Clinical trial NCT01730534
Conditions: Diabetes Mellitus, Non-Insulin-Dependent High Risk for Cardiovascular Event
Keywords: Phase IIIb T2DM cardiovascular events
Sponsor: AstraZeneca
Start date: 2013-04-25; Completion date: 2018-09-11
Enrollment: 17190 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is being carried out to determine the effect of dapagliflozin on cardiovacular outcomes when added to current background therapy in patients with type 2 diabetes with either established cardiovacular disease or cardiovascular risk factors.

Detailed description:

Arms: arm 1: Dapagliflozin + standard of care therapy for Type 2 Diabetes and for co-morbidities and cardiovascular risk factors arm 2: Placebo + standard of care therapy for Type 2 Diabetes and for co-morbidities and cardiovascular risk factors
Interventions: intervention 1: Dapagliflozin 10 mg intervention 2: Placebo tablet
Intervention descriptions: intervention 1: Oral dose (od) intervention 2: Oral dose (od)

Protocol documents:
Prot_000.pdf: 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
2
PROTOCOL SYNOPSIS
DECLARE
Dapagliflozin Effect on CardiovascuLAR Events 
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to 
Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of 
Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in 
Patients with Type 2 Diabetes
International Co-ordinating Investigator or Principal Investigator or National Co-
ordinating Investigator
Marc S. Sabatine, MD, MPH, 
Itamar Raz, MD, 
Stephen D. Wiviott, MD, 
Study center(s) and number of patients planned
This international study will be conducted at approximately 1200 centers. It is estimated that 
approximately 27000 patients will be enrolled to reach the target of approximately 17150 
randomized patients during a recruitment period of approximately 3 years.
Study period
Phase of development
Estimated date of first patient enrolled
Q2 2013
3b
Estimated date of last patient completed
Q2 2019
Objectives
Primary objective
The primary objective is to determine the effect of dapagliflozin relative to placebo on 
cardiovascular outcomes when added to current background therapy in patients with type 2 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
3
diabetes mellitus (T2DM) with either established cardiovascular disease or at least two 
cardiovascular risk factors.
This objective will be evaluated in two steps. The first step will determine if dapagliflozin is 
non-inferior to placebo for the incidence of the composite endpoint of cardiovascular death, 
myocardial infarction (MI), or ischemic stroke assessed with a non-inferiority margin of 1.3.
If this is met the second step will determine if dapagliflozin reduces the incidence of the co-
primary endpoints: the composite of cardiovascular death, myocardial infarction (MI), or 
ischemic stroke and the composite of hospitalization for heart failure or CV death compared to 
placebo
Secondary objective
The secondary objective is to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM with either 
established cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM 
will result in a reduction of: 
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 
ml/min/1.73m2 and/or ESRD (dialysis ≥90 days or kidney transplantation, confirmed 
sustained eGFR <15ml/min/1.73m2) and/or renal or CV death
!
All-cause mortality
Safety objectives
Safety and tolerability will be assessed from overall adverse events, serious adverse events, 
adverse events of special interest, and laboratory test results. The assessment will include an 
evaluation of the incidence of adjudicated bladder cancer and liver injury.
Exploratory objectives
Other efficacy objectives are to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM and either established 
cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM will result 
in a reduction of:
!
The individual components of the co-primary efficacy endpoints (cardiovascular 
death, MI, ischemic stroke  or hospitalization for heart failure)
!
The composite endpoint of cardiovascular death, MI, ischemic stroke, hospitalization 
for heart failure, hospitalization for unstable angina pectoris, or hospitalization for 
coronary or non-coronary revascularization and the additional individual components 
of hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
4
!
Glycosylated hemoglobin A1c (HbA1c)
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for any of the following: An increase in dose for an oral anti-diabetes 
medication, a ≥ 25% increase in insulin dose or the  addition of new anti-diabetes 
medication for > 3 months
!
Major hypoglycemia and/or hospitalization for hypoglycaemia
!
Development of Albuminuria 
!
Development of albuminuria
!
Albuminuria
!
Decrease in eGFR
!
Albumin to Creatinine ratio
!
Body weight
!
Retinal laser and/or intraocular treatment due to development of and/or deterioration in 
diabetic retinopathy
!
Blood pressure 
!
Peripheral revascularization/limb ischemic event
!
Surgical amputation and related events 
!
Any stroke (ischemic, hemorrhagic, or undetermined)
 
 
 
Study design
This is a multicenter, randomized, double blind, placebo-controlled Phase 3b study to evaluate 
whether treatment with dapagliflozin reduces major adverse cardiovascular events in patients 
with T2DM and with either known cardiovascular disease or at least two risk factors for 
cardiovascular disease in addition to T2DM. In addition, this study will seek to definitively 
exclude unacceptable cardiovascular risk in these patients from dapagliflozin. All patients should 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
5
receive standard of care therapy for T2DM as well as for co-morbidities and cardiovascular risk 
factors (e.g., dyslipidemia, hypertension) based on accepted guidelines and local best practices. 
Target patient population
Approximately 17150 patients (see Section 12.3 Determination of sample size) with documented 
history of established cardiovascular disease (secondary prevention) or two or more risk factors 
for cardiovascular disease in addition to T2DM (e.g., age, hyperlipidemia, hypertension, recent 
smoking history-primary prevention) will be randomized from sites throughout the world. For 
example, recruitment will be monitored to randomize approximately 30% of patients each from 
North America and Europe. The proportions of primary and secondary prevention patient 
populations overall and by region will be monitored to ensure a minimum of approximately 33 % 
of randomized patients from the secondary prevention patient population overall and to avoid 
large differences between regions.
Patients who are treated with any oral and/or parenteral glucose-lowering medications (with the 
exception of rosiglitazone, pioglitazone, and other sodium glucose cotransporter 2 [SGLT2] 
inhibitors) at the time of enrollment, as well as treatment naïve or non-medically treated (e.g., 
diet) patients will be enrolled and will receive either dapagliflozin 10 mg qd or matching placebo 
in addition to standard of care treatment for T2DM and co-morbidities. 
Investigational product, dosage and mode of administration
Dapagliflozin 10 mg tablets administered orally once daily for a predicted median of 4.5 years 
and an anticipated total duration of a 6-year double-blind treatment period.
Comparator, dosage and mode of administration
Matching placebo for dapagliflozin 10 mg administered orally once daily for the 4-8 week 
placebo run-in period and for a predicted median of 4.5 years and an anticipated total duration of 
a 6-year double-blind treatment period. 
Duration of treatment
The study is cardiovascular event–driven with a predicted median of 4.5 years and an anticipated 
total duration of 6 years.
Outcome variable(s): 
Primary variables:
The co-primary outcome variables of the study are the composite endpoint of cardiovascular 
death, myocardial infarction, or ischemic stroke (time to first event) and the composite endpoint 
of hospitalization for heart failure or CV death (time to first event). All components of these 
composites will be adjudicated.
Secondary variables:


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
6
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 
ml/min/1.73m2 (using CKD-EPI equation) and/or ESRD (dialysis ≥90 days or kidney 
transplantation, confirmed sustained eGFR <15ml/min/1.73m2) and/or renal or CV 
death (time to first event)
!
All-cause mortality (time to event)
Exploratory variables:
!
The individual components of the co-primary endpoints (cardiovascular death, MI, 
ischemic stroke, and hospitalization for heart failure) (time to first event)
!
The composite endpoint of cardiovascular death, MI, ischemic stroke, hospitalization 
for heart failure, hospitalization for unstable angina pectoris, or hospitalization for 
coronary or non-coronary revascularization and the additional individual components 
of hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization (time to first event)
!
HbA1c
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for an increase in dose for oral anti-diabetes medication or ≥25% increase in 
insulin dose for ≥3 months or addition of new anti-diabetes medication 
!
Major hypoglycemia and/or hospitalization for hypoglycaemia
!
Development of confirmed sustained macroalbuminuria (UACR ≥300 mg/g) in 
subjects without macroalbuminuria at baseline (time to first event)
!
Development of confirmed sustained albuminuria in patients without albuminuria at 
baseline (UACR ≥30 mg/g; time to first event)
!
Regression in sustained confirmed albuminuria (defined in three ways: 1. Baseline 
microalbuminuria to normoalbuminuria, 2. Baseline macroalbuminuria to 
microalbuminuria, 3. The previous two combined) (proportions)
!
eGFR (sustained confirmed decrease ≥30% to sustained confirmed eGFR <60 
ml/min/1.73m2 using CKD-EPI equation; time to first event)
!
eGFR (sustained confirmed decrease ≥40% to sustained confirmed eGFR <60 
ml/min/1.73m2 using CKD-EPI equation; time to first event)
!
Albumin to Creatinine Ratio (adjusted mean percent change after 2 and at 3 years)
!
Change in body weight at 2 years and at 3 years


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
7
!
Proportion of patients with 5% body weight loss and 10 % body weight loss after 2 
years and after 3 years
!
Retinal laser and/or intraocular treatment due to development of and/or deterioration in 
diabetic retinopathy
!
Blood pressure change from baseline
!
Peripheral revascularization/limb ischemic event
!
Surgical amputation and related events 
!
Any stroke (ischemic, hemorrhagic, or undetermined)
Primary safety variable:
The primary safety variable is the composite endpoint of cardiovascular death, MI or ischemic 
stroke (time to first event).
Other safety variables
Safety and tolerability will be assessed from overall adverse events, serious adverse events, 
adverse events of special interest and laboratory test results. The assessment will include an 
evaluation of the incidence of bladder cancer and liver injury. All possible malignancies 
(excluding non-melanoma skin cancer) and liver injury will be independently adjudicated.
Statistical methods
1390 MACE events will be required to have 85% power to demonstrate superiority of 
dapagliflozin to placebo if the true HR is 0.85, i.e., a 15% relative risk reduction, with a one-
sided alpha of 2.31%. To achieve this number of MACE events, we have designed the study with 
the following condition. 17150 randomized patients will be required for the study if both patients 
from a primary prevention population and from a secondary prevention population will be 
included, with an assumed annual event rate of 2.1% on placebo, and an annual withdrawal rate 
of 1.0% over a 3-year accrual period and 3-year minimum follow-up.
The co-primary variables are the time to first event included in the composite endpoint of 
cardiovascular death, MI, or ischemic stroke and the composite for hospitalization for heart 
failure or cardiovascular death. The primary analyses will be based on the Full Analysis Set 
(FAS), using events adjudicated and confirmed to meet endpoint definitions by the Clinical 
Event adjudication Committee (CEC). The analysis will be performed using the Cox 
proportional hazards model with a factor for treatment group stratified by cardiovascular risk 
category (established cardiovascular disease, or multiple risk factors without established 
cardiovascular disease), and baseline hematuria.
A closed test procedure will control for overall Type I error rate across the analyses of the 
primary and secondary objectives.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
8
A Data Monitoring Committee (DMC) will be appointed jointly by the Sponsors and the 
academic leadership of the study. The DMC will be responsible for safeguarding the interests of 
the patients in the outcome study by assessing the safety of the intervention during the trial, and 
for reviewing the overall conduct of the trial. They will review overall safety in the trial and 
specifically the incidence of bladder cancers and potential drug induced liver injury (DILI) cases. 
In addition, the DMC will have the responsibility to assess the data at the 2 interim analyses
occurring when 1/3 and 2/3 of the MACE events have accumulated, and make recommendations 
based upon stopping guidelines. 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
9
TABLE OF CONTENTS
PAGE
TITLE PAGE .......................................................................................................... 1
PROTOCOL SYNOPSIS........................................................................................ 2
TABLE OF CONTENTS........................................................................................ 9
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ......................... 15
1.
INTRODUCTION................................................................................................. 18
1.1
Background ........................................................................................................... 18
1.1.1
Cardiovascular data on dapagliflozin.................................................................... 18
1.1.2
Effect of dapagliflozin on cardiovascular risk factors........................................... 19
1.1.2.1
Effect on blood pressure........................................................................................ 19
1.1.2.2
Effect on body weight and composition................................................................ 19
1.1.2.3
Effect on lipids ...................................................................................................... 20
1.1.2.4
Effect on uric acid and inflammatory markers...................................................... 21
1.2
Research hypothesis .............................................................................................. 21
1.3
Rationale for conducting this study....................................................................... 21
1.4
Benefit/risk and ethical assessment....................................................................... 21
2.
STUDY OBJECTIVES......................................................................................... 22
2.1
Primary objective .................................................................................................. 22
2.2
Secondary objectives............................................................................................. 22
2.3
Safety objectives.................................................................................................... 22
2.4
Exploratory objectives........................................................................................... 23
3.
STUDY PLAN AND PROCEDURES ................................................................. 24
3.1
Overall study design and flow chart...................................................................... 24
3.2
Rationale for study design, doses and control groups........................................... 36
4.
PATIENT SELECTION CRITERIA.................................................................... 37
4.1
Inclusion criteria.................................................................................................... 37
4.2
Exclusion criteria................................................................................................... 38
5.
STUDY CONDUCT ............................................................................................. 40
5.1
Restrictions during the study................................................................................. 40
5.2
Patient enrollment and randomization and initiation of investigational product .. 40
5.2.1
Procedures for randomization ............................................................................... 40


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
10
5.3
Procedures for handling patients incorrectly enrolled or randomized or 
initiated on investigational product....................................................................... 41
5.4
Blinding and procedures for unblinding the study................................................ 42
5.4.1
Methods for ensuring blinding .............................................................................. 42
5.4.2
Methods for unblinding patients treatment assignment ........................................ 42
5.5
Treatments............................................................................................................. 43
5.5.1
Identity of investigational product(s) .................................................................... 43
5.5.2
Doses and treatment regimens............................................................................... 43
5.5.3
Additional IP (Not applicable) .............................................................................. 43
5.5.4
Labeling................................................................................................................. 43
5.5.5
Storage................................................................................................................... 44
5.6
Concomitant and post-study treatment(s).............................................................. 44
5.6.1
Prohibited medication............................................................................................ 44
5.6.2
Use with medications known to cause hypoglycemia........................................... 44
5.6.3
Anti-diabetes medication....................................................................................... 44
5.6.4
Other medications.................................................................................................. 45
5.7
Treatment compliance........................................................................................... 45
5.7.1
Accountability ....................................................................................................... 45
5.8
Discontinuation of investigational product ........................................................... 46
5.8.1
Procedures for discontinuation of a patient from investigational product ............ 47
5.9
Withdrawal from study.......................................................................................... 48
5.10
Lost to follow up patients...................................................................................... 48
6.
COLLECTION OF STUDY VARIABLES.......................................................... 48
6.1
Recording of data .................................................................................................. 48
6.2
Data collection at enrollment, randomization and follow-up................................ 49
6.2.1
Enrollment procedures .......................................................................................... 49
6.2.2
Randomization....................................................................................................... 50
6.2.3
Follow-up procedures............................................................................................ 50
6.3
Efficacy ................................................................................................................. 53
6.3.1
Primary variable .................................................................................................... 53
6.3.2
Secondary variables............................................................................................... 53
6.3.3
Exploratory variables ............................................................................................ 53
6.4
Safety..................................................................................................................... 55
6.4.1
Primary safety variable.......................................................................................... 55
6.4.2
Definition of adverse events.................................................................................. 55
6.4.3
Definitions of serious adverse event ..................................................................... 55
6.4.4
Recording of adverse events.................................................................................. 56
6.4.4.1
Hepatic disorders................................................................................................... 58
6.4.4.2
Hematuria.............................................................................................................. 59
6.4.4.3
Possible malignancies............................................................................................ 59


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
11
6.4.4.4
Renal disorders...................................................................................................... 59
6.4.4.5
Hypoglycemic events ............................................................................................ 60
6.4.4.6
Volume depletion .................................................................................................. 61
6.4.4.7
UTI ........................................................................................................................ 61
6.4.4.8
Asymptomatic bacteriuria ..................................................................................... 61
6.4.4.9
Adjudication of suspected CV endpoints.............................................................. 61
6.4.4.10
Fractures ................................................................................................................ 61
6.4.4.11
Genital infections .................................................................................................. 62
6.4.4.12
Hypersensitivity reactions..................................................................................... 62
6.4.4.13
Amputation and related events.............................................................................. 62
6.4.5
Reporting of serious adverse events...................................................................... 62
6.4.5.1
Protocol-specific exceptions to SAE reporting by the sponsor............................. 63
6.4.6
Laboratory safety assessment................................................................................ 63
6.4.6.1
Unscheduled laboratory assessments .................................................................... 64
6.4.7
Physical examination............................................................................................. 65
6.4.8
Vital signs.............................................................................................................. 65
6.4.8.1
Pulse and blood pressure....................................................................................... 65
6.4.8.2
Body weight and height......................................................................................... 65
6.4.8.3
Waist and hip circumference................................................................................. 65
6.4.8.4
Waist-hip ratio (WHR)......................................................................................... 65
6.5
Patient reported outcomes (PRO) (Not applicable)............................................... 65
6.6
Pharmacokinetics (Not applicable) ....................................................................... 65
6.7
Pharmacodynamics (Not applicable)..................................................................... 65
6.8
........................................................................................ 65
6.8.1
................................................................ 65
7.
BIOLOGICAL SAMPLING PROCEDURES...................................................... 66
7.1
Volume of blood.................................................................................................... 66
7.2
Handling, storage and destruction of biological samples...................................... 66
7.2.1
Handling, storage and destruction of biological samples for future research ....... 66
7.3
Labeling and shipment of biohazard samples ....................................................... 67
7.4
Chain of custody of biological samples ................................................................ 67
7.5
Withdrawal of informed consent for donated biological samples......................... 67
8.
ETHICAL AND REGULATORY REQUIREMENTS ........................................ 68
8.1
Ethical conduct of the study.................................................................................. 68
8.2
Patient data protection........................................................................................... 68
8.3
Ethics and regulatory review................................................................................. 68
8.4
Informed consent................................................................................................... 69
8.5
Changes to the protocol and informed consent form ............................................ 70


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
12
8.6
Audits and inspections........................................................................................... 70
9.
STUDY MANAGEMENT BY ASTRAZENECA OR DELEGATE................... 70
9.1
Pre-study activities ................................................................................................ 70
9.2
Training of study site personnel............................................................................ 71
9.3
Monitoring of the study......................................................................................... 71
9.3.1
Source data ............................................................................................................ 72
9.4
Study agreements .................................................................................................. 72
9.4.1
Archiving of study documents .............................................................................. 72
9.5
Study timetable and end of study .......................................................................... 72
10.
DATA MANAGEMENT BY COGNIZANT DMG............................................. 72
11.
EVALUATION AND CALCULATION OF VARIABLES ................................ 73
11.1
Calculation or derivation of efficacy variable(s)................................................... 73
11.2
Calculation or derivation of safety variable(s)...................................................... 74
11.2.1
Other significant adverse events (OAE)................................................................ 74
11.3
Calculation of renal variables................................................................................ 74
11.4
Calculation or derivation of patient reported outcome variables (Not 
applicable) ............................................................................................................. 75
11.5
Calculation or derivation of pharmacokinetic variables (Not applicable) ............ 75
11.6
Calculation or derivation of pharmacodynamic variable(s) (Not applicable)....... 75
11.7
....................................... 75
12.
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ........... 75
12.1
Description of analysis sets................................................................................... 75
12.1.1
Full analysis set (FAS) .......................................................................................... 75
12.1.2
Safety analysis set ................................................................................................. 75
12.1.3
An on-treatment analysis set ................................................................................. 76
12.2
Methods of statistical analyses.............................................................................. 76
12.2.1
Demographics and baseline characteristics........................................................... 76
12.2.2
Primary variables................................................................................................... 76
12.2.3
Secondary variables............................................................................................... 78
12.2.4
Summary of closed test procedure ........................................................................ 78
12.2.5
Exploratory efficacy variables............................................................................... 79
12.2.6
Safety analyses ...................................................................................................... 80
12.2.7
Considerations of incomplete follow-up............................................................... 81
12.2.8
Interim analyses..................................................................................................... 81
12.3
Determination of sample size................................................................................ 83
12.4
Data monitoring committee................................................................................... 84


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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12.4.1
Clinical Event Adjudication Committee ............................................................... 84
12.4.2
Data Monitoring Committee (DMC)..................................................................... 85
12.5
Study organization................................................................................................. 85
12.5.1
Committee organizations....................................................................................... 85
12.5.1.1
Executive Committee ............................................................................................ 85
12.5.1.2
Steering Committee............................................................................................... 86
12.5.1.3
Strategy and Tactics Groups.................................................................................. 86
12.5.1.4
Joint Working Group............................................................................................. 86
12.5.2
Study Project Operational Procedures (TIMI) ...................................................... 86
13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED BY THE 
INVESTIGATOR.................................................................................................. 86
13.1
Medical emergencies and trial contacts................................................................. 86
13.2
Overdose................................................................................................................ 87
13.3
Pregnancy.............................................................................................................. 87
14.
LIST OF REFERENCES ...................................................................................... 88
LIST OF TABLES
Table 1
Study Plan................................................................................................ 32
Table 2                  Visit design and visit windows................................................................ 36
Table 3                  Volume of blood to be drawn from each patient ..................................... 66
Table 4
Confirmatory Testing Procedures Using One-sided Alphas.................... 78
Table 5
Levels of bladder cancer relative risks and incidence rate differences 
that can be ruled out under different assumptions ................................... 84
LIST OF FIGURES
Figure 1
Study flow chart....................................................................................... 31
LIST OF APPENDICES
Appendix A
Signatures
Appendix B
Additional Safety Information 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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Appendix C
IATA 6.2 Guidance document
Appendix D
Algorithm on Management of Sustained Elevated Liver Safety Abnormalities
Appendix E
Disease State Definitions
Appendix F
ADA/EASD treatment algorithm for antihyperglycemic therapy in T2DM
Appendix G
AUA recommendations for evaluation of asymptomatic microscopic hematuria
Appendix H
Appendix I
Biomarker Research


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
15
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
ACS
Acute coronary syndrome
AE
Adverse event (see definition in Section 6.4.2)
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ANCOVA
Analysis of Covariance
AZ
AstraZeneca
BMI
Body Mass Index
BMS
Bristol-Myers Squibb
CBC
Complete blood count
CEC
Clinical Event Adjudication Committee
CI
Confidence Interval
CrCl
Creatinine Clearance
CRF
Case Report Form (electronic/paper)
CRO
Contract Research Organization
CSA
Clinical Study Agreement
CT
Computed Tomography
CV
Cardiovascular
DAE
Discontinuation of Investigational Product due to Adverse Event
DBP
Diastolic blood pressure
DES
Data Entry Site
DILI
Drug induced liver injury
DMC
Data Monitoring Committee
DMG
Data Monitoring Group (Cognizant)
DNA
Deoxyribonucleic acid
DXA
Dual energy x-ray absorptiometry


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
16
Abbreviation or 
special term
Explanation
EC
Ethics Committee, synonymous to Institutional Review Board (IRB) and 
Independent Ethics Committee (IEC)
Ecode
Enrollment Code
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EoT
End of Treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FPG
Fasting Plasma Glucose
GCP
Good Clinical Practice
GPV&E
Global Pharmacovigilance and Epidemiology (BMS)
GRAND
Global Randomization system
HbA1c
Glycosylated hemoglobin A1c
HR
Hazard Ratio
HsCRP
High sensitivity C-reactive protein
ICH
International Conference on Harmonization
International 
Co-ordinating 
Investigator
If a study is conducted in several countries the International Co-ordinating 
Investigator is the Investigator co-ordinating the investigators and/or 
activities internationally. 
IP
Investigational Product
IVRS
Interactive Voice Response System
IWRS
Interactive Web Response System
LIMS
Laboratory Information Management System
MACE
Major adverse cardiac event
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
MI
Myocardial infarction
MODY
Maturity-onset diabetes of the young
NMP-22
Nuclear Matrix Protein-22
OAD
Oral anti-diabetes medication


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
17
Abbreviation or 
special term
Explanation
OAE
Other Significant Adverse Event (see definition in Section 11.2.1)
PAI-1
Plasminogen activator inhibitor
POP
Project Operational Procedures
PI
Principal Investigator 
SAE
Serious adverse event (see definition in Section 6.4.3).
SAP
Statistical Analysis Plan
SCSM
Supply Chain Study Management
SBP
Systolic blood pressure
SEER
Surveillance, Epidemiology and End Results
SGLT2
Sodium glucose cotransporter 2
SUSARs
Suspected Unexpected Serious Adverse Reactions
T2DM
Type 2 diabetes mellitus
TB
Total bilirubin
TIA
Transient ischemic attack
TIMI
Thrombolysis in Myocardial Infarction
USA
United States of America
UTI
Urinary tract infection
WBDC
Web Based Data Capture
WOCBP
Women of child bearing potential


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
18
1.
INTRODUCTION
1.1
Background
Dapagliflozin is the first in a new class of compounds referred to as sodium glucose 
cotransporter 2 (SGLT2) inhibitors. SGLT2 is localized to the renal proximal tubule where it 
reabsorbs most of the ~180 g of glucose normally filtered through the glomeruli each day. 
SGLT2 inhibition therefore leads to pharmacologically controlled glucosuria. Dapagliflozin is a 
highly selective and reversible inhibitor of SGLT2. A pharmacokinetic half-life of 12.5 hours, 
due to the C-aryl glucoside-derived chemical structure, allows for the oral administration of 
dapagliflozin once daily. Inhibition of glucose reabsorption leads to subsequent glycemic effects, 
including fasting plasma glucose (FPG) lowering and ultimately, effects on hemoglobin A1c 
(HbA1c). The glycemic-lowering effect induced by SGLT2 inhibition is independent of the 
presence of insulin. Because of this insulin-independent mechanism of action, dapagliflozin is 
expected to have consistent effects on glycemic control in a wide spectrum of patients with 
T2DM, whether used as monotherapy at an early stage of disease or in combination with other 
oral anti-diabetes drugs (OADs) and/or insulin at a later stage, and may also be more likely to 
maintain its efficacy over time. 
More than 85% of patients with T2DM are overweight or obese, which also perpetuates the 
disease (Campbell 2009). Additional weight gain further augments insulin resistance and 
negatively impacts cardiovascular risk factors such as hypertension and dyslipidemia. Efforts by 
patients to lose weight as part of a therapeutic lifestyle program can be undermined by therapies 
that lead to weight gain, such as thiazolidinediones (TZDs), sulfonylureas (SUs), or insulin. 
Hypoglycemia is also a clinically important barrier to optimizing treatment with insulin and SUs, 
both of which are second-line options in current treatment algorithms. Hypertension (JNC-7 
2004) and dyslipidemia (Gastaldelli A et al 2007) commonly coexist with T2DM and are risk 
factors for both micro and macrovascular complications. The UKPDS (UKPDS 1998) and HOT 
(Hanson L 1999) trials demonstrated reductions in cardiovascular events among patients with 
T2DM when treated to blood pressures of approximately 140/80 to 85 mmHg, and substantial 
benefits have been seen when multiple risk factors in combination are addressed. Despite these 
data, more than 50% of patients fail to achieve target values for blood pressure, and only ~12% 
meet combined target values for blood pressure, low-density lipoprotein cholesterol, and glucose. 
Efforts to identify new treatment paradigms that are independent of insulin and have a potentially 
positive impact on weight and blood pressure and little or no negative effect on lipids have led to 
the development of dapagliflozin. 
1.1.1
Cardiovascular data on dapagliflozin
Anti-diabetes medications have been proven to reduce microvascular complications, but the 
reduction of macrovascular complications (myocardial infarction and stroke) remains elusive. A 
meta-analysis of 145 adjudicated cardiovascular (CV) events from the comprehensive Phase 2b 
and 3 dapagliflozin clinical program (Cardiovascular events meta-analysis report: Dapagliflozin) 
resulted in an estimate for the hazard ratio for dapagliflozin versus comparator for the primary 
composite endpoint(adjudicated CV death, myocardial infarction, stroke or hospitalization for 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
19
unstable angina) of 0.819 (95% Confidence Interval (CI): 0.583, 1.152). The estimated incidence 
rate ratio versus comparator was 0.820, 0.527 and 0.757 for 2.5, 5 and 10 mg dapagliflozin, 
respectively. The results of the secondary composite endpoint and other sensitivity analyses 
(including the major adverse cardiovascular events [MACE] of CV death, MI and stroke only) 
were consistent with the primary result. These hypothesis-generating data, along with an overall 
positive benefit-risk profile for dapagliflozin and positive effects on CV risk factors as described 
below in Section 1.1.2 “Effect of dapagliflozin on CV risk factors”, indicate that dapagliflozin 
treatment may lower CV risk in patients with T2DM. 
1.1.2
Effect of dapagliflozin on cardiovascular risk factors
1.1.2.1
Effect on blood pressure
Blood pressure reductions were expected in the dapagliflozin Phase 3 program due to the mode 
of action of SGLT2 inhibition, which is associated with an osmotic diuretic and natriuretic effect. 
Because the studies were primarily designed to evaluate glycemic and body weight endpoints, 
and were not designed to rigorously evaluate blood pressure efficacy, background
antihypertensive medications were not controlled. Change in systolic blood pressure (SBP) and 
diastolic blood pressure (DBP) in overall study populations was primarily analyzed as a safety 
endpoint due to the potential risks of hypotension and hypovolemia, and as an exploratory 
efficacy variable in select studies. Exploratory efficacy analyses for SBP were pre-specified in 4 
of the 11 Phase 3 studies and analyzed post hoc for the remainder of the studies to evaluate 
consistency of effect across the program. 
Change in SBP and DBP in patients with baseline SBP >140 mmHg was a pre-specified 
exploratory efficacy endpoint in the majority of the Phase 3 dapagliflozin studies. Patients in this 
subgroup meet JNC-7 criteria for stage 1 hypertension and are expected to gain the greatest 
benefit from reductions in blood pressure. Although there were few patients in this subgroup 
(n=32 to 123 per treatment group), modest SBP reductions were observed. In the three add-on 
combination therapy studies in the Phase 3 dapagliflozin program, SBP decreases versus placebo 
ranged from -2.8 mmHg to -4.9 mmHg in the 10 mg groups. 
In all of the Phase 3 monotherapy and placebo-controlled add-on combination therapy studies, 
numerical reductions versus placebo in SBP were observed in the dapagliflozin treatment groups. 
Placebo-corrected changes in SBP ranged from -1.3 mmHg to -5.3 mmHg for patients treated 
with dapagliflozin 10 mg. Similar reductions in SBP were observed in the active comparator and 
initial combination therapy studies. In both subgroups (SBP >140 mmHg and SBP ≤ 140 
mmHg), dapagliflozin 2.5, 5, and 10 mg resulted in placebo-corrected SBP and DBP reductions; 
reductions in both SBP and DBP appeared to be greater in the hypertensive subgroup. 
1.1.2.2
Effect on body weight and composition
Dapagliflozin, with its unique mechanism of action leading to persistent loss of calories in the 
urine and subsequent negative energy balance, causes a body weight loss with reduction in total 
body fat. In the 6 placebo controlled studies in the dapagliflozin Phase 3 program, the placebo-
corrected mean weight reductions over 24 weeks ranged from -0.46 to -2.16 kg and were 
statistically significant for the 5 and 10 mg doses of dapagliflozin in all but one study. In patients 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
20
receiving stable doses of metformin and SU, dapagliflozin 5 and 10 mg induced a statistically 
significant reduction in weight compared to placebo over 24 weeks. Dapagliflozin added to 
insulin also resulted in significant weight loss compared to placebo-treated patients. Patients 
treated with pioglitazone and placebo gained 1.64 kg during the 24 weeks of the study period, 
while the weight of patients treated with pioglitazone and dapagliflozin remained close to 
baseline. When directly compared to SU, treatment with dapagliflozin resulted in weight loss of -
3.22 kg versus weight gain of 1.44 kg with glipizide on metformin background. A significantly 
greater proportion of patients in the dapagliflozin group (33.3%), compared to glipizide (2.5%), 
experienced body weight loss by at least 5% from baseline to Week 52. Treatment with 
dapagliflozin 5 or 10 mg in combination with metformin also resulted in greater mean reductions 
in total body weight at 24 weeks compared to treatment with metformin alone. The type of 
weight loss achieved is of clinical importance as total body fat correlates positively with key CV 
risk factors, most strongly with insulin resistance (Vega GL 2006). Study D1690C00012 was 
designed to address this question, with reduction in total body weight as the primary endpoint. 
Treatment with dapagliflozin 10 mg as add-on to metformin in patients with treatment failure on 
metformin resulted in a statistically significant mean weight reduction of -2.08 kg (p<0.0001) 
compared to placebo plus metformin. The majority of weight loss was attributable to a reduction 
in total body fat mass, as measured by dual energy X-ray absorptiometry (DXA). A statistically 
significant mean placebo-corrected reduction of 1.5 cm in waist circumference was observed in 
the dapagliflozin group, consistent with the reduction in body weight and loss of body fat mass. 
The proportion of patients attaining a weight loss of 5% or more was also statistically 
significantly greater in the dapagliflozin group (30.5%) compared to the placebo group (4.3%). 
Exploratory analyses in Study D1690C00012 also showed favorable effects on the distribution of 
body mass. Due to the relatively greater amount of fat loss in patients treated with dapagliflozin 
versus placebo, there was an increase in the percentage of lean tissue mass relative to total body 
weight in the dapagliflozin treated patients (difference between treatment groups of 0.9% as 
measured by DXA). An exploratory analysis in a subset of patients utilizing magnetic resonance 
imaging suggested that the decrease in body fat mass was partly attributable to a decrease in 
visceral adipose tissue, which is associated with abnormalities in glucose and lipid metabolism 
(Gastaldelli A et al 2007); an approximately 10% reduction in visceral adipose tissue volume 
was observed in the dapagliflozin group compared to a <1.5% change in the placebo group. 
1.1.2.3
Effect on lipids
Fasting lipids were an exploratory efficacy variable in all of the Phase 3 studies with the 
exception of D1690C00012. No consistent treatment effect was observed for changes in total 
cholesterol or free fatty acids; small numerical increases in high-density lipoprotein cholesterol 
(HDL-C) and low-density lipoprotein cholesterol (LDL-C), and decreases in triglycerides (TG) 
were observed across the studies. Placebo-corrected adjusted mean percent changes for 
dapagliflozin 10 mg ranged across short-term studies as follows: 2.0 to 6.5 for HDL-C, -0.9 to 
10.6 for LDL-C, and -10.8 to 1.4 for TG. 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
21
1.1.2.4
Effect on uric acid and inflammatory markers
Uric acid has been implicated as a cardiovascular risk marker (Heinig M et al 2006). Uric acid 
concentrations decreased in all dapagliflozin groups; placebo-corrected mean reductions ranged 
from -0.45 to -0.8 mg/dL (-26.77 to -47.58 μmol/L) and in the initial combination therapy 
studies, mean reductions were -0.75 and -0.72 mg/dL (-44.61 to -42.83 μmol/L). Mean baseline 
uric acid concentrations in all groups were approximately 5 mg/dL. 
No consistent pattern was seen for other inflammatory biomarkers including high sensitivity C-
reactive protein (hsCRP), plasminogen activator inhibitor-1 (PAI-1), and fibrinogen.
1.2
Research hypothesis
The goal of this study is to determine the effect of dapagliflozin on CV outcomes relative to 
placebo. As discussed in Section 3.2, hypothesis-generating data derived from a meta-analysis of 
the Ph2b and 3 adjudicated MACE and hospitalization for heart failure suggests a possible 
favorable effect of dapagliflozin on CV risk.
1.3
Rationale for conducting this study
CV disease is the major cause of mortality and an important cause of morbidity in patients with 
T2DM. While epidemiological data suggest that poor glycemic control is linked to an increased 
CV risk, so far, clinical trials have failed to definitively demonstrate that glucose lowering 
reduces this risk. Data from several large outcome studies demonstrated no significant reduction 
in CV risk with intensive glycemic control (Duckworth et al 2009, Skyler et al 2009, ACCORD 
Study Group 2008). Furthermore, the Action to Control Cardiovascular Risk in Diabetes 
(ACCORD) study showed increased mortality in patients receiving intensive glycemic control 
with a target HbA1c of <6% (Skyler et al 2009, ACCORD Study Group 2008). Thus, an anti-
diabetes therapy that provides reduced CV risk in addition to glucose lowering properties may be 
of great importance to clinical care of patients with T2DM. Preliminary, hypothesis-generating 
data from the Phase 2b and 3 program as well as the beneficial effects of dapagliflozin on CV 
risk factors (i.e., body weight, visceral adiposity, blood pressure) as described above in Section 
1.1.2 suggest that dapagliflozin may have a CV protective effect. The purpose of this Phase 3b 
clinical study is to determine the effect that dapagliflozin has on the incidence of the composite 
endpoints MACE (CV death, MI, and ischemic stroke) and the composite of CV death or
hospitalization for heart failure in patients with T2DM compared to placebo.
1.4
Benefit/risk and ethical assessment
For an overall risk/benefit assessment of dapagliflozin, see the Investigator’s Brochure/package 
leaflet.
The results from the completed and ongoing studies in the dapagliflozin Phase 2b/3 program in 
over 6,000 patients combined with the results from clinical pharmacology studies support the 
oral dose of dapagliflozin 10 mg once daily in a wide range of patients with T2DM, as either 
monotherapy, or add-on combination therapy with metformin, a sulphonylurea, Dipeptidyl 
peptidase-4 (DPP4) inhibitor or insulin.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
22
At the time of writing this clinical study protocol no available anti-diabetes agents are indicated 
for CV risk reduction in patients with T2DM. The Phase 2b/3 program has not only established 
the efficacy and safety of dapagliflozin in lowering glucose concentrations (as assessed by 
HbA1c) but also provided hypothesis-generating data suggesting lower incidence of MACE with 
dapagliflozin treatment. This clinical study will test this hypothesis in a rigorous fashion. The 
potential results of such a study may offer substantial benefit to patients with T2DM.
2.
STUDY OBJECTIVES
2.1
Primary objective
The primary objective is to determine the effect of dapagliflozin relative to placebo on 
cardiovascular outcomes when added to current background therapy in patients with type 2 
diabetes mellitus (T2DM) with either established cardiovascular disease or at least two 
cardiovascular risk factors.
This objective will be evaluated in two steps. The first step will determine if dapagliflozin is 
non-inferior to placebo for the incidence of the composite endpoint of cardiovascular death, 
myocardial infarction (MI), or ischemic stroke assessed with a non-inferiority margin of 1.3. If 
this is met the second step will determine if dapagliflozin reduces the incidence of the 
co-primary endpoints: the composite of cardiovascular death, myocardial infarction (MI), or 
ischemic stroke and the composite of hospitalization for heart failure or CV death compared to 
placebo.
2.2
Secondary objectives
The secondary objective is to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM with either 
established cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM 
will result in a reduction of: 
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60 
ml/min/1.73m2 and/or ESRD (dialysis ≥90 days or kidney transplantation, confirmed 
sustained eGFR <15ml/min/1.73m2) and/or renal or CV death
!
All-cause mortality
2.3
Safety objectives
Safety and tolerability will be assessed from overall adverse events, serious adverse events, 
adverse events of special interest and laboratory test results. The assessment will include an 
evaluation of the incidence of adjudicated bladder cancer and liver injury.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
23
2.4
Exploratory objectives 
Other efficacy objectives are to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM and either established 
cardiovascular disease or at least two cardiovascular risk factors in addition to T2DM will result 
in a reduction of:
!
The individual components of the co-primary efficacy endpoints (cardiovascular 
death, MI, ischemic stroke or hospitalization for heart failure)
!
The composite endpoint of cardiovascular death, MI, ischemic stroke, hospitalization 
for heart failure, hospitalization for unstable angina pectoris, or hospitalization for 
coronary or non-coronary revascularization and the additional individual components 
of hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization
!
HbA1c
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for any of the following: An increase in dose for an oral anti-diabetes 
medication, a ≥ 25% increase in insulin dose, or the addition  of new anti-diabetes 
medication for > 3 months 
!
Major hypoglycemia and/or hospitalization for hypoglycaemia
!
Development of macrolbuminuria 
!
Development of albuminuria
!
Albuminuria
!
Decrease in eGFR
!
Albumin to Creatinine ratio
!
Body weight
!
Retinal laser and/or intraocular treatment due to development of and/or deterioration in 
diabetic retinopathy
!
Blood pressure 
!
Peripheral revascularization/limb ischemic event
!
Surgical amputation and related events 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
24
!
Any stroke (ischemic, hemorrhagic, or undetermined)
 
 
 
.
3.
STUDY PLAN AND PROCEDURES
This Clinical Study Protocol has been subject to a peer review according to AstraZeneca (AZ) 
and Bristol-Myers Squibb (BMS) standard procedures.
3.1
Overall study design and flow chart
This is a multicenter, randomized, double-blind, placebo-controlled Phase 3b study to determine 
the effect of dapagliflozin relative to placebo on MACE and the composite of CV death or
hospitalization for heart failure in patients with T2DM and with either known cardiovascular 
disease or at least two risk factors for cardiovascular disease in addition to T2DM. It is estimated 
that approximately 27000 patients will be enrolled to reach the target of 17150 randomized 
patients. The anticipated duration of the study is approximately 6 years, including an anticipated 
enrollment period of 3 years and a median follow-up period of 4.5 years. Closeout of the trial 
will commence when a predetermined number of adjudicated CV events required to test the 
study hypothesis is reached. 
All patients should be treated according to regional standards of care for diabetes (HbA1c goals) 
and other cardiovascular risk factors (e.g., hypertension, hyperlipidemia).
The study will recruit T2DM patients at increased risk for CV events according to the two 
categories below:
!
Patients with established CV disease (secondary prevention)
!
Patients with at least 2 CV risk factors, but without established CV disease (primary 
prevention)
Approximately 17150 patients meeting all eligibility criteria at approximately 1200 study sites 
will be randomized (1:1) to receive either dapagliflozin or placebo. 
Enrollment of patients based on disease state, geographic region, and gender will be monitored 
and may be capped to ensure adequate representation.
All potentially eligible patients will undergo an enrollment visit. Each patient will sign an 
Informed Consent Form (ICF) prior to having any enrollment evaluations performed. Patients 
who fulfill all eligibility requirements will enter into a 4 to 8 week placebo run-in period during 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
25
which they will be given placebo in a single-blind fashion (blind to patient only) and assessed for 
compliance (80 to 120%, unless a reason for non-compliance is judged acceptable by the 
Investigator). 
Approximately 4 to 8 weeks after entering the run-in period, based upon Investigator discretion, 
patients will be expected to undergo a randomization visit. Patients may withdraw prior to the 
randomization visit, or be withdrawn by study staff for any reason. At this visit patients will be 
re-evaluated by study staff to determine if after testing performed at enrollment, after assessment 
of compliance, and any clinical changes that may have occurred during the run-in period, the 
patient remains eligible and committed to participation in the study. If for any reason, prior to or 
during the randomization visit the patient is no longer eligible or interested in participating in the 
trial, he or she will be considered a run-in failure, will not be randomized and will not have 
additional follow up. 
If a patient is committed to participation, completes placebo run-in period and continues to meet 
criteria at the randomization visit, he or she will be randomized and will receive either 
dapagliflozin 10 mg daily or matching placebo in a double-blind fashion.
During the randomized treatment period, diet and life-style modification will continue to be 
reinforced.
An independent Data Monitoring Committee (DMC), a blinded independent Clinical Event 
adjudication Committee (CEC) (see Section 12.4) and Executive and Steering Committees (see 
Section 12.5) will be selected by the Sponsors and the academic leadership.
The study plan, including enrollment, randomization and follow-up visits, is outlined in Table 1. 
If the study would need to be prolonged to accrue the predetermined number of the primary 
endpoint events (1390), visits and assessments will be added according to the same schedule as 
described in the study plan (Table 1).
Patients will return every 6 months for assessment of events related to the objectives of the 
study, tolerability and safety. Assessment of treatment compliance and provision of IP will be 
done at these 6-month visits. In addition, phone contacts will be performed at a 3-month interval 
in between regular visits. Patients have the option to visit the center at these 3-month time points 
if desired; however, this is not required. If a patient prematurely discontinues IP, an End of 
Treatment (EoT) visit will be completed, with the patient continuing in the study for follow-up. 
Following the decision of the Executive Committee to close the trial, all Investigators will 
receive communication to complete a Closing Visit for both patients still being treated with 
investigational product (IP) and patients who have prematurely discontinued IP. The latter 
patients should have completed the EoT visit in connection with the discontinuation of IP and 
subsequently attended the scheduled visits to capture any adverse events (AEs), suspected CV 
events, body weight and anti-diabetes medication. Refer to Section 5.8 for details on procedures 
for discontinuing patients from IP.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
26
The Investigator/qualified designee will arrange for the Closing Visit as soon as possible after 
the date estimated by the Executive Committee as the end-of-study date. Patients who have a 
regularly scheduled visit (according to Table 1) within approximately 8 weeks after the end of 
study date can use the scheduled visit as the closing visit.
All randomized patients, whether taking randomized IP or not, should be followed up to the end 
of the study for vital status, CV events and occurrence of malignancies. Vital status based on 
publicly available sources and local data privacy laws/practices in cases where patients have 
withdrawn consent will also be investigated at the study end. It is recommended that anyone 
being followed by regular telephone contacts or a contact at study closure attend the final visit in 
person. The approach taken should be registered in the eCRF, and medical records.
Visit 1 Enrollment (within 4 to 8 weeks prior to randomization)
Potentially eligible patients will undergo an enrollment visit (which should occur 4 to 8 weeks 
prior to the anticipated date of randomization) and following their signed informed consent, 
inclusion/exclusion criteria will be reviewed. Demography (date of birth, gender, race and ethnic 
group), prior and concomitant medication and relevant medical history will be recorded. Patients 
will have their vital signs (pulse and BP), height and body weight recorded along with a blood 
sample for laboratory assessments of HbA1c, serum creatinine, TB, ALT, and AST . 
 
Women 
of childbearing potential (WOCBP) will be tested for pregnancy. 
Patients will be tested for hematuria at the enrollment visit using a dipstick at the site and an 
urinalysis using microscopy at the central laboratory. Patients with hematuria (confirmed by 
microscopy) in whom no immediate or benign cause for hematuria is identified as judged by the 
Investigator (e.g., menstruation, kidney stone, urinary tract infection [UTI] where hematuria is 
subsequently resolved after successful treatment), should be referred by the Investigator to their 
primary care physician to consider conducting an evaluation of the hematuria for the potential 
existence of bladder cancer as a reason for the hematuria. The evaluation should be performed as 
per local standard of care and/or professional society guidance (see Appendix G for AUA 
guidelines). Patients who are diagnosed with bladder cancer and patients with hematuria in 
whom an evaluation (as judged by the Investigator) did not exclude bladder cancer are not 
allowed to be randomized.
Placebo run-in period (within 4 to 8 weeks prior to randomization) 
Patients determined to be eligible for the study will be entered into a run-in period and will be 
given placebo to assess compliance. Patients also must adhere to reasonable placebo compliance 
in the run-in period in order to be randomized (80 – 120%, unless a reason for non-compliance is 
judged acceptable by the Investigator).
Diet and life-style advice will be reinforced.
If at any time during the run-in period, patients are determined to be non-compliant, develop a 
condition that would not meet entry criteria, laboratory assessment reveals exclusions, or the 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
27
patient chooses not to participate, the patient will be considered a run-in failure. If for any reason 
during the run-in period, the Investigator feels the patient is not likely to be compliant with study 
therapy and procedures the patient should be considered a run-in failure and not randomized. The 
Investigator should document the reason for run-in failure. 
Visit 2 Randomization
Patients who meet all inclusion criteria and none of the exclusion criteria (described in Section 
4.1) and are not run-in failures for reasons listed above will be randomized into the study at Visit 
2. This visit should occur 4-8 weeks after the enrollment visit.
Patients will have the following evaluations performed: concomitant medication and additional 
medical history will be recorded and patients will be asked about any AEs that may have 
occurred since the previous visit. Patients will be asked whether they have undergone any 
urinary tract investigations since last visit. If a urinary tract investigation has been performed it 
should be recorded in the eCRF (for instructions on recording of AE’s see section 6.4.4.) A 
physical exam will be performed. Vital signs (pulse and BP), body weight and waist and hip 
circumference will be recorded. WOCBP will be tested for pregnancy. Diet and life-style advice 
will be reinforced.
Run in medication will be returned and compliance assessed. Blood sample for laboratory 
measurements of CBC, serum creatinine, TB, ALT, AST, ALP, fasting serum glucose and lipids 
(LDL-Cholesterol, HDL Cholesterol, Triglyceride, Total Cholesterol), uric acid and electrolytes 
(sodium, potassium, chloride, bicarbonate, calcium, phosphorus and magnesium) will be 
obtained and sent to the central laboratory. A Urine sample for urinalysis including microscopy 
and urine albumin to creatinine ratio will be obtained and sent to the central laboratory. 
Biomarker 
 samples will be obtained where applicable.
Patients will be tested for hematuria using urine dipstick at the site. Patients who meet all 
criteria, but have a urine dipstick result indicative (positive or trace) of hematuria at 
randomization may be randomized into the study. If hematuria is confirmed by microscopy at the 
central laboratory, and if no immediate or benign cause is identified as judged by the Investigator 
(e.g., menstruation, kidney stone, urinary tract infection [UTI] where hematuria is subsequently 
resolved after successful treatment), patients should undergo evaluation by the investigator or 
another qualified professional. The evaluation may include but is not limited to tests such as 
urine cytology, NMP-22 or abdominal CT scans. The choice of tests should be per local standard 
of care and/or professional society guidance (see Appendix G for AUA guidelines). 
Patients meeting all inclusion criteria and none of the exclusion criteria will be randomized in a 
1:1 ratio to receive either 10 mg per day dapagliflozin or matching placebo Randomization will 
be stratified by CV risk category (established CV disease; multiple risk factors without 
established CV disease) and baseline hematuria status. Refer to section 5.2.1. 


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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Telephone contacts/visits 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 (months 3, 9, 15, 21, 27, 33, 
39, 45, 51, 57, 63 and 69)
The patients will be contacted every 3 months between regular site visits by the 
Investigator/study site personnel to record any AEs, suspected CV events, IP status and use of 
concomitant medication. Patients will be asked whether they have undergone any urinary tract 
investigations since the last visit. If a urinary tract investigation has been performed it should be 
recorded in the eCRF. Patients have the option to visit the center at these time points if desired; 
however, this is not required. An unscheduled visit may be conducted as a result of the phone 
contact (e.g., to follow-up on suspected CV events).
Visits 4, 8, 12, 16, 20 and 24 (months 6, 18, 30, 42, 54 and 66)
Suspected CV events and AEs will be recorded and reported in accordance with the Event 
Reporting Manual. Patients will be asked whether they have undergone any urinary tract 
investigations since the last visit. If a urinary tract investigation has been performed it should be 
recorded in the eCRF. WOCBP will be tested for pregnancy. Vital signs (pulse and BP) and body 
weight will be taken. An optional physical examination may be performed to evaluate an AE or 
as judged by the Investigator. IP will be returned and compliance assessed and new bottles of IP 
will be dispensed via the Interactive voice response system/Interactive web response system 
(IVRS/IWRS). Concomitant medication will be recorded and diet and life-style advice will be 
reinforced. 
At Visit 4 only, a blood sample for laboratory measurements HbA1c, serum creatinine, TB, 
ALT, AST, fasting serum glucose and lipids (LDL-Cholesterol, HDL-Cholesterol, Triglyceride, 
Total Cholesterol) will be obtained and sent to the central laboratory. Biomarker sampling will 
be obtained at Visit 4 where applicable. Urinalysis including microscopy and urine albumin to 
creatinine ratio will be obtained and sent to the central laboratory.
Visits 6, 10, 14, 18 and 22 (months 12, 24, 36, 48 and 60)
Suspected CV events and AEs will be recorded and reported in accordance with the Event 
Reporting Manual. Patients will be asked whether they have undergone any urinary tract 
investigations since the last visit. If a urinary tract investigation has been performed it should be 
recorded in the eCRF. An optional physical examination may be performed to evaluate an AE or 
as judged by the Investigator. Vital signs (pulse and BP), body weight, as well as blood sampling 
for laboratory assessments of HbA1c, CBC, fasting serum glucose and lipids (LDL-Cholesterol, 
HDL Cholesterol, Triglyceride, Total Cholesterol), serum creatinine, TB, ALT, AST, uric acid 
and ALP will be done. WOCBP will be tested for pregnancy. IP will be returned and compliance 
assessed and new bottles of IP via the IVRS/IWRS will be dispensed. Concomitant medication 
will be recorded. Urinalysis including microscopy and urine albumin to creatinine ratio will be 
completed. Diet and life-style advice will be reinforced. 


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
29
End of Treatment Visit (completed for patients who prematurely discontinue IP)
Patients who prematurely discontinue IP will have a full assessment completed at time of 
discontinuation. Suspected CV events and AEs will be recorded and reported in accordance with 
the Event Reporting Manual. Patients will be asked whether they have undergone any urinary 
tract investigations since the last visit. If a urinary tract investigation has been performed it 
should be recorded in the eCRF. A physical examination will be performed. Vital signs (pulse 
and BP), body weight measurement, as well as blood sampling for laboratory assessments of 
HbA1c, CBC, fasting serum glucose and lipids (LDL-Cholesterol, HDL Cholesterol, 
Triglyceride, Total Cholesterol), serum creatinine, TB, ALT, AST, ALP, uric acid and 
electrolytes (sodium, potassium, chloride, bicarbonate, calcium, phosphorus and magnesium) 
will be done. For patients who are discontinued before Visit 4, a sample for biomarker analysis 
should be obtained.
WOCBP will be tested for pregnancy. IP will be returned and compliance assessed. Concomitant 
medication will be recorded. Urinalysis including microscopy and urine albumin to creatinine 
ratio will be completed. Diet and life-style advice will be reinforced. 
End of treatment is not indicative of end of follow up and is not the same as withdrawn consent. 
Following the End of Treatment visit, patients who prematurely discontinued IP are expected to 
continue the regularly scheduled study visits as planned. All efforts must be made to maintain 
follow up according to the original visit schedule, ideally with in-person visits. If that is not 
possible, regular telephone follow-up should be performed according to the original visit 
schedule. AEs, suspected CV events, body weight and anti-diabetes medications will be recorded 
at these visits. AEs will be followed up (see Section 6.4.4). Lab assessment could be performed 
at all onsite visits also after End of Treatment as described for the scheduled study visits based 
on investigator judgment. All patients that discontinued IP due to predefined liver or renal 
criteria need to be monitored until abnormalities stabilize and the patient is asymptomatic (see 
Appendix D). 
All efforts should be made to obtain all relevant information, including information on 
malignancies. Where permissible by local law, the informed consent forms will include language 
to grant the option to employ outside companies to assist in ascertainment of the vital status of 
lost patients using publicly available source.
Closing Visit (completed for all patients at the end of the study)
The Closing Visit should occur within approximately 8 weeks following the closing date as 
declared by the Executive Committee. 
1. Patients still on randomized IP at the time of Closing Visit - For patients currently on 
randomized IP, a full assessment should be completed at the Closing Visit as described in 
Table 1. They comprise the following: recording of suspected CV events and AEs will be 
recorded and reported in accordance with the Event Reporting Manual. Patients will be 
asked whether they have undergone any urinary tract investigations since the last visit. If 
a urinary tract investigation has been performed it should be recorded in the eCRF. A 


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
30
physical examination, vital signs (pulse and BP), body weight measurement, as well as 
blood sampling for laboratory assessments of HbA1c, CBC, fasting serum glucose and 
lipids (LDL-Cholesterol, HDL Cholesterol, Triglyceride, Total Cholesterol), serum 
creatinine, TB, ALT, AST, ALP, uric acid and electrolytes (sodium, potassium, chloride, 
bicarbonate, calcium, phosphorus and magnesium) will be done. Urinalysis including 
microscopy and urine albumin to creatinine ratio, pregnancy testing of WOCBP, 
recording of concomitant medication, and return of IP, including compliance assessment, 
will be done.
2. Patients who prematurely discontinued from randomized IP (have already 
completed full assessment at EoT visit) – For patients who prematurely discontinued 
randomized IP and completed the End of Treatment visit as described in Table 1, the 
modified Closing Visit will be completed and will comprise the following: recording of 
suspected CV events and AEs, body weight and anti-diabetes medications, ideally with 
an in-person visit. Patients will be asked whether they have undergone any urinary tract 
investigations since the last visit. If a urinary tract investigation has been performed it 
should be recorded in the eCRF. All efforts should be made to obtain all relevant 
information, including information on malignancies outcomes, taking into account locally 
applicable privacy laws. Where permissible by local law, the informed consent forms 
may include language to grant the option to employ outside companies to track down 
updated contact information or vital status of lost patients using publicly available source.
1. Suspected CV events include all fatal events and all events comprised by the primary 
objective and the secondary objective (see Sections 2.1 and 2.2).
Unscheduled visits
Unscheduled visits or phone contacts may be performed for safety laboratory follow-up (see 
Section 6.4.6), or event follow-up in case of early discontinuation of IP. Phone contacts or 
unscheduled visits can also be done any time during the study at the discretion of the 
Investigator.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
31
Figure 1
Study flow chart
E = Enrollment, R = Randomization, EoT = End of Treatment
1
Documented phone calls with each patient will be performed at a 3-month interval in between regular visits (i.e., 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23,
25). This visit has an option to be a center visit if patient requests
2
The study is CV-event driven with an anticipated total duration of 6 years, including an enrollment period of 3 years and follow-up period of 3 to 6 
years. If study duration is reduced or extended, visits will be withdrawn or added as required every 3 months until the study is closed.
-1 to -2 
24
Visit
1
1
2
10
Placebo
Month 
3
6
9
12
15
18
21
//
3
4
5
6
7
8
9
Added to current background therapy
Added to current background therapy
R 
722
EoT/Closing visit
Dapagliflozin 10 mg od
Placebo 
Run-in
Placebo 
Run-in
E 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
32
Table 1
Study Plan
Activity
Enrollment
Randomization
Year 1
Year 2+l
Visit numbera,b,c,d
1
2
3
phone 
contact
4
5
phone 
contact
6
7 
phone 
contact
8
9 
phone 
contact
10
EoT/ 
Closing 
visit
Study month
Week –4 to –8
Day 1
3
6
9
12
15
18
21
24
72
Informed consent
X
Demography and relevant 
history (including smoking 
status)
X
Additional medical history
X
Inclusion/exclusion criteria
X
X
Randomization
X
Physical examinatione
X
X
Vital signs (BP, pulse and 
body weight)f
X
X
X
X
X
X
X
Waist and Hip 
circumference
X
Height
X
Concomitant medicationg
X
X
X
X
X
X
X
X
X
X
X
Pregnancy testingh
X
X
X
X
X
X
X


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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Activity
Enrollment
Randomization
Year 1
Year 2+l
Visit numbera,b,c,d
1
2
3
phone 
contact
4
5
phone 
contact
6
7 
phone 
contact
8
9 
phone 
contact
10
EoT/ 
Closing 
visit
Study month
Week –4 to –8
Day 1
3
6
9
12
15
18
21
24
72
Non fasting Laboratory 
assessments i
X
Fasting Laboratory 
assessmentsj
X
X
X
X
X
Urine dipstick (for 
hematuria)
X
X
Urinalysis with microscopy
X
X
X
X
X
X
 
 
 
 
Sample for biomarker 
research where applicablek
X
X
Adverse events and CV 
events m
X
X
X
X
X
X
X
X
X
X
X
Recording of Urinary Tract 
Investigations
X
X
X
X
X
X
X
X
X
X


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
34
Activity
Enrollment
Randomization
Year 1
Year 2+l
Visit numbera,b,c,d
1
2
3
phone 
contact
4
5
phone 
contact
6
7 
phone 
contact
8
9 
phone 
contact
10
EoT/ 
Closing 
visit
Study month
Week –4 to –8
Day 1
3
6
9
12
15
18
21
24
72
Dispense pre-randomization 
placebo through 
IVRS/IWRS
X
Dispense investigational 
product through 
IVRS/IWRS
X
X
X
X
X
IP compliance
X
X
X
X
X
X
X
X
X
X
Diet and lifestyle advice
X
X
X
X
X
X
X
a
Documented phone calls with each patient will be performed at a 3-month interval in between regular visits to follow up on events, concomitant 
medication and adherence to treatment. This visit has an option to be a center visit if patient requests.
b
Unscheduled visits may be done for safety lab follow-up, event follow-up or in case of early discontinuation of IP.
c
Visits will be repeated every 6 months and also phone calls every 3 months, according to the previous pattern until the Closing Visit as required. If the 
study needs to be prolonged to accrue the number of required primary endpoint events, visits would be added, i.e. assessments according to Year 2 may be 
repeated
d
At the close of the study all patients will return for the Closing Visit. Patients who prematurely discontinued IP will come in for an EoT visit at the time of 
their discontinuation from IP. Subsequently, these patients need only be assessed for AEs, CV events, body weight and anti-diabetes medications at 
follow-up visits and a final closing visit at the close of the study.
e
Physical exam according to Section 6.4.7 at randomization and EoT/Closing visit. An optional physical examination may be performed at any other in-
office visit to evaluate an AE or as judged by the Investigator.
f 
For patients who prematurely discontinued from randomized IP and have already completed full assessment at EOT visit only Body weight needs to be 
performed at the closing visit
g
Concomitant medications will be recorded according to Section 5.6
h
Women of child bearing potential.
i
j
Laboratory assessments will be done at a central laboratory, details on each visit see 3.1. Electrolytes to be obtained at V2 and EoT/Closing visit


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
35
k
ICF for biomarker sample is an addendum to the main ICF. For patient who is discontinued before Visit 4 , a biomarker sample should be drawn at the 
End of Treatment visit.
l
Assessment and procedure schedule for Year 3 onwards will be the same as for Year 2 until the Closing visit
m
To be recorded also for patients who prematurely discontinued IP, includes all AEs and all events comprised by the primary objective and the secondary 
objective. Please see section 6.4.4. Only events that fall into the following categories are collected in this study: serious AEs (as defined in 6.4.3), AEs 
leading to discontinuation of IP, suspected CV events and AEs of special interest. AEs of special interest in this study fall into the following categories: 
suspect neoplasm (benign, malignant or unspecified), hepatic events, hypoglycemic events that are major (as defined in 6.4.4.5), fractures, renal events, 
symptoms of volume depletion, hypersensitivity reactions (serious or lead to discontinuation of IP), urinary tract infections (serious or lead to 
discontinuation of IP) and genital infections (serious or lead to discontinuation of IP).


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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A description of the visit structure including the window for completion of the 
planned visits is depicted in Table 2.
Table 2                  Visit design and visit windows
Visit ID
Visit description
Visit window
Visit 1
Enrollment/ Placebo Run-In Period
4 weeks minimum – 8 weeks (+ 14 
days) maximum 
Visit 2
Randomization
Day 1 
Visit 3 
Telephone contact
3 months (±14 days) after Visit 2
Visit 4
Treatment
6 months (±14 days) after Visit 2
Visit 5
Telephone contact
9 months (±14 days) after Visit 2
Visit 6
Treatment
12 months (±14 days) after Visit 2
Visit 7
Telephone contact
15 months (±14 days) after Visit 2
Visit 8
Treatment
18 months (±14 days) after Visit 2
Visit 9
Telephone contact
21 months (±14 days) after Visit 2
Visit 10
Treatment
24 months (±14 days) after Visit 2
Visit Xa
Telephone contact
XX months (±14 days) after Visit 2
Visit Xa
Treatment
XX months (±14 days) after Visit 2
End of Treatmentb
Once patient prematurely 
discontinues IP
Closing Visit
Within approximately 8 weeks of 
the study closing date
a
Visits will be repeated according to the previous pattern until the Closing visit as required. 
b
EoT assessments will be done at a planned or unscheduled visit when a patient is prematurely discontinuing 
randomized treatment.
3.2
Rationale for study design, doses and control groups
The aims of the study are to definitively exclude unacceptable CV risk with dapagliflozin 
treatment and to test the hypothesis that treatment with dapagliflozin reduces CV events in 
high-risk patients. As described above, a meta-analysis of 145 adjudicated CV events from the 
comprehensive Phase 2b and 3 clinical program resulted in an estimate for the hazard ratio for 
dapagliflozin versus comparator for the primary composite endpoint of adjudicated CV death, 
myocardial infarction, stroke or hospitalization for unstable angina of 0.819 (95% CI: 0.583, 
1.152), and thus supports testing the hypothesis. Currently, there is no clearly established risk 
benchmark for approved anti-diabetes agents in terms of CV events, and, therefore, placebo is 
the appropriate comparator in this study. The patient population of T2DM at higher risk for 
CV events is appropriate as this population may benefit the most from a treatment that, in 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
37
addition to glucose lowering may also reduce CV risk. A composite assessment that includes 
CV death, MI or ischemic stroke, is the most rigorous way to assess CV effects of any given 
treatment. The study will be double-blind, single-dummy, to minimize the risk of bias.
4.
PATIENT SELECTION CRITERIA
Investigator(s) should keep a record of patients who were considered for participation.
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.
4.1
Inclusion criteria
Patients should meet all inclusion criteria at the time of randomization. If at the time of 
enrollment it is known that the patient will not meet criteria after a successful run-in period 
they should not be entered into run in.
For inclusion in the study patients should fulfill the following criteria:
1. Provision of informed consent prior to any study specific procedures (including run-in) 
2. Female or male aged ≥ 40 years
3. Diagnosed with T2DM (See Appendix E for details)
4. High Risk for CV event defined as having either established CV disease and/or 
multiple risk factors:
-
Established CV Disease (See Appendix E for details)
OR
No known cardiovascular disease AND at least two cardiovascular risk factors in addition to 
T2DM, defined as:
-
Age > 55 years in men and > 60 in women
AND presence of at least 1 of the following additional risk factors (see Appendix E for details)
-
Dyslipidemia 
-
Hypertension
-
Current Tobacco use
5. WOCBP must take precautions to avoid pregnancy throughout the study and for 4 
weeks after intake of the last dose. 
-
WOCBP must have a negative urine pregnancy test. WOCBP include any female who has 
experienced menarche and who has not undergone successful surgical sterilization 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
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(hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not 
postmenopausal.
-
WOCBP must be willing to use a medically accepted method of contraception that is 
considered reliable in the judgment of the Investigator.
 
4.2
Exclusion criteria
Patients should not meet any exclusion criteria at the time of randomization. If at the time of 
enrollment, it is known that the patient will not meet criteria after a successful run-in period 
he/she should not be entered into run in.
1. Use of the following excluded medications:
-
Current or recent (within 24 months) treatment with pioglitazone and/or use of 
pioglitazone for a total of 2 yearsor more during lifetime 
-
Current or recent (within 12 months) treatment with rosiglitazone
-
Previous treatment with any SGLT2 inhibitor
-
Any patient currently receiving chronic (>30 consecutive days) treatment with an oral 
steroid at a dose equivalent to oral prednisolone ≥10 mg (e.g., betamethasone ≥1.2 mg, 
dexamethasone ≥1.5 mg, hydrocortisone ≥40 mg) per day
2. Acute cardiovascular event[e.g., acute coronary syndrome (ACS), transient ischemic 
attack (TIA), stroke, any revascularization, decompensated HF, sustained ventricular 
tachycardia <8 weeks prior to randomization. Patients with acute cardiovascular events 
can be enrolled in the run-in period as long as randomization does not occur within 8 
weeks of the event. 
3. Systolic BP >180 or diastolic BP >100 mmHg at randomization. Patient should be 
excluded if either the systolic BP is elevated (> 180 mmHg) or the diastolic BP is 
elevated (> 100 mmHg) on both measurements (see section 6.4.8.1) 
4. Diagnosis of Type 1 diabetes mellitus, MODY, or secondary diabetes mellitus
5. History of bladder cancer or history of radiation therapy to the lower abdomen or 
pelvis at any time
6. History of any other malignancy within 5 years (with the exception of successfully 
treated non-melanoma skin cancers)
7. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year) 
8. Any conditions that, in the opinion of the Investigator, may render the patient unable 
to complete the study including but not limited to cardiovascular (NYHA class IV 
CHF, recurrent ventricular arrhythmias) or non-cardiovascular disease (e.g., active 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
39
malignancy with the exception of basal cell carcinoma, cirrhosis, chronic lung disease, 
severe autoimmune disease) and/or a likely fatal outcome within 5 years
9. Pregnant or breast-feeding patients 
10. Involvement in the planning and/or conduct of the study or other dapagliflozin studies 
(applies to AZ, BMS, Hadassah and Thrombolysis in Myocardial Infarction [TIMI] or 
representative staff and/or staff at the study site)
11. Previous enrollment or randomization in the present study
12. Active participation in another clinical study with IP and/or investigational device
13. Individuals at risk for poor protocol or medication compliance during run-in period 
(reasonable compliance defined as 80 – 120%, unless a reason for non-compliance is 
judged acceptable by the Investigator). If for any reason, the Investigator believes that 
the patient will not tolerate or be compliant with IP or study procedures, the patient 
should not be randomized and considered a run-in failure.
Patients will be excluded during run-in and should not be randomized if the 
following are observed from laboratory or observation during enrollment and run-in 
assessments:
14. HbA1c ≥12% or HbA1c<6.5% from the central laboratory (nb, the proportion of 
subjects with an HbA1c between 6.5 % and < 7.0 % will be capped at approximately 5 
% of the study)
15. AST or ALT >3x ULN or Total bilirubin >2.5 x ULN
16. CrCl < 60 ml/min (based on the Cockroft-Gault equation)
17. Hematuria (confirmed by microscopy at Visit 1) with no explanation as judged by the 
Investigator up to randomization. If bladder cancer is identified, patients are not 
eligible to participate.
18. Any reason the Investigator believes the patient is not likely to be compliant with the 
study medication and protocol.
Procedures for withdrawal of incorrectly enrolled patients see Section 5.3.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
40
5.
STUDY CONDUCT
5.1
Restrictions during the study
There are no specific dietary or activity restrictions.
Restricted concomitant medications are listed in Section 5.6.1.
5.2
Patient enrollment and randomization and initiation of
investigational product
The Principal Investigator or delegate will: 
1. Obtain signed informed consent from the potential patient before any study specific 
procedures are performed.
2. Determine patient eligibility. See Sections 4.1 and 4.2
3. Assign potential patient a unique enrollment number via an IVRS/IWRS, consisting of 
country, study center and a patient specific number, beginning with ‘E’ on Visit 1.
4. Dispense placebo run-in treatment at enrollment to confirm compliance. Placebo run-
in period should be a minimum of 4 weeks before randomizing the patient.
5. Assign eligible patient unique randomization code (patient number) via an 
IVRS/IWRS on Visit 2.
Patients can only be randomized into the study once.
If a patient withdraws from participation in the study, then his/her enrollment/randomization 
code cannot be reused.
5.2.1
Procedures for randomization
To help identify non-adherent patients, the study includes a 4 to 8 week placebo run-in period 
(+ 14 days)starting at Visit 1. Randomization to IP will be done via an IVRS/IWRS at Visit 2 
in balanced blocks in order to ensure approximate balance between the two treatment arms 
(1:1). Randomization will be stratified by CV risk category (established CV disease; multiple 
risk factors without established CV disease) and baseline hematuria status. Approximately 
17150 patients will be randomized in this study. Enrollment of patients based on disease state, 
geographic region, and gender will be monitored and may be capped to ensure adequate 
representation. For example, recruitment will be monitored to randomize approximately 30% 
of patients each from North America and Europe.
The enrollment code (E-code) assigned at Visit 1 will be used to identify the patient 
throughout study participation. 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
41
The IVRS/IWRS will allocate the IP through the AZ prepared randomization scheme and 
provide the randomization number and the appropriate Kit IDs from IP available at the study 
center. Randomization numbers will be prepared by the global randomization administrator at 
AstraZeneca and made available for IVRS/IWRS use.
The randomization codes will be computer generated by AstraZeneca R&D or representative 
using AZ Global Randomization system (GRAND) using balanced blocks and allowing an 
approximately equal number of patients per treatment group within each country. The 
randomization codes will be loaded into the IVRS/IWRS database. 
Detailed instruction on use of the IVRS/IWRS system will be provided to the Investigational 
sites.
5.3
Procedures for handling patients incorrectly enrolled or
randomized or initiated on investigational product 
Patients who fail to meet the inclusion/exclusion criteria should not knowingly, under any 
circumstances, be randomized or receive IP. There can be no exceptions to this rule.
The following steps should be taken in the event that a patient who does not meet 
Inclusion/Exclusion criteria is found to have been inadvertently randomized. 
(a)
The Investigator or monitor should inform the TIMI Hotline Physician immediately. 
Ensuring patient safety must always be the number one priority.
(b)
If, after discussion between the TIMI Hotline Physician and the Investigator, it is 
judged that continued treatment would pose an undue safety risk to the patient, IP 
should be discontinued. The patient should remain in the study for follow-up in 
accordance with defined study procedures including follow-up of clinical outcomes.
(c)
In those cases where continuation on IP is judged to not pose a concern related to 
safety and disease management, IP should be continued and the rationale for 
allowing the patient to remain on IP must be clearly documented.
If a patient receives the incorrect randomized treatment at any time during the study, this must 
be corrected as soon as discovered. An unscheduled visit should be completed as soon as 
possible. The treatment should be corrected at that visit but in any event no later than the next 
scheduled visit. Until the treatment is corrected, the patient should discontinue the IP.
The TIMI Hotline is to ensure all such decisions are appropriately documented. 
All randomized patients are expected to continue in the study with regularly scheduled 
follow-up per Section 3.1, whether on or off IP.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
42
5.4
Blinding and procedures for unblinding the study 
5.4.1
Methods for ensuring blinding
The blinding is ensured by using double-blind, single-dummy technique. The active tablets 
and the respective placebo tablets will be identical in size, color, smell, and taste. The bottles 
with investigational products will be labeled with unique identification numbers allocated 
from the IVRS/IWRS.
No member of the study delivery team at AZ, BMS, Hadassah, TIMI, or personnel at study 
centers or any clinical research organization (CRO) handling data will have access to the 
randomization scheme during the conduct of the study, with the exception of the AZ personnel 
generating the randomization scheme as well as AZ Supply Chain Study Management 
(SCSM),  AZ Patient Safety Department and the CRO companies providing the IVRS/IWRS 
and carrying out the packaging and labeling of investigational products. The DMC will be 
provided with fully or partially unblinded data at regular intervals to fulfill their review 
commitment as specified in the DMC charter. 
5.4.2
Methods for unblinding patients treatment assignment
Unblinding can be carried out in emergencies by the Investigator(s) or pharmacists at the 
study center and the personnel who are independent of the study evaluation at AZ Patient 
Safety Department. The DMC will have access to the individual treatment codes and will be 
able to merge these with the collected study data while the study is ongoing (see Section 
12.4.2). 
Individual treatment codes, indicating the treatment randomization for each randomized 
patient, will be available to the Investigator(s) or pharmacists and to AZ Patient Safety 
Department from the IVRS/IWRS. Routines for this will be described in the IVRS/IWRS user 
manual that will be provided to each center.
The treatment code should not be broken except in medical emergencies when the appropriate 
management of the patient requires knowledge of the treatment assignment. In such an 
emergency, the Investigator will, if time and circumstances permit, contact the TIMI Hotline 
prior to breaking the treatment code. The Investigator documents and reports the action to the 
TIMI Hotline without revealing the treatment given to subject to the TIMI Hotline-
AZ Patient Safety Department retains the right to break the code for Serious Adverse Events 
(SAEs) that are unexpected and are suspected to be causally related to an investigational 
product 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.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
43
5.5
Treatments
5.5.1
Identity of investigational product(s)
Investigational product
Dosage form and strength
Manufacturer
Dapagliflozin 10 mg
Biconvex, diamond shape, 
green tablet 10 mg (Size: 11 
mm)
Bristol-Myers Squibb
Matching placebo for 
dapagliflozin 10 mg
Biconvex, diamond shape, 
green tablet 10 mg (Size: 11 
mm)
Bristol-Myers Squibb
Each bottle for placebo run-in contains 35 tablets. Each bottle for treatment contains 210 tablets (6 months 
treatment).
The formulation number and batch number will be recorded in the Study Master File and 
identified in the Clinical Study Report.
Dapagliflozin and its matching placebo tablets will be packed in bottles. The tablets may 
contain lactose, which may cause discomfort in lactose-intolerant individuals.
5.5.2
Doses and treatment regimens
Duration of dosing:
!
Dapagliflozin 10 mg tablets, administered orally once daily for a predicted median 
of 4.5 years and an anticipated total duration of a 6-year double-blind treatment 
period.
!
Matching placebo for dapagliflozin 10 mg administered orally once daily for the 4-8 
week placebo run-in period and for a predicted median of 4.5 years and an 
anticipated total duration of a 6-year double-blind treatment period.
The investigational product (IP) dapagliflozin or matching placebo will be taken orally. The 
IP should be taken once daily in the morning and at approximately the same time of the day 
during the study period. 
At the randomization visit, IP should be ingested during the patient visit after completing the 
BP measurements and all other visit procedures. 
5.5.3
Additional IP (Not applicable)
5.5.4
Labeling
Single panel labels or booklet labels will be prepared in accordance with Good Manufacturing 
Practice (GMP) and local regulatory guidelines. The labels will fulfill GMP Annex 13 
requirements for labeling. Label text will be translated into local language.


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5.5.5
Storage
All IPs should be kept in a secure place under appropriate storage conditions. The 
investigational product label on the bottle and the Investigator Brochure specify the 
appropriate storage conditions. 
5.6
Concomitant and post-study treatment(s)
Background medication and post-study treatment will not be provided by the Sponsor.
5.6.1
Prohibited medication
Treatment with pioglitazone, rosiglitazone, and any SGLT2 inhibitors other than IP is not 
permitted for the duration of the study.
5.6.2
Use with medications known to cause hypoglycemia
Insulin secretagogues, such as sulphonylureas, may cause hypoglycemia. Therefore, a lower 
dose of the insulin secretagogue or injectable insulin may be considered by the Investigator to 
reduce the risk of hypoglycemia when used in combination with study medication.
5.6.3
Anti-diabetes medication
Patients should be treated for diabetes with glycemic goals as recommended by the American 
Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) in 
their 2012 joint Position Statement (Inzucchi et al 2012). In brief, the ADA/EASD 
recommends lowering HbA1c to < 7.0% in most patients. Less stringent HbA1c goals, e.g. 7.5 
to 8% or even slightly higher may be appropriate for patients with a history of severe 
hypoglycemia, advance complications, extensive comorbid conditions and those in whom the 
target is difficult to attain despite intensive self-management education, repeated counseling, 
and effective doses of multiple glucose-lowering agents, including insulin. The proposed 
treatment algorithm recommends healthy eating, weight control, and increased physical 
activity; if drug therapy is required, metformin should be considered as initial therapy, and 
then additional drug classes may be added as outlined in Appendix F.
Patients are eligible for adjustments in their anti-diabetes treatment at the Investigator’s 
discretion and based on local treatment guidelines and best practices. This may include 
discontinuing or changing the dose(s) of concomitant anti-diabetes medication(s) as well as 
adding other anti-diabetes treatments. Regardless of the need for a change in a concomitant 
medication, patients will remain on the randomized IP unless they meet specific criteria for 
discontinuation of IP. 
Anti diabetic medication needs to be recorded in the appropriate sections of the eCRF. At visit 
2 (randomization) all antidiabetic medications (including dose changes) should be 
documented even if with a duration of < 3 months.


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Drug Substance Dapagliflozin  
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Edition Number 5.0
Date 25 Sep 2016
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5.6.4
Other medications
All patients should be treated according to regional standards of care for CV risk factors (e.g., 
blood pressure, lipids, antithrombotic treatment) and HbA1c. 
Other medication(s), which are considered necessary for the patient’s safety and well-being, 
may be given at the discretion of the Investigator. 
Concomitant medications need to be recorded  in the appropriate sections of the eCRF only if 
they are taken for a duration of > 3 months. At visit 2 (randomization) all antihypertensive 
medications should be documented even if with a duration of < 3 months.. 
In addition, all new or changed concomitant medications that the patient is treated with when 
an AE (as defined by the CSP section 6.4.4.) occur needs to be recorded on a specific eCRF 
page, regardless of the treatment duration. Note that this should also apply to concomitant 
medications which have been discontinued before the start of the AE, if judged as important 
by the investigator.. 
5.7
Treatment compliance
The administration of all medications (including IP) should be recorded in the appropriate 
sections of the eCRF, for all concomitant medication this is described in detail in section 5.6.3 
and 5.6.4.
Patients will be asked to return all unused IP and empty bottles to the site at each scheduled 
visit. Tablet counts will be recorded in the eCRF. Compliance will be discussed at each study 
visit and assessed based on returned IP as follows: the Investigator will make a subjective 
judgment of the compliance based on 2 categories (“reasonable”: ≤ 20% deviation from 
expected number of tablets; and “questionable”: >20% deviation). If compliance is 
“questionable”, the Investigator should counsel or instruct the patient on the importance of 
taking his/her IP as prescribed. Patients judged to have questionable compliance (defined as 
taking less than 80% or more than 120% of the prescribed dose of IP) will continue in the 
study, but should be counseled on the importance of taking their IP as prescribed. 
5.7.1
Accountability
The IP provided for this study will be used only as directed in the study protocol.
The study personnel will account for all IP dispensed to and returned from the patient.
AZ or its representative will oversee that study personnel account for IPs received at the study 
center, unused IP and IP for appropriate destruction. At the termination of the Clinical Study 
or at the request of AZ, the Investigator will either return any unused IP to AZ, or destroy 
investigational product at the site depending on local regulations. If the IP is destroyed at site, 
the site personnel will account for all unused IP and for appropriate destruction. If the IP is 
returned to AZ, the study site personnel or the AZ monitor will account for all received IP and 
return all unused IP to AZ. Certificates of delivery and return should be signed.


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
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5.8
Discontinuation of investigational product
Patients may be discontinued from IP in the following situations:
!
Patient decision. The patient is at any time free to discontinue IP, without prejudice to 
further treatment. Patients who choose to discontinue IP are expected to continue in 
the study until the closing of the study (see Section 5.8.1)
!
Safety reasons as judged by the Investigator, or by AZ and/or a representative.
Study-specific discontinuation criteria are listed below: 
!
Liver criteria:
∀
ALT and/or AST >3 times the upper limit of normal (ULN) and concomitant 
TB >2 times ULN confirmed at a repeated measurement at the central 
laboratory (which should be obtained within 3 days, whenever possible, 
following receipt of the initial laboratory results)
∀
ALT and/or AST >8 times ULN confirmed at a repeated measurement at the 
central laboratory (which should be obtained within 3 days, whenever possible, 
following receipt of the initial laboratory results)
∀
ALT and/or AST >5 times ULN confirmed at the central laboratory and 
sustained over a period of 14 days or more
(See Appendix D for further details)
!
Kidney criteria:
If at any time the patient´s CrCl (based on Cockroft-Gault) falls below 30 ml/min 
calculated at the central laboratory and confirmed at a repeated central laboratory 
measurement (to be obtained within 4 days, whenever possible), the patient should 
be discontinued from IP.
If at any time the patient´s CrCl (based on Cockroft-Gault) falls below 30 ml/min 
calculated at local laboratory, a central laboratory CrCl should be obtained 
promptly. If the CrCl is confirmed by the central laboratory and persists at a 
repeated central laboratory measurement (to be obtained within 4 days, whenever 
possible), the patient should be permanently discontinued from IP.
!
Bladder cancer:
∀
If at any time the patient is diagnosed with bladder cancer, the patient should 
be discontinued from IP.
!
Pregnancy:
∀
Pregnancy (discontinue IP and notify the TIMI Hotline), see Section 13.3.


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
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Temporary discontinuations for any reason and for any duration are allowed; if the 
Investigator judges that the potential benefit outweighs the risk in any patient who 
discontinued IP, administration of IP may be re-started. 
If during the placebo run-in period IP is discontinued, this would be considered a run-in 
failure and not study discontinuation. Such a patient would not be randomized into the study.
!
Cases where patients are incorrectly randomized (i.e., the patient does not meet the 
required inclusion/exclusion criteria for the study) should be discussed with the 
TIMI Hotline prior to any actions being taken (see Section 5.3).
!
Discontinuation of IP does not mean discontinuation of follow-up. Study 
assessments should be continued in all patients (see Section  5.8.1).
5.8.1
Procedures for discontinuation of a patient from investigational product 
A patient who decides, and/or is recommended by treating physician or the Investigator to 
permanently discontinue IP, will always be asked about the reason(s) and the presence of any 
AEs. All efforts must be taken to ensure that the patient will be seen and assessed by an 
Investigator, and as scheduled for other patients, complete all assessments of the EoT Visit. 
Following the EoT, regularly scheduled study visits are expected to continue as planned. AEs, 
suspected CV events, body weight and anti-diabetes medications will be recorded at the 
follow up visits (see Section 6.2). At the end of the study, the Closing Visit should preferably 
be an in-person visit to the site and should include collection of AEs, suspected CV events, 
body weight and anti-diabetes medications.
Alternatively, if the patient does not agree to this option, a modified follow up through regular 
telephone contacts or a contact at study closure should be arranged.
Whether a patient attends a visit or is contacted by telephone, once a possible event that may 
require adjudication is noted, medical records must be obtained and submitted to the CEC for 
adjudication of the event.
Restart of IP
Whenever possible, restart of IP should be encouraged. Even if an EoT visit was completed 
due to the discontinuation of IP, this should not prevent complete study follow-up procedures 
including restart of randomized treatment. All efforts must be taken to assure that the patient 
will be seen and assessed by an Investigator, and as scheduled for other patients. Patients 
fulfilling a study specific discontinuation criterion should never be restarted on IP.
Patients suspected of pregnancy will discontinue IP immediately. If it is confirmed by 
pregnancy test that there is no pregnancy, the IP can be restarted. (See Section 13.3).
If a patient is withdrawn from the study, see Section 5.9.


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
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5.9
Withdrawal from study
Patients are at any time free to completely withdraw from the study (which means permanent 
discontinuation of IP and all follow-up assessments) without prejudice to further treatment. 
Discontinuation of IP in itself is not considered withdrawal of consent. 
Withdrawal of consent should only occur if the patient refuses any further assessments or 
contact whatsoever. Patients who do not want regular in-person follow up after cessation of IP 
should be offered alternative methods of follow up including periodic telephone follow up, 
contact at study closure, or assessment of health status via treating physicians or medical 
records. Such patients would then not be viewed as withdrawal of consent. The Investigator 
must explain to the patient all options for continued participation, and document which 
options were refused by the patient and the reason for refusal. Withdrawal of consent must be 
ascertained and documented in writing by the Investigator who must inform the TIMI Hotline 
and document the withdrawal of consent in the eCRF and medical records. Patients will be 
asked about the reason(s) for withdrawal. Adverse events will be accessed (See Sections 6.4.4
and 6.4.5) and IP returned. For patients who withdraw from the study, direct ascertainment of 
health status at the end of the study or vital status via public records will be performed in 
compliance with local privacy laws/practices.
Withdrawn patients will not be replaced. 
5.10
Lost to follow up patients
To prevent patients being lost to follow-up, their contact details, including next of kin contacts 
should be collected initially and updated regularly by the site staff or representative. The 
Investigator should educate the patient on the importance of contact with the Investigator 
throughout the study. Repeated attempts will be made to locate and obtain pertinent medical 
information for patients who are initially lost to follow up. A patient will be classified as lost 
to follow up only if he/she has failed to return for the required study visits and his/her vital 
status remains unknown despite multiple attempts to contact him/her via telephone, fax, e-
mail, certified letter or through patient locator agencies (if allowed by national regulation). 
Where permissible by local law, the informed consent forms will include language to grant the 
option to employ outside companies to assist in obtaining updated contact information or 
ascertainment of vital status of lost patients using publicly available source.
6.
COLLECTION OF STUDY VARIABLES
6.1
Recording of data
A Web-Based Data Capture (WBDC) system will be used for data collection and query 
handling. The Investigator will ensure that data are recorded on the eCRF as specified in the 
study protocol and in accordance with the instructions provided.


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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 eCRF. A copy of the completed eCRF will be 
archived at the study site.
All suspected events included in the composite endpoint of CV death, MI, or ischemic stroke 
and secondary CV endpoints will be recorded in the respective appropriate modules of the 
eCRF. Investigators are also required to provide the CEC copies of source documents, e.g., 
medical records (discharge summary, death certificate, autopsy report, etc). Refer to the Event 
Reporting Manual for further details. 
6.2
Data collection at enrollment, randomization and follow-up
6.2.1
Enrollment procedures
The following data will be collected at enrollment (V1) and recorded in the appropriate 
sections of the eCRF (see Table 1). 
!
Date of signed informed consent
!
Inclusion and exclusion criteria
!
Demography: Date of birth, gender, race, and ethnic group
!
WOCBP must have a negative urine pregnancy test 
!
Blood sampling for laboratory assessments of HbA1c, serum creatinine (creatinine 
clearance will be based on the Cockroft-Gault equation), TB, ALT, AST, 
!
Urinalysis (including microscopy) 
!
Urine dipstick for assessment of hematuria
!
Medical history information including presence of T2DM, history of CV disease, 
CV risk factors, smoking status 
!
Vital signs (pulse and BP), height, and body weight
!
Prior and concomitant medication
!
Dispensing of IP for run-in period via an IVRS/IWRS
!
 


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Drug Substance Dapagliflozin  
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Edition Number 5.0
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6.2.2
Randomization
The following data will be collected at randomization (V2) and recorded in the appropriate 
sections of the eCRF (see Table 1)
!
Inclusion /exclusion criteria
!
Additional medical history including history of malignancies
!
Date of randomization
!
WOCBP must have a negative urine pregnancy test 
!
Recording of AEs 
!
Recording of Urinary Tract Investigations
!
Recording of concomitant medication
!
vital signs (pulse and BP), body weight and waist and hip circumference
!
Blood sampling for laboratory assessments of CBC, fasting serum glucose and 
lipids (LDL-Cholesterol, HDL-Cholesterol,Triglyceride, Total Cholesterol), serum 
creatinine (creatinine clearance will be based on the Cockroft-Gault equation), TB, 
ALT, AST, ALP, uric acid, electrolytes (sodium, potassium, chloride, bicarbonate, 
calcium, phosphorus and magnesium) 
!
Urinalysis (including microscopy and urine albumin to creatinine ratio)
!
Urine dipstick for assessment of hematuria. 
!
Dispensing of IP via an IVRS/IWRS
!
Blood sampling for biomarker 
, where applicable
6.2.3
Follow-up procedures
Patients on randomized treatment, also where IP was interrupted and restarted, should attend 
all remaining visits for assessments, procedures, and provision of IP (according to Table 1) 
until the end of the study.
Randomized patients who discontinue randomized IP prematurely should complete the 
procedures described for EoT Visit at the time of the discontinuation of IP. Following 
discontinuation of IP, these patients should attend the remaining study visits or will be 
contacted by phone to have AEs and suspected CV events recorded until the end of the study. 
The Closing Visit should preferably be a visit at the site.


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Edition Number 5.0
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The following assessments will be done at the follow-up visits: 
!
Telephone contact (or optional center visit) visits 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 
(months 3, 9, 15, 21, 27, 33, 39, 45, 51, 57, 63 and 69):
∀Recording of AEs 
∀Recording of CV events 
∀Recording of Urinary Tract Investigations
∀Recording of use of IP
∀Recording of concomitant medication
!
Visits 4, 8, 12, 16, 20 and 24 (months 6, 18, 30, 42, 54 and 66):
∀Recording of AEs 
∀Recording of CV events 
∀Recording of Urinary Tract Investigations
∀Vital signs: body weight, pulse and BP 
∀An optional physical examination may be performed to evaluate an AE or as 
judged by the Investigator.
∀Pregnancy test for WOCBP 
∀Return of IP and assessment of compliance
∀Dispensing of new IP
∀Recording of concomitant medication
∀Visit 4 only: 
∀
Blood sample for laboratory measurements of, HbA1c, serum creatinine 
(creatinine clearance will be based on the Cockroft-Gault equation), TB, ALT, 
AST, fasting serum glucose and lipids (LDL-Cholesterol, HDL Cholesterol, 
Triglyceride, Total Cholesterol)
∀
Sampling for biomarker research where applicable
∀
Urinalysis including microscopy and urine albumin to creatinine ratio
!
Visits 6, 10, 14, 18 and 22 (months 12, 24, 36, 48 and 60):
∀Recording of AEs 
∀Recording of CV events
∀Recording of Urinary Tract Investigations


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Drug Substance Dapagliflozin  
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Edition Number 5.0
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∀Pregnancy test for WOCBP 
∀Return of IP and assessment of compliance
∀Dispensing of new IP
∀Recording of concomitant medication
∀Blood sampling for assessments of HbA1c, CBC, fasting serum glucose and lipids 
(LDL-Cholesterol, HDL-Cholesterol,Triglyceride, Total Cholesterol), serum creatinine 
(creatinine clearance will be based on the Cockroft-Gault equation), TB, ALT, AST, 
ALP, uric acid 
∀Urinalysis including microscopy and urine albumin to creatinine ratio
∀Vital signs: body weight, pulse and BP
∀An optional physical examination may be performed to evaluate an AE or as 
judged by the Investigator. 
!
End of Treatment (for patients who prematurely discontinued from randomized IP):
∀Recording of AEs 
∀Recording of CV events 
∀Recording of Urinary Tract Investigations
∀Pregnancy test for WOCBP
∀Return of IP and assessment of compliance
∀Recording of concomitant medication
∀Blood sampling for laboratory assessments of HbA1c, CBC, fasting serum glucose 
and lipids (LDL-Cholesterol, HDL-Cholesterol,Triglyceride, Total Cholesterol) serum 
creatinine (creatinine clearance will be based on the Cockroft-Gault equation), TB, 
ALT, AST, ALP, uric acid, electrolytes (sodium, potassium, chloride, bicarbonate, 
calcium, phosphorous and magnesium), and urinalysis including microscopy and, 
urine albumin to creatinine ratio
∀For patient who is discontinued before Visit 4 a biomarker sample should be 
drawn.
∀Physical examination including vital signs: body weight, pulse and BP 
!
Closing Visit (completed for all patients at the end of the study, regardless of IP status)
∀
Patients still on randomized IP at the time of Closing Visit:
∀Recording of AEs 
∀Recording of CV events 
∀Recording of Urinary Tract Investigations
∀Pregnancy test for WOCBP


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∀Return of IP and assessment of compliance
∀Recording of concomitant medication
∀Blood sampling for laboratory assessments of HbA1c, CBC, fasting glucose 
and lipids (LDL-Cholesterol, HDL-Cholesterol,Triglyceride, Total Cholesterol),
serum creatinine (creatinine clearance will be based on the Cockroft-Gault 
equation), TB, ALT, AST, ALP, uric acid, electrolytes (sodium, potassium, 
chloride, bicarbonate, calcium, phosphorous and magnesium) and 
urinalysis including microscopy and urine albumin to creatinine ratio
∀Physical examination including vital signs: body weight, pulse and BP 
∀Patients who prematurely discontinued from IP (have already completed full 
assessment at EoT):
∀Recording of AEs 
∀Recording of CV events 
∀Recording of Urinary Tract Investigations
∀Body weight 
∀Recording of anti-diabetes medications
6.3
Efficacy 
6.3.1
Primary variable
The primary outcome variables of the study are the composite endpoint of cardiovascular 
death, myocardial infarction, or ischemic stroke (time to first event) and the composite 
endpoint of hospitalization for heart failure or CV death (time to first event). All components 
of these composites will be adjudicated.
6.3.2
Secondary variables
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR 
<60 ml/min/1.73m2 (using CKD-EPI equation) and/or ESRD (dialysis ≥90 days or 
kidney transplantation, confirmed sustained eGFR <15ml/min/1.73m2) and/or renal 
or CV death (time to first event)
!
All-cause mortality (time to event)
6.3.3
Exploratory variables
!
The individual components of the primary endpoint (cardiovascular death, MI, 
ischemic stroke and hospitalization for heart failure) (time to first event)
!
The composite endpoint of cardiovascular death, MI, ischemic stroke, 
hospitalization for heart failure, hospitalization for unstable angina pectoris, or 
hospitalization for coronary or non-coronary revascularization and the additional 


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individual components of hospitalization for unstable angina pectoris and 
hospitalization for coronary or non-coronary revascularization (time to first event)
!
HbA1c
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for any of the following: an increase in dose for an oral anti-diabetes 
medication, a ≥ 25% increase in insulin dose, or the addition of  new anti-diabetes 
medication for > 3 months
!
Major hypoglycemia and/or hospitalization for hypoglycaemia
!
Development of confirmed sustained macroalbuminuria (UACR ≥300 mg/g) in 
subjects without macroalbuminuria at baseline
!
Development of confirmed sustained albuminuria in patients without albuminuria at 
baseline (UACR ≥30 mg/g; time to first event)
!
Regression in sustained confirmed albuminuria (defined in three ways: 
!
1. Baseline microalbuminuria to normoalbuminuria, 2. Baseline macroalbuminuria 
to microalbuminuria, 3. The previous two combined) (proportions)
!
eGFR (sustained confirmed decrease ≥30% to sustained confirmed eGFR <60 
ml/min/1.73m2 using CKD-EPI  equation; time to first event)
!
eGFR (sustained confirmed decrease ≥40% to sustained confirmed eGFR <60 
ml/min/1.73m2 using CKD-EPI  equation; time to first event)
!
Albumin to Creatinine Ration (adjusted mean percent change after 2 and at 3 years)
!
Change in body weight at 2 years and at 3 years
!
Proportion of patients with 5% body weight loss and 10 % body weight loss after 2 
years and after 3 years
!
Retinal laser and/or intraocular treatment due to development of and/or 
deterioration in diabetic retinopathy
!
Blood pressure change from baseline
!
Peripheral revascularization/limb ischemic event
!
Surgical amputation and related events 
!
Any stroke (ischemic, hemorrhagic, or undetermined)


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6.4
Safety 
6.4.1
Primary safety variable
The primary safety outcome variable of the study is the composite endpoint of cardiovascular 
death, MI, or ischemic stroke (time to first event). These events will be adjudicated.
The Principal Investigator is responsible for ensuring that all staff involved in the study is 
familiar with the content of this section.
6.4.2
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, electrocardiogram). 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.
Refer to section 6.4.4 for definitions of AEs to be collected in this study. 
6.4.3
Definitions of serious adverse event
An SAE is an AE occurring during any study phase (i.e., run-in, treatment, washout, follow-
up), that fulfills one or more of the following criteria:
!
Results in death
!
Is immediately life-threatening
!
Requires in-patient hospitalization or prolongation of existing hospitalization 
!
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.
Any event representing a known or possible malignancy or neoplasm not known to be benign 
(e.g. mass observed on imaging felt to be a possible malignancy), laboratory abnormalities 
fulfilling the Hy’s law definition (ALT/AST>3xULN and total bilirubin >2xULN) or 
overdose (defined as the accidental or intentional ingestion of any dose of the investigational 
product that is considered both excessive and medically important, for further dosing 


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information please refer to the IB.) should be reported as an SAE using the most relevant SAE 
criteria, as judged by the Investigator.
For further guidance on the definition of a SAE, see Appendix B to the Clinical Study 
Protocol.
6.4.4
Recording of adverse events
From signing of the informed consent and throughout the study until and including the last 
visit/contact (i.e., Closing Visit), patients should be asked whether they experienced any AEs.
Only events that fall into the following categories are collected in this study: serious AEs (as 
defined in 6.4.3), AEs leading to discontinuation of IP, suspected CV events, elective 
coronary and non-coronary revascularisations, heart failure, potential diabetic ketoacoidosis, 
amputation and related events and AEs of special interest. AEs of special interest in this study 
fall into the following categories: suspect neoplasm (benign, malignant or unspecified), 
hepatic events, hypoglycemic events that are major (as defined in 6.4.4.5), fractures, renal 
events, symptoms of volume depletion, hypersensitivity reactions (serious or lead to 
discontinuation of IP), urinary tract infections (serious or lead to discontinuation of IP) and 
genital infections (serious or lead to discontinuation of IP).
Prior to first intake of randomized IP, an event should be recorded on the AE and SAE pages 
only if it qualifies as an SAE. 
Follow-up of unresolved adverse events
Any AEs that are recorded according to the CSP and are unresolved at the last visit/contact 
(i.e., Closing Visit) in the study are followed up by the Investigator for as long as medically 
indicated, but without further recording in the eCRF. AZ retain the right to request additional 
information for any patient with ongoing AE(s)/SAE(s) at the end of the study, if judged 
necessary, except for patients who have withdrawn consent and explicitly did not allow any 
further contact from Study personnel.
Any follow-up of ongoing SAEs after database lock will be reported to the AZ representative,
who will notify the Patient Safety data entry site. 
Variables
The following variables will be collected for each recorded AE; 
!
AE (verbatim)
!
The date when the AE started and stopped
!
Maximum intensity
!
Whether the AE is serious or not


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!
Investigator causality rating against the Investigational Product (yes or no)
!
Action taken with regard to investigational product
!
Whether this event is potentially a clinical endpoint /event of special interest
!
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 hospitalization
!
Date of discharge
!
Probable cause of death
!
Date of death
!
Autopsy performed
!
Causality assessment in relation to Study procedure(s)
!
Causality assessment in relation to 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 in Section 6.4.3. 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. 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. If the intensity of an AE changes, only the maximum intensity of the event will be 
recorded; however, the AE intensity should be recorded at the time of reporting. 
Maximum intensity will be graded according to the following rating scale:
!
Mild (awareness of event but easily tolerated)
!
Moderate (discomfort enough to cause some interference with usual activity)
!
Severe (inability to carry out usual activity)


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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 investigational product?’
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 B to the Clinical 
Study Protocol.
Adverse Events based on examinations and tests
The results from protocol mandated laboratory tests and vital signs will be summarized in the 
clinical study report. Deterioration as compared to baseline in protocol-mandated laboratory 
values, vital signs and other safety variables should therefore only be reported as AEs if they 
fulfill 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., anemia versus low hemoglobin value). 
In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AE(s).
Any new or aggravated clinically relevant abnormal medical finding at a physical examination 
as compared with the baseline assessment will be reported as an AE if they fulfill any of the 
SAE criteria or are the reason for discontinuation of treatment with the investigational 
product.
6.4.4.1
Hepatic disorders
All patients with a confirmed result of AST and/or ALT >3x ULN, will have additional 
central laboratory tests performed throughout the study. For patients who are discontinued 
from the IP as a result of sustained elevated liver safety abnormalities, additional central 
laboratory tests will be performed at the time of end of Treatment Visit, see CSP Appendix D 
Algorithm on Management of Sustained Elevated Liver Safety Abnormalities.
Pre-defined liver enzyme elevations will undergo adjudication. The definitions of events to be 
adjudicated are provided in the Event Reporting Manual. For all events identified for 
adjudication, the Investigator will complete the appropriate eCRF pages and provide source 
documentation as detailed in the Event Reporting Manual. 


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6.4.4.2
Hematuria
All events of hematuria (microscopic and/or macroscopic) during the study should be worked 
up for a possible cause. If no immediate or benign cause is identified as judged by the 
Investigator (e.g., menstruation, kidney stone, urinary tract infection [UTI] where hematuria is 
subsequently resolved after successful treatment), patients should undergo further evaluation 
by the investigator or another qualified professional. The evaluation may include but is not 
limited to tests such as urine cytology, NMP-22 or abdominal CT scans. The choice of tests 
should be per local standard of care/professional society guidance (see Appendix G for AUA 
guidelines). The patient should continue to receive IP treatment during these investigations 
(unless otherwise contraindicated). All confirmed events of bladder cancer should lead to the 
discontinuation of investigational product. (Refer to sections 5.8 and 5.8.1).
6.4.4.3
Possible malignancies 
All possible malignancies (except for non-melanoma skin cancer) will be reported by the site 
into a malignancy specific form in the eCRF in addition to the SAE form. All possible 
malignancies will be identified from entries in the eCRF malignancy form.
The identified events will be independently adjudicated. For all events identified for 
adjudication, the Investigator will complete the appropriate eCRF pages and provide source 
documentation as detailed in the Event Reporting Manual. The Investigator should clearly 
describe the event as benign or malignant if known. All confirmed events of bladder cancer 
should lead to the discontinuation of investigational product. (Refer to sections 5.8 and 5.8.1).
6.4.4.4
Renal disorders 
The efficacy and safety of dapagliflozin use in patients with type 2 diabetes has not been fully 
characterized for those who develop moderate renal impairment during ongoing treatment.  
Patients with a decrease in renal function defined as creatinine clearance (CrCl, based on 
Cockroft-Gault) <60 ml/min (but ≥ 30 ml/min) should continue on IP, but additional 
monitoring is required as specified below. 
Patients with creatinine clearance (CrCl, based on Cockroft-Gault) < 60 ml/min:
At all scheduled and unscheduled visits patients should be asked for symptoms of volume 
depletion as well as other adverse events and vital signs should be assessed (including blood 
pressure measurement).
Renal function should be monitored by central lab at least every 6 months but frequency might 
be increased depending on clinical situation and judgement of the investigator.
Patients with creatinine clearance (CrCl, based on Cockroft-Gault) < 45 ml/min:
If the creatinine clearance (CrCl, based on Cockroft-Gault) falls below 45 ml/min the patient 
should be scheduled for a re-test within 4 days whenever possible.
If CrCl (based on Cockroft-Gault) is ≥45 ml/min the patient can resume normal visit schedule. 


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If CrCl is still <45 ml/min the Investigator should consider re-testing CrCl within one to two 
weeks whenever possible. In addition, the Investigator should consider evaluating the patient 
for potentially reversible causes of renal dysfunction including: concurrent use of NSAIDS, 
antibiotics, or other medications known to affect creatinine clearance; volume depletion; 
urinary tract infection and obstructive uropathy. Further re-testing and evaluation should be 
done every second week until stabilization. The Investigator should also repeat the CrCl test at 
the next scheduled 3-month visit.
Patients with creatinine clearance (CrCl, based on Cockroft-Gault) < 30 ml/min:
If at any time the patient´s CrCl (based on Cockroft-Gault) falls below 30 ml/min calculated at 
the central laboratory and confirmed at a repeated central laboratory measurement (to be 
obtained within 4 days, whenever possible), the patient should be discontinued from IP.
If at any time the patient´s CrCl (based on Cockroft-Gault) falls below 30 ml/min calculated at 
local laboratory, a central laboratory CrCl should be obtained promptly. If the CrCl is 
confirmed by the central laboratory and persists at a repeated central laboratory measurement 
(to be obtained within 4 days, whenever possible), the patient should be discontinued from IP.
Estimated GFR (eGFR) will also be calculated and used for analysis, however decisions on IP 
discontinuation will be based on CrCl (refer to Section 12.2).
Any patient that is discontinued from IP due to deterioration in renal functions should be 
monitored closely by the investigator until abnormalities stabilize and the patient is 
asymptomatic.
6.4.4.5
Hypoglycemic events
At each visit the Investigator will inquire about occurrence of major hypoglycemic events 
according to the below definition.
!
Major hypoglycemic event defined as symptomatic events requiring external 
assistance due to severe impairment in consciousness or behavior, and prompt 
recovery after glucose or glucagon administration. Plasma glucose measurements 
may not be available during such an event, but neurological recoveryattributable to 
the restoration of plasma glucose to normal is considered sufficient evidence that 
the event was induced by a low blood glucose concentration.
Hypoglycemic episodes or symptoms of hypoglycemia should only be reported in the eCRF if 
the event fulfills the definition of a major hypoglycemic event, the protocol criteria for an 
SAE (see Section 6.4.3) or leads to discontinuation of IP. For major hypoglycemic episodes 
additional details (e.g., glucose measurements) will be recorded in the eCRF.


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6.4.4.6
Volume depletion
Dapagliflozin has a modest diuretic effect. The risk of volume depletion is enhanced when 
two diuretics are used in combination and in patients that otherwise are at risk for volume 
depletion. Therefore, caution should be exercised when administering to patients at risk for 
volume depletion due to co-existing conditions or concomitant medications, such as loop 
diuretics. These patients should be carefully monitored for volume status, electrolytes, and 
renal function.
6.4.4.7
UTI
If the Investigator believes that a UTI may be present, a properly collected set of urine 
cultures should be obtained and sent to a local laboratory prior to initiation of antibiotic 
therapy to confirm a presumptive diagnosis of cystitis, urinary tract infection, pyelonephritis. 
Clinical judgment and local standards of care should apply to decisions concerning therapy. 
In patients with clinical evidence of upper UTI (e.g., pyelonephritis) or presumed urosepsis, 
the Investigator may consider temporarily stopping IP until the course of treatment of the 
infection has been completed and clinical recovery has occurred. It is recommended that a 
follow-up urine culture is obtained within 7 days of clinical recovery from a documented UTI.
UTIs that are serious or lead to discontinuation of IP should be reported in the eCRF.
6.4.4.8
Asymptomatic bacteriuria
During enrollment, randomized treatment and follow up of patients in this trial, the 
Investigator may discover a patient with asymptomatic bacteriuria. Asymptomatic bacteriuria 
is defined as the presence of ≥ 105 colony forming units/mL of bacteria, in a properly 
collected voided urine specimen, without signs or symptoms typically attributed to urinary 
tract infection. Asymptomatic bacteriuria is prevalent among diabetic women, and is 
associated with pyuria in 70% of cases. Neither guideline from the US (Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang Y(L), Castro AF, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T and Coresh J. A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009 May 5; 150(9): 604–612.
Nicolle et al 2005, USPST 2004) nor Europe (European Association of Urology 2008)
recommend treatment of asymptomatic bacteriuria in non-pregnant diabetic patients. 
6.4.4.9
Adjudication of suspected CV endpoints
Suspected CV outcome events in the study including the primary objective and secondary 
objective will be centrally adjudicated by an independent clinical events committee. 
Suspected CV outcome events in the study will be identified either by the Investigator or by 
electronic review of reported AEs. For all events identified for adjudication the Investigator 
will complete the appropriate modules of the eCRF and provide source documentation. 
Guidance for “reporting potential clinical endpoints” is provided in the Event Reporting 
Manual. Definitions of CV events are detailed in the CEC Charter.


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6.4.4.10
Fractures
Published data suggest the presence of diabetes is associated with an increased risk in bone 
fractures, and bone fracture has been included as a potential risk for dapagliflozin due to the 
possible effects of dapagliflozin on body weight, renal tubular handling of calcium and 
phosphorus, or metabolism of vitamin D. However, in the clinical development programme, 
treatment with dapagliflozin was not associated with any clinically relevant changes in 
markers of bone formation and resorption. Also there was no indication of an increased risk of 
fractures in patients with mild renal impairment or normal renal function. All fractures should 
be reported in the eCRF.
6.4.4.11
Genital infections
Increase in the urinary excretion of glucose may create a potential substrate for genital tract 
pathogens. The diagnosis of vaginitis, vulvovaginitis, vulvitis or balanitis can be made 
basedon physical examinations, culture of secretions or a therapeutic response to treatment of 
fungal or other vaginal pathogens. Clinical judgment and local standards of care should apply 
to decisions concerning therapy. Genital infections that are serious or lead to discontinuation 
of IP should be reported in the eCRF.
6.4.4.12
Hypersensitivity reactions
Hypersensitivity reactions (e.g., generalized urticaria), some serious, have been reported for other 
SGLT2-inhibitors. However, it is not known if it is a class effect or not. Hypersensitivity 
reactions that are serious or lead to discontinuation of IP should be reported in the eCRF.
6.4.4.13
Amputation and related events 
Patients with diabetes have an increased risk for amputations. To ensure that data on 
amputation will be systematically collected, amputations and related events should be 
recorded. Events related to amputation should be reported as AE/SAE if relevant, and details 
regarding the amputation procedure will be captured in a specific eCRF.  
6.4.5
Reporting of serious adverse events 
Investigators and other study site personnel must inform appropriate AZ representatives and 
TIMI via the WBDC system of any SAE that occurs in the course of the study immediately or 
within 24 hours of when he or she becomes aware of it. Follow-up information on SAEs must 
also be reported by the Investigator with the same time frame.
The AZ representative or delegate will work with the Investigator to compile all the necessary 
information and ensure that all the necessary information is provided to the Patient Safety data 
entry site within one calendar day of initial receipt for fatal and life threatening events and 
within three calendar days of initial receipt for all other SAEs.
All SAEs have to be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). All SAEs will be recorded in the eCRF. SAEs will be 
recorded from the time of informed consent. 


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The Investigator and/or Sponsor are responsible for informing the Ethics Committee (EC) 
about the SAE as per local requirements. 
An automated email alert will be sent to the designated AZ representative, when the page with 
SAE information is saved in WBDC system by the Investigators or other site personnel. If the 
WBDC system is not available, then the Investigator or other study site personnel reports by 
fax an SAE to the appropriate AZ representative or delegate. A paper back-up SAE report is 
used for this purpose. The same reporting time frames still apply. The Investigator is 
responsible for completing the eCRF as soon as the system becomes available again. The AZ 
representative will forward all information relevant to the SAE to the Patient Safety data entry 
site via fax or email.
6.4.5.1
Protocol-specific exceptions to SAE reporting by the sponsor
The sponsor will separate potential cardiovascular events included in the primary objectives as 
well as the secondary objective from other SAEs reported by the Investigator. Events 
confirmed to meet the defined criteria of the CV adjudication will not be reported to health 
authorities to avoid unnecessary unblinding of efficacy endpoints. Events failing to meet the 
criteria will be processed as normal following final adjudication. (See 6.4.4.9 for further 
information on the adjudication of CV events).
6.4.6
Laboratory safety assessment 
The laboratory variables that will be measured to assess safety and the visits at which they 
will be measured are shown in the Study Plan (see Table 1 and section 3.1).
The date and time of sampling will be recorded on the laboratory requisition form. A central 
laboratory will process the samples and results will be reported back to the site.
Due to the fasting laboratory assessments at Visit 2, 4 6, 10, 14, 18, 22 end of treatment 
visit/closing Visit patients will be instructed to abstain from all food and beverages for 12 
hours prior to the clinic visit (drinking water and taking prescribed medications are allowed). 
Patients should not drink alcohol within 24 hours of each visit. 
All samples should be taken by adequately trained study 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 to the laboratory standard normal 
ranges and flagged if they are outside the normal range. The Investigator should make an 
assessment of the available results with regard to clinically significant abnormalities. The 
laboratory reports should be signed and retained at each center as source data for laboratory 
variables.
Regarding procedures for blood collection, labeling and shipment, see section 7.3.
For blood volume see Section 7.1.


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For information on how AEs based on laboratory tests should be recorded and reported, see 
Section 6.4.4. 
6.4.6.1
Unscheduled laboratory assessments
!
Patients will be tested for hematuria at the enrollment and randomization visits as 
well as during randomized treatment. For further details see Table 1 and Section 
6.4.4.2. 
!
If ALT and/or AST >3 times ULN and increase of TB >2 times ULN (based on 
either local or central laboratory results), the investigator should obtain a repeated 
measurement at the central laboratory (and at a local laboratory in addition to the 
central laboratory if deemed appropriate) within 3 days (see Appendix D). If the 
increase is confirmed or worsens, the patient should be discontinued from IP. 
Similarly, an increase of ALT or AST >8 times ULN – confirmed at a repeated 
measurement within up to 3 days, as well as ALT or AST > 5 time ULN confirmed 
over a period of 14 days or more, should lead to discontinuation of IP (see Section 
5.8). 
!
If a doubling of serum creatinine (from baseline), a serum creatinine >6.0 mg/dL 
(530 umol/L), a decrease in eGFR of ≥30% from baseline to eGFR <60 
ml/min/1.73m2 or an eGFR value of <15 ml/min is observed, based on either a 
central or a local laboratory result, a new central laboratory measurement of serum 
creatinine must be obtained at earliest possible time.
!
In addition, if a doubling of serum creatinine (from baseline), a serum creatinine 
>6.0 mg/dL (530 umol/L), a decrease in eGFR of ≥30% to eGFR <60 
ml/min/1.73m2 or an eGFR value of <15 ml/min based on a central laboratory 
result, a new central laboratory measurement of serum creatinine must be obtained 
after at least four weeks.
!
If the creatinine clearance (CrCl, based on Cockroft-Gault) falls below 45 ml/min 
the patient should be scheduled for a re-test within 4 days whenever possible. A 
new central laboratory measurement of serum creatinine must be obtained, 
creatinine clearance will be calculated and provided by the central laboratory.
!
If at any time the patient´s CrCl (based on Cockroft-Gault) falls below 30 ml/min 
calculated at the central laboratory and confirmed at a repeated central laboratory 
measurement (to be obtained within 4 days, whenever possible). A new central 
laboratory measurement of serum creatinine must be obtained, creatinine clearance 
will be calculated and provided by the central laboratory.
!
For cases of suspected urinary tract infection, a properly collected set of urine 
cultures should be obtained and sent to a local laboratory prior to initiation of 
antibiotic therapy.


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!
For other safety laboratory follow-up at the discretion of the investigator, as 
available in the unscheduled laboratory kit.
6.4.7
Physical examination
A physical examination including cardiovascular system will be performed at Visit 2 and End 
of Treatment or Closing Visit.
An optional physical examination may be performed at any other in-office visit to evaluate an 
AE or as judged by the Investigator.
6.4.8
Vital signs
Vital signs will be assessed following the study plan (see Table 1). Body weight and height 
will be measured as part of vital signs.
6.4.8.1
Pulse and blood pressure
Pulse and BP will be measured twice (5 minutes apart) before any blood sampling is done 
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. For timings of assessments, see Table 1. 
6.4.8.2
Body weight and height 
The patient’s body weight will be recorded in kilograms, to 1 decimal place, with light 
clothing and no shoes and recorded at Visits 1 and each subsequent study visit. The patient’s 
height will be recorded at Visit 1 in centimeters, with no shoes.
6.4.8.3
Waist and hip circumference
The waist circumference should be measured in the standing position at the natural waist 
(smallest waist circumference). If there is no natural waist, the measurement should be made 
at the level of the umbilicus. Measurements should be made at the end of a normal expiration. 
The hip circumference is measured in the standing position at the maximal circumference over 
the buttocks with a measuring tape.
6.4.8.4
Waist-hip ratio (WHR)
WHR is a calculated ratio between waist circumference and hip circumference (waist 
circumference/hip circumference, measured in centimeters) and will be computed by 
AstraZeneca.  


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6.5
Patient reported outcomes (PRO) (Not applicable)
6.6
Pharmacokinetics (Not applicable)
6.7
Pharmacodynamics (Not applicable)
 
 
7.
BIOLOGICAL SAMPLING PROCEDURES 
7.1
Volume of blood
The total volume of blood that will be drawn from each patient in this study is as follows:
Table 3                  Volume of blood to be drawn from each patient
Assessment
Sample volume 
(mL)
No. of samples
Total volume 
(mL)
Safety
Clinical chemistry
5 (approx.)
9
45 (approx.)
Hematology
2 (approx.)
7
14 (approx.)
HbA1c
2 (approx.)
8
16 (approx.)
Total
75-160ab
a
Includes a margin for additional visits in case study lasts >72 months as well as for unscheduled sampling
b
 
biomarker samples (see Appendix I, where applicable) is an additional approximately 32 mL.


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7.2
Handling, storage and destruction of biological samples
After the analyses are complete the samples will be either completely consumed during the 
analytical process, disposed of after analysis or retained for further use as described in section 
7.2.1. A Laboratory Manual for Investigators giving detailed instructions will be provided to 
each study center prior to the start of the study. The Investigator should follow the procedures 
defined in the Laboratory Manual.
7.2.1
Handling, storage and destruction of biological samples for future research
Biological samples for future research can be retained at AstraZeneca, or a representative on 
behalf of AstraZeneca, for a maximum of 20 years following the finalization of the CSR. The 
results from future analysis will not be reported in the CSR but separately in a CSR 
Amendment/Errata/Scientific Report or Scientific Publication. 
 
For further guidance regarding the 
optional biomarker samples refer to Appendix I.
7.3
Labeling and shipment of biohazard samples
The Principal Investigator ensures that samples are labeled 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 C ‘IATA 6.2 Guidance Document’.
Any samples identified as Infectious Category A materials are not shipped and no further 
samples will be taken from the patient unless agreed with AstraZeneca and appropriate 
labeling, shipment and containment provisions are approved.
7.4
Chain of custody of biological samples
A full chain of custody is maintained for all samples throughout their lifecycle.
The Principal Investigator at each center keeps full traceability of collected biological samples 
from the patients while in storage at the center 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.
7.5
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 analyzed, AZ is not 
obligated to destroy the results of this research.


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As collection of the biological samples is an optional part of the study, then the patient may 
continue in the study.
The Principal Investigator:
!
Ensures patients’ withdrawal of informed consent to the use of donated samples is 
notified immediately to AZ or its representative
!
Ensures that biological samples from that patient, if stored at the study site, are 
immediately identified, disposed of /destroyed, and the action documented
!
Ensures the laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed/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 ensure the central laboratory(ies) holding the samples is/are informed about the withdrawn 
consent immediately and that samples are disposed of/destroyed and the action documented 
and returned to the study site.
8.
ETHICAL AND REGULATORY REQUIREMENTS
8.1
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)/Good Clinical Practice (GCP), applicable regulatory requirements and the AZ policy on 
Bioethics and Human Biological Samples.
 
8.2
Patient 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.
AZ will not provide individual 
 results to patients, any insurance company, any 
employer, their family members, general physician or any other third party, unless required to 
do so by law.
Extra precautions are taken to preserve confidentiality and prevent 
c data being linked to 
the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the 
 data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AZ Physician or representative or an Investigator might know a 
patient’s identity and also have access to his or her 
 data. Also Regulatory authorities 


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may require access to the relevant files, though the patient’s medical information and the 
 files would remain physically separate.
8.3
Ethics and regulatory review
An Ethics Committee (EC) or Institutional Review Board (IRB) should approve the final 
study protocol, including the final version of the Informed Consent Form 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 Ethics Committee, and to the 
study site staff.
The opinion of the ECs/IRBs should be given in writing. The Investigator should submit the 
written approval to the AZ representative before enrollment of any patient into the study. 
The ECs/IRBs should approve all advertising used to recruit patients for the study.
AZ or its delegate 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 ECs/IRBs annually.
Before enrollment 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, ECs/IRBs and Principal Investigators with safety 
updates/reports according to local requirements, including Suspected Unexpected Serious 
Adverse Reactions (SUSARs), where relevant.
Each Principal Investigator is responsible for providing the ECs/IRBs with reports of any 
serious and unexpected adverse drug reactions from any other study conducted with the 
investigational product. AZ will provide this information to the Principal Investigator so that 
he/she can meet these reporting requirements.
8.4
Informed consent
The Principal Investigator(s) at each center 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


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!
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 informed consent form that is approved by an EC/IRB.
 
 
 
 
 
8.5
Changes to the protocol and informed consent form
Study procedures will not be changed without the mutual agreement of the Study Chairman 
and AZ, TIMI and Hadassah.
If there are any substantial changes to the study protocol, then these changes will be 
documented in a study protocol amendment and where required in a new version of the study 
protocol (Revised Clinical Study Protocol).
The amendment is to be approved by the relevant ECs/IRBs and if applicable, also the 
national regulatory authority approval, before implementation. Local requirements are to be 
followed for revised protocols.
AZ or its delegate will distribute any subsequent amendments and new versions of the 
protocol to each Principal Investigator(s). For distribution to ECs/IRBs see Section 8.3.
If a protocol amendment requires a change to a center’s ICF, AZ and the center’s ECs/IRBs 
are to approve the revised ICF before the revised form is used. 
If local regulations require, any administrative change will be communicated to or approved 
by each ECs/IRBs.


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8.6
Audits and inspections
Authorized representatives of AZ, a regulatory authority, or an EC/IRB may perform audits or 
inspections at the center on historical performance, including retention records and source data 
verification. The purpose of an audit or inspection is to systematically and independently 
examine all study-related activities and documents, to determine whether these activities were 
conducted, and data were recorded, analyzed, and accurately reported according to the 
Clinical Study Protocol, (GCP, ICH guidelines and any applicable regulatory requirements). 
The Investigator will contact AZ immediately if contacted by a regulatory agency about an 
inspection at the center.
9.
STUDY MANAGEMENT BY ASTRAZENECA OR DELEGATE
9.1
Pre-study activities
Sites that the TIMI study organization, the Hadassah Medical Center, BMS and/or AZ have 
had previous experience with will participate in the study. A new determination of the 
suitability of the Investigator site will be based on a number of factors, including but not 
limited to historical performance including retention records and confirmatory telephone 
contact with site personnel. In cases where the site personnel are markedly changed or the site 
has not worked previously with the TIMI study organization, the Hadassah Medical Center, 
BMS and/or AZ, further examination may be needed. The information on the site suitability 
will be documented.
9.2
Training of study site personnel
Before the first patient is entered into the study, a representative of the TIMI study Group, of 
the Hadassah Medical Center or an AZ or other representative will review and discuss the 
requirements of the Clinical Study Protocol and related documents with the investigational 
staff and also train them in any study specific procedures and the WBDC system(s) utilized.
The Principal Investigator will ensure that appropriate training relevant to the study is given to 
all of the staff, and that any new information relevant to the performance of this study is 
forwarded to the staff involved.
The Principal Investigator will maintain a record of all individuals involved in the study 
(medical, nursing and other staff).
9.3
Monitoring of the study
Monitoring of the site, site documents and data will be performed based on the monitoring 
plan. 
Site visits will occur on a regularly scheduled basis unless “for cause”.
The monitor will confirm the following:


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!
There is a complete patient file for each patient enrolled in the study
!
There is an informed consent for the patient and this consent process has been 
administered correctly
!
The monitor will review the patient file to ensure that all study endpoints (i.e., the 
composite endpoint of CV death, MI or ischemic stroke and other secondary 
endpoints) have been recorded onto the eCRF and that the adjudication packets are 
complete. Likewise, the monitor will review all AEs or SAEs that have been 
recorded on the eCRF. Also key is the need to ensure that all events and data are 
adequately captured according to the Event Reporting Manual.
At the time of the monitor visit, it is appropriate to discuss the study progress with site 
personnel to confirm all processes and procedures in the protocol are being adhered to 
correctly, data in the eCRFs are being recorded in a timely manner, 
 samples are being 
handled correctly, and IP accountability checks are being performed.
9.3.1
Source data
Refer to the Clinical Study Agreement (CSA) for location of source data.
9.4
Study agreements
The Principal Investigator at each center 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 Principal Investigator should be in place before any study-
related procedures can take place, or patients are enrolled.
9.4.1
Archiving of study documents
The Investigator follows the principles outlined in the CSA.
9.5
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 Q2 2013 and to end by Q2 2019.
However, as the study is event driven, the accrual of the predetermined number of events 
included in the composite endpoint of CV death, MI or ischemic stroke will finally determine 
the duration of the study.


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The study may be terminated at individual centers 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.
10.
DATA MANAGEMENT BY COGNIZANT DMG
The data collected through third party sources will be obtained and reconciled against study 
data.
Adverse events and medical/surgery history will be classified according to the terminology of 
the latest version the MedDRA. Medications will be classified according to the AZDD 
(AstraZeneca Drug Dictionary). 
Data queries will be raised for inconsistent, impossible or missing data. All entries to the study 
database will be available in an audit trail.
The data will be validated as defined in the Data Management Plan. Quality control 
procedures will be applied to each stage of data handling to ensure that all data are reliable 
and have been processed correctly.
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.
Management of external data
Data Management determines the format of the data to be received from external vendors and 
coordinates the flow of data to an external environment or clinical database (if applicable). 
Data Management will ensure that the data collection tool (for e.g. eDiary, IVRs etc) will be 
tested / validated as needed. External data reconciliation will be done with the clinical 
database as applicable.
Serious Adverse Event (SAE) Reconciliation
SAE Reconciliation Reports are produced and reconciled with Patient Safety database and/or 
the Investigational Site. 
Management of 
 data
data generated in this study will be stored in the AZ database, or other appropriate 
secure system, separate from the database used for the main study. Some or all of the clinical 
datasets from the main study may be duplicated within the AZ, and/or TIMI Study Group 
secure databases to facilitate exploratory 
analyses.
Any results from this 
 will be reported separately from the clinical study 
report for the main study.


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11.
EVALUATION AND CALCULATION OF VARIABLES 
11.1
Calculation or derivation of efficacy variable(s)
The co-primary efficacy endpoints are MACE (composite of CV death, MI or ischemic 
stroke) and the composite of CV death or heart failure. Each will be evaluated as the time to 
the first event included in the composite. The general intent is to analyze patients from the 
date of randomization up until the date of study closure visit. For the primary endpoint, the 
time of event will be determined by the adjudicated date of first primary event. Patients 
without an adjudicated primary event will be censored at the earliest date among the 
following: non-CV death, withdrawal of consent, and last documented contact (e.g. the study 
closure visit). The last documented contact may be by office visit or by telephone call directly 
with the patient or by contact with a caregiver where it is possible to gain knowledge of 
possible CV events or death. Other sources of contact may also include written response to a 
mailed inquiry or email, and review of medical records.
The rules for censoring for the secondary time to event endpoints are the same, with the two 
exceptions: 1) that CV death will be included as a censoring point for the endpoint of 
hospitalization for heart failure and 2) non-CV deaths are events for the endpoint of all-cause 
mortality (and not censoring points).
A patient may have 1 or more events. However, only a patient’s first occurring event will 
contribute to the analysis of each specified endpoints. 
Only events adjudicated and confirmed by the CEC will be included in the time-to-event 
endpoints.
11.2
Calculation or derivation of safety variable(s)
The baseline value of each safety laboratory test or physical exam endpoint is defined as the 
last assessment on or before the date of randomization. Change from baseline will be 
calculated.
11.2.1
Other significant adverse events (OAE)
During the evaluation of the AE data, an AstraZeneca medically qualified expert will review 
the list of AEs that were not reported as SAEs and DAEs. Based on the expert’s judgment, 
significant adverse events of particular clinical importance may, after consultation with the 
Global Patient Safety Physician, be considered OAEs and reported as such in the Clinical 
Study Report. 
Examples of these are marked hematological and other laboratory abnormalities, and certain 
events that lead to intervention (other than those already classified as serious), dose reduction 
or significant additional treatment. 


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11.3
Calculation of renal variables
The following formulas will be used to determine creatinine clearance and estimate 
glomerular filtration rate.
Estimated creatinine clearance using the method of Cockcroft and Gault:
CrCl = (140 - age) x (weight in kg)
(x 0.85 for females)
serum creatinine (mg/dL) x 72
Estimated GFR using MDRD equation:
eGFR (mL/min/1.73m2) = 175 x (SCr)-1.154 x (Age)-0.203 x (0.742 if female) x (1.212 if 
black)
Estimated GFR using CKD-EPI equation (Levey et al 2009): 
eGFR (mL/min/1.73m2) = 141 x min (SCr/k,1)a x max (SCr/k,1)-1.209 x 0.993Age x [1.018 if 
female] x [1.159 if black]
k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, min 
indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 1.
11.4
Calculation or derivation of patient reported outcome variables 
(Not applicable)
11.5
Calculation or derivation of pharmacokinetic variables (Not 
applicable)
11.6
Calculation or derivation of pharmacodynamic variable(s) (Not 
applicable)
 
 
12.
STATISTICAL METHODS AND SAMPLE SIZE 
DETERMINATION 
12.1
Description of analysis sets
12.1.1
Full analysis set (FAS)
All patients who have been randomized to study will be included irrespective of their protocol 
adherence and continued participation in the study. Patients will be analyzed according to 
their randomized IP assignment (not to which treatment they actually received) irrespective of 
whether the event occurred before or following discontinuation of IP. Patients who withdraw 
consent to participate in the study (or are lost to follow-up) will be included up to the date of 


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their study termination except for vital status known through public records (for use in the 
analysis of all cause mortality). All primary and secondary variables will be analyzed using 
the FAS. The FAS will be considered the primary analysis set for the primary and secondary 
variables and for the exploratory efficacy variables.
12.1.2
Safety analysis set
All patients who received at least 1 dose of randomized dapagliflozin or placebo and who 
have data observed at any time after first randomized dose till the end of the study will be 
included in the safety population. Throughout the safety results sections, erroneously treated 
patients (patients randomized to one of the treatment groups but actually given the other 
treatment) will be accounted for in the actual treatment group. Patients with erroneous 
treatment would be analyzed according to that treatment only if they only received the 
erroneous treatment and none of the correct treatment. All safety variables, except for the non 
inferiority testing of the primary composite variable, will be analyzed using the safety analysis 
set. The Safety analysis set will be considered the primary analysis set for malignancies and 
fractures.
12.1.3
An on-treatment analysis set
An on-treatment analysis set will also be created. The on-treatment population is defined as all 
randomized patients who have received at least one dose of investigational product and who 
have data observed at any time after first randomized dose till the end of the study. However, 
only those observations collected during treatment with IP or within a certain number of days 
of the last dose of investigational product will be part of this analysis set, as noted below:
!
Primary, secondary, and categorical exploratory variables: 30 days
!
Continuous exploratory and safety variables (e.g. changes in lab values and vital 
signs): 7 days
!
SAEs: 30 days
AEs of special interest, that are not serious: 7days
12.2
Methods of statistical analyses
12.2.1
Demographics and baseline characteristics
Demographic and baseline characteristics will be summarized, using frequency distributions 
and summary statistics based on the FAS data set, for each treatment group as well as for all 
patients combined. 
Additional summaries of demographic and baseline characteristics may be performed for 
specific subgroups of interest.
12.2.2
Primary variables
The primary variables are the time to first event included in the composite endpoint of CV 
death, MI, or ischemic stroke and the time to first event included in the composite endpoint of 


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CV death or hospitalization for heart failure. The primary analysis will be based on the FAS 
population, using events adjudicated and confirmed by the CEC.
Hazard Ratios (HR) and Confidence Intervals (CIs) will be derived from a Cox proportional 
hazards model with a factor for treatment group stratified by CV risk category (established 
CV disease, or multiple risk factors without established CV disease) and baseline hematuria.
The assumption of proportional hazards for the factor for treatment groups will be assessed 
visually using log-cumulative hazard plots. The effect of any departures from proportional 
hazards will be discussed as part of the presentation of results of the analyses. Additionally a 
stratified log-rank test will be assessed to further investigate the assumption of proportional 
hazards. Additionally, the assumption of proportional hazards for the factor for treatment 
group will be evaluated with a model which assess the treatment effect in categorized time 
intervals (< 1 year and >= 1 year).
The primary analysis will use each patient's last contact as the censoring date for patients that 
complete the study without any primary events. To test the robustness of the primary endpoint 
results, censoring at the fixed calendar end-of-study date (the date that the executive 
committee instructs the sites to commence final visits) will be used in a sensitivity analysis.
The contribution of each component of each of the primary composite endpoints to the overall 
treatment effect will be examined. Methods similar to those described for the primary analysis 
will be used to separately analyze the time from randomization to the first occurrence of each 
component of the primary composite endpoints. This will be done for CV death all MI, all 
ischemic stroke and all hospitalizations for heart failure. Nominal p-values will be presented. 
Non-fatal MI and Non-fatal stroke will only be presented descriptively.
Subgroup analyses to evaluate variation in treatment effect will be performed on the basis of 
tests for interaction using the Cox model. Tests for the interaction with treatment for each of 
these subgroup variables will be performed. Additionally, Cox proportional hazards models 
will be performed to examine treatment effects within each subgroup 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. HRs and 95% confidence intervals will be 
reported for each subgroup. Relevant subgroups will be detailed in the SAP. 
A sensitivity analysis of the primary objectives will be performed using an on-treatment 
analysis set. Additionally, exploratory proportional hazards models will determine whether 
control for baseline CV risk category and baseline hematuria has any effect on the relative risk 
associated with randomized treatment. 
HRs and CIs for overall analysis and subgroups will be presented with forest plots. 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 three individual 
components.


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Kaplan-Meier plots by CV risk category will be presented, by treatment, for overall analysis 
and for the individual components.
Control of Type I error
The Type I error rate for the analysis of the primary endpoint will be adjusted for the interim 
analyses performed by the DMC.
For the primary endpoint the following hypothesis will be tested at the 2.31% 1-sided level:
H01: HR [dapagliflozin:placebo] ≥1.30
vs
H11: HR [dapagliflozin:placebo] <1.30. 
If the null hypothesis is rejected, then an increased CV risk of 1.30 for dapagliflozin-treated 
patients is ruled out and superiority will then be tested in terms of:
H02: HR [dapagliflozin:placebo] ≥1
vs
H12: HR [dapagliflozin:placebo] <1
and
H03: HR [dapagliflozin:placebo] ≥1
vs
H13: HR [dapagliflozin:placebo] <1
in a closed test procedure. See Section 12.2.4 for a description of the full closed testing 
procedure including the secondary variables.
12.2.3
Secondary variables
Secondary efficacy time to event variables will be analyzed similar to the primary variable.
For time to decrease of ≥40% to eGFR <60 ml/min/1.73m2 or an eGFR value of <15 
ml/min/1.73m2, confirmation is required, meaning that the observation should be present at 
two central laboratory measurements separated with at least 4 weeks. Time to onset would be 


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the first of the two subsequent laboratory assessments. If no confirmation can be obtained the 
observation will not be included in the main analyses, but a sensitivity analysis will be 
conducted including also all non confirmed observations. Initiation of renal replacement 
therapy is defined as dialysis for at least 90 days or kidney transplantation.
12.2.4
Summary of closed test procedure
Type I error will be controlled at a one-sided 0.025 level for multiplicity across primary and 
secondary objectives and in consideration of planned interim analyses. Table 4 provides a plan 
for how the procedure will function.
Table 4
Confirmatory Testing Procedures Using One-sided Alphas
H1: Non-inferiority for the primary composite endpoint (alpha = 0.0231)a
Now the alpha will split into independent testing of the co-primary composites in parallel
H02: Superiority for the primary composite 
endpoint (alpha = 50% of primary alpha)c
H03: Superiority for hospitalization for heart 
failure or CV death (alpha = 50% of primary 
alpha)c
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to 
eGFR <60 ml/min/1.73m2 and/or ESRD (initiation of renal replacement therapy
or kidney transplantation, confirmed sustained eGFR <15ml/min/1.73m2) and/or 
renal or CV death b
!
All-cause mortalityd
a
The alpha of 0.0231 represents the final one-sided significance level to be used when the study has been 
completed in entirety. At an interim analysis, testing for superiority will occur, and the alpha for superiority 
will be replaced by 0.000095 at the first and 0.00614 at the second interims. Non-inferiority will be tested 
only at the completion of the study.
b
With the exception of all-cause mortality, secondary endpoints will only be tested once, at the completion 
of the trial or if the decision is made to terminate the trial early. The alpha will be controlled for the overall 
Type I error across the primary and secondary endpoints and across the interims and final analysis.
c
If this analysis occurs at completion of the trial, the alpha will be 0.01155 (50% of 0.0231) for superiority 
for MACE and 0.01155 (50% of 0.0231) for superiority for hospitalization for heart failure or CV death.
Details of the closed testing procedure and control of multiplicity across the primary and secondary 
objectives are contained within the statistical analyses plan section 4.4.3.
d
All-cause mortality is assessed at interim analyses as part of the stopping guidelines. At the interim 
analyses, it will be tested second following MACE. If the study terminates at an interim analysis, all-cause 
mortality will remain as the 2nd endpoint following the test for superiority of MACE. If the final analysis 
occurs at the completion of the trial, all-cause mortality will be tested as presented in this table.
12.2.5
Exploratory efficacy variables
Change from baseline to each visit measurement for HbA1c, BP variables, and other non-
categorical variables will be analyzed by a repeated measures method. The model will include 
terms for treatment group, CV risk category, baseline hematuria, visit, visit*treatment group 
and baseline as a covariate. The model will be used to derive a least squares estimate of the 
treatment difference with 95% confidence interval and corresponding two-sided nominal p-


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value. Further, two-sided 95% confidence intervals for the mean change within each treatment 
group will be calculated. Missing data will not be imputed. This model will be used to assess 
the timepoints at 2 and 3 years as specifically noted in the objectives although summaries at 
all visits will also be presented.
For time to albuminuria/macroalbuminuria, and for time to decrease in eGFR (using CKD-EPI 
equation), confirmation is required, meaning that the observation should be present at two 
central laboratory measurements separated with at least 4 weeks. Time to onset would be the 
first of the two subsequent laboratory assessments. If no confirmation can be obtained the 
observation will not be included in any analyses. Initiation of renal replacement therapy is 
defined as dialysis for at least 90 days or kidney transplantation.
Change from baseline to each visit measurement for body weight will be analyzed by a 
repeated measures method. All non missing visit data will be used. The model will include 
terms for treatment group, CV risk category, baseline hematuria, visit, visit*treatment group 
and baseline measurement as a covariate. The model will be used to derive a least squares 
estimate of the treatment difference with 95% confidence interval and corresponding two-
sided p-value. Further, two-sided 95% confidence intervals for the mean change within each 
treatment group will be calculated. Missing data will not be imputed. This model will be used 
to assess the timepoint of 3 years corresponding to the objectives although summaries at all 
visits will also be presented.
Percent change from baseline to each visit measurement for Albumin to Creatinine ratio will 
be analyzed by a repeated measures method. All non missing visit data will be used. The 
model will include terms for treatment group, CV risk category, baseline hematuria, visit,
visit*treatment group and baseline measurement as a covariate. The model will be used to 
derive a least squares estimate of the treatment difference with 95% confidence interval and 
corresponding two-sided p-value. Further, two-sided 95% confidence intervals for the mean 
percent change within each treatment group will be calculated. Missing data will not be 
imputed. This model will be used to assess the timepoint of 3 years corresponding to the 
objectives although summaries at all visits will also be presented. If data suggests, the analysis 
might be performed applying a logarithm scale instead.
The proportions of patients with at least a 5% body weight loss after 2 and 3 years compared 
to baseline will be analyzed using the methodology of Cochran-Mantel-Haenszel (using CMH 
option in PROC FREQ procedure, SAS version 8.2 or higher). Estimates for treatment effects 
and differences between treatment groups will be obtained along with 95% confidence 
intervals and p-values using this methodology with stratification for CV risk category and 
baseline hematuria. The same method will be repeated for the additional body weight 
endpoints: proportions of patients with at least a 10% body weight loss after 2 and 3 years.
The body weight analyses will be performed for all patients and also for the subgroup with 
patients taking insulin during the study excluded.
All body weight analyses will also be performed for the subgroup of patients with BMI greater 
than 30 separately.


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Retinal laser and/or intraocular treatment due to development of and/or deterioration in 
diabetic retinopathy, all strokes, need for an increase in dose of current anti-diabetes 
medication or in addition of new anti-diabetes medication, initiation of insulin therapy in 
patients not receiving insulin therapy at baseline, major hypoglycemia, hospitalization for 
hypoglycemia and regression in albuminuria, will be examined using statistics according to 
analysis of proportions that will include 95% confidence intervals for treatment effects and for 
the comparison between treatments as well as nominal 2-sided p-values. Time to event 
analyses will also be performed.
12.2.6
Safety analyses
The number and percent of patients with adverse events, leading to discontinuation of IP, 
serious adverse events and adverse events of special interest will be summarized by system 
organ class and preferred term for each treatment group using terms coded by MedDRA. The 
assessment will include an evaluation of the incidence of bladder and breast cancers, liver 
injury and bone fractures. All events of possible malignancies (excluding non-melanoma skin 
cancer) and liver injury will be independently adjudicated, in addition to the cardiovascular 
endpoints.
Incidence rate ratios and corresponding confidence intervals will be provided using exact 
methods with Proc StatXact for the Mantel-Haenszel relative risk estimates for Bladder cancer 
and for Breast cancer.
Changes from baseline to each scheduled time point for each clinical laboratory test, including 
estimated GFR and estimated creatinine clearance and non-categorical vital sign 
measurements will be summarized by treatment group. In addition, the number and percent of 
patients with a marked abnormality in clinical laboratory tests will be summarized by 
treatment group.
For safety analyses other than the primary endpoint, summaries will be provided using both on-
treatment observations and using all observations regardless of whether patients are on or off 
study treatment.
12.2.7
Considerations of incomplete follow-up
It is expected that complete information on the components of the primary composite endpoint 
(and as much as possible of the eCRF data for patients contacted by telephone) will be 
obtained for all treatment dropouts (patients who prematurely discontinue IP), unless they 
refuse any form of follow-up and withdraw consent or are lost to follow-up. Thus, event free 
treatment dropouts will not be censored before study closure (if not lost to follow-
up/withdrawn consent) in the primary FAS analysis. Other points of censoring, e.g., last in-
person visit, may be considered in sensitivity analyses.
The time-to-event analysis (Cox regression) relies on the assumption of non-informative 
censoring. To examine this assumption, presence of informative censoring will be assessed by 
comparing the event rates between subjects with incomplete follow-up and subjects with 
complete follow-up. Potential informative censoring will be investigated. The rates of study 


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dropouts will also be compared between treatment arms to assess potential differential 
dropouts.
Depending on the results of the above assessments concerning informative censoring, 
appropriate sensitivity analyses may be performed to assess the robustness of the primary 
analysis of treatment effect on the primary composite endpoint and all-cause mortality. 
The options of sensitivity analyses may include, but are not limited to:
!
Imputing expected number of events for withdrawn subjects using event rate similar to 
that observed in the study and allocating these residual events in different proportions 
to the treatment groups
!
CV death replaced with all-cause mortality, including vital status information from 
patients who have withdrawn consent (or are lost to follow-up)
!
Censoring at the last in-person visit for event free patients after permanent premature 
discontinuation of IP.
12.2.8
Interim analyses 
A DMC will be appointed jointly by the Sponsors and the academic leadership of the study. 
The DMC will be responsible for safeguarding the interests of the patients in the outcome 
study by assessing the safety of the intervention during the trial, and for reviewing the overall 
conduct of the clinical trial. In addition, the DMC will have the responsibility to assess the 
efficacy data of the interim analysis and make recommendations based upon stopping 
guidelines. A detailed plan of interim monitoring for bladder cancer will be provided in the 
Statistical Analysis Plan (SAP) and the DMC Charter. 
We plan a group sequential design with 2 interim analyses to assess the MACE and all-cause 
mortality. The analyses will take place at 1/3 and 2/3 of the primary events using an O’Brien–
Fleming alpha-spending rule. The interim analyses will assess superiority of dapagliflozin to 
placebo for MACE because the study will only be considered for early termination if 
superiority is met. All-cause mortality is included as an endpoint to the interim analyses for an 
additional assessment of benefit. The first interim analysis will have a one-sided alpha level of 
0.00095.  The second interim analysis will have a one-sided alpha level of 0.00614. According 
to the O’Brien-Fleming spending rule this will leave a 1-sided alpha level of 0.023095 for the 
final analysis. At each interim analysis, MACE will be tested first at the specified alpha level, 
and if found to be statistically significant, all-cause mortality will then be assessed for 
significance at the same alpha level. If superiority is achieved for both endpoints, an action is 
triggered whereby the DMC will evaluate the CV data and safety data, including bladder 
cancers and liver events, to determine if benefit is unequivocal and overwhelming such that 
the DMC recommends ending the study.
With the exception of all-cause mortality, secondary endpoints will only be tested at the 
completion of the trial or if the decision is made to terminate the trial early. The alpha will be 
controlled for the overall Type I error across the primary and secondary endpoints and across 


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the interims and final analysis. The same alpha level used for MACE at the time of stopping 
the trial will also be used for testing the secondary endpoints according to the confirmatory 
testing procedure as explained in detail in Table 4.
If, outside of the 2 pre-specified interim efficacy analyses, the DMC feels compelled for 
safety concerns to examine efficacy data formally with consideration of stopping the trial 
early for overwhelming efficacy, then the alpha applied to such efficacy analyses would be 
determined according to the O’Brien-Fleming spending function, and subsequent alpha-levels 
for any remaining planned efficacy interim and final analyses would also be adjusted 
according to the O’Brien-Fleming spending function to maintain the  control of the Type I 
error. Any unscheduled interim analysis would evaluate both MACE and all-cause mortality 
in the same way as for a scheduled interim analysis
The SEER rate for the general US population of 0.044% per person-year for bladder cancer 
may be conservative; higher bladder cancer rates could be observed in this trial. If the SEER 
rate is adjusted to reflect an increased risk in a diabetes population, an estimated annual rate of 
0.06% could occur.
We assume that the rate of bladder cancers observed in this study will be 0.06%, which would 
correspond to a total of 46 bladder cancers.
Interim monitoring for bladder cancers is planned for the purposes of communicating potential 
signals with regulatory authorities. The accumulation of patients with bladder cancer would 
suggest 4 interim analyses at 8, 16, 24 and 32 events. The interim analysis would take place at 
approximately 26, 37, 46 and 55 months. The interim analyses would be assessed at an overall 
alpha-level of 0.10 with a Pocock spending rule. If an interim analysis is significant, the DMC 
would inform others according to a strict communication plan. The number of interim 
analyses for bladder cancers may be adjusted if the event rate is different than expected.
12.3
Determination of sample size
1390 MACE events will be required to have 85% power to demonstrate superiority of 
dapagliflozin to placebo if the true HR is 0.85, i.e., a 15% relative risk reduction, with a one-
sided alpha of 2.31%. To achieve this number of MACE events, we have designed the study 
with the following condition. 17150 randomized patients will be required for the study, with 
an assumed annual event rate of 2.1% on placebo, and an annual study withdrawal rate of 
1.0% over a 3-year accrual period and 3-year minimum follow-up. With above assumptions 
and 1390 MACE events it is estimated to have >99% power to test the hypothesis of non-
inferiority H0:HR [dapa:placebo] ≥ 1.3 vs H1:HR < 1.3.
We anticipate approximately 770 events for the composite of CV death or hospitalization for 
heart failure, which would provide 87% power to detect a hazard ratio of 0.80 with a 1-sided 
alpha of 2.31%. The alpha levels at the final analysis will depend on the alpha spending 


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Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
84
function, the observed number of events for each endpoint at interim and final analyses and 
the hierarchical testing procedure.
The final sample size will depend on multiple factors including the rate of accrual of primary 
endpoint events and rate of IP discontinuation. Therefore the sample size may be changed if 
planning assumptions are modified by blinded data review. The Executive Committee of the 
trial will monitor the aggregate event rate and rate of IP discontinuation and may alter the 
sample size, number of primary endpoints or duration of the trial in accordance with the goals 
of the trial. Such changes will be made in consultation with the Sponsor. 
Assuming the rate of bladder cancer is 0.06% per person-year, 46 bladder cancers may be 
expected during the study. With 46 events, a relative risk of 2.28 can be ruled out with one-
sided 97.5% confidence and 80% power under the hypothesis that the true relative risk is 1. In 
parallel, a difference in incidence rates of 0.049% could be ruled out using the same 
assumptions. 
The SEER rate for the general US population of 0.044% per person-year for bladder cancer 
may be conservative; higher bladder cancer rates could be observed in this trial. If the SEER
rate is adjusted to reflect an increased risk in a diabetes population, an estimated annual rate of 
0.06% could occur. The rate observed for dapagliflozin in the complete Phase 2b and 3 
programs was 0.16% per person-year. When those patients with baseline hematuria are 
screened out, an annual rate of 0.07% was found among the dapagliflozin-treated patients and 
0.046% amongst all treated patients (dapagliflozin and comparator combined). Detection of 
early bladder cancers may be higher than for the general population (i.e., SEER) since this 
study proposal plans a more thorough assessment of hematuria following randomization than 
would be found in standard medical practice. Table 5 illustrates the levels of risk that can be 
ruled out at different event rates of bladder cancer.
Table 5
Levels of bladder cancer relative risks and incidence rate differences 
that can be ruled out under different assumptions
One-sided 97.5% confidence level
Event rate
Expected 
number of 
events
Power
True RR that can 
be ruled out
True rate diff that 
can be ruled out
Max value that can be 
observed and rule out 
true RR, rate diffa
Bladder cancers
0.044%
34
80%
2.62
0.042%
1.33, 0.013%
0.06%
46
80%
2.28
0.049%
1.28, 0.015%
0.07%
54
80%
2.14
0.053%
1.26, 0.016%
0.16%
123
80%
1.66
0.080%
1.16, 0.024%
RR = relative risk; risk diff = absolute incidence rate difference


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
85
a
The max values that can be observed and rule out the true RR and rate diff are the same for both confidence 
levels
The number of patients that will agree to participate in the 
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.
12.4
Data monitoring committee 
12.4.1
Clinical Event Adjudication Committee
An independent, blinded CEC will be appointed jointly by the Sponsors and the academic 
leadership of the study.
The CEC will adjudicate all primary and secondary CV endpoints. Investigators will report 
potential events via electronic case report forms (CRFs) in real time. Additionally, the clinical 
trial database will be searched at least monthly for other AEs, or laboratory data that might 
also indicate a potential event. Once a potential event has been identified, a complete package 
of information will be collected with the goal to send to the CEC within two weeks of 
identification. A packet would be considered complete after translation and would allow for 
assessment if all required data are present. The CEC reviewers would set a target to evaluate 
the complete package within four weeks of receipt. 
All possible malignancies (excluding non-melanoma skin cancer), pre-defined liver enzyme 
elevations and all events of potential diabetic ketoacidosis will undergo adjudication.
The CEC will determine the probability that drug-induced liver injury (DILI) is the cause of 
liver related abnormalities, included but not limited to:
!
Hepatic disorders leading to discontinuation from study treatment and/or death
!
Significant liver laboratory abnormalities 
Additional details are provided in the CEC charter.
12.4.2
Data Monitoring Committee (DMC)
An independent DMC will be appointed jointly by the Sponsors and the academic leadership 
of the study.
The DMC will be responsible for safeguarding the interests of the patients in the outcome 
study by assessing the safety of the intervention during the trial, and for reviewing the overall 
conduct of the clinical trial. They will review overall safety in the trial and specifically the 
incidence of bladder cancers and potential drug induced liver injury (DILI) cases. In addition, 
the DMC will have the responsibility to assess the efficacy data of the interim analysis and 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
86
decide if stopping guidelines are met. The DMC will have access to the individual treatment 
codes and will be able to merge these with the collected study data while the study is ongoing.
The 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.
12.5
Study organization 
12.5.1
Committee organizations
In consideration of the large nature of this trial, several key groups will act as alliances to 
provide direction and guidance throughout this study. The Executive and Steering Committees 
focus mainly on the scientific aspects of the trial whereas the Operations Committee and Joint 
Working Group are study tactics and operational in nature.
All committee meetings, unless otherwise noted, are considered open in that others may join 
in a listening-only mode.
A joint governance process will be issued by members of the academic institutions and the 
Sponsors.
12.5.1.1
Executive Committee 
The Executive Committee will be responsible for the overall design, conduct, and supervision 
of the study, including the development of the committee and any protocol amendments. The 
EC will make a recommendation to the Sponsor based on the information from the DMC. The 
Executive Committee membership will comprise designated academic leaders and members 
of the Sponsor. 
12.5.1.2
Steering Committee 
The Steering Committee will be responsible for providing clinical guidance on study 
implementation and conduct of the study, and interpretation of results. The Steering 
Committee will comprise designated members from among the Principal Investigators (PI) 
and recognized leaders in the field of diabetes and CV disease, and all members of the 
Executive Committee.
12.5.1.3
Strategy and Tactics Groups 
The Strategy and Tactics Group will include key members from the academic leadership 
institutions for the study in addition to representatives from the Sponsors. This group is 
charged with developing strategies and tactics of key aspects of this study providing guidance 
in aspects of study operations.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
87
12.5.1.4
Joint Working Group 
The Joint Working Group will include key leaders of the study aspects from the academic 
institutions and the study Sponsors. The group, meeting frequently, will direct, on a daily 
level, all aspects of study operations.
12.5.2
Study Project Operational Procedures (TIMI)
For this study, a Project Operational Procedures (POP) manual was developed jointly between 
AstraZeneca, BMS, the TIMI study group and Hadassah Medical Center. Updates to the POP 
will be developed jointly between AstraZeneca, the TIMI study group and Hadassah Medical 
Center.
All procedures (aligned with Standard Operating Procedures), Operational Procedural 
Information and guidances will be described in detail in the POP. As such, the POP will 
supersede internal AZ documents where there is a case of overlapping procedures. Any 
compliance monitoring will be performed using the procedures, processes, or guidances listed 
in the POP.
The POP will be reviewed, discussed and signed by members of senior management of both 
the Sponsors and academic institutions.
13.
IMPORTANT MEDICAL PROCEDURES TO BE FOLLOWED 
BY THE INVESTIGATOR
13.1
Medical emergencies and trial contacts
The PI is responsible for ensuring that procedures and expertise are available to handle 
medical emergencies during the study. A medical emergency usually constitutes an SAE 
and is to be reported as such (see Section 6.4.5) 
In the case of a medical emergency, the Investigator may contact the TIMI Study Hotline.
The TIMI hotline #
 or 
The treatment code may not be broken unless in an emergency situation when the appropriate 
management of the patient necessitates knowledge of the treatment allocation. In such an 
emergency, the Investigator will, if time and circumstances permit, contact the TIMI Hotline 
prior to breaking the treatment code. If the treatment code is broken, the date, time, and reason 
should be recorded and the Investigator should sign the record (see also Section 5.4.2).
For reporting of unsolicited SAE 30 days after end of study, see Section 6.4.4.
13.2
Overdose 
Overdose is defined as the accidental or intentional ingestion of any dose of investigational 
product that is considered both excessive and medically important. For further dosing 


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
88
information please refer to the IB. Once an Investigator decides that a particular occurrence is 
an overdose, it must be reported as a Serious Adverse Event. If an overdose is suspected, 
monitoring of vital functions as well as treatment as appropriate should be performed. It 
should be noted that even extreme doses are likely to be asymptomatic.
If an overdose on dapagliflozin occurs in the course of the study, then Investigators or other 
site personnel inform appropriate TIMI representatives immediately or within 24 hours of 
when he or she becomes aware of it. 
13.3
Pregnancy
All outcomes of pregnancy should be reported to the TIMI Hotline.
If a patient becomes pregnant during the course of the study investigational product should be 
discontinued immediately.
Pregnancy itself is not regarded as an adverse event unless there is a suspicion that the 
investigational product under study may have interfered with the effectiveness of a 
contraceptive medication. Congenital 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 in the course of the study, then investigators or other site personnel 
inform appropriate TIMI representatives immediately or within 24 hours of when he or she 
becomes aware of it.
The PREGREP module in the eCRF is used to report the pregnancy. This module in the eCRF 
should be completed by the Investigator and the AstraZeneca representative will forward the 
information to AZ DES using the same procedure and timelines as for SAE reporting. An 
AstraZeneca paper Pregnancy Outcome Report, part 2, is used to report the outcome of the 
pregnancy.
The same timelines apply when outcome information is available.
14.
LIST OF REFERENCES
ACCORD Study Group 2008
The Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive 
glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
Campbell 2009
Campbell RK. Type 2 diabetes: where we are today: an overview of disease burden, current 
treatments, and treatment strategies. Journal of the American Pharmaceutical Association. 
2009; 49; S3-9


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
89
Cardiovascular events meta analysis report; Dapagliflozin. (available upon request)
Duckworth et al 2009
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control 
and ascular complications in veterans with type 2 diabetes. N Engl J Med 2009; 360:129-39
European Association of Urology 2008
European Association of Urology Guidelines on the management of urinary and male genital 
tract infections 2008. Available at http//www.uroweb.org/.
Gastaldelli A et al 2007
Gastaldelli A, Cusi K, Hardies J, et al. Relationship between hepatic/visceral fat and hepatic 
insulin resistance in non diabetic subjects. Gastroenterology 2007; 133: 496506. 
Hanson L 1999
Hanson L. The hypertension optimal treatment study and the importance of lowering blood 
pressure. Journal of Hypertension Supplement. 1999; 17:S9-S13
Heinig M et al 2006
Heinig M, Johnson RJ, Role of uric acid in hypertension, renal disease, and metabolic 
syndrome. Cleveland Clinic Journal of Medicine. 2006; 73:1059-1064
Inzucchi et al 2012
Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, FerranniniE, Nauck M. Management of 
Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care 2012; 35: 
1364-1379
JNC7 2004
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, 
and Treatment of High Blood Pressure. US Department of Health and Human Services. 
National Institutes of Health, National Hear Lung and Blood Institute. NIH Publication No.04-
5230. August 2004 
Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang Y(L), Castro AF, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T and Coresh J. A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009 May 5; 150(9): 604–612.
Nicolle et al 2005
Nicolle LE, Bradley S, Colgan R, Rice JC, Shaeffer A, Hooton M. Infectious Diseases Society 
of America: Guidelines for the diagnosis and treatment of asymptomatic Bacteriuria in adults. 
Clin Infect Dis 2005;40:643-54.


Revised Clinical Study Protocol
Drug Substance Dapagliflozin  
Study Code D1693C00001
Edition Number 5.0
Date 25 Sep 2016
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Skyler et al 2009
Skyler JS, Bergenstal R, Bonow RO, Deedwania P, EAM, et al. Intensive glycaemic control 
and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and 
VA diabetes trials: A position statement of the American Diabetes Association and a scientific 
statement of the American College of Cardiology Foundation and the American Heart 
Association. Diabetes Care 2009:32: 187-92.
UKPDS 1998
UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of 
macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. British 
Medical Journal. 1998; 317:713-720.
USPST 2004
US Preventative Services Taskforce. Recommendation Statement Screening for 
Asymptomatic Bacteriuria. Revised 2004. Available at 
http//www.ahrq.gov/clinic/uspstf/uspsbact.htm
Vega GL 2006
Vega GL, Adams-Huet B, Peshock R, Shah B, Grundy SM. Influence of body fat content and 
distribution on variation in metabolic risk. Journal of Clinical Endocrinology and Metabolism. 
2006; 91 (11):4459-66.


Clinical Study Protocol Appendix A
Drug Substance
Dapagliflozin
Study Code
D1693C00001
Edition Number
Final 5.0
Date
25 Sep 2016
Protocol Dated
12 November 2012
Appendix A
Signatures














Clinical Study Protocol Appendix B
Drug Substance
Dapagliflozin
Study Code
D1693C00001
Edition Number
Final 2.0
Date
25 Sep 2016
Appendix B
Additional Safety Information


Clinical Study Protocol Appendix B
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 2.0
Date 25 Sep 2016
2(3)
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 patient’s 
death.  ‘Life-threatening’ does not mean that had an AE occurred in a more severe form it 
might have caused death (eg, hepatitis that resolved without hepatic failure).
Hospitalization
Outpatient treatment in an emergency room is not in itself a serious AE, although the reasons 
for it may be (eg, bronchospasm, laryngeal edema).  Hospital admissions and/or surgical 
operations planned before or during a study (e.g. elective hospital admissions) 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. Elective 
hospitalizations meeting this definition should be reported on the hospitalization pages only.  
Elective revascularization without an associated clinical event (e.g. new or worsening illness 
or disease) should be recorded on the revascularization and AE form. 
Important medical event or medical intervention
Medical and scientific judgment should be exercised in deciding whether a case is serious in 
situations where important medical events may not be immediately life threatening or result in 
death, hospitalization, disability or incapacity but may jeopardize the 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.
Examples of such events are:
!
Angioedema not severe enough to require intubation but requiring iv hydrocortisone 
treatment
!
Hepatotoxicity caused by paracetamol (acetaminophen) overdose requiring 
treatment with N-acetylcysteine
!
Intensive treatment in an emergency room or at home for allergic bronchospasm
!
Blood dyscrasias (eg, neutropenia or anemia requiring blood transfusion, etc) or 
convulsions that do not result in hospitalization
!
Development of drug dependency or drug abuse.


Clinical Study Protocol Appendix B
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 2.0
Date 25 Sep 2016
3(3)
A GUIDE TO INTERPRETING THE CAUSALITY QUESTION
The following factors should be considered when deciding if there is a “reasonable 
possibility” that an AE may have been caused by the drug.
!
Time Course.  Exposure to suspect drug. Has the 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?
!
Dechallenge 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.
!
Rechallenge experience. Did the AE reoccur if the suspected drug was reintroduced 
after having been stopped? AstraZeneca would not normally recommend or support 
a rechallenge.
!
Laboratory tests. A specific laboratory investigation (if performed) has confirmed 
the relationship?
A “reasonable possibility” could be considered to exist for an AE where one or more of these 
factors exist.
In contrast, there would not be a “reasonable possibility” of causality if none of the above 
criteria apply or where there is evidence of exposure and a reasonable time course but any 
dechallenge (if performed) is negative or ambiguous or there is another more likely cause of 
the AE.
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?
Ambiguous cases should be considered as being a “reasonable possibility” of a causal 
relationship unless further evidence becomes available to refute this.  Causal relationship in 
cases where the disease under study has deteriorated due to lack of effect should be classified 
as no reasonable possibility.


 
 
Clinical Study Protocol Appendix C 
 
Drug Substance 
Dapagliflozin 
 
Study Code 
D1693C00001 
 
Edition Number 
Final 1.0 
 
Date 
12 November 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix C 
International Airline Transportation Association (IATA) 6.2 Guidance 
Document 
 


Clinical Study Protocol Appendix C 
Drug Substance Dapagliflozin 
Study Code D1693C00001  
Edition Number Final 1.0 
Date 12 November 2012 
2(3) 
LABELLING AND SHIPMENT OF BIOHAZARD SAMPLES 
International Airline Transportation Association (IATA) classifies biohazardous agents into 3 
categories (http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm).  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 eg, Ebola, Lassa fever virus: 
x
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 eg, 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: 
x
UN 3373 – Biological Substance, Category B 
x
are to be packed in accordance with UN3373 and IATA 650 
Exempt - all other materials with minimal risk of containing pathogens 
x
Clinical trial samples will fall into Category B or exempt under IATA regulations 
x
Clinical trial samples will routinely be packed and transported at ambient 
temperature in IATA 650 compliant packaging 
(http://www.iata.org/whatwedo/cargo/dangerous_goods/infectious_substances.
htm) 
x
Biological samples transported in dry ice require additional dangerous goods 
specification for the dry-ice content 
x
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 


Clinical Study Protocol Appendix C 
Drug Substance Dapagliflozin 
Study Code D1693C00001  
Edition Number Final 1.0 
Date 12 November 2012 
3(3) 
x
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. 
 


Clinical Study Protocol Appendix D
Drug Substance
Dapagliflozin
Study Code
D1693C00001
Edition Number
Final 3.0
Date
25 Sep 2016
Appendix D
Algorithm on Management of Sustained Elevated Liver Safety 
Abnormalities


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
2(6)
ALGORITHM ON MANAGEMENT OF SUSTAINED ELEVATED 
LIVER SAFETY ABNORMALITIES
The monitoring for liver safety will be performed using the serum levels of AST, ALT and TB 
(see Figure 1 algorithm flow chart).
Patients with a laboratory ALT and/or AST >3X ULN should be scheduled for a follow-up 
visit within 3 days, whenever possible, following receipt of the initial laboratory results, to 
obtain repeat central laboratory ALT, AST, TB and Alkaline Phosphatase (ALP). In the event 
that the repeat laboratory assessments cannot be obtained within 3 days, the Investigator is 
encouraged to discuss possible alternatives with the TIMI. Patients should remain on study 
medication until confirmatory results are obtained, unless otherwise contraindicated.
!
If the repeat ALT and AST are ∀3X ULN, patient should continue double-blind 
treatment according to their original visit schedule unless otherwise contraindicated.
!
If the repeat ALT and/or AST are >3X ULN but ∀8X ULN and TB ∀2X ULN, 
the patient’s medical history, including details of risk factors for liver diseases, 
should be evaluated for potential underlying aetiologies. In addition, specialized 
blood sampling will be performed to evaluate liver function as well as identify 
potential causes of laboratory elevation(s). The Investigator should continue to 
monitor the patient’s liver tests every 3 days following receipt of the prior 
laboratory results until the ALT and AST are ∀2X ULN or until ALT and AST are 
at or below baseline levels. The frequency of retesting can decrease to once a week 
or less if abnormalities stabilize and the patient is asymptomatic. Patients should 
remain on study medication unless confirmatory results indicate that a criterion for 
discontinuation has been met or continuing study medication would be otherwise 
contraindicated.
Patients must be discontinued from the study medication if an initial and repeat 
confirmatory laboratory tests meet any of the following criteria:
!
ALT and/or AST are #3 x ULN and TB #2 x ULN
!
ALT and/or AST are >5 x ULN confirmed over a period of 14 days or more
!
ALT and/or AST are >8 x ULN
In each of these situations, study medication will be discontinued, the Sponsor notified and the 
End of Treatment Visit performed within 3 days of the confirmed laboratory results (see 
Section 5.8.1). At the End of Treatment Visit, medical history including details of risk factors 
for liver diseases (if not previously assessed) will be requested and additional blood sampling 
performed (Hy’s law panel, see detailed below). 


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
3(6)
A referral consultation to a hepatologist or gastroenterologist (specializing in liver 
abnormalities) should be obtained. 
Following the End of Treatment Visit, the Investigator should continue to monitor the 
subject’s liver tests every 3 days following receipt of the prior laboratory results until the ALT 
and AST are ≤2 x ULN or until ALT and AST are at or below baseline levels. The frequency 
of retesting can decrease to once a week or less if abnormalities stabilize and the subject is 
asymptomatic.
Any additional tests and/or examinations should be carried out at the discretion of the 
Investigator. Any further investigations and laboratory results for patients with abnormal 
laboratory values at the Follow-up Visit should be made available to the Sponsor upon 
request.
Additional information, including but not limited to completion of supplemental eCRFs may 
be requested for certain adverse events and/or laboratory abnormalities which are 
reported/identified as part of the hepatic safety surveillance.
Guidance on Assessment of Hepatic Laboratory Abnormalities
The following is presented to assist in the evaluation and management of hepatic laboratory 
values. It is not intended to supplant Investigators’ clinical judgment.
Patients who experience ALT and/or AST values >3 x ULN confirmed with a repeated test 
will have the following performed within 3 days of the confirmed laboratory results:
!
AE assessment
!
Physical Examination for jaundice and other signs of liver diseases 
!
Review of relevant risk factors and current history focusing on possible causes of 
the increased ALT and/or AST and/or TB, including:
∃
Use of suspect concomitant medication [including over-the-counter (ie, 
acetaminophen/paracetamol), herbal and vitamin preparations]
∃
Recent alcohol consumption or recreational drug/narcotic use
∃
Recent unaccustomed physical exertion
∃
Occupational or environmental exposure to hepatotoxins 
∃
Other conditions which may cause liver diseases or which may cause abnormal 
test results
!
Hy’s law Panel (see below)


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
4(6)
Hy’s law Panel
For patients who are being monitored frequently as a result of confirmed AST and/or ALT 
>3X ULN, additional central laboratory tests should be performed within 3 days of receipt of 
confirmatory results. These laboratory tests will study the possible causes of the increased 
ALT and/or AST and/or TB, and may include, but are not limited to, the following tests:
!
Hepatitis A IgM
!
Hepatitis BsAg
!
Hepatitis B Core Ab IgM
!
Hepatitis C virus RNA
!
Hepatitis C Ab
!
Hepatitis E IgM
!
Epstein-Barr Virus (EBV) IgM Ab
!
Lactate Dehydrogenase (LDH)
!
Gamma-glutamyl-transpeptidase (GGT)
!
Carbohydrate deficient transferrin (CDT)
!
Prothrombin time (PT/INR)
!
Iron Panel - iron, ferritin, total iron binding capacity (TIBC)
!
Immunology Panel including Antinuclear Antibody (ANA), Anti-Smooth Muscle 
Antibody (SMA) and Anti-Liver/Kidney Microsomal Antibody (Anti-LKM)
!
Anti-tissue Transglutaminase Antibody
!
Cytomegalovirus (CMV) IgM Ab
!
Herpes Simplex Virus (HSV) 1 and 2
!
Ceruloplasmin
!
Toxoplasmosis
!
Alpha-1 antitrypsin


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
5(6)
For specific details regarding the Hy’s law Panel laboratory tests, refer to the Central 
Laboratory Manual for this study.


Clinical Study Protocol Appendix D
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
6 (6)
Figure 1
Sustained elevated liver safety abnormalities flow chart
Obtain confirmatory repeat AST, ALT, ALP and TB at central 
laboratory within 3 days. Do NOT hold study medication.
Step 1: Laboratory Criteria 
ALT and/or AST > 3x ULN
a
In patients with repeat ALT or AST > 3x ULN but ∀ 8x ULN, only patients with TB ∀ 2 x ULN at Step 1 should be followed according to Step 2b. Patients with an initial TB and 
confirmatory repeat TB > 2x ULN should be followed according to Step 2d.
b
Please see text above in the Appendix for details on additional assessments to be performed (AE assessment, PE, review of current medical history including focused review of 
current medical history including focused review of risk factors for liver diseases and collection of blood samples [Hy’s law panel]).
c
Confirmatory repeat AST, ALT, ALK-P and TB should be obtained every 3 days following receipt of prior laboratory results, until the ALT and AST are ∀ 2x ULN or until ALT and 
AST are at or below baseline levels. The frequency of retesting can decrease to once a week or less if abnormalities stabilize and the patient is asymptomatic.
If repeat ALT and/or AST > 5x ULN for % 14 consecutive days, at 
any time after initial confirmatory results
Each time AST, ALT, AL-P and TB results are received, go back 
to Step 2 to review and implement the appropriate follow-up
Step 2d:
If repeat ALT and/or AST
> 3x ULN with a second 
confirmed TB > 2 x ULNª
Step 2e:
If repeat ALT and/or 
AST > 8x ULN
Step 2c:
If repeat ALT and/or AST 
> 5x ULN BUT ∀ 8x ULN 
and TB ∀ 2x ULN
Step 2b:
If repeat ALT and/or AST # 3x 
ULN BUT ∀ 5x ULN and TB 
∀ 2x ULN
Step 2a:
If first repeat ALT and
AST ∀ 3x ULN 
OR after additional 
repeat testing ALT and 
AST % 2x ULN or at/or 
below baseline
Continue the patient 
in the double-blind 
treatment according 
to the original visit 
schedule, unless 
otherwise 
contraindicated.
-
Continue study medication
-
Perform additional 
assessments, including 
Hy’s law panelb
-
Obtain confirmatory 
repeat AST, ALT, ALP 
and TB every 3 days.c
-
Continue study medication
-
Perform additional 
assessments, including the 
Hy’s law panel panelb
-
Obtain confirmatory 
repeat AST, ALT, ALP 
and TB every 3 days.c
-
Discontinue the patient immediately from 
the study medication
-
Notify the Sponsor
-
Perform the End of Treatment visit and 
additional assessments, including the Hy’s law 
panelb
-
Obtain confirmatory repeat AST, ALT, 
ALP and TB every 3 days.c


 
 
Clinical Study Protocol Appendix E 
 
Drug Substance 
Dapagliflozin 
 
Study Code 
D1693C00001 
 
Edition Number 
Final 2.0 
 
Date 
19 December 2013 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix E 
Disease State Definitions  
 


Clinical Study Protocol Appendix E 
Drug Substance Dapagliflozin 
Study Code D1693C00001  
Edition Number Final 2.0 
Date 19 December 2013 
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DISEASE STATE DEFINITIONS 
1. 
Type 2 Diabetes Mellitus (T2DM) 
x
Diagnosis of T2DM can be based on the following: 

Prior documentation of type 2 diabetes AND/OR 

Treatment with anti-hyperglycemic medications and/or diet AND/OR 

ADA criteria: fasting >126 mg/dl (7.0 mmol/L) or HbA1C 6.5% or 2-h 
plasma glucose>200 mg/dl (11.1 mmol/L) during an oral glucose tolerance test, 
or a random plasma glucose > 200 mg/dL (11.1 mmol/L) in patients with 
classic symptoms of hyperglycemia or hyperglycemic crisis. In the absence of 
unequival hyperglycemia, results should be confirmed by repeat testing. 
2. 
Cardiovascular disease: 
2.1 
     Established Vascular Disease 
x
Ischemic heart disease (any of the following): 

Documented Myocardial Infarction 

Percutaneous Coronary Intervention 

Coronary Artery Bypass Grafting 

Objective Findings of Coronary Stenosis (> 50%) in at least 2 coronary artery  
territories (ie, left anterior descending, ramus intermedius, left circumflex, right 
coronary artery) involving the main vessel, a major branch, or a bypass graft 
x
Cerebrovascular disease (any of the following): 

Documented ischemic Stroke 

 Known transient ischemic attack, primary intracerebral haemorrhage or 
sub-arachnoid hemorrhage do not qualify. 

Carotid stenting or endarterectomy  
Please note, transient ischemic attack, primary intracerebral haemorrhage or sub-
arachnoid hemorrhage do not qualify 
x
Peripheral Arterial Disease (any of the following): 


Clinical Study Protocol Appendix E 
Drug Substance Dapagliflozin 
Study Code D1693C00001  
Edition Number Final 2.0 
Date 19 December 2013 
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
peripheral arterial intervention, stenting or surgical revascularization 

lower extremity amputation as a result of peripheral arterial obstructive disease 

Current symptoms of intermittent claudication AND ankle/brachial index 
(ABI) < 0.90 documented within last 12 months 
OR 
2.2 
Multiple Cardiac Risk Factors  
No known cardiovascular disease AND 

Age > 55 years in men and > 60 in women 
AND presence of at least 1 of the following additional risk factors 

Dyslipidemia (at least one of the following) 

Low-density lipoprotein cholesterol (LDL-C) >130 mg/dl (3.36 mmol/L) 
within last 12 months 

On lipid lowering therapy prescribed by a physician for 
hypercholesterolemia (ie LDL-C > 130 mg/dl (3.36 mmol/L)) for greater 
than 12 months. This should be verified by documentation of lab value 
LDL-C > 130 mg/dl (3.36 mmol/L). 

Hypertension (at least one of the following) 

BP >140/90 mm/Hg at enrollment visit. The patient must have both an 
elevated systolic BP (> 140 mmHg) and an elevated diastolic BP (> 90 
mmHg) on both measurements (see section 6.4.8.1) 

On anti-hypertensive therapy prescribed by a physician for blood pressure 
lowering 

Tobacco use (5 cigarettes/day or more for at least 1 year at randomization) 
 


 
 
 
Clinical Study Protocol Appendix F 
 
Drug Substance 
Dapagliflozin 
 
Study Code 
D1693C00001 
 
Edition Number 
Final 1.0 
 
Date 
12 November 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix F 
ADA/EASD Treatment Algorithm for Antihyperglycemic Therapy in 
T2DM 
 


2


3


4


 
 
 
Clinical Study Protocol Appendix G 
 
Drug Substance 
Dapagliflozin 
 
Study Code 
D1693C00001 
 
Edition Number 
Final 1.0 
 
Date 
12 November 2012 
 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix G 
AUA Recommendations For Evaluation of Asymptomatic Microscopic 
Hematuria 
 


2


Clinical Study Protocol Appendix H
Drug Substance
Dapagliflozin
Study Code
D1693C00001
Appendix Edition Number
Final 3.0
Appendix Date
25 Sep 2016
Appendix H


Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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!
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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Clinical Study Protocol Appendix H
Drug Substance Dapagliflozin
Study Code D1693C00001
Appendix Edition Number Final 3.0
Appendix Date 25 Sep 2016
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Clinical Study Protocol Appendix I
Drug Substance
Dapagliflozin
Study Code
D1693C00001
Edition Number
Final 3.0
Date
25 Sep 2016
Appendix I
Biomarker Research


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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TABLE OF CONTENTS
PAGE
TABLE OF CONTENTS.........................................................................................2
1.
BACKGROUND AND RATIONALE....................................................................3
2.
OBJECTIVES..........................................................................................................5
3.
BIOLOGIC RESEARCH PLAN AND PROCEDURES ........................................5
3.1
Selection of biologic research population................................................................5
3.1.1
Study selection record..............................................................................................5
3.1.2
Inclusion criteria ......................................................................................................5
3.1.3
Exclusion criteria .....................................................................................................5
3.1.4
Discontinuation of patients from this biologic research ..........................................5
3.2
Collection of samples for biologic research.............................................................6
3.3
Coding and storage of samples ................................................................................6
3.4
Analytes ...................................................................................................................6
4.
ETHICAL AND REGULATORY REQUIREMENTS...........................................7
5.
DATA MANAGEMENT.........................................................................................8
6.
STATISTICAL ANALYSIS PLAN........................................................................8
7.
LIST OF REFERENCES.........................................................................................9


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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1.
BACKGROUND AND RATIONALE
Diabetes is a chronic disease with activation of multiple pathologic inflammatory, thrombotic, 
and metabolic pathways (Pradhan and Ridker 2002).  Elevated levels of circulating pro-
inflammatory and thrombotic biomarkers can successfully identify patients at particularly high 
risk of developing incident diabetes (Meigs et al. 2004; Festa et al. 2006). However, the 
potential for biomarkers to predict the risk for future macro and microvascular adverse 
outcomes in patients with established diabetes has yet to be realized. By way of analogy, in 
terms of atherosclerosis, circulating biomarkers have proven extremely valuable in helping 
define which patients are at high risk for developing incident cardiovascular disease as well as 
defining which patients with prevalent cardiovascular disease are at highest risk for adverse 
clinical outcomes (Nozaki et al 2009 and Sabatine et al 2012).Thus, diabetic subjects with risk 
factors for or with established cardiovascular disease are an ideal patient population in which 
to leverage circulating biomarkers for risk stratification. 
Building on that concept, biomarkers that identify patients at higher risk for major adverse 
clinical outcomes can provide important insights in terms of tailoring therapy. Specifically, 
patients at higher risk for adverse events will, by definition, enjoy a greater absolute risk 
reduction for a given relative risk reduction from a therapy and hence require a smaller 
number needed to treat to prevent an adverse event. Moreover, patho-biologically relevant 
biomarkers may identify a specific subset of patients who enjoy a larger relative risk reduction 
with a given pharmaco-therapeutic intervention, and thus an even greater absolute risk 
reduction.
In addition to established biomarkers, new insights into mechanistic pathways and 
consequences of diabetes and atherothrombosis have fostered a steady pace of emergence of 
candidate novel cardiovascular and metabolic biomarkers. Using novel biomarkers that reflect 
the inflammatory, thrombotic, metabolic, and hemodynamic mediators of risk in subjects with 
diabetes and atherosclerotic disease, it may be possible to characterize noninvasively the 
participation of these different pathobiologic contributors in an individual subject and to 
monitor response to therapy (Morrow and Braunwald 2003). Thus, there is a tremendous 
opportunity to gain insight into pathobiology.
In terms of categories of biomarkers, those of interest for this study are broadly twofold-(1) 
those related to diabetes and metabolic disarray and its complications such as markers of 
glycation, metabolism, adiposity and renal dysfunction, and (2) those related to cardiovascular 
disease such as markers of atherosclerosis, ischemia, inflammation, thrombosis, hemodynamic 
stress and lipid dysregulation. A few select examples follow.
In terms of markers reflecting the vascular effects associated with glucose dysregulation, 
circulating advanced glycation products (AGEs), the soluble receptor for these AGEs 
(sRAGE), as well plasma phospholipid levels and ratios have been proposed as prognostic 
markers for vascular disease and heart failure. (Katakami et al 2006, Guo et al 2008 and 
Koyama et al 2008). 
Central obesity is a major underlying factor in insulin resistance. Adipocytes produce 
inflammatory molecules and adipokines such as adiponectin, leptin, angiotensinogen and 


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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resistin. These adipokines together play a major role in the development of atherosclerosis 
(Pittas et al 2004).
Increased serum cystatin C in the absence of explicit chronic kidney disease (CKD) has shown 
a graded association with increased cardiovascular disease (CVD) morbidity and mortality 
(Menon et al 2007).
Cardiac troponin is commonly used for diagnosis of acute myocardial infarction.  More 
recently, however, the advent of high-sensitivity assays has now permitted quantification of 
troponin in stable individuals and the demonstration that higher levels of troponin are 
associated with an increased risk of cardiovascular mortality (Omland et al 2009).
Similarly, the natriuretic peptides (eg, BNP, ANP and their N-terminal prohormones) have 
been used to risk stratify patients with ACS, and now have also been shown to act as robust 
predictors of the short and long-term risk of cardiovascular death in patients with stable 
ischemic heart disease (Kragelund et al 2005 and Omland et al 2007).
Inflammation is central to atherothrombosis and insulin resistance and thus biomarkers that 
provide insight into the inflammatory processes that preceed and lead up to atherothrombosis 
such as oxidative stress, leukocyte recruitment and activation, and fibrous cap degradation 
offer predictive value.  For example, high-sensitivity measurement of C-reactive protein (hs-
CRP), an acute phase reactant and global barometer of inflammation, has been shown to 
predict risk of first MI in healthy cohorts (Ridker et al 2000 and Danesh et al 2004) and future 
coronary events in patients with stable CHD (Haverkate et al 1997 and Sabatine et al 2007).  
Enzymes such as lipoprotein-associated and secretory type II phospholipase A2 (Lp-PLA2 
and sPLA2) that hydrolyze phospholipids to generate pro-atherogenic compounds are 
independent predictors of recurrent coronary events in stable patients (Koenig et al 2006, 
Sabatine et al 2007, Kugiyama et al 1999 and Mallat et al 2007).
Elevated circulating levels of several biomarkers of platelet activation, thrombosis, and 
endothelial dysfunction not only predict events, but may offer insight into which patients 
benefit the most from potentially cardioprotective therapy. For example, soluble CD40 ligand, 
(a marker of platelet activation and potential direct participant in plaque destabilization) and 
myeloid-related protein (MRP)-8/14 (discovered using transcriptomics to be upregulated 
during ACS) are independent predictors of cardiovascular events (Heeschen et al 2003) 
(Healy et al 2006 and Morrow et al 2008).
Finally, biomarkers may also help detect adverse safety signals with diabetes and other 
cardiovascular medications.
Thus, the evaluation of biomarkers in patients in this trial may provide important insight into 
pathobiology of diabetes and cardiovascular disease, improve our ability to risk stratify 
patients, and provide information that can be used to tailor therapy. This study may also 
provide additional insights into the possible mechanistic pathways leading to CV benefit with 
dapagliflozin.
.


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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2.
OBJECTIVES
1.
To evaluate the value of individual biomarkers and a multi-marker approach for 
predicting major adverse cardiovascular outcomes in a diabetic population.
2.
To evaluate whether diabetic patients identified at higher risk on the basis of 
biomarkers experience greater absolute and /or relative risk reduction in major 
adverse cardiovascular outcomes with dapagliflozin versus placebo.
3.
To evaluate the change over time in biomarkers in patients with diabetes; to assess 
whether treatment with dapagliflozin alters this natural history; and to examine the 
correlation of change in biomarkers with subsequent clinical outcomes.
3.
BIOLOGIC RESEARCH PLAN AND PROCEDURES
This appendix to the Clinical Study Protocol has been subjected to peer review according to 
AstraZeneca and Bristol-Myers Squibb standard procedures.
3.1
Selection of biologic research population
3.1.1
Study selection record
All patients in select countries will be asked to participate in this biologic research.  
Participation is voluntary and if a patient declines to participate there will be no penalty or 
loss of benefit. The patient will not be excluded from any aspect of the main study.
3.1.2
Inclusion criteria
For inclusion in this biologic research, patients must fulfil all of the inclusion criteria 
described in the main body of the Clinical Study Protocol.
3.1.3
Exclusion criteria
Exclusion from this biologic research may be for any of the exclusion criteria specified in the 
main study.
3.1.4
Discontinuation of patients from this biologic research
Specific reasons for discontinuing a patient from this biologic research are:
!
Withdrawal of consent for biologic research: Patients may withdraw from this 
biologic 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 the main Clinical 
Study Protocol.


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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3.2
Collection of samples for biologic research
All patients in participating countries will be asked to participate in this biologic research at 
Visit 2. If the patient agrees to participate, blood samples will be taken at Visit 2 
(Randomization) and Visit 4 (month 6) in patients in select countries. Detailed procedures are 
described in the Laboratory Manual of Operations.
3.3
Coding and storage of samples
The processes adopted for the coding and storage of samples for biologic analysis are 
important to maintain patient confidentiality. The biomarker samples will be labeled (or 
“coded”) with a study specific code. Samples do not carry any patient identifying information. 
Samples will be stored for a maximum of 20 years following the finalization of the CSR, after 
which they will be destroyed. Samples will be stored and used until no further analyses are 
possible or the maximum storage time has been reached.
3.4
Analytes
Categories of biomarkers of interest and select examples are listed below; specific biomarkers 
to be explored will depend on the totality of published data at the time analyses are ready to 
commence. Examples of categories and biomarkers are listed below.
Biomarkers of Inflammation and Atherothrombosis:
• hs-CRP
• phospholipases (eg, Lp-PLA2 and sPLA2)
• metalloproteinases (eg, PAPP-A, MMP-9, MMP-11)
• cytokines (eg, IL-1β, IL-1Ra, IL-6, IL-18, GDF-15, PlGF)
• chemotactic molecules (eg, MCP-1)
Glycation end products and associated receptors
• For example: AGE, sRAGE, RAGE
Biomarkers of Metabolic/Lipid Dysregulation/Insulin Resistance
• Adipokines (eg, adiponectin)
• Lipoproteins and modified/oxidized lipoproteins
• Lp(a)


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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Biomarkers of Oxidative Stress
• Myeloperoxidase
• ADMA and other arginine metabolism products
Biomarker of Renal Dysfunction
• For example: cystatin-C, FGF-23, NGAL
Biomarkers of Endothelial Function
• For example: VCAM-1, ICAM-1, vWF, E-selectin, 
Biomarkers of Thrombosis
• For example: sCD40L
Biomarkers of Ischemia/Necrosis
• For example: cardiac troponin, FABP
Biomarkers of Hemodynamic Stress
• Natriuretic peptides (eg, BNP, ANP and their NT-prohormones)
• MR-adrenomedullin, C-terminal proendothelin 1, copeptin
• ST-2
• Galectin-3 
As the field of biomarkers is rapidly evolving, future data may suggest a role of additional 
biomarkers in the risk for cardiovascular outcomes and the response to treatment, which may 
lead to additional exploratory research. In addition to analysis of existing biomarkers, 
proteomics and metabolomic analyses may be performed on samples to develop and test novel 
protein markers of cardiovascular outcomes.
Blood samples may be analyzed by the TIMI Study Group, AstraZeneca and potentially their
collaborators and/or vendors. Samples will be stored for up to 20 years (or sooner as required 
by local regulations) and then destroyed. 
4.
ETHICAL AND REGULATORY REQUIREMENTS
The principles for ethical and regulatory requirements for the study, including this biologics 
research component, are outlined in Section 8 of the main Clinical Study Protocol.


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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Informed consent
The biologic component of this study is optional and the patient may participate in other 
components of the main study without participating in the biologic component. The principal 
investigator(s) is responsible for ensuring that consent is given freely and that the patient 
understands that they may freely discontinue from the biologic aspect of the study at any time.
Patient data protection
AstraZeneca will not provide individual results to patients, any insurance company, any 
employer, their family members, general physician or any other third party, unless required to 
do so by law.
Extra precautions are taken to preserve confidentiality and prevent biologic data being linked 
to the identity of the patient. In exceptional circumstances, however, certain individuals might 
see both the biologic data and the personal identifiers of a patient. For example, in the case of 
a medical emergency an AstraZeneca Physician or an investigator might know a patient’s 
identity and also have access to his or her biologic data.  Also Regulatory authorities may 
require access to the relevant files, though the patient’s medical information and the biologic 
files would remain physically separate.
5.
DATA MANAGEMENT
Biomarker data from the TIMI Biomarker Core Lab will be merged with the clinical database 
for statistical analysis.
The results from this biologic research may be reported in the CSR for the main study, or in a 
separate report as appropriate.
Some or all of the clinical datasets from the main study may be merged with the biologic data 
in a suitable secure environment separate from the clinical database. 
6.
STATISTICAL ANALYSIS PLAN
A sample size of 15,000 patients will provide 80% power to detect an odds ratio of ≥1.20 for 
the primary endpoint for patients above vs. those below the median level of a biomarker.  This 
sample size will also provide approximately 80% power to detect interaction hazard ratios (the 
ratio of HRs for the benefit of dapagliflozin on the primary endpoint in those above and below 
the median of a biomarker) of ≤0.70 (assuming a treatment effect of 0.85 and a risk of 1.20 for 
the biomarker).  These values are in keeping with risk estimates and interactions seen with 
other biomarkers and represent the thresholds of clinical importance.  These calculations 
assume an event rate as outlined in the main protocol and that 10% of samples will be 
non-evaluable for a given biomarker, and uses a two-sided alpha threshold of 0.05 (no 
correction for multiple hypotheses testing as all analyses are exploratory).  


Clinical Study Protocol Appendix I
Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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7.
LIST OF REFERENCES 
Danesh et al 2004
Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. C-Reactive 
Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart 
Disease. N Engl J Med. 2004;350(14):1387-1397.
Festa et al 2006
Festa, A, Williams K, et al. "Progression of plasminogen activator inhibitor-1 and fibrinogen 
levels in relation to incident type 2 diabetes." Circulation. 2006;113(14): 1753-9.
Guo et al 2008
Guo, ZJ, Niu HX, et al. "Advanced oxidation protein products activate vascular endothelial 
cells via a RAGE-mediated signaling pathway." Antioxid Redox Signal. 2008;10(10): 1699-
712.
Haverkate et al 1997
Haverkate F, Thompson SG, Pyke SD, Gallimore JR, Pepys MB. Production of C-reactive 
protein and risk of coronary events in stable and unstable angina. European Concerted Action 
on Thrombosis and Disabilities Angina Pectoris Study Group. Lancet. 1997;349(9050):462-
466.
Healy et al 2006
Healy AM, Pickard MD, Pradhan AD, Wang Y, Chen Z, Croce K, et al. Platelet expression 
profiling and clinical validation of myeloid-related protein-14 as a novel determinant of 
cardiovascular events. Circulation. 2006;113(19):2278-2284.
Heeschen et al 2003
Heeschen C, Dimmeler S, Hamm CW, van den Brand MJ, Boersma E, Zeiher AM, et al. 
Soluble CD40 ligand in acute coronary syndromes. N Engl J Med. 2003;348(12):1104-1111.
Katakami et al 2006
Katakami, N, Matsuhisa M, et al. "Endogenous secretory receptor for advance glycation end 
product levels are inversely associated with HbA1c in type 2 diabetic patients." Diabetes 
Care. 2006;29(2): 469.
Koyama et al 2008
Koyama, Y, Takeishi Y, et al. "Soluble Receptor for advanced glycation end products 
(RAGE) is a prognostic factor for heart failure." J Card Fail. 2008;14(2): 133-9. 
Koenig et al 2006
Koenig W, Twardella D, Brenner H, Rothenbacher D. Lipoprotein-associated phospholipase 
A2 predicts future cardiovascular events in patients with coronary heart disease independently 
of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. 
Arterioscler Thromb Vasc Biol. 2006;26(7):1586-1593.


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Drug Substance Dapagliflozin
Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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Kragelund et al 2005
Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type 
natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med. 
2005;352(7):666-675.
Kugiyama et al 1999
Kugiyama K, Ota Y, Takazoe K, Moriyama Y, Kawano H, Miyao Y, et al. Circulating levels 
of secretory type II phospholipase A(2) predict coronary events in patients with coronary 
artery disease. Circulation. 1999;100(12):1280-1284.
Mallat et al 2007
Mallat Z, Benessiano J, Simon T, Ederhy S, Sebella-Arguelles C, Cohen A, et al. Circulating 
secretory phospholipase A2 activity and risk of incident coronary events in healthy men and 
women: the EPIC-Norfolk study. Arterioscler Thromb Vasc Biol. 2007;27(5):1177-1183.
Meigs et al 2004
Meigs, JB, Hu FB, et al. "Biomarkers of endothelial dysfunction and risk of type 2 diabetes 
mellitus." JAMA. 2004;291(16): 1978-86
Menon et al 2007
Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L, Kusek JW, Beck GJ, Collins 
AJ, Levey AS, Sarnak MJ. Cystatin C as a risk factor for outcomes in chronic kidney disease. 
Ann Intern Med. 2007;147:19–27 
Morrow and Braunwald 2003
Morrow DA, Braunwald E. "Future of biomarkers in acute coronary syndromes: moving 
toward a multimarker strategy." Circulation. 2003;108(3): 250-2
Morrow et al 2008
Morrow DA, Wang Y, Croce K, Sakuma M, Sabatine MS, Gao H, et al. Myeloid-related 
protein 8/14 and the risk of cardiovascular death or myocardial infarction after an acute 
coronary syndrome in the Pravastatin or Atorvastatin Evaluation and Infection Therapy: 
Thrombolysis in Myocardial Infarction (PROVE IT-TIMI 22) trial. Am Heart J. 
2008;155(1):49-55.
Nozaki et al 2009
Nozaki T, Sugiyama S, Koga H, Sugamura K, Ohba K, Matsuzawa Y, Sumida H, Matsui K, 
Jinnouchi H, Ogawa H. Significance of a multiple biomarkers strategy including endothelial 
dysfunction to improve risk stratification for cardiovascular events in patients at high risk for 
coronary heart disease. J Am Coll Cardiol. 2009;Aug 11;54(7):601-8.
Omland et al 2007
Omland T, Sabatine MS, Jablonski KA, Rice MM, Hsia J, Wergeland R, et al. Prognostic 
value of B-Type natriuretic peptides in patients with stable coronary artery disease: the 
PEACE Trial. J Am Coll Cardiol. 2007;50(3):205-214.


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Study Code D1693C00001
Edition Number Final 3.0
Date 25 Sep 2016
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Omland et al 2009
Omland T, de Lemos JA, Sabatine MS, Christophi CA, Rice MM, Jablonski KA, et al. A 
sensitive cardiac troponin T assay in stable coronary artery disease. N.Engl.J.Med. 2009;Dec 
24;361(26):2538-2547.
Pittas et al 2004
Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin
Endocrinol Metab. 2004;89:447–452.
Pradhan and Ridker.2002
Pradhan AD, Ridker PM. "Do atherosclerosis and type 2 diabetes share a common 
inflammatory basis?" Eur Heart J 2002;23(11): 831-4
Ridker et al 2000
Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of 
inflammation in the prediction of cardiovascular disease in women. N. Engl. J. Med.
2000;342(12):836-843. 
Sabatine et al 2007
Sabatine MS, Morrow DA, Jablonski KA, Rice MM, Warnica JW, Domanski MJ, et al. 
Prognostic significance of the Centers for Disease Control/American Heart Association high-
sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with 
stable coronary artery disease. Circulation. 2007;115(12):1528-1536
Sabatine et al 2012
Sabatine MS, Morrow DA, de Lemos JA, Omland T, Sloan S, Jarolim P, Solomon SD, Pfeffer 
MA, Braunwald E. Evaluation of multiple biomarkers of cardiovascular stress for risk 
prediction and guiding medical therapy in patients with stable coronary disease. Circulation.
2012 Jan 17;125(2):233-40

SAP_001.pdf: 
Statistical Analysis Plan
Study Code
D1693C00001
Edition Number
8
Date
31 May 2018
DECLARE
Dapagliflozin Effect on CardiovascuLAR Events
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to
Evaluate the Effect of Dapagliflozin 10 mg Once Daily on the Incidence of
Cardiovascular Death, Myocardial Infarction or Ischemic Stroke in 
Patients with Type 2 Diabetes






Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
4
TABLE OF CONTENTS
PAGE
TITLE PAGE.......................................................................................................................1
SIGNATURE OF STUDY STATISTICIAN........................................................................2
SIGNATURE OF GLOBAL PRODUCT STATISTICIAN ..................................................3
TABLE OF CONTENTS.....................................................................................................4
LIST OF ABBREVIATIONS ..............................................................................................7
INTRODUCTION .............................................................................................................12
1.
STUDY DETAILS.............................................................................................12
1.1
Study objectives................................................................................................. 12
1.1.1
Primary objectives .............................................................................................12
1.1.2
Secondary objectives..........................................................................................12
1.1.3
Safety objectives................................................................................................12
1.1.4
Exploratory objectives .......................................................................................13
1.2
Study design ...................................................................................................... 14
1.3
Randomization...................................................................................................16
1.4
Number of patients.............................................................................................17
1.4.1
Sample size calculations.....................................................................................17
2.
ANALYSIS SETS .............................................................................................19
2.1
Definition of analysis sets .................................................................................. 19
2.1.1
Full analysis set (FAS).......................................................................................19
2.1.2
Safety analysis set..............................................................................................20
2.1.3
On-treatment analysis set ...................................................................................20
2.1.4
Summary of analysis sets and variables to be analyzed.......................................21
2.2
Protocol deviations............................................................................................. 21
3.
PRIMARY AND SECONDARY VARIABLES.................................................22
3.1
Primary variables ...............................................................................................22
3.2
Secondary variables ........................................................................................... 22
3.3
Other efficacy variables .....................................................................................23
3.4
Safety variables..................................................................................................24
3.5
Exploratory variable - DNA ............................................................................... 24
3.6
Analysis of biomarkers ...................................................................................... 24
4.
ANALYSIS METHODS....................................................................................25
4.1
General principles.............................................................................................. 25


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
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4.1.1
Baseline value....................................................................................................27
4.1.2
Baseline hematuria:............................................................................................27
4.1.3
Change from baseline.........................................................................................27
4.1.4
eGFR and Creatinine Clearance formulas...........................................................27
4.1.5
Body Mass Index ...............................................................................................28
4.1.6
Descriptive summaries of continuous variables ..................................................28
4.1.7
Descriptive summaries of categorical variables ..................................................28
4.1.8
Summaries of shifts from baseline in categorical variables.................................28
4.1.9
Cox Proportional Hazards Model .......................................................................28
4.1.10
Analysis of repeated measures............................................................................30
4.1.11
Analysis of proportions ......................................................................................31
4.1.12
Analysis of incidence rate ratios and differences ................................................31
4.1.13
Kaplan-Meier curve and estimates for time-to-event analyses ............................32
4.1.14
Stratification of analyses ....................................................................................32
4.2
Study population................................................................................................ 32
4.2.1
Patient disposition..............................................................................................32
4.2.2
Protocol deviations.............................................................................................32
4.2.3
Demographic and other baseline characteristics..................................................32
4.2.4
Specific and General Disease Histories ..............................................................36
4.3
Extent of exposure .............................................................................................36
4.3.1
Medication at randomization and Concomitant Medications...............................37
4.3.2
Measurements of Treatment Compliance ...........................................................37
4.4
Analysis methods for primary, secondary and exploratory efficacy 
variables.............................................................................................................37
4.4.1
Primary variables ...............................................................................................37
4.4.1.1
Hypotheses ........................................................................................................37
4.4.1.2
Analyses of the primary variables ......................................................................38
4.4.1.3
Considerations of incomplete follow-up.............................................................40
4.4.2
Secondary and exploratory variables analysed as time to event...........................42
4.4.3
The closed testing procedure..............................................................................43
4.4.4
Other efficacy variables .....................................................................................44
4.5
Analysis methods for safety variables.................................................................46
4.5.1
Adverse events, including hypoglycaemia..........................................................47
4.5.1.1
Procedures for counting AEs.............................................................................. 47
4.5.1.2
Serious Adverse Events......................................................................................47
4.5.1.3
Adverse Events leading to discontinuation .........................................................48
4.5.1.4
Adverse events of special interest.......................................................................48
4.5.2
Laboratory Evaluation........................................................................................50
4.5.2.1
Marked Laboratory Abnormalities .....................................................................51
4.5.2.2
Changes from baseline values ............................................................................51
4.5.3
Physical findings and other observations related to safety...................................51
4.5.3.1
Vital signs.......................................................................................................... 51
4.5.3.2
Amputations and related events.......................................................................... 51
4.5.3.3
Potential diabetic ketoacidosis............................................................................51


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
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5.
INTERIM ANALYSES .....................................................................................52
6.
CHANGES OF ANALYSIS FROM PROTOCOL .............................................54
7.
REFERENCES ..................................................................................................54
LIST OF TABLES
Table 1
Levels of bladder and breast cancer relative risks and incidence 
rate differences that can be ruled out under different assumptions .........18
Table 2
Clarification on what analysis sets will be considered as primarily 
and as sensitivity for efficacy and safety variables.................................21
Table 3
Summaries of Demographic, Diabetes-Related Characteristics and 
Cancer risk factors at Baseline...............................................................33
Table 4
Summary of Baseline CV Risk Level and Risk Factors .........................36
Table 5
Confirmatory Testing Procedures Using One-sided Alphas ...................44
Table 6
Imbalance of bladder cancers. Significant difference (binomial) 
between bladder cancers at different alpha levels. Under the 
condition that there is no true difference in bladder cancer 
incidence between Dapagliflozin and Placebo. ......................................54
Table 7
Marked Abnormality Criteria for Safety Laboratory Parameters
Marked abnormality criteria for safety laboratory variables and 
elevated AT (ALT and/or AST) and total bilirubin................................56
LIST OF APPENDICES
Appendix A
Laboratory Abnormality Criteria ...........................................................56
Appendix B
Definition of Regions............................................................................58


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
7
LIST OF ABBREVIATIONS 
The following abbreviations and special terms are used in this Statistical Analysis Plan (SAP).
Abbreviation or 
special term
Explanation
AE
ARB
Adverse Event
Angiotensin Receptor Blocker
ACEi
Angiotensin-Converting-Enzyme inhibitor
BMI
Body Mass Index
BP
Blood pressure
CEC
Clinical Event Adjudication Committee
CI
CrCl
Confidence interval  
Creatinine Clearance
CRF
Case Report Form (electronic/paper)
CV
Cardiovascular
CKD-EPI
Chronic Kidney Disease Epidemiology Collaboration
DAE
DMC
DNA
DPP4
AE leading to discontinuation of study drug
Data Monitoring Committee
Deoxyribonucleic acid
Dipeptidyl peptidase 4
E-code
eCRF
Enrolment code
electronic Case Report Form
eCVD
Established CardioVascular Disease
eGFR
Estimated Glomerular Filtration Rate
Ethics Committee
EoT
Synonymous to Institutional Review Board and Independent Ethics 
Committee
End of Treatment
ESRD
End State Renal Disease
FAS
Full Analysis Set
FPG
GFR
GLP-1
Fasting plasma glucose
Glomerular Filtration Rate
Glucagon-like peptide-1
HbA1c
Glycated haemoglobin 
HDL-C
High-density lipoprotein-cholesterol


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
8
Abbreviation or 
special term
Explanation
HR
ICF
Hazard ratio
Informed Consent Form
IP
Investigational Product
IVRS/IWRS
Interactive voice response system/interactive web response system
LDL-C
Low-density lipoprotein-cholesterol
LS
MA
MACE
Least Squares
Marked Abnormality
Major Adverse Cardiovascular Events (CV Death, MI, Ischemic Stroke)
MedDRA
Medical Dictionary for Regulatory Activities
MI
MRF
Myocardial infarction
Multiple Risk Factors
PT
RR
Preferred Term
Relative Risk
SAE
Serious Adverse Event
SAP
SAS
Statistical Analysis Plan
Statistical Analysis System
SCr
SD
SE
SEER
Serum Creatinine
Standard Deviation
Standard Error
Surveillance, Epidemiology and End Results
SOC
SU
System Organ Class
Sulphonylurea
T2DM
Type 2 diabetes mellitus
ULN
Upper Limit of Normal
WHO
World Health Organization


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
9
Notable Changes in SAP Edition 8, as compared to SAP Edition 7
Section
Description of Change
Rationale
Section 1.1.4 
(Exploratory 
Objectives); 
Section 3.3 (Other 
efficacy variables)
Moved “Surgical Amputation and 
related events” from the list of 
exploratory efficacy objectives to 
the safety section. 
To consolidate the analysis of 
amputations and related events as 
a safety variable in the safety 
section. 
Section 2.1 
(Definition of 
analysis sets)
Removed the following provision 
regarding site 5709 in SAP Edition 
7, “Sensitivity analyses on primary 
endpoints and for bladder cancer 
may be performed including these 
patients.”
To improve clarity.
Section 3 
(PRIMARY AND 
SECONDARY 
VARIABLES)
Clarified how the deaths 
adjudicated as undetermined cause 
will be handled in the statistical 
analyses. 
To improve clarity.
Section 3.3 (Other 
efficacy variables)
Added eGFR slopes as a new 
exploratory efficacy variable.
In consideration of the 
NKF/EMA/FDA workshop on 
albuminuria and GFR in March
2018. 
Section 3.3 (Other 
efficacy variables)
Added a new renal composite 
endpoint under “Other efficacy 
variables”. As compared to the 
secondary renal composite 
endpoint, this new exploratory 
endpoint excludes CV death as a 
component.    
To further characterize the 
treatment effect on the 
components specifically for renal 
outcomes.
Section 4.1 
(General 
principles)
Clarified imputation of partially 
missing dates. 
To improve clarity.
Section 4.1.9 (Cox 
Proportional 
Hazards Model)
Specified that HR estimates will 
not be generated for subgroups with 
fewer than 15 total events across 
the two treatment groups. 
In consideration of the large 
variability associated with few 
events. 


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
10
Section
Description of Change
Rationale
Section 4.1.9 (Cox 
Proportional 
Hazards Model); 
Section 4.1.12 
(Analysis of 
incidence rate 
ratios and 
differences); 
Section 4.5.1.4 
(Adverse events of 
special interest)
Clarified how event rates will be 
calculated. 
To improve clarity.
Section 4.3.2 
(Measurements of 
Treatment 
Compliance)
Changed definition for study drug 
compliance from visit specific to 
study specific. 
To adapt to the data where study 
drug returned was associated 
with not only the preceding 
dispense visit but also earlier 
dispense visits. 
Section 4.4.1.2
(Analyses of the 
primary variables)
Added a sensitivity analysis of 
competing risks with respect to the 
primary endpoints. 
As requested by the FDA. 
Section 4.4.1.3 
(Considerations of 
incomplete follow-
up)
Added sensitivity analyses 
regarding LTFU patients, 
specifically, multiple imputations 
and tipping point analysis. 
As requested by the FDA.
Section 4.4.1.2 
(Analysis of the 
primary variables); 
Section 4.4.1.3 
(Considerations of 
incomplete follow-
up)
Re-organized the sensitivity 
analyses between the two sections. 
To improve clarity and 
readability.
Various sections
Minor clarifications and editorial 
changes. 
To improve clarity and 
readability. 


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
11
Section
Description of Change
Rationale


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
12
INTRODUCTION
This statistical analysis plan (SAP) is a comprehensive and detailed description of the 
strategy, rationale and statistical techniques that will be used to assess the safety and efficacy 
of dapagliflozin compared to placebo in patients with Type 2 diabetes mellitus (T2DM) and 
with either known cardiovascular (CV) disease or at least two risk factors for CV disease in 
addition to T2DM.
1.
STUDY DETAILS
1.1
Study objectives
1.1.1
Primary objectives
The primary objective is to determine the effect of dapagliflozin relative to placebo on 
cardiovascular outcome when added to current background therapy in patients with T2DM 
with either established cardiovascular disease or at least two cardiovascular risk factors.
This objective will be evaluated in two steps. The first step will determine if dapagliflozin is 
non-inferior to placebo for the incidence of the composite endpoint of CV death, MI or 
ischemic stroke, assessed with a non-inferiority margin of 1.3. If this is met the second step 
will determine if dapagliflozin reduces the incidence of the co-primary endpoints: the 
composite of cardiovascular death, myocardial infarction (MI), or ischemic stroke, and the 
composite of hospitalization for heart failure or CV death compared to placebo 
1.1.2
Secondary objectives
Secondary objectives
The secondary objective is to determine whether treatment with dapagliflozin compared with 
placebo when added to current background therapy in patients with T2DM with either 
established CV disease or at least two CV risk factors in addition to T2DM will result in a 
reduction of:
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR 
<60 mL/min/1.73m2 and/or ESRD (dialysis ≥90 days or kidney transplantation, 
confirmed sustained eGFR <15 mL/min/1.73m2) and/or renal or CV death
!
All-cause mortality
1.1.3
Safety objectives
Safety and tolerability will be assessed from overall adverse events, serious adverse events, 
adverse events of special interest, and laboratory test results. The safety assessment will 
include an evaluation of the incidence of adjudicated bladder cancer and liver injury.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
13
1.1.4
Exploratory objectives
Other efficacy objectives are to determine whether treatment with dapagliflozin compared 
with placebo when added to current background therapy in patients with T2DM and either 
established CV disease or at least two CV risk factors in addition to T2DM will result in a 
reduction of:
!
The individual components of the co-primary efficacy endpoints (cardiovascular 
death, MI, ischemic stroke, hospitalization for heart failure)
!
The composite endpoint of CV death, MI, ischemic stroke, hospitalization for heart 
failure, hospitalization for unstable angina pectoris, or hospitalization for coronary 
or non-coronary revascularization and the additional individual components of 
hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization
!
Glycosylated hemoglobin A1c (HbA1c)
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for any of the following: an increase in dose for an oral anti-diabetes 
medication or ≥ 25% increase in insulin dose or the addition of new anti-diabetes 
medication, for ≥ 3 months
!
Major hypoglycaemia and/or hospitalization for hypoglycaemia
!
Confirmed sustained macroalbuminuria (UACR ≥300 mg/g) in subjects without 
macroalbuminuria at baseline
!
Development of albuminuria
!
Albuminuria
!
Decrease in eGFR
!
Albumin to creatinine ratio
!
Body weight
!
Retinal laser and/or intraocular treatment due to development of and/or 
deterioration in diabetic retinopathy
!
Blood pressure 
!
Peripheral revascularization/Limb ischemic events
!
Any stroke (ischemic, hemorrhagic, or undetermined)


Statistical Analysis Plan 
Study Code D1693C00001
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Date 31 May 2018
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An exploratory objective is to collect and store biomarkers for future exploratory research that 
may influence response, (e.g., distribution, safety, tolerability and efficacy) to treatment with 
dapagliflozin or other drugs that may influence susceptibility to T2DM and/or associated CV 
conditions and their risk factors.
1.2
Study design
This is a multicenter, randomized, double-blind, placebo-controlled Phase 3b study to 
determine the effect of dapagliflozin relative to placebo on the primary composite endpoints in 
patients with T2DM and with either known CV disease or at least two risk factors for CV 
disease in addition to T2DM. It is estimated that approximately 27000 patients will be 
enrolled to reach the target of 17150 randomized patients. The anticipated duration of the 
study is approximately 6 years, including an anticipated enrollment period of 3 years and a 
median follow-up period of 4.5 years. Closeout of the trial will commence when 1390 subjects 
with adjudicated MACE events required to test the primary objective has been reached.
All patients should be treated according to regional standards of care for diabetes (HbA1c 
goals) and other CV risk factors (e.g., hypertension, hyperlipidemia).
The study will recruit T2DM patients at increased risk for CV events according to the two 
categories below:
!
Patients with established CV disease (eCVD)
!
Patients with at least 2 CV risk factors (age and one additional), but without 
established CV disease (Multiple Risk Factors; MRF)
Approximately 17150 patients meeting all eligibility criteria at approximately 1200 study sites 
will be randomized (1:1) to receive either dapagliflozin or placebo.
Enrollment of patients based on disease state (MRF vs. eCVD), geographic region and sex 
will be monitored and may be capped to ensure adequate representation.
All potentially eligible patients will undergo a screening visit. Each patient will sign an 
Informed Consent Form (ICF) prior to having any screening evaluations performed. Patients 
who fulfill all eligibility requirements will enter into a 4 to 8 weeks placebo run-in period 
during which they will be given placebo in a single-blind fashion (blind to patient only) on top 
of previous treatment and assessed for compliance (80 to 120%, unless a reason for non-
compliance is judged acceptable by the Investigator).


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
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Approximately 4 to 8 weeks after entering the run-in period, based upon Investigator 
discretion, patients will be expected to undergo a randomization visit. Patients may withdraw 
prior to the randomization visit, or be withdrawn by study staff for any reason. At this visit 
patients will be re-evaluated by study staff to determine if after testing performed at screening, 
after assessment of compliance, and any clinical changes that may have occurred during the 
run-in period, the patient remains eligible and committed to participation in the study. If for 
any reason, prior to or during the randomization visit the patient is no longer eligible or 
interested in participating in the trial, he or she will be considered a run-in failure, will not be 
randomized and will not have additional follow up.
If a patient is committed to participation, completes placebo run-in period and continues to 
meet criteria at the randomization visit, he or she will be randomized and will receive either 
dapagliflozin 10 mg daily or matching placebo in a double-blind fashion.
During the randomized treatment period, diet and life-style modification will continue to be 
reinforced, in addition to adjustments of drug treatments for diabetes and or CV risk factors, 
as applicable.
An independent Data Monitoring Committee (DMC), a blinded independent Clinical Event 
Adjudication Committee (CEC) (see Section 12.4 in protocol) and Executive and Steering 
Committees (see Section 12.5 in protocol) will be selected by the Sponsors and the academic 
leadership.
The study plan, including screening, randomization and follow-up visits, is outlined in the 
protocol. If the study would need to be prolonged to accrue the predetermined number of 
subjects with the MACE events (1390), visits and assessments will be added according to the 
same schedule as described in the study plan.
Patients will return every 6 months for assessment of events related to the objectives of the 
study, tolerability and safety. Assessment of treatment compliance and provision of study drug 
will be done at these 6-month visits. In addition, phone contacts will be performed at a 3-
month interval in between regular visits. Patients have the option to visit the center at these 3-
month time points if desired; however, this is not required. If a patient prematurely and 
permanently discontinues study drug, an End of Treatment (EoT) visit will be completed, with 
the patient continuing in the study for follow-up. If recommended by the Executive 
Committee, the Sponsor may make a decision to close the trial, and all Investigators will 
receive a communication to complete a Closing Visit for both patients still being treated with
study drug and patients who have prematurely and permanently discontinued study drug. The 
latter patients should have completed the EoT visit in connection with the discontinuation of 
study drug and subsequently attended the scheduled visits to capture any adverse events 
(AEs), suspected CV events, body weight and diabetes medication. Refer to Section 5.8 in 
protocol for details on procedures for discontinuing patients from study drug.
The Investigator/qualified designee will arrange for the Closing Visit as soon as possible after 
the date estimated by the Executive Committee as the start of close out period. Patients who 


Statistical Analysis Plan 
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Date 31 May 2018
16
have a regularly scheduled visit within approximately 8 weeks after start of close out period
can use the scheduled visit as the closing visit.
All randomized patients, whether taking randomized study drug or not, should be followed up 
to the end of the study for vital status, CV events and occurrence of cancer. Survival based on 
publicly available sources, where possible, will be investigated at study end for patients who 
have withdrawn consent or are lost to follow-up. It is recommended that anyone being 
followed by regular telephone contacts or a contact at study closure attend the final visit in 
person. The approach taken should be registered in the eCRF, and medical records.
1.3
Randomization
Randomization will be stratified by CV risk category (2 levels: established CV disease; 
multiple risk factors without established CV disease) and hematuria status (2 levels: positive 
and negative). 
Positive hematuria is defined as a positive microscopy (≥3 RBCs) at the screening visit and/or 
a urine dipstick result indicative of hematuria (positive or trace) at the randomization visit. 
Negative hematuria would include patients with negative results for hematuria at both the 
screening visit (by microscopy) and randomization visit (by dipstick).
Randomization will be performed using a fixed block size. Blocks will be divided into four 
stratification groups, 1, 2, 3 and 4. When a patient is to be randomized, randomization code 
will be selected according to the following scheme:
1.
If patient has hematuria=positive and MRF use the next consecutive number from 
stratification group 1.
2.
If patient has hematuria=positive and eCVD use the next consecutive number from 
stratification group 2.
3.
If patient has hematuria=negative and MRF use the next consecutive number from 
stratification group 3.
4.
If patient has hematuria=negative and eCVD use the next consecutive number from 
stratification group 4.
AstraZeneca will create the randomization via GRand. The list will be kept securely within 
AstraZeneca, with access only by GRand group and Patient Safety. The list will be shared 
with the IVRS which will assign patients to randomization numbers and allow emergency 
unblinding by investigators. It will also be shared with the independent statistics group 
supporting the DMC. Country, sex and CV risk category will also be tracked within the IVRS 
to be able to control patient recruitment.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
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17
1.4
Number of patients
1.4.1
Sample size calculations
This study is a group sequential design study with two interim analyses, using O-Brian 
Fleming boundaries, leaving a one-sided alpha of 2.31% for the final analysis.
Non-Inferiority for MACE
The non-inferiority hypothesis to be tested in this trial is H0:HR[dapa:placebo] ≥ 1.3 vs H1:HR 
< 1.3. Assuming 2.1% common annual event rate, a 3-year accrual period, a 6-year maximum 
follow-up period, 1.0% annual study withdrawal rate, randomizing 17150 patients is expected 
to yield 1390 MACE events, which would provide >99% power to test the stated hypothesis at 
the 2.31% 1-sided level.
The annual study withdrawal rate of 1.0% are considering patients that are lost to follow up 
and patients that withdraw their consent.
Superiority for MACE
1390 MACE events will be required to have 85% power to demonstrate superiority of 
dapagliflozin to placebo if the true HR is 0.85, i.e., a 15% relative risk reduction, with a one-
sided alpha of 2.31%. To achieve this number of MACE events, we have designed the study 
with the following conditions: 17150 randomized patients will be required for the study, with 
assumed annual event rate of 2.1% on placebo, and an annual study withdrawal rate of 1.0% 
over a 3-year accrual period and 3-year minimum follow-up.
The final sample size will depend on multiple factors including the rate of accrual of MACE 
events. Therefore the sample size may be changed if planning assumptions are modified by 
blinded data review. The Executive Committee of the trial will monitor the aggregate event 
rate and rate of study drug discontinuation and may suggest to alter the sample size, number of 
primary endpoints or duration of the trial in accordance with the goals of the trial. Such 
changes will be made in consultation with the Sponsor.
The composite of CV death or hospitalization for heart failure:
We anticipate approximately 770 events for the composite of CV death or hospitalization for 
heart failure, which would provide 87% power to detect a hazard ratio of 0.80 with a 1-sided 
alpha of 2.31%. The alpha levels at the final analysis upon study completion will depend on 
the alpha spending function, the observed number of events for each endpoint at interim and 
final analyses and the hierarchical testing procedure.
Bladder and breast cancer
The SEER rate for the general US population of 0.044% per person-year for bladder cancer 
may be conservative; higher bladder cancer rates could be observed in this trial. If the SEER 
rate is adjusted to reflect an increased risk in a diabetes population, an estimated annual rate of 
0.06% could occur. In the dapagliflozin Phase 2b and 3 program, the bladder cancer rate was 
0.16% in dapagliflozin-treated patients. When patients with baseline hematuria were excluded, 


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
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18
the bladder cancer rate was 0.07% in dapagliflozin-treated patients and 0.046% amongst all 
treated patients (dapagliflozin and comparator combined). 
In planning for this study, it is assumed that the detection of early bladder cancers may be 
higher than for the general population (i.e., SEER) since this study is in diabetics and will 
stipulate yearly assessments of hematuria, more than would be expected in standard medical 
practice. Table 1 illustrates the levels of risk that can be ruled out if the rate were the same as 
the SEER population or slightly higher. We assume that the overall bladder cancer rate will be 
0.06% per person-year for this study. With this assumption, 46 bladder cancers may be 
expected during the study. With 46 events, a relative risk of 2.28 can be ruled out with one-
sided 97.5% confidence and 80% power under the hypothesis that the true relative risk is 1. In 
parallel, an absolute difference in incidence rates of 0.049% could be ruled out using the same 
assumptions.
For breast cancer, assuming 40% of the patients in the study are female, and predicted 
background breast cancer rate of 292 cases per 100,000 person-years (also based on 
background rates of breast cancer in the general U.S. population using SEER data, for women 
aged between 45 to 79 years). With this assumption, 90 breast cancers may be expected during 
the study. With 90 events, a relative risk of 1.80 can be ruled out with one-sided 97.5% 
confidence and 80% power under the hypothesis that the true relative risk is 1. In parallel, an 
absolute risk difference of 0.171% (over the whole study) could be ruled out using the same 
assumptions. Corresponding calculations are also provided if the study population is 30% 
females.
These cancer rate estimates are intended to be realistic but also conservative. If the rates of 
cancers are actually observed at higher rates, even smaller relative risks and risk differences 
can be ruled out.
Table 1
Levels of bladder and breast cancer relative risks and incidence rate 
differences that can be ruled out under different assumptions
One-sided 97.5% confidence level
Event rate
Expected
number of
events
Power
True RR that 
can be ruled 
out
True rate diff 
that can be 
ruled out
Max value that 
can be
observed and 
rule out
true RR, rate 
diff
Bladder cancers
0.044%
34
80%
2.62
0.042%
1.33, 0.013%
0.06%
46
80%
2.28
0.049%
1.28, 0.015%
Breast cancers 


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
19
One-sided 97.5% confidence level
Event rate
Expected
number of
events
Power
True RR that 
can be ruled 
out
True rate diff 
that can be 
ruled out
Max value that 
can be
observed and 
rule out
true RR, rate 
diff
Assuming 40% 
women in the 
study, 0.292%
90
80%
1.80
0.171%
1.19, 0.052%
Assuming 30% 
women in the 
study, 0.292%
68
80%
1.98
0.198%
1.23, 0.060%
RR = relative risk; risk diff = absolute incidence rate difference
 
2.
ANALYSIS SETS
2.1
Definition of analysis sets
Patients could by error have been randomized more than once. These patients will be analyzed 
according to their first randomization assignment. SAEs, hematuria forms, medication and 
endpoint forms will be consolidated and re-entered under the patient identifier used in the first 
randomization. The redundant records associated with the same patients will be stored in a 
separate dataset for future references.
Patients that were randomized at site 5709 will not be included in primary statistical analysis. 
AstraZeneca has reported the investigator to regulatory authorities for potential scientific 
misconduct in another AstraZeneca study and made the decision to exclude the patients from 
this site from the analyses. 
2.1.1
Full analysis set (FAS)
All patients who have been randomized to study treatment will be included irrespective of
their protocol adherence and continued participation in the study. Patients will be analyzed 
according to their randomized study drug assignment (not to which treatment they actually 
received) irrespective of whether the event occurred before or following discontinuation of 
study drug. Patients who withdraw consent to participate in the study (or are lost to follow-up) 
will be included up to the date of their study termination except for vital status known through 
public records (for use in the analyses of deaths). All primary, secondary, and exploratory 
efficacy variables will be analyzed using the FAS. The FAS will be considered the primary 
analysis set for the primary and secondary variables and for the exploratory efficacy variables.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
20
2.1.2
Safety analysis set
All patients who received at least 1 dose of randomized dapagliflozin or placebo and who 
have data observed at any time after first randomized dose until the end of the study, will be 
included in the safety population. Throughout the safety results sections, erroneously treated 
patients (patients randomized to one of the treatment groups but actually given the other 
treatment) will be accounted for in the actual treatment group. Patients with erroneous 
treatment would be analyzed according to that treatment only if they only received the 
erroneous treatment and none of the correct treatment. All safety variables will be analyzed 
using the safety analysis set. The Safety analysis set will be considered the primary analysis 
set for malignancies and fractures.
2.1.3
On-treatment analysis set
An on-treatment analysis set will also be created. The on-treatment population is defined as all 
randomized patients who have received at least one dose of investigational product and who 
have data observed at any time after first randomized dose till the end of the study. However, 
only those observations collected during treatment with study drug or within a certain number 
of days of the last dose of investigational product will be part of this analysis set, as noted 
below:
!
Primary, secondary, and categorical exploratory variables: 30 days
!
Continuous exploratory and safety variables (e.g. changes in lab values and vital 
signs): 7 days
!
SAEs: 30 days
!
AEs of special interest, that are not serious: 7days
For the primary and secondary efficacy variables, analyses will be repeated using the on-
treatment set as sensitivity analyses.  
All safety variables will be analyzed using the on-treatment analysis set. The on-treatment 
analysis will be considered as the main analysis for these safety variables (with exception for 
cancers and fractures). 
Primary and secondary efficacy analyses based upon the On-treatment analysis set will 
evaluate patients strictly according to their randomized assignment. In contrast, safety 
analyses using the On-treatment analysis set will evaluate patients according to the treatment 
received. Patients who receive the wrong investigational product and never receive any correct 
investigational product will be evaluated for safety in the treatment group for which they 
received medication.


Statistical Analysis Plan 
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Edition Number 8
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2.1.4
Summary of analysis sets and variables to be analyzed
Table 2
Clarification on what analysis sets will be considered as primarily and 
as sensitivity for efficacy and safety variables 
Variable
Primarily analysis
Sensitivity analysis
Primary variables
FAS
On-Treatment set
Secondary variables
FAS
On-Treatment set
Exploratory Efficacy variables
FAS
On-Treatment set for selected 
variables
Cancer, Amputations and Fractures
Safety analysis set
On-Treatment set
Other Safety variables
On-Treatment set
Safety analysis set
2.2
Protocol deviations
The below listed important protocol deviations will be summarised by randomized treatment 
group and will include:
!
Patients who received incorrect investigational product, completely or at any time 
during the study
!
Patients previously randomized into the study
!
Patients randomized but took no investigational product
!
Patients assigned a randomization code according to incorrect entry of baseline 
stratification factors
!
Patients without type 2 diabetes
!
Patients with end stage renal disease at baseline
!
Current or recent (within 24 months prior to randomization) treatment with 
pioglitazone and/or use of pioglitazone for a total of 2 years or more during lifetime
!
Current or recent (within 12 months prior to randomization) treatment with 
rosiglitazone
!
Previous treatment with any SGLT2 inhibitor
!
Study drug non-compliance - Patients identified as >120% or <80 compliant with 
study drug during run-in will be termed non-compliant.
!
Patients without established CV disease and less than 2 risk factors


Statistical Analysis Plan 
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!
Patients with acute CV disease at randomization
!
History of bladder cancer
!
NYHA Class IV HF at randomization
!
Screening or run-in HbA1c out of range (≥12% or <6.5%)
!
CrCl < 60ml/min at enrolment
!
Unexplained hematuria at randomization
!
Abnormal LFTs (AST or ALT >3xULN or Total bilirubin >2.5xULN) at enrolment.
Patients meeting criteria for protocol deviations will be identified by statistical programming 
prior to unblinding.
3.
PRIMARY AND SECONDARY VARIABLES
The primary and secondary CV efficacy variables will be adjudicated by the independent, 
blinded CEC.  
Note that, MI will include both non-fatal and fatal MI, Ischemic stroke will include both non-
fatal and fatal ischemic stroke. The causes of deaths, as adjudicated by the CEC, will include 
CV cause (death due to Sudden Cardiac Death, Acute MI, Stroke, Heart Failure, CV 
Procedure, CV Hemorrhage and Other CV death), non-CV cause, and undetermined cause. 
The primary analyses of the endpoints concerning CV deaths, either as a component of a 
composite or on its own, will include deaths adjudicated as CV cause. Deaths adjudicated as 
undetermined cause will not be counted as CV deaths in these analyses.
3.1
Primary variables
The primary outcome variables of the study are the composite endpoint of CV death, MI or 
ischemic stroke (time to first event) and the composite of hospitalization for heart failure and 
CV death (time to first event).  
3.2
Secondary variables
The secondary variables comprise the following:
!
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR 
<60 mL/min/1.73m2 using CKD-EPI equation and/or ESRD (dialysis ≥90 days or 
kidney transplantation, confirmed sustained eGFR <15 mL/min/1.73m2) and/or
renal or CV death (time to first event)
!
All-cause mortality (time to event)


Statistical Analysis Plan 
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3.3
Other efficacy variables 
The other efficacy variables comprise the following:
!
The individual components of the co-primary efficacy endpoints (cardiovascular 
death, MI, ischemic stroke, hospitalization for heart failure) (time to first event)
!
The composite endpoint of CV death, MI, ischemic stroke, hospitalization for heart 
failure, hospitalization for unstable angina pectoris, or hospitalization for coronary 
or non-coronary revascularization and the additional individual components of 
hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization (time to first event)
!
Exploratory renal composite endpoint: Confirmed sustained ≥40% decrease in 
eGFR to eGFR <60 mL/min/1.73m2 using CKD-EPI equation and/or ESRD 
(dialysis ≥90 days or kidney transplantation, confirmed sustained eGFR <15 
mL/min/1.73m2) and/or renal death (time to first event)
!
Change from baseline in HbA1c (mean change)
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline 
(proportion)
!
Need for any of the following: an increase in dose for an oral anti-diabetes 
medication or ≥ 25% increase in insulin dose or the addition of new anti-diabetes 
medication, for ≥ 3 months (proportion)
!
Major hypoglycaemia and/or hospitalization for hypoglycaemia (proportion)
!
Confirmed sustained macroalbuminuria (UACR ≥300 mg/g) in subjects without 
macroalbuminuria at baseline (time to first event)
!
Development of sustained confirmed albuminuria in patients without albuminuria at 
baseline (UACR≥30 mg/g ; time to first event)
!
Regression in sustained confirmed albuminuria (defined in three ways:  1. Baseline 
microalbuminuria to normoalbuminuria  2. Baseline macroalbuminuria to 
microalbuminuria or normoalbuminuria  3. The previous two combined) 
(proportions)
!
eGFR total slope and chronic slope using CKD-EPI equation
!
eGFR (sustained confirmed decrease ≥30% to sustained confirmed eGFR <60 
mL/min/1.73m2 using CKD-EPI equation; time to first event)
!
eGFR (sustained confirmed decrease ≥40% to sustained confirmed eGFR <60 
mL/min/1.73m2 using CKD-EPI equation; time to first event)


Statistical Analysis Plan 
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Edition Number 8
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!
Change in Albumin to Creatinine Ratio (adjusted mean percent change after 2 years 
and 3 years)
!
Change in body weight at 2 years and at 3 years
!
Proportion of patients with 5% body weight loss and 10% body weight loss after 2 
years and after 3 years
!
Retinal laser and/or intraocular treatment due to development of and/or 
deterioration in diabetic retinopathy (proportion)
!
Blood pressure change from baseline (mean change) (blood pressure values used in 
analyses will be the mean of two measurements for each applicable time point)
!
Peripheral revascularization/Limb ischemic events (proportion)
!
Any stroke (ischemic, hemorrhagic, or undetermined) (proportion)
3.4
Safety variables
Safety and tolerability will be assessed from serious adverse events, adverse events leading to 
discontinuation, adverse events of special interest, and laboratory test results. The assessment 
will include an evaluation of the incidence of bladder cancer, liver injury and diabetic 
ketoacidosis. All possible malignancies (excluding non-melanoma skin cancer), liver injury 
and all potential diabetic ketoacidosis will be independently adjudicated.
Only events that fall into the following categories are collected in this study: serious AEs, AEs 
leading to discontinuation of study drug, suspected CV events, elective coronary and non-
coronary revascularisations, heart failure, potential diabetic ketoacidosis, amputation and 
related events and AEs of special interest. AEs of special interest in this study fall into the 
following categories: malignancies, hepatic events, hypoglycemic events that are major or 
lead to hospitalization, fractures, renal events, symptoms of volume depletion, 
hypersensitivity reactions (serious or lead to discontinuation of study drug), urinary tract 
infections (serious or lead to discontinuation of study drug) and genital infections (serious or 
lead to discontinuation of study drug). Therefore, AE summaries will be limited to these 
particular categories and general summaries of all AEs are not planned.
 
 
 
3.6
Analysis of biomarkers
Will be specified in a supplementary SAP.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
25
4.
ANALYSIS METHODS
All statistical analyses will be performed using Version 9.4 (or higher) of the SAS® statistical 
analysis system (SAS Institute Inc., Cary, NC) and, where appropriate, additional validated 
software.
4.1
General principles
All tables and figures will present results by treatment group, except for presentation of the 
disposition of patients prior to randomization which will be summarized for all patients who 
signed an informed consent. Select tables (e.g. demographics) may also have a column for the 
total population.
Incomplete dates
In statistical analysis, it is sometimes necessary to impute incomplete dates for the purpose of 
data derivations such as treatment period, time to event, etc. In such situations, the general 
rules for imputations are:  
If only the year of a date is given (YY), then the date shall be set to ‘YY0701’. If only the year 
and month of a date is given (YYMM), then the date shall be set to ‘YYMM15’.
Appropriate rules will be applied to ensure that dates will not be imputed as prior to 
randomization, not as prior to date of first dose, not after date of death, not after date of 
closing visit, not after date of withdrawal of consent, and not as start date occurs after end date 
for an event.
If the onset date of an adverse event is completely missing then the maximum of date of 
randomisation and date of first dose will be imputed as onset date.
Special cases for date of death:
For a patient that died with the date of death imputed, the maximum of the imputed date and
last date the patient was known to be alive will be used as date of death.
If adjudicated date of death is completely missing, the site-reported date of death will be used.
For a patient that died that have a completely missing date of death, the last date the patient 
was known to be alive will be imputed and used as date of death.
By-patient presentations
Treatment group, CV risk category, age, sex and E-code (patient identifier) will be present in 
all data listings. Study visit/month will be included in all data listings whenever an assessment 
date is presented.    
Descriptive statistics


Statistical Analysis Plan 
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Edition Number 8
Date 31 May 2018
26
Numerical variables will be summarised using standard summary statistics including the 
number of patients, mean, standard deviation (SD), median, Q1, Q3 and range (i.e., minimum 
and maximum) as appropriate.  For categorical data, proportions will be presented in a 
frequency table format.  
Tabulation of events and censoring
For CV outcomes, events will be cross-tabulated by initial investigator assessment and final 
adjudicated result. Only CV events adjudicated and confirmed by the CEC will be included in 
the analyses of CV events. 
A patient may have one or more events. For composite endpoints, the time to first event 
within the composite list will be used. For each component of a composite (e.g. MI), the time 
to first component event will be used, regardless of other events occurring earlier (e.g., if a 
stroke precedes an MI in a patient, then the stroke counts in the composite as the first event, 
but the MI counts in the time to first MI analysis). 
The Executive Committee will monitor the accrual of the aggregate number of MACE events
and when the required MACE events have occurred, upon confirmation from the Sponsor, will 
instruct all sites that to perform all Closing Visits by a certain defined date.
The end-of-study will be defined as the time of the last visit or study contact (where a clinical 
event assessment was performed) for each individual patient. If no event occurs for an 
endpoint, withdrawal of consent, last clinical event assessment, or death (whichever is 
earliest) will be treated as the censoring event. If none of these are available, date of last 
documented contact (i.e. last visit) will be used for censoring. For all-cause mortality and CV 
death, censoring will occur at Closing Visit for patients known to be alive, or otherwise at the 
date last known to be alive. If none of these are available, date of last documented contact (i.e. 
last visit) will be used for censoring. For analysis of CV death, a patient who dies of a non-CV 
cause (or undetermined cause) would be censored at the time of death. Deaths occurring after 
the date of withdrawal of consent (and for patients lost to follow-up) and documented in 
publicly available source data will be recorded in the eCRF, adjudicated if possible, and 
included in the analyses of deaths.
For the On-Treatment analyses, censoring will occur according to the same pattern that 
defines the on-treatment analysis set.
To test the robustness, censoring at the fixed calendar date (the date that the executive 
committee instructs the sites to commence Closing Visits) will be used in a sensitivity 
analysis. See section 4.4.1.2.
Clinical events will be handled in the following manner according to their timing with respect 
to study milestones   
!
Events that are recorded as beginning prior to the date of randomization will not be 
included in the event analyses


Statistical Analysis Plan 
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Edition Number 8
Date 31 May 2018
27
!
Events that occur at any time after randomization and up to and including the last 
visit/contact and reported before database lock will be adjudicated, if possible, and 
included in all efficacy and safety analyses.
!
Events that occur at any time after randomization and up to and including the last 
visit/contact and reported after database lock may be adjudicated but will not be 
included in the primary efficacy and safety analyses. They will be recorded in a 
tabular fashion as part of the final study report and may be included in sensitivity 
analyses.
!
Events that occur after last visit/contact will not be included in the primary efficacy 
and safety analyses but may be included in sensitivity analyses for the study. 
Adverse events occurring after the study will be included in the Sponsor’s Safety 
database if they fulfill safety reporting criteria.
4.1.1
Baseline value
For each patient, the baseline value of each laboratory parameter or physical examination 
endpoint is defined as the last assessment on or before randomization, and on the same day or 
before the first dose of double-blind study drug. 
4.1.2
Baseline hematuria:
Positive hematuria is defined as a positive microscopy (≥3 RBCs) at the screening visit and/or 
a urine dipstick result indicative (positive or trace) of hematuria at the randomization visit. 
Negative hematuria would include patients with negative results for hematuria at both the 
screening visit (by microscopy) and randomization visit (by dipstick).
4.1.3
Change from baseline
Change from baseline to any randomized treatment period Time t is defined as follows:
CTime t = MTime t – Mbaseline, where:
- CTime t is the change from baseline at Time t
- MTime t is the measurement at Time t 
- Mbaseline is the baseline measurement.  
4.1.4
eGFR and Creatinine Clearance formulas
Estimated creatinine clearance using the method of (Cockcroft and Gault 1976):
CrCl = (140 - age) x (weight in kg)         (x 0.85 for females)
            serum creatinine (mg/dL) x 72
Estimated GFR using MDRD equation:


Statistical Analysis Plan 
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Edition Number 8
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eGFR (mL/min/1.73m2) = 175 x (Scr)-1.154x (Age)-0.203x (0.742 if female) x (1.212 if 
black) 
Estimated GFR using CKD-EPI equation (Levey et al 2009): 
eGFR (mL/min/1.73m2) = 141 x min (SCr/k,1)a x max (SCr/k,1)-1.209 x 0.993Age x 
[1.018 if female] x [1.159 if black]
k is 0.7 for females and 0.9 for males, a is -0.329 for females and -0.411 for males, 
min indicates the minimum of SCr/k or 1, and max indicates the maximum of SCr/k or 
1.
4.1.5
Body Mass Index 
BMI is calculated as the ratio of patient’s weight (kg) to the square of the patient’s height (m): 
BMI = kg/m2. 
4.1.6
Descriptive summaries of continuous variables
Summaries for continuous variables will present absolute values and changes from baseline, 
for each treatment group. They will include mean, SD, median, Q1, Q3, minimum and 
maximum, and will be presented by visit when applicable. Summaries for some continuous 
variables will include 95% CIs for means or mean treatment differences. Summaries for 
continuous variables known to have skewed distributions will also include the interquartile 
range.
4.1.7
Descriptive summaries of categorical variables
Summaries of categorical variables will provide frequencies and percentage, for each 
treatment group. Summaries for some categorical variables will include 95% CIs for the 
difference in percent from placebo.
4.1.8
Summaries of shifts from baseline in categorical variables 
Changes from baseline in certain categorical variables might be summarized using shift tables. 
Frequencies and percentage of patients within each treatment group will be generated for 
levels of cross-classifications of baseline and the on-treatment value of the variable. The on-
treatment value can be either the value at a certain time point, or, for e.g. laboratory tests, the 
minimum/maximum value in the direction of toxicity, which has been observed during a study 
period. Treatment group differences will not be assessed in summaries of shifts.
4.1.9
Cox Proportional Hazards Model    
Cox proportional hazards model will be used to analyze the time-to-events variables.  The 
model will be stratified by baseline hematuria and baseline CV risk category, with treatment 
as a model term.


Statistical Analysis Plan 
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Edition Number 8
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The following model will be used:
Log[ hijk(t)/ hij0(t)] = β1xijk
Where
∀
hijk(t) hazard function at time t for subject k in CV risk category stratum i and 
baseline hematuria stratum j given covariate value xijk 
∀
β1 is the regression coefficient associated with treatment group
With respect to randomized treatment, hazard ratio estimates and 2-sided confidence intervals 
(CIs) will be presented as defined in section 4.4. No hazard ratio estimates will be given for 
subgroups with less than 15 events in total, both arms combined. P-values will be presented 
from the Wald’s test.
The co-primary efficacy endpoints are MACE (composite endpoint of CV death, MI or 
ischemic stroke) and the composite of hospitalization for heart failure or CV death. Each will 
be evaluated as the time to the first event included in the composite. The general intent is to 
analyze patients from the date of randomization up until the date of study closure visit. For the 
primary endpoints, the time of event will be determined by the date of first adjudicated event. 
Patients without an adjudicated event will be censored at the earliest date among the 
following: non-CV death (and undetermined death), withdrawal of consent and last clinical 
event assessment. If none of these would be available, the last documented contact (i.e. the 
last visit) will be used for censoring. The last documented contact may be by office visit, by 
telephone call directly with the patient or by contact with another person (family member, 
caregiver, primary or treating physician) where it is possible to gain knowledge of possible 
CV events or death. Indirect contact such as medical records, letter, e-mail or text message, if 
applicable, will be used to inquire for possible events and may lead to adjudicated events and 
a last documented contact. The person who made the contact (i.e. investigator or study 
nurse/coordinator) will also be documented.
The rules for censoring time to events for secondary and exploratory efficacy endpoints are 
the same, with the two exceptions: 1) that CV death will be included as a censoring point for 
the single components of the composite time to event endpoints and 2) non-CV deaths and 
undetermined deaths are events for the endpoint of all-cause mortality (and not censoring 
points).
A patient may have 1 or more events. However, only a patient’s first applicable event will 
contribute to the analysis of each specified endpoints.


Statistical Analysis Plan 
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Event rates will have denominators which represent the total number of years in the study or 
time to first event (whichever occurs first). Patients without events will be censored using the 
rules above. The rates will be derived as total number of patients with an event divided by the 
corresponding number of patient-years. The rates will be expressed in units of “per 1000 
patient-years”. The number of patients with an event and the corresponding number of patient-
years will be truncated as appropriate for analyses using the On-treatment analysis set.
4.1.10
Analysis of repeated measures    
Repeated measure analysis (using MIXED model) will be used to analyze the response 
variable change from baseline in body weight, HbA1c, blood pressure variables (and other 
applicable continuous variables) to each relevant time point.  The model contains terms for 
randomized treatment group, baseline measurement, CV risk category, baseline hematuria, 
time (each relevant visit) and time by randomized treatment group. The following model will 
be used:
Cijk = intercept + ß [Mbaseline,ij ]+ τi + α k+   (α τ)ik +  xa + Yb + errorijk  
where
!
Cijk is the each relevant visit change from baseline of patient j in treatment group i
!
ß is the slope of Cij regressing on the baseline measurement
!
Mbaseline,ij is the baseline measurement of patient j in treatment group i
!
τi , is the mean effect of treatment group i
!
α k, is the mean effect at time k and
!
(α τ)ik is the interaction term between treatment group i and time k
!
xa , is the mean effect of CV risk category a 
!
Yb , is the mean effect of baseline hematuria category b 
The MIXED model will present least squares (LS) mean estimates for Time k by treatment 
group and 2-sided 95% confidence intervals (CIs) for mean changes from baseline within and 
between treatments.
To model the covariance structure, the within patients unstructured covariance structure will 
be used. The MIXED model is computationally intensive, if the algorithm does not converge, 
the Toeplitz first-order autoregressive or compound symmetric covariance structure will be 
used.


Statistical Analysis Plan 
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4.1.11
Analysis of proportions
The proportions of patients with at least a 5% (and 10%) body weight loss after 2 and 3 years 
compared to baseline will be analyzed using the methodology of Cochran-Mantel-Haenszel 
with stratification for CV risk category and baseline hematuria. Weighted proportions for 
treatment groups and differences between treatment groups will be obtained along with 95% 
confidence intervals using Mantel-Haenszel weights, with stratification for CV risk category 
and baseline hematuria.
Other proportions, such as the following, will be examined using summary statistics that will 
include 95% confidence intervals for treatment effects and for the difference between 
treatments as well as nominal 2-sided p-values. These variables will also be analyzed using 
the time to first event approach by Cox modeling, and corresponding Kaplan-Meier curves 
will be produced.
!
Initiation of insulin therapy in patients not receiving insulin therapy at baseline
!
Need for any of the following: an increase in dose for an oral anti-diabetes 
medication or ≥25% increase in insulin dose or the addition of new anti-diabetes 
medication, for ≥3 months  
!
Major hypoglycaemia and/or hospitalization for hypoglycaemia
!
Regression in albuminuria
!
Retinal laser and/or intraocular treatment due to development of and/or 
deterioration in diabetic retinopathy
!
Peripheral revascularization/Limb ischemic events
!
Surgical amputation and related events
!
Any stroke (ischemic, hemorrhagic, or undetermined)
4.1.12
Analysis of incidence rate ratios and differences
Selected safety endpoints (e.g. malignancies) will be analyzed with incidence rates, incidence 
rate ratios and corresponding 95% confidence intervals using exact methods for the Mantel-
Haenszel relative risk estimates. Exact methods will be used to determine the 95% confidence 
intervals for incidence rate differences also (Lu Tian et al 2008). Analyses will be stratified by 
CV risk category and baseline hematuria. 
Incidence rates will have denominators which represent the total number of years in the study
or time to first event (whichever occurs first). Patients without events will be censored using 
the same rules as for the Time to event analyses described in section 4.1.9. Incidence rates will 
be derived as total number of patients with an event divided by the corresponding number of 
patient-years. Incidence rates will be expressed in units of “per 1000 patient-years”.    


Statistical Analysis Plan 
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4.1.13
Kaplan-Meier curve and estimates for time-to-event analyses 
Kaplan-Meier plots (Kaplan EL and Meier P 1958) of time to event variables will be 
displayed by treatment group.  A table will accompany the plot and will display the Kaplan-
Meier estimates of the cumulative proportion (with 95% CI calculated based on Greenwood’s 
method) of patients with event at specific time points by treatment group. The curves will be 
truncated as appropriate
4.1.14
Stratification of analyses 
Stratification of analyses will be performed using the stratification values as entered in IVRS 
to determine the randomization assignment. 
4.2
Study population
4.2.1
Patient disposition
The number and percent of patients who completed the study, discontinued from the study, 
and reasons for discontinuation from the study will be summarized by treatment group and 
overall, for all randomized patients. Listings of patients who prematurely discontinued from 
the study will be provided. 
The number and percent of patients who discontinued randomized treatment and reasons for 
discontinuation of treatment will be summarized by treatment group and overall, for all 
randomized patients. Listings of patients who prematurely and permanently discontinued 
treatment and for whom post-discontinuation data are excluded from the on-treatment 
population will be provided. 
Kaplan-Meier estimates of the cumulative probabilities to discontinue from the study and to 
discontinue from randomized treatment will be calculated and plotted, by treatment.
4.2.2
Protocol deviations
Patients having important protocol deviations (see section 2.2) will be summarized by 
treatment group and overall, using the FAS population. By-patient listings will also be 
presented.
4.2.3
Demographic and other baseline characteristics
Demographic and other baseline characteristics will be summarized by treatment group and 
overall using the FAS. Baseline demographics will also be summarized for the eCVD and 
MRF subgroups.  Demographic and diabetes-related characteristics at baseline to be 
summarized are listed in Table 3. CV risk levels and risk factors at randomization to be 
summarized are listed in Table 4. Number of CV risk factors per patient will also be 
summarized. Summaries of concomitant medication drug class at randomization will be based 
on data collected on concomitant case report forms. No statistical test will be performed for 
comparison of any baseline measurement among treatment groups.


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All summaries of continuous characteristics will be based on non-missing observations. For 
categorical characteristics, percentage will be calculated out of the total number of patients in 
the data set, overall and by treatment group (i.e., each denominator includes the number of 
patients with missing/unknown values for the variable).
Duration of type 2 diabetes is calculated from date of diagnosis to date of randomization. 
Table 3
Summaries of Demographic, Diabetes-Related Characteristics and 
Cancer risk factors at Baseline.    
Characteristic
Summarized as 
Categories
Age
Categorical and 
Continuous
<65, #65, <75 and #75 years
Sex
Categorical   
Female
Male
Race
Categorical
White
Black or African American
Asian
American Indian or Alaska Native
Native Hawaiian or Other Pacific Islander
Other
Ethnicity
Categorical
Hispanic or Latino
Not Hispanic or Latino
Waist/Hip ratio
Categorical and 
Continuous 
High (>0.90 for males and >0.85 for females)
Low (∃0.90 for males and ≤0.85 for females)
BMI
Categorical and 
Continuous 
<30 kg/m2 and #30 kg/m2  
Weight
Continuous 
-
Duration of Type 2 
Diabetes
Categorical and 
Continuous 
∃5 years 
>5 years 
>10 years
>20 years 
HbA1C
Categorical and 
Continuous 
<7% (<53 mmol/mol)
≥7 - <8% (≥53-<64 mmol/mol)
≥8 - <9% (≥64-<75 mmol/mol)
≥9% (75 mmol/mol)


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Characteristic
Summarized as 
Categories
FPG 
Categorical and 
Continuous
<100 mg/dL [<5.6 mmol/L]
#100 - <126 mg/dL [≥5.6 mmol/L - <7.0 mmol/L]
#126 - <150 mg/dL [≥7.0 mmol/L - <8.3 mmol/L]
#150 - <250 mg/dL [≥8.3 mmol/L - <14.0 mmol/L] 
#250 mg/dL [≥14.0 mmol/L]
Diastolic and 
Systolic Blood 
Pressure
Categorical and 
Continuous
Diastolic Blood Pressure:
<80 mmHg
≥80 mmHg
Systolic Blood Pressure:
<130 mmHg
≥130 mmHg
Diastolic Blood Pressure / Systolic Blood Pressure:
<80 and <130 mmHg
≥80 and ≥130 mmHg
Pulse Pressure:
<60 mmHg 
≥60 mmHg
eGFR
(CKD-EPI)
Categorical and 
Continuous
<60 mL/min/1.73m2
60 - <90 mL/min/1.73m2
≥90 mL/min/1.73m2
eGFR
(MDRD)
Categorical and 
Continuous
<60 mL/min/1.73m2
60 - <90 mL/min/1.73m2
≥90 mL/min/1.73m2
Urinary 
Albumin/creatinine 
ratio
Categorical and 
Continuous
<30 mg/g [≥1.7 mg/mmol - <3.4 mg/mmol]
≥30 - ≤300 mg/g [≥3.4 mg/mmol - ≤33.9 mg/mmol]
>300 mg/g [>33.9 mg/mmol]
Creatinine Clearance
Categorical and 
Continuous
<60 mL/min
60 - <90 mL/min
≥90 mL/min
Region and Country
Categorical
North America 
Latin America
Asia/Pacific
Europe (Western, Eastern)
Countries (see Appendix B)
Baseline Insulin use
Categorical
Yes/No


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Characteristic
Summarized as 
Categories
Baseline Diabetic  
Medication use in 
addition to Insulin
Categorical
Metformin 
Metformin + SU
Metformin + DPP4 inhibitor
Metformin + GLP-1 agonists
Metformin + Other diabetic medication
SU 
DPP4 inhibitor
GLP-1 agonists
Other drugs or drug combinations
Baseline Diabetic  
Medication use (for 
patients without 
Insulin)
Categorical
Metformin
Metformin + SU
Metformin + DPP4 inhibitor
Metformin + GLP-1 agonists
Metformin + Other diabetic medication
SU 
DPP4 inhibitor
GLP-1 agonists
Other drugs or drug combinations
Baseline Diabetic  
Medication use 
(regardless of Insulin
use)
Categorical
Metformin 
SU 
DPP4 inhibitor
GLP-1 agonists
Other drugs 
Baseline CV 
Medication Use
Categorical
Acetylsalicylic Acid
Statin/Ezetimibe
ACE Inhibitor/ARB
Dual Antiplatelets
Any Antiplatelets
Anticoagulants
Beta blockers
Calcium channel blockers
Diuretics – Loops 
Diuretics –Thiazides
MRA (Mineralcorticoid receptor antagonist)
Baseline Hematuria 
status
Categorical
Positive
Negative


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Table 4
Summary of Baseline CV Risk Level and Risk Factors
Characteristic
Summarized 
as 
Categories
Baseline CV 
Disease
Categorical
MRF- Patients with multiple risk factors for CV events, but 
without established CV disease 
eCVD- Patients with established CV disease
MRF
Categorical 
In addition to being ≥55 years male or ≥60 years female, at least 
one of the following:
- Dyslipidemia 
- Hypertension 
- Current Tobacco use
Number of risk 
factors
Categorical
1 additional risk factor (dyslipidemia, hypertension, or smoking)
2 additional risk factors (dyslipidemia, hypertension, or smoking)
3 additional risk factors (dyslipidemia, hypertension, and 
smoking)
eCVD
(Established 
CV Disease)
Categorical
Ischaemic heart disease
Cerebrovascular disease
Peripheral Arterial Disease
Number of 
documented 
CV Diseases
Categorical
1 CV disease
2 CV diseases
3 CV diseases
History of HF
Categorical
No
Yes
LVEF at 
baseline
Categorical
HFrEF (Heart Failure reduced Ejection Fraction, <=45%)
HFpEF (Heart Failure preserved Ejection Fraction, >45%)
4.2.4
Specific and General Disease Histories
The numbers and percentage of patients with specific disease history such as diabetes-related 
disease and vascular disease histories will be provided for the FAS population. 
4.3
Extent of exposure
Extent of exposure is defined as the number of days between the start and the end dates of 
study therapy. 
Extent of exposure (days) = Last dosing date - First dosing date + 1.
Extent of exposure to treatments will be summarized using the Safety population. Also the 
mean, SD, median, Q1, Q3 and range of extent of exposure will be presented. 


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Duration of follow-up (time from randomization to last contact) will also be summarized by 
treatment group, using FAS and Safety analysis set.
4.3.1
Medication at randomization and Concomitant Medications 
Concomitant medications defined as medications taken on at least 1 day between the date of 
randomization and date of last contact, inclusive, will be summarized using the FAS 
population by Anatomical Therapeutic Chemical class (ATC class) and preferred name. 
Medications will be classified according to the AstraZeneca Drug Dictionary. A summary will 
be produced for concomitant medications during the treatment period.
Medication at randomization is defined as medication with at least one dose taken before date 
of randomization and with no stop date before date of randomization. This will also be 
summarized. 
Changes in concomitant diabetes medications will be summarized, by identifying these 
categories from the medicines module in the eCRF (an increase for oral medications, 
addition/replacement of non-insulin medications, addition of insulin for ≥3 months, > 25% 
increase in insulin dose for ≥3 months).
The dose of insulin at randomization will also be summarized.
4.3.2
Measurements of Treatment Compliance
Patients are considered compliant if percent compliance is ≥80% and ≤120% for the treatment 
period. The number and percent of compliant patients will be displayed using the FAS 
population. 
4.4
Analysis methods for primary, secondary and exploratory efficacy 
variables
4.4.1
Primary variables
4.4.1.1
Hypotheses
The Type I error rate for the analysis of the primary endpoints will be adjusted for the interim 
analyses performed by the DMC.
For the MACE the following hypothesis will be tested at the 2.31% 1-sided level:
H01: HR [dapagliflozin:placebo] ≥1.30
vs
H11: HR [dapagliflozin:placebo] <1.30.
If the null hypothesis is rejected, then an increased CV risk of 1.30 for dapagliflozin-treated 
patients is ruled out and superiority will then be tested in terms of:


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H02: HR [dapagliflozin:placebo] ≥1
vs
H12: HR [dapagliflozin:placebo] <1
and
H03: HR [dapagliflozin:placebo] ≥1
vs
H13: HR [dapagliflozin:placebo] <1
in a closed test procedure. See Section 4.4.3 for a description of the full closed testing 
procedure including the secondary variables.
4.4.1.2
Analyses of the primary variables
The primary variables are the time to first event included in the composite endpoint of CV 
death, MI, or ischemic stroke and the time to first event included in the composite endpoint of 
hospitalization for heart failure or CV death. The primary analysis will be based on the FAS 
population, using events adjudicated and confirmed by the CEC.
Hazard Ratios (HR) and Confidence Intervals (CIs) will be derived from a Cox proportional 
hazards model with a factor for treatment group stratified by CV risk category (established 
CV disease, or multiple risk factors without established CV disease) and baseline hematuria. 
Event rates by 1000 patient years will be presented.
The assumption of proportional hazards for the factor for treatment groups will be assessed 
visually using log-cumulative hazard plots. The effect of any departures from proportional 
hazards will be discussed as part of the presentation of results of the analyses. Additionally, 
the assumption of proportional hazards for the factor for treatment group will be evaluated 
with a model which assess the treatment effect in categorized time intervals (< 1 year and ≥1 
year).
The contribution of each component of the primary composite endpoints to the overall 
treatment effect will be examined. Methods similar to those described for the primary analysis 
will be used to separately analyze the time from randomization to the first occurrence of each 
component of the primary composite endpoints. This will be done for CV death, all MI, all 
ischemic stroke and all hospitalizations for heart failure. Nominal p-values will be presented. 
Non-fatal MI and Non-fatal stroke will be presented descriptively. Events of non-fatal MI are 
defined as events that are adjudicated to be MI and for which the patient did not die due to MI. 
The same goes for non-fatal Stroke.


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HRs and CIs for overall analysis and subgroups will be presented with forest plots. Kaplan-
Meier estimates of the cumulative incidence to the first occurrence of any event in the primary 
endpoints will be calculated and plotted, for the overall analysis and for the individual 
components.
Kaplan-Meier plots, overall and by CV risk category will be presented, by treatment, for the 
primary analyses as well as for the individual components.
Subgroup analyses to evaluate variation in treatment effect will be performed on the basis of 
tests for interaction using the Cox model. 
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. 
Subgroup analyses will be performed for the stratification factors as well as for all variables in 
Tables 3 and 4.
A sensitivity analysis of the primary objectives will be performed using the same methods as 
above on the on-treatment analysis set.      
The primary analysis will use each patient's last contact as the censoring date for patients that 
complete the study without any primary events, see 4.1 for detailed definition. To test the 
robustness of the co-primary endpoints result, censoring at the fixed calendar date (the date 
that the Executive Committee instructs the sites to commence closing visits) will be used in a 
sensitivity analysis.
A sensitivity analysis of completers will be performed for the primary variables. Completers is 
defined as all patients except those that have incomplete follow-up of primary endpoints or 
withdraw consent (who did not have a primary endpoint event prior to withdrawal of consent).
A sensitivity analysis of CV death replaced with all-cause mortality, including vital status 
information from patients who have withdrawn consent (or have incomplete follow-up of 
primary endpoints), will be performed for the co-primary endpoints.
Non-CV death (and undetermined death) is considered a competing risk for the co-primary 
efficacy endpoints. A sensitivity analysis will be performed to estimate the cumulative 
incidence functions corrected for the competing risk based on Fine and Gray (1999). This 
analysis will take into account the same covariates as in the primary Cox model. Sub-
distribution hazard ratios will be presented.
As a patient can have recurrent events, an exploratory analysis of the total number of co-
primary composite events will be performed using the Andersen-Gill modified Cox regression 
approach, for Dapagliflozin versus Placebo.


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4.4.1.3
Considerations of incomplete follow-up
In the primary analysis of the primary endpoints, the patients who withdraw consent or have 
incomplete follow-up of primary endpoints will be censored at the date of last clinical contact 
on study according to Section 4.1, if they have not developed an event for the primary 
endpoints. For these patients, the data between the date of last clinical contact on study and 
planned study closure date are considered missing.
The time-to-event analysis (Cox regression) relies on the assumption of non-informative 
censoring. To examine this assumption, presence of informative censoring will be assessed by 
comparing the event rates between subjects receiving study drug until end of study or death 
and subjects prematurely and permanently discontinued from study drug with information 
related to co-primary endpoint events. The rates of subjects prematurely and permanently 
discontinued from study drug will also be compared between treatment arms to assess 
potential differential dropouts.
Subjects prematurely and permanently discontinuing study drug, for other reason than death, 
prior to study end could have a different event and hazard rate from those who stay on 
treatment throughout the study, and their corresponding dropout could be considered 
informative. This subgroup can be divided into subjects with information and subjects with 
missing information regarding events related to primary endpoints, see figure below. 
Diagram showing subjects divided into subgroups related to missing information during 
follow up


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In a sensitivity analysis, subjects with information related to the co-primary endpoint events 
will be used to impute data in subjects without information in the subgroup described above.
For subjects with missing data, time to event will be imputed during the follow up time (i.e. 
time from censoring to study end). This will be done by using random values from
exponential distributions based on the observed data in the subgroup. In the imputation 
models, CV history will be included as a covariate for both primary endpoints. For the 
composite endpoint of Hospitalization for heart failure or CV death, history of heart failure 
will also be added as a covariate in the imputation model. Imputations will be done separately 
in each treatment arm.
In addition, a tipping point analysis will be performed, where time to events will be imputed 
during the follow up time (i.e. time from censoring to study end) using the same covariates in 
the imputation models as described above and vary the hazard rates for subjects with missing 
information. This will be done separately in each treatment arm in the subgroup of subjects 
prematurely and permanently discontinuing study drug. The goal of the analyses is to find the 
scenarios where the result from the primary endpoints analyses will be “tipped”, i.e. the 
conclusion will change.
When the imputation models are used, if the simulated time is less than the elapsed time 
between the last contact and end of study, an event is imputed for the corresponding subject 
with the time to event set to be last contact plus the simulated time. Otherwise, the subjects 
will be censored at end of study. Imputed events and time to events will be integrated with the 
observed data and the Cox proportional hazard model described in section 4.1.9 will be used. 
For each scenario, this will be repeated 1000 times and the results will be combined into 


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overall estimates of HR and 95% CI using Rubin’s rules (Rubin, D. B. 1987 ; Little R et al 
2016).
4.4.2
Secondary and exploratory variables analysed as time to event  
Time to event for secondary and exploratory efficacy variables will be analyzed in the same 
way as for the primary efficacy variables:
Renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR <60
mL/min/1.73m2 using CKD-EPI equation and/or ESRD (dialysis ≥90 days or kidney 
transplantation, confirmed sustained eGFR <15 mL/min/1.73m2) and/or renal or CV death
!
All-cause mortality
!
Exploratory renal composite endpoint: Confirmed sustained ≥40% decrease in 
eGFR to eGFR <60 mL/min/1.73m2 using CKD-EPI equation and/or ESRD 
(dialysis ≥90 days or kidney transplantation, confirmed sustained eGFR <15 
mL/min/1.73m2) and/or renal death
!
The individual components of the co-primary efficacy endpoints (cardiovascular 
death, MI, ischemic stroke, hospitalization for heart failure)
!
The composite endpoint of CV death, MI, ischemic stroke, hospitalization for heart 
failure, hospitalization for unstable angina pectoris, or hospitalization for coronary 
or non-coronary revascularization and the additional individual components of 
hospitalization for unstable angina pectoris and hospitalization for coronary or non-
coronary revascularization
!
Confirmed sustained macroalbuminuria (UACR ≥300 mg/g) in subjects without 
macroalbuminuria at baseline
!
Development of sustained confirmed albuminuria in patients without albuminuria at 
baseline (UACR≥30 mg/g)
!
eGFR (sustained confirmed decrease ≥30% to sustained confirmed eGFR <60 
mL/min/1.73m2 using CKD-EPI equation)
!
eGFR (sustained confirmed decrease ≥40% to sustained confirmed eGFR <60 
mL/min/1.73m2 using CKD-EPI equation)
The secondary variables will be analyzed by the same subgroups as for the primary variables. 
The 4 individual components included in the co-primary endpoints will also be analyzed for 
all subgroups. 


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The secondary variables will also be analyzed for the on-treatment population as sensitivity 
analyses.
Time to the Exploratory renal composite endpoint: Confirmed sustained ≥40% decrease in 
eGFR to eGFR <60 mL/min/1.73m2 using CKD-EPI equation and/or ESRD (dialysis ≥90 days 
or kidney transplantation, confirmed sustained eGFR <15 mL/min/1.73m2) and/or renal death
will be analyzed separately per the subgroups of baseline urinary albumin to creatinine ratio
(<30mg/g, >=30mg/g).
For time to albuminuria/macroalbuminuria, and for time to decrease in eGFR (using CKD-EPI 
equation), confirmation is required, meaning that the observation should be present at two 
consecutive visits separated with at least 4 weeks. Time to onset would be the first of the two 
subsequent laboratory assessments. If no confirmation can be obtained the observation will 
not be included in the main analyses. A sensitivity analysis for time to 
albuminuria/macroalbuminuria will be conducted including also all non-confirmed 
observations.
4.4.3
The closed testing procedure
Type I error will be controlled at a one-sided 0.025 level for multiplicity across primary and 
secondary objectives and in consideration of planned interim analyses. If the trial goes to 
completion, statistical significance will be assessed in the order of the endpoints given in 
Table 5. If statistical significance is met for non-inferiority for MACE, the alpha will split and 
testing will be performed in parallel for superiority for MACE and for superiority for 
hospitalization for heart failure/CV death. Recycling of alpha will be used, and if both 
superiority for MACE and superiority for hospitalization for heart failure/CV death are 
reached, then testing will proceed with full alpha further down the hierarchy. (Burman et al 
2009). Alpha-levels for the interim analyses are described in Section 5.
Recycling:
STEP1: Test the non-inferiority hypothesis for MACE, H01 (α = 0.0231, one-sided).  
If H01 is rejected, then proceed to STEP2, otherwise testing will be stopped 
STEP2: The two hypotheses H02 (α = 0.01155, one-sided, weight = 50%), and H03 
(α = 0.01155, one-sided, weight = 50%) are tested at their initial α levels. If none of the two 
hypotheses can be rejected, testing stops at that point. If at least one of the hypotheses is 
rejected, then the α can be recycled to the non-rejected hypothesis.


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Table 5
Confirmatory Testing Procedures Using One-sided Alphas
H01: Non-inferiority for MACE (alpha = 0.0231)a
Now the alpha will split into independent testing of the co-primary composites in parallel:
H02: Superiority for MACE (alpha = 50% of 
primary alpha)c
H03: Superiority for hospitalization for heart 
failure/CV death (alpha = 50% of primary 
alpha)c
!
H04: Superiority for renal composite endpoint: Confirmed sustained ≥40% 
decrease in eGFR to eGFR <60 mL/min/1.73m2 and/or ESRD (dialysis for at least 
90 days or kidney transplant, confirmed sustained eGFR <15 mL/min/1.73m2) 
and/or renal or CV death b
!
H05: Superiority for all-cause mortalityd
a
The alpha of 0.0231 represents the final one-sided significance level to be used when the study has been 
completed in entirety. At an interim analysis, testing for superiority will occur, and the alpha for superiority 
will be replaced by 0.000095 at the first and 0.00614 at the second interims. Non-inferiority will be tested 
only at the completion of the study.
b
With the exception of all-cause mortality, secondary endpoints will only be tested once, at the completion 
of the trial or if the decision is made to terminate the trial early. The alpha will be controlled for the overall 
Type I error across the primary and secondary endpoints and across the interims and final analysis.
c
If this analysis occurs at completion of the trial, the alpha will be 0.01155 (50% of 0.0231) for superiority 
for MACE and 0.01155 (50% of 0.0231) for superiority for hospitalization for heart failure/CV death.
d
All-cause mortality is assessed at interim analyses as part of the stopping guidelines. At the interim 
analyses, it will be tested second following MACE. If the study terminates at an interim analysis, all-cause 
mortality will remain as the 2nd endpoint following the test for superiority of MACE. If the final analysis 
occurs at the completion of the trial, all-cause mortality will be tested as presented in this table,.
4.4.4
Other efficacy variables  
Body weight:
Change from baseline to each visit for body weight will be analyzed by a repeated measures 
method. All non-missing visit data will be used, including off-treatment measurements. The 
model will include terms for treatment group, CV risk category, baseline hematuria, visit, 
visit*treatment group and baseline measurement as a covariate. The model will be used to 
derive a least squares estimate of the treatment difference with 95% confidence interval and 
corresponding two-sided p-value. Further, two-sided 95% confidence intervals for the mean 
change within each treatment group will be calculated. Missing data will not be imputed. This 
model will be used to assess the timepoints of 1 year, 2 years, 3 years and 4 years although 
summaries at all visits will also be presented.
The proportions of patients with at least a 5% body weight loss after 1, 2, 3 and 4 years 
compared to baseline will be analyzed using the methodology of Cochran Mantel-Haenszel. 
Estimates for treatment effects and differences between treatment groups will be obtained 


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along with 95% confidence intervals and p-values using this methodology with stratification 
for CV risk category and baseline hematuria. The same method will be repeated for the 
additional body weight endpoints: proportions of patients with at least a 10% body weight loss 
after 1, 2, 3 and 4 years.
The body weight analyses will be performed for all patients and for the subgroups of patients 
with/without insulin at baseline. And for the subgroup of patients with baseline BMI >=30 and 
<30 separately.
Albumin to creatinine ratio:
Percent change from baseline to each visit measurement for urinary albumin to creatinine ratio 
will be analyzed by a repeated measures method. All non-missing visit data will be used, 
including off-treatment measurements. The model will include terms for treatment group, CV 
risk category, baseline hematuria, visit, visit*treatment group and baseline measurement as a 
covariate. The model will be used to derive a least squares estimate of the treatment difference 
with 95% confidence interval and corresponding two-sided p-value. Further, two-sided 95% 
confidence intervals for the mean percent change within each treatment group will be 
calculated. Missing data will not be imputed. This model will be used to assess the timepoints
of 1 year, 2 years, 3 years and 4 years although summaries at all visits will also be presented. 
If data suggests, the analysis might be performed applying a logarithm scale instead. This 
analysis will also be performed separately per the subgroups of baseline urinary albumin to 
creatinine ratio (<30mg/g, >=30mg/g).
eGFR (using CKD-EPI equation):
Change in eGFR from baseline to each visit will be analyzed by a repeated measures model. 
The model will include fixed effect terms for treatment group, CV risk category, baseline 
hematuria, time, time*treatment group and baseline eGFR, with time coded as a categorical 
variable defined by the follow-up visit. The variance-covariance matrix structure is assumed 
to be unstructured. 
The model will be used to derive least squares mean changes within each treatment group and 
the treatment difference in mean changes, along with 95% confidence intervals and 
corresponding nominal two-sided p-values. The estimates of the treatment effect will be 
provided for 6 months, 1 year, 2 years, 3 years, and 4 years after randomization. The total 
slopes (between randomization and 1 year, 2 years, 3 years, and 4 years, respectively) and the 
chronic slopes (between 6 months and 1 year, 2 years, 3 years, and 4 years, respectively) will 
be estimated via linear contrasts within the same model. The comparison of the mean total 
slopes will serve as the primary assessment of the effect of the treatment on eGFR slope; the 
comparison of the mean chronic slopes will serve as a secondary comparison. 
The main analysis, based on the Full Analysis Set (FAS), will include all randomized subjects 
and available on- and off-treatment scheduled measurements. The unscheduled eGFR 
assessments will not be included. No imputation will be carried out for missing data. A 
secondary analysis will be conducted in a similar way by excluding off-treatment 


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measurements. These analyses will also be performed separately per the subgroups of baseline 
urinary albumin to creatinine ratio (<30mg/g, >=30mg/g).
Other continuous variables:
Change from baseline to each visit for HbA1c, DBP, SBP and BMI will be analyzed by a 
repeated measures method following the method in Section 4.1.10. All non-missing visit data 
will be used, including off-treatment measurements. The model will be used to derive a least 
squares estimate of the treatment difference with 95% confidence interval and corresponding 
two-sided nominal p-value. Further, two-sided 95% confidence intervals for the mean change 
within each treatment group will be calculated. Missing data will not be imputed. This model 
will be used to assess the timepoints at 1, 2, 3 and 4 years although summaries at all visits will 
also be presented.
The definition of the 1 year time point in these analyses is each patient’s visit within +/- 3 
months that is closest to 1 year. Corresponding logic applies also for the definition of the other 
time points. Patients without measurements within a time interval will be counted as failures, 
and will be included in the denominator.
All continuous endpoints will be plotted over time presenting LS means and SE.
Proportions:
Retinal laser and/or intraocular treatment due to development of and/or deterioration in 
diabetic retinopathy, all strokes, need for an increase in dose for an oral diabetes medication or 
≥ 25% increase in insulin dose or the addition of new diabetes medication, for ≥ 3 months, 
initiation of insulin therapy in patients not receiving insulin therapy at baseline, major 
hypoglycaemia and/or hospitalization for hypoglycaemia, peripheral revascularization/limb 
ischemic events and regression in albuminuria will be examined using statistics according to 
analysis of proportions described in Section 4.1.11 that will include 95% confidence intervals 
for treatment effects and for the comparison between treatments as well as nominal 2-sided p-
values. Time to event analyses will also be performed for these variables.
The Modified Rankin Scale values for strokes will be summarized by treatment.
4.5
Analysis methods for safety variables
Safety observations will be summarized in two ways. The first way will include patients in the 
on-treatment analysis set, and additionally, all safety data will be summarized for all patients 
from the safety analysis set regardless if study treatment was discontinued or not. The 
adjudicated outcome will be considered the main analysis, and applies to malignancies, 
hepatic events and DKA.


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4.5.1
Adverse events, including hypoglycaemia
Only events that fall into the following categories are collected in this study: serious AEs, AEs 
leading to discontinuation of IP, suspected CV events, elective coronary and non-coronary 
revascularisations, heart failure, potential diabetic ketoacidosis, amputation and related events 
and AEs of special interest. AEs of special interest in this study fall into the following 
categories: suspect neoplasm (benign, malignant or unspecified), hepatic events, 
hypoglycemic events that are major, fractures, renal events, symptoms of volume depletion, 
hypersensitivity reactions (serious or lead to discontinuation of IP), urinary tract infections 
(serious or lead to discontinuation of IP) and genital infections (serious or lead to 
discontinuation of IP). Therefore, AE summaries will be limited to these particular categories 
and general summaries of all AEs are not planned.
AEs will be coded using the current version of MedDRA at the time of the database lock.
No statistical tests will be performed to compare AE rates between treatment groups.
For the on-treatment set, adverse events will be included if they occurred on or after the date 
of first randomized dose and within the windows listed below:
!
AEs of special interest which are not serious AEs will be summarized if their onset 
dates were on or before the 7th day after the last blinded drug dose date, or at the 
Closing visit (whichever is earlier)
!
Serious AEs will be summarized if their onset dates were on or before the 30th day 
after the last blinded drug dosing date, or at the closing visit (whichever is earlier).
!
All AEs leading to discontinuation of investigational product will be summarized, 
and no upper day range applies
A summary table of the total numbers of patients with SAEs, discontinuations due to AEs, and 
any AE in each category of special interest will be provided. In summaries by system organ 
class (SOC) and preferred term (PT), or only PT where applicable, AEs will be sorted by 
decreasing frequency within each PT and SOC according to the “dapagliflozin” patient 
incidence. Summaries by PT will be sorted by decreasing frequency according to the 
“dapagliflozin” patient incidence.
4.5.1.1
Procedures for counting AEs
A patient will be counted once for a reported AE by PT even if the patient had multiple 
occurrences.
4.5.1.2
Serious Adverse Events
The patient incidence of all SAEs will be presented by SOC, PT and treatment group. 
The patient incidence of the most common SAEs will be presented by PT and treatment 
group. A most common SAE is defined as a PT that has been reported by at least 0.2% of 
patients in any treatment group. 


Statistical Analysis Plan 
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A listing of all SAEs will be provided.
4.5.1.3
Adverse Events leading to discontinuation
AEs reported with an action taken of “Investigational product permanently stopped” will be 
summarized by SOC, PT, and treatment group. 
The patient incidence of the most common AEs leading to discontinuation (DAE) of 
investigational product will be presented by PT and treatment group. A most common DAE is 
defined as a PT that has been reported by at least 0.2% of patients in any treatment group. 
In addition, a patient listing of discontinuations due to AEs will be produced.
4.5.1.4
Adverse events of special interest 
Analyses will be performed separately for AEs of special interest. AEs of special interest in 
this study fall into the following categories: malignancies, hepatic events, hypoglycemic 
events that are major, fractures, renal events, symptoms of volume depletion hypersensitivity 
reactions that are serious or lead to discontinuation of investigational product, urinary tract 
infections that are serious or lead to discontinuation of investigational product and genital 
infections that are serious or lead to discontinuation of investigational product. At the end of 
the study, AEs of special interest will be identified as:
!
AE of special interest category collected on the eCRF or 
!
AE MedDRA PT matching the current MedDRA version prespecified PT list for 
AEs of special interest or  
!
the laboratory criteria for a marked abnormality (liver and renal categories only) 
specified in Appendix A.
For each category of AE of special interest, frequency and proportion of patients with AEs 
will be summarized by PT, overall and by subgroups (see Table 3) based on:
Fractures: baseline eGFR using CKD-EPI equation, age, sex
Osteoporetic fractures (WHO definition by location): baseline eGFR using CKD-EPI 
equation, age, sex
Renal events: baseline eGFR using CKD-EPI equation, age, urinary albumin/creatinine ratio, 
baseline systolic and diastolic blood pressure, diabetes duration, ACEi/ARB, diuretic use
Volume depletion: baseline eGFR using CKD-EPI equation, age, diuretic use, loop diuretics, 
baseline systolic and diastolic blood pressure, ACEi/ARB
SAE/DAE of urinary tract infection: sex, age
SAE/DAE of genital infection: sex, age


Statistical Analysis Plan 
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49
Malignancies: 
-
Overall: sex, age
-
Bladder: baseline hematuria 
-
Prostate: males only
Time to first onset of each AE of special interest will be summarized by treatment group using 
Kaplan-Meier estimates of the cumulative proportion (with 95% CI) within each treatment 
group (see Section 4.1.13). 
SAE/DAE of urinary tract infections and SAE/DAE of genital infections will each be 
summarized by treatment group.
The number and percentage of patients with AE of special interest will be summarized by 
category and preferred term for each treatment group. 
Specific patient data listings for selected AEs of special interest will be performed.
Event rates per 1000 patient years will be calculated per AE of special interest. The same rules 
for censoring (for patients both with and without events) will be used as described in section 
4.1.9.
More information on hypoglycaemic events, cancer events and hepatic events is presented 
below.  
Hypoglycaemic Adverse Events:
At each visit the Investigator will inquire about occurrence of major hypoglycemic events 
according to the below definition. 
Major hypoglycemic event defined as symptomatic events requiring external assistance due to 
severe impairment in consciousness or behavior, and prompt recovery after glucose or 
glucagon administration. Plasma glucose measurements may not be available during such an 
event, but neurological recovery attributable to the restoration of plasma glucose to normal is 
considered sufficient evidence that the event was induced by a low blood glucose 
concentration.
Hypoglycemic episodes should be reported if the event fulfills the definition of a major 
hypoglycemic event, the protocol criteria for an SAE or leads to discontinuation of 
investigational product. For major hypoglycemic episodes additional details will be recorded 
in the eCRF. Other definitions for hypoglycemic events may also be applied and summarized, 
for example hypoglycemic events requiring external assistance.
Cancer Adverse Events:


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All potential neoplasms, excluding non-melanoma skin cancers, will undergo blinded 
adjudication by the CEC, and only those that are adjudicated to be malignant will be included 
in the analysis of cancer events. Patients with any cancer will be summarized. Plus, the 
subcategories of cancers will be analyzed according to the adjudication outcome, incidence
rate ratios and confidence intervals will be tabulated and depicted in a forest plot.
Incidence rate differences and corresponding confidence intervals will be provided according 
to the methodology in Section 4.1.12 for bladder cancer, breast cancer and prostate cancer. 
These cancers will also be examined using the time to event approach using the Cox model as 
described in Section 4.1.9.
Hepatic Adverse Events:
Summary statistics by treatment group will be presented by severity and causality.
Severity Scale:
1 ALT or AST > 3X ULN, usually transient and reversible by adaptation (mild)
2 Also TB > 2X ULN, after or concurrent, indicating early functional loss (Hy’s Law Case)
3 Serious, meaning disabling, requiring or prolonging hospitalization because of liver 
dysfunction
4 Acute liver failure, with secondary failure of brain or kidney function due to liver injury
5 Fatal, or requiring liver transplantation due to liver failure
Causality
Likelihood
Description
Definite
> 95%
The evidence for the study drug causing the injury is beyond a 
reasonable doubt
Highly Likely 
75 - 95%
The evidence for the study drug causing the injury is clear and 
convincing but not definite
Probable 
50 - 74%
The preponderance of the evidence supports the link between the 
study drug and the liver injury
Possible
25 - 49%
The evidence for the study drug causing the injury is equivocal 
but present
Unlikely
< 25%
There is evidence that an etiological factor other
than the study drug caused the injury is clear
4.5.2
Laboratory Evaluation
All scheduled laboratory evaluations are performed by central laboratories. Evaluations done 
by local laboratories will not be included in summaries of changes from baseline but will be 
included in Marked Laboratory Abnormalities.
Laboratory parameters will be presented in SI units and summarized by treatment group with 
descriptive statistics.
In the on-treatment safety analysis, safety laboratory results will be summarized only if 
measured on or before the 7th day after the last blinded drug dosing. 


Statistical Analysis Plan 
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51
Changes from baseline to each scheduled time point for each clinical laboratory test, including 
estimated GFR and estimated creatinine clearance will be summarized by treatment group. In 
addition, the number and percent of patients with a marked abnormality in clinical laboratory 
tests will be summarized by treatment group. 
4.5.2.1
Marked Laboratory Abnormalities
Laboratory abnormalities will be evaluated based on marked abnormality (MA) criteria. The 
list of MAs is provided in Appendix A. If both the baseline and on-treatment values of a 
parameter are beyond the same MA limit for that parameter, then the on-treatment value will 
be considered a MA only if it is more extreme (farther from the limit) than was the baseline 
value. If the baseline value is beyond the low MA limit, and the on-treatment value is beyond 
the high MA limit (or vice-versa), then the on-treatment value will be considered a MA. 
Laboratory MAs occurring during treatment period will be summarized by treatment group. 
The directions of changes (high or low) in MAs will be indicated in the tables. Additionally, 
for each patient with a MA for a parameter, all the patient’s values of that parameter over the 
treatment period will be listed.
4.5.2.2
Changes from baseline values
Changes from baseline will be summarized over all scheduled visits, presenting n, mean, 
median, SD, Q1, Q3 and 95% CI.
This applies to all laboratory variables.
4.5.3
Physical findings and other observations related to safety
4.5.3.1
Vital signs
The values and changes from baseline for systolic and diastolic blood pressures and heart rate 
will be summarized by treatment group at each scheduled time of assessment. 
4.5.3.2
Amputations and related events
Surgical or spontaneous/non-surgical amputations, AEs leading to amputation, contributing 
factors and conditions that triggered amputations will be summarized and analyzed, including 
an investigation of competing risks and baseline parameters and medications. Time to event 
analyses as well as KM plots will be performed. Hazard Ratios (HR) and Confidence Intervals 
(CIs) will be derived from a Cox proportional hazards model, see section 4.1.9. Differences in 
proportions will also be analyzed and presented, see section 4.1.11. The competing risks of 
peripheral revascularization and all-cause mortality will be looked upon using time to event 
analyses.
4.5.3.3
Potential diabetic ketoacidosis
Potential diabetic ketoacidosis will be adjudicated and reported as definite, probable, possible 
or not diabetic ketoacidosis.


Statistical Analysis Plan 
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Edition Number 8
Date 31 May 2018
52
5.
INTERIM ANALYSES
A DMC will be appointed jointly by the Sponsors and the academic leadership of the study. 
The DMC will be responsible for safeguarding the interests of the patients in the outcome 
study by assessing the safety of the intervention during the trial, and for reviewing the overall 
conduct of the clinical trial. In addition, the DMC will have the responsibility to assess the 
efficacy data of the interim analysis and make recommendations based upon stopping 
guidelines. 
A group sequential design with 2 interim analyses will be assessed for MACE and all-cause 
mortality. The analyses will take place at 1/3 and 2/3 of the MACE events using an O’Brien–
Fleming alpha-spending rule. The interim analyses will assess superiority of dapagliflozin to 
placebo for MACE because the study will only be considered for early termination if 
superiority is met. All-cause mortality is included as an endpoint to the interim analyses for an 
additional assessment of benefit. The first interim analysis will have a one-sided alpha level of 
0.000095.  The second interim analysis will have a one-sided alpha level of 0.00614.  
According to the O’Brien-Fleming spending rule this will leave a 1-sided alpha level of 
0.023095 for the final analysis. At each interim analysis, MACE will be tested first at the 
specified alpha level, and if found to be statistically significant, all-cause mortality will then 
be assessed for significance at the same alpha level. If superiority is achieved for both 
endpoints, an action is triggered whereby the DMC will evaluate the CV data and safety data, 
including bladder cancers and liver events, to determine if benefit is unequivocal and 
overwhelming such that the DMC recommends ending the study.
If an interim analysis leads to a decision to terminate the trial early based on pre-
defined stopping guidelines, the interim analysis database will become the basis of 
statistical inference for the endpoints of MACE and All-cause mortality. Following 
such a decision, study closeout procedures will commence toward database lock. A 
follow-up analysis based on the locked database will be conducted to support the full 
reporting of the trial. The consistency between the interim analysis database and the 
subsequently locked database will be assessed.
In the follow-up analysis based on the locked database, the date when the Executive 
Committee instructs the sites to commence final visits will be used as a common study 
end date and as a date for censoring endpoint events for efficacy analyses. All endpoint 
events that occur on or prior to this date will be included in the analyses, regardless 
when they are identified relative to this date. All events occurring after the common 
study end date will be documented and adjudicated by the same procedures as events 
occurring up to this date, and will be summarized in the reporting. 
In the follow-up analysis based on the locked database, nominal p-values will be 
presented for all efficacy endpoints. The alpha level for those endpoints that have not 
been formally tested at the interim analyses will be calculated by controlling the 


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
53
overall Type I error across the primary and secondary endpoints and across the interim 
analyses and the follow-up analysis.
If, outside of the 2 pre-specified interim efficacy analyses, the DMC feels compelled for 
safety concerns to examine efficacy data formally with consideration of stopping the trial 
early for overwhelming efficacy, then the alpha applied to such efficacy analyses would be 
determined according to the O’Brien-Fleming spending function, and subsequent alpha-levels 
for any remaining planned efficacy interim and final analyses would also be adjusted 
according to the O’Brien-Fleming spending function to maintain the  control of the Type I 
error. Any unscheduled interim analysis would evaluate both MACE and all-cause mortality 
in the same way as for a scheduled interim analysis. The SEER rate for the general US 
population of 0.044% per person-year for bladder cancer may be conservative; higher bladder 
cancer rates could be observed in this trial. If the SEER rate is adjusted to reflect an increased 
risk in a diabetes population, an estimated annual rate of 0.06% could occur.
We assume that the rate of bladder cancers observed in this study will be 0.06%, which would 
correspond to a total of 46 bladder cancers.
Interim monitoring for bladder cancers is planned for the purposes of communicating potential 
signals with regulatory authorities. The accumulation of patients with bladder cancer would 
suggest 4 interim analyses at 8, 16, 24 and 32 events, followed by the final analysis. The 
earliest difference where a result could possibly be significant is with 7 events, and with a 
minimum split of bladder cancers 7 versus 0. The interim analysis would take place at 
approximately 26, 37, 46 and 55 months. The bladder analyses would be assessed at an overall 
alpha-level of 0.10 with a Pocock spending rule. If an interim analysis is significant, the DMC 
would inform others according to a strict communication plan. Note that this rule is not a 
reason for stopping the study. An analysis of the primary CV variables may be performed 
additionally in order to allow the DMC to assess benefit and risk concurrently. The number of 
interim analyses for bladder cancers may be adjusted if the event rate is different than 
expected.
The overall type I error will be set to 0.10. Using a Pocock spending rule, the alpha levels for 
the five bladder analyses will be as follows:
First interim analysis: 
alpha level of 0.026
Second interim analysis: 
alpha level of 0.029
Third interim analysis: 
alpha level of 0.031
Fourth interim analysis: 
alpha level of 0.034
Final analysis: 
alpha level of 0.043


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
54
Table 6
Imbalance of bladder cancers. Significant difference (binomial) 
between bladder cancers at different alpha levels. Under the condition 
that there is no true difference in bladder cancer incidence between 
Dapagliflozin and Placebo.
Total number of patients 
with bladder cancer
Analysis
Minimum split of cancers for statistical 
significance (binomial) 
8
IA1
1 versus 7
16
IA2
3 versus 13
24
IA3
6 versus 18
32
IA4
9 versus 23
6.
CHANGES OF ANALYSIS FROM PROTOCOL
eGFR total slope and chronic slope have been added as new exploratory efficacy variables.
Exploratory renal composite endpoint: Confirmed sustained ≥40% decrease in eGFR to eGFR 
<60 mL/min/1.73m2 using CKD-EPI equation and/or ESRD (dialysis ≥90 days or kidney 
transplantation, confirmed sustained eGFR <15 mL/min/1.73m2) and/or renal death (time to 
first event) has been added as new exploratory efficacy variable.
Amputations and related events was specified as an exploratory efficacy objective in the 
protocol. It has been moved to the safety section in the Statistical Analysis Plan.
7.
REFERENCES
Cockroft D, Gault MK 1976
Cockroft D, Gault MK. Prediction of Creatinine Clearance from Serum Creatinine. Nephron 
1976;16:31-41. 
Kaplan EL and Meier P 1958
Kaplan EL and Meier P. Nonparametric Estimation From Incomplete Observations.  Journal 
of the American Statistical Association 1958;53:457-481.
Levey et al 2006
Levy AS, Coresh J, Greene T, Stevens, LA, Zhang YL, Hendriksen S, et al. Chronic Kidney 
Disease Epidemiology Collaboration. Using standardized serum creatinine values in the 
modification of diet in renal disease study equation for estimating glomerular filtration rate. 
Ann Intern Med 2006;145(4):247-54.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
55
Lu Tian et al 2008
Exact and efficient inference procedure for meta-analysis and its application to the analysis of 
independent 2 × 2 tables with all available data but without artificial continuity correction. 
Biostatistics 2009;10(2):275–281.
Andersen and Gill 1982
Cox’s Regression Model for Counting Processes: A Large Sample Study. Ann Statist. 
1982;4(10):1100-1120. 
Levey et al 2009
Levey AS, Stevens LA, Schmid CH, Zhang Y(L), Castro AF, Feldman HI, Kusek JW, Eggers 
P, Van Lente F, Greene T and Coresh J. A New Equation to Estimate Glomerular Filtration 
Rate. Ann Intern Med. 2009 May 5; 150(9): 604–612.
Burman et al 2009
Burman CF, Sonesson C, Guilbaud O. A recycling framework for the construction of 
Bonferroni-based multiple tests. Statistics in Medicine. 2009;28:739–761.
Bretz et al 2009
Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to sequentially rejective 
multiple test procedures. Statistics in Medicine. 2009;28:586–604.
Holm 1979
A Simple Sequentially Rejective Multiple Test Procedure
Author(s): Sture Holm
Source: Scandinavian Journal of Statistics, Vol. 6, No. 2 (1979), pp. 65-70
Jason P. Fine and Robert J. Gray 1999
A Proportional Hazards Model for the Subdistribution of a Competing Risk
Journal of the American Statistical Association 
Vol. 94, No. 446 (Jun., 1999), pp. 496-509
Rubin, D. B. 1987
Rubin, D. B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John
Wiley & Sons.
Little R et al 2016
The treatment of missing data in a large cardiovascular clinical outcomes study. Clin Trials. 
2016;13(3):344-351.


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
56
Appendix A
Laboratory Abnormality Criteria
The set of labs requested in this study is summarized in Table 7, along with the laboratory 
abnormality criteria. 
Fasting Designation for Labs:  Fasting labs are evaluated under fasting criteria (if applicable) 
and unspecified (if applicable).
Table 7 provides the criteria for assessing marked abnormalities in safety laboratory 
parameters.  If both the baseline and on-treatment values of a parameter are beyond the same 
MA limit for that parameter, then the on-treatment value will be considered a MA only if it is 
more extreme (farther from the limit) than was the baseline value. Also, if the on-treatment 
value of a parameter is beyond a MA limit and the baseline value is not beyond the same limit 
then the on-treatment value will be considered a MA.
The following three criteria will also be summarized by treatment group in examination of the 
elevated AT (ALT and/or AST) and total bilirubin:
!
(AST or ALT > 3XULN) and (Total Bilirubin > 1.5XULN within 14 days on or 
after AT elevation)
!
(AST or ALT > 3XULN) and (Total Bilirubin > 2XULN within 14 days on or after 
AT elevation)
!
(AST or ALT > 3XULN) and {(Total Bilirubin > 2XULN and no ALP ≥2XULN) 
within 14 days on or after AT elevation}
The following criteria will be summarized by treatment group:
!
Estimated Creatinine Clearance < 45 mL/min
!
Estimated GFR < 45 mL/min/1.73m2
Table 7
Marked Abnormality Criteria for Safety Laboratory Parameters
Marked abnormality criteria for safety laboratory variables and 
elevated AT (ALT and/or AST) and total bilirubin
Marked Abnormality Criteria
Clinical laboratory variables
Units
Low
High
Hematology
HCT males/females
vol
<0.20
>0.55


Statistical Analysis Plan 
Study Code D1693C00001
Edition Number 8
Date 31 May 2018
57
Marked Abnormality Criteria
Clinical laboratory variables
Units
Low
High
HCT males/females
vol
>0.60
Hemoglobin males/females
g/L
<60 g/L
>180 g/L
Hemoglobin males/females
g/L
>200 g/L
Blood Chemistry
ALP
U/L
>1.5X ULN
ALP
U/L
>3X ULN
ALT
U/L
>3X ULN
AST
U/L
>3X ULN
AST or ALT
U/L
>3X ULN
ALT
U/L
>5X ULN
AST
U/L
>5X ULN
AST or ALT
U/L
>5X ULN
ALT
U/L
>10X ULN
AST
U/L
>10X ULN
AST or ALT
U/L
>10X ULN
ALT
U/L
>20X ULN
AST
U/L
>20X ULN
AST or ALT
U/L
>20X ULN
Total Bilirubin
μmol/L
>1.5X ULN 
>2X ULN
Na (Sodium)
mmol/L
<130 mmol/L
>150 mmol/L
Na (Sodium)
mmol/L
<120 mmol/L
K (Potassium)
mmol/L
∃2.5 mmol/L
#6.0 mmol/L
HCO3 (Bicarbonate)
mmol/L
∃13 mmol/L
Creatinine
μmol/L
#1.5X PreRx CREAT
Creatinine
μmol/L
#2X PreRx CREAT
Creatinine
μmol/L
#221 μmol/L


Statistical Analysis Plan 
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Edition Number 8
Date 31 May 2018
58
Marked Abnormality Criteria
Clinical laboratory variables
Units
Low
High
Calcium
mmol/L
<1.875 mmol/L
#0.25 mmol/L from 
ULN and #0.125 
mmol/L from PreRx CA
Magnesium
mmol/L
<0.5 mmol/L
>2.0 mmol/L
Phosphorus
mmol/L
Age 17-65: ∃0.58 
mmol/L
Age 66: ∃0.68 mmol/L
Age 17-65: #1.81 
mmol/L
Age# 66: #1.65 mmol/L 
Urine
UACR (Urinary Albumin-to-
Creatinine Ratio)
mg/mmol
>203.62 mg/mmol
Appendix B
Definition of Regions 
Region
Countries
North America
Canada
United States
Latin America
Argentina
Brazil
Mexico
Asia/Pacific
Australia
China
Hong Kong
India
Taiwan
Thailand
Japan
Philippines
South Korea
Vietnam


Statistical Analysis Plan 
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Edition Number 8
Date 31 May 2018
59
Region
Countries
Europe
Western:
France
Germany
Italy
Netherlands
Spain
Sweden
United Kingdom
Turkey
Belgium
Eastern:
Hungary
Bulgaria
Czech Republic
Poland
Romania
Russia
Slovakia
Ukraine
Israel
South Africa