
10.5
Changes to the protocol and informed consent form (ICF)
Study procedures will not be changed without the mutual agreement of the International 
Coordinating Investigator and AZ.  
If there are any substantial changes to the study protocol, then these changes will be 
implemented in a new version of the protocol.
The new version of the study protocol is to be approved by the relevant IRB/IEC and if 
applicable, also the national regulatory authority, before implementation.  Local requirements 
are to be followed for new version protocols.  

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AZ will distribute any subsequent new versions of the protocol to each PI.  For distribution to 
IRB/IEC see Section 10.3.  
If a new version of the protocol requires a change of a study sites’ ICF, AZ and the study site’s 
IRB/IEC are to approve the revised ICF before the revised form is used.
10.6
Audits and inspections
Authorised representatives of AZ, a regulatory authority, or an IRB/IEC may perform audits or 
inspections at the study site, 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, 
analysed, and accurately reported according to the protocol, GCP, guidelines of the ICH, and 
any applicable regulatory requirements.  The investigator will contact AZ immediately if 
contacted by a regulatory agency about an inspection at the study site.  

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11.
LIST OF REFERENCES
Baker et al 2015
Baker WL, Smyth LR, Rich DM, Bourret EM, Chamberlin KW, White WB.  Effects of sodium-glucose 
co-transporter 2 inhibitors on BP: A systematic review and meta-analysis. J Am Soc Hypertens 2014; 8 
(4): 262-275.  
Barnett et al 2014
Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle H, et al, on behalf of EMPA-REG 
RENAL trial investigators. Efficacy and safety of empagliflozin added to existing antidiabetics 
treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, 
placebo-controlled trial. Lancet Diabetes Endocrinol 2014; 2(5): 369-384. 
Bays et al 2013
Bays HE, Weinstein R, Law G, Canovatchel W.    Canagliflozin: effects in overweight and obese 
subjects without diabetes mellitus.  Obesity (Silver Spring) 2014 Apr; 22(4):1042-9.
De Nicola et al 2014
De Nicola L, Gabbai FB, Liberti ME, Sagliocca A, Conte G, Minutolo R.  Sodium/glucose cotransporter 
2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.  Am J Kidney 
Dis.  2014; 64(1):16-24.  
EASD 2016
Abstracts of 52nd EASD Annual Meeting.  Diabetologia; 2016 Aug. 59 Suppl 1:1-581.
Eckart et al 2013
Eckardt KU, Coresh J, Devuyst O, Johnson RJ, Köttgen A, Levey AS, et al.Evolving importance of 
kidney disease: from subspecialty to global health burden.  Lancet 2013 Jul 13;382(9887).
EMA 2016
Guideline on clinical investigation of medicinal products 4 for the treatment of chronic heart failure 
(draft), Committee for Medicinal Products for Human Use (CHMP).  EMA/CHMP/392958/2015.
Fioretto et al 2016
Fioretto P, Stefansson BV, Johnsson E, Cain VA, Sjöström CD.  Dapagliflozin reduces albuminuria 
over 2 years in patients with type 2 diabetes mellitus and renal impairment.  Diabetologia 2016 Sep; 
59(9):2036-9.
Gilbert RE 2016
Gilbert RE. SGLT2 inhibitors: β blockers for the kidney?. Lancet Diabetes Endocrinol 2016 
Oct;4(10):814.  
Go et al 2004
Go AS, Chertow GM, Fan D, McCulloch CE, Hsu C-Y.  Chronic kidney disease and the risks of death, 
cardiovascular events, and hospitalisation.  N Engl J Med 2004; 351:1296-305.  

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Heerspink et al 2013
Heerspink H.  J.  L, Zeeuw, D, Wie L, Leslie B & List J.  Dapagliflozin a glucose-regulating drug with 
diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013 Sep;15(9):853-62.  
Heerspink et al 2016a
Heerspink HJ, Johnsson E, Gause-Nilsson I, Cain VA, Sjöström CD.  Dapagliflozin reduces 
albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers.  Diabetes 
Obes Metab 2016 Jun;18(6):590-7.  
Heerspink at al 2016b
Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ.  Sodium Glucose Cotransporter 2 
Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential 
Mechanisms, and Clinical Applications.  Circulation 2016 Sep 6;134(10):752-72.  
Kasichayanula et al 2014
Kasichayanula S, Liu X, Lacreta F, Griffen SC, Boulton DW.  Clinical pharmacokinetics and 
pharmacodynamics of dapagliflozin, a selective inhibitor of sodium-glucose co-transporter type 2.  Clin 
Pharmacokinet.  2014 Jan;53(1):17-27.  
Kohan et al 2014
Kohan DE, Fioretto P, Tang W and List JF.  Long-term study of patients with type 2 diabetes and 
moderate renal impairment shows that dapagliflozin educes weight and blood pressure but does not 
improve glycemic control.  Kidney International 2014; 85:962–971.  
Kosiborod et al 2016
Kosiborod M, Xu J, Sjostrand M, Sjostrom CD.  Safety and Efficacy of Dapagliflozin in Combination 
with Potassium-sparing Agents.  American Diabetes Association; June 2016: New Orleans. Abstract 
1094-P.
Komala et al 2013
Komala MG, Panchapakesan U, Pollock C, Mather A.  Sodium glucose cotransporter 2 and the diabetic 
kidney.  Curr Opin Nephrol Hypertens 2013, 22:113–119.  
Korner et al 1994
Körner A, Eklöf AC, Celsi G, Aperia A.Increased Renal Metabolism in Diabetes Mechanism and 
Functional Implications.  Diabetes 1994 May;43(5):629-33.
Levey at al 2009
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al. et al. A new equation 
to estimate glomerular filtration rate.  Ann Intern Med  2009 May 5;150(9):604-12.
Mudaliar et al 2016
Mudaliar S, Alloju S, Henry RR.  Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal 
Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis.  Diabetes Care 2016 
Jul;39(7):1115-22.  

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Pollock et al 1991
Pollock CA, Field MJ, Bostrom TE, Dyne M, Gyory AZ, Cockyane DJH.  Proximal tubular cell sodium 
concentration in early diabetic nephropaty assessed by electron microprobe analysis.  Pflügers Arch 
1991; 418(1-2):14-17.
Rajasekeran et al 2016
Rajasekeran H, Lytvyn Y,Cherney DZI.  Sodium–glucose cotransporter 2 inhibition and cardiovascular 
risk reduction in patients with type 2 diabetes: the emerging role of natriuresis.  Kidney International 
2016; 89:524–526.  
Sjöström et al 2015a
Sjöström CD, Johansson P, Ptaszynska A, List J, Johnsson E. Dapagliflozin lowers blood pressure in 
hypertensive and non-hypertensive patients with type 2 diabetes.  Diab Vasc Dis Res.  2015 
Sep;12(5):352-8.  
Sjöström et al 2015b
Sjostrom CD, Johansson P, Sugg J, Johnsson E.  Dapagliflozin reduces albuminuria on top of renin 
angiotensin system blockade in diabetic patients with moderate renal impairment.  ISN World Congress 
of Nephrology; March 2015; Cape Town. Abstract  SAT-461. 
Sjöström et al 2016
Sjöström CD, Greasley PJ, Xu J, Heerspink HJL.  Differential effects of dapagliflozin on cardiovascular
risk factors at varying degrees of renal function.  European Association for the Study of Diabetes 
(EASD), Sept 2016, Munich. Abstract 54.
Thomas 2014
Thomas MC.  Renal effects of dapagliflozin in patients with type 2 diabetes.  Ther Adv Endocrinol 
Metab 2014; 5(3):53-61.  
Wanner et al 2016
Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, et al; EMPA-REG 
OUTCOME Investigators. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N 
Engl J Med. 2016 Jul 28;375(4):323-34.
Yale et al 2013
Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L et al.  Efficacy and safety of canagliflozin in 
subjects with type 2 diabetes and chronic kidney disease.  Diabetes, Obesity and Metabolism 15: 463–
473, 2013.
Zinman et al 2015
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S et al.  Empagliflozin, cardiovascular 
outcomes, and mortality in type 2 diabetes.  N Engl J Med 2015; 373:2117-2128.  

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Appendix A
Additional Safety Information
Further Guidance on the Definition of a Serious Adverse Event (SAE)
Life threatening
‘Life-threatening’ means that the patient was at immediate risk of death from the AE as it 
occurred or it is suspected that use or continued use of the product would result in the subject’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (e.g., hepatitis that resolved without hepatic failure).  
Hospitalisation
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (e.g., bronchospasm, laryngeal oedema).  Hospital admissions and/or surgical 
operations planned before or during a study are not considered AEs if the illness or disease 
existed before the patient 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 judgement should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalisation, disability or incapacity but may jeopardize the patient 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 
judgement must be used.  

Angioedema not severe enough to require intubation but requiring iv 
hydrocortisone treatment

Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine

Intensive treatment in an emergency room or at home for allergic 
bronchospasm

Blood dyscrasias (e.g., neutropenia or anaemia requiring blood transfusion, 
etc.) or convulsions that do not result in hospitalisation

Development of drug dependency or drug abuse
A Guide to Interpreting the Causality Question
When making an assessment of causality consider the following factors when deciding if there 
is a ‘reasonable possibility’ that an AE may have been caused by the drug.  

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
Time Course.  Exposure to suspect drug.  Has the patient actually received 
the suspect drug?  Did the AE occur in a reasonable temporal relationship 
to the administration of the suspect drug?

Consistency with known drug profile.  Was the AE consistent with the 
previous knowledge of the suspect drug (pharmacology and toxicology) or 
drugs of the same pharmacological class? Or could the AE be anticipated 
from its pharmacological properties?

De-challenge experience.  Did the AE resolve or improve on stopping or 
reducing the dose of the suspect drug?

No alternative cause.  The AE cannot be reasonably explained by another
aetiology such as the underlying disease, other drugs, other host or 
environmental factors.  

Re-challenge experience.  Did the AE reoccur if the suspected drug was 
reintroduced after having been stopped? AZ would not normally 
recommend or support a re-challenge.  

Laboratory tests.  A specific laboratory investigation (if performed) has 
confirmed the relationship.  
In difficult cases, other factors could be considered such as:

Is this a recognized feature of overdose of the drug?

Is there a known mechanism?
Causality of ‘related’ is made if following a review of the relevant data, there is evidence for a 
‘reasonable possibility’ of a causal relationship for the individual case.  The expression 
‘reasonable possibility’ of a causal relationship is meant to convey, in general, that there are 
facts (evidence) or arguments to suggest a causal relationship.  
The causality assessment is performed based on the available data including enough 
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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Appendix B
International Airline Transportation Association (IATA) 6.2 
Guidance Document
Labelling and shipment of biohazard samples
International Airline Transportation Association (IATA) classifies biohazardous agents into 
3 categories.  For transport purposes the classification of infectious substances according to risk 
groups was removed from the Dangerous Goods Regulations (DGR) in the 46th edition (2005).  
Infectious substances are now classified either as Category A, Category B or Exempt.  There is 
no direct relationship between Risk Groups and categories A and B.  
Category A Infectious Substances are infectious substances in a form that, when exposure to 
it occurs, is capable of causing permanent disability, life-threatening or fatal disease in 
otherwise healthy humans or animals.  Category A pathogens are e.g., Ebola, Lassa fever virus:

Are to be packed and shipped in accordance with IATA Instruction 602 
Category B Infectious Substances are infectious Substances that do not meet the criteria for 
inclusion in Category A.  Category B pathogens are e.g., Hepatitis A, B, C, D, and E viruses, 
Human immunodeficiency virus (HIV) types 1 and 2.  They are assigned the following UN 
number and proper shipping name:

UN 3373 – Biological Substance, Category B

Are to be packed in accordance with UN3373 and IATA 650
Exempt - all other materials with minimal risk of containing pathogens

Clinical trial samples will fall into Category B or exempt under IATA 
regulations.

Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging.

Biological samples transported in dry ice require additional dangerous 
goods specification for the dry-ice content.

IATA compliant courier and packaging materials should be used for 
packing and transportation and packing should be done by an IATA 
certified person, as applicable.

Samples routinely transported by road or rail are subject to local 
regulations which require that they are also packed and transported in a 
safe and appropriate way to contain any risk of infection or contamination 
by using approved couriers and packaging / containment materials at all 
times.  The IATA 650 biological sample containment standards are 
encouraged wherever possible when road or rail transport is used.  

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Appendix C
New York Heart Association (NYHA) Functional 
Classification
NYHA Functional Classification
Class
Patient symptoms
I
No limitation of physical activity.  Ordinary 
physical activity does not cause undue fatigue, 
palpitation, dyspnoea (shortness of breath).  
II
Slight limitation of physical activity.  
Comfortable at rest.  Ordinary physical activity 
results in fatigue, palpitation, dyspnoea (shortness 
of breath).  
III
Marked limitation of physical activity.  
Comfortable at rest.  Less than ordinary activity 
causes fatigue, palpitation, or dyspnoea.  
IV
Unable to carry on any physical activity without 
discomfort.  Symptoms of heart failure at rest.  If 
any physical activity is undertaken, discomfort 
increases.  

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Study Number:
Site Number:
Subject Number: E_ _ _ _ _ _ _
Visit Number:
Assessment Date:
Your Health
This survey includes a wide variety of questions about your health and your 
life. We are interested in how you feel about each of these issues.
1. In general, would you say your health is: [Mark an             in the one box that 
best describes your answer.]
Excellent
Very good
Good
Fair
Poor

                       1

                         2

                      3

                        4

                         5
The following items are about activities you might do during a typical day. 
Does your health now limit you in these activities? If so, how much?
[Mark an
in a box on each line.]
Yes, 
limited a 
lot
Yes, 
limited a 
little
No, not 
limited at 
all
2.
Moderate activities, such as moving a table, 
pushing a vacuum cleaner, bowling, or
playing golf ................................................
1 ............
2 ............
3
3.
Climbing several flights of stairs ................
1 ............
2 ............
3

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Site Number:
Subject Number: E_ _ _ _ _ _ _
Visit Number:
Assessment Date:
During the past 4 weeks, have you had any of the following problems with 
your work or other regular daily activities as a result of your physical health?
Yes
No


4.
Accomplished less than you would like ...............
1............
2
5.    Were limited in the kind of work or other
activities ...............................................................
1............
2
During the past 4 weeks, have you had any of the following problems with 
your work or other regular daily activities as a result of any emotional 
problems (such as feeling depressed or anxious)?
Yes
No


6.
Accomplished less than you would like ...............
1............
2
     7.    Didn’t do work or other activities as carefully
as usual .................................................................
1............
2
8. During the past 4 weeks, how much did pain interfere with your
normal work (including both work outside the home and
housework)?
Not at all
A little bit
Moderately
Quite a bit
Extremely





1                                          2                                      3
                                  4
                                        5

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Subject Number: E_ _ _ _ _ _ _
Visit Number:
Assessment Date:
These questions are about how you feel and how things have been with you 
during the past 4 weeks. For each question, please give the one answer that 
comes closest to the way you have been feeling.
How much of the time during the past 4 weeks…
All of the 
time
Most of 
the time
A good bit 
of the time
Some of the 
time
A little 
of the 
time
None 
of
the
time






9.
Have you felt calm 
and peaceful?...........
             1...........          2 ............          3 ...............        4............         5 .....
6
10. Did you have a lot
of energy? ...............
             1...........          2 ............          3 ...............         4............          5 .....
6
11. Have you felt 
downhearted and 
blue? ........................
             1...........          2 ............          3 ...............         4............          5 .....
6
12. During the past 4 weeks, how much of the time has your physical health or
emotional problems interfered with your social activities (like visiting with 
friends, relatives, etc.)?
All
of the time
Most
of the time
Some
of the time
A little
of the time
None
of the time





                         1
2
3
4
5

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Visit Number:
Assessment Date:
Your Kidney Disease
How true or false is each of the following statements for you?
Definitely 
true
Mostly 
true
Don’t 
know
Mostly 
false
Definitely 
false





13. My kidney disease 
interferes too much 
with my life ...........
                            1 ...........             2............                3 ............               4...........               5
14. Too much of my 
time is spent 
dealing with my
kidney disease .......
                            1 ............            2............                3 ...........                4...........               5
15. I feel frustrated 
dealing with my 
kidney disease .......
                            1 ............            2............                3 ............               4...........               5
16. I feel like a burden 
on my family .........
                            1 ............            2............                3 ...........                4...........               5

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Visit Number:
Assessment Date:
During the past 4 weeks, to what extent were you bothered by each of the 
following?
Not 
bothered
Somewhat
bothered
Moderately
bothered
Very much
bothered
Extremely
bothered





17. Soreness in your muscles?
................
               1 ..............         2 .................         3 ...............         4................       5
18. Chest pain? ............
                1 …...........
2… .............
3 ...............
4................
5
19. Cramps? ................
1 ..............
2 .................
3 ...............
4................
5
20. Itchy skin? .............
1 ..............
2 .................
3 ...............
4................
5
21. Dry skin? ...............
1 ..............
2 .................
3 ...............
4................
5
22. Shortness of
breath? ...................
1 ..............
2 .................
3 ...............
4................
5
23. Faintness or 
dizziness? ..............
1 ..............
2 .................
3 ...............
4................
5
24. Lack of appetite? ...
1 ..............
2 .................
3 ...............
4................
5
25. Washed out or 
drained? .................
1 ..............
2 .................
3 ...............
4................
5
26. Numbness in hands or
feet? ..................
1 ..............
2 .................
3 ...............
4................
5
27. Nausea or upset stomach?
................
1 ..............
2 .................
3 ...............
4................
5
28a.(Hemodialysis patient 
only) Problems with your 
access site? ............
1 ..............
2 .................
3 ...............
4................
5
28b.(Peritoneal dialysis patient 
only) Problems with your
catheter site? ..........
1 ..............
2 .................
3 ...............
4................
5

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Study Code D169AC00001
Version 4.0
Date 17 March 2020
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Subject Number: E_ _ _ _ _ _ _
Visit Number:
Assessment Date:
Effects of Kidney Disease on Your Daily Life
Some people are bothered by the effects of kidney disease on their daily life,
while others are not. How much does kidney disease bother you in each of the
following areas?
Not at all Somewhat Moderately Very much Extremely
bothered
bothered
bothered
bothered
bothered





29. Fluid restriction? ...
1 ..............
2 ................
3................
4...............
5
30. Dietary
restriction? ............
1 ..............
2 ................
3................
4...............
5
31. Your ability to
work around the
house?
1 ..............
2 ................
3................
4...............
5
32. Your ability to 
travel?
1 ..............
2 ................
3................
4...............
5
33. Being dependent
on doctors and
other medical staff
1 ..............
2 ................
3................
4...............
5
34. Stress or worries 
caused by kidney 
disease?
1 ..............
2 ................
3................
4...............
5
35. Your sex life? ........
1 ..............
2 ................
3................
4...............
5
36. Your personal 
appearance?
1 ..............
2 ................
3................
4...............
5
Thank you for completing these questions!

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
KDQOL-36_v1_2000_Orig_WS_Paper_English-US_11Oct2016_D0000C00000
D2
EuroQol five-dimensional five-level questionnaire (EQ-5D-5L
Health Questionnaire
English version for the UK

UK (English) © 2009EuroQol Group EQ-5D™is a trade mark of the EuroQol Group
Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
Under each heading, please tick the ONE box that best describes your health TODAY.
MOBILITY
I have no problems in walking about                                                 
I have slight problems in walking about                                            
I have moderate problems in walking about                                     
I have severe problems in walking about                                          
I am unable to walk about                                                                  
SELF-CARE
I have no problems washing or dressing myself                                
I have slight problems washing or dressing myself                          
I have moderate problems washing or dressing myself                   
I have severe problems washing or dressing myself                        
I am unable to wash or dress myself                                                 
USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities                                   
I have slight problems doing my usual activities                               
I have moderate problems doing my usual activities                        
I have severe problems doing my usual activities                            
I am unable to do my usual activities                                                
PAIN / DISCOMFORT
I have no pain or discomfort                                                              
I have slight pain or discomfort                                                          
I have moderate pain or discomfort                                                   
I have severe pain or discomfort                                                       
I have extreme pain or discomfort                                                     
ANXIETY / DEPRESSION
I am not anxious or depressed                                                          
I am slightly anxious or depressed                                                    
I am moderately anxious or depressed                                             
I am severely anxious or depressed                                                  
I am extremely anxious or depressed                                               

UK (English) © 2009EuroQol Group EQ-5D™is a trade mark of the EuroQol Group
Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
•
We would like to know how good or bad your health is TODAY.
•
This scale is numbered from 0 to 100.
•
100 means the best health you can imagine.
0 means the worst health you can imagine.
•
Mark an X on the scale to indicate how your health is TODAY.
•
Now, please write the number you marked on the scale in the box 
below.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
96 (98)
Appendix E
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 section 3.1 of the main body of the Clinical Study Protocol and:

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 
section 3.2 of the Clinical Study Protocol or any of the following:

Previous allogeneic bone marrow transplant

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 5.6 of the main Clinical Study Protocol.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
97 (98)
Collection of samples for genetic research
The blood sample for genetic research will be obtained from the subjects at Visit 2 at
randomisation.  Although DNA is stable, early sample collection is preferred to avoid 
introducing bias through excluding subjects who may withdraw due to an adverse event (AE), 
such subjects would be important to include in any genetic analysis. If for any reason the 
sample is not drawn at Visit 2, it may be taken at any visit until the last study visit. Only one 
sample should be collected per 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 last subject last visit, after which they will be destroyed.  DNA is a finite resource 
that is used up during analyses.  Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached.
An additional second code will be assigned to the blood sample either before or at the time of 
DNA extraction replacing the information on the sample tube.  Thereafter, the sample will be 
identifiable 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 enrolment/randomisation 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 10 of the main Clinical Study 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 centre.  The 
Principal Investigator(s) is responsible for ensuring that consent is given freely and that the 
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.

Clinical Study Protocol
Drug Substance Dapagliflozin
Study Code D169AC00001
Version 4.0
Date 17 March 2020
98 (98)
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 analyse 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 organisations may share summary results (such as genetic 
differences from groups of individuals with a disease) from this genetic research with other 
researchers, such as Hospitals, Academic 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.

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: d169ac00001-csp-v4
Document Title:
D169AC00001 Clinical Study Protocol version 4
Document ID:
Doc ID-003216276
Version Label:
5.0 CURRENT LATEST APPROVED
Server Date
(dd-MMM-yyyy HH:mm ‘UTC’Z)
Signed by
Meaning of Signature
20-Mar-2020 09:28 UTC
Content Approval
19-Mar-2020 15:38 UTC
Content Approval
19-Mar-2020 15:12 UTC
Content Approval
19-Mar-2020 15:19 UTC
Content Approval
Notes: (1) Document details as stored in ANGEL, an AstraZeneca document management system.